NOVEL COMPOUNDS FOR THE DIAGNOSIS, TREATMENT AND PREVENTION OF DISEASES ASSOCIATED WITH ALPHA-SYNUCLEIN AGGREGATION

Abstract

The present invention relates to compounds represented by the general formulas Ia, Ib, IIa, or IIb (see Formulas). These compounds are suitable for imaging alpha-synuclein and for diagnosing diseases associated with alpha-synuclein aggregation. The compounds are also useful for the treatment and prevention of diseases associated with alpha-synuclein aggregation.

Description

NOVEL COMPOUNDS FOR THE DIAGNOSIS, TREATMENT AND PREVENTION OF DISEASES ASSOCIATED WITH THE AGGREGATION OF ALPHA-SINUCLEIN FIELD OF INVENTION The present invention relates to novel compounds suitable for imaging alpha-synuclein and diagnosing diseases associated with alpha-synuclein aggregation. The compounds are useful for the treatment and prevention of diseases associated with alpha-synuclein aggregation. BACKGROUND OF THE INVENTION There are a large number of known neurological and neurodegenerative diseases, many of which currently have no cure and are difficult to diagnose. All neurodegenerative diseases are characterized by the misfolding, aggregation, and deposits of specific proteins in the brain. These diseases include medical conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, Creutzfeldt-Jakob disease, and many others. Synucleinopathies are a group of diseases LRcnn / zznz / E / YiAi Ref. 333409 characterized by the accumulation and deposition of aggregated and misfolded alpha-synuclein (aSYN) proteins. Synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). These diseases differ in the distribution of accumulation and deposition of aggregated and misfolded alpha-synuclein proteins in the central and peripheral nervous system. Neuropathologically, they can be distinguished from other neurodegenerative diseases by the accumulation and deposition of specific aggregated and misfolded alpha-synuclein proteins, while other neurodegenerative diseases are characterized by the accumulation and deposition of other aggregated and misfolded proteins.For example, Alzheimer's disease is characterized by aggregated and misfolded Abeta (Αβ) and tau proteins, progressive supranuclear palsy and corticobasal degeneration are characterized by aggregated and misfolded tau protein, and some cases of frontotemporal dementia are characterized by aggregated and misfolded tau protein. Creutzfeldt-Jakob disease is characterized by an aggregated and misfolded prion protein. The accumulation and deposits of disease-specific aggregated and misfolded proteins are a target for both therapy and diagnosis through compounds that bind to these aggregated protein deposits. LRcnn / zznz / E / YiAi and poorly folded. One option for the diagnostic detection of disease-specific accumulation and deposits of misfolded and aggregated proteins is the use of detectably labeled compounds that show high specific and selective binding affinity to protein aggregate deposits. This can be done, for example, by using compounds that are labeled with suitable radioactive isotopes and using PET imaging for detection. While compounds are available for clinical use for PET imaging of Abeta and tau, so far no compounds have been invented that can be used for diagnostic PET imaging of alpha-synuclein deposits in synucleinopathies. (Kotzbauer, P.T., Tu, Z. and Mach, R.H., Current status of the development of PET radiotracers for imaging alpha synuclein aggregates in Lewy bodies and Lewy neurites. Clin. Trans. Imaging, 2017. 5: p. 3-14) .The compounds developed and tested by other groups so far lack a suitable combination of properties including high binding affinity to aggregated and misfolded alpha-synuclein, sufficiently selective in binding affinity compared to other aggregated and misfolded proteins, especially Abeta and tau (required for differential diagnosis of the various diseases characterized by the accumulation and deposition of disease-specific aggregated and misfolded proteins) and for. LRcnn / zznz / E / YiAi the ability to accurately detect the presence of aggregated and misfolded alpha-synuclein also in patients with more than one disease at the same time, i.e., dementia with Lewy bodies and Alzheimer’s disease). Furthermore, the required properties do not include the ability to cross the blood-brain barrier and bind to intracellular stores, low nonspecific binding to brain tissue, and rapid clearance of unbound compound from the brain. WO 2009 / 146343 relates to certain pyrazoles, 1,2,4-oxadiazoles, and 1,3,4-oxadiazoles that are tracers in positron emission tomography (PET) imaging for studying amyloid deposits in the brain in vivo to enable the diagnosis of Alzheimer's disease. Alzheimer's disease is characterized by protein aggregation of Abeta and tau proteins, and the aforementioned PET tracers bind to aggregates of these proteins. In contrast, the present invention is directed to diseases characterized by alpha-synuclein aggregation. Selective imaging of alpha-synuclein aggregates requires selective binding to alpha-synuclein and no or low binding to Abeta and tau aggregates. WO 00 / 66578 describes specific NPY antagonists that are useful in the treatment of NPY-mediated diseases / conditions such as obesity. It was mentioned that in addition to the direct effect of the compounds of WO0066578 on the LRcnn / zznz / E / YiAi NPY5 subtype, there are diseases / conditions that benefit from weight loss, such as insulin resistance, impaired glucose tolerance, type II diabetes, hypertension, hyperlipidemia, cardiovascular disease, gallstones, certain cancers, sleep apnea, etc. WO 2010 / 000372 relates to a specific compound that is useful in the treatment or prevention of protein aggregation-associated diseases and / or neurodegenerative diseases. The compounds of WO 2010 / 000372 are particularly suitable for the treatment of protein aggregation-associated diseases, including Parkinson's disease. They have been shown to bind to several different aggregated proteins, including Abeta and tau. Therefore, they can be used to diagnose protein aggregation-associated disorders, but it is not possible to reliably distinguish between alpha-synuclein aggregation-associated disorders and other amyloid protein aggregation-associated disorders, such as tautopathies or Alzheimer's disease.This, however, would be important since the clinical manifestations of disorders associated with protein aggregation are very similar, and it would be highly desirable to distinguish, for example, between the various disorders in order to tailor treatment accordingly. Furthermore, the molecules described in WO 2010 / 000372 have high nonspecific binding to lipids. LRcnn / zznz / E / YiAi and hydrophobic proteins, resulting in nonspecific binding in brain and other tissues. Thus, they do not achieve the required specific binding and signal-to-noise ratio for alpha-synuclein as required for a PET tracer. In view of the above, there was a need for compounds with improved diagnostic properties. In particular, the specificity of alpha-synuclein binding must be improved. Nonspecific binding in brain and other tissues must be reduced, binding affinity must be increased, and the physiological half-life must be shortened. US 2005 / 0075375 describes specific heterocyclic compounds for the treatment of hepatitis C virus. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Autoradiograph using brain tissue from a patient suffering from Lewy body dementia using [3H]compound 1 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound represented by the general formula la, Ib, lia or Ilb LRcnn / zznz / E / YiAi LRcnn / zznz / E / YiAi X1, X2, and X3 are independently selected from CR2, N, and NR1, provided that at least two of X1, X2, and X3 are either N or NR1. It is understood that N and NR1 are present whenever valencies permit, i.e., N can only be present in a =X1-, =X2-, or =X3- position and NR1 can only be present in a -X1- or -X2- position. Examples of Examples of In a preferred embodiment, LRcnn / zznz / E / YiAi Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are independently selected from CR3 and N, provided that at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is N. In a preferred embodiment in the formulas la or Ib, Y1, Y2, Y3, Y4, Y5, and Y6 are independently selected from CR3 and N, with the proviso that at least one of Y1, Y2, Y3, Y4, Y5, and Y6 is N. In a more preferred embodiment, one or two or three of Y1, Y2, Y3, Y4, Y5, and Y6 is N, even more preferably one or two of Y1, Y2, Y3, Y4, Y5, and Y€ is N, even more preferably one of Y1, Y2, Y3, Y4, Y5, and Y6 is N. In a preferred embodiment, Y1 is N. In a preferred embodiment in formulas la or Ib, at least one of Y1, Y3, Y4, and Y6 is N. In an even more preferred embodiment in formulas la or Ib, Y1 is N and at least one of Y3, Y4, and Y6 is N. In a preferred embodiment in formulas la or Ib, at least one of Y1, Y3, Y4, and Y6 is N and the others of Y1, Y2, Y3, Y4, Y5, and Y6 are CR3 (such as CH). In an even more preferred embodiment in formulas la or Ib, Y1 is N, at least one of Y3, Y4, and Y6 is N and the others of Y2, Y3, Y4, Y5, and Y6 are CR3 (such as CH). In a preferred embodiment in formulae Ia or Ib, Y1 is N and the others of Y2, Y3, Y4, Y5, and Y6 are CR3, more preferably Y1 is N and Y2, Y3, Y4, Y5, and Y6 are CH. In a preferred embodiment in formulae 1a or 1lb, Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are independently selected from CR3 and N, with the proviso that at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is N. In a more preferred embodiment, one or two or three of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is N, even more preferably one or two of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is LRcnn / zznz / E / YiAi N, even more preferably one of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is N. In a preferred embodiment, Y1 is N. In a preferred embodiment in formulae lia or Ilb, at least one of Y1, Y3, Y4, Y5, Y6, Y7, and Y8 is N. In a preferred embodiment in formulae lia or Ilb, at least one of Y1, Y3, Y4, Y5, and Y7 is N. In an even more preferred embodiment in formulae lia or Ilb, Y1 is N and at least one of Y3, Y4, Y5, Y6, Y7, and Y8 is N. In a preferred embodiment in formulae lia or Ilb, at least one of Y1, Y3, Y4, Y5, Y6, Y7, and Y8 is N and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are CR3 (such as CH). In a preferred embodiment in formulae lia or Ilb, at least one of Y1, Y3, Y4, Y5, and Y7 are N and the others of Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are CR3 (such as CH). In an even more preferred embodiment in formulas 1a or Ilb, Y1 is N, at least one of Y3, Y4, Y5, Y6, Y7e Y8is N and the others of Y2, Y3, Y4, Y5, Y6, Y7e Y8are CR3 (such as CH). In a preferred embodiment in formulae lia or Ilb, Y1is N, at least one of Y3, Y4, Y5, and Y7is N and the others of Y2, Y3, Y4, Y5, Y6, Y7e Y8are CR3 (such as CH). In a preferred embodiment in formulae lia or Ilb, Y1 is N and the others of Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are CR3, more preferably Y1 is N and Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are CH. Surprisingly, it has been found that the introduction of one or more nitrogen atoms such as Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 strongly increases the selectivity of alpha binding. LRcnn / zznz / E / YiAi synuclein, so that corresponding disorders associated with alpha-synuclein aggregation, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, can be distinguished from disorders with aggregates of other proteins, such as Alzheimer's disease, where Abeta and tau aggregates predominate. Additionally, the signal-to-noise ratio is improved. R1 is selected from hydrogen, C1-4 alkyl and -(CH2)-OP(=O) (OR) (OR), where the C1-4 alkyl may be optionally substituted with one or more halogens. In a preferred embodiment, R1 is hydrogen, methyl or 2-fluoroethyl. If present, it is preferred that -(CH2)-OP(=O) (OR) (OR) is bonded to X1 or X2. R is hydrogen or a cation. The cation can be any pharmaceutically acceptable cation. Preferably, the cation is a monovalent cation. Examples are sodium, lithium, potassium, ammonium, and protonated forms of ethanolamine, choline, lysine, meglumine, piperazine, and tromethamine. Preferably, the cation is sodium. In the compounds of the present invention, both R's can be hydrogen, both R's can be cations (same or different cations), or one R's can be hydrogen and the other can be a cation. Preferably, both R's are sodium. Divalent cations such as Ca2+, Mg2+, and Zn2+ or trivalent cations such as Al3+ are possible, but not preferred, since the resulting salts are less soluble in water. Compounds in which R1 is - (CH2)-OP(=0) (OR) (OR) LRcnn / zznz / E / YiAi and its synthesis are described in WO 2017 / 102893, which is incorporated herein by reference. R2 is independently selected from hydrogen, halogen, and C1-4 alkyl, where C1-4 alkyl may be optionally substituted with one or more halogens. In a preferred embodiment, R2 is hydrogen. R3 is hydrogen, halogen, C1-4 alkyl, OH, and C1-4 alkoxy, where the C1-4 alkyl and C1-4 alkoxy may be optionally substituted with one or more halogens. In a preferred embodiment, R3 is hydrogen or fluorine. Even more preferably, R3 is hydrogen. R4 and R5 are independently selected from H and C1-4 alkyl, where C1-4 alkyl may be optionally substituted with one or more halogens or where R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing one or more heteroatoms selected from O and N in addition to the nitrogen atom to which R4 and R5 are attached, where the 4- to 6-membered saturated heterocyclic ring may be optionally substituted with one or more R6. In one embodiment, R4 and R5 are independently selected from H and C1-4 alkyl, where the C1-4 alkyl may be optionally substituted with one or more halogens. Preferably, R4 and R5 are independently selected from H and C1-4 alkyl. In a preferred embodiment, at least one LRcnn / zznz / E / YiAi of R4 and R5 is C1-4 alkyl, where the C1-4 alkyl may be optionally substituted with one or more halogens. In a more preferred embodiment, R4 is hydrogen and R5 is C1-4 alkyl, where the C1-4 alkyl may be optionally substituted with one or more halogens. In a more preferred embodiment, at least one of R4 and R5 is C1-4 alkyl. In a more preferred embodiment, R4 is hydrogen and R5 is C1-4 alkyl. In a further embodiment, R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing one or more (e.g., one) heteroatoms selected from O and N in addition to the nitrogen atom to which R4 and R5 are attached, wherein the 4- to 6-membered saturated heterocyclic ring may be optionally substituted with one or more R6. In a preferred embodiment, the 4- to 6-membered saturated heterocyclic ring is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, wherein the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl may be optionally substituted with one or more R6. More preferably, the 4- to 6-membered saturated heterocyclic ring is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, where the N atom of the piperazinyl may be optionally substituted with R6. R6 is independently selected from halogen, LRcnn / zznz / E / YiAi C1-4 alkyl, OH and C1-4 alkoxy, where the C1-4 alkyl and C1-4 alkoxy may be optionally substituted with one or more halogens, preferably R6 is C4-4 alkyl or fluorine. Hal is halogen, such as Br, C1 and F, preferably Hal is Br or F. m is the number of non-hydrogen R3 groups in the ring containing Y1, Y2, Y3, and Y4, m is an integer from 0 to mmax, with mmaxbeing the number of carbon atoms in the ring containing Y1, Y2, Y3, and Y4. Preferably, m is 0. n is the number of non-hydrogen R3 groups in the ring containing Y5, Y6, Y7, and Y8 (formula lia and Ilb). n is an integer from 0 to ninax, with nraax being the number of carbon atoms in the ring containing Y5, Y6, Y7, and Y8. Preferably, n is 0. p is the number of non-hydrogen R3 groups in the ring containing Y5e Y6 (formula Ia and Ib). p is an integer from 0 to pmax, with pmax being the number of carbon atoms in the ring containing Y5e Y6. Preferably, p is 0. The compounds of the present invention may also be present in the form of prodrugs, solvates or salts thereof. The compounds of the present invention form salts which are also within the scope of this invention. References to a compound of the present invention should be understood as including references to the salts of the compounds. LRcnn / zznz / E / YiAi themselves, unless otherwise indicated. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in the isolation or purification steps which may be employed during the preparation or in in vitro methods. Salts of the compounds of the present invention may be formed, for example, by reacting a compound with an amount of acid, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Compounds containing a basic residue can form salts with a variety of organic or inorganic acids. Examples of acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanpropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, LRcnn / zznz / E / YiAi oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates (e.g., those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as used herein represents a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce a compound of the present invention or a salt and / or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates. All stereoisomers of the present compounds (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be mixed, for example, as a racemate or with all other, or other stereoisomers. LRcnn / zznz / E / YiAi selected. The chiral centers of the compounds of the present invention may have the S- or R- configuration according to definitions in the 1974 IUPAC recommendations. Racemic forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or chiral column separation. Individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, salt formation with an optically active acid followed by crystallization. All isomeric configurations of the compounds of the present invention are contemplated, whether in the form of a mixture or in pure or substantially pure form. The definition of compounds of the present invention encompasses both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocyclic rings. Deuterated versions of the claimed compounds may also be provided. The position at which deuteration occurs is not particularly limited, but may, for example, be at the C1-4 alkyl of R4 and R5. Throughout the description, groups and substituents of these may be selected to provide stable residues and compounds. LRcnn / zznz / E / YiAi The compounds of the present invention may be provided in the form of a diagnostic or pharmaceutical composition optionally including a pharmaceutically acceptable carrier or excipient. According to the present invention, the term diagnostic composition relates to a composition for determining the presence of alpha-synuclein aggregates underlying a disease associated with alpha-synuclein aggregates. In a preferred embodiment, the compound of the present invention is detectable or detectably labeled. It is to be understood in accordance with the present invention that a compound is detectable or detectably labeled if its presence can be monitored by conventional techniques, such as, NMR spectroscopy, single photon emission computed tomography (SPECT), optical detection, positron emission tomography (PET), electron microscopy, magnetic resonance imaging (MRI), spectrometry, chromatography, ELISA assay, radioactive emission detection, preferably by means of PET, scintillation counting or gamma counting, more preferably by means of PET. When the compounds of the present invention are to be used as probes for alpha-synuclein aggregates, they must be labeled. The specific nature of the label will depend LRcnn / zznz / E / YiAi of the method used to obtain the image. Generally, positron-emitting radioactive (PET) labels having a short half-life, such as 18F, nC, 125I, 123I, 131I, 77Br and 76Br, in particular 18F and 1]-C, will be useful. Because of their short half-life, the labeled compounds of the present invention must be prepared shortly before they are used for the test. Accordingly, the diagnostic composition of the present invention may also be provided in the form of a kit, consisting of at least two precursors of a compound of the present invention, which are reacted to form the desired compound of the present invention. One skilled in the art will be able to develop methods in which the detectable label can be attached to the compound of the present invention. The following reaction schemes may serve as illustrative examples. Marked with 18F: 2-[18F]Fluoroethyl tosylates are useful as precursors for incorporating18F via fluoroethylation of compounds containing nucleophiles such as nitrogen, oxygen and sulfur as described in WO2010 / 000372, page 32, Reaction Scheme A for the preparation of compound 21 and compound 22 starting from compound 23 . Compounds A and B can be prepared in the same way. Another method includes a direct nucleophilic replacement of a suitable leaving group as shown for the transformation of C to D (cf. J. Med. LRcnn / zznz / E / YiAi Chem. 2013, 56, 4568-4579, reaction scheme 2) or the transformation of compound 24 to compound 12 in Scheme LRcnn / zznz / E / YiAi reaction 1. Reaction scheme 1 18FK, Kryptofix 2.2.2 DMSO, 140 °C Marked with 11C: The X1C-labeled compounds of the invention can be prepared by direct nucleophilic alkylation of the appropriate precursor with [1:LC]-MeI as described in WO 2010 / 000372, page 32, Reaction scheme B for the preparation of compound 27 and compound 28 starting from compound 23. Compound 1 of the present invention can be synthesized analogously from compound 2. In the same way, compound 18 and compound 19 can be synthesized from compound 9 as shown in reaction scheme 2. Alternatively, a simple and accessible method (J.M. Hooker et al., Angew. Chem. Int. Ed. 2008, 47, 5989-5992) for the production of [nC]formaldehyde as a solution in dimethylformamide by converting [^CJmethyl iodide to [nC]formaldehyde under mild conditions without loss of specific activity for the transformation of the compound to the compound by reductive amination. reaction 2: Scheme N Br [11C] Mel K2CO3, CH3CN ,0 N Br Br provides a method of obtaining The LRcnn / zznz / E / YiAi imaging of alpha-synuclein aggregate deposits, comprising the steps of: (i) introducing a detectable amount of a composition comprising a detectably labeled compound of the present invention into a subject; allowing sufficient time for the compound to associate with the alpha-synuclein aggregates; and (iii) detecting the compound associated with the alpha-synuclein aggregates. The composition comprising the detectably labeled compound can be introduced to the subject by any of the routes of administration described below, such as, for example, orally or parenterally. The labeled compound can be introduced to a patient, and after a period of time sufficient for the compound to associate with alpha-synuclein aggregates, the labeled compound is non-invasively detected within the patient. Alternatively, the labeled compound can be introduced into a patient, sufficient time is allowed for the compound to associate with alpha-synuclein aggregates, and then a tissue sample is taken from the patient, and the labeled compound is detected in the tissue, separate from the patient. A tissue sample can also be removed from a patient prior to introducing the labeled compound into the tissue sample.After allowing a sufficient amount of time for the compound to bind to the alpha-synuclein aggregates, the compound can be detected. Imaging of alpha-synuclein aggregates can also be performed quantitatively so that the amount of alpha-synuclein aggregates can be determined. The present invention further relates to the compound of the present invention as well as to a LRcnn / zznz / E / YiAi prodrug, solvate or salt thereof for use in the treatment or prevention of a disease associated with alpha-synuclein aggregation. Additional embodiments include the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment or prevention of a disease associated with alpha-synuclein aggregation, as well as a method of treating or preventing a disease associated with alpha-synuclein aggregation comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. This includes the application of the compound as a pharmaceutical composition as described below. The term aggregation, according to the present invention, refers to the formation of oligomeric or multimeric alpha-synuclein complexes, which may be accompanied by the integration of additional biomolecules, such as carbohydrates, nucleic acids, lipids and / or metal ions, into the complexes. The term alpha-synuclein aggregation-associated disease, as used here, refers to those diseases characterized by the presence of alpha-synuclein aggregates. Alpha-synuclein aggregates may form deposits in specific tissues, most preferably in nervous tissue or brain tissue. The extent of the LRcnn / zznz / E / YiAi aggregates depend on the particular disease. According to the present invention, the term "pharmaceutical composition" refers to a composition for administration to a patient, preferably a mammal, more preferably a human patient. The pharmaceutical composition of the invention comprises the compounds mentioned above, and optionally additional molecules capable of altering the characteristics of the compounds of the invention, for example, stabilizing, modulating and / or activating their function. The composition may be in solid, liquid or gaseous form and may be, inter alia, in the form of (a) powder(s), (a) tablet(s), (a) solution(s) or (an) aerosol(s). The pharmaceutical composition of the present invention may, optionally and additionally, comprise a pharmaceutically acceptable carrier or excipient.Examples of suitable pharmaceutical carriers are well known in the art and include phosphate-buffered saline solutions, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, organic solvents including DMSO, etc. Compositions comprising such carriers may be formulated by well-known conventional methods. The pharmaceutical composition will be formulated and dosed in a manner consistent with good medical practices, taking into consideration the patient's clinical condition. LRcnn / zznz / E / YiAi individual, the site of administration of the pharmaceutical composition, the method of administration, the timing of administration, and other factors known to practitioners. The effective amount of the pharmaceutical composition for the purposes of the present invention is thus determined in accordance with such considerations. One skilled in the art knows that the effective amount of pharmaceutical compositions administered to an individual, among others, will depend on the nature of the compound. The pharmaceutical compositions of the invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, drops, or transdermal patches), orally, or as an oral or nasal spray. Preferably, they will be administered intravenously when used as a diagnostic PET tracer and orally when used to treat or prevent a disease. A pharmaceutically acceptable carrier means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or auxiliary formulation of any kind. The term parenteral as used herein refers to administration that includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and infusion injection and infusion. LRcnn / zznz / E / YiAi intra-articular. For therapeutic purposes, the pharmaceutical composition can also be suitably administered via sustained-release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., sheets or microcapsules. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gammaethyl-L-glutamate (Sidman, U. et al., Biopolimers 22:547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277 (1981), and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene vinyl acetate (R. Langer et al., Id.), or poly-D-(-)-3-hydroxybutyric acid (EP 133,988). Sustained-release pharmaceutical compositions may also include liposomally entrapped compounds.Liposomes containing the pharmaceutical composition are prepared by methods known per se: DE 32 18 121; Epstein et al., Proc. Nati. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Nati. Acad. Sci. (USA) 77:4030-4034 (1980); EP 52 322; EP 36 676; EP 88 046; EP 143 949; EP 142 641; Japanese Pat. Sol. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102324. Generally, liposomes are of a small unilamellar type (around 200 - 800 Angstroms) in which the lipid content is greater than about 30 mol of cholesterol, the ratio. LRcnn / zznz / E / YiAi selected being adjusted for optimal treatment. For parenteral administration, the pharmaceutical composition is generally formulated by mixing it to the desired degree of purity, in an injectable unit dosage form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, that is, one that is non-toxic to the recipients at the doses and concentrations employed and is compatible with other ingredients of the formulation. Generally, formulations are prepared by uniformly and intimately contacting the components of the pharmaceutical composition with liquid carriers or finely divided solid carriers, or both. Then, if necessary, the product is molded into the desired formulation. Preferably, the carrier is a parenteral vehicle, more preferably a solution that is isotonic with the recipient's blood. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as are liposomes. The suitable vehicle contains minor amounts of additives such as substances that enhance isotonicity and chemical stability.Such materials are non-toxic to the recipients at the doses and concentrations employed, and include lampones such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as. LRcnn / zznz / E / YiAi ascorbic acid; low molecular weight (poly)peptides (less than about ten residues), e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and / or nonionic surfactants such as polysorbates, poloxamers, or PEG. The components of the pharmaceutical composition to be used for therapeutic administration must be sterile. Sterility is easily achieved by filtration through sterile filtration membranes (e.g., 0.2 µm membranes). The therapeutic components of the pharmaceutical composition are generally placed in a container with a sterile access port, e.g., an intravenous solution bag or a vial with a stopper that can be pierced with a hypodermic injection needle. The components of the pharmaceutical composition will generally be stored in unit-dose or multi-dose containers, e.g., sealed ampoules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, LRcnn / zznz / E / YiAi 10 mL vials are filled with 5 mL of sterile filtered 1% (w / v) aqueous solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized compound(s) using bacteriostatic water for injection. The present invention further relates to a method of treating or preventing a disease associated with alpha-synuclein aggregation comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce the desired biological response. In the present invention, the desired biological response is the inhibition of alpha-synuclein aggregation and / or the reduction in the amount of alpha-synuclein aggregates present in the tissue. The present invention also relates to the use of a compound as previously defined for inhibiting alpha-synuclein aggregation in vitro or ex vivo. The disease associated with alpha-synuclein aggregation is not particularly limited and is generally selected from Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The following examples are intended to illustrate the invention. However, they should not be construed as limiting. LRcnn / zznz / E / YiAi Examples Example 1: Synthesis and essays Chemical synthesis processes The following methods are presented in detail regarding the preparation of compounds of the invention and illustrative examples. A compound of the invention can be prepared by one skilled in the art of organic synthesis from known or commercially available starting materials and reagents. All raw materials and solvents were commercial grade and used as received unless otherwise noted. Thin layer chromatography (TLC) was performed using Macherey-Nagel pre-coated sheets, ALUGRAM® SIL G / UV254 0.25 mm plates, with UV and / or carbonization detection with 10 wt% ethanolic phosphomolybdic acid reagent followed by heating at 200 °C. Flash column chromatography was performed using Merck 60 silica gel (0.063-0.100 mm). High-performance liquid chromatography (HPLC) was performed using a Waters HPLC system with a Waters 996 Photodiode Array Detector. All separations involved a mobile phase of 0.1% (v / v) trifluoroacetic acid (TFA) in water and 0.1% TFA in acetonitrile. HPLC was performed using a phase column LRcnn / zznz / E / YiAi reverse (RP) Eurospher RP 18, 100 Á, 5 pm, 250x4, 6 mm at a flow rate of 1 mL-min-1. Electrospray ionization mass spectrometry (ESI-MS) and liquid chromatography / mass spectrometry (LC / MS) analyses were obtained using a Waters Micromass ZQ 4000 mass spectrometer in conjunction with the Waters HPLC apparatus described previously. NMR spectra were recorded using a 400 MHz Bruker Avance spectrometer (Bruker AG, Rheinstetten, Germany) equipped with a z-TXI HCN gradient probe. All spectra were processed using TOPSPIN 3.1 (Bruker AG, Karlsruhe, Germany). 3H NMR chemical shifts (δ) are reported in parts per million (ppm) relative to CHCl3, DMSO-d5, and TFA-dl as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qi = quintet, dd = doublet of doublets, dt = doublet of triplets, b = broadened, m = multiplet), coupling constants (J, given in Hz), integration. Chemical shifts (δ) from 13C NMR are reported in parts per million (ppm) relative to CDCI3, DMSO-d6, and TFA-dl as internal standards.The following experiments were used to record the resonances of the compounds: 1H-1D, 13C-1D NMR spectra and 13C-APT (attached, the proton test spectrum with a single J evolution time of 1 / 145 s) were. LRcnn / zznz / E / YiAi processed such that quaternary and methylene groups have a positive sign and methyl and methine groups have a negative sign). To resolve the resonance overlap and recover undetectable resonances in the 3H and APT spectra, 2D-[13C,1H]-HSQC (heteronuclear single quantum coherence), 2D-[13C,3Η]-HMBC (heteronuclear multiple bond correlation), and 2D-NOESY were recorded for some compounds. Selected compounds (compound 1, compound 2, compound 12, compound 18) were tritiated for binding assays by RC TRITEC AG, Teufen, Switzerland using H / T exchange labeling with 99% tritium gas / Kerr catalyst. The compounds were delivered as ethanolic solutions with a packing of 185 MBq, concentration of 37 MBq / mL, and specific activity in the range of 1.1 to 2.3 GBq / mmol. Method A: synthesis of lH-pyrazoles Those skilled in the art will recognize that compound 11A and compound 11B depicted below are two tautomeric forms of the same compound. All tautomeric forms are considered to be part of this invention. As an illustration, all tautomeric forms of the pyrazole residue as depicted, for example, for compound 11 below are included in this invention. In a related manner, those skilled in the art will recognize that LRcnn / zznz / E / YiAi The names of the compounds contained herein are based on a naming convention where the tautomeric configuration is represented with respect to compound 11A, below. Thus, the 1,3-benzodioxole substituent is at the three-position. An alternative naming convention would be based on the tautomer of compound 11B, below, and in that convention the 1,3-benzodioxole substituent is at the five-position. LRcnn / zznz / E / YiAi AB Illustrative example: 2-[3-(1,3-Benzodioxol-5-yl)-1Hpyrazol-5-yl]-6-fluoropyridine compound 11 Sodium hydride (FW 24.00, 60% in oil, 3.9 mmol, 156 mg) was added to a solution of 1-(1,3-benzodioxol-5-yl)ethanone (FW 164.16, 492 mg, 3.00 mmol) and methyl 6-fluoropyridine-2-carboxylate (FW 155.13, 605 mg, 3.9 mmol) in DMSO (7.5 mL) and THF (1.9 mL), and the reaction mixture was stirred at 20 °C for 15 h. The reaction mixture was poured into 60 mL of ice and water containing AcOH (450 pL). The mixture was stirred for 1 h. The resulting precipitate was filtered, washed with water (10 mL), hexane : EtOH = 5:1 (10 mL), hexane (10 mL), and air dried to obtain a crude intermediate 1-(1,3-benzodioxol-5-yl) 3-(6-Fluoropyridin-2-yl)propan-1,3-dione (594 mg) was obtained as a yellow solid. To a suspension of this crude intermediate in EtOH (20 mL) was added hydrazine hydrate (146 pL, 150 mg, 3 mmol). The reaction mixture was stirred at 70 °C for 5 h, cooled, and concentrated in vacuo. The residue was suspended in MeOH (10 mL), boiled with stirring for 5 min, cooled, filtered, washed with MeOH (10 mL), and dried under high vacuum at 20 °C for 15 h to afford compound 11 as pure product (471 mg, 1.66 mmol, 55% over two steps) as a white solid. Method B: Synthesis of lH-pyrazoles Illustrative example: 4-[3-(1,3-Benzodioxol-5-yl)-1Hpyrazol-5-yl]-2-bromopyridine compound 9 LRcnn / zznz / E / YiAi A solution of potassium tert-butoxide (FW 112.21, 281 mg, 2.5 mmol) in dry THF (5 mL) was added under nitrogen to a stirred solution of 1-(1,3-benzodioxol-5-yl)ethanone (FW 164.16, 328 mg, 2 mmol) and methyl 2-bromopyridine-4-carboxylate (FW 216.03, 518 mg, 2.4 mmol) in dry THF (5 mL). The reaction mixture was stirred for 15 h at 20 °C. A 20 pL aliquot was sampled, quenched with 1M phosphate buffer pH 7, extracted with EtOAc, and analyzed by TLC. Complete ketone conversion was observed. The mixture was poured into 1M phosphate buffer pH 7 (15 mL) and ice-cold water (15 mL) and stirred at 0 °C for 30 min. The resulting yellow solid was filtered, washed with water (5 < 10 mL), and air dried to give 656 mg (1.88 mmol, 94%) of crude intermediate 1-(1,3-benzodioxol-5-yl)-3-(2-bromopyridin-4-yl)propan-1,3-dione which was used for the next step without purification.A mixture of this intermediate and hydrazine monohydrate (FW 50.06, d 1.03; 274 pL, 282 mg, 5.64 mmol) was stirred in THF (10 mL) at 50 °C for 15 h. The cooled mixture was poured into water (40 mL) and stirred at 0 °C for 30 min. The resulting precipitate was filtered, washed with water, and air-dried. The crude product was crystallized from n-BuOH (10 mL) and DMF (1 mL) to give compound 9 as pure product (458 mg, 1.33 mmol, 67% over 2 steps) as a white powder. Method C: Removal of the Boc protecting group Illustrative Example: 4-[5-(2-Bromopyridin-4-yl)-1H-pyrazol-3-yl]aniline compound 7 LRcnn / zznz / E / YiAi Trifluoroacetic acid (2 mL, 2.96 g, 26 mmol) was added to a suspension of crude tert-butyl {4-[5-(2-bromopyridin-4-yl)-lH-pyrazol-3-yl]phenyl}carbamate (FW 415.28, 865 mg, 2.08 mmol) prepared from tert-butyl N-(4-acetylphenyl)carbamate and methyl 2-bromopyridine-4-carboxylate according to Method B. The mixture was stirred at room temperature for 15 h and concentrated in vacuo. 1M phosphate buffer was added to pH 7 (20 mL), the resulting precipitate was filtered, washed with water (2^10 mL) and air dried to give 543 mg (1.72 mmol, 69% over 3 steps) of the desired product as a yellow-orange solid. Method D: Synthesis of lH-pyrazoles Illustrative example: 4-[3-(1,3-Benzodioxol-5-yl)-1Hpyrazol-5-yl]-2-fluoropyridine compound 12 F F LRcnn / zznz / E / YiAi iPr2NEt (1.79 mL, 1.33 g, 10.26 mmol) was added to a stirred mixture of 1-(1,3-benzodioxol-5-yl)ethanone (561 mg, 3.42 mmol) and MgBr2-Et2O (1.56 g, 6.04 mmol) in CH2Cl2 (35 mL). The resulting suspension was stirred for 5 min, and then pentafluorophenyl 2-fluoropyridine-4-carboxylate (1.37 g, 4.45 mmol) in CH2C12 (7 mL) was added dropwise. The reaction mixture was stirred for 48 h. Then 1N aqueous HCl (20 mL) was added and stirring was continued for 5 min. The aqueous layer was extracted with CH2CO2 (20 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was triturated with Et2O (10 mL) and filtered. The solid was washed with Et2O and air dried to give the crude product (1.14 g, orange solid). The crude product was recrystallized from EtOAc (8 mL) and hexane (4 mL) to afford intermediate 1 (1,3-benzodioxol-5-yl)-3-(2-fluoropyridin-4-yl)propan-1,3-dione (900 mg, 3.13 mmol, 92%) as an orange solid.This intermediate was suspended in THE (20 mL) and hydrazine monohydrate (292 pL, 300 mg, 6 mmol) was added. The reaction mixture was stirred at 70 °C for 5 h, cooled, and concentrated in vacuo. The residue was suspended in Et2O (10 mL), boiled with stirring for 5 min, cooled, filtered, washed with Et2O (2x10 mL), and dried under high vacuum at 20 °C for 15 h to afford the product, compound 12 (722 mg, 2.55 mmol, 76% over 2 steps) as a white solid. Method E: Synthesis of pentafluorophenyl esters Illustrative example: Pentafluorophenyl 2-fluoropyridine-4-carboxylate compound 59 LRcnn / zznz / E / YiAi DCC (FW 206.33, 2.27 g, 11 mmol) was added to a stirred suspension of 2-fluoropyridine-4-carboxylic acid (1.41 g, 10 mmol) and pentafluorophenol (1.84 g, 10 mmol) in 1,4-dioxane (40 mL). Stirring was continued for 15 h, at which time a colorless precipitate formed. The mixture was filtered through Celite® and evaporated to give a semi-solid. Silica gel chromatography gave the ester of compound 59 (2.21 g, 7.2 mmol, 72%) as a pure colorless oil. Method F: Synthesis of lH-pyrazoles Illustrative example: 6-[3-(3-Bromophenyl)-lH-pyrazol-5yl]-1,3-dioxolo[4,5-c]pyridine compound 20 OO Ba(OH>,. NaOH or 1 H,.0,.. NaOHo- Bí MéOH 25 Co- Br DMSO 25 CQ. oN O 'N2. Ν,Η / Η,Ο. PTSA'HiO.N toluene, reflux20 Step 1 To a suspension of 1,3-dioxolo[4,5-c]pyridine-6-carboxaldehyde (WO / 2019 / 208509) (35 mg, 0.23 immol) and l—(3 — bromophenyl)ethanone (46 mg, 0.23 mmol) in methane! (0.7 mL) was added Ba(OH)2*8H2O (5 mg) and NaOH (0.5 mg) and the resulting mixture was stirred at room temperature (RT) overnight. After evaporation of methanol in vacuo the residue was triturated in water (5 mL), the solid was collected by filtration, washed with cold methanol (0.5 mL) and dried to yield an intermediate compound 1-(3-bromophenyl)-3-([1,3]dioxolo[ 4,5c]pyridin-6-yl)prop-2-en-l-one (67 mg, 88%) as a white solid. Step 2 To a vigorously stirred suspension of l-(3-bromophenyl)-3([1,3]dioxolo[4,5-c]pyridin-6-yl)prop-2-en-l-one (67 mg, 0.2 mmol) in DMSO (0.8 mL) was added aqueous H2O2 solution (30%, 45 mg, 0.4 mmol) followed by dropwise addition of aqueous NaOH (10%, 16 pL, 0.04 mmol). The yellow mixture was stirred at RT for 1.5 h and poured into ice-cold phosphate buffer (20 mL, 0.1 M, pH 7). The oily precipitate was extracted with ethyl acetate (2*15 mL), the combined organic fractions were dried over Na2SO4, concentrated in vacuo, and the residue was resuspended in toluene (0.8 mL). The toluene suspension was treated with hydrazine hydrate (35 mg, 0.7 mmol) and PTSA hydrate (5 mg), and the mixture was stirred under reflux for 1.5 h. After cooling, phosphate buffer (0.3 M, 20 mL) was added, and the product was extracted with ethyl acetate (2*20 mL). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (15 g, salicylic acid gel 63-100, CHCls / MeOH = 100 / 1) to give a yellow solid which was washed with Et2O (1 mL) to afford compound 20 (25 mg, 36%) as a white solid. Method G: Synthesis of lH-pyrazoles Illustrative example: 4-[4-(1,3-Benzodioxol-5-yl)-1Himidazol-2-yl]-2-bromopyridine compound 48 LRcnn / zznz / E / YiAi A mixture of 1-(1,3-benzodioxol-5-yl)methanone (138 mg, 0.84 mmol), MgBr2-Et2O (542 mg, 2.1 mmol) in DCM (5 mL) was treated with DIPEA (323 mg, 426 pL, 2.5 mmol) and stirred at RT for 10 minutes. Then, the crude mixture of IH-benzotriazol-l-yl(3,6-dichloropyridazin-4yl)methanone, which was prepared separately by stirring 3,6-dichloropyridazine-4-carboxylic acid (203 mg, 1.05 mmol), benzotriazole (125 mg, 1.05 mmol), and DCC (216 mg, 1.05 mmol) in dry DCM (5 mL) at 25 °C for 3 h, was added dropwise over 5 minutes. The resulting mixture was stirred at 25 °C for 12 h, then treated with 0.5 M aqueous HCl (2 mL) and stirred for another 10 min at 25 °C. After the addition of water (20 mL), the mixture was extracted with DCM (2 x 15 mL). The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated in vacuo.The crude product was purified by column chromatography to afford the intermediate 1-(1,3-benzodioxol-5-yl)-3-(3,6-dichloropyridazin-4-ί1)propane-1,3-dion (190 mg, 67%) as an orange solid which was used in the next step without further purification. This intermediate was suspended in THE (4 mL) and hydrazine monohydrate (40 mg, 0.8 mmol) was added. The reaction mixture was stirred at 40 °C overnight, cooled and concentrated in vacuo. The crude product was purified by column chromatography (Salicylic acid 63-100, 20 g, chloroform / methanol = 100 / 1) to afford compound 48 (100 mg, 36% over two steps) as a light yellow solid. Method H: Synthesis of lH-imidazoles Illustrative example: 4-[4-(1,3-Benzodioxol-5-yl)-1HLRcnn / zznz / E / YiAi imidazole-2-yl]-2-bromopyridine compound 33 LRcnn / zznz / E / YiAi Step 1 A suspension of 1-(1,3-benzodioxol-5-yl)2-bromoethanone (729 mg, 3 mmol), 2-bromopyridine-4-carboxylic acid (606 mg, 3 mmol) and K2CO3 (414 mg, 3 mmol) in DMF (6 mL) was stirred at 55 to 60 °C for 6 h. After cooling, the mixture was poured into water (60 mL), stirred for 10 min and the resulting precipitate was collected by filtration, washed with water (20 mL) on the filter and dried to give an intermediate compound 2-(1,3-benzodioxol-5-yl)-2-oxoethyl 2-bromopyridine-4-carboxylate (899 mg, 87%) which was used in the next step without further purification. Step 2 A suspension of intermediate compound 2-(1,3-benzodioxol-5-yl)-2-oxoethyl 2-bromopyridine-4-carboxylate (364 mg, 1 mmol) and ACONH4 (924 mg, 12 mmol) in toluene (7 mL) was heated at 100 °C with intensive stirring for 4 h. After cooling, the reaction mixture was treated with phosphate buffer (50 mL, 0.25 M, pH 7) and extracted with ethyl acetate (2*50 mL). The combined organic fractions were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 63-100, 30 g, CHCl / MeOH = 100 / 1-100 / 3). The purified product was recrystallized from aqueous ethanol (90%) to provide compound 33 (140 mg, 41%) as a pale solid. Method I: Synthesis of 1H-1,2,4-triazoles Illustrative example 4-[3-(1,3-Benzodioxol-5-yl)-1H1,2,4-triazol-5-yl]-2-bromopyridine Compound 30 LRcnn / zznz / E / YiAi To a solution of t-BuOK (84 mg, 0.75 mmol) in n-BuOH (2 mL) was added benzo[1,3]dioxole-5-carboxamidine hydrochloride (100 mg, 0.5 mmol) at 0 °C and the mixture was stirred at RT for 20 min. After addition of 2-bromoisonicotinic acid hydrazide (108 mg, 0.5 mmol), a yellow suspension was stirred at 85 °C for 3 h. After cooling to room temperature, ethanol (4 mL) was added and CO2 was bubbled into the suspension for 5 min. After removal of solvents in vacuo the residue was triturated in water (10 mL), the resulting precipitate was collected by filtration, washed with water (5 mL) and dried to afford compound 30 (85 mg, 49%) as a gray solid. Method J: Synthesis of 1H-1,2,4-triazoles Illustrative example 4-[3-(2-Bromopyridin-4-yl)-1H43 1,2,4-triazol-5-yl]-N,N-dimethylaniline compound 44 LRcnn / zznz / E / YiAi A mixture of 2-bromoisonicotinic acid hydrazide (151 mg, 0.7 mmol), 4-(dimethylamino)benzonitrile (307 mg, 2.1 mmol) and K2CO3 (48 mg, 0.5 mmol) in n-BuOH (2 mL) was stirred at 145 °C for 8 h. The mixture was concentrated in vacuo and the crude product was purified by two column chromatographies (salt gel 63-100, 20 g, CHC13 / MeOH=100 / L) and (salt gel 63-100, 20 g, acetone / hexane = 1 / 5) to afford compound 44 (20 mg, 8%) as a beige solid. Method K: Synthesis of 4-chloro-lH-pyrazoles 4-[3-(1,3-Benzodioxol-5-yl)-4-chloro-lH-pyrazol-5-yl]-2bromopyridine, compound 28 N NH Br NCS,3g„3 N'NH Br70”C Ox -λ- / i' :¡ । v zzN► ( ΐ Γ xv zN O'A b·· ci A suspension of compound 9 (100 mg, 0.29 mmol) and NCS (80 mg, 0.6 mmol) in water (3 mL) was stirred at 70 °C for 16 h, TLC showed consumption of the starting material. After cooling to RT, the precipitate was collected by filtration, washed with water (2.5 mL) and recrystallized from ethanol (8 mL) to afford compound 28 (52 mg, 47%) as a gray solid. Method L: Synthesis of 1-[4-(4-R-piperazin-lyl)phenyl]ethanones Illustrative example 1-{4-[4-(2-Methoxyethyl)piperazin-1yl]phenyl}ethenone LRcnn / zznz / E / YiAi A mixture of 1-[4-(Piperazin-1-yl)phenyl]ethanone (408 mg, 2 mmol), l-bromo-2-methoxyethane (417 mg, 3 mmol), and CS2CO3 (1304 mg, 4 mmol) in DMF (5 mL) was stirred at 25 °C overnight. After evaporation of DMF in vacuo, the residue was partitioned between water (25 mL) and ethyl acetate (35 mL), the aqueous phase was extracted with ethyl acetate (25 mL), and the combined organic fractions were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified with column chromatography (30 g of silica gel 63-100, chloroform / MeOH = 100 / 2) to provide 1-{4-[4-(2-methoxyethyl)piperazin-1yl]phenyl}ethenone (525 mg, 99%) as a yellow solid. 2-Methoxyethyl 2,6-dibromopyridine-4-carboxylate and 2-methoxyethyl 2,6-dichloropyridine-4-carboxylate were prepared according to a published protocol (Journal of Medicinal Chemistry (2012), 55, 10564-10571). tert-Butyl (4-acetylphenyl)methylcarbamate, tert-butyl (4-acetylphenyl)-N-(2¾)methylcarbamate, tert-butyl (4-acetylphenyl)ethylcarbamate, and tert-butyl (4-acetylphenyl)(2fluoroethyl)carbamate were prepared according to a published protocol (Organic Letters (2020), 22, 5522-5527). 1-[4-(4-Fluoropiperidin-l-yl)phenyl]ethanone and l—[4—(3— fluoroazetidin-l-yl)phenyl]ethanone were prepared according to a published protocol (WO 2011071570 Al). Pentafluorophenyl 2-fluoropyridine-4-carboxylate and pentafluorophenyl 2-chloropyridine-4-carboxylate were prepared according to method E. l-{4-[4-(2Methoxyethyl)piperazin-l-yl]phenyl}ethenone and l—{4—[4—(2— fluoroethyl)piperazin-l-yl]phenyl}ethenone were prepared according to method L. Exemplary compounds of the present invention are shown in Tables 1 and 2. Table 1 shows the name, structure, IUPAC name, starting materials for preparation, method of synthesis, and chemical yield for the particular example compound. Table 2 shows the high performance liquid chromatography (HPLC) retention times, molecular weight found using low resolution mass spectrometry coupled with HPLC, and proton nuclear magnetic resonance (1H-NMR) for a particular exemplary compound. LRcnn / zznz / E / YiAi Table 1: i? LRcnn / zznz / E / YiAi No. Structure IUPAC Reagents Mtd. / Rend. (%) 1 N-NH Br NX^ / 4-[3-(4dimethylaminephenyl)-1Hpyrazol-5-yl]-2bromopyridine o II CO2Me I Br n A / 69 2 N-NH Br X N-^X^ H 4-[5-(2- bromopyridin-4yl)-1 H-pyrazol-3-yl-o Jl CC^Me xJU I Br Ν Boc B,C / 47 3 N-NH F 'νΌ^Ό 1 4-(5-(2fluoropyridine-4- 11)-1 H-pyrazol-3yl]- / V, / Vdimethylaniline O II CO2Pfp Λ IFND / 53 N-H NH> 5-[5-(2-bromopyridin-4-¡l)-1 / - / pyrazol-3-yl]N,Ndimethylpyridin-2amine O jl CO2Me ^n^n'^' JI Br NA / 40 5 N-NH beta 5-[5-(2-bromop¡r¡d¡n-4-¡l)-1Hp¡razol-3-¡l]A / ,A / -dimethylp¡rimidin-2amina OU CO2M© ,0 n I Br n A / 40 7 N-NH βΓ h2n Yn 4-[5-(2-bromop¡r¡d¡n-4-¡l)-1Hpirazol-3¡l]an¡l¡na 0 / 7- AZ xj H Br NB,C / 69 8 N-NH F Ν'Χ^Λ Br ζθ-τ-^ΑΑ-Ζ^ί oXZ^VN 4-(3-(1,3benzod¡oxol-5¡l)-1H-p¡razol-5- il]-2bromopyridine O CO2Me Λ Br^N^ B / 67 10 Λ N-NH Br XyaZZZX íXX^t; 2-[3-(1,3benzod¡oxol-5- ¡l)-1 / - / -pyrazol-5- 0 CO2Me ccXó B / 79 LRcnn / zznz / E / YiAi yl]-5- bromopyridine 11 z 7 T [ z- / °^o 2-[3-(1,3benzodioxol-5yl)-1 H-pyrazol-5yl]-6fluoropyridine O CO2Me CKi'XA / 55 12 4-[3-(1,3benzodioxol-5- yl]-fluoropyridine-25 o CO2Pfp 1C ,1' D / 76 13 N-NH F ÓyxAA / Ó 3-(3-(1,3benzodioxol-5- yl)-1 H-pyrazol-5- yl]-5- fluoropyridine o CO2Me A / 65 14 ~ N-NH Cl οΧν^Χν 4-[3-(1,3benzodioxol-5yl)-1 H-pyrazol-5yl]-2chloropyridine 0 CO2Pfp <°:Ο^ JÓ D / 60 15 N-NH .. Br ζ0^χ 1 / χΝχ 2-[3-(1,3-benzodioxol-5yl)-1 / 7-p¡razol-5yl]-6bromopyridine O CO2Me co 1,-1 A / 67 LRcnn / zznz / E / YiAi 16 N-NH Br 2-(3-(1,3benzodioxol-5- yl)-1 H-pyrazol-5- yl]-4- bromopyridine O CO2Me B / 80 17 N-NH Br ú'NV=d 4-{3-[4- (azetidin-1- yl)phenyl]-1-chromopyrizol-25-l 0 CO2Me A / 40 18 _ NN Br oXú^x>n 4-(3-(1,3benzodioxol-5yl)-1-methyl-1 / - / - pyrazol-5-yl]-2bromopyridine o CO2Me <οχ^ OW Br>VA / 34 19 _ XN-Br-NονΧΧΧ 4-(5-(1,3benzodioxol-5yl)-1-methyl-1Hpyrazol-3-yl]-2bromopyridine O CO2Me <°^Λ Br^N^ A / 23 20 N-NH Br <0£ru 6-[3-(3-bromophenyl)-1Hpyrazol-5-yl-dioxol-pyrazol-1,3,5¡[4] 0 F / 32 21 N-NH Br D3C / / / N nA < / H 4-[5-(2-bromopirid¡n-4-¡l)-1 / - / p¡razol-3-¡l]-W(2H3)metilanil¡na 0 CO2Me d3%jO χ] 1 BH N Boc B,C / 60 LRcnn / zznz / E / YiAi 22 N-NH C| H 4-(5-(2chloropyridine-4yl)-1 H-pyrazol-3yl]- / \ / -met¡lan¡l¡na 0 .....C . cr n Boc D, C / 32 23 N-NH H \ Br 4-[5-(2-bromopyr¡din-4-¡l)-1Hp¡razol-3-¡l]-Wethylaniline O i] CO2Me ,C a I Br^ N Boc B, C / 62 24 N-NH FH 4-[5-(2-fluoropyrid¡n-4-¡l)-1 / - / pyrazol-3-yl]-A / methylaniline 0 ..CA d IFN Boc D, C / 32 25 N-NH Br H 4-[5-(2-bromopind¡n-4-yl)-1Hpirazol-3-a-fluorine / 2-a-fluoline] 0 aY ó 1 Br N Boc A, C / 46 26 N-NH 'V Λ 1-{4-[5-(2bromopyridin-4yl)-1 H-pyrazol-3- yl]phenyl}-4- methylpiperazine / N0 Br NB / 63 27 N-NH 4-{4-[5-(2- fluoropyridin-4yl)-1 / 7-p¡razol-3yl]phenyl}morpholine 0 .........y- ” OFND / 79 LRcnn / zznz / E / YiAi 28 N-NH Br < / YA / oAA ci 4-[3-(1,3benzodioxol-5yl)-4-chloro-1 H- pyrazol-5-yl]-2bromopyridine N-NH Br Z° / X:.J'AA( < oAA K / 47 29 ΗΝ-λ zBr A Ya\ T\a N o^a / Λ 4-[2-(1,3benzodioxol-5- yl)-1 / 7-imidazol4-¡l]-2bromopyridine II Br (Ια \ ll J r Br 0 H / 26 30 N-NH Br \ ¡i A n Λ zzn οΆ 4-[3,3,3-benzol-15-yl) H-1,2,4- triazol-5-yl]-2- bromopyridine NH HCI 0 <1T 2 YY h O' / NXJ 1 / 49 31 ^NH Br -nAa no / 4-[2-(2-bromopyrid¡n-4-¡l)-1Himidazol-4-NH methylene] 'xAL'1'1* ΒΓ^ΑΥΟΗ i NAH / 25 32 NAH Br ο^ζχΑΑ / A < YY 'La ° A 6-[5-(2-bromopyrid¡n-4-¡l)-1Hpyrazol-3-yl]-1,3dioxolo CO[2-Pridine O

[25] .±1 D / 54 33 ^NH x A 4-[4-(1,3benzodioxol-5yl)-1 H-imidazol- 2-¡l]-2bromopyridine 0 0 < YY AA 0H xoaa Br nA H / 36 . LRcnn / zznz / E / YiAi 34 N-NH Br <1 θ ΙΨ 6-(5-(3- bromophenyl)-1Hpyrazol-3-yl]-1,3dioxolo[4,5b]pyrid¡na o CO2Pfp to ,ύ D / 33 35 ^nh Cl 2-chloro-4-{4-[4(pyrrolidin-1-yl)phenyl]-1Himidazol-2¡l}pyr¡d¡na 0 jO^Br CIX^f^0H \ / NN·^ H / 20 36 N-NH n HN 4-[5-(6-chloropyrazine-12-1) Hpyrazol-3-yl]- / \ / methylaniline 0 on co2h XX Λ cr Boc G, C / 21 37 N-NH Br / / 'λ N^Xí^ H Br 4-[5-(2,6- dibromopyridin4-¡l)-1 H-pyrazol3-¡l]-na C / V methylan, Boc G / 49 N'NH Br N'XX4 H ' 4-[5-(2-bromo- 6-methylp¡r¡din-4yl)-1 H-pyrazol-3yl]- / \ / -meth¡lan¡l¡na O :A and Boc G, 0 / 28 39 N-NH Cl v 7 -N XN^Cl-(4-W-Cl-6-H pyridazin-4-yl)- 1 H-pyrazol-3-yl]A / -met¡lan¡l¡na 0 ,ο· AG, C / 44 LRcnn / zznz / E / YiAi 40 n-nh m ci / / \L xN 'n XH 4-[5-(2-chloro- pyrim¡d¡n-4-yl)- 1 H-pyrazol-3-yl] / V-methylaniline 0 Cl Boc G, C / 10 41 n-nh m Cl _ / / x 4 NXH 4-[5-(6-chlorop¡ridin-2-yl)-1 / - / p¡razol-3-¡l]-Wmethylaniline •x / £ Boc G, C / 30 42 n-nh Cl I Cl 4-[5-(2,6- dichloropyridine-4yl)-1 H-pyrazol-3, / Vdimethylaniline] A / 34 43 N-NH Cl XN '\íZ'XZ^N -XN 4-[5-(6-chloro- pyrimidin-4-yl)- 1 H-pyrazol-3-yl]- N,N- dimethylaniline o ii CO2Pfp X íí Ó D / 9 44 TMX-NB1o N15 4-[3-(2-bromopyridine-4-¡l)-1 / - / 1,2,4-triazol-5yl]-A / ,A / dimethylaniline CN 0 j J ¿IJHJ / 8 45 k Z | o Z\ 4-[4-(2-bromopyrid¡n-4-¡l)-1Himidazol-2-yl]N,Ndimethylaniline 0 „ Br XN Χ'Χρ ΌΗ LX, JL Λ JY ^ Br IH / 14 LRcnn / zznz / E / YiAi 46 N'NH zBr Br 4-[3-(1,3benzod¡oxol-5- ¡l)-1 Hp¡razol-5yl]-2,6-dibromopyridine Φ so ώ Έ A / 14 47 N-NH Br ji ''X \\ z N uJ \ 4-[3,3-benzol-5-dio ¡l)-1 / - / -pyrazol-5- yl]-2-bromo-6methylpyridine O C02Me cr' A. A / 50 48 Cl n-nh tN <°2TT^^ 4-[5-(1,3- benzodioxol-5- ¡l)-1 / - / -pyrazol-3. 0 W cl G / 36 49 n-nh f / / S' HN 1-{4-[5-(2- fluoropyridin-4¡l)-1H-p¡razol-3¡I]phen¡l}p¡peraz¡na ü. Boc G, C / 10 50 o Vz €} I / τΑ z <y o 0 1-{4-[5-(2-clorop¡r¡din-4-¡l)-1Hp¡razol-3-¡l]fenil}-4-(2fluoroetil)piperazina o \ — / o Q 5 D / 29 LRcnn / zznz / E / YiAi 51 MeO^ 1-{4-[5-(2bromopyridin-4yl)-1 H-pyrazol-3- yl]phenyl}-4-(2methoxyethyl)- piperazine 0 H CO2Me Ó. ON Br MeO^ B / 70 52 pb^J 2-bromo-4-{3[4-(4-fluoropiperidin-1-yl)phenyl]-1Hpyrazol-5yl}pyr¡d¡na b o. \_ / o ) N> W ϕ B / 61 53 N-NH Cl N\^ / 4-(5-(2chloropyridine-4yl)-1 H-pyrazol-3¡Ι]-Λ / ,Λ / dimethylaniline 0 |i CO2Me I cr n B / 66 54 N'NH / AXAv / Ab 2-(3-(1,3benzodioxol-5- yl)-1 H-pyrazol-5- yl]-4- fluoropyridine 0 CO2Me CO'lÓ B / 18 55 N-NH Cl . / / NF 'Y 2-chloro-4-{3-[4(3fluoroazetidin1-¡l)phenyl]-1 / - / pyrazol-5-yl}pyridine CO2Me FB / 85 ? LRcnn / zznz / E / YiAi 56 H N-NH Br 4-[5-(5-bromopyrid¡n-3-¡l)-1Hp¡razol-3-yl]- / Vmethylaniline o .o.......,5 Boc B,C / 31 57 χνΆ? H N-NH Br κ / / JN^ 4-[5-(4-bromo¡ridin-2-yl)-1 / - / pyrazol-3-yl]- / \ / methylaniline O v 1.5 Boc B,C / 31 58 χνΆ? H 4-[5-(6-bromopind¡n-2-yl)-1Hpyrazol-3-¡l]-A / methylaniline O oil Boc B,C / 49 i? LRcnn / zznz / E / YiAi Table 2: Comp. no. Tiempo de retención del HPLC (min) Espec. de Masa [M+H]+ Datos de RMN-1H (ppm) δ (solvente, T) 1 4,8a 343,1 (100%), 345,2 (97%) 8,42 (d, J = 5,2 Hz, 1H), 8,05 (d, J = 1,4 Hz, 1H), 7,93 (d, J = 8,7 Hz, 2H), 7,87 (dd, J = 5,2,1,4 Hz, 1H), 7,66 (bd, J = 7,8 Hz, 2H), 7,51 (s, 1H), 3,11 (s, 6H) (DMSO-d6 + 1% DCI, 298K) 2 4,0a 329,1 (98%), 331,1 (100%) 8,41 (d, J = 5,2 Hz, 1H), 8,04 (d, J= 1,1 Hz, 1H), 7,93 (d, J = 8,6 Hz, 2H), 7,86 (dd, J = 5,2, 1,4 Hz, 1H), 7,57 (d, J = 8,6 Hz, 2H), 7,48 (s, 1H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 313K) 3 3,9a 283,2 (100%) 8,28 (d, J = 5,2 Hz, 1H), 7,93 (bd, J = 8,7 Hz, 2H), 7,78 (dt, J = 5,2, 1,6 Hz, 1H), 7,67 (bd, J = 8,7 Hz, 2H), 7,55 (s, 1H), 7,45 (s, 1H), 3,12 (s, 6H) (DMSO-d6 + 1% DCI, 313K) 4 3,6a 344,1 (98%), 346,1 (100%) 8,71 (dd, J= 6,2,1,1 Hz, 1H), 8,55 (s, 1H), 8,35 (m, 2H), 8,27 (d, J = 9,6 Hz, 1H), 7,41 (d, J = 1,1 Hz, 1H), 7,26 (d, J = 9,6 Hz, 1H), 3,38 (s, 6H) (TFA-d1, 313K) 5 9,2a 344,1 (100%), 346,1 (98%) 9,07 (s, 2H), 7,82 (s, 1H), 7,60 (d, J = 8,0 Hz, 2H), 7,29 (t, J = 8,0 Hz, 1H), 7,26 (s, 1H), 3,37 (s, 6H) (TFA-d1, 298K) 6 6,2a 345,1 (100%), 347,3 (98%) 8,70 (s, 2H), 8,46 (d, J = 6,4 Hz, 1H), 8,30 (s, 1H), 8,10 (dd, J = 6,4,1,6 Hz, 1H), 7,24 (s, 1H), 3,19 (s, 6H) (TFA-d1,298K) 7 3,3a 315,1 (98%), 317,1 (100%) 13,22 (bs, 1H), 8,39 (d, J = 5,2 Hz, 1H), 8,01 (d, J= 0,8 Hz, 1H), 7,83 (dd, J = 5,2,1,4 Hz, 1H), 7,47 (ddd, J = 7,5,1,7, 0,9 Hz, 2H), 7,19 (s, 1H), 6,64 (ddd, J = 7,5,1,7,0,9 Hz, 2H), 5,49 (bs, 2H) (DMSO-d6, 298K) 8 5,2a 285,2 (100%) 8,69 (s, 2H), 8,31 (dd,J= 6.4, 2.0 Hz, 1H), 7.94 (dd, J = 6.4,1.3 Hz, 1H), 7.76 (dd, J = 3.2,1.3 Hz, 1H), 7.22 (s, 1H),3.17(s, 6H,) do form 29-d1 10 / 1, the major form) 9 10.4a 344.1 (100%), 346.2 (98%) 8.41 (d, J = 5.1 Hz, 1H), 8.01 (d, J= 1.2 Hz, 1H), 7.84 (dd, 1.7 J= 1.5, Hz (H= 5.1), 1.7 Hz, 1H), 7.34 (s, 1H), 7.33 (dd, J= 8.1, 1.7 Hz, 1H), 7.00 (d, J= 8.1 Hz, 1H), 6.06 (s, 2H) (DMSO-d6 + 1% DKCI, 313% DKCI, LRcnn / zznz / E / YiAi 10 9,8a 344,1 (100%), 346,2 (98%) 9,05 (d, J = 1,2 Hz, 1H), 8,67 (d, J = 2,0 Hz, 1H), 8,46 (bs, 1H), 7,37 (d, J= 2,0 Hz, 1H), 7,32 (dd, J = 8,1,1,5 Hz, 1H), 7,27 (s, 1H), 6,99 (d, J = 8,1 Hz, 1H), 6,06 (s, 2H) (DMSO-d6 + 1% DCI, 313K) 11 8,7a 284,2 8,04 (q, J = 8,0 Hz, 1H), 7,89 (dd, J = 7,5, 2,4 Hz, 1H), 7,44 (d, J = 1,7 Hz, 1H), 7,38 (dd, J = 8,1,1,7 Hz, 1H), 7,22 (s, 1H), 7,09 (dd, J= 8,0, 2,4 Hz, 1H), 6,98 (d, J = 8,1 Hz, 1H), 6,05 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 12 8,4a 284,2 (100%) 8,26 (d, J = 5,2 Hz, 1H), 7,76 (dt, J = 5,2,1,7 Hz, 1H), 7,53 (s, 1H), 7,39 (d, J= 1,7 Hz, 1H), 7,37 (s, 1H), 7,33 (dd, J = 8,1,1,8 Hz, 1H), 7,01 (d, J = 8,1 Hz, 1H), 6,06 (s,2H) (DMSO-d6 + 1% DCI) 13 7,4a 284,2 8,98 (t, J = 1,7 Hz, 1H), 8,62 (d, J = 2,7 Hz, 1H), 8,21 (ddd, J= 8,1, 2,7,1,7 Hz, 1H), 7,37 (d, J= 1,7 Hz, 1H), 7,32 (dd, J= 8,1,1,8 Hz, 1H), 7,32 (s, 1H), 7,01 (d, J= 8,1 Hz, 1H), 6,07 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 14 9,8a 300,1 (100%) 8,43 (d, J = 5,2 Hz, 1H), 7,87 (s, 1H), 7,81 (dd,J = 5,2,1,4 Hz, 1H), 7,39 (d, J = 1,6 Hz, 1H), 7,34 (s, 1H), 7,34 (dd, J = 8,2,1,6 Hz, 1H), 7,00 (d, J = 8,1 Hz, 1H), 6,06 (s,2H) (DMSO-d6 + 1% DCI, 313K) 15 11,2a 344,2 (100%), 346,2 (97%) 7,97 (d, J = 7,8 Hz, 1H), 7,80 (t, J = 7,8 Hz, 1H), 7,55 (d, J = 7,8 Hz, 1H), 7,45 (d, J = 1,6 Hz, 1H), 7,39 (dd, J = 8,1,1,6 Hz, 1H), 7,20 (s, 1H), 6,97 (d, J = 8,1 Hz, 1H), 6,04 (s,2H) (DMSO-d6 + 1% DCI, 298K), LRcnn / zznz / E / YiAi 16 7,3a 344,0 (100%), 346,0 (97%) 9,47 (d, J = 1,7 Hz, 1H), 9,44 (d, J = 6,4 Hz, 1H), 9,04 (dd, J = 6,4,1,7 Hz, 1H), 8,21 (s, 1H), 8,12 (dd, J = 8,1,1,7 Hz, 1H), 8,04 (d, J = 1,7 Hz, 1H), 7,80 (d, J = 8,1 Hz, 1H), 6,86 (s, 2H) (TFA-d1, 298K) 17 7,5a 355,2 (100%), 357,2 (98%) 8,40 (d, J = 5,2 Hz, 1H), 8,02 (d, J = 1,4 Hz, 1H), 7,84 (dd, J = 5,2,1,4 Hz, 1H), 7,74 (d, J = 8,6 Hz, 2H), 7,31 (s, 1H), 7,11 (bd, J = 8,4 Hz, 2H), 3,76 (t, J = 7,0 Hz, 2H), 3,31 (t, J = 7,0 Hz, 2H), 2,10 (qi, J = 7,0 Hz, 2H) (DMSO-d6 + 1% DCI, 313K) 18 12,6a 358,2 (100%), 360,2 (98%) 8,51 (d, J = 5,1 Hz, 1H), 7,89 (d, J = 0,7 Hz, 1H), 7,69 (dd, J= 5,1,1,3 Hz, 1H), 7,35 (s, 1H), 7,33 (d, J = 9,3 Hz, 1H), 7,12 (s, 1H), 6,96 (d, J= 7,9 Hz, 1H), 6,05 (s, 2H), 3,97 (s, 3H) (DMSO-d6, 298K) 19 13,7a 358,1 (100%), 360,2 (98%) 8,36 (d, J = 5,0 Hz, 1H), 7,90 (s, 1H), 7,64 (d, J = 4,7 Hz, 1H), 6,92 (s, 1H), 6,91 (d, J = 8,9 Hz, 2H), 6,61 (s, 1H), 6,06 (s, 2H), 3,92 (s, 3H) (CDCh, 298K) 20 17,3b 344,2 (97%), 346,2 (100%) 8,37 (s, 1H), 8,07 (t, J = 1,8 Hz, 1H), 8,03 (s, 1H), 7,89-7,82 (m, 2H), 7,61 (ddd, J = 8,0,2,0, 0,9 Hz, 1H), 7,47 (t, J = 7,9 Hz, 1H), 6,52 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 21 17,7b 329,1 (98%), 331,1 (100%) 8,46 (d, J = 6,4 Hz, 1H), 8,31 (s, 1H), 8,12 (d, J = 6,4 Hz, 1H), 7,70 (d, J = 8,6 Hz, 2H), 7,43 (d, J = 8,6 Hz, 2H), 7,22 (s, 1H) (TFA-d1, 298K), LRcnn / zznz / E / YiAi 22 15,2b 285,2 (100%) 287,2 (34%) 8,46 (d, J = 5,2 Hz, 1H), 7,97 (d, J = 8,6 Hz, 2H), 7,94 (s, 1H), 7,85 (dd, J= 5,2,1,4 Hz, 1H), 7,64 (d, J = 8,6 Hz,2H), 7,56 (s, 1H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 23 15,9b 343,2 (99%) 345,2 (100%) 8,43 (d, J = 5,2 Hz, 1H), 8,07 (d, J = 1,2 Hz, 1H), 7,98 (d, J = 8,6 Hz, 2H), 7,88 (dd, J = 5,2,1,5 Hz, 1H), 7,69 (d, J = 8,6 Hz, 2H), 7,57 (s, 1H), 3,34 (q, J = 7,3 Hz, 2H), 1,27 (t J= 7,3 Hz, 3H) (DMSO-d6 + 1% DCI, 298K) 24 14,3b 269,2 (100%) 8,30 (d, J = 5,3 Hz, 1H), 7,98 (d, J = 8,6 Hz, 2H), 7,80 (m, 1H), 7,66 (d, J= 8,6 Hz, 2H), 7,59 (s, 1H), 7,54 (s, 1H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 25 21,2b 361,3 (100%) 363,2 (100%) 8,42 (d, J = 5,2 Hz, 1H), 8,07 (d, J = 0,8 Hz, 1H), 7,92-7,84 (m, 3H), 7,49 (s, 1H), 7,41 (d, J = 8,6 Hz, 2H), 4,73 (dt, J = 47,3, 4,8 Hz, 2H), 3,61 (dt, J = 27,2, 4,8 Hz, 2H) (DMSO-d6 + 1% DCI, 298K) 26 15,9b 398,3 (99%) 400,4 (100%) 8,40 (d, J = 5,2 Hz, 1H), 8,05 (s, 1H), 7,87 (d, J = 5,2 Hz, 1H), 7,74 (d, J= 8,7 Hz,2H), 7,39 (s, 1H), 7,11 (d, J= 8,7 Hz, 2H), 3,97-3,87 (m, 2H), 3,52-3,43 (m, 2H), 3,27-3,10 (m, 4H), 2,80 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 27 19,5b 325,3 (100%) 8,28 (d, J = 5,3 Hz, 1H), 7,88 (d, J = 8,8 Hz, 2H), 7,82-7,77 (m, 1H), 7,60-7,52 (m, 3H), 7,47 (s, 1H), 3,44 (m, 4H), 3,96 (m, 4H) (DMSO-d6 + 1% DCI, 298K), LRcnn / zznz / E / YiAi 28 25,8b 378,0 (76%) 380,1 (100%) 8,49 (dd, J = 5,3, 0,6 Hz, 1H), 8,05 (dd, J = 1,5, 0,6 Hz, 1H), 7,93 (dd, J= 5,3,1,4 Hz, 1H), 7,33-7,28 (m, 2H), 7,08 (d, J = 8,6 Hz, 1H), 6,10 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 29 15,0b 344,1 (100%) 346,1 (98%) 8,52 (s, 1H), 8,51 (d, J = 5,3 Hz, 1H), 8,18 (s, 1H), 7,92 (d, J = 5,2,1,3 Hz, 1H), 7,68-7,60 (m, 2H), 7,21 (d, J= 8,1 Hz, 1H), 6,19 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 30 22,6b 345,2 (100%) 347,2 (93%) 8,50 (d, J = 5,1 Hz, 1H), 8,14 (s, 1H), 8,01 (d, J = 5,1 Hz, 1H), 7,66 (dd, J = 8,1,1,6 Hz, 1H), 7,61 (d, J = 1,6 Hz, 1H), 7,08 (d, J = 8,1 Hz, 1H), 6,12 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 31 13,3b 343,2 (100%) 345,1 (98%) 8,59 (dd, J = 5,2, 0,6 Hz, 1H), 8,28 (dd, J = 1,6, 0,6 Hz, 1H), 8,07 (s, 1H), 8,03 (dd, J= 5,3,1,6 Hz, 1H), 7,75 (d, J = 8,9 Hz, 2H), 6,94 (d, J = 8,9 Hz, 2H), 3,00 (s, 6H) (DMSO-d6 + 1% TFA-d1,298K) 32 20,4b 345,1 (99%) 347,1 (100%) 8,43 (d, J = 5,3 Hz, 1H), 8,12 (d, J = 1,9 Hz, 1H), 8,03 (s, 1H), 7,84 (dd, J= 5,2,1,4 Hz, 1H), 7,66 (d, J = 1,8 Hz, 1H), 7,49 (s, 1H), 6,20 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 33 16,2b 344,2 (100%) 346,2 (96%) 8,60 (dd, J = 5,2, 0,6 Hz, 1H), 8,27 (dd, J = 1,5, 0,6 Hz, 1H), 8,12 (s, 1H), 8,02 (dd, J= 5,2,1,5 Hz, 1H), 7,46 (d, J = 1,8 Hz, 1H), 7,41 (dd, J= 8,1,1,8 Hz, 1H), 7,06 (d, J = 8,1 Hz, 1H), 6,09 (s, 2H) (DMSO-d6 + 1%TFA-d1,298K), LRcnn / zznz / E / YiAi 34 24,1b 344,1 (96%) 346,1 (100%) 8,12 (d, J = 1,8 Hz, 1H), 8,03 (t, J= 1,8 Hz, 1H), 7,83 (d, J = 7,7 Hz, 1H), 7,66 (d, J = 1,8 Hz, 1H), 7,53 (m, 1H), 7,42 (t, J = 7,9 Hz, 1H), 7,30 (s, 1H), 6,19 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 35 17,8b 325,3 (100%) 327,4 (35%) 8,71 (dd, J= 5,3, 0,6 Hz, 1H), 8,21 (dd, J= 1,6, 0,6 Hz, 1H), 8,18 (s, 1H), 8,04 (dd, J= 5,3,1,6 Hz, 1H), 7,71 (d, J = 8,9 Hz, 2H), 6,69 (d, J = 8,9 Hz, 2H), 3,30 (m,4H), 1,98 (m,4H) (DMSO-d6 + 1 % TFA-d1, 298K) 36 15,0b 286,2 (100%) 288,2 (33%) 9,20 (s, 1H), 8,72 (s, 1H), 8,04 (d, J = 8,7 Hz, 2H), 7,64 (d, J = 8,7 Hz, 2H), 7,49 (s, 1H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 37 19,3b 407,1 (52%) 409,1 (100%) 411,1 (50%) 8,13 (s, 2H), 7,96 (d, J = 8,6 Hz, 2H), 7,66 (d, J = 8,6 Hz, 2H), 7,65 (s, 1H), 2,91 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 38 16,3b 343,2 (100%) 345,1 (98%) 7,94 (d, J = 8,7 Hz, 2H), 7,86 (s, 1H), 7,76 (s, 1H), 7,58 (d, J = 8,7 Hz, 2H), 7,50 (s, 1H), 2,91 (s, 3H), 2,49 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 39 13,4b 286,2 (100%) 288,2 (34%) 9,71 (d, J = 1,8 Hz, 1H), 8,26 (d, J = 1,8 Hz, 1H), 7,94 (d, J = 8,6 Hz, 2H), 7,67 (s, 1H), 7,61 (d, J = 8,6 Hz, 2H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 40 14,2b 286,2 (100%) 288,2 (30%) 8,80 (d, J = 5,2 Hz, 1H), 8,09-8,01 (m, 3H), 7,64 (d, J = 8,6 Hz, 2H), 7,54 (s, 1H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 298K), LRcnn / zznz / E / YiAi 41 15,2b 285,2 (100%) 287,2 (34%) 8,02 (d, J = 8,7 Hz, 2H), 7,99-7,92 (m, 2H), 7,59 (d, J = 8,7 Hz, 2H), 7,46 (dd, J= 6,7, 2,0 Hz, 1H), 7,37 (s, 1H), 2,92 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 42 19,6b 333,1 (100%) 334,1 (61%) 335,1 (61%) 8,01-7,96 (m, 4H), 7,89 (d, J= 8,8 Hz, 2H), 7,67 (s, 1H), 3,14 (s, 6H) (DMSO-d6 + 1% DCI, 298K) 43 15,4b 300,2 (100%) 302,2 (33%) 9,02 (s, 1H), 8,05 (s, 1H), 7,65 (d, J = 8,6 Hz, 2H), 7,24 (s, 1H), 6,78 (d, J = 8,6 Hz, 2H), 2,94 (s, 6H) (DMSO-d6 + 2% ácido acético-d4, 298K) 44 19,2b 344,2 (100%) 346,3 (100%) 8,53 (d, J = 5,1 Hz, 1H), 8,27 (d, J = 8,8 Hz, 2H), 8,24 (s, 1H), 8,08 (dd, J= 5,1,1,3 Hz, 1H), 7,76 (d, J = 8,6 Hz, 2H), 3,13 (s, 6H) (DMSO-d6 + 1% DCI, 298K) 45 16,9b 343,2 (100%) 345,2 (98%) 8,50 (d, J = 5,3 Hz, 1H), 8,48 (s, 1H), 8,20 (d, J = 1,0 Hz, 1H), 7,97-7,91 (m, 3H), 6,89 (d, J = 9,1 Hz, 2H), 3,04 (s, 6H) (DMSO-d6 + 1 % TFA-d1,298K) 46 26,5b 422,1 (52%) 424,1 (100%) 426,1 (49%) 8,08 (s, 2H), 7,49 (s, 1H), 7,38 (d, J = 1,6 Hz, 1H), 7,33 (dd,J= 8,1,1,6 Hz, 1H), 7,03 (d, J= 8,1 Hz, 1H), 6,07 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 47 24,2b 358,1 (100%) 360,1 (98%) 7,84 (s, 1H), 7,75 (s, 1H), 7,39 (d, J = 1,7 Hz, 1H), 7,37 (s, 1H), 7,33 (dd, J = 8,1,1,7 Hz, 1H), 7,01 (d, J = 8,1 Hz, 1H), 6,06 (s, 2H), 2,49 (s, 3H) (DMSO-d6 + 1% DCI, 298K), LRcnn / zznz / E / YiAi 48 22,5b 335,1 (100%) 337,2 (66%) 8,31 (s, 1H), 7,48-7,45 (m, 2H), 7,38 (dd, J = 8,1,1,8 Hz, 1H), 7,03 (d, J= 8,1 Hz, 1H), 6,08 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 49 14,9b 324,3 (100%) 9,02-8,84 (m, 1H), 8,28 (d, J= 5,2 Hz, 1H), 7,78 (d, J = 5,1 Hz, 1H), 7,71 (d, J= 8,7 Hz, 2H), 7,54 (s, 1H), 7,34 (s, 1H), 7,11 (d, J = 8,7 Hz, 2H), 3,48-3,40 (m, 4H), 3,30-3,21 (m, 4H) (DMSO-d6 + 1 % TFA-d1,298K) 50 16,3b 386,3 (100%) 388,3 (37%) 8,43 (d, J = 5,2 Hz, 1H), 7,91 (s, 1H), 7,84 (dd, J = 5,2,1,3 Hz, 1H), 7,74 (d, J = 8,8 Hz, 2H), 7,38 (s, 1H), 7,11 (d, J = 8,8 Hz, 2H), 4,96 (dt, J = 47,2,4,3 Hz, 2H), 4,00-3,88 (m, 2H), 3,67-3,50 (m, 4H), 3,343,20 (m, 4H) (DMSO-d6 + 1% DCI, 298K) 51 17,1b 442,4 (93%) 444,2 (100%) 8,41 (d, J = 5,2 Hz, 1H), 8,04 (s, 1H), 7,87 (dd, J = 5,2,1,2 Hz, 1H), 7,73 (d, J = 8,8 Hz, 2H), 7,38 (s, 1H), 7,11 (d, J = 8,8 Hz, 2H), 3,96-3,87 (m, 2H), 3,78 (t, J = 4,6 Hz, 2H), 3,61-3,52 (m, 2H), 3,36 (t, J = 4,6 Hz, 2H), 3,31 (s, 3H), 3,29-3,15 (m, 4H) (DMSO-d6 + 1% DCI,298K) 52 19,1b 401,2 (100%) 403,2 (98%) 8,43 (d, J = 5,2 Hz, 1H), 8,07 (s, 1H), 8,00 (s, 4H), 7,88 (dd, J = 5,3,1,3 Hz, 1H), 7,60 (s, 1H), 5,17-4,96 (m, 1H), 3,79-3,53 (m, 4H), 2,57-2,36 (m, 2H), 2,342,17 (m,2H) (DMSO-d6 + 1% DCI, 298K) 53 4,7a 299,3 (100%) 8,46 (dd, J = 5,2, 0,2 Hz, 1H), 8,00 (ddd, J = 8,8, 2,2, 2,2 Hz, 2H), 7,94 (d, J = 0,9 Hz, 1H), 7,89-7,79 (m, 3H), 7,58 (s, 1H), 3,14 (s, 6H) (DMSO-d6 + 1% DCI, 298K), LRcnn / zznz / E / YiAi 54 17,0b 284,2 (100%) 8,79 (t, J = 6,5 Hz, 1H), 8,19 (dd, J = 9,3,2,5 Hz, 1H), 7,67 (ddd, J= 7,8, 6,5, 2,5, Hz, 1H), 7,60 (s, 1H), 7,42 (d, J = 1,8 Hz, 1H), 7,35 (dd, J = 8,1,1,8 Hz, 1H), 7,04 (d, J = 8,1 Hz, 1H), 6,08 (s, 2H) (DMSO-d6 + 1% DCI, 298K) 55 12,2a 329,2 (100%) 331,1 (33%) 8,42 (d, J = 5,2 Hz, 1H), 7,88 (s, 1H), 7,82 (dd, J = 5,2,1,4, Hz, 1H), 7,64 (ddd, J= 8,6, 2,3,2,3 Hz, 2H), 7,30 (bs, 1H), 6,58 (ddd, J= 8,6, 2,3, 2,3 Hz, 2H), 5,58 and 5,43 (dtt, J= 57,6, 5,8, 3,1 Hz, 2x0,5 H), 4,20 (dddd, J = 20,7, 9,4, 5,7,1,0 Hz, 2H), 3,93 (dddd, J = 24,3, 9,4,3,1,1,2 Hz, 2H) (DMSO-d6, 298K) 56 15,3b 329,2 (100%) 331,1 (98%) 9,08 (d, J = 1,8 Hz, 1H), 8,71 (d, J = 2,2 Hz, 1H), 8,53 (t, J = 2,0 Hz, 1H), 7,91 (bd, J = 8,6 Hz, 2H), 7,50 (bd, J = 8,6 Hz, 2H), 7,44 (s, 1H), 2,90 (s, 3H) (DMSO-d6 + 1% DCI, 298K) 57 14,6b 329,2 (100%) 331,1 (98%) 8,48 (d, J = 5,3 Hz, 1H), 8,15 (d, J = 1,8 Hz, 1H), 7,57 (d, J = 8,6 Hz, 2H), 7,56 (m, 1H), 7,08 (s, 1H), 6,60 (bd, J= 8,6 Hz, 2H), 2,71 (s,3H) (DMSO-d6, 298K) 58 16.4b 329.2 (100%) 331.1 (98%) 8.02-7.98 (m, 3H), 7.83 (t, J= 7.8 Hz, 1H), 7.60-7.57 (m,3H), 7.35 (s, 1H), 2.92 (s, 3H) (DMSO-d6 + 1% DCI, 298K), gradient 50% CH3CN / 50% H2O —> 100% CH3CN in 30 min gradient 5% CH3CN / 100% H2O —> 100% CH3CN in 30 min Example 2: Binding studies with alpha-synuclein, tau, and Abeta aggregates To analyze binding affinity and selectivity LRcnn / zznz / E / YiAi target compounds, two types of in vitro fibril binding assays were used: a saturation assay and a competition assay. 1) Preparation of fibrils Alpha-synuclein and tau46 were purified from E. coli according to established protocols (Nuscher B, et al., J. Biol. Chem., 2004;279(21):21966-75), and αβι-42 was obtained from rPeptide, Watkinsville, GA, USA. Fibrils were prepared by aggregation of recombinant protein under constant stirring. In detail, 70 μM of alpha-synuclein mixed with 100 mM NaCl in 50 mM Tris, pH 7.0 + 0.02% NaN3 was incubated at 1,400 rpm, 37°C for 96 h. 10 μΜ of tau46 was incubated with 0.03 mg / mL heparin in 50 mM Tris, pH = 7.0 at 1,000 rpm, 37°C for 72 h. Αβι-42 was dissolved in 20 mM NaPi, pH = 8.0 + 0.2 mM EDTA + 0.02% NaN3 (Deeg AA, et al., Biochim. Biophys. Acta, 2015; 1850 (9): 1884-90; Goedert M, et al. Nature, 1996; 383(6600): 550-3). 2a) Saturation binding test Sonicated SYN (0.04 μM) or tau46 (0.4 μM) or Aβι-42 (6 μM) fibrils diluted in PBS were incubated with decreasing concentrations of [3H]-labeled compound (48 nM or 24 nM - 23 pM) in 50 mM Tris-base, 10% ethanol, 0.05% Tween20, pH 7.4. To determine non-specific binding, the respective labeled compound (400 nM) was added to a duplicate set of binding reactions. LRcnn / zznz / E / YiAi The assay plates were incubated under shaking at 37°C for 2 h, covered with a plastic film (resealable tape, PerkinElmer, Waltham, MA, USA). Before harvesting, a filter (Printed filtermat B, PerkinElmer, Waltham, MA, USA) was incubated with 5 mg / mL polyethyleneimine solution (PEI, Poly(ethyleneimine), Sigma Aldrich Chemie GmbH, Taufkirchen, Germany) at 4°C for 30 min. After incubation, bound and free ligands were separated by vacuum filtration using a harvester (Filtermate harvester, PerkinElmer, Waltham, MA, USA). The filter was washed three times with Lampon cooled to 4°C and subsequently dried in a microwave oven for 2 min at medium power. Fusible scintillation films (MeltiLex™ B / HS, PerkinElmer, Waltham, MA, USA) were cast onto the filter using a hot plate at 120°C.After solidification at room temperature, the filter was sealed in a plastic bag (MicroBeta® sample bag, PerkinElmer, Waltham, MA, USA). Tritium accumulation was immediately counted in a liquid scintillation counter (Wallac MicroBeta® TriLux, 1450 LSC & Luminescence Counter, PerkinElmer, Waltham, MA, USA). Radioactivity was plotted against increasing tritium-labeled compound or cold compound concentrations. Data points were fitted using nonlinear regression analysis in GraphPad Prism (GraphPad Software, Inc., version 7.03, La Jolla, CA, USA). LRcnn / zznz / E / YiAi 2b) Modified saturation binding assay For the binding saturation assay, a fixed concentration of sonicated recombinant human αSYN (15 nM / well) or tau46 (250 nM / well) or αβι-42 (1 μM / well) fibrils diluted in phosphate-buffered saline (PBS) was incubated in low-binding plates (96-well assay microplate, Ratiolab GmbH, Dreieich, Germany) with compound 1-[3H] or compound 2-[3H] at increasing concentrations (from 0.05 nM to 12 nM / 24 nM) in 30 mM Tris HCl, 10% ethanol, 0.05% Tween20, pH 7.4 (hereafter referred to as incubation buffer) in a total volume of 200 µl. pL / well. Nonspecific radiotracer binding was determined by coincubation with 400 nM of unlabeled compound 1 or compound 2. Optimal fibril concentrations were determined using a concentration determination assay. Plates covered with removable seal tape (PerkinElmer) were incubated on a shaker (MaxQ™ 6000, orbit diameter 1.9 cm, Thermo Fisher Scientific Inc., Marietta, OH, USA) at 45 rpm for two hours at 37 °C. After incubation, bound and free radioligands were separated by vacuum filtration through a glass fiber filter B (PerkinElmer) using a filter harvester (PerkinElmer). To harvest plaques containing αSYN and αβι-42 fibrils, the filter was further incubated with 5 mg / mL polyethyleneimine for 30 minutes at 4 °C before filtration. LRcnn / zznz / E / YiAi harvest. The filter was washed three times with 100 mL (approximately 1 mL / well) of ice-cold incubation buffer and subsequently dried in a microwave oven for 2.5 minutes at medium power. Meltable scintillation wafers (MeltiLex™ B / HS, PerkinElmer) were fused to the filter using a hot plate at 120 °C. After curing at room temperature, the filter was sealed in a plastic sample bag (PerkinElmer). Tritium accumulation was immediately counted in a Wallac MicroBeta® TriLux liquid scintillation counter (PerkinElmer). Radioactivity was plotted against the concentration of the 3H-labeled compound. Data points were fitted using nonlinear regression analysis in GraphPad Prism (GraphPad Software, Inc., version 7.03, La Jolla (CA), USA). 3a) Binding competition test A fixed combination of sonicated recombinant human aSYN (200 nM / well) or tau46 (208 nM / well) fibrils diluted in phosphate-buffered saline (PBS) was incubated in low binding plates (96-well microplate assay, Ratiolab GmbH, Dreieich, Germany) together with 1 nM of compound 1-[3H] and serial 1:4 dilutions of the cold compound of interest starting from 1 μM diluted in 50 mM Tris-base, 10% EtOH, 0.05% Tween20, pH 7.4. For K± value calculations, the Kd value of compound 1 towards human aSYN fibrils Sonicated recombinant LRcnn / zznz / E / YiAi was adjusted to 3 nM. The assay plates were incubated under shaking at 37°C for 2 h covered with plastic wrap (resealable tape, PerkinElmer, Waltham, MA, USA). Before harvesting, a filter (Printed filtermat B, PerkinElmer, Waltham, MA, USA) was incubated with 5 mg / mL polyethyleneimine solution (PEI, Poly(ethyleneimine), Sigma Aldrich Chemie GmbH, Taufkirchen, Germany) at 4°C for 30 min. After incubation, free and bound ligands were separated by vacuum filtration using a harvester (Filtermate harvester, PerkinElmer, Waltham, MA, USA). The filter was washed three times with buffer cooled to 4°C and subsequently dried in a microwave for 2 min at medium power. The filter was sealed in a plastic bag (MicroBeta® sample bag, PerkinElmer, Waltham, MA, USA) together with the added scintillator (BETAPLATE SCINT, PerkinElmer, Waltham, MA, USA).Tritium accumulation was immediately counted in a liquid scintillation counter (Wallac MicroBeta® TriLux, 1450 LSC & Luminescence Counter, PerkinElmer, Waltham, MA, USA). Radioactivity was plotted against tritium-labeled compound or cold compound concentrations. Data points were fitted using nonlinear regression analysis in GraphPad Prism (GraphPad Software, Inc., version 7.03, La Jolla, CA, USA). LRcnn / zznz / E / YiAi 3b) Modified binding competition assay For competition binding assays, a fixed concentration of recombinant «SYN» fibrils (sonicated, 15 nM / well) was incubated with 1 nM of compound 1-[3H] or compound 2-[3H] and decreasing concentrations of a serial dilution of an unlabeled competitor (1:4 or 1:3.5 or 1:3 serial dilution as long as the concentration ranges of the unlabeled competitor 1 μM-1 pM or 1 μM-4 nM or 1 μM-17 pM, respectively) in 30 mM Tris-HCl, 10% ethanol, 0.05% Tween20, pH 7.4 in a total volume of 200 pL / well. The plates were incubated for 4.5 hours at RT covered by removable sealing tape (PerkinElmer, Waltham, MA, USA). Filtration and reading were performed as described for the saturation binding assays. Binding of the [3H]-labeled ligand [in CMP] was plotted against increasing concentrations of competitor and data points were fitted using nonlinear regression analysis to calculate IC50 and Ki values ​​(GraphPad Software, Inc., version 7.03, La Jolla (CA) , USA). In the competition binding assay with sonicated recombinant SYN fibrils, calculation of Ki values ​​was performed based on Kd values ​​of 0.6 nM and 0.2 nM for compound 1 and compound 2, respectively. The fibril binding saturation assay provides Kd values. This assay is performed with directly radioactively labeled compounds (e.g., labeled LRcnn / zznz / E / YiAi con3H). Kd values ​​are shown in Tables 3a and 3b. Binding saturation assays were performed using fibrillar aggregate structures produced from recombinant human alpha-synuclein, αβι-42, and tau46 as targets, respectively. The results show a high affinity for alpha-synuclein fibrils. Compound 1, compound 2, and compound 12 showed very high affinity with Kd values ​​less than 10 nM. Compound 1 and compound 2 were also tested for binding to Abeta and tau46 fibrils and showed good to excellent selectivity, demonstrating the suitability of these compounds for the diagnostic detection of alpha-synuclein aggregates. Table 3a: Saturation test according to protocol 2a i? LRcnn / zznz / E / YiAi Comp. No . Kd [nM] for alpha-synuclein aggregates Kd [nM] for tau4 aggregates 6 Kd [nM] for Abeta aggregates 1 < 2 > 5 > 100 2 < 1 > 15 > 100 12 7 N / AN / A 18 126 N / AN / A Table 3b: Saturation test according to the LRcnn / zznz / E / YiAi protocol 2b Comp. no. Kd [nM] for alpha-synuclein aggregates 1 0.6 2 0.2 The fibril competition assay provides Ki values. Ki is a quantitative measurement that represents the concentration of the non-radioactive test compound (competing ligand) required to replace 50% of a reference compound, in this case compound 1-[3H] (1 nM) or compound 2-[3H] (1 nM), that binds to the target structures, in our case recombinant alpha-synuclein and tau46 fibrils. This assay is suitable for the detection of non-radioactive ligands. The Ki values ​​obtained for the tested compounds are shown in Tables 4a, 4b and 5. Table 4a: Competition assay according to protocol 3a (reference ligand compound 1-[3H] (InM)) comp. no. Experiment A Ki (nM) alpha-synuclein (fibrils) Experiment B Ki (nM) alpha-synuclein (sonicated fibrils) Ki (nM) tau46 (fibrils) 2 N / A < 2 9 3 < 0.1 3 4 4 8 13 31 5 27 >60 N / A 6 24 >300 N / A 8 43 N / AN / A 9 2 < 4 28 10 34 25 >100 12 47 9 na 12* 42 N / AN / A 17 N / A 2 1 * repeat LRcnn / zznz / E / YiAi Table 4b: Competition assay according to protocol 3b (reference ligand compound 1-[3H] (InM)) comp. no. Ki (nM) alpha-synuclein (sonicated fibrils) 2 0.3 1 0.4 9 2.1 56 2.6 20 3.1 57 3.3 58 5.1 16 5.2 15 6.7 Table 5: Competition assay according to protocol 3b (reference ligand compound 2-[3H] (InM)) comp. no. Structure Ki (nM) alpha-synuclein (sonicated fibrils) Compounds with non-cyclic amine groups 1 N-NH Br X ZN / 0.1 45 Un / 0.2 21 N-NH βΓ °3^. NH 0, 3 22 N-NH C| ^nXG^GXn H 0, 3 43 N-NH C| axací / 0, 5 23 N-NH Br H 0, 5 44 N-NH Br \XGnGXn / 0, 6 25 N-NH Br ΑΌΥ H 0, 7 4 N-NH Br NN> n-nh 24 N-NJ H 5 x_XY N'NY- 1 0, 8 3 N-NH F axYgxn / 0, 95 57 N-NH Br Ν'-γΥ nG H 2,8 56 N-NH Br nXGGX 3, 3 40 r^X'lX NY H 3, 9 NH Q|| \ XY^YTY <_Í-NHN 4,2 58 N-NH Rr J / λ N^ / Br ^XGGX H 5 6 N-NH Br >λΧ^^Χν 8, 9 LRcnn / zznz / E / YiAi 8 N-NH f NN> 9, 9 36 N-NH Cl yyyj H 12 5 N-NH Br 13 31 N Vn / 13 41 N^CI yyj H 14 37 N-NH Br H [Br H \ Br 16 42 N-NH i NyH] / \ \ Cl 113 Compounds with cyclic amine groups 17 N-NH Br yy^^yyN Λν^ 0, 8 50 n-nh ^ci nOy? 0, 9 26 N-NH Br yyv· 1 55 N-NH Cl 1,2 27 N-NH f ycyy 1.3 51 N-NH Br r^Nxyy? 0-^-N^J 2,7 52 N-NH Br í N-^í^ 3, 1 LRcnn / zznz / E / YiAi 49 N-NH F HN^J 61 35 r-NH__Cl / ΠγΝ t / N 168 Compounds with methylenedioxy groups 14 0 N-NH Cl 1,3 9 N-NH Br 3, 3 12 3, 4 28 N-NH Br 3, 3 12 3, 4 28 N-N-jNH χn Br 4,2 16 N-NH Br / °yaZAZA OA^ N^Z 4,7 20 „ N-NH Br A'VÁA / ^f οΖΖζ 5, 5 29 OV H 6, 3 15 O^x TT N^Br 6, O^ 6 , 4-11 Br ,Ζ-Ζ^Ζ 7,8 54 O..^ AT z^F 8,4 30 N-NH Br oAJi N 12 32 „ N-NH Br U 18 33 οΓlλΑ^<NΒΓ oAjn~An 33 BZA 34 N-N-NH LRcnn / zznz / E / YiAi 48 N-NH C -N oiAn 59 47 _ N-NH Br ch3 97 13 n-nh f 189 LRcnn / zznz / E / YiAi The results of the different competition assays indicate a high binding affinity to alpha-synuclein fibrils for the tested compounds (lower Ki values ​​indicating higher binding affinity). In the case of the competition assay for compound 1 (Table 4a), the similar Ki values ​​for alpha-synuclein and tau46 fibrils indicate a similar selectivity as compound 1; for those compounds with higher Ki values ​​for tau46 fibrils than for alpha-synuclein fibrils, the data suggest further enhanced selectivity. Additionally, compounds 63, 64 and 65 were tested in direct comparison to the corresponding compounds with the nitrogen atom in one of the phenyl rings. While in Table 6 for compound 1 the Ki value of 0.4 nM was obtained, the Ki value for compound 65 (which lacks a nitrogen atom in the phenyl ring) was much higher (1.9 nM) indicating a significantly improved binding affinity for compound 1. Analysis of the binding properties based on Ki values ​​revealed significantly improved binding affinities for the N-containing compounds. The K± values ​​obtained for the compounds tested in the binding competition assay with the reference ligand compound 1 [3H] (1 nM) are shown in Table 6. Table 6: Competition assay according to protocol 3b (reference ligand compound 1-[3H] (InM)) LRcnn / zznz / E / YiAi # Ki (nM) structure * Comparison series 1 9 2, 1 20 N-NH Br / XY o 3, 1 16 „ N-NH Br O'XP NX 5, 2 15 χτ ν-βγ 6, 7 63 N-NH / Ζ8 Br / Δά 9 series comparison 2 N-NH Br x JlN H 0, 3 57 N-NH Br H 3, 3 64 N-NH Br N' H 3, 4 Comparison series 3 1 N-NH Br \ ^Y / ^Y\n N'x^ / 0, 4 65 N–NH Br / 1, 9 * sonicated alphasynuclein fibrils LRcnn / zznz / E / YiAi Example 3: Therapeutic Effect in Cell Cultures To identify potential therapeutically useful effects, compounds were tested in two cellular models of alpha-synuclein aggregate-dependent toxicity in H4 cells. These cellular models allow for inducible overexpression of either hemiVenus (V1S+SV2) alpha-synuclein fusion constructs or full-length alpha-synuclein (the model is described in detail in: Bartels M, Weckbecker D, Kuhn PH, Ryazanov S, Leonov A, Griesinger C, Lichtenthaler SF, Bótzel K, Giese A: Iron-mediated aggregation and toxicity in a novel neuronal cell culture model with inducible alpha-synuclein expression, Sci. Rep. 2019 Jun 24;9(1):9100). Furthermore, the addition of DMSO and FeC13 promotes alpha-synuclein aggregation which is associated with increased cytotoxicity.The cell culture assay uses these effects by determining the change in cell number and the change in the percentage of condensed nuclei, which is indicative of apoptosis, to gain insight into which compounds show the most promising effects and thus may be therapeutically useful. The data are summarized in Table 7 below. In these experiments, cells were incubated with 100 μM of FeCl3 and 0.75% DMSO in the presence of 10 μM of anlel38c as a positive control, compounds 1 to 19 (10 μM), or DMSO as a negative control. After 48 h, cells were imaged with an OPERA high-performance imaging system and analyzed using Acapella software (Perkin Elmer). The table shows the change in cell number and the change in the fraction of cells with condensed nuclei (i.e., apoptotic cells) relative to the DMSO control. A reduction in the fraction of condensed nuclei (in the absence of a strong reduction in cell number) is indicative of a beneficial therapeutic effect. Table 7: Effects of the therapeutic compound in cellular models LRcnn / zznz / E / YiAi Comp. No. V1S+SV Change in cell number (relative to DMSO control) [%] 2 (H4 cells) Change in fraction of condensed nuclei (relative to DMSO control) [%] alpha-synuclein Change in cell number (relative to DMSO control) [%] a (H4 cells) Change in fraction of condensed nuclei (relative to DMSO control) [%] 1 21.2 11.7 27.3 65.4 2 25.8 49.4 -44.2 79.0 3 11.3 31.9 34.8 79.1 4 36.9 33.7 -48.6 30.1 5 12.4 27.3 14.6 34.2 6 -34.0 53.6 -31.0 5.4 7 30.8 46.1 37.8 62.5 8 4.5 14.2 5.7 10.7 9 22.5 31.8 35.3 23.8 10 32.8 50.3 35.3 60.2 11 17.4 123.2 -20.0 13.7 12 -22.2 24.9 -9.8 28.4 13 6.1 46.0 18.1 55.5 14 21.9 61.0 32.0 47.3 15 11.3 23.1 -11.2 20.3 16 -40.2 56.8 47.1 0.8 17 8.2 38.3 -28.9 55.0 18 -11.8 -19.9 -21.3 -18.2 19 5.7 3.2 30.3 13.2 Example 4: In vivo biodistribution of compound 1 and compound 2 labeled with [1:LC] [1:LC]-labeled compound 1 and compound 2, respectively, were injected intravenously into the tail vein of mice. The mice were then imaged on a small animal PET instrument. Good blood-brain barrier penetration was observed for both compounds, with SUV values ​​> 1.5. Additionally, rapid washout from the brain was found. The clearance half-lives for [nC]-labeled compound 1 and compound 2 were 12 minutes and 9 minutes, respectively. Example 5: Autoradiograph using human brain tissue Autoradiography was performed on histological sections of frozen brain tissue using tritiated compound 1 and brain tissue derived from the cingulate gyrus of a patient with dementia with Lewy bodies. When [3H]-labeled compound 1 was used at a concentration of 3 nM for tissue incubation followed by washing steps, preferential binding to gray matter was observed, which is identical to the known distribution of alpha-synuclein aggregates (Figure 1, left panel). When specific binding was blocked by an excess of non-tritiated (i.e., cold) compound 1, little or no nonspecific binding of compound 1 to brain tissue was observed (Figure 1, right panel). These findings indicate that compound 1 binds specifically and with high affinity to pathologically aggregated alpha-synuclein present in a human synucleinopathy patient and allows for the diagnostic detection of alpha-synuclein aggregates. It is noted that in relation to this date, the best method known to the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the following claims are claimed as property:

1. A compound represented by the general formulas Ia, Ib, Ia or Ilb Hal Ha Ilb or a prodrug, solvate or salt thereof, characterized in that X1, X2, and X3 are independently selected from CR2, N and NR1, provided that at least two of X1, X2, and X3 are N or NR1; Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are independently selected from CR3 and N, provided that at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is N; R1 is independently selected from hydrogen, C1-4 alkyl and -(CH2)-OP(=0)(OR)(OR), where the C1-4 alkyl may be optionally substituted with one or more halogens; R2 is independently selected from hydrogen, halogen, and C1-4 alkyl, where the C1-4 alkyl may be optionally substituted with one or more halogens; R is hydrogen or a cation;R3 is hydrogen, halogen, C1-4 alkyl, OH and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy may be optionally substituted with one or more halogens; R4 and R5 are independently selected from H and C1-4 alkyl, wherein the C1-4 alkyl may be optionally substituted with one or more halogens or wherein R4 and R° together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered heterocyclic ring optionally containing one or more heteroatoms selected from O and N in addition to the nitrogen atom to which R4 and R5 are attached, wherein the saturated 4- to 6-membered heterocyclic ring may be optionally substituted with one or more R6; R6 is independently selected from halogen, C1-4 alkyl, OH and C1-4 alkoxy, wherein the C1-4 alkyl and alkoxy CiLRcnn / zznz / E / YiAi 4 may be optionally substituted with one or more halogens; LRcnn / zznz / E / YiAi Hal is a halogen.; 2. The compound according to claim 1, characterized in that The compound according to claim 2, characterized in that where R1 and R2 are in accordance with claim 4. The compound according to any of claims 1 to 3, characterized in that one or two or three of Y1, Y2, Y3, Y4, Y5, Y6, Y7 and Y8 is / are N.

5. The compound according to any of claims 1 to 4, characterized in that in formulas Ia or Ib, Y1 is N and at least one of Y3, Y4, and Y6 is N; or in formulas Ia or Ilb, Y1 is N and at least one of Y3, Y4, Y5, Y6, Y7, and Y8 is N.

6. The compound according to any of claims 1 to 5, characterized in that Y1 is N and Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are CR3, preferably Y1 is N and Y2, Y3, Y4, Y5, Y6, Y7 and Y8 are CH.

7. The compound according to any of claims 1 to 6, characterized in that R2 is H.

8. The compound according to any one of claims 1 to 7, characterized in that at least one of R4 and R5 is C1-4 alkyl, wherein the C1-4 alkyl may be optionally substituted with one or more halogens.

9. The compound according to any of claims 1 to 7, characterized in that R4 and R5 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 4 to 6 members which optionally contains one or more heteroatoms selected from O and N in addition to the nitrogen atom to which R4 and R5 are attached, wherein the saturated heterocyclic ring of 4 to 6 members may be optionally substituted with one or more R6.

10. The compound according to claim 9, characterized in that the saturated 4- to 6-membered heterocyclic ring is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl, wherein the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl may be optionally substituted with one or more R6 groups.

11. The compound according to any of claims 1 to 10 or a prodrug, solvate or salt thereof, characterized in that the compound is detectably labeled, preferably where the compound is detectably labeled with 18F, 14C, 125I, 123I, 131I, 77Br and 76Bn more preferably where the compound is detectably labeled with Ί8ρ or ng.

12. A diagnostic composition, characterized in that it comprises a compound according to any one of claims 1 to 11 or a solvate or salt thereof and optionally a pharmaceutically acceptable vehicle.

13. A pharmaceutical composition, characterized in that it comprises a compound in accordance with any of claims 1 to 10 of LRcnn / zznz / E / YiAi 89 or a prodrug, solvate or salt thereof and optionally a pharmaceutically acceptable vehicle.

14. A compound according to any of claims 1 to 11 or a prodrug, solvate or salt thereof for use in the diagnosis of a disease associated with alpha-synuclein aggregation.

15. A compound according to any of claims 1 to 10 or a prodrug, solvate or salt thereof for use in the treatment of a disease associated with alpha-synuclein aggregation.

16. The compound for use according to claim 14 or 15, wherein the disease associated with alpha-synuclein aggregation is selected from Parkinson's disease, Lewy body dementia, and multiple system atrophy.

17. Use of a compound according to any of claims 1 to 11 or a prodrug, solvate or salt thereof for the inhibition of alpha-synuclein aggregation in vitro or ex vivo.

18. A compound according to any of claims 1 to 11 or a solvate or salt thereof for use in imaging alpha-synuclein aggregates.

19. A method for imaging alpha-synuclein aggregate deposits, characterized in that it comprises the steps of: LRcnn / zznz / E / YiAi (i) introducing a detectable amount of labeled compound according to claim 11 into a subject; (ii) allowing sufficient time for the compound to associate with alpha-synuclein aggregates; and (iii) detecting the compound associated with alpha-synuclein aggregates.

20. A kit for the preparation of a detectably labeled compound according to claim 11 or a solvate or salt thereof, characterized in that it comprises at least two precursor compounds which, when reacted, form the compound according to claim 11 or a solvate or salt thereof.