Novel compounds for diagnosis

Abstract

To provide compounds that can be used for the diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates (e.g., Parkinson's disease), the prognosis of such a disease, disorder or abnormality, and the monitoring of the progression of such a disease, disorder or abnormality.SOLUTION: The present invention relates to novel compounds of Formula (I), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, which can be used for imaging and determining the amount of alpha-synuclein aggregates. Furthermore, the compounds can be used to diagnose a disease, disorder or abnormality associated with alpha-synuclein aggregates including, but not limited to, Lewy bodies and / or Lewy neurites (e.g., Parkinson's disease), to determine a predisposition to such a disease, disorder or abnormality, to prognose such a disease, disorder or abnormality.SELECTED DRAWING: None

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, determine a predisposition to, prognose, or monitor the progression of, a disease, disorder, or disorder associated with alpha-synuclein (α-synuclein, A-synuclein, a-synuclein, A-syn, α-syn, aSyn, a-syn) aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, and to predict the responsiveness of patients with such diseases, disorders, or disorders to treatment. The invention also relates to methods for preparing the compounds and precursors thereof, 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 listed as synucleinopathies (or α-synucleinopathies), including, but not limited to, Parkinson's disease (PD). 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-Rakev 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), 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; Smith et al., J Pathol. 2014; pp. 232:509-521; Lippa et al., Ann Neurol. 1999 March; 45(3):353-7; Schmitz et al., Mol Neurobiol. 2018 August 22; Charles et al., Neurosci Lett. 2000 July 28; pp. 289(1):29-32; Wilhelmsen et al., Arch Neurol. 2004 March;61(3):398-406; Yamaguchi et al., J Neuropathol Exp Neurol. 2004, 80th Annual Meeting, Vol. 63; Askanas et al., J Neuropathol Exp Neurol. 2000 July;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), 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), 309-312).

[0006] Abnormal protein aggregation appears to be a common feature of the aging brain and several neurodegenerative diseases (Trojanowski et al., 1998, 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. While PD is primarily idiopathic, 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, R48-59). 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 with 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-syn, phosphorylated at Ser-129 (Outeiro et al., Mol Neurodegener. 2019, 14, 5). Alpha-synuclein aggregates are also found in multiple system atrophy (MSA), a rare, sporadic neurodegenerative disorder manifested by rapidly progressive autonomic and motor dysfunction and heterogeneous cognitive decline. Such disorders include Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy. The 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, primarily composed of fibrillar forms of alpha-synuclein, are the neuropathological hallmark of MSA and are found throughout the neocortex, hippocampus, brainstem, spinal cord, and dorsal root ganglia (Galvin et al., Arch Neurol. 2001;58, 186-90). GCIs are thought to play a central role in the pathogenesis of MSA. A correlation between GCI amount and the degree of neuronal loss has been reported in both the striatonigral and olivopontocerebellar regions (Stefanova et al., Neuropathol Appl Neurobiol. 2016, 42, pp. 20-32). Furthermore, a causal link between GCI and the induction of neuronal loss has been shown 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 ('prion-like' propagation) of misfolded alpha-synuclein.

[0009] 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), 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.

[0010] Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal. These techniques are nevertheless useful in ruling out other conditions that may be secondary causes of 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 ( 123 I) (trade name DaTSCAN) and iometopan (Dopascan), or fluorodeoxyglucose ( 18 F)( 18 F-FDG) and dihydrotetrabenazine ( 11 C)( 11The 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).

[0011] 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, no approved alpha-synuclein diagnostics are currently on the market or available for clinical trials, despite the critical need for Parkinson's disease research and drug development (Eberling et al., J Parkinsons Dis. 2013;3(4):565-7).

[0012] The ability to image alpha-synuclein deposits in the brain would be a major advancement for alpha-synucleopathies research, including Parkinson's disease research, diagnosis, and drug development. The accumulation of aggregated alpha-synuclein in the brain is considered a key pathological hallmark of PD and can begin years before the onset of symptoms. Therefore, alpha-synuclein is a priority target for drug development, not only considering its possible contribution to neurodegeneration but also offering 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 crucial for the accurate diagnosis of synucleinopathies and for supporting the clinical development of alpha-synuclein-targeting therapeutics, starting with the ideal selection of a study population (Eberling, Dave, and Frasier, J. Parkinson's Disease, 3, 565-567 (2013)). Despite numerous attempts to identify alpha-synuclein PET ligands, only compounds that bind to artificial alpha-synuclein fibrils with reasonably high affinity have been identified to date, but none of these have been validated in human clinical trials.These are not ideal for several reasons: low affinity or no binding has been observed to pathological aggregates of alpha-synuclein present in diseased brains, there is little or no reported selectivity for alpha-synuclein over other aggregated proteins, and the physicochemical properties are inadequate for use as brain-penetrating PET agents (Eberling et al., J Parkinson's Dis. 2013;3(4):565-7; Neal et al., Mol Imaging Biol. 2013;15:585-595; Bagchi et al., PLoS One 2013;8(2):e55031; Yu et al., Bioorganic and Medicinal Chemistry 2012;20:4625-4634; Zhang et al., Appl Sci (Basel) 2014;4(1):66-78; Chu et al., J Med Chem, 2015, 58(15):6002-17).

[0013] Therefore, there is a clear need to find molecular probes with high alpha-synuclein selectivity that recognize and bind to pathological alpha-synuclein. To suppress background signal interference arising from nonspecific off-target binding and to ease administration requirements, alpha-synuclein imaging compounds should bind to their targets with high affinity and selectivity. To image alpha-synuclein aggregates associated with neurological diseases, such as Parkinson's disease, imaging compounds must penetrate the blood-brain barrier and pass into the relevant areas of the brain. To target intracellular amyloid-like inclusions, such as alpha-synuclein, cell permeability is a further requirement for imaging compounds. To avoid unnecessary accumulation of the compound, which may increase the risk of undesirable side effects, a further prerequisite is rapid efflux of the compound from the brain (or other target organs).

[0014] 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.

[0015] 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 labelled with an in vivo imaging moiety, the in vivo imaging agent binding to alpha-synuclein with binding affinity.

[0016] 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.

[0017] 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.

[0018] WO2016 / 033445 refers to certain compounds for imaging huntingtin protein.

[0019] WO2017 / 153601 and WO2019 / 234243 refer to bicyclic compounds for diagnosing a-synuclein aggregates.

[0020] It has been surprisingly found that a new class of compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are capable of binding to alpha-synuclein. Thus, when the compounds of the invention are radiolabeled with a suitable radioisotope, the compounds qualify as PET tracers for imaging pathological a-syn aggregates in PD and other alpha-synucleinopathies. [Prior art documents] [Patent documents]

[0021] [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 [Non-patent literature]

[0022] [Non-Patent Document 1] Jellinger, Mov Disord 2003, 18 Suppl. 6, S2~12 [Non-patent document 2] Galvin JAMA Neurology 2001, 58 (2), pages 186~190 [Non-licensed Document 3] Kovari, Acta Neuropathol. 2007, 114(3), pp. 295-28 [Non-licensed Document 4] Saito, J Neuropathol Exp Neurol. 2004, 63(4), pp. 323-328 [Non-licensed Document 5] McKeeら, Brain, 2013, 136(Pt 1), pages 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) [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, pages 14, 5 [Non-licensed Document 42] Fanciulli, N Engl J Med, 2015; pp. 372, 249-63 [Non-licensed Document 43] Galvin, Arch Neurol. 2001, 58, pp. 186-90. [Non-licensed Document 44] Stefanova, Neuropathol Appl Neurobiol. 2016, 42, 20~32 pages [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] Neal, Mol Imaging Biol. 2013; 15: 585-595 [Non-licensed Document 52] Bagchiら, PLoS One 2013;8(2):e55031 [Non-licensed Document 53] Yu, Bioorganic and Medicinal Chemistry, 2012; 20: 4625-4634 [Non-licensed Document 54] Zhang, Appl Sci (Basel), 2014; 4(1): 66-78 [Non-licensed Document 55] Chuら, J Med Chem, 2015, 58(15): 6002~17 pages [Non-licensed Document 56] Synthesis (1982), pp. 85-125, Table 2, Carey and Sundberg [Non-licensed Document 57] Organische Synthese (1995), pp. 279-281, table 5.8 [Non-licensed Document 58] Netscher, Recent Res. Dev. Org. Chem., 2003, 7, 71~83 pages, スキーム1, 2, 10 and 15, etc. [Non-licensed Document 59] 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 60] Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA, 1990, 1445 pages. [Non-Patent Document 61] Remington's Pharmaceutical Sciences, 15th ed., Mack Publishing Co., New Jersey (1975) [Non-Patent Document 62] Ying-hui Chou et al., JAMA Neurol. April 1, 2015;72(4):432-440 [Non-Patent Document 63] Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49 [Non-Patent Document 64] L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem 2008, pp. 2853-2873 [Non-Patent Document 65] J. Fluorine Chem., 27 (1985): pp. 177-191 Summary of the Invention [Problem to be solved by the invention]

[0023] It is an object of the present invention to provide compounds that can be used for the diagnosis of diseases, disorders, or disorders associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites (e.g., Parkinson's disease), for determining the prognosis of such diseases, disorders, or disorders, and for 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, for monitoring the progression of the disease, disorder, or disorder, or for predicting the responsiveness of a patient suffering from such a disease, disorder, or disorder to treatment with a certain pharmaceutical agent.

[0024] Furthermore, there is a clinical need for compounds that can be used as imaging agents for alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. In particular, it is an object of the present invention to provide compounds suitable for diagnostic compositions for positron emission tomography imaging of alpha-synucleinopathies, e.g., compounds comprising: 18 Detectably labeled with F or other labeled moiety. [Means for solving the problem]

[0025] The inventors have surprisingly found that these objects can be achieved by a compound of formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof as described hereinafter.

[0026] Compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, exhibit strong binding affinity to alpha-synuclein aggregates in mammalian (e.g., human) tissue. Furthermore, compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, exhibit strong selectivity for alpha-synuclein over other protein aggregates associated with neurodegeneration, enabling differentiation of PD from other proteinopathies that share common clinical and pathological features. Due to unique design features, these compounds exhibit properties, such as suitable lipid solubility and molecular weight, brain uptake and pharmacokinetics, cell permeability, solubility, and autofluorescence, that make them suitable imaging probes for the detection and quantification of alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, in vivo, ex vivo, and in vitro.

[0027] The present invention discloses novel compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds thereof, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, or subformulas thereof disclosed herein, that have improved binding properties to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. The compounds of the present invention can be labeled (e.g., radiolabeled) for use in in vitro, ex vivo, and in vivo imaging to detect alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. The present invention provides methods for detecting alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites ex vivo using a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof. The present invention provides compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, for use as diagnostic imaging agents, particularly for the presymptomatic or prodromal detection of Parkinson's disease and / or other synucleinopathies, e.g., using positron emission tomography (PET). The compounds of the present invention can serve as biomarkers for monitoring the topographical and temporal evolution of pathology, leading to improved design and outcome of clinical diagnostic studies.The present invention further provides diagnostic compositions comprising a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier, diluent, or adjuvant.

[0028] The present invention is summarized in the following items:

[0029] The present invention relates to a compound of formula (I): [ka] (In the formula, [ka] is aryl or heteroaryl, which is [ka] are selected with directionality from R 0 is H or C1-C4 alkyl, R 1 is -CN, or halo, or C1-C4 alkyl, or C1-C4 alkoxy, or -N(C1-C4 alkyl)2, or -NH(C1-C4 alkyl), or H; or R 1 is —NH—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo; R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 But the following: [ka] is selected from R 2a , R 2a'is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, * is the position of attachment), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0030] In another aspect, the present invention provides a compound of formula [ka] Also covered are compounds having the formula: or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0031] In another aspect, the present invention provides a compound of formula [ka] Also covered are compounds having the formula: or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0032] In one aspect, a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, is for use in imaging alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, and the compound is preferably for use in positron emission tomography imaging of alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites.

[0033] In a further aspect, the present invention provides a method of imaging a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. This refers to a method including:

[0034] In a further aspect, the present invention provides a method of imaging a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) imaging the subject's brain; The present invention covers a method including:

[0035] In a further aspect, the present invention provides a method for positron emission tomography (PET) imaging of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a tissue of a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) allowing the compound to penetrate into the tissue of the subject; and (c) acquiring a positron emission tomography (PET) image of the tissue of interest. wherein the tissue is central nervous system (CNS) tissue, eye tissue or brain tissue, preferably the tissue is brain tissue.

[0036] In a further aspect, the present invention provides a method for detecting a neurological disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a subject, comprising the steps of: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) measuring the radioactive signal of the compound that binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. The present invention covers a method including:

[0037] In a further aspect, the present invention provides a method for detecting and / or quantifying alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a tissue of a subject, comprising: (a) contacting a tissue of a subject with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) detecting and / or quantifying compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, using positron emission tomography. The present invention covers a method including:

[0038] In yet another aspect, the present invention provides a method of imaging the brain of a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) obtaining an image of the subject's brain using positron emission tomography. This refers to a method including:

[0039] The present invention also provides a method of collecting data as disclosed herein for diagnosing a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. The present invention also covers methods including the following.

[0040] The present invention provides a method of collecting data for determining a predisposition to a disease, disorder, or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. It also refers to a method including:

[0041] In a further aspect, the present invention provides a method of collecting data for prognosing a disease, disorder, or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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:

[0042] In another aspect, the invention provides a method of collecting data to monitor the progression of a disease, disorder or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a patient, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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:

[0043] In a further aspect, the present invention provides a method of collecting data for predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, to treatment for the disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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:

[0044] The present invention is further directed to a diagnostic or pharmaceutical composition comprising a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier, diluent or adjuvant.

[0045] In another aspect, the present invention provides a compound of formula (IV-F) [ka] (In the formula, R 3 teeth, [ka] is selected from R 4 is aryl or 5- or 6-membered heteroaryl, and R 4 teeth, [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2eis selected from H, OH, CH3 or F, Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, * is the position of attachment), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0046] In another aspect, the present invention provides a compound of formula (IV-H) [ka] (In the formula, R 5 teeth, [ka] is selected from R 6 is aryl or 5- or 6-membered heteroaryl, and R 6 But the following: [ka] is selected from R 2a , R 2a' is independently selected from H, X, or F; R 2b is independently selected from X, F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy, where C1-C4 alkyl, haloC1-C4 alkyl, or C1-C4 alkoxy is optional and includes one or more X; R2c , R 2c' are independently selected from X, H, F, OH, OCH3 or CH3; R 2d is selected from X, H, F or —OH; R 2e is selected from X, H, OH, CH3 or F; Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, * is the position of the bond, Fluoro is 19 F X is bromo, chloro or iodo; R 6

[0033] Also covered are compounds of the formula:

[0047] In another aspect, the present invention provides a method for preparing a compound of formula (III-F), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprising reacting a compound of formula (IV-F) with a compound of formula (IV-F) in which the leaving group (LG) is 18 so that it can be replaced by F 18 Further directed to methods comprising the step of reacting with an F-fluorinating agent.

[0048] The present invention provides a method for preparing a compound of formula (III-H), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprising reacting a compound of formula (IV-H) with a compound of formula (IV-H) wherein X is3 Further directed to methods include reacting with a tritating agent such that H is replaced by H.

[0049] In another aspect, the present invention provides a compound of formula (IV-J): [ka] (In the formula, R 7 teeth, [ka] is selected from R 8 is the following: [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; p is 0, 1 or 2; R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; If valence allows, [ka] is a combination of a single bond and a double bond, Fluoro is 19 F, * is the position of attachment), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0050] In another aspect, the present invention provides a method for preparing a compound of formula (III-H), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprising reacting a compound of formula (IV-J): 3 3H radiolabeling agent.

[0051] The present invention is further directed to the use of a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, as an in vitro analytical standard or in vitro screening tool.

[0052] 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, comprising at least one compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0053] 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 (IV-F) or (IV-H) or (IV-J), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0054] Hereinafter, compounds of formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are referred to as compounds of the invention. Compounds of formulae (IV-F), (IV-H), and (IV-J) are referred to as precursors of compounds of the invention.

[0055] The invention is also defined by the following clauses: A1. Formula (I) [ka] (In the formula, R 1 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl being optionally substituted with methyl; * is the position of attachment), and all detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0056] A2. R 1 But, [ka] Like 18 The compound of formula (I) according to clause A1, which is pyrrolidine substituted with F.

[0057] A3. R 1 But, [ka] Like 19 is a pyrrolidine substituted with F, The compound of formula (I) 3 A compound of formula (I) according to clause A1, detectably labeled at least in one available position with H (tritium).

[0058] A4. [ka] A compound according to any one of clauses A1 to A3, wherein

[0059] A5. A compound according to any one of clauses A1 to A4 for use in imaging alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, preferably for use in positron emission tomography imaging of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites.

[0060] A6. A compound according to any one of clauses A1 to A4 for use in a method for the diagnosis of, or a predisposition to, a disease, disorder or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, wherein the disorder 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). , Dementia with Lewy Bodies (LBD), Dementia with Lewy Bodies (DLB) (including "pure" Lewy Body Dementia), Parkinson's Disease Dementia (PDD), Diffuse Lewy Body Disease (DLBD), 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 (Shy-Drager Syndrome), Striatonigral Disease Dementia 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, frontotemporal dementia with parkinsonism linked to chromosome 17), Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (including sporadic, familial or Guam ALS-dementia complex), neuroaxonal dystonia a compound selected from: ataxia-telangiectasia, neurodegeneration with brain iron accumulation type 1 (including 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, preferably Parkinson's disease.

[0061] A7. A method of collecting data for diagnosing a disease, disorder, or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a sample or in a patient, comprising: (a) contacting a sample or a specific body part or body region suspected of containing alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, with a compound as defined in any one of clauses A1 to A4; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. A method comprising:

[0062] A8. A diagnostic composition comprising a compound according to any one of paragraphs A1 to A4 and a pharmaceutically acceptable excipient, carrier, diluent or adjuvant.

[0063] A9. Formula (II-F) [ka] (In the formula, R 3 is as follows: [ka] is a pyrrolidine substituted with a leaving group (LG) such as R 4 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl optionally being substituted with methyl; * is the position of attachment), and all detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0064] A10. LG is halogen, C 1~4 Alkyl sulfonates and C 6~10 Compounds of formula (II-F) according to section A9 selected from aryl sulfonates.

[0065] A11. [ka] Compounds of formula (II-F) according to clause A9 or A10, wherein

[0066] A12. Formula (II-H) [ka] (In the formula, R 5 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 6 is a 5- or 6-membered heteroaryl containing one or two N, wherein the heteroaryl is optionally substituted with methyl and / or the heteroaryl is optionally substituted with one or more X; X is halogen or H, provided that at least one X is halogen; * is the position of attachment), and all detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0067] A13. [ka] The compound of formula (II-H) according to clause A12, wherein

[0068] A14. A compound according to any one of clauses A9 to A11 is 18so that it can be replaced by F 18 A method for preparing a compound according to paragraph A2, comprising reacting with an F-fluorinating agent.

[0069] A15. 18 F-fluorinating agent is K 18 F, H 18 F, Cs 18 F, Na 18 F and tetrabutylammonium [ 18 F] fluoride.

[0070] A16. Use of a compound according to any one of sections A1 to A4 as an in vitro analytical standard or an in vitro screening tool.

[0071] A17. A test kit for detecting and / or diagnosing a disorder or abnormality associated with alpha-synuclein aggregates, the test kit comprising at least one compound defined in any one of clauses A1 to A4.

[0072] A18. A kit for preparing a radiopharmaceutical preparation, comprising a sealed vial containing at least one compound as defined in any of paragraphs A9 to A11.

[0073] The invention is also defined by the following clauses: B1. Formula (I) [ka] (In the formula, R 1 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl optionally being substituted with methyl; *is the position of attachment), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0074] B2. The compound of formula (I) according to clause B1, wherein the compound is a detectably labeled compound.

[0075] B3. The detectably labeled compound is a radioisotope, preferably 2 H, 3 H or 18 A compound of formula (I) according to clause B2, comprising a detectable label selected from F.

[0076] B4. R 1 But, [ka] Like 18 The compound of formula (I) according to clause B3, which is pyrrolidine substituted with F.

[0077] B5. R 1 But, [ka] Like 19 is a pyrrolidine substituted with F, The compound of formula (I) is, at least in one available position, 3 A compound of formula (I) according to clause B3, detectably labeled with H (tritium).

[0078] B6. [ka] and T is 3 H (tritium), and F is 19 F means a compound according to any one of clauses B1 to B5.

[0079] B7. A compound according to any one of clauses B1 to B6 for use in imaging alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, preferably for use in positron emission tomography imaging of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites.

[0080] B8. A compound for use according to clause B7, wherein the use is for brain imaging.

[0081] B9. A compound for use according to any one of clauses B1 to B6 for use in a diagnostic method.

[0082] B10. A compound for use according to clause B9 for use in a method for the diagnosis of, or a predisposition to, a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, wherein the disease, disorder or abnormality is optionally Parkinson's disease (sporadic, familial with alpha-synuclein mutations, familial with non-alpha-synuclein mutations), pure autonomic failure, or Lewy body dysphagia. (including "pure" Lewy body dementia), dementia with Lewy bodies (LBD), dementia with Lewy bodies (DLB) (including "pure" Lewy body dementia), Parkinson's disease dementia (PDD), diffuse Lewy body disease (DLBD), 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 (Shy-Drager syndrome) group, 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, 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) a compound selected from the group consisting of neuropathies, neuroaxonal dystrophies, neurodegeneration type 1 with cerebral iron accumulation (including 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.

[0083] B11. A compound for use according to clause B10, wherein the disease is Parkinson's disease.

[0084] B12. A compound for use according to any one of clauses B7 to B11, wherein the use is in humans.

[0085] B13. A method for diagnosing a disease, disorder, or condition associated with, or a predisposition to, alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in a patient, comprising: a) administering to a patient a diagnostically effective amount of a compound as defined in any one of clauses B1 to B6; b) distributing the compound to the tissue of interest; and c) imaging the tissue of interest, wherein an increase in binding of the compound to the tissue of interest compared to normal control levels of binding indicates that the patient is suffering from or at risk of developing a disease, disorder or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. A method comprising:

[0086] B14. A method of collecting data for diagnosing a disease, disorder, or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a patient, comprising: (a) contacting a sample or a specific body part or body region suspected of containing alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, with a compound as defined in any one of clauses B1 to B6; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. A method comprising:

[0087] B15. A method for collecting data for diagnosing an alpha-synuclein aggregate-associated disease, disorder, or abnormality in a patient, comprising: (a) contacting a sample or a specific body part or body region suspected of containing alpha-synuclein aggregates with a compound as defined in clauses B1 to B6; (b) binding the compound to alpha-synuclein aggregates; (c) detecting a compound that binds to alpha-synuclein aggregates; and (d) 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 region. A method comprising:

[0088] B16. A method for determining the amount of alpha-synuclein aggregates in tissues and / or body fluids, comprising: (a) providing a sample representative of the tissue and / or body fluid under investigation; (b) testing the sample for the presence of alpha-synuclein aggregates using a compound defined in paragraphs B1 to B6; (c) determining the amount of the compound that binds to the alpha-synuclein aggregates; and (d) calculating the amount of alpha-synuclein aggregates in the tissue and / or body fluid A method comprising:

[0089] B17. A method of collecting data to determine a predisposition in a patient to a disease, disorder, or condition associated with alpha-synuclein aggregates, comprising detecting specific binding of a compound as defined in paragraphs B1 to B6 to alpha-synuclein aggregates in a sample or in a specific body part or region, comprising: (a) contacting a sample or a specific body part or body region suspected of containing alpha-synuclein aggregates with a compound as defined in clauses B1 to B6; (b) binding the compound to the alpha-synuclein aggregates to form a compound / alpha-synuclein aggregate complex; (c) detecting the formation of a compound / alpha-synuclein aggregate complex; (d) optionally correlating the presence or absence of compound / alpha-synuclein aggregate complexes with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally, comparing the amount of compound / alpha-synuclein aggregates to a normal control value; A method comprising:

[0090] B18. A method for collecting data to monitor residual disease, disorder, or abnormality in a patient suffering from a disease, disorder, or abnormality associated with alpha-synuclein aggregates and treated with a pharmaceutical agent, comprising: (a) contacting a sample or a specific body part or body region suspected of containing alpha-synuclein aggregates with a compound as defined in clauses B1 to B6; (b) binding the compound to the alpha-synuclein aggregates to form a compound / alpha-synuclein aggregate complex; (c) detecting the formation of a compound / alpha-synuclein aggregate complex; (d) optionally correlating the presence or absence of compound / alpha-synuclein aggregate complexes with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally, comparing the amount of compound / alpha-synuclein aggregates to a normal control value; A method comprising:

[0091] B19. A method for collecting data to predict the response of a patient suffering from a disease, disorder, or abnormality associated with alpha-synuclein aggregates and being treated with a pharmaceutical agent, comprising: (a) contacting a sample or a specific body part or body region suspected of containing alpha-synuclein aggregates with a compound as defined in clauses B1 to B6; (b) binding the compound to the alpha-synuclein aggregates to form a compound / alpha-synuclein aggregate complex; (c) detecting the formation of a compound / alpha-synuclein aggregate complex; (d) optionally correlating the presence or absence of compound / alpha-synuclein aggregate complexes with the presence or absence of alpha-synuclein aggregates in the sample or in a particular body part or region; and (e) optionally, comparing the amount of compound / alpha-synuclein aggregates to a normal control value; A method comprising:

[0092] B20. A diagnostic composition comprising a compound according to any one of clauses B1 to B6 and a pharmaceutically acceptable excipient, carrier, diluent or adjuvant.

[0093] B21. Formula (II-F) [ka] (In the formula, R 3 is as follows: [ka] is a pyrrolidine substituted with a leaving group (LG) such as R 4 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl optionally being substituted with methyl; * is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0094] B22. LG is halogen, C 1~4 Alkyl sulfonates and C 6~10Compounds of formula (II-F) according to clause B21 selected from arylsulfonates.

[0095] B23. [ka] The compound of formula (II-F) according to clause B21 or B22, wherein

[0096] B24. Formula (II-H) [ka] (In the formula, R 5 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 6 is a 5- or 6-membered heteroaryl containing one or two N, wherein the heteroaryl is optionally substituted with methyl and / or the heteroaryl is optionally substituted with one or more X; X is halogen or H, provided that at least one X is halogen; * is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0097] B25. [ka] The compound of formula (II-H) according to clause B24, wherein

[0098] B26. A compound according to any one of clauses B21 to B23 is 18 so that it can be replaced by F 18 A method for preparing a compound according to paragraph B2, B3 or B4, comprising reacting with an F-fluorinating agent.

[0099] B27. 18 F-fluorinating agent is K 18 F, H 18 F, Cs 18 F, Na 18 F and tetrabutylammonium [ 18 The method according to paragraph B26, wherein the fluoride is selected from the group consisting of: F] fluoride.

[0100] B28. A compound according to any one of clauses B24 or B25, 3 A method of preparing a compound according to paragraph B2, B3 or B5 comprising reacting with a H radiolabeled agent.

[0101] B29. Use of a compound according to any one of clauses B1 to B6 as an in vitro analytical standard or an in vitro screening tool.

[0102] B30. 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 defined in any one of clauses B1 to B6.

[0103] B31. A kit for preparing a radiopharmaceutical preparation, comprising a sealed vial containing at least one compound as defined in any of paragraphs B21 to B25.

[0104] Within sections A and B, "heterocyclyl" may refer to a carbocyclic group as defined above in which at least one of the carbon atoms is replaced by a heteroatom, e.g., selected from N, O, or S, or a heteroatom (e.g., N, O, and / or S)-containing moiety. A heterocyclyl group may be unsaturated or saturated. It covers both heteroalkyl and heteroaryl groups. A heterocyclyl may also be a cyclic ring connected by bridging means or connected by spiro means, e.g., a 6-membered bicyclic ring, a 7-membered bicyclic ring, an 8-membered bicyclic ring, a 6-membered spirocyclic ring, a 7-membered spirocyclic ring, or an 8-membered spirocyclic ring. Examples are azetidine, pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, isothiazolidine, thiazole, isothiazole, dioxolane, dithiolane, triazole, furazan, oxadiazole, thiadiazole, dithiazole, tetrazole, piperidine, oxane, thiane, pyridine, pyran, thiopi Examples of suitable heterocyclyl groups include lanes, piperazines, diazines (including pyrazines and pyrimidines), morpholines, oxazines, thiomorpholines, thiazines, dioxanes, dioxines, dithianes, dithiines, triazines, trioxanes, tetrazines, azepanes, azepines, oxepanes, oxepines, thiepanes, thiepines, 3-azabicyclo[3.1.0]hexane, azaspiro[3.3]heptane, diazaspiro[3.3]heptane, azabicyclo[3.2.1]octane, and diazabicyclo[3.2.1]octane. Examples of suitable heterocyclyl groups include azetidine, morpholine, piperazine, pyrrolidine, tetrahydrofuran, piperidine, azaspiro[3.3]heptane, and the like. Examples of possible heteroaryl groups include pyridine, pyrazole, and the like.

[0105] With respect to sections A and B, the following preferred definitions may apply:

[0106] Preferably, R 2 teeth, [ka] is.

[0107] More preferably, R 2 teeth, [ka] is.

[0108] Even more preferably, R 2 teeth, [ka] is.

[0109] In each of the above embodiments, R 2 is optionally substituted with methyl.

[0110] F is preferably 19 F or 18 F, more preferably 18 It's F.

[0111] In one embodiment of sections A and B, the compound of formula (I) [ka] (In the formula, R 1 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl optionally being substituted with methyl; * is the point of attachment) is a detectably labeled compound, and the detectable label is a radioisotope.

[0112] Preferably, the detectable label is 18 F, 2 H and 3H, most preferably 18 F and 3 H.

[0113] In one embodiment of sections A and B, the compound of formula (I) has the formula (IF) [ka] (In the formula, R 1 is as follows: [ka] Like 18 is a pyrrolidine substituted with F, R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl optionally being substituted with methyl; * is the position of attachment).

[0114] In one embodiment of sections A and B, the compound of formula (I) has the formula (IH): [ka] (In the formula, R 1 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl being optionally substituted with methyl; Fluoro is 19 F, * is the position of attachment), which is detectably labeled at at least one available position 2 H or 3 H (tritium), preferably 3Detectably labeled with H.

[0115] Preferably, the detectably labeled compound of formula (IH) is of formula (I-Ha): [ka] (In the formula, R 1 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, wherein the heteroaryl is optionally substituted with methyl and / or the heteroaryl is optionally substituted with at least one T, wherein T is 3 H (tritium), n is 0 to 3, provided that the compound of formula (I-Ha) contains at least one T, and T is 3 H (tritium), Fluoro is 19 F, * is the position of the bond).

[0116] Preferably, the detectably labeled compound of formula (I-Ha) contains one or two Ts.

[0117] Preferably, n is 1.

[0118] In a further embodiment, in the compound of formula (IH), R 2 is a 6-membered heteroaryl containing one N atom, the heteroaryl being substituted with one or more T. Preferably, R 2 teeth, [ka] More preferably, R 6 teeth, [ka] is.

[0119] In preferred embodiments of sections A and B, the compound of formula (I) is [ka] (In the formula, R 1 is as follows: [ka] and fluoro-substituted pyrrolidines such as R 2 is a 6-membered heteroaryl containing 1 or 2 N atoms, the heteroaryl being optionally substituted with methyl; * is the position of the bond), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0120] Preferably, R 2 is a 6-membered heteroaryl containing one N atom. More preferably, R 2 teeth, [ka] is.

[0121] R 2 In each of the above embodiments, the 6-membered heteroaryl may be optionally substituted with methyl.

[0122] 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.

[0123] "Alkyl" refers to a saturated, straight-chain or branched organic moiety consisting of carbon and hydrogen atoms. Alkyl groups typically do not contain any saturation and are usually attached to the remainder of the molecule by a single bond. Examples of suitable alkyl groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term "C1-C4 alkyl" should be construed accordingly. Examples of "C1-C4 alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-methylethyl, n-butyl, t-butyl, and isobutyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl.

[0124] "C1-C4 alkoxy" refers to a radical of the 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.

[0125] "Halogen C1-C4 alkyl" or "halo C1-C4 alkyl" refers to a C1-C4 alkyl group as defined above that is substituted by one or more 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.

[0126] "C3-C6 cycloalkyl" refers to a stable monocyclic saturated hydrocarbon group consisting solely of carbon and hydrogen atoms, having from 3 to 6 carbon atoms. Examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0127] "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, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl. Examples of preferred heterocyclyl groups include, but are not limited to, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl.

[0128] "Aryl" refers to a homocyclic aromatic organic moiety (e.g., containing one or two rings) consisting of carbon and hydrogen atoms, preferably having from 5 to 12 carbon atoms, preferably from 6 to 12 carbon atoms, more preferably from 6 to 10 carbon atoms, even more preferably from 5 to 10 carbon atoms, and even more preferably from 5 or 6 carbon atoms. Examples include, but are not limited to, phenyl, biphenyl, and naphthyl.

[0129] "Heteroaryl" refers to an aryl group, as defined above, in which at least one carbon atom is replaced by a heteroatom selected from, for example, N, O, or S, or a heteroatom (e.g., N, O, and / or S)-containing moiety. Typically, a heteroaryl is a 5- to 8-membered ring system, preferably a 5- to 6-membered ring system, in which at least one carbon atom is replaced by a heteroatom selected from, for example, N, O, or S. Examples of possible heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl. Preferred examples thereof include pyridine, pyrazole, etc., more preferably pyridine.

[0130] "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.

[0131] 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 1~4 Alkyl sulfonates and C 6~10 aryl sulfonates, C 6~10 The aryl can be optionally substituted with -CH3 or -NO2.

[0132] Unless otherwise specified, the term "compound of the invention" refers to a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound thereof, stereoisomer (including diastereomeric mixtures and individual diastereoisomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof. It is understood that each reference to a compound of Formula (I) as defined herein also covers its subformulas (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)).

[0133] 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. Compounds described herein containing olefinic double bonds include E and Z geometric isomers.

[0134] All salt forms, polymorphs, hydrates and solvates (eg, ethanolates) are included in the present invention.

[0135] "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.

[0136] "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.

[0137] The compounds of the present invention may also be provided in the form of prodrugs, ie compounds which are metabolized in vivo to active metabolites.

[0138] The patient or subject in the present invention is typically an animal, particularly a mammal, and more particularly a human.

[0139] 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.

[0140] 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.

[0141] 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, Parkinson's disease, and multiple system atrophy.

[0142] The terms "disease," "disorder," or "condition" are used interchangeably herein.

[0143] A compound of formula (I), or a detectably labeled compound thereof, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, may bind to alpha-synuclein aggregates. The type of bond between a compound of formula (I), or a detectably labeled compound thereof, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, is not defined, and any type of bond is covered by the present invention. The terms "compound that binds to alpha-synuclein aggregates," "compound / (alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites) complex," "compound / alpha-synuclein aggregate complex," "compound / protein aggregate complex," and the like are used interchangeably herein and are not intended to be limited to any particular type of bond.

[0144] 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. [Brief explanation of the drawings]

[0145] [Figure 1]Target engagement of [3H]-Example 1 / Example 1[3H-1] in tissues from different a-synucleinopathies. Bottom row: Accumulation of silver grains in Lewy bodies and Lewy neurites. Top row: Immunofluorescence staining with a-syn-pS129 antibody was performed on the same section to co-label a-syn aggregates. PD, Parkinson's disease; PDD, Parkinson's disease with dementia; MSA, multiple system atrophy; DLB, dementia with Lewy bodies; LBV, Lewy body variant of Alzheimer's disease. Scale bar, 20 μm. [Figure 2A] Evaluation of the binding affinity of Example 1 [3H-1] in human PDD brain tissue by autoradiography. Autoradiography image. "-", total binding; "+", self-blocking nonspecific binding. [Figure 2B] Evaluation of the binding affinity of Example 1 [3H-1] in human PDD brain tissue by autoradiography. Immunofluorescence staining using a-syn-pS129 antibody. Scale bar, 2 mm. [Figure 2C] Evaluation of the binding affinity of Example 1 [3H-1] in human PDD brain tissue by autoradiography. Specific binding of Example 1 [3H-1] (RU: relative units). [Figure 3A] Evaluation of the binding affinity of Example 1 [3H-1] in human brain tissue from a familial PD case (G51D missense mutation) by autoradiography. Autoradiography image. "-", total binding; "+", self-blocking nonspecific binding. [Figure 3B] Evaluation of the binding affinity of Example 1 [3H-1] in human brain tissue from a familial PD case (G51D missense mutation) by autoradiography. Immunofluorescence staining using a-syn-pS129 antibody. Scale bar, 5 mm. [Figure 3C] Evaluation of the binding affinity of Example 1 [3H-1] in human brain tissue from a familial PD case (G51D missense mutation) by autoradiography. Specific binding of Example 1 [3H-1] (RU: relative units). [Figure 4A]Assessment of binding specificity of Example 1 [3H-1] by autoradiography and head-to-head comparison with a reference a-syn binder ([3H]-a-syn-Ref). Autoradiography images. PDD, Parkinson's disease with dementia; PD_SNCA, a-synuclein [SNCA] gene G51D missense mutation; NDC, non-demented control. "-", total binding; "+", self-blocking nonspecific (NS) binding. [Figure 4B] Evaluation of binding specificity of Example 1 [3H-1] by autoradiography and head-to-head comparison with a reference a-syn binder ([3H]-a-syn-Ref). Immunofluorescence staining with a-syn-pS129 antibody. Scale bar, 2 mm. [Figure 5] Saturation binding of [H]-Example 1 to PD brain-derived a-syn aggregates and a head-to-head comparison with [H]-a-syn-Ref by microradiobinding. The plot shows specific binding (RU: relative units). [Figure 6] Competitive binding of Example 1 [3H-1] with a-syn-Ref on idiopathic PD brain-derived a-syn aggregates. Percent competition values ​​for Example 1 [3H-1] are plotted against increasing concentrations of unlabeled a-syn-Ref (left) or the compound of Example 1 (right). Average values ​​of two technical replicates are shown. [Figure 7] Evaluation of the K value of the compound of Example 1 for displacement of the reference Abeta compound ([H]-Abeta-Ref) with the non-radiolabeled compound of Example 1 in AD brain homogenates. Percent competition values ​​for [H]-Abeta-Ref binding are plotted against increasing concentrations of the non-radiolabeled compound of Example 1. The average of two technical replicates is shown. [Figure 8A] Evaluation of target engagement of Example 1 [3H-1] in AD tissue containing pathological tau aggregates. Immunofluorescence staining using MC1 antibody in the same tissue labeled tau aggregates. [Figure 8B]Evaluation of target engagement of Example 1 [3H-1] in AD tissue containing pathological tau aggregates. No accumulation of silver particles in tau tangles with Example 1 [3H-1] compared to the reference tau ligand ([3H]-Tau-Ref). [Figure 9] Evaluation of target engagement of Example 1 [3H-1] in frontotemporal lobar degeneration (FTLD) TDP type C brain tissue containing pathological TDP-43 aggregates. Immunofluorescence staining using phospho-TDP-43 antibody in the same tissue-labeled TDP-43 aggregates (top row). No accumulation of silver grains in TDP-43 aggregates with Example 1 [3H-1] (bottom row). Scale bar, 20 μm. [Figure 10] Example 1: iv NHP PK in whole brain monkeys using [18F-1]. [Figure 11A] Assessment of binding specificity of Example 1 [3H-1] for various α-synucleinopathies and non-demented control (NDC) cases by autoradiography. Autoradiography images. PDD, Parkinson's disease with dementia; MSA, multiple system atrophy; LBV, Lewy body variant of Alzheimer's disease; NDC, non-demented control. "Total", total binding; "NSB", non-specific binding. [Figure 11B] Evaluation of the binding specificity of Example 1 [3H-1] for various a-synucleinopathies and non-demented control (NDC) cases by autoradiography. Immunofluorescence staining using a-syn-pS129 antibody for diseased donors. Scale bar, 5 mm. PDD, Parkinson's disease with dementia; MSA, multiple system atrophy; LBV, Lewy body variant of Alzheimer's disease. [Figure 12] Target engagement of [3H]-Example 4 / Example 4[3H-4] in PD tissue. Bottom row: Accumulation of silver grains in Lewy bodies and Lewy neurites. Top row: Immunofluorescence staining with a-syn-pS129 antibody was performed on the same section to co-label a-syn aggregates. Scale bar, 20 μm. [Figure 13A]Assessment of binding specificity of Example 4 [3H-4] for various a-synucleinopathies and non-demented controls by autoradiography. Autoradiography images. SNCA, a-synuclein [SNCA] gene G51D missense mutation; PD, Parkinson's disease; MSA, multiple system atrophy; NDC, non-demented controls. "Total," total binding; "NSB," non-specific binding. [Figure 13B] Autoradiographic evaluation of the binding specificity of Example 4 [3H-4] for various a-synucleinopathies and non-demented controls. Immunofluorescence staining using a-syn-pS129 antibody for diseased donors. Scale bar, 2 mm. SNCA, a-synuclein [SNCA] gene G51D missense mutation; PD, Parkinson's disease; MSA, multiple system atrophy. [Figure 14] Saturation binding of [H]-Example 4 to a-syn aggregates from PD brains by microradiobinding. The plot shows specific binding (counts per minute per mm). The average values ​​of four independent experiments are shown (mean ± SD). [Figure 15] Evaluation of the K value of the compound of Example 4 for displacement of the reference Abeta compound ([H]-Abeta-Ref) with the non-radiolabeled compound of Example 4 in AD brain homogenates. Percent competition values ​​for [H]-Abeta-Ref binding are plotted against increasing concentrations of the non-radiolabeled compound of Example 4. The average values ​​of two independent experiments with two technical replicates are shown (mean ± SD). [Figure 16] Evaluation of target engagement of Example 4[3H-4] in AD tissue containing pathological tau aggregates by microautoradiography. No accumulation of silver particles is observed in tau tangles with Example 4[3H-1] compared to the reference tau ligand ([3H]-Tau-Ref). DETAILED DESCRIPTION OF THE INVENTION

[0146] 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.

[0147] The present invention relates to a compound of formula (I) [ka] (In the formula, [ka] is aryl or heteroaryl, which is [ka] are selected with directionality from R 0 is H or C1-C4 alkyl, R 1 is -CN, or halo, or C1-C4 alkyl, or C1-C4 alkoxy, or -N(C1-C4 alkyl)2, or -NH(C1-C4 alkyl), or H; or R 1 is —NH—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo; R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 But the following: [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, * is the position of attachment), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0148] In another embodiment, the present invention provides a compound of formula (IIa) or (IIb) [ka] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, having formula (I):

[0149] In another embodiment, the present invention provides a compound of formula (IIIa), (IIIb) or (IIIc) [ka] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, having formula (I):

[0150] R 0 is H or C1-C4 alkyl. Preferably, R 0 is H or CH3, more preferably R 0is H.

[0151] In one embodiment, R 1 is H, —CN, halo, C1-C4 alkyl, C1-C4 alkoxy, —N(C1-C4 alkyl)2, or —NH(C1-C4 alkyl). Preferably, R 1 is -CN, halo, C1-C4 alkyl, C1-C4 alkoxy, -N(C1-C4 alkyl)2 or -NH(C1-C4 alkyl). More preferably, R 1 is -CN, F, C1-C3 alkyl, C1-C3 alkoxy or -N(C1-C3 alkyl). Even more preferably, R 1 is -CN, -CH(CH3)2, -OCH3, -OCH(CH3)2, -N(CH3)2 or -NH-CH(CH3)2.

[0152] In one embodiment, R 1 is —NH—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo. Preferably, R 1 is the following: [ka] is selected from R 1' is independently halo and s=0, 1, 2 or 3.

[0153] More preferably, R 1 is the following: [ka] is selected from.

[0154] Even more preferably, R 1 teeth, [ka] is selected from.

[0155] In a preferred embodiment, F is preferably 19 F or 18 F, more preferably 18 It's F.

[0156] In one embodiment, R 2 is the following: [ka] (In the formula, R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1 If valence allows, [ka] is a combination of a single bond and a double bond, * is the position of the bond).

[0157] Preferably, R 2 is the following: [ka] (In the formula, R 2a , R2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond).

[0158] Preferably, R 2 is the following: [ka] (In the formula, R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond).

[0159] More preferably, R 2 is the following: [ka] (In the formula, R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond).

[0160] Even more preferably, R 2 teeth, [ka] is selected from * is the position of the bond.

[0161] In another embodiment, the present invention provides compounds of sub-formula (IIa) or (IIb) [ka] (In the formula, R 0 is methyl or H, and R 1 is CH3 or H, preferably R 1 is CH3 and R 2 contains at least one fluoro and is preferably: [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of attachment), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0162] Most preferably, R 2 teeth, [ka] (In the formula, R 2a , R 2a' , R 2b , R 2e , R 2c , R 2c' , R z and p are as defined herein above, and R 2a , R 2a' , R 2b , R 2c , R 2c ' and R 2e At least one of is F. F is preferably 19 F or 18 F, more preferably 18 F).

[0163] In another embodiment, the present invention provides compounds of sub-formula (IIIa), (IIIb) or (IIIc) [ka] (In the formula, R 0 is methyl or H, preferably R 0 is H, R 1 is selected from -CN, halo, C1-C4 alkyl; or C1-C4 alkoxy, -N(C1-C4 alkyl)2, -NH(C1-C4 alkyl), H, or R 1 is —NH—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo; Preferably, R 1 is the following: [ka] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0164] F is preferably 19 F or 18 F, more preferably 18 F, R 2 is preferably the following: [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c'are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond.

[0165] In another embodiment, the present invention provides a compound of formula (IIIa): [ka] (In the formula, R 0 is methyl or H, preferably R 0 is H, R 1 is —NH—C-C cycloalkyl, C-C cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo, and preferably R 1 is the following: [ka] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0166] R 1 is preferably [ka] and is substituted with fluoro, such as More preferably R 1 teeth, [ka] and preferably R 1 teeth, [ka] is.

[0167] R 2 is preferably the following: [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond.

[0168] Preferably, R 2 is the following: [ka] is selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0169] More preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0170] Preferably, R 2 teeth, [ka] and more preferably, R 2 teeth, [ka] and even more preferably, R 2 teeth, [ka] is.

[0171] In each of the above embodiments, R 2 may be optionally substituted with one or more substituents disclosed herein above. F is preferably 19 F or 18 F, more preferably 18 It's F.

[0172] In another embodiment, the present invention provides a compound of formula (IIIb): [ka] (In the formula, R 0 is methyl or H, preferably R 0 is H, R 1is —NH—C-C cycloalkyl, C-C cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo, and preferably R 1 is the following: [ka] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0173] R 1 is preferably [ka] and is substituted with fluoro, such as More preferably R 1 teeth, [ka] and preferably R 1 teeth, [ka] is.

[0174] R 2 is preferably the following: [ka] (In the formula, R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond).

[0175] Preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0176] More preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0177] Preferably, R 2 teeth, [ka] and more preferably, R 2 teeth, [ka] and even more preferably, R 2 teeth, [ka] is.

[0178] In each of the above embodiments, R 2 may be optionally substituted with one or more substituents disclosed herein above. F is preferably 19 F or 18 F, more preferably 18 It's F.

[0179] In another embodiment, the present invention provides a compound of formula (IIIc): [ka] (In the formula, R 0 is methyl or H, preferably R 0 is H, R 1 is —NH—C-C cycloalkyl, C-C cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo, and preferably R 1 is the following: [ka] or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0180] R 1 is preferably [ka] and is substituted with fluoro, such as More preferably R 1 teeth, [ka] and preferably R 1 teeth, [ka] is.

[0181] R 2 is preferably the following: [ka] (In the formula, R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; p is 0, 1 or 2; * is the position of the bond).

[0182] Preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0183] More preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0184] Preferably, R 2 teeth, [ka] and more preferably, R 2 teeth, [ka] and even more preferably, R 2 teeth, [ka] is.

[0185] In each of the above embodiments, R 2 may be optionally substituted with one or more substituents disclosed herein above. F is preferably 19 F or 18 F, more preferably 18 It's F.

[0186] In another embodiment, the present invention provides a compound of formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, with preferred compounds being: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0187] More preferably, the stereoisomers of the preferred compounds are: [ka] is.

[0188] In one embodiment, the present invention provides a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound of Formula (I) is a detectably labeled compound.

[0189] One embodiment of the present invention provides a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is a detectably labeled compound, and the detectable label is a radioisotope, and the compound of Formula (I) comprises at least one radioisotope.

[0190] Preferably, the detectable label is 18 F, 2 H and 3 H, most preferably 18 F or 3 H.

[0191] In one embodiment, the present invention provides a compound of formula (I), preferably a compound of sub-formula (IIIa), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has the formula (III-F): [ka] (In the formula, R 1 is as follows: [ka] Like, 18 is substituted with F, R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 teeth, [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2b are independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; R 2c , R 2c' are independently selected from H, F, OH, OCH3 or CH3; R 2d is selected from H, F or —OH; R 2e is selected from H, OH, CH3 or F, Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, * is the position of attachment), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0192] Preferably R 2 teeth, [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e and p are as defined herein above, and R z is selected from H, C1-C4 alkyl or haloC1-C4 alkyl.

[0193] More preferably, R 2 is the following: [ka] Selected from R 2a , R2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R z and p is as defined herein above.

[0194] More preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2e , R z and p is as defined herein above.

[0195] Preferably, the detectably labeled compound of formula (III-F), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, comprises at least one 18 Contains F. Preferably, R 2 The substituents (e.g., R 2a , R 2a' , R 2b , R 2c , R 2c' , R z and R 2e ) is optional, 18 More preferably, the detectably labeled compound of formula (III-F), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, may be one or two 18 F, more preferably one 18 Contains F.

[0196] Preferred compounds are [ka] or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0197] The most preferred compounds are [ka] or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0198] In one embodiment, the present invention provides a compound of formula (I), preferably a compound of sub-formula (IIIa), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has the formula (III-H): [ka] (In the formula, R 1 is -CN, or halo, or C1-C4 alkyl, or C1-C4 alkoxy, or -N(C1-C4 alkyl)2, or -NH(C1-C4 alkyl), or H; or R 1 is —NH—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo; R 1 is preferably [ka] is selected from R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 But the following: [ka] is selected from R 2a , R 2a' is independently selected from H, T, or F; R 2b is independently selected from T, F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, CT3 or C1-C4 alkoxy; R 2c , R2c' is independently selected from T, H, F, OH, OCH3, CT3, or CH3; R 2d is selected from T, H, F or —OH; R 2e is selected from T, H, OH, CH3, CT3 or F; Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, Fluoro is 19 F, C1-C4 alkyl, haloC1-C4 alkyl or C1-C4 alkoxy optionally contains one or more T; * is the position of attachment), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, which has at least one available position: 2 H (deuterium "D") or 3 H (tritium "T"), preferably 3 Detectably labeled with H.

[0199] Preferably, the detectably labeled compound of formula (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, contains one, two, or three T's. Preferably, the detectably labeled compound of formula (III-Ha), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, contains one T. More preferably, the detectably labeled compound of formula (III-Ha) contains two T's. Even more preferably, the detectably labeled compound of formula (III-Ha) contains three T's.

[0200] Preferably, the detectably labeled compound of formula (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, is of formula (III-Ha): [ka] (In the formula, R 1 is -CN, or halo, or C1-C4 alkyl, or C1-C4 alkoxy, or -N(C1-C4 alkyl)2, or -NH(C1-C4 alkyl), or H; or R 1 is —NH—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or heterocyclyl, each of which is optionally substituted with at least one halo; R 1 is preferably [ka] is selected from R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 is as follows: [ka] Selected from R 2 is optionally replaced by at least one T, R 2a , R 2a' is independently selected from H, T, or F; R 2b are independently selected from T, F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, CT3, or C1-C4 alkoxy, where C1-C4 alkyl, haloC1-C4 alkyl, or C1-C4 alkoxy optionally contains one or more T; R 2c , R 2c' is independently selected from T, H, F, OH, OCH3, CT3, or CH3; R 2d is selected from T, H, F or —OH; R 2e is selected from T, H, OH, CH3, CT3 or F; Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, T is 3 H (tritium), n is 0 to 3, provided that the compound of formula (I-Ha) contains at least one T; Fluoro is 19 F, * is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0201] Preferably, the detectably labeled compound of Formula (III-Ha), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, contains one, two, or three T. Preferably, n is 1.

[0202] Preferably, the detectably labeled compound of formula (III-Ha), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one T. More preferably, the detectably labeled compound of formula (III-Ha), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises two T. Even more preferably, the detectably labeled compound of formula (III-Ha), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises three T.

[0203] In a further embodiment, the present invention provides a detectably labeled compound of formula (III-H) or (III-Ha) as disclosed hereinabove, or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 2 teeth, [ka] and R is an aryl or a 5- or 6-membered heteroaryl selected from 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e and p are as defined herein above, and R z is selected from T, H, C1-C4 alkyl, CT3, or haloC1-C4 alkyl, where C1-C4 alkyl or haloC1-C4 alkyl optionally contains one or more T.

[0204] Preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e , R zand p is as defined herein above.

[0205] More preferably, R 2 is the following: [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2e , R z and p is as defined herein above.

[0206] Preferably, R 2 teeth, [ka] and R z contains at least one T.

[0207] More preferably, R 2 teeth, [ka] is.

[0208] Preferred detectably labeled compounds of formula (III-H) or (III-Ha), pharmaceutically acceptable salts, hydrates or solvates thereof are [ka] and T is 3 H (tritium). Preferably, F is 19 It means F.

[0209] In a preferred embodiment, the present invention provides a detectably labeled compound of formula (III-H) or (III-Ha), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof: 3 H Tritium ("T") 2H may be replaced by deuterium (“D”).

[0210] Preferably, the detectably labeled compound of formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, comprises a detectable label, preferably the detectable label is a radioisotope, particularly 18 F, 2 H and 3 H.

[0211] The compounds of the present invention, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, and precursors thereof, can be detectably labeled. The type of label is not specifically limited and depends on the detection method selected. Examples of possible labels include isotopes, such as radionuclides, positron emitters, and gamma emitters. For detectably labeled compounds of the present invention, or their stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, and precursors thereof, which contain radioisotopes, positron emitters, or gamma emitters, it should be understood that the radioisotopes, positron emitters, or gamma emitters must be present in amounts that are not the same as the natural amounts of the radioisotopes, positron emitters, or gamma emitters, respectively. Furthermore, the amounts used should allow their detection by the detection method selected.

[0212] Examples of suitable isotopes, e.g., radionuclides, positron emitters and gamma emitters, are: 2 H, 3 H, 18 F, 11 C. 13 N and 15 O, preferably 2 H, 3 H, 11 C. 13 N, 15 O and 18 F, more preferably 2 H, 3 H and18 F, even more preferably 3 H and 18 Contains F.

[0213] 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.

[0214] Additionally, isotopes such as deuterium, i.e. 2 Substitution with H 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.

[0215] Isotopic variations of the compounds of the present invention, or detectably labeled compounds thereof, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof, and precursors thereof, can generally be prepared by conventional procedures, e.g., by the exemplified methods described in the Examples and Preparations, or by preparation using appropriate isotopic variations of suitable reagents that are commercially available or prepared by known synthetic techniques.

[0216] Radionuclides, positron emitters and gamma emitters can be incorporated into the compounds of the present invention, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, 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, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, and their precursors.Exemplary methods for incorporating detectable labels are described, for example, in US2012 / 0302755.

[0217] The position at which the detectable label should be attached to the compounds of the present invention and their precursors is not particularly limited.

[0218] Radionuclides, positron emitters and gamma emitters, for example, can be attached at any position where a 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, 18 F to R 1 It is preferable to attach it by 3 The H can be attached at any available position. Preferably, it is attached to the pyridine ring. 2 When H is used as the detectable label, it may be attached at any available position. Preferably, it is attached to the pyridine ring.

[0219] In another embodiment, the present invention provides a compound of formula (IV-F) which is a precursor of the compound of formula (III-F) [ka] (In the formula, R 3 is as follows: [ka] It is substituted with a leaving group (LG) as shown below. R 4 is aryl or 5- or 6-membered heteroaryl, and R 4 is the R of the compound of formula (III-F) disclosed herein above 2 The present invention further relates to compounds of the formula (selected from the same list as in

[0220] Preferably, the leaving group (LG) is a halogen, C 1~4 Alkyl sulfonate, C1-C4 alkyl ammonium, nitro or C 6~10 Aryl sulfonate, C 6~10The aryl may be optionally substituted with -CH3 or -NO2. More preferably, the leaving group (LG) is selected from the group consisting of bromo, chloro, iodo, C 1~4 Alkyl sulfonate or C 6~10 Aryl sulfonate, C 6~10 The aryl may be optionally 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. Preferably, the leaving group (LG) is mesylate.

[0221] Preferably, R 4 teeth, [ka] is.

[0222] More preferably, R 4 teeth, [ka] is.

[0223] Even more preferably, R 4 teeth, [ka] is.

[0224] Preferably, R 4 is optional, 18 It is replaced by F.

[0225] Preferred compounds are [ka] is.

[0226] In another embodiment, the present invention provides a compound of formula (IV-H) [ka] (In the formula, R 5 is the R of the compound of formula (III-H) disclosed herein above 1 and preferably selected from the same list as [ka] is selected from R 6 is aryl or 5- or 6-membered heteroaryl, and R 6 But the following: [ka] is selected from R 2a , R 2a' is independently selected from H, X, or F; R 2b is independently selected from X, F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy, where C1-C4 alkyl, haloC1-C4 alkyl, or C1-C4 alkoxy is optional and includes one or more X; R 2c , R 2c' are independently selected from X, H, F, OH, OCH3 or CH3; R 2d is selected from X, H, F or —OH; R 2e is selected from X, H, OH, CH3 or F; Z is independently N, NH, N(C1-C4 alkyl), N(haloC1-C4 alkyl), O, or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, [ka] is a combination of a single bond and a double bond, *is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a precursor of a compound of formula (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0227] Fluoro is 19 F, X is bromo, chloro or iodo; R 6 contains at least one X.

[0228] In a further embodiment, in a compound of formula (IV-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, R 6 is preferably aryl or 6-membered heteroaryl optionally substituted with one or more X, where X is [ka] Selected from R 2a , R 2a' , R 2b , R 2c , R 2c' , R 2d , R 2e and p is as defined herein above, and where valence permits, [ka] is a combination of a single bond and a double bond, and fluoro is 19 F, * is the position of the bond.

[0229] Preferably, R 6 teeth, [ka] More preferably, R 6 teeth, [ka] is.

[0230] Even more preferably, the compound of formula (IV-H) is [ka] a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof; X is selected from bromo, chloro and iodo.

[0231] Preferably, X is bromine.

[0232] Preferred compounds are [ka] , a detectably labeled compound thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0233] In another embodiment, the present invention provides a compound of formula (IV-J) [ka] (In the formula, R 7 is the R of the compound of formula (III-H) disclosed herein above 1 is selected from the same enumeration as Preferably [ka] is selected from R 8 is the following: [ka] is selected from R 2a , R 2a' is independently selected from H or F; R 2bare independently selected from F, —OH, C1-C4 alkyl, haloC1-C4 alkyl, —NH2, —CN, or C1-C4 alkoxy; p is 0, 1 or 2; R z is selected from H, C1-C4 alkyl, or haloC1-C4 alkyl; If valence allows, [ka] is a combination of a single bond and a double bond, Fluoro is 19 F, * is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a precursor of a compound of formula (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0234] Preferably, R z is H.

[0235] In further embodiments of the compound of Formula (IV-J), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, R 8 is preferably [ka] Selected from R 2a , R 2a' , R 2b and p is as defined herein above; More preferably, R 8 teeth, [ka] is selected from.

[0236] Preferred compounds are [ka] or a detectably labeled compound, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0237] Methods for synthesizing detectably labeled compounds The present invention further relates to a process for preparing a compound of formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, particularly a compound of formula (III-F) or (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, comprising a detectable label.

[0238] In one embodiment, the present invention provides a compound of formula (IV-F) containing a radioisotope. 18 A process for preparing a compound of formula (III-F), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, by radiolabeling with F, [ka] R 1 , R 2 , R 3 and R 4 is as defined herein.

[0239] 18 Suitable solvents for F-fluorination include DMF, DMSO, acetonitrile, DMA, or mixtures thereof, preferably acetonitrile or DMSO.

[0240] 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] 18F and tetrabutylammonium [ 18 F] fluoride.

[0241] In one embodiment, the present invention provides a method for radioisotopically isotopically isotopically isotopic radioiso ... 3 A method for preparing a compound of formula (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, by radiolabeling with H, [ka] R 1 , R 2 , R 5 and R 6 is as defined herein; T is 3 H (tritium), n is 0 to 3, preferably n is 1 or 2, more preferably n is 1, provided that the compound of formula (III-Ha) contains at least one T; Fluoro is 19 F, X is bromo, chloro, iodo or H, preferably X is bromine.

[0242] 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).

[0243] In a preferred embodiment, F (fluoro) is 19 It's F.

[0244] In one embodiment, the present invention relates to a method for preparing a compound of formula (III-H), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, by radiolabeling a compound of formula (IV-J) with a CT3 radiolabeling agent, wherein T is 3 It's H. [ka] CT3 radiolabeled agent is ICT3( 3 The process may be carried out in the presence of a solvent such as dimethylformamide (DMF) and a base such as cesium carbonate or sodium hydride.

[0245] Diagnostic Compositions The compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are particularly suitable for imaging alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. 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. Imaging can be performed in mammals, preferably humans. Imaging is preferably in vitro imaging, ex vivo imaging, or in vivo imaging. More preferably, imaging is in vivo imaging; even more preferably, imaging is preferably brain imaging. Imaging can also be ocular / retinal imaging. The compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are particularly suitable for use in diagnostic methods.

[0246] The diagnostic method can be performed on a mammal, preferably a human. 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) or other tissue, or a body fluid, such as cerebrospinal fluid (CSF). The tissue is preferably brain tissue.

[0247] Due to their design and binding properties, the compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are suitable for use in the diagnosis of diseases, disorders, and abnormalities associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. The compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are particularly suitable for positron emission tomography imaging of alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. Diseases associated with alpha-synuclein aggregates are generally listed as synucleinopathies (or α-synucleinopathies). The compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof, are suitable for use in the diagnosis of diseases, disorders or abnormalities including, but not limited to, Parkinson's disease (sporadic, familial with alpha-synuclein mutations, familial with non-alpha-synuclein mutations, 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. Synucleinopathies associated with neuronal and glial aggregates of alpha-synuclein include 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).

[0248] In a method of diagnosing a disease, disorder or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, e.g., Parkinson's disease, or a predisposition thereto, in a subject, the method comprising: a) administering to a subject a diagnostically effective amount of a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; b) distributing a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, into a tissue of interest (e.g., the brain or other tissue, or a body fluid, e.g., cerebrospinal fluid (CSF)); and c) imaging the tissue of interest, wherein an increase in binding of a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, to the tissue of interest compared to normal control levels of binding indicates that the subject is suffering from or at risk of developing a disease, disorder or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. Includes.

[0249] The compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, can be used to image alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in any patient sample or specific body part or region suspected of containing alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites. The compounds can cross the blood-brain barrier. As a result, they are particularly suitable for imaging alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the brain or peripheral organs, such as the intestine, and in body fluids, such as cerebrospinal fluid (CSF).

[0250] For diagnostic applications, the compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, preferably compounds of Formula (I) or its subformulas (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), are preferably administered in the form of a diagnostic composition comprising a compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof. A "diagnostic composition" is defined herein as a composition comprising one or more compounds of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, 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 physiologically acceptable excipient, carrier, diluent, or adjuvant. Administration is preferably carried out by injecting the composition as an aqueous solution, 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., a cyclodextrin or a surfactant, e.g., Pluronic, Tween, or a phospholipid); and a pharmaceutically acceptable stabilizer or antioxidant (e.g., ascorbic acid, gentisic acid, or para-aminobenzoic acid). The dosage of the compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, will vary depending on the exact compound administered, the mass of the patient, and other variables apparent to a practitioner of ordinary skill in the art.

[0251] While it is possible for the compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, 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, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, optionally in admixture with at least one pharmaceutically acceptable excipient, carrier, diluent, or adjuvant.

[0252] 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.

[0253] Pharmaceutically useful excipients, carriers, adjuvants and diluents that can be used to formulate the diagnostic composition of the present invention 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, etc. These may include buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavorings, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins.

[0254] Routes for administering (delivering) the compounds of the present invention, preferably compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, include, but are not limited to, one or more of intravenous, gastrointestinal, intrathecal, intraperitoneal, intramuscular, oral (e.g., as a tablet, capsule, or as an ingestible liquid), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., via an injectable form), intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual. Preferably, the route of administration (delivery) of a compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, is intravenous.

[0255] 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.

[0256] 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.

[0257] Preferably, for diagnostic applications, the compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are administered parenterally. When the compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, 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 using injection techniques. For parenteral administration, the compounds are 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.

[0258] As indicated, the compounds of the present invention, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, can be administered intranasally or by inhalation, and are conveniently delivered 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, hydrofluoroalkanes, for example, 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 may contain a solution or suspension of the active compound, using, for example, a mixture of ethanol as a solvent and a propellant, which may further contain a lubricant, for example, 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, for example, lactose or starch.

[0259] Alternatively, the compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, 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, liquid, cream, ointment, or powder. The compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, can also be administered dermally or transdermally, for example, by using a skin patch.

[0260] 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.

[0261] For topical application to the skin, the compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, can be formulated as 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 as a suitable lotion or cream 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.

[0262] 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.

[0263] 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).

[0264] The compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, are useful as in vitro analytical standards or in vitro screening tools. They are also useful in in vivo diagnostic methods.

[0265] The compound according to the present invention, or a detectably labeled compound thereof, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, may also be provided in the form of a mixture comprising the compound according to the present invention, or a detectably labeled compound thereof, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, 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.

[0266] Diagnosis of a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, or a predisposition to a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a patient may be achieved by detecting the specific binding of a compound according to the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a sample or in a specific body part or region, which comprises: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with a compound of the invention that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof; (b) binding a compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, to form a compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies or Lewy neurites) complex (hereinafter, "compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex" will be abbreviated as "compound / protein aggregate complex"); (c) detecting the formation of a compound / protein aggregate complex; (d) optionally correlating the presence or absence of compound / protein aggregate complexes with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; and (e) optionally, comparing the amount of the compound / protein aggregate complex with a normal control value, wherein an increase in the amount of the compound / protein aggregate complex compared to the normal control value may indicate that the patient is suffering from or at risk of developing a disease, disorder or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. Includes:

[0267] A compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, may be contacted by any suitable method with a sample or specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. For in vitro methods, a compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a liquid sample may simply be mixed. For in vivo testing, a compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, is typically administered to a patient by any suitable means. These routes of administration include, but are not limited to, one or more of oral (e.g., as a tablet, capsule, or as an ingestible liquid), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., via an injectable form), gastrointestinal, intrathecal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual. In some instances, parenteral administration may be preferred.

[0268] After contacting the sample or a specific body part or region with a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, the compound is allowed to bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. 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 of ordinary skill in the art through routine experimentation.

[0269] Compounds bound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, can then be detected by any suitable method. The particular method selected will depend on the detectable label selected. Examples of possible methods include, but are not limited to, fluorescent imaging 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 amyloid biomarkers. Fluorescent and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of detectably labeled compounds within a sample or specific body parts or regions.

[0270] The presence or absence of the compound / protein aggregate complex is then optionally correlated with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. Finally, the amount of the compound / protein aggregate complex may be compared to a normal control value determined in the sample or in a particular body part or region from healthy subjects, and an increase in the amount of the compound / protein aggregate complex compared to the normal control value may indicate that the patient is suffering from or at risk of developing a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites.

[0271] The present invention also relates to a method for determining the amount of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a tissue and / or body fluid, the method comprising: (a) obtaining a sample representative of the tissue and / or body fluid under investigation; (b) testing the sample for the presence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, using a compound of the invention; (c) determining the amount of the compound that binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) calculating the amount of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in the tissue and / or body fluid. include.

[0272] A sample may be tested for the presence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, using a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, by contacting the sample with a compound of the invention, allowing the compound of the invention to bind to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites to form a compound / protein aggregate complex, and detecting the formation of the compound / protein aggregate complex as described above.

[0273] Monitoring minimal residual disease, disorder or abnormality in patients afflicted with a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, and treated with a medicament containing a compound according to the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, to form a compound / protein aggregate complex; (c) detecting the formation of a compound / protein aggregate complex; (d) optionally correlating the presence or absence of the compound / protein aggregate complex with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; and (e) optionally, comparing the amount of compound / protein aggregate complex with a normal control value, wherein an increase in the amount of aggregate compared to the normal control value may indicate that the patient may still be suffering from minimal residual disease, disorder, or abnormality. This can be achieved by:

[0274] The manner in which steps (a) to (e) can be carried out has already been described above.

[0275] In a method for monitoring minimal residual disease, disorder or abnormality, the method may comprise, 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, including but not limited to, Lewy bodies and / or Lewy neurites, with a compound of the invention that specifically binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof; (ii) binding the compound to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, to form a compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex; (iii) detecting the formation of compound / (alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites) complexes; (iv) correlating the presence or absence of the compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; (v) optionally, comparing the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes with a normal control value; and (vi) treating the patient with a medicament It may further include:

[0276] Optionally, the method further comprises, after step (d) or step (e), step (A): (A) comparing the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes determined in step (iv) with the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes determined in step (d). It may further include:

[0277] Steps (a) through (c), and optionally steps (d) and (e) of the method for monitoring minimal residual disease, disorder or abnormality, may be repeated one or more times to monitor minimal residual disease, disorder or abnormality over time.

[0278] In methods for monitoring minimal residual disease, disorder, or abnormality, the amount of compound / protein aggregate complex 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. A change, particularly a decrease, in the amount of compound / protein aggregate complex can indicate that the residual disease, disorder, or abnormality is being suppressed.

[0279] 2. Predicting the responsiveness of a patient suffering from a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, and being treated with a pharmaceutical agent, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, to form a compound / protein aggregate complex; (c) detecting the formation of a compound / protein aggregate complex; (d) optionally correlating the presence or absence of the compound / protein aggregate complex with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; and (e) optionally, comparing the amount of compound / protein aggregate complex with a normal control value; This is achieved by:

[0280] The manner in which steps (a) to (e) can be carried out has already been described above.

[0281] 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, including but not limited to, Lewy bodies and / or Lewy neurites, with a compound of the invention that specifically binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof; (ii) binding the compound to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, to form a compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex; (iii) detecting the formation of compound / (alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites) complexes; (iv) correlating the presence or absence of the compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; (v) optionally, comparing the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes with a normal control value; and (vi) treating the patient with a medicament It may further include:

[0282] Optionally, the method further comprises, after step (d) or step (e), step (A): (A) comparing the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes determined in step (iv) with the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes determined in step (d). It may further include:

[0283] Steps (a) through (c), and optionally steps (d) and (e) of the method for predicting reactivity, may be repeated one or more times to determine reactivity over time.

[0284] In methods for predicting responsiveness, the amount of compound / protein aggregate complex 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. A change, particularly a decrease, in the amount of compound / protein aggregate complex can indicate that the patient is likely to be responsive to the respective treatment.

[0285] 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).

[0286] In a further embodiment of the invention, the diagnostic composition may be used in a method of collecting data to monitor residual disease, disorder or abnormality in a patient afflicted with a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, and treated with a surgical procedure or a non-invasive brain stimulation procedure, the method comprising: (a) contacting a sample or a particular body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of the invention that specifically binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, to form a compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex; (c) detecting the formation of compound / (alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites) complexes; (d) optionally correlating the presence or absence of the compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complex with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; and (e) optionally, comparing the amount of compound / (alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites) complexes with a normal control value; Includes.

[0287] The term "monitoring minimal residual disease" referred to herein is understood to relate to monitoring the progression of a disease, for example, monitoring the progression of a disease, disorder or condition in a patient suffering from a disease, disorder or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites.

[0288] The compounds according to the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, or precursors thereof, may also be incorporated into test kits for detecting alpha-synuclein protein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. The test kit typically includes a container holding one or more compounds according to the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, or precursors thereof, and instructions for use of the compound to bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, to form compound / protein aggregate complexes, and to detect the formation of the compound / protein aggregate complexes, thereby correlating the presence or absence of the compound / protein aggregate complexes with the presence or absence of alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites.

[0289] 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.

[0290] The detectably labeled compounds of the present invention, or their stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates, preferably 18 The dose of the F-labeled compound of formula (III-F) will vary depending on the exact compound to be administered, the patient's mass, the size and type of sample, and other variables apparent to a practitioner skilled in the art. In general, the dose may be preferably 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.

[0291] In another embodiment, the present invention provides a method of imaging a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a sample or in a particular body part or region, particularly in the brain or in a sample obtained from the brain of a patient, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) imaging the sample, specific body part, or body region using an imaging system. The present invention provides a method comprising:

[0292] In another embodiment, the present invention provides a method for determining the amount of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a sample or in a particular body part or region, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) determining the amount of compound that binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (e) optionally calculating the amount of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in the sample, in a particular body part or body region; The present invention provides a method comprising:

[0293] In another embodiment, the present invention provides a method for diagnosing a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with a disease, disorder, or abnormality associated with alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites. The present invention provides a method comprising:

[0294] In another embodiment, the present invention provides a method of collecting data for diagnosing a disease, disorder, or abnormality associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. The present invention provides a method comprising:

[0295] In another embodiment, the present invention provides a method of collecting data to determine a predisposition to a disease, disorder, or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample or a specific body part or region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region. The present invention provides a method comprising:

[0296] If the amount of compound that binds to alpha-synuclein aggregates is greater than the normal control value for healthy / reference subjects, this indicates that the patient is suffering from or at risk of developing a disease, disorder or disorder associated with alpha-synuclein aggregates. In particular, if the amount of compound that binds to alpha-synuclein aggregates is greater than that expected in someone who does not show clinical evidence of a neurodegenerative disease, the patient can be presumed to have a predisposition to a disease, disorder or disorder associated with alpha-synuclein aggregates, or a synucleinopathy.

[0297] In another embodiment, the present invention provides a method of collecting data for prognosing a disease, disorder, or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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 provides a method comprising:

[0298] The progression of, and / or likelihood of recovery from, the disease, disorder, or abnormality (e.g., likelihood, duration, and / or extent) 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 abnormality, and thus to make the estimation more reliable.

[0299] In another embodiment, the present invention provides a method of collecting data to monitor disease progression in a patient afflicted with a disease, disorder, or condition associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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 provides a method comprising:

[0300] 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.

[0301] In another embodiment, the present invention provides a method of collecting data to monitor the progression of a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a patient, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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 provides a method comprising:

[0302] Typically, the patient is undergoing or has undergone treatment for a disease, disorder or condition associated with alpha-synuclein aggregates, or is undergoing or has undergone treatment for a synucleinopathy. In particular, treatment may involve the administration of a medicament suitable for treating a disease, disorder or condition associated with alpha-synuclein aggregates.

[0303] In another embodiment, the present invention provides a method of collecting data for predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, to treatment for the disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, comprising: (a) contacting a sample, a particular body part, or a body region suspected of containing alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; (c) detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; (d) optionally correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, 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 provides a method comprising:

[0304] Typically, the patient is undergoing or has undergone treatment for a disease, disorder or condition associated with alpha-synuclein aggregates, or is undergoing or has undergone treatment for a synucleinopathy. In particular, treatment may involve the administration of a medicament suitable for treating a disease, disorder or condition associated with alpha-synuclein aggregates.

[0305] 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.

[0306] 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.

[0307] In yet another embodiment, the present invention provides a method for detecting alpha-synuclein aggregates, optionally comprising: correlating the presence or absence of a compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the presence or absence of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in a sample or in a particular body part or region; - determining the amount of the compound that binds to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites; - correlating the amount of the compound that binds to alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, with the amount of alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region; and - optionally comparing the amount of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in the sample or in a particular body part or region with normal control values ​​in healthy control subjects. The method as defined herein comprises:

[0308] The control value can be, for example, a normal control value, a preclinical control value and / or a clinical control value.

[0309] A "healthy control subject" or "healthy volunteer (HV) subject" is one who does not show clinical evidence of a neurodegenerative disease, selected as defined herein in Section 15 "First-in-Human (FIH) Studies" in the "Description of Biological Assays and Corresponding Results" paragraph.

[0310] 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.

[0311] Any compound of the present invention can be used in the methods summarized above. Preferably, the detectably labeled compounds of the present invention disclosed herein are used in the methods summarized above.

[0312] The particular body part or body region may be that of a mammal, more preferably a human, including the whole body or a partial body region or body part of a patient suspected of containing alpha-synuclein aggregates.

[0313] The sample may be selected from tissues or body fluids suspected of containing alpha-synuclein aggregates, and the sample is obtained from a patient. Preferably, the tissue is selected from brain tissue. Examples of body fluids include cerebrospinal fluid (CSF) or blood. The sample is obtained from a mammal, more preferably a human. Preferably, the sample is an in vitro sample from a patient.

[0314] In in vivo methods, a particular body part or region can be contacted with a compound of the invention by administering to a patient an effective amount of the compound of the invention, the effective amount being an amount suitable to allow the presence or absence of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in the particular body part or region to be determined using a selected analytical technique.

[0315] The step of binding a compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, includes allowing a sufficient amount of time for the compound of the present invention to bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. 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 of ordinary skill 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, including, but not limited to, Lewy bodies and / or Lewy neurites. The amount of time should not be excessively extended to avoid washout and / or metabolism of the compound of the present invention.

[0316] Methods for detecting compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, are not particularly limited and depend on, among other things, 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. Possible detection 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). Fluorescent and / or nuclear imaging techniques can be used to monitor and / or visualize the distribution of the compounds of the present invention in a sample or body. The imaging system is adapted to obtain 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 region being tested. Preferably, compounds that bind to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, are detected by an imaging device, such as a PET or SPECT scanner.

[0317] The amount of compound binding to alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, can also be determined by visual or quantitative analysis using, for example, PET scan images.

[0318] In any of the above methods, steps (a) to (c), and, if present, optional step (d), may be repeated at least once. Repetition of the steps is particularly useful for methods of collecting data for determining prognosis, for monitoring disease progression, for monitoring progression, and for predicting responsiveness. In these methods, it may be advisable to monitor the patient over time and repeat the above steps after a certain period of time has passed. The time interval before the above-mentioned steps are repeated may be determined by a physician depending on the severity of the disease, disorder, or abnormality associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, or synucleinopathy.

[0319] In a further aspect, the present invention provides a method of imaging a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) detecting compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. This refers to a method including:

[0320] In a further aspect, the present invention provides a method of imaging a disease, disorder, or condition associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) imaging the subject's brain; The present invention covers a method including:

[0321] The subject's brain should be imaged if the compound binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. Compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, can then be imaged in the subject's brain.

[0322] In a further aspect, the present invention provides a method for positron emission tomography (PET) imaging of alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a tissue of a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) allowing the compound to penetrate into the tissue of the subject; and (c) acquiring a positron emission tomography (PET) image of the tissue of interest. wherein the tissue is central nervous system (CNS) tissue, eye tissue or brain tissue, preferably the tissue is brain tissue.

[0323] PET imaging should be performed to allow the compound to penetrate into tissue and bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites.

[0324] In a further aspect, the present invention provides a method for detecting a neurological disease, disorder or abnormality associated with alpha-synuclein aggregates, including but not limited to Lewy bodies and / or Lewy neurites, in a subject, comprising the steps of: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) measuring the radioactive signal of the compound that binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. The present invention covers a method including:

[0325] The radioactive signal referred to herein is a signal from at least one radioactively labeled atom (e.g. 3 H, 2 H or 18 F) is observed when a detectably labeled compound of the invention binds to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites.

[0326] In a further aspect, the present invention provides a method (e.g., an in vivo or in vitro method) for detecting and / or quantifying alpha-synuclein aggregates, including but not limited to, Lewy bodies and / or Lewy neurites, in a tissue of a subject, comprising: (a) contacting a tissue of a subject with a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; (b) binding the compound to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites; and (c) detecting and / or quantifying compounds that bind to alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites, using positron emission tomography. The present invention covers a method including:

[0327] In yet another aspect, the present invention provides a method of imaging the brain of a subject, comprising: (a) administering to a subject a compound of Formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) obtaining an image of the subject's brain using positron emission tomography. This refers to a method including:

[0328] In the methods of the present invention, a compound of formula (I) or a subformula thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof is typically administered in a detectable amount, i.e., an amount that can be detected by a device used to detect the compound in each method. 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 a person skilled in the art.

[0329] Radiopharmaceutical Preparations The compounds of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, preferably compounds of Formula (I) or subformulas thereof (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)), may also be used in kits for preparing radiopharmaceutical preparations. Due to radioactive decay, radiopharmaceuticals are usually prepared immediately prior to use. The kit typically includes a precursor of the compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, and an agent that reacts with the precursor to introduce a radiolabel into the compound of the present invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof. A compound of the invention, or a detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate precursor thereof, can be, for example, a compound having formula (IV-F), (IV-H) or (IV-J). The agent can be a radiolabel, e.g. 18 F or 3 It can be an agent that introduces H.

[0330] Pharmaceutical Composition The compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof, can be used to treat, prevent or alleviate diseases, disorders or conditions associated with alpha-synuclein aggregates.

[0331] The compounds of the present invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof, preferably compounds of formula (I), are suitable for treating, preventing or alleviating diseases, disorders or conditions associated with alpha-synuclein aggregates, including, but not limited to, Lewy bodies and / or Lewy neurites. Diseases associated with alpha-synuclein aggregates are generally listed as synucleinopathies (or α-synucleinopathies). The compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof, are suitable for treating, preventing or ameliorating diseases, disorders or conditions including, but not limited to, Parkinson's disease (sporadic, familial with alpha-synuclein mutations, familial with non-alpha-synuclein mutations, 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. Synucleinopathies associated with neuronal and glial aggregates of alpha-synuclein include multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy). Other diseases that may have alpha-synuclein-immunoreactive pathologies 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, as well as 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. 295-8; 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), 312-315; Ferman et al., J Int Neuropsychol Soc. 2002, 8(7), 907-914). Preferably, the compounds of the present invention are suitable for treating, preventing or alleviating Parkinson's disease (PD).

[0332] In pharmaceutical applications, the compounds of the present invention, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates, are preferably administered in pharmaceutical compositions containing the compounds of the present invention. A "pharmaceutical composition" is defined herein as a composition containing one or more compounds of the present invention, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates, in a form suitable for administration to a patient, e.g., a mammal, e.g., a human, and suitable for treating, alleviating, or preventing the specific disease, disorder, or condition in question. Preferably, the pharmaceutical composition further comprises a physiologically acceptable carrier, diluent, adjuvant, or excipient. The dosage of the compounds of the present invention, or their detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates, will vary depending on the exact compound administered, the mass of the patient, and other variables apparent to a practitioner skilled in the art.

[0333] While it is possible for the compounds of the invention, or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, to be administered alone, it is preferable to formulate them into pharmaceutical compositions, in accordance with standard pharmaceutical practice. Accordingly, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), or detectably labeled compounds, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, or solvates thereof, optionally in admixture with at least one pharmaceutically acceptable excipient, carrier, diluent, or adjuvant.

[0334] 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.

[0335] Pharmaceutically useful excipients that can be used to formulate the pharmaceutical composition of the present invention, or the detectably labeled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof, include, for example, carriers, vehicles, diluents, 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, and the like. These may include agents such as thickeners, 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, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins.

[0336] The compounds of the present invention, or detectably labeled compounds thereof, stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates or solvates thereof, and precursors thereof, can be synthesized by one of the general methods shown in the following schemes, which are presented for illustrative purposes only and should not be construed as limiting.

[0337] [Table 1]

[0338] General synthetic scheme for preparing compounds and precursors of the present invention: [ka] Commercially available hydrazines can be condensed with an appropriate ketone to give the corresponding hydrazones. The crude hydrazones can undergo cyclization using DMF / DMA to give intermediate A. SNAr can be carried out with a suitable nucleophile in a suitable solvent and base to give intermediate B. Alternatively, thermal conditions can be applied without a metal catalyst. Deprotection under suitable conditions gives intermediate C. Finally, intermediate C can be further functionalized using palladium-catalyzed amidation or Ullmann reaction to give compounds of formula (I) or its subformulas (e.g., (IIa), (IIb), (IIIa), (IIIb), (IIIc), (III-F), (III-H)). In this example, the starting material is R 0 Contains R 0 is H. The general scheme above applies to starting materials, R 0 is C1-C4 alkyl. [ka] An alternative approach (Scheme 1A) involves deprotecting intermediate A, followed by an SNAr reaction with a suitable nucleophile, preferably carried out in the presence of CsF in DMSO. Intermediates C and D can be further functionalized, preferably using copper(I) (Ullmann reaction) in the presence of a base and a solvent, to give formula (IIIa) and intermediate E. Finally, LG can be introduced into intermediate E to give formula (IV-F). In this example, the starting material is R 0 Contains R 0 is H. The general scheme above applies to starting materials, R 0 is C1-C4 alkyl. [ka] The general approach is depicted in Scheme 1B, following the same preferred conditions as described in General Scheme 1 or 1A.

[0339] 18 The F-precursor can be obtained by treating intermediate A with hydroxypyrrolidine in a suitable solvent under heating.4 The group can be introduced by palladium catalyzed amidation or Ullmann reaction. Finally, the alcohol intermediate E can be modified to a leaving group using standard conditions to give compounds of formula (IV-F).

[0340] 3 The H-precursor can be prepared by palladium-catalyzed amidation or Ullmann reaction to afford the appropriate R 4 The compound of formula (IV-H) can be obtained by introducing a group into intermediate C. Finally, halogenation of pyridine, for example using NBS in a suitable solvent, gives compounds of formula (IV-H).

[0341] The present invention 18 General synthesis of F-labeled compounds 18 The compound having formula (I) labeled with F can be prepared by treating a precursor compound with LG in the precursor compound. 18 F, as described below, 18 It can be prepared by reacting with an F-fluorinating agent.

[0342] 18 Reagents, 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.

[0343] 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.

[0344] as a radioactive label 18 Although the reaction for F is shown above, other radiolabels may be introduced following similar procedures.

[0345] This invention is illustrated by the following examples which should not be construed as limiting. [Example]

[0346] All reagents and solvents were obtained from commercial sources and used without further purification. 1 H spectra were recorded in deuterated solvents on a Bruker DRX-400 MHz NMR spectrometer, a Bruker AV-400 MHz NMR spectrometer, or a Spinsolve 80 MHz NMR spectrometer. Mass spectra (MS) were recorded on a Waters Advion CMS mass spectrometer, or a UPLC H-Class Plus and Qda mass spectrometer equipped with a photodiode array detector. Chromatography was performed using silica gel (Fluka: Silica Gel 60, 0.063-0.2 mm) and the appropriate solvents indicated in the examples. Flash purification was performed on a Biotage Isolera One flash purification system using HP-Sil or KP-NH SNAP cartridges (Biotage) and the solvent gradients indicated in the examples. Thin-layer chromatography (TLC) was performed on silica gel plates with UV detection.

[0347] (Preparation Example 1) [ka] Step A: A suspension of 2-bromo-5-hydrazinylpyridine (3.21 g, 17.07 mmol) and tert-butyl 2,4-dioxopyrrolidine-1-carboxylate (3.40 g, 17.07 mmol) in ethanol (150 mL) was refluxed for 3 hours and monitored by TLC. The crude product was concentrated under reduced pressure and diluted with dichloromethane and water. The layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 50 g column, 60-80% ethyl acetate in heptane) to give (E)-tert-butyl 4-(2-(6-bromopyridin-3-yl)hydrazono)-2-oxopyrrolidine-1-carboxylate as a brown solid (4.97 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ = 9.22 (s, 1H), 8.41 (s, 1H), 7.89 (d, 1H), 7.40 (d, 1H), 7.11 (dd, 1H), 4.57 (s, 1H), 4.30 (s, 2H), 1.45 (s, 9H). MS: 369.06 [M+H] +

[0348] Step B: The compound from Step A (3.9 g, 10.56 mmol) was stirred in 1,1-dimethoxy-N,N-dimethylmethanamine (80 mL) at 50° C. for 3 hours and 15 minutes. The reaction mixture was concentrated to approximately 10 mL, and ethanol was added. The solid was filtered and washed with a small amount of ethanol to give tert-butyl 2-(6-bromopyridin-3-yl)-4-oxo-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate as a light brown powder (2.30 g, 57%). 1 H NMR (400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 9.00 (d, 1H), 8.28 (dd, 1H), 7.89 (d, 1H), 4.84 (s, 2H), 1.53 (s, 9H). MS: 324.83 [M-tBu + H] +

[0349] (Preparation examples 1A to 1H) Following the procedure described in Preparative Example 1, the following preparative examples were prepared using 1,1-dimethoxy-N,N-dimethylmethanamine or N,N-dimethylacetamide dimethyl acetal and the appropriate hydrazone.

[0350] [Table 2]

[0351] (Preparation example A) [ka] Preparation 1 (1000 mg, 2.64 mmol) was stirred in 4 M HCl in dioxane (37 mL) at room temperature for 1 hour 45 minutes. The solvent was evaporated under reduced pressure, and the solid was dissolved in dichloromethane. A solution of saturated NaHCO3 was added, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were filtered to give 2-(6-bromopyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one as a beige solid (682 mg, 93%). 1 H NMR (80 MHz, DMSO-d6) δ 8.96 (d, 2H), 8.37 - 8.14 (m, 2H), 7.83 (d, 1H), 4.39 (s, 2H). MS: 280.95 [M+H] +

[0352] (Preparation examples A1 to A6) The following preparations were prepared according to the procedure described in Preparation A.

[0353] [Table 3]

[0354] (Preparation Example 2) [ka] Palladium(II) acetate (41.4 mg, 0.185 mmol) and Xantphos (320 mg, 0.554 mmol) were mixed in 1,4-dioxane (18 mL) in a flask under argon and heated at 100°C for a few seconds on a preheated block to form the pd-Xantphos complex. (R)-3-Fluoropyrrolidine hydrochloride (348 mg, 2.77 mmol), cesium carbonate (1804 mg, 5.54 mmol), and Preparation 1 (700 mg, 1.846 mmol) were added. The flask was evacuated and backfilled with argon three times, and the reaction mixture was heated at 120°C for 30 minutes. The reaction mixture was cooled at room temperature, and the residue was taken up in ethyl acetate and water. The phases were separated, and the aqueous phase was extracted twice. The organic layers were combined, dried over Na2SO4, and evaporated. The product was purified by flash chromatography (silica, silica 25 g column, 0-60% ethyl acetate in dichloromethane) to give (R)-tert-butyl 2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-4-oxo-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate as a white solid (200.5 mg, 28%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.92 (s, 1H), 8.60 (d, 1H), 8.01 (dd, 1H), 6.67 (d, 1H), 5.46 (d, 1H), 4.80 (s, 2H), 3.86 - 3.57 (m, 2H), 3.54 - 3.44 (m, 2H), 2.36 - 2.12 (m, 2H), 1.53 (s, 9H). MS: 388.15 [M+H] +

[0355] (Preparation examples 3~3D) Following the Pd coupling procedure described in Preparative Example 2, the following preparative examples were prepared using the halogenated starting materials and appropriate amines shown in Table 1a below.

[0356] [Table 4]

[0357] (Preparation Example 4) [ka] In a microwave vial, Preparation 1 (250 mg, 0.659 mmol) and (S)-pyrrolidin-3-ol (172 mg, 1.978 mmol) were mixed in ethanol (10 mL). The vial was irradiated in a microwave at 150° C. for 30 minutes. (S)-pyrrolidin-3-ol (172 mg, 1.978 mmol) was added again, and the reaction mixture was irradiated again at 150° C. for 45 minutes. The reaction mixture was filtered and washed with ethanol to give (S)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one as a white solid (83.5 mg, 44.4%). 1 H NMR (80 MHz, DMSO-d6) δ = 8.60 (s, 1H), 8.51 (d, 1H), 8.07 (s, 1H), 7.92 (dd, 1H), 6.56 (d, 1H), 4.97 (d, 1H), 4.34 (s, 3H), 3.69 - 3.37 (m, 4H), 2.24 - 1.80 (m, 2H). MS: 286.05 [M+H] +

[0358] (Preparation Example 5) [ka] Preparation 2 (160 mg, 0.413 mmol) was stirred in 4 M HCl in dioxane (10 mL) at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure, and the solid was dissolved in dichloromethane. A solution of saturated NaHCO was added, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over NaSO, filtered, and concentrated to dryness to give (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one as a white solid (101.5 mg, 86%). 1H NMR (80 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.55 (d, 1H), 7.96 (dd, 1H), 6.63 (d, 1H), 5.75 (s, 1H), 4.34 (s, 2H), 3.92 - 3.37 (m, 4H), 2.45 - 1.78 (m, 2H). MS: 287.80 [M+H] +

[0359] (Alternative Preparation Example 5) [ka] In a vial under argon, Preparation A (400 mg, 0.1433 mmol), (R)-3-fluoropyrrolidine hydrochloride (720 mg, 5.73 mmol), and cesium fluoride (1306 mg, 8.60 mmol) were mixed in dry DMSO (4 mL). The reaction mixture was flushed with argon and stirred at 120° C. for 6 hours and 30 minutes. The reaction mixture was cooled and poured into cold water (pre-cooled in an ice bath). The resulting solution was filtered, and the solid was rinsed with water. The solid was triturated directly in a frit with 1 mL of isopropanol, and the solid was dried to give the product as a beige solid (287 mg, 0.998 mmol, 70%). 1 H NMR (80 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.55 (d, 1H), 8.15 - 7.79 (m, 2H), 6.64 (d, 1H), 5.46 (d, 1H), 4.34 (s, 2H), 3.96 - 3.40 (m, 4H), 2.28 - 1.56 (m, 2H). MS: 288.11 [M+H] +

[0360] (Alternative Preparations 4-4K) Following the SNAr procedure described in Alternative Preparative Example 5, the following preparative examples were prepared using the appropriate amines shown in Table 1b below.

[0361] [Table 5-1]

[0362] [Table 5-2]

[0363] [Table 5-3]

[0364] (Preparation examples 6-6D) Following the deprotection procedure of Preparation 5, the following Preparations were prepared.

[0365] [Table 6-1] [Table 6-2]

[0366] (Preparation Example 7) [ka] Palladium(II) acetate (13.14 mg, 0.059 mmol) and Xantphos (50.8 mg, 0.088 mmol) were mixed in 1,4-dioxane (3 mL) in a vial under argon, degassed with argon, and heated at 100°C on a preheated block for several seconds to form the Pd-Xantphos complex. Preparation 4 (83.5 mg, 0.293 mmol), 3-iodopyridine (66.0 mg, 0.322 mmol), and cesium carbonate (286 mg, 0.878 mmol) were then added, and the mixture was degassed with argon and heated at 100°C for 45 minutes. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was collected and evaporated to give the product as a yellow gummy solid (134.5 mg, 0.371 mmol, quantitative yield). 1H NMR (80 MHz, DMSO-d6) δ = 9.04 (d, 1H), 8.83 (s, 1H), 8.57 (d, 1H), 8.43 - 8.13 (m, 2H), 7.96 (dd, 1H), 7.44 (dd, 1H), 6.58 (d, 1H), 5.08 (s, 2H), 4.99 (d, 1H), 4.42 (d, 1H), 3.64 - 3.40 (m, 4H), 2.17 - 1.75 (m, 2H). MS: 363.08 [M+H] +

[0367] (Preparation Example 8) Following the Pd coupling procedure described in Preparative Example 7, the following preparative examples were prepared using the amide starting materials and appropriate heteroaryl halides shown in Table 3 below.

[0368] [Table 7]

[0369] (Preparation Example 9) [ka] Step A Under an argon atmosphere, to a solution of 2-(6-bromopyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (0.5 g, 1.79 mol) in dioxane (20 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.451 g, 2.7 mmol), [(dppf)PdCl] (146 mg, 0.179 mmol), and CsCO (1.16 g, 3.58 mmol) in HO (0.2 mL). The mixture was heated at 80 °C for 2 h. The mixture was cooled, and the solvent was evaporated under high vacuum. The residue was dissolved in ethyl acetate, and the solid was filtered. The filter residue was washed with water and dried to give 0.450 g of product. MS: 241.1 [M+H]+.

[0370] Step B To a solution of 2-(6-(prop-1-en-2-yl)pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (1 g, 4.16 mmol) in MeOH (75 mL) was added Pd / C (100 mg, 5%). The mixture was stirred under H (15 psi) at room temperature for 12 hours. Upon completion, the reaction slurry was filtered and the filtrate was concentrated to give 2-(6-(propan-2-yl)pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (0.85 g). MS: 243.2 [M+H].

[0371] (Preparation Example 10) Following the procedure described in Alternative Preparation 9, the following preparations were prepared using the appropriate boronic esters shown in Table 3b below.

[0372] [Table 8]

[0373] (Preparation Example 11) [ka] 2-Propanol (50 μL, 0.7176 mmol) in 0.4 mL of DMF was added to a suspension of sodium hydride (36 mg / 60% in mineral oil, 0.9 mmol) in 2 mL of DMF at room temperature. The mixture was stirred for 30 minutes and then added to a stirred solution of 2-(6-bromopyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (100 mg, 0.358 mmol) in 2 mL of DMF at 60° C. The reaction mixture was heated at 60° C. for 20 hours. After cooling to room temperature, water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organics were combined, dried over MgSO, filtered, and concentrated under reduced pressure to give 2-(6-isopropoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (0.16 g, 35%). MS: 259.2 [M+H].

[0374] (Preparation Example 12) [ka] In a sealed tube under nitrogen, (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (120 mg, 0.417 mmol), 2-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (253 mg, 0.835 mmol), copper(I) iodide (16 mg, 0.0835 mmol), and potassium carbonate (115 mg, 0.835 mmol) were charged, and the system was flushed with nitrogen. 1,4-Dioxane (6 mL) and N,N'-dimethylethylenediamine (0.017 mL, 0.167 mmol) were added, and the mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10 mL of water and extracted with DCM / MeOH (9:1, 50 mL × 2). The combined organic layers were dried over NaSO (5 g), filtered, and concentrated to give 80 mg of a pale yellow solid crude product. The crude product was purified by column chromatography on basic silica gel (100-200 mesh) using a dichloromethane / methanol gradient (100 / 0 → 98 / 2) to give the desired product as a pale yellow solid (50 mg, 23% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.60 (d, 1H), 8.42 - 8.33 (m, 1H), 8.18 (dd, 1H), 8.01 (dd, 1H), 7.58 (dd, 1H), 6.66 (d, 1H), 5.54 (s, 1H), 5.28 (s, 2H), 5.05 (s, 2H), 3.85 - 3.54 (m, 5H), 3.54 - 3.42 (m, 1H), 2.39 - 2.08 (m, 2H), 0.90 (dd, 2H), -0.01 (s, 9H). MS: 511.3 [M+H] +

[0375] (Preparation Examples 13 to 31) Following the Cu coupling procedure described in Preparative Example 12, the following preparative examples were prepared using the amide starting materials and appropriate heteroaryl halides shown in Table 3c below.

[0376] [Table 9-1]

[0377] [Table 9-2]

[0378] [Table 9-3]

[0379] [Table 9-4]

[0380] [Table 9-5]

[0381] Examples 1 to 4 Following the Pd coupling procedure described in Preparative Example 7, the following compounds were prepared using the amide starting materials and the appropriate heteroaryl halides shown in Table 4 below.

[0382] [Table 10]

[0383] (Alternative example 1) [ka] Preparation 5 (285 mg, 0.992 mmol), 3-bromopyridine (0.191 mL, 1.984 mmol), potassium carbonate (274 mg, 1.984 mmol), and copper(I) iodide (37.8 mg, 0.198 mmol) were mixed in a flask under argon, and the system was flushed with argon. Dioxane (12 mL) and N1,N2-dimethylethane-1,2-diamine (0.042 mL, 0.397 mmol) were added, and the mixture was stirred at 110 °C for 4 hours. The crude product was concentrated under reduced pressure and dissolved in 20 mL of water. Aqueous ammonia (16.30 mL, 114 mmol) was added until the solution became basic (pH 12). The aqueous layer was extracted twice with a solution of DCM / MeOH (9:1). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The solid was suspended in DCM and stirred at 40°C for 15 minutes. The mixture was cooled and filtered to give the product as a white solid (234.3 mg, 65%). 1 H NMR (80 MHz, DMSO-d6) δ 9.03 (d, 1H), 8.86 (s, 1H), 8.60 (d, 1H), 8.42 - 8.15 (m, 2H), 8.01 (dd, 1H), 7.45 (dd, 1H), 6.67 (d, 1H), 5.41 (d, 1H), 5.09 (s, 2H), 4.00 - 3.37 (m, 4H), 2.28 - 1.48 (m, 2H). MS: 365.12 [M+H] +

[0384] (Examples 5 to 138) The following examples were prepared according to the procedures described in Preparative Example 7, Alternative Example 1, or using the amide starting material and appropriate heteroaryl halide shown in Table 4a below. Alternatively, Pd(dba), BINAP, and CsCO conditions could be applied.

[0385] [Table 11-1]

[0386] Table 11-2

[0387] Table 11-3

[0388] Table 11-4

[0389] Table 11-5

[0390] Table 11-6

[0391] Table 11-7

[0392] Table 11-8

[0393] Table 11-9

[0394] Table 11-10

[0395] Table 11-11

[0396] Table 11-12

[0397] Table 11-13

[0398] Table 11-14

[0399] Table 11-15

[0400] Table 11-16

[0401] Table 11-17

[0402] Table 11-18

[0403] Table 11-19

[0404] Table 11-20

[0405] Table 11-21

[0406] Table 11-22

[0407] Table 11-23

[0408] Table 11-24

[0409] Table 11-25

[0410] Table 11-26

[0411] Table 11-27

[0412] Table 11-28

[0413] Table 11-29

[0414] Table 11-30

[0415] Table 11-31

[0416] Table 11-32

[0417] [Table 11-33]

[0418] [Table 11-34]

[0419] Example 139 [ka] A suspension of 2-(6-(pyrrolidin-1-yl)pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (0.08 g, 0.286 mmol), 2,6-difluoropyrazine (0.199 g, 1.72 mmol), and CsF (0.348 g, 2.293 mmol) in DMSO (4 mL) was heated at 130 °C for 30 min under microwave irradiation. The reaction mixture was then cooled and poured into ice-cold water (3 mL). The resulting slurry was filtered, and the solid was rinsed with water (5 mL). The residue was purified by silica gel (100-200 mesh) column chromatography using 2-5% MeOH in DCM to give the desired product (32 mg, 29%). 1 H-NMR (400 MHz, DMSO-d6) δ 9.65 - 9.59 (m, 1H), 8.96 (s, 1H), 8.60 - 8.55 (m, 1H), 8.38 (dd, 1H), 7.97 (dd, 1H), 6.59 (d, 1H), 5.03 (s, 2H), 3.46 - 3.41 (m, 4H), 2.01 - 1.93 (m, 4H). MS: 366.1 [M+H] +

[0420] (Examples 140 to 161) Prepare the following examples according to the procedure described in Example 54 using the amide starting material and the appropriate amide and fluoroheteroaryl shown in Table 4b below.

[0421] [Table 12-1]

[0422] [Table 12-2]

[0423] [Table 12-3]

[0424] [Table 12-4]

[0425] [Table 12-5]

[0426] [Table 12-6]

[0427] Example 162 [ka] (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-5-(5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (50 mg, 0.098 mmol) was dissolved in DCM (1.5 mL) and cooled to 0 °C in an ice bath with stirring. 4 M HCl in 1,4-dioxane (0.2 mL) was added to the solution, and stirring was continued at room temperature for 4 h. After completion of the reaction, the solvent was removed under reduced pressure. The resulting residue was dissolved in ice-cold water and basified with saturated aqueous sodium bicarbonate to pH 8-9. The compound precipitated, and the solid was removed by filtration. The solid was washed with pentane (3 mL) and further dried under high vacuum for 30 min to give the desired compound as a pale yellow solid (10 mg, 27%). 1 H NMR (500 MHz, CF3COOD) δ 8.85 (s, 1H), 8.72 (d, 1H), 8.57 (dd, 1H), 8.52 - 8.32 (m, 2H), 7.90 (d, 1H), 7.46 (s, 1H), 5.86 - 5.62 (m, 1H), 5.53 (s, 2H), 4.52 - 4.01 (m, 4H), 2.87 (s, 1H), 2.75 - 2.44 (m, 1H). MS: 381.1 [M+H] +

[0428] (Examples 163 to 181) Following the deprotection procedure described in Example 162, the following examples were prepared using the O-protected starting materials shown in Table 4c below.

[0429] [Table 13-1]

[0430] [Table 13-2]

[0431] [Table 13-3]

[0432] [Table 13-4] [Table 13-5]

[0433] Precursor 1 [ka] In a flask under argon, Preparation 7 (135 mg, 0.373 mmol) was dissolved in dichloromethane. Triethylamine (1.038 ml, 7.45 mmol) was added, and the reaction mixture was stirred for 5 minutes. Methanesulfonyl chloride (0.290 ml, 3.73 mmol) was then added dropwise to the reaction mixture. The mixture was stirred at room temperature for 20 minutes. Methanesulfonyl chloride (0.290 ml, 3.73 mmol) was added, and the reaction mixture was stirred for 25 minutes. The reaction mixture was quenched with an aqueous solution of 1N NaOH and then extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The product was purified by flash chromatography (silica, silica 12 g column, 0-10% methanol in dichloromethane) to give (S)-1-(5-(4-oxo-5-(pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2-yl)pyrrolidin-3-yl methanesulfonate as a white solid (17.4 mg, 11%). 1H NMR (80 MHz, DMSO-d6) δ = 9.03 (d, 1H), 8.87 (s, 1H), 8.61 (d, 1H), 8.44 - 8.15 (m, 2H), 8.03 (dd, 1H), 7.45 (q, 1H), 6.68 (d, 1H), 5.45 (s, 1H), 5.09 (s, 2H), 3.67 (d, 4H), 3.27 (s, 3H), 2.41 - 2.08 (m, 2H). MS: 441.08 [M+H] +

[0434] Alternative Procedure In a vial cooled to 0° C. under argon, (S)-2-(6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one (100 mg, 0.276 mmol) and 4-dimethylaminopyridine (337 mg, 2.76 mmol) were mixed in pyridine (17 mL). Mesyl-Cl (0.108 mL, 1.380 mmol) was added, and the mixture was flushed with argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, after which 4-dimethylaminopyridine (169 mg, 1.380 mmol) and mesyl-Cl (0.054 mL, 0.690 mmol) were added at 0° C. After 40 minutes, 0.1 N NaOH in water (20 mL) was added to the mixture to make it basic. The solution was poured into ice water and filtered. It was washed with water until the pH of the water was 7. The solid was dried under high vacuum for 30 minutes to give the compound as an orange solid (86 mg, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, 1H), 8.87 (s, 1H), 8.61 (d, 1H), 8.35 (d, 1H), 8.26 (d, 1H), 8.02 (dd, 1H), 7.45 (dd, 1H), 6.68 (d, 1H), 5.44 (s, 1H), 5.08 (s, 2H), 3.86 - 3.42 (m, 4H), 3.27 (s, 3H), 2.40 - 2.24 (m, 2H). MS: 441.1 [M+H] +

[0435] Precursor 2 [ka] N-Bromosuccinimide (22 mg, 0.126 mmol) was added to a solution of Preparation 8 (43 mg, 0.097 mmol) in dimethylformamide (3 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with acetonitrile, and the solid was collected by filtration. The crude solid was then purified by flash chromatography (silica, 12 g silica column, 2-5% methanol in dichloromethane). The fractions were concentrated under reduced pressure, and the residue was triturated with acetonitrile. The solid was collected by filtration to give (R)-2-(5-bromo-6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-5-(5-bromopyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one as a beige solid (16 mg, 32%). 1 H-NMR δ 8.88 (d, 1H), 8.83 - 8.70 (m, 1H), 8.51 - 8.32 (m, 2H), 8.22 - 7.83 (m, 2H), 5.75 - 4.77 (m, 3H), 4.32 - 3.72 (m, 4H), 0.98 - 0.67 (m, 2H). MS: 523.10 [M+H] +

[0436] Precursor 3 [ka] To a solution of Preparation 7 (70 mg, 0.193 mmol) in DCM (3.5 mL) was added triethylamine (0.08 mL, 0.5797 mmol) at room temperature under a N atmosphere. The reaction mixture was cooled to 0°C, and then p-toluenesulfonyl chloride (73 mg, 0.3865 mmol) was added, followed by DMAP (23 mg, 0.193 mmol), in portions over 10 minutes. The reaction mixture was then warmed to room temperature and stirred for 12 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with saturated aqueous NaHCO (5 mL) at room temperature and extracted twice with 5% MeOH in DCM (2 x 20 mL). The combined organic layers were dried over NaSO. The solvent was evaporated under reduced pressure to give a pale yellow solid. The crude compound was purified by column chromatography on basic silica gel (100-200 mesh) by eluting with a DCM / MeOH gradient (100 / 0 to 98 / 2) to give the desired compound as an off-white solid (20 mg, 20%). 1 H NMR (400 MHz, DMSO-D6) δ 9.03 (d, 1H), 8.86 (d, 1H), 8.58 (dd, 1H), 8.35 (dd, 1H), 8.32 - 8.18 (m, 1H), 7.99 (ddd, 1H), 7.69 - 7.54 (m, 2H), 7.44 (td, 3H), 6.62 (dd, 1H), 5.25 - 5.01 (m, 3H), 3.76 - 3.39 (m, 4H), 2.39 (d, 3H), 2.36 - 2.01 (m, 2H). MS: [M+H] + 517.3

[0437] Precursor 4 [ka] In a flask under argon, Preparation 7 (700 mg, 1.93 mmol) and 4-DMAP (236 mg, 1.93 mmol) were suspended in 9.4 mL of pyridine and cooled to 0°C. 4-Nitrobenzenesulfonyl chloride (2.14 g, 9.66 mmol) was added, and the suspension was stirred at room temperature for 4 hours. 4-DMAP (118 mg, 0.97 mmol) and 4-nitrobenzenesulfonyl chloride (1.07 g, 4.83 mmol) were added at 0°C. The reaction mixture was stirred overnight. Further 4-DMAP (118 mg, 0.97 mmol) and 4-nitrobenzenesulfonyl chloride (1.07 g, 4.83 mmol) were added at 0°C, and the reaction mixture was stirred at room temperature for 1 day. 40 mL of 1 M NaOH was added, and the resulting mixture was centrifuged at 6000 ppm for 5 minutes. The centrifuge vial was decanted and the resulting solid was washed four times with 40 mL of water. The water was removed by centrifugation / decantation after each washing step. The resulting solid was suspended in water, transferred to a flask, and evaporated to give the desired product as a brownish solid (871 mg, 83%). 1 H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.85 (s, 1H), 8.68-7.90 (m, 8H), 7.46 (bs, 1H), 6.63 (d, 1H), 5.42 (s, 1H), 5.09 (s, 2H), 3.86-3.39 (m, 4H), 2.36 - 2.05 (m, 2H). MS: [M+H] + 547.97

[0438] Radioligand synthesis (Example 1 3 H-1]) [ka] Precursor 2 (0.5 mg) was dissolved in dimethylformamide (DMF) (0.3 mL) and N,N-diisopropylethylamine (DIEA) (5 μL) in a tritium reaction vessel. 10% Pd / C (0.5 mg) was added, and the vessel was pressurized to 0.5 atm with tritium gas at -200 °C. The solution was stirred at room temperature for 1 h, cooled to -200 °C, and excess gas was removed. The reaction flask was rinsed with 4 × 1 mL of CHOH, and each of the CHOH washes was passed through a Celite pad. The combined methanol was removed under vacuum. The material was purified by HPLC. The mobile phase was removed, and the product was redissolved in absolute ethanol (5 mCi, with a radiochemical purity of >99% and a specific activity of 43.6 Ci / mmol). T refers to tritium ( 3 MS (ESI): m / z = 369 (100%) [M+H]+.

[0439] (Example 1 18 F-1]) [ka] Drying Step: In a typical procedure, [ 18 The [F] fluoride was transferred to an ion exchange cartridge and captured. It was then eluted with a solution of potassium carbonate and Kryptofix 222 into the reaction vessel (RV1) of the TRACERlab® module. First, the solution was evaporated by heating at 95°C for 4 minutes under vacuum and helium flow. Acetonitrile (1 mL) was added to RV1, and evaporation continued for 2 minutes under the same conditions under vacuum and helium flow. After the addition of a second acetonitrile (1 mL), final evaporation was carried out at 95°C for 2 minutes under vacuum and helium flow. The reactor was then cooled to 60°C.

[0440] Radiolabeling: A solution of precursor 1 (1 mg) in anhydrous dimethyl sulfoxide (0.7 mL) was added to the reaction vessel and the reaction mixture was heated at 100°C for 10 min. The reactor was cooled to 40°C, diluted with HPLC mobile phase (1.8 mL), and the contents were transferred to a loop-loading vial (RV2). The reactor was rinsed with water for injection (2.5 mL) and the rinse was transferred to RV2. The contents of RV2 were transferred to an HPLC injector loop for purification.

[0441] HPLC Purification: Purification was performed by HPLC using a semi-preparative Phenomenex Synergi C18 column (5 μm, 250 × 10 mm) and eluted with a mixture of acetonitrile / ammonium acetate solution (20 mM) (35 / 65, v / v) at a flow rate of 4 mL / min. Product fractions were collected in Flask 1 containing 20 mL of sodium ascorbate (5 mg / mL) in WFI. The diluted product mixture was passed through a C18 solid-phase extraction cartridge, and the cartridge was rinsed with 10 mL of sodium ascorbate (5 mg / mL) in WFI. The radiolabeled product was eluted from the SPE cartridge with 1.0 mL of 200-proof USP-grade ethanol into a formulation flask pre-filled with 10 mL of formulation base (sodium ascorbate (4.67 mg / mL) in saline). The cartridge was rinsed with 4.0 mL of formulation base, and the rinse water was combined with the contents of the formulation flask. The resulting solution was transferred through a sterile 0.2 μm filter membrane into a sterile filter-vented vial (final product vial, FPV) pre-filled with 15 mL of saline (27% decay-corrected yield).

[0442] (Example 4 3 H-4]) [ka] Example 4 (1.0 mg) was added to the tritium reaction vessel, followed by cesium carbonate (1.0 mg), then DMF (0.1 mL), and finally iodomethane, [H] (100 mCi). The vessel was sealed, and the solution was stirred at room temperature for 18 hours. The reaction mixture was transferred to a larger flask, and the reaction vessel was rinsed with 4 x 2 mL of methanol. The combined methanol was removed under vacuum. Crude yield: 38 mCi. The material was purified by silica gel column chromatography. The mobile phase was removed under vacuum, and the product was redissolved in 0.05% TFA in water / acetonitrile. The material was further purified by semi-preparative reverse-phase HPLC. The mobile phase was removed under vacuum, and the product was redissolved in absolute ethanol (4.8 mCi, purity >99%). The specific activity was determined to be 79.98 Ci / mmol by MS. MS (ESI): m / z = 374 (100%) [M+H]+.

[0443] 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 mM 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. 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 a-syn aggregates, was resuspended in PBS and stored at −80°C until use.

[0444] 2. Micro-radiobinding competition assay for determination of binding affinity A-syn aggregates from PD brain were spotted onto microarray slides. The slides were then incubated with a tritiated reference ligand, [ 3The slides were incubated with [H]-a-syn-Ref (described in WO2017 / 153601) at 20 nM and with exemplary compounds of the present invention (non-radiolabeled) at 1 μM or higher concentrations ranging from 50 pM to 2 μM. After incubation, the slides were washed and exposed to a storage phosphor screen (GE Healthcare, BAS-IP TR 2025). Following exposure, the storage phosphor screen was scanned with a laser imaging system (Typhoon FLA 7000) to read out the signal from the radiobinding experiment described above. Signal quantification was performed using the ImageJ software package. Nonspecific signal was determined using an excess of non-radiolabeled reference ligand (1 μM), and specific binding was calculated by subtracting the nonspecific 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 ligand. All measurements were performed with at least two technical replicates. i Values ​​were calculated in GraphPad Prism7 by applying nonlinear regression curve fitting using a one-site specific binding model.

[0445] Exemplary compounds were evaluated for their potency in competing with the binding of [H]-radiolabeled reference ligands to a-syn aggregates derived from PD patient brains. The results of the microradio binding competition assay for the exemplary compounds tested are shown in Table 5, with % competition and K at 1 μM. i All measurements were performed on the same PD brain-derived a-syn aggregates. The K values ​​of Compound 1 reported herein are i Values ​​are the mean of two independent experiments.

[0446] [Table 14]

[0447] Table 5: Evaluation of binding affinity to a-syn aggregates from human PD brain by microradio binding competition assay. Left, percent competition (%) over tritiated reference ligand in the presence of 1 μM of exemplary compounds 1 and 2. Right, K for exemplary compound 1. i As shown in Table 5, the exemplary compounds 1 and 2 of the present invention exhibit good binding to a-syn aggregates derived from PD brain.

[0448] 3. Example 1 in α-synucleinopathy and AD tissues 3 Evaluation of target engagement of [H-1] 3A: High-resolution microautoradiography The protocol was adapted from Marquie et al., 2015. Sections were incubated with tritiated Exemplary Compound 1 (Example 1 [H-1]) or reference tau ligand ([H]-Tau-Ref) at 60 nM for 1 hour at room temperature (RT). The sections were then washed as follows: once for 1 minute with ice-cold 50 mM Tris-HCl pH 7.4 buffer, twice for 1 minute with 70% ice-cold ethanol, once for 1 minute with ice-cold 50 mM Tris-HCl pH 7.4 buffer, and finally briefly rinsed with ice-cold distilled water. The sections were then dried and then exposed to Ilford nuclear emulsion type K5 (Agar Scientific, AGP9281) in a light-proof slide storage box. After 5 days, sections were developed by sequential immersion in the following solutions: 1) Ilford Phenisol developer (diluted 1:5 in H2O, Agar Scientific, AGP9106), 2) Ilfostop solution (diluted 1:20 in H2O, Agar Scientific, AGP9104), 3) Ilford Hypam Fixer (diluted 1:5 in H2O, Agar Scientific, AGP9183), and finally rinsed in H2O.

[0449] Where indicated, immunostaining was also performed on the same sections. For image acquisition, sections were mounted using ProLong Gold antifade agent (Invitrogen P36930) and imaged on a Panoramic150 slide scanner (3DHistech) with a 20x objective that captured brightfield and fluorescent images separately.

[0450] 3B. By staining sections with antibodies Brain sections were immunostained using commercially available antibodies specific for phosphorylated serine at amino acid 129 of a-synuclein (a-syn-pS129, rabbit monoclonal, Abcam 51253) or mouse conformation-dependent anti-tau antibody (MC1, kindly provided by Peter Davies, Northwell, USA), or TDP-43 phosphorylated serine at amino acids 409 / 410 (anti-pTDP-43 pS409 / 410, Biolegend 829901). Sections were fixed with 4% formaldehyde (Sigma, 252549) for 15 min at 4°C and washed three times for 5 min each with 1x PBS (Dulbecco's phosphate-buffered saline, Sigma, D1408) at room temperature. Next, sections were saturated and permeabilized in blocking buffer (PBS, 10% NGS, 0.25% Triton X-100) for 1 hour at room temperature and incubated overnight at 4°C with primary antibodies corresponding to a-syn-pS129 or MC1 (in PBS, 5% NGS, 0.25% Triton X-100). The next day, sections were washed three times with 1x PBS for 5 minutes each and then incubated for 45 minutes at room temperature with AlexaFluor 647-conjugated goat anti-rabbit (Abcam, ab150079) or goat anti-mouse (115-605-166, Jackson ImmunoResearch) secondary antibodies. Following incubation with the secondary antibodies, sections were washed three times with PBS before further processing. For image acquisition, sections were mounted using ProLong Gold antifade agent (Invitrogen P36930) and imaged with a Panoramic150 slide scanner (3DHistech, Hungary).

[0451] Results: Example 1 3 High-resolution microautoradiography at 1H-1 was performed on frozen human brain sections from different α-synucleinopathy cases. 3 Strong autoradiographic signals from [H-1] were detected in the form of accumulating silver grains (Figure 1, bottom row) and were colocalized with immunofluorescent signals from the a-syn-pS129 antibody (Figure 1, top row), suggesting strong target engagement in Lewy bodies and Lewy neurites, as well as very small a-syn aggregates, in PD and other a-synucleinopathies, including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Lewy body variant of Alzheimer's disease (LBV), and PDD.

[0452] 4. Example 1 in brain sections from PD, PDD, and non-demented control (NDC) donors by autoradiography 3 Evaluation of specific binding of [H-1] Frozen human brain sections from one familial PD case (α-synuclein [SNCA] gene G51D missense mutation), one PDD case, and two non-demented control (NDC) cases labeled with SNCA (G51D) were first briefly fixed in 4% paraformaldehyde (Sigma, 252549) at 4°C for 15 minutes and washed three times with PBS (Dulbecco's phosphate-buffered saline, Sigma) for 5 minutes at room temperature. All slides were then equilibrated in 50 mM Tris-HCl pH 7.4 buffer for 20 minutes before use in experiments. Each brain section was treated with a fixed concentration (10 nM) of tritiated exemplary compound 1 (Example 1 [ 3 H-1]) or reference a-syn ligand ([3H]-a-syn-Ref), or tritiated compound at increasing concentrations ranging from 1.25 nM to 80 nM of Example 1 [ 3 H-1] in Tris-HCl buffer at room temperature for 2 hours (total binding, "-"). 3To determine [H-1] or [3H]-a-syn-Ref, the slides were mixed with 1 μM of unlabeled compound (Example 1 or a-syn-Ref, self-blocked, "+"), respectively. The slides were washed and placed under a Phosphor imaging screen (GE healthcare, BAS-IP TR 2025) in an imaging cassette. The imaging screen was scanned using a laser imaging system (Typhoon FLA 7000), and the resulting images were analyzed using the ImageJ software package. Specific binding was determined by subtracting nonspecific signals from the total signals. K d Values ​​were calculated in GraphPad Prism7 by applying nonlinear regression curve fitting using a one-site specific binding model.

[0453] Results: Example 1 3 H-1] demonstrated dose-dependent autoradiographic signals in different a-synucleinopathy tissues, including PDD (Figure 2A) and genetic PD cases (Figure 3A). The displaceable signals correlated well with the localization of a-syn pathology in both cases, as determined by staining with the a-syn-pS129 antibody, demonstrating specific binding of the compound to PDD and PD tissues (Figures 2B and 3B). Quantifying the specific signals allowed the determination of the dissociation constant (K d ) was calculated to be 11-13 nM (Figure 2C / Table 6 and Figure 3C / Table 6), suggesting good binding affinity for pathological α-synuclein aggregates.

[0454] [Table 15]

[0455] Table 6: Example 1 in human brain tissue from idiopathic PD cases (PDD) and familial PD cases (G51D missense mutation) by autoradiography 3 Evaluation of the binding affinity of [H-1]. Dissociation constant (K d ) and binding site occupancy (B max) was calculated in GraphPad Prism 7 by applying nonlinear regression curve fitting using a single-site specific binding model. 2 is the coefficient of determination.

[0456] In addition, when compared to the reference a-syn ligand, Example 1 [ 3 H-1] showed improved overall and excellent specific binding in tissues from different α-synucleinopathy cases, as well as weak binding in non-diseased tissues (NDC) (Figures 4A and 4B).

[0457] 5. Saturation binding test of PD brain-derived a-syn aggregates by microradiobinding A-syn aggregates derived from PD brains were spotted onto microarray slides. 3 The slides were incubated with either [H-1] or [H]-a-syn-Ref at increasing concentrations ranging from 300 pM to 150 nM. After incubation, the slides were washed and exposed to a storage phosphor screen (GE Healthcare, BAS-IP TR 2025). Following exposure, the storage phosphor screen was scanned with a laser imaging system (Typhoon FLA 7000) to read out the signal from the radiobinding experiment described above. Signal quantification was performed using the ImageJ software package. Nonspecific signal was determined using an excess of non-radiolabeled reference ligand (Example 1 or a-syn-Ref, each at 2 μM), and specific binding was calculated by subtracting the nonspecific signal from the total signal. K d Values ​​were calculated in GraphPad Prism7 by applying nonlinear regression curve fitting using a one-site specific binding model.

[0458] Results: Example 1 3 H-1] was evaluated in a saturation binding assay in PD tissue homogenates by microradiobinding and compared head-to-head with a reference a-syn binder. 3H-1] showed high and improved binding site occupancy in PD brain-derived a-syn aggregates.

[0459] 6. Example 1: Microradiobinding of PD brain-derived a-syn aggregates 3 Evaluation of substitution of a-syn-Ref with H-1] A-syn aggregates derived from PD brains were spotted onto microarray slides. 3 The slides were incubated with 20 nM of [H-1] and either a-syn-Ref or the compound of Example 1 (non-radiolabeled) at increasing concentrations ranging from 50 pM to 2 μM. After incubation, the slides were washed and exposed to a storage phosphor screen (GE Healthcare, BAS-IP TR 2025). Following exposure, the storage phosphor screen was scanned with a laser imaging system (Typhoon FLA 7000) to read out the signal from the radiobinding experiment described above. Signal quantification was performed using the ImageJ software package. Nonspecific signal was determined using an excess of non-radiolabeled example compound 1 (2 μM), and specific binding was calculated by subtracting the nonspecific 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 ligand. All measurements were performed with at least two technical replicates.

[0460] Results: Example 1 3 We evaluated whether the a-syn-Ref compound [H-1] could be substituted for the non-radiolabeled a-syn-Ref compound. Only the a-syn-Ref compound exhibited the same activity as Example 1 [H-1] in brain-derived a-syn aggregates from an idiopathic PD case (Figure 6). 3 H-1], suggesting that Exemplified Compound 1 binds to a different or partially overlapping binding pocket on pathological a-syn aggregates compared to the a-syn-Ref compound.

[0461] 7. Radiobinding competition assay for determination of the inhibition constant (Ki) of exemplified compound 1 in AD brain homogenate Preparation of human Alzheimer's disease (AD) brain homogenate: The procedure was adapted from the protocol described in Bagchi et al. (2013). Frozen tissue blocks from AD donors were thawed on ice and homogenized at 4°C using a glass Dounce homogenizer in high-salt buffer (50 mM Tris-HCl pH 7.5, 0.75 M NaCl, 5 mM EDTA) supplemented with protease inhibitors (Complete, Roche 11697498001). The homogenate was centrifuged at 100,000 × g (38,000 RPM) in a pre-cooled 70.1 rotor (Beckman, 342184) in an ultracentrifuge (Beckman, XL100K) for 1 hour at 4°C. The pellet was resuspended in high-salt buffer supplemented with 1% Triton X-100 and homogenized at 4°C using a glass Dounce homogenizer. The homogenate was centrifuged again at 100,000 × g (38,000 RPM, 70.1 rotor) for 1 hour at 4°C. The pellet was resuspended in high-salt buffer supplemented with 1% Triton X-100 and 1 M sucrose and homogenized using a glass Dounce homogenizer at 4°C. The homogenate was centrifuged at 100,000 × g (38,000 RPM, 70.1 rotor) for 1 hour at 4°C. The resulting pellet, containing the insoluble fraction, was resuspended in PBS, aliquoted, and stored at -80°C until use.

[0462] A fixed concentration of AD, which is insoluble in the fraction, was added to the tritiated reference Abeta ligand ([ 3The cells were incubated for 2 hours at room temperature with unradiolabeled exemplary compound 1 at 10 nM with [H]-Abeta-Ref) and increasing concentrations ranging from 400 pM to 2 μM. The samples were then filtered under vacuum onto GF / C filter plates (PerkinElmer) to capture aggregates containing bound radioligand and washed five times with 50 mM Tris pH 7.5. The GF / C filters were then dried, and scintillation fluid (UltimateGold, PerkinElmer) was added to each well. The filters were analyzed in a Microbeta2 scintillation counter (PerkinElmer). Nonspecific signal was determined using an excess of unradiolabeled reference ligand (2 μM), and specific binding was calculated by subtracting the nonspecific 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 excess unradiolabeled reference ligand. i Values ​​were calculated in GraphPad Prism 7 by applying nonlinear regression curve fitting using a single-site specific binding model. Measurements were performed with at least two replicates.

[0463] Results: As shown in Figure 7 and Table 7, the K value of Exemplified Compound 1 in AD brain homogenate was i The value was determined at 330 nM. Example 1 [ 3 Based on the binding affinity of [H-1], Exemplary Compound 1 showed good selectivity for a-syn over Abeta pathological aggregates present in human AD brain homogenates. 3 H-1] did not show specific target engagement with tau aggregates in AD brain tissue compared to the reference tau binder used as a positive control (FIG. 8), suggesting good selectivity over tau pathological aggregates. 3H-1] showed weak to no binding to TAR DNA-binding protein 43 (TDP-43) aggregates present in frontotemporal lobar degeneration (FTLD-TDP) type C brain tissue (Figure 9), demonstrating good selectivity over TDP-43 pathological aggregates. Overall, these data demonstrate the selectivity of exemplified compound 1.

[0464] [Table 16]

[0465] Table 7: Determination of the Ki value of exemplary compound 1 for the displacement of [3H]-Abeta-Ref with non-radiolabeled exemplary compound 1 in AD brain homogenate. i and R 2 Values ​​were calculated in GraphPad Prism7 by applying nonlinear regression curve fitting using a one-site specific binding model.

[0466] 8. PK study in healthy monkeys Non-human primates (NHPs) were treated with 1 mL of ethanol and 14 mL of ascorbate / saline. 18 F-labeled Example 1 18 F-1] (6.5 mCi) was injected intravenously (iv) (ascorbate solution was prepared at a concentration of 9.3 mg / mL). Monkey PET scans were performed using a Siemens Focus 220. PET acquisition began immediately before the injection of the radiation dose. Images were generated as dynamic scans over 120 minutes with head focus. Example 1 [ 18 F-1] showed rapid uptake in the whole brain (3.5 minutes after injection) with a SUVmax of 2.0. 18 F-1] underwent rapid efflux from the peak to half of the peak at 14 minutes (Figure 10). This data supports the results of Example 1 [in non-human primates], which is suitable for its use as a brain PET agent in humans. 18 F-1] to demonstrate the PK profile.

[0467] 9. Example 1 in brain sections from PD, PDD, MSA, LBV, and non-demented control (NDC) donors by autoradiography 3 Evaluation of specific binding of [H-1] Frozen human brain sections from one PD case, two PDD cases, two MSA cases, one LBV case, and three non-demented control (NDC) cases were first briefly fixed with 4% paraformaldehyde (Sigma, 252549) for 15 minutes at 4°C and washed three times with PBS (Dulbecco's phosphate-buffered saline, Sigma) for 5 minutes at room temperature. All slides were then equilibrated in 50 mM Tris-HCl pH 7.4 buffer for 20 minutes before use in experiments. Each brain section was fixed with a fixed concentration (10 nM) of tritiated exemplary compound 1 (Example 1 [ 3 H-1]) in Tris-HCl buffer at room temperature for 2 hours (total binding, "total"). Non-specific binding (NSB) Example 1 [ 3 To determine the H-1, the slides were mixed with 5 μM of non-radiolabeled compound Example 1. The slides were washed, then exposed and scanned in a real-time autoradiography system (BeaQuant instrument, ai4R).

[0468] Results: Example 1 3 H-1 demonstrated target engagement in a variety of a-synucleinopathy tissues, including two MSA, one LBV, and two PDD cases (Fig. 11A). The displaceable signal correlated well with the localization and burden of a-syn pathology, as determined by staining with the a-syn-pS129 antibody (Fig. 11B), demonstrating specific binding of the compound. Furthermore, autoradiographic signals were more abundant in diseased donors compared with numerous non-demented controls, although the signals were weaker.

[0469] 10. Microradiography binding competition assay for determination of binding affinity A-syn aggregates derived from PD brains were spotted onto microarray slides. 3H-1 at 6 nM or 20 nM, and with the example compounds (non-radiolabeled) at 1 μM and 100 nM. In some cases, non-radiolabeled example compounds were further evaluated against a range of different concentrations, varying 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 Beamage image analysis software (ai4R). Non-specific signal was determined using an excess of non-radiolabeled Example 1 (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 excess non-radiolabeled Example 1. 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.

[0470] Results: The exemplary compounds were tested in Example 1 against brain-derived a-syn aggregates from PD patients. 3 The compounds were evaluated for their potency in competing with the binding of the [H-1] ligand. The results of the microradio binding competition assay for the exemplary compounds tested are shown in Table 8: % competition at 1 μM and 100 nM. Table 8 also shows the K i Indicates the value.

[0471] [Table 17-1]

[0472] [Table 17-2]

[0473] [Table 17-3]

[0474] [Table 17-4]

[0475] [Table 17-5]

[0476] Table 8: Evaluation of binding affinity to human PD brain-derived a-syn aggregates by microradio binding competition assay. Tritiated Example 1 in the presence of 1 μM and 100 nM of exemplary compounds 2-181 3 Percent competition (%) for [H-1] ligand. K i Values ​​are also shown for selected example compounds. * * denotes Ki values ​​in independent experiments using PD brain homogenates from three different donors. ** * denotes Ki values ​​in independent experiments using PD brain homogenates from two different donors. As shown in Table 8, exemplary compounds 2 to 181 of the present invention exhibit strong binding to PD brain-derived a-syn aggregates.

[0477] 11. Example 4 in α-synucleinopathy 3 H-4] target engagement assessment 11A: High-resolution microautoradiography The protocol was adapted from Marquie et al., 2015. Sections were irradiated with tritiated exemplary compound 4 (Example 4 [ 3 H-4]) or a reference tau ligand ([ 3The sections were incubated with 20 nM [H]-tau-Ref) at room temperature for 1 hour. The sections were then washed as follows: once for 1 minute with ice-cold 50 mM Tris-HCl pH 7.4 buffer, twice for 1 minute with 70% ice-cold ethanol, once for 1 minute with ice-cold 50 mM Tris-HCl pH 7.4 buffer, and finally briefly rinsed with ice-cold distilled water. The sections were then dried and then exposed to Ilford nuclear emulsion type K5 (Agar Scientific, AGP9281) in a light-proof slide storage box. After 5 days, sections were developed by sequential immersion in the following solutions: 1) Ilford Phenisol developer (diluted 1:5 in H2O, Agar Scientific, AGP9106), 2) Ilfostop solution (diluted 1:20 in H2O, Agar Scientific, AGP9104), 3) Ilford Hypam Fixer (diluted 1:5 in H2O, Agar Scientific, AGP9183), and finally rinsed in H2O.

[0478] Where indicated, immunostaining was also performed on the same sections. For image acquisition, sections were mounted using ProLong Gold antifade agent (Invitrogen P36930) and imaged on a Panoramic150 slide scanner (3DHistech) with a 20x objective that captured brightfield and fluorescent images separately.

[0479] 11B. By staining sections with antibodies Brain sections were immunostained using a commercially available antibody specific for phosphorylated serine at amino acid 129 of a-synuclein (a-syn-pS129, rabbit monoclonal, Abcam 51253). Sections were fixed with 4% formaldehyde (Sigma, 252549) for 15 minutes at 4°C and washed three times with 1x PBS (Dulbecco's phosphate-buffered saline, Sigma, D1408) for 5 minutes at room temperature. Sections were then saturated and permeabilized in blocking buffer (PBS, 10% NGS, 0.25% Triton X-100) for 1 hour at room temperature and incubated overnight at 4°C with the primary antibody corresponding to a-syn-pS129. The next day, sections were washed three times with 1x PBS for 5 minutes each and then incubated with AlexaFluor 647-conjugated goat anti-rabbit (Abcam, ab150079) secondary antibody for 45 minutes at room temperature. Following incubation with the secondary antibody, sections were washed three times with PBS before further processing. For image acquisition, sections were mounted using ProLong Gold antifade agent (Invitrogen P36930) and imaged with a Panoramic150 slide scanner (3DHistech, Hungary).

[0480] Results: Example 4 3 High-resolution microautoradiography with H-4 was performed on frozen human brain sections from PD donors. 3 A strong autoradiographic signal from [H-4] was detected in the form of accumulating silver grains (Fig. 12, bottom row) and was colocalized with the a-syn-pS129 antibody (Fig. 12, top row), suggesting strong target engagement in Lewy bodies and Lewy neurites, as well as immunofluorescence signals from very small a-syn aggregates in PD tissues.

[0481] 12. Example 4 in brain sections from PD, MSA, and non-demented control (NDC) donors by autoradiography 3 Evaluation of specific binding of [H-4] Frozen human brain sections labeled with SNCA from one familial PD case (α-synuclein [SNCA] gene G51D missense mutation), one idiopathic PD case, one MSA case, and two non-demented control (NDC) cases were first briefly fixed in 4% paraformaldehyde (Sigma, 252549) at 4°C for 15 minutes and washed three times with PBS (Dulbecco's phosphate-buffered saline, Sigma) for 5 minutes at room temperature. All slides were then equilibrated in 50 mM Tris-HCl pH 7.4 buffer for 20 minutes before use in experiments. Each brain section was treated with a fixed concentration (10 nM) of tritiated exemplary compound 4 (Example 4 [ 3 H-4]) in Tris-HCl buffer at room temperature for 2 hours (total binding, "total"). 3 To determine the H-4, the slides were mixed with 5 μM of a non-radiolabeled compound (Example 4, "NSB") The slides were washed, then exposed and scanned in a real-time autoradiography system (BeaQuant instrument, ai4R).

[0482] Results: Example 4 3 H-4] showed specific binding in various α-synucleinopathy tissues, including MSA, familial PD, and idiopathic PD cases (Fig. 13A). Autoradiography signals appeared larger in diseased donors compared to non-demented controls, confirming target engagement, and correlated well with the distribution of pathological α-synuclein burden (Fig. 13B). In addition, Example 4 [ 3 H-4] showed displaceable signals in the various α-synucleinopathy cases examined and faint signals in many non-diseased controls.

[0483] 13. Saturation binding test of PD brain-derived a-syn aggregates by microradiobinding A-syn aggregates derived from PD brains were spotted onto microarray slides. 3The slides were incubated with increasing concentrations of 1.56 nM to 80 nM of HCl. After incubation, the slides were scanned using a real-time autoradiography system (BeaQuant instrument, ai4R). Signal quantification was performed using Beamage image analysis software (ai4R). Nonspecific signals were determined using an excess of non-radiolabeled reference ligand (Example 4 at 2 μM), and specific binding was calculated by subtracting the nonspecific signals from the total signals. d Values ​​were calculated in GraphPad Prism7 by applying nonlinear regression curve fitting using a one-site specific binding model.

[0484] Results: Example 4 3 H-4] was evaluated in a saturation binding assay with PD tissue homogenates by microradiobinding (Figure 14). d ) was calculated to be 21 nM (Figure 14 / Table 9), suggesting good binding affinity to pathological α-synuclein aggregates.

[0485] [Table 18]

[0486] Table 9: Example 4 in human PD brain tissue homogenate by microradiobinding 3 Evaluation of the binding affinity of [H-4]. Dissociation constant (K d ) and binding site occupancy (B max ) was calculated in GraphPad Prism 7 by applying nonlinear regression curve fitting using a single-site specific binding model. 2 is the coefficient of determination.

[0487] 14. Inhibition constant (K) of exemplary compound 4 in AD brain homogenate i Radiobinding competition assay for the determination of Human Alzheimer's disease (AD) brain homogenates were prepared according to the procedure disclosed in Example 7 (see above).

[0488] A fixed concentration of AD, which is insoluble in the fraction, was added to the tritiated reference Abeta ligand ([ 3 The cells were incubated for 2 hours at room temperature with unradiolabeled exemplary compound 1 at 10 nM with [H]-Abeta-Ref) and increasing concentrations ranging from 400 pM to 2 μM. The samples were then filtered under vacuum onto GF / C filter plates (PerkinElmer) to capture aggregates containing bound radioligand and washed five times with 50 mM Tris pH 7.5. The GF / C filters were then dried, and scintillation fluid (UltimateGold, PerkinElmer) was added to each well. The filters were analyzed in a Microbeta2 scintillation counter (PerkinElmer). Nonspecific signal was determined using an excess of unradiolabeled reference ligand (2 μM), and specific binding was calculated by subtracting the nonspecific 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 excess unradiolabeled reference ligand. i Values ​​were calculated in GraphPad Prism 7 by applying nonlinear regression curve fitting using a one-site specific binding model. Measurements were performed in two independent experiments with two technical replicates.

[0489] Results: As shown in Figure 15 and Table 10, the K value of exemplary compound 4 in AD brain homogenate was i The value was determined to be 297 nM. The value reported in Example 4 in PD brain homogenate by microradiobinding is reported in Example 13 (above) with a value of 21 nM. 3Based on the binding affinity of [H-4] and specific binding in a-synucleinopathy brain tissue by autoradiography, Example Compound 4 showed good selectivity for a-syn over Abeta pathological aggregates present in human AD brain homogenates. 3 H-4] did not demonstrate specific target engagement of tau aggregates in AD brain tissue compared to a reference tau binder used as a positive control (Figure 16), suggesting good selectivity over tau pathological aggregates. Overall, these data demonstrate the desired selectivity of exemplary compound 4 against a-syn aggregates.

[0490] [Table 19]

[0491] Table 10: AD brain homogenate [ 3 Determination of the Ki value of exemplary compound 4 for the displacement of [H]-Abeta-Ref with non-radiolabeled exemplary compound 4. i and R 2 Values ​​were calculated in GraphPad Prism7 by applying nonlinear regression curve fitting using a one-site specific binding model.

[0492] 15. First-in-Human (FIH) Testing 18 A Phase 1 study is underway to evaluate F-Example 1 as a potential PET radioligand for imaging a-synuclein deposits in the brains of patients suspected of having a-synuclein pathology compared to healthy volunteers (HV). The study objective is to: 18 F - To characterize the safety and imaging and pharmacokinetic properties of Example 1. A total of up to 10 subjects may be enrolled (up to 5 HV subjects in the target and up to 5 idiopathic PD subjects).

[0493] Inclusion criteria for all subjects: Subjects are able to provide written informed consent, which must be obtained before any assessments are performed. Female subjects must not be of childbearing potential, or if of childbearing potential, must agree to use contraception and must not donate eggs. Subjects without documentation of non-childbearing potential, in the inventor's judgment, may undergo pregnancy testing. Male subjects with partners of childbearing potential must use two methods of contraception, one of which must be a barrier method for male subjects for the duration of the study and for 90 days after the end of the study. Male subjects must not donate sperm during the study or for 90 days after the study ends. For subjects undergoing arterial cannulation, adequate circulation to the hand for safe placement of the arterial pathway (determined by Allen's test) and blood clotting (prothrombin time [PT] and partial thromboplastin time [PTT]). If the subject is taking bupropion, the subject must agree to hold this medication for at least 12 hours prior to DaT scan imaging (if performed).

[0494] Additional inclusion criteria for HV subjects: · Men and women must be 21 years of age or older. Healthy individuals with no relevant clinical findings upon reporting to the clinic for the screening physical examination and tracer imaging visit. No family history of alpha-synucleinopathy, including PD, or other early-onset dementia-related neurological disorders. · No history of clinically significant neurological and / or psychiatric disorders. No evidence of dopamine transporter deficiency on a dopamine activated transporter (DaT) scan performed as part of screening or a previously obtained DaT scan (within 6 months prior to signing the consent form). · Montreal Cognitive Assessment (MoCA) score of 26 or higher. No cognitive impairment as determined by the PI.

[0495] Additional inclusion criteria for subjects with α-synucleinopathy: · Men and women must be 40 years of age or older. Subjects diagnosed with any of the following: Idiopathic PD PD with genetic risk factors (excluding leucine-rich repeat kinase 2 [LRRK2] mutations) Brain magnetic resonance imaging (MRI) consistent with a diagnosis of alpha-synucleinopathy, with no evidence of focal disease that is the primary cause of the subject's neurological symptoms. Evidence of dopamine transporter deficiency on a DaT scan performed as part of any screening or previously obtained DaT scan. Medications taken for the symptomatic treatment of alpha-synucleinopathy should be maintained on a stable dosage regimen for at least 30 days prior to the screening visit. Ability to tolerate lying in the scanner for up to approximately 180 minutes without excessive head or jaw tremors or dyskinesias sufficient to cause significant motion artifacts on the PET scan.

[0496] After registration, subjects are required to have a blood glucose level of 10 mCi or less. 18 F - Receive one intravenous injection of Example 1. 18 F - The brain uptake and pharmacokinetics of Example 1 will be assessed visually and quantitatively, and safety data will be obtained. 18 F - PET signal of Example 1 cross-sectionally compared with HV.

[0497] 16. Formulation 18 Capture and elution of F: 18The [F] fluoride was transferred to an ion exchange cartridge and captured. It was then eluted in a reaction vessel (RV1) with a solution of potassium carbonate (1.6 mg) and Kryptofix 222 (10 mg) in acetonitrile. The solution was first evaporated by heating at 95 °C for 4 minutes under vacuum and helium flow. Then, acetonitrile (1 mL) was added to RV1, and evaporation was continued under the same conditions under vacuum and helium flow for 2 minutes. After the addition of a second acetonitrile (1 mL), a final evaporation was carried out at 95 °C for 2 minutes under vacuum and helium flow. Finally, the reactor was cooled to 60 °C.

[0498] Radiolabeling reaction: A solution of the precursor (1.0 mg) in anhydrous dimethyl sulfoxide was added to the reaction vessel and the reaction mixture was heated at 100°C for 10 minutes. The reactor was cooled to 40°C, diluted with HPLC mobile phase (1.8 mL), and the contents were transferred to a loop-filled vial (RV2). The reactor was rinsed with water for injection (2.5 mL), and the rinse was transferred to RV2. The contents of RV2 were transferred to an HPLC injector loop for purification.

[0499] Purification and Drug Product Formulation: Purification was performed by HPLC using a semi-preparative Agilent Eclipse XDB C18 column (5 μm, 250 × 9.4 mm) and eluted with a mixture of methanol / ammonium acetate solution (20 mM, 50 / 50, v / v) at a flow rate of 4 mL / min. Product fractions were collected in a flask containing 20 mL of sodium ascorbate (5 mg / mL) in water for injection (WFI). The diluted product mixture was passed through a C18 solid-phase extraction cartridge, and the cartridge was rinsed with 10 mL of sodium ascorbate (5 mg / mL) in WFI. The radiolabeled product was eluted from the SPE cartridge with 1.0 mL of 200-proof USP-grade ethanol into a formulation flask pre-filled with 10 mL of sodium ascorbate (10 mg / mL) in saline. The cartridge was rinsed with 4.0 mL of sodium ascorbate (10 mg / mL) in saline, and the rinse water was mixed with the contents of the formulation flask. The resulting solution was transferred through a sterile 0.2 μm filter membrane into a sterile filter-vented vial (final product vial, FPV) pre-filled with 15 mL of saline.

[0500] The stability of the radiolabeled product over time was tested and validated to remain within specifications for 8 hours after completion of synthesis.

[0501] The batch formulation amounts are presented in Table 11:

[0502] [Table 20]

[0503] The final formulation of the radiolabeled product developed in this study will have a volume of 30 mL, with the intention of achieving the following contents in the final dosage form, based on an injection volume of 10 mL, as shown in Table 12:

[0504] [Table 21]

Claims

1. Formula (IV-F) 【Chemistry 1】 (In the formula, R 3 teeth, 【Chemistry 2】 is selected from R 4 is aryl or 5- or 6-membered heteroaryl, and R 4 but: 【Transformation 3】 is selected from R 2a , R 2a' is independently selected from H or F; R 2b are F, -OH, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, -NH 2 , -CN or C 1 ~C 4 independently selected from alkoxy; R 2c , R 2c' are H, F, OH, OCH 3 or CH 3 are independently selected from R 2d is selected from H, F or —OH; R 2e are H, OH, and CH 3 or F, Z is independently N, NH, N(C 1 ~C 4 alkyl), N(haloC 1 ~C 4 alkyl), O or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, 【Chemistry 4】 is a combination of a single bond and a double bond, * is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. LG is bromo, chloro, iodo, C 1～4 Alkyl sulfonates and C 6～10 aryl sulfonates, C 6～10 Aryl is optionally -CH 3 OR -NO 2 2. The compound of formula (IV-F) according to claim 1, which may be substituted by: 【Request Item 3】 【Chemistry 5】 3. The compound of formula (IV-F) according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

4. Formula (IV-H) 【Transformation 6】 (In the formula, R 5 teeth, 【Transformation 7】 is selected from R 6 is aryl or 5- or 6-membered heteroaryl, and R 6 But the following: 【Transformation 8】 is selected from R 2a , R 2a' is independently selected from H, X, or F; R 2b X, F, -OH, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, -NH 2 , -CN or C 1 ~C 4 independently selected from alkoxy, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl or C 1 ~C 4 alkoxy optionally contains one or more X; R 2c , R 2c' are X, H, F, OH, OCH 3 or CH 3 are independently selected from R 2d is selected from X, H, F or —OH; R 2e are X, H, OH, and CH 3 or F, Z is independently N, NH, N(C 1 ~C 4 alkyl), N(haloC 1 ~C 4 alkyl), O or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, 【Chemistry 9】 is a combination of a single bond and a double bond, * is the position of the bond, Fluoro is 19 F, X is bromo, chloro or iodo; R 6 contains at least one X), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Request Item 5】 【Chemistry 10】 5. The compound of formula (IV-H) according to claim 4, wherein:

6. Formula (IV-J) 【Chemistry 11】 (In the formula, R 7 teeth, 【Chemistry 12】 is selected from R 8 is the following: 【Chemistry 13】 is selected from R 2a , R 2a' is independently selected from H or F; R 2b are F, -OH, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, -NH 2 , -CN or C 1 ~C 4 independently selected from alkoxy; p is 0, 1 or 2; R z is H, C 1 ~C 4 Alkyl or haloC 1 ~C 4 alkyl, If valence allows, 【Chemistry 14】 is a combination of a single bond and a double bond, Fluoro is 19 F, * is the position of the bond), or a stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Request Item 7】 【Chemistry 15】 7. The compound of formula (IV-J) according to claim 6, wherein:

8. The compound according to any one of claims 1 to 3, 18 so that it can be replaced by F 18 reacting with an F-fluorinating agent, 18 Formula (I) labeled with F 【Chemistry 16】 (In the formula, 【Chemistry 17】 is aryl or heteroaryl, which is [Chemistry 18] are selected with directionality from R 0 is H or C 1 ~C 4 is alkyl, R 1 is -CN, or halo, or C 1 ~C 4 Alkyl or C 1 ~C 4 Alkoxy or -N(C 1 ~C 4 alkyl) 2 , or -NH(C 1 ~C 4 alkyl), or H, or R 1 But -NH-C 3 ~C 6 Cycloalkyl, C 3 ~C 6 cycloalkyl or heterocyclyl, each of which is optionally substituted with at least one halo; R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 But the following: 【Chemistry 19】 is selected from R 2a , R 2a' is independently selected from H or F; R 2b is F, OH, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, NH 2 , CN or C 1 ~C 4 independently selected from alkoxy; R 2c , R 2c' are H, F, OH, OCH 3 or CH 3 are independently selected from R 2d is selected from H, F or OH, R 2e are H, OH, and CH 3 or F, Z is independently N, NH, N(C 1 ~C 4 alkyl), N(haloC 1 ~C 4 alkyl), O or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, 【Chemistry 20】 is a combination of a single bond and a double bond, * is the position of the bond.

9. 18 F-fluorinating agent is K 18 F, Rb 18 F, Cs 18 F, Na 18 F, Rb 18 F, Kryptofix[222]K 18 F, 18 F Tetra (C 1～6 Alkyl)ammonium salts and tetrabutylammonium [ 18 9. The method of claim 8, wherein the compound is selected from the group consisting of [F] fluoride.

10. The compound according to claim 4 or 5, 3 H radiolabeling agent, 3 Formula (I) labeled with H 【Chemistry 21】 (In the formula, 【Chemistry 22】 is aryl or heteroaryl, which is 【Chemistry 23】 are selected with directionality from R 0 is H or C 1 ~C 4 is alkyl, R 1 is -CN, or halo, or C 1 ~C 4 Alkyl or C 1 ~C 4 Alkoxy or -N(C 1 ~C 4 alkyl) 2 , or -NH(C 1 ~C 4 alkyl), or H, or R 1 But -NH-C 3 ~C 6 Cycloalkyl, C 3 ~C 6 cycloalkyl or heterocyclyl, each of which is optionally substituted with at least one halo; R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 But the following: 【Chemistry 24】 is selected from R 2a , R 2a' is independently selected from H or F; R 2b is F, OH, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, NH 2 , CN or C 1 ~C 4 independently selected from alkoxy; R 2c , R 2c' are H, F, OH, OCH 3 or CH 3 are independently selected from R 2d is selected from H, F or OH, R 2e are H, OH, and CH 3 or F, Z is independently N, NH, N(C 1 ~C 4 alkyl), N(haloC 1 ~C 4 alkyl), O or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, 【Chemistry 25】 is a combination of a single bond and a double bond, * is the position of the bond.

11. The compound according to claim 6 or 7 is treated with CT 3 a step of reacting with a radiolabeling agent, wherein T is 3 H, 3 Formula (I) labeled with H 【Chemistry 26】 (In the formula, 【Chemistry 27】 is aryl or heteroaryl, which is 【Chemistry 28】 are selected with directionality from R 0 is H or C 1 ~C 4 is alkyl, R 1 is -CN, or halo, or C 1 ~C 4 Alkyl or C 1 ~C 4 Alkoxy or -N(C 1 ~C 4 alkyl) 2 , or -NH(C 1 ~C 4 alkyl), or H, or R 1 But -NH-C 3 ~C 6 Cycloalkyl, C 3 ~C 6 cycloalkyl or heterocyclyl, each of which is optionally substituted with at least one halo; R 2 is aryl or 5- or 6-membered heteroaryl, and R 2 But the following: 【Chemistry 29】 is selected from R 2a , R 2a' is independently selected from H or F; R 2b is F, OH, C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, NH 2 , CN or C 1 ~C 4 independently selected from alkoxy; R 2c , R 2c' are H, F, OH, OCH 3 or CH 3 are independently selected from R 2d is selected from H, F or OH, R 2e are H, OH, and CH 3 or F, Z is independently N, NH, N(C 1 ~C 4 alkyl), N(haloC 1 ~C 4 alkyl), O or S; Z 1 are independently N, NH, O or S, p is 0, 1 or 2; m is 0 or 1; If valence allows, 【Transformation 30】 is a combination of a single bond and a double bond, * is the position of the bond.

12. 8. A kit for preparing a radiopharmaceutical preparation, comprising a sealed vial containing at least one compound as defined in any one of claims 1 to 7.

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