TW201206485A - Compounds for binding and imaging amyloid plaques and their use - Google Patents

Abstract

The present invention relates to novel compounds (benzothiazolopyrazoles and thiazolopyridin-pyrazoles) useful for binding and imaging amyloid deposits and their use in detecting or treating Alzheimer's disease and amyloidosis.

Description

201206485 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds (benzothiazole and pyrazole and thiazolidine _π-pyrazole) suitable for binding and imaging amyloid deposits, and Use in the detection or treatment of Alzheimer's disease and amyloidosis. [Prior Art] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory, cognition, and behavioral stability. AD is pathologically defined by extracellular senile plaques (including fibrillar deposits of β-amyloid peptides (Αβ)) and neurofibrillary tangles (paired helical neurofilaments containing hyperphosphorylated tau). The larger starch-like precursor protein (ΑΡΡ) derives 39 to 43 amino acids containing Αρ peptide. In the amyloidogenic pathway, the Αβ peptide is autolyzed by continuous proteolysis caused by secretase and γ-secretase. The Αβ peptide is released as a soluble protein and can be detected as a low content in cerebrospinal fluid (CSF) in a normal aged brain. During AD progression, Αβ peptides accumulate in the membrane tissue and blood structure of the brain and form amyloid deposits that can be detected as diffuse plaques and senile plaques and vascular amyloid proteins during postmortem tissue testing ( For a recent review, see: menn〇w et al., Lancet July 29, 2006; 368 (9533): 387-403). Alzheimer's disease is becoming a major health and socio-economic problem in the world. Strive to develop technologies and methods for early detection and effective treatment of the disease. S, the accuracy of AD diagnosis in academic institutions' memory disorder clinics is about 85-90% (Petrella JR et al., Radi〇i〇gy 2003 226: 315-156931.doc 201206485 3 6). The diagnosis is based on the exclusion of a variety of diseases that cause similar symptoms, as well as meridian and psychiatric tests and neuropsychological tests. However, post-mortem brain histology remains the only definitive diagnosis of the disease. Therefore, it is considered that the in vivo detection of one of the pathological features of the disease (deposition of amyloid aggregates in the brain) has a great influence on the early detection of AD and from other dementias. In addition, most disease-modifying therapies under development aim to reduce amyloid load in the brain. Therefore, amyloid load imaging such as brain can provide the basic tools for patient stratification and therapeutic monitoring. In addition, amyloid deposits are also known to play a role in amyloidosis in which amyloid proteins are abnormally deposited in different organs and/or tissues to cause disease. For a recent review, see Chiti et al., Annu Rev Biochem. 2006; 75:333-66 可能 Possible ligands for the characterization of amyloid aggregates in the brain must exhibit high binding affinity for amyloid-like proteins and must cross blood. Brain barrier. The PET tracer that has been studied in humans for binding patterns in the brains of AD patients is [F-18]FDDNP (Shoghi-Jadid et al, Am J Geriatr Psychiatry 2002; 10:24-35), [C-11] PIB (Klunk et al, Ann Neurol. 2004 55: 306-319), [C-11] SB-13 (Verhoeff et al, Am J Geriatr Psychiatry 2004; 12: 584-595), [F-18] Bay 94 -9172 (Rowe et al., Lancet Neurol 2008, 7: 129-135), [C-11] BF227 (Kudo et al., J Nucl. Med 2007; 49: 554-561) and [F-18] PIB (Farrar Et al., Turku PET Symposium 2007, abstract 49). For a recent review, see Lockhardt, Drug Discov Today, 2006 1 1:1093-1099; Henriksen et al., Eur J Nucl Med Mol Imaging. 2008 156931.doc 201206485 March; 35 Volume Supplement 1: S75-81; Cohen, Mol. Imaging Biol. 2007 9:204-216 ; Nordberg, Curr. Opin Biol. 2007, 20:398-402 ; Small et al., Neurology 2008 7:161-172 ; Nordberg, Eur· J· Nucl. Med. Mol · Imaging 2008, 35, S46-S50. In addition to specific binding to amyloid deposits in the brain, the most promising PET tracers currently exhibit unfavorable non-specific accumulation, especially in patients with ad and white matter brain regions in HC. In general, non-specific background binding can impair image quality and can, for example, interfere with the quantification of the granule protein and the diagnosis of the disease at a very early stage. The present invention provides novel tracers which have a affinity for the class of powdered protein beta and which are not specifically bound, which can be rapidly eliminated from the brain. [Abstract] ’

Powdery degeneration, preferably in the early stages of the disease. The present invention relates to a compound of formula I, and thus, in one aspect, the invention relates to a compound of formula I,

Prodrug, indoleamine, complex or music, and all isomerized isomers of this compound as well as racemic mixed salts, esters, enriched amines, suitable for you 忐 15693 丨.doc 201206485 where -R1 is selected Free group consisting of: Η, C(0)CH3, C(0)(CH2)nCH2X, C(0)CF3, C(0)〇C(CH3)3, C(0)C6H4X, C(0) C6H3YZ, C(0)C6H3XZ, C(O)heteroaryl, substituted c(〇)heteroaryl, c(o)och3, c(o)och2ch3, c(o)och2c6h5, C(0)0CH2CH =CH2, Fmoc, C(0)〇CH2CH2Si(CH3)3, C(0)0CH2CC13; -R2 is selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)mCH2X, R1; -R3 It is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3, C(0)0(CH2)mCH2X, C(0)NH2, C(0)NH(CH2) nCH3, C(0)NH(CH2)mCH2X; -R4 and R5 are independently selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, 0-cyclopentyl-X, 〇·cyclohexyl-x, 0(CH2CH20)nCH2CH2X, SH, SCH3, S(CH2)nCH3, S(CH2)nCH2X , NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, Y, Z; -W Is selected from CH or N; -X is selected from the group consisting of 18F, F, CM, Br, I, 125I, 123I ' 0S02CH3 ' OSO2CF3 ' OSO2C4F9 '0S02C6H5 ' oso2c6h4ch3 , 0S02C6H4N02 , 0S02C6H4Br , 0S02C6H2 ( CH ( CH3 2) 3, oso2c6h3(och3)2; -Y is selected from the group consisting of N02, N+Me3, I+ aryl, S + 156931.doc -6 - 201206485 aryl 2; -Z is selected from the following Group of constituents: η, CF3, CN, C(0)H, C(0)CH3, C(0)0(CH2)nCH3; -m is defined as 1-4; and π is 0-4, including All isomeric forms of the compounds, including enantiomers and diastereomers as well as racemic mixtures, and any pharmaceutically acceptable salts, esters, guanamines, complexes or prodrugs thereof. In a preferred embodiment, -R1 is selected from the group consisting of Η, (:(9)CH3, C(0)CF3, C(0)0C(CH3)3, C(0)C6H4X, c(o) C6h3yz, c(o)c6h3xz, c(o)c6h4y, c(〇)heteroaryl, substituted c(〇)heteroaryl, C(0)0CH2C6H5, C(0)0CH2CH=CH2, Fmoc; R2 is selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)mCH2X, R1; R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2) nCH3, C(0)0(CH2)mCH2X, C(0)NH2, C(0)NH(CH2)nCH3, C(0)NH(CH2)mCH2X; -R4 and R5 are independently selected from the group consisting of Group: H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, 0-cyclopentyl-X, 0 ( CH2CH20)nCH2CH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, 156931.doc 201206485 γ, z ; -W is selected from CH or Ν -X is selected from the group consisting of 18F, F, Cl, Br, I, 125Ι, 123I ' OSO2CH3 ' OSO2CF3 ' OSO2C4F9'0S02C6H5'0S02C6H4CH3 , 0S02C6H4N02, OS02C6H4Br, 0S02C6H2(CH(CH3)2)3, oso2c6h3 (och3) 2 ; -Y is selected from the group consisting of: N 2. N+Me3, I+ aryl, S + aryl 2; -Z is selected from the group consisting of Η, CF3, CN, C(0)H, C(0)CH3; -m is defined as 1 -3 ; and π is 0 - 3, in addition, including pharmaceutically acceptable salts and prodrugs thereof, and all isomeric forms of the compound, including enantiomers and diastereomers, and exogenous Spinning mixture, and any pharmaceutically acceptable salt, ester, guanamine, complex or prodrug thereof. In a more preferred embodiment, -R1 is selected from the group consisting of hydrazine, C(0)CH3, C(0)(CH2)nCH2X, (:(0)CF3, c(o)oc(ch3)3, C(0)C6H4X, C(0)C6H3YZ, c(o)c6h3xz, c(o)och3, c(o)och2ch3, c(o)och2c6h5, Fmoc; -R2 is selected from the group consisting of H, CH3, (CH2)nCH3, R1; -R3 is selected from the group consisting of H, C (0 0H, C(0)0(CH2)nCH3 156931.doc 201206485 'C(0)0(CH2)mCH2X; -R4 and R5 are independently selected from the group consisting of Η, (CH2)nCH2X, OH, OCH3, 〇(CH2)nCH2X, 〇_cyclobutyl_χ, 0(CH2CH20)nCH2CH2X, χ, γ, z; -W is selected from CH or N; -X is selected from the group consisting of: i8p, ρ Ci , Br, I, oso2ch3 ' oso2cf3 ' 〇s〇2C4p9 % 〇s〇2C6H5 , 〇s〇2C6H4CH3 0S02C6H4N02 > 〇S02C6H4Br ' 0S02C6H2(CH(CH3)2)3 ' oso2c6h3(och3)2 ; -Y is selected from * Groups of the following composition: N〇2, N+Me3i+aryl, S. aryl 2; z is selected from the group consisting of: Η.群, CF3, CN, C(0)H; 1-2; and η is 0-2; in addition, including its medicinal Chinese 璺, 可接受 acceptable salts and prodrugs, and the compound 斤, 冓 form & enantiomers and diastereoisomers Body and racemic mixture:: and any pharmaceutically acceptable salts, amines, amines, complexes or prodrugs. In a more preferred embodiment, the compound is selected from the group consisting of: 1-(6-bromobenzothiazol-2-yl)·1Η_pyridin

Azylamine 1 -ylamine 2 1-(6-fluorobenzopyrene-salt-2-yl)_出_pyrrole_3 156931.doc 201206485

NH2

F 1-(6-iodobenzothiazol-2-yl)-1 H-. Bizal-3-ylamine 3

2-(3-Amino.pyrazol-1-yl)-6-fluorobenzothiazole-5-carbonitrile 4 nh2

1-(6-Fluoro-5-trifluoromethylbenzothiazol-2-yl)-1 Η-. Bizal-3-ylamine 5

F F

F 2- (3-amino group ° 峻                ～ ～ ～ ～ ～ ～ ～ ～ ～ ～

1-(6-Nitro-5-trifluoromethylbenzothiazole-2-ylpyrazol-3-ylamine 7 F

[2 - (3-amino group. -1 -yl group than β) benzopyrene σ -6-yl] σ 吩 _ 2 - yl-pin 8 νη2 2-(3-aminopyrazole-1- Base)-6-fluorobenzothiazole-5-formaldehyde 9 Η

156931.doc •10· 201206485 2-(3-Aminocarbazol-1-yl)-6-nitrobenzothiazol-5-furfural 10 °

2-(3-Aminopyrazol-1-yl)-benzothiazole-6-olol 11

-N N, /NH 2 1 -amino group _ 1_ (6 - mercapto-benzoquinone. sigma sigma - 2 -yl) -1 Η - ° ratio ° -4- 曱 乙 旨 旨 12

-[6-(2-Fluoro-ethoxy)-benzothiazol-2-yl]-1Η-. Bizal-3-ylamine 13

Ethyl 3-amino-1-[6-(2-fluoro-ethoxy)-benzothiazol-2-yl]-indole-indazole-4-carboxylate 14 oxime.

0, /CH, Ο 1-(6-fluorodecyloxybenzothiazol-2-yl)-1Η-ηpyrazol-3-ylamine 15 l-[6-(3-fluoro-propoxy) -benzothiazol-2-yl]-1H-. Biazo-3-ylamine 16 - jOcHt l-[6-(3-fluoro-cyclobutoxy)-benzothiazol-2-yl]-1H-. Bizol-3-ylamine 17 156931.doc -11 - 201206485

F

NH2 toluene-4-sulfonic acid 2-[2-(3-aminocarbazol-1-yl)-benzothiazol-6-yloxy]-ethyl S

Ethyl 3-amino-1-{6-[2-(toluene-4-sulfonyloxy)ethoxy]-benzothiazol-2-yl}-111-pyrazole-4-carboxylate 19

3-[2-(3-Aminopyrazol-1-yl)-benzothiazol-6-yloxy]propyl ester of toluene-4-sulfonic acid 20

Toluene-4-sulfonic acid 3-[2-(3-amino.bisazol-1-yl)benzothiazole-6-yloxy]cyclobutyl ester 21

Indole-4-sulfonic acid 2-[2-(3-di-t-butoxycarbonylamino-pyrazol-1-yl) benzopyrene. Sodium-6-yloxy]-B is intended to be 22 156931.doc -12- 201206485

CH, N-[ 1-(6-Bromobenzothiazol-2-yl)-1 H-indazol-3-yl]acetamide 23

Br, ν, s decane-sulfonic acid 3-[2-(3-aminopyrazol-1-yl)-benzothiazol-6-yl]propyl ester 24 Η¥^ΧΧΗτΥΗ3 Ν-{1-[6 -(3-Fluoropropyl)benzothiazol-2-yl]-1Η-. Bisazo-3-yl}acetamamine 25

-[6-(3-Fluoro-propyl)-benzothiazol-2-yl]-1Η-. Biazol-3-ylamine 26 -Ν μ ^,ΝΗ2 4-fluoro-N-[ 1-(6-methoxybenzothiazol-2-yl)-1 Η-"Bizozol-3-yl] Phenylamine 27

3 - 乱基-4-乱-N_[l-(6-decyloxy-benzoquinone °. sit-2-yl)-lH-°tba-sodium 3-yl]-benzamide 28 156931. Doc -13· 201206485 c

4-fluoro-N-[ 1-(6-methoxy-benzothiazol-2-yl)-1 H-pyrazol-3-yl]-3-trifluoromethyl-benzoguanamine 29

C

{4-[1-(6-Methoxy-benzothiazol-2-yl)-1Η-pyrazol-3-ylamine fluorenyl]-phenyl}-diphenyl-fluorene 30

{4-[1-(6-Methoxybenzothiazol-2-yl)-1Η-pyrazol-3-ylaminecarboxylidene]phenylphenyl 丨 塞 -2 -2-2 - yl-pin 31

{2-]-[4-(6-methoxybenzo[epsilon-2-yl]-1Η-ϋΛσ sit-3-ylaminoindolyl]phenyl}trimethyl-ammonium 32 Ch3

{4·[1-(6-Methoxy-benzothiazol-2-yl)-1Η-pyrazol-3-ylaminecarbamyl 156931.doc • 14- 201206485 yl]-2-trifluoromethyl- Phenyl}trimethyl-ammonium 33

3-amino-1-(6-methoxy-benzothiazol-2-yl)-1 Η-pyrazole-4-furoic acid 2-fluoro-ethyl ester 34

N-[1-(5-Cyano-6-fluorobenzothiazol-2-yl)-1Η-pyrazol-3-yl]-acetamidine 35

1-(6-Fluorothiazolo[5,4-1)]pyridin-2-yl)-111-pyrazol-3-amine 36 ΧΪΗΤ FN s 1-(6-bromothiazolo[5,4-13] .Biidine-2-yl)-111-pyrazol-3-amine 37

-N nl /NH. 1-(6-iodothiazolo[5,4-13]pyridin-2-yl)-111-pyrazole-3-amine 38

L-[6-(2-[18F]fluoroethoxy)benzothiazol-2-yl]-1H-. Bizo-3-ylamine [18FJ-39 156931.doc -15· 201206485 18f, 3_ylamine 1 [6_(3·[18ρ]fluoropropoxy) benzothiazol-2-yl]-1Η-η Biazole _ [18FJ-40 [([F] oxooxy)benzopyrimidin-2-yl]-1Η· ° than salivary _3_ylamine [18FJ-41 , eF octagonal t (3-amine Pyrazole-1·yl)-6-[丨8F]fluorobenzothiazole-5-carbonitrile [18F]. 42

1_(6'[F]fluoro[1,3]thiazolo[5,4_b]pyridine_2_yl)_1H•pyrazole-3-amine [18FJ-43 The right compound is an ion, and the present invention is also related to a compound and A combination of suitable phase ions. For the purpose of in vitro and in vivo diagnostic purposes, the formula preferably comprises or contains a detectable label such as a radionuclide. For in vitro use, tissue sections can be analyzed (such as fresh frozen samples or paraffin samples), "hospital based" means linear or branched chain groups consisting only of carbon and hydrogen, 1 free of unsaturation and having sputum 8 carbon atoms, such as fluorenyl, octa-octapropyl propyl methyl (isopropyl), n-butyl, ruthenium II > X _ —. 156931.doc -16- 201206485 methyl ethyl (first Tributyl), n-heptyl and the like. "Alkoxy" refers to a radical of the formula -alkyl, wherein alkyl is as defined above. In the context of the present invention, preferably i is present A pharmaceutically acceptable salt of the compound of the invention. The invention also encompasses salts which are not themselves suitable for pharmaceutical use but which are useful, for example, for isolating or purifying the compounds of the invention. The pharmaceutically acceptable salts of the compounds of the invention include inorganic acids, An acid addition salt of a carboxylic acid and a sulfonic acid, such as a hydrochloride, a hydrobromide, a sulfate, a phosphate, a decane sulfonate, an ethane sulfonate, a sulfonate sulfonate Monosulfonate, acetate, trifluoroacetate, propionate, lactic acid tartar I salt, apple Salts, citrates, fumarates, maleates, and benzoates. The pharmaceutically acceptable salts of the compounds of the present invention also include conventional bases such as (for example and prioritized) Metal salts (such as sodium salts and salt removal salts), alkaline earth metal salts (such as calcium salts and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as (for example and preferred) Amine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, diethanolamine, dicyclohexylamine, dimercaptoethanol, procaine (Pr〇Caine), two Benzylamine, N-mercaptomorpholine, arginine, lysine, ethylenediamine and N.methylpiperidine. The invention also includes a prodrug of the compound of the invention. The term "prodrug" includes itself. A compound which is biologically active or inactive, but which is converted to a compound of the invention (for example, by metabolic means or by hydrolysis) during its residence in the body. In particular, the present invention also encompasses the carboxylic acid of formula (1). Hydrolyzed ester derivative. 156931.doc •17- 201206485 These hydrolyzable Derivatives are understood to mean esters of free carboxylic acids which can be produced by enzymatic or chemical hydrolysis in physiological media and especially in vivo. These oximes are preferably straight or branched (Ci-C6) vinegars. Wherein the alkyl group may be substituted by a trans group, a (CrC4) alkoxy group, an amine group, a mono-(c"c4)alkylamino group and/or a di-(C-C4)alkylamino group. In the context of the present invention, unless otherwise stated, a substituent has the following definition: aryl means monocyclic, bicyclic or tricyclic aromatic or heteroaromatic Ring system, optionally substituted by one or two alkyl, alkylene, alkyne substituents and/or alkoxy substituents. In the context of the present invention, 'alkyl denotes carbon having the various conditions described A direct bond or a branched chain of atoms. By way of example and preference, mention may be made of the following groups: mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, Isoamyl, iethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-decylbutyl, n-hexyl, 1-methylpentyl, 2-decylpentyl, 3- Mercaptopentyl, 4-mercaptopentyl, 3,3-didecylbutyl, 1-ethylbutyl, 2-ethylbutyl, 丨'屯dimethylpentyl, 4,4-dimethyl Base amyl and anthracene, 4,4-trimethylpentyl. In the context of the present invention, a cycloalkyl group means a monocyclic saturated alkyl group having 3 to 7 carbon atoms. By way of example and preference, mention may be made of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the context of the present invention, alkoxy represents a straight or branched alkoxy group having from 4 to 4 carbon atoms. By way of example and preference, mention may be made of the following radicals 156931.doc -18- 201206485 oxime oxime, ethoxy, n-propoxy, isopropoxy, fluorenyl propyloxy, n-butoxy, iso Butoxy and tert-butoxy. In the context of the present invention, halogen includes fluorine, gas, bromine and iodine. It is preferably fluorine. If a group of the compounds of the invention is substituted, unless otherwise stated, the groups may be mono- or polysubstituted. In the context of the present invention, the definition of all groups that occur more than once is independent of each other. Preferably, one, two or three identical or different substituents are substituted. It is extremely preferred to substitute a substituent. The compound of the present invention or a pharmaceutically acceptable salt thereof may have an asymmetric carbon atom in its structure. Thus, the compounds of the invention and their pharmaceutically acceptable salts can exist as single enantiomers, diastereomers, racemates and mixtures of enantiomers and diastereomers. . All such enantiomers, diastereomers, racemates and mixtures thereof are within the scope of the invention. In a preferred embodiment of the invention, the compounds as described above and herein are incorporated in a beta form. Another aspect of the invention is the use of a compound of formula I or otherwise disclosed as described above and herein, for use in diagnosing and/or treating a patient, particularly a mammal, such as a human Alzheimer's disease and / or halliac degeneration. The treatment of patients with Alzheimer's disease and/or amyloidosis may preferably be carried out with a compound of the formula of the present invention without radiolabeling, but gamma is, for example, hydrogen. The use of the compounds of the invention in diagnostics preferably uses positron emission tomography 156931.doc 201206485 Layer View > surgery (PET), single photon emission computed tomography (SpECT), magnetic resonance (MR)-spectroscopy or Tomography is carried out. Another aspect of the invention pertains to methods of imaging amyloid deposits. The method comprises a) administering to a mammal a compound having a detectable label as described above and herein, and b) detecting a signal derived from a compound that specifically binds to a powder of protein powder. Specific binding results in a high binding affinity of the compounds of the invention for amyloid deposits. In another aspect, the invention is directed to a method of diagnosing a patient with Alzheimer's disease or amyloidosis. The method comprises a) administering to a human in need of such diagnosis, a compound of the invention as described above and herein, having a detectable marker for detecting the compound in humans as described above and herein. And b) measuring a signal from a detectable marker caused by administration of the compound in humans, preferably using a gamma camera, positron emission tomography (PET) or single photon emission computed tomography (spECT). Another embodiment of the invention includes a method of diagnosis of a neurological disorder other than Alzheimer's disease in a patient (including excluding Alzheimer's disease), the method comprising administering to the patient the invention as described above and herein Compounds and imaging methods of the invention. Another aspect of the invention refers to a diagnostic composition for imaging amyloid deposits' which comprises a radiolabeled compound of formula j or a compound as described above or otherwise herein. The diagnostic method of the invention can also be used as a post-mortem diagnostic method using a compound as described above and herein. Further, the use of the compounds disclosed above or herein disclosed in the present invention 156931.doc -20-201206485 neurodegenerative disorders or amyloidosis methods can also be used to monitor Alzheimer's disease-like therapies. Further, the diagnostic method of the present invention using the compound described above or in (4) herein can also be used to diagnose a neurological disorder other than Alzheimer's disease by excluding Alzheimer's disease. In another aspect of the invention 'the invention comprises a method of treating or preventing amyloidosis or Alzheimer's disease, #includes administering a human formula I compound in need of such treatment or otherwise described above or herein Compound. A further aspect of the invention refers to a pharmaceutical composition comprising a compound as described herein and optionally a suitable carrier and/or additive. Furthermore, the compounds of the invention may also be used as screening means, for example High-throughput screening and in vitro assays. A further aspect of the invention refers to a method for inhibiting amyloid formation or modulating the pathogenicity of amyloid-like proteins in a mammal. The method comprises administering an effective inhibitory effect; forming or regulating amyloidosis A pathogenic amount of a compound of the formula described herein as described herein. The invention also refers to a method of synthesizing a compound of the formula j of the invention as described herein. The general synthetic method of the compound of the present invention is as follows. F-18 Radiolabeling Another aspect of the invention refers to a method of radiofluorinating a compound which is used to produce a radiolabeled compound, the method comprising the step of reacting a compound of formula I with a fluorinating agent . Useful radiofluorination methods are well known to those skilled in the art. 156931.doc -21- 201206485 In a preferred embodiment 'the fluorinating agent is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]- Hexane 〖181? (crown ether salt 1^1^ such as K18F), K18F, H18F, KHi8F2, or up tetraalkylammonium salt. The fluorinating agent is more preferably K18F, h18f or kh18f2. The solvent used may be dimethylformamide (DMF), diterpene; Emethyl (Dimethylsulfoxyde, DMSO), acetonitrile (MeCN), dimethylacetamide (DMA), DMAA, etc., preferably DMS0, MeCN Or DMF. The solvent may also be a mixture of solvents as indicated above. [F-18] Radiolabeling procedures are well known to those skilled in the art. For example, radiolabeling can be carried out as described below. [F_18] fluoride can be produced by bombardment with a proton in a cyclotron (1 mL) filled with silver [0-18] water for 180 (mouth, 11) 1> reaction. Fluoride can be passed through the cartridge (eg QMA Resin Tube Waters, Sep Pak Light QMA Part Number: WAT023525). Then by adding, for example

Kryptofix K2.2.2/K2C03 solution (Kryptofix is 4,7,13,16,21,24_hexaoxa-1,10-diazabicyclo[8.8.8]hexadecane) captured from the cartridge [ F-18] Fluoride. The nucleophilic substitution of the precursor is preferably carried out in the presence of a base such as NBu40H, (NBu4)2C03, NBu4HC03, K2C03, Cs2C03, etc., at elevated temperatures. The addition of a crown ether such as Krypt(R) fix (K2.2.2) can positively affect the reaction, especially in the presence of k2c〇3 as a base. Preferably, the fluorination is dried by repeating the azeotropic distillation column under continuous addition of acetonitrile.

Kryptofix complex. A solvent such as acetonitrile, dmF, DMS0 or the like can be used as the reaction solvent. The labeled product can be purified by solid phase extraction using a cartridge. The preferred cartridge is a Sep-Pak Plus C18 cartridge (Waters, WAT020515). The cartridge can be 156931.doc -22· 201206485 rinsed with water and the compound can be dissolved in acetonitrile. The dissolved compound can be diluted with water and then purified by preparative HPLC. The preferred HPLC column is a reverse phase column such as Gemini 5 μ C 18 110 A, 250 x 10 mm (Phen〇menex, 00G-4435-N0). A mixture of a buffer solution, an acid, water, or the like with an organic solvent such as acetonitrile, methanol, ethanol, or the like can be used as the mobile phase. The solution can then be diluted, for example with water, to pass through the cartridge for concentration and solvent exchange.

General Synthetic Method for F-18 Compounds: Alkyl-1? and (Hetero)aryl-F The alkyl-F-18 compound of Formula I (y=i8f in Formula I) is a precursor such as phthalic acid Salt, bromobenzene acid salt, succinic acid salt, acid salt, trifluorosulfonate, nonafluorobutanesulfonate, etc. (Form ItY=dissociative group), which can be used according to the technology Known methods are synthesized from individual hydroxy compounds (j

March, Advanced Organic Chemistry, 4th edition 1992, John

Wiley & Sons, page 352 and below). Another method is described in Examples 3f, 4e and 5a and comprises synthesis by suitable bis(indolyl sulfonate) and the like (e.g., TsO-(CH2)n-OTs). Other precursors of the alkyl-F-18 compounds of formula I (y = 18F in formula I) are, for example, iodides and bromides and analogs thereof, which are also converted into individual fluorides. Known (J. March, see above). The precursor of the aryl-F-18 compound of formula I is, for example, an aryl or heteroaryl bromide, a nitro compound, a trialkylammonium, an aryl oxime, which can be by methods known in the art. Each of the F-18 compounds converted to the invention (L. Cai, S. Lu, V. Pike, Eur. J. Org. Chem 2008, 2853-2873). Starting materials for such precursors are commercially available or may be known by the art as 156931.doc -23- 201206485 ^^^ (R.C. Larock, Comprehensive 〇rganic Transformations VCH Press 1989). A further aspect of the invention is a kit comprising a non-radiolabeled compound of the invention, optionally in dry conditions or with added inert, pharmaceutically acceptable carrier and/or solvent and / or substance. The compounds of the invention may act on the body and/or on the body. To achieve this, it can be administered in a suitable manner, such as oral, parenteral, transpulmonary, nasal, sublingual, translingual, buccal, rectal, transdermal, transdermal, transconjunctival, menstrual The ear is administered either as an implant or stent. For such routes of administration, the compounds of the invention may be administered in a suitable pharmaceutical form. Administration forms suitable for oral administration are those which function according to the prior art and which release the compounds of the invention rapidly and/or modified and which comprise crystalline and/or amorphous and/or soluble compounds of the invention Form, such as a lozenge (a coating without a coating or a coating, such as a coating coated with an enteric coating or dissolved or insoluble in a delayed manner and controlling the release of the compound of the invention), film/powder Or lozenges, films/lyophilized products, capsules (such as hard gelatin capsules or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions which dissolve rapidly in the oral cavity. Parenteral administration can be carried out without bioabsorption steps (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or in bioabsorption (eg intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal) . Suitable for parenteral administration, especially in the form of solutions, suspensions, emulsions, lyophilized products, 156931.doc •24·201206485 or sterile powders for injection or infusion. Applicable to other routes of administration. 并 私 》 》 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马 马, solution or spray; through the ear to cut into a thin film 'powder or capsule; suppository; preparation of deafness or eye; vaginal shake-m, with capsules, aqueous suspension (lotion, sputum Ointment; cream; transdermal treatment of the powder; implant or stent. paste, foaming thank; for perfusion: Jiaojiao oral or parenteral administration 'especially for oral and intravenous administration. The compound can be converted into the form of administration mentioned. This conversion method can be: "in a known manner" by means of a pharmaceutically acceptable non-toxic pharmaceutically acceptable auxiliary agent, especially including a carrier ( For example, microcrystalline cellulose, milk 2, mannitol), dissolved in liquid polyethylene: alcohol), emulsifier and dispersion 1 or wetting agent (such as sodium sulfate, polyoxysorbate, vinegar) , binders (such as polyethylene phase), synthetic and natural polymers (:] such as albumin), stabilizers (such as antioxidants such as ascorbic acid), colorants (such as inorganic pigments such as iron oxide) and aromatics Agent and/or flavoring agent 0 Another aspect of the invention relates to the preparation of formula I The method and composition of 2-chloro-thiazole-pyrazol-3_ in DMF amine condensation under the presence of potassium carbonate is shown in Scheme 1. The compounds 1-5, 23 and the intermediates were synthesized correspondingly using the respective stupid and thiazole and carbazole building blocks. 156931.doc -25· 201206485 Process 1

1-5, 23 benzopyrene-pyr ratio substituted by fluoroalkoxy. The synthesis of the sitting derivatives 13-16 is shown in Scheme 2. Using a hydrazine in a two-gas methane to give a 6-fluorenylbenzothiazole _ ° ratio " sitting derivative deamination group, to give an intermediate 11/12, yield 99%. The compound is directly alkylated with 1-fluorosilane in the presence of carbonic acid in DMF to give a fluoro-ovaporated compound which can be used as a cold reference for radiolabeling and affinity studies. Process 2

The synthesis of the corresponding benzothiazole-pyrazole labeled precursors 18-22 is shown in Scheme 3. Reaction of intermediate 11 with bis-p-toluenesulfonate yields compound 18. Compounds 19 and 21 were synthesized accordingly. The compound 20 can be synthesized from the intermediate 12 accordingly. To increase the yield in the subsequent radiolabeling step, the free amine (if scale 1 and R2 = H) is protected in compound 22 with two Boc groups. It is also marked without other protection. 156931.doc -26- 201206485 Process 3

The radiolabel of the benzopyrene-labeled precursor 22 is shown in Scheme 4. Treatment with 22 F-18 potassium fluoride and Kryptofix 222 in DMSO/MeCN to give F-18 fluoroalkylated compound 18F-39 » Scheme 4

«F-39 As exemplified in Scheme 5, a fluoroalkylated compound can also be synthesized by indirect labeling. The compound 18F-41 was synthesized by converting the compound η with F-18 toluene chloroformate. Compounds 18F-39 and 18F-40 can be correspondingly synthesized via the corresponding F_18 fluoroalkyl tosylate. Process 5

An exemplary synthesis of 18F-41 gas-fired stupid and thiazole-pyrazole derivatives 26 is shown in Scheme 6. The hydration of the compound (if ri &r2; = h) produces a protected derivative 23 which is subsequently subjected to palladium catalyzed alkylation to give 6-(hydroxypropyl)benzothiazole. Next, the alcohol is subjected to, for example, methanesulfonation to give an intermediate and a cold fluorination reaction of 156931.doc -27-201206485 〇6 8 1 to produce compound 25, . The protecting group of substance 25 gives product 26.26 can be used as a subtractive (four) reference for radiolabeling and affinity studies. Process 6

Record the precursor 24. An exemplary synthesis of w TD Ατ^ ” 氟 笨 笨 醯 苯 benzothiazole _ β-biazole derivative and its precursor 28-33 is shown in Scheme 7. Deuteration of benzothiazole-pyrazolamine The action produces a fluorobenzylated derivative 28 which can be used as a radioactive reference for radiolabeling and affinity studies. Compounds 29-33 can be synthesized using the respective benzothiazole and fluorenyl building blocks, with no radioactive reference. And the corresponding precursor. Process 7

An exemplary synthesis of 6-halogenated 1 _(π塞塞和[5,4-b]. °定-2-yl)-1Η-° than saliva is shown in Scheme 8. The 2-aminothio group was synthesized by the formation of a thiourea followed by copper (I)-mediated thiazole cyclization using a 2,6-tagged 3-amino ratio bite as a starting material. Sit and [5,4-b] ° than pyridine. 2-Chloroththiazolo[5,4-b]pyridine (derived from an amine via the Sandmeyer reaction 156931.doc -28 - 201206485 (Sandmeyer reaction)) with a 3-amino group 0-0 sitting in DMF in a carbonic acid planer Condensation in the presence of compound 36-38. 36 (Hal = F) can be used as a radioactive reference for radiolabeling and affinity studies and 37 and 38 (Hal = Br/I) can be used as a precursor for radiolabeling. Process 8

CsjCOj, DMSO catalytic amount of proline. Cul,

Figure 1 summarizes the exemplified compounds. In particular, the invention relates to 1 · a compound of formula I,

among them

• R1 is selected from the group consisting of Η, C(0)CH3, C(0)(CH2)nCH2X, c(〇)cf3, c(o)oc(ch3)3, C(0)C6H4X, C (0) C6H3XZ, c(〇)heteroaryl, substituted qQ)heteroaryl; (CH2)nCH3(CH2)mCH2X, R1; _R3 is selected from the group consisting of: τ 义群·Η, C(0 0H, C(0)0(CH2)t ... is selected from the group consisting of: h, ch3, CH3 156931.d0) '29- 201206485, C(0)0(CH2)mCH2X, C(0) NH2, C(0)NH(CH2)nCH3, C(0)NH(CH2)mCH2X; -R4 and Rs are independently selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, 0-cyclopentyl-X, 0-cyclohexyl-X, 0(CH2CH20)nCH2CH2X, SH, SCH3, S (CH2)nCH3, S(CH2)nCH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, Z; -W is selected from CH or N; -X is selected from the group consisting of F, 18F, I, 125I, 123I; -Z is selected from the group consisting of h, CF3, CN, C(0)H, C(0)CH3' C(0)0(CH2)nCH3; • m is defined as 1_4; and n is defined as 0-4; includes all isomeric forms of the compound, including enantiomers Isomers and racemic mixtures, and diastereomers thereof, and any pharmaceutically acceptable salt, ester, acyl amines, complex or prodrug thereof, wherein the formula contains only 1 X. 2. The compound according to item 1 (count 1), wherein: R1 is selected from the group consisting of Η, c(0)CH3, C(0)(CH2)nCH2X, c(〇)CF3, C(0 0C(CH3)3, C(〇)C6H4X, C(0)C6H3XZ, c(〇)heteroaryl, substituted c(0)heteroaryl; _R2 is selected from the group consisting of: CH3, (CH2)nCH3, 156931.d〇c -30- 201206485 (CH2)mCH2X, R1; -R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3 , C(0)0(CH2)mCH2X, C(0)NH2, C(0)NH(CH2)nCH3, C(0)NH(CH2)mCH2X; -R4 and R5 are independently selected from the group consisting of :H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, O-cyclopentyl-X, 0 (CH2CH20 nCH2CH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, Z; -W is selected from CH or N; -X is selected from the following Group of constituents: F, 18F, I, 125I, 123I; -Z is selected from the group consisting of H, CF3, CN, C(0)H, c(o)ch3; -m is defined as 1 - 3 And n is defined as 0-3; includes all isomeric forms of the compound, including enantiomers and diastereoisomers Isomers and racemic mixtures, and any pharmaceutically acceptable salt, ester, acyl amines, complex or prodrug thereof, wherein the formula contains only 1 X. 3. The compound according to Item 1 or 2, wherein -R1 is selected from the group consisting of Η, C(0)CH3, C(0)(CH2)nCH2X, C(0)CF3, C(0)0C (CH3)3, C(0)C6H4X, C(0)C6H3XZ; -R2 is selected from the group consisting of H, CH3, (CH2)nCH3, 156931.doc • 31·201206485 R1; Groups of the following composition: Η, C(0)0H, C(0)0(CH2)nCH3, C(0)0(CH2)mCH2X: -R4 and Rs are independently selected from the group consisting of: Η, ( CH2)nCH2X, OH, OCH3, 0(CH2)nCH2X, Ο-cyclobutyl-X, 0(CH2CH20)nCH2CH2X, X, Z; -w is selected from CH or N; -X is selected from the group consisting of :F, 18F; -Z is selected from the group consisting of Η, CF3, CN, C(0)H; -m is defined as 1-2; and n is defined as 0-2, including all of the compound Isomers, including enantiomers and diastereomers, as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, guanamine, complex or prodrug thereof, wherein the formula comprises only 1 X. 4. A compound according to item 1, 2 or 3 wherein X is 18F. 5. a compound of formula I,

among them

-R1 is selected from the group consisting of Η, C(0)CH3, C(0)(CH2)nCH2X 156931.doc -32- 201206485, (:(o)cf3, c(o)oc(ch3)3 , c(o)c6h4x, c(o)c6h3yz, C(0)C6H3XZ, c(o)heteroaryl, substituted c(0)heteroaryl, c(o)och3, c(o)och2ch3, c(o)och2c6h5, c(o)och2ch=ch2, Fmoc, C(0)0CH2CH2Si(CH3)3, C(0)0CH2CC13; -R2 is selected from the group consisting of H, CH3, (CH2)nCH3 (CH2)mCH2X, R1; -R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3, (:(0)0(CH2)mCH2X, C( 0) NH2, C(0)NH(CH2)nCH3, C(0)NH(CH2)mCH2X; -R4 and Rs are independently selected from the group consisting of H, CH3, (CH2)nCH3, (CH2) nCH2X, OH, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, O-cyclopentyl-X, O-cyclohexyl-X, 0(CH2CH20)nCH2CH2X, SH, SCH3 , S(CH2)nCH3, S(CH2)nCH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, Y, Z; -W It is selected from CH or N; -X is selected from the group consisting of F, Cl, Br, I, 0S02CH3, 0S02CF3, 0S02C4F9, 0S02C6H5, 0S02C6H4CH3, 0S02C6H4N02, 0S02C6H4 Br, 0S02C6H2(CH(CH3)2)3, OS02C6H3(OCH3)2; -Y is selected from the group consisting of N02, N+Me3, anthracene aryl, S + aryl 2; -Z is selected from the following Group of constituents: Η, CF3, CN, C(0)H, C(0)CH3, C(0)0(CH2)nCH3; 156931.doc -33- 201206485 -m is defined as 1 -4 ; and η Is defined as 0-4; includes all isomeric forms of the compound, including enantiomers and diastereomers as well as racemic mixtures, and any 4 pharmaceutically acceptable salts thereof, g, hydrazine An amine, a complex or a prodrug, wherein the formula comprises only one X, and wherein the formula comprises only one Y. 6. The compound according to item 5, wherein -R1 is selected from the group consisting of: Η, ( :(0)(3⁄4,(:(〇ΧTM2)η(:ϋ2Χ , (:(0)CF3, C(0)OC(CH3)3, c(〇)c6H4X, C(0)C6H3YZ, C (0) C6H3XZ, C(0)C6H4Y, c(〇)heteroaryl, substituted c(0)heteroaryl, C(0)0CH2C6H5, C(0)〇CH2CH=CH2, Fmoc; -R2 The group consisting of H, CH3, (CH2)nCH3, (CH2)mCH2X, R1; -R3 is selected from the group consisting of H, C(0)OH, C(0)0(CH2)nCH3 , C(0)0(CH2)mCH2X, C(0)NH2, C(0) NH(CH2)nCH3, C(0)NH(CH2)mCH2X; -R4 and Rs are independently selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0 ( CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, O-cyclopentyl-X, 0(CH2CH20)nCH2CH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH( CH2)mCH2X, NCH3(CH2)mCH2X, X, Y, Z; 156931.doc 34- 201206485 -W is selected from CH or N; -X is selected from the group consisting of F, Cl, Br, I, OS02CH3 , OSO2CF3, oso2c4f9, oso2c6h5, oso2c6h4ch3, 0S02C6H4N02, 0S02C6H4Br, 0S02C6H3(0CH3)2; -Y is selected from the group consisting of N02, N+Me3, fluorene aryl, S + aryl 2; Z series is selected from the following Group of constituents: Η, CF3, CN, C(0)H, C(0)CH3; -m is defined as 1-3; and n is defined as 0-3; including all isomeric forms of the compound, including Enantiomers and diastereomers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, guanamine, complex or prodrug thereof, wherein the formula contains only one X, and Wherein the formula contains only one γ. 7. The compound according to item 5 or 6, wherein R1 is selected from the group consisting of hydrazine, C(0)CH3, C(0)(CH2)nCH2X, C(0)CF3, C(0)0C ( CH3)3, C(0)C6H4X, C(0)C6H3YZ, c(o)c6h3xz, c(o)och3, c(o)och2ch3, c(o)och2c6h5, Fmoc; -R2 is selected from the group consisting of Group: H, CH3, (CH2)nCH3, R1; -R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3 156931.doc -35- 201206485 'C( 0)0(CH2)mCH2X; -R4 and Rs are independently _, L^t is selected from the group consisting of H, (CH2)nCH2X, OH, OCH Λ CH3, 〇(CH2)nCH2X, 〇 丁- (, 0(CH2CH20)nCH2CH2X, χ, γ, z; -W is selected from CH or Ν; -X is selected from the group consisting of the following groups: F, CM, Br, I, OS02CH3, 〇 So2cf3 ^ oso2c4f9 ^ 〇s〇2c6h5 , 〇s〇2c6h4ch3 ; -Y is selected from the group consisting of N〇2, Ν+Μ. , I+ aryl, s + aryl 2; -Z is selected from the group consisting of Η, CF3, CN, C(0)H; -m is defined as i_2; and n is defined as 〇_2, And any pharmaceutically acceptable salt thereof, ester 'guanamine, complex or pre-formula wherein the formula contains only one oxime, and wherein the formula contains only one gamma. 8. A compound which is selected from the group consisting of: H6-fluorobenzonitrile·2•yl)_1η_μ_3·ylamine 2 (3 amine group than sulphur-based benzopyrene. Sit _5·甲猜4 All such isomeric forms, including enantiomers and diastereomers, as well as racemic mixtures, 156931.doc -36 - 201206485

1-(6-fluoro-5-trifluoromethylbenzothiazol-2-yl)-1 Η-"Bizozol-3-ylamine 5

F

N, N^/NH2 S

F

2-(3-Aminopyrazol-1-yl)-6-fluorobenzothiazol-5-carboxaldehyde 9 〇

, hehe. 1-[6-(2-deficient ethyl carbyl) benzopyrene σ sitting -2 -yl]· 1 Η - ° ratio. Sitting -3 -ylamine 13

3-Amino-1·[6-(2-fluoroethoxy)benzothiazole stomach 2-yl]-1Η-. Butyrazole-4-decanoic acid ethyl ester 14

Νν [6-(Fluoromethoxy)benzothiazol-2-yl]-1Η-. Bizol-3-ylamine 15-indole, /ΝΗ2 l-[6-(3-fluoropropoxy)benzothiazol-2-yl]-1H-indazol-3-ylamine 16 •NN, / NH2 l-[6-(3-Fluorocyclobutoxy)benzothiazol-2-yl]-1Η-°Bizozol-3-ylamine 17

156931.doc -37· 201206485 Ν-{1-[6-(3-Fluoropropyl)benzothiazol-2-yl]-1Η-°boxazol-3-yl}acetamidine 25

[6-(3-Fluoropropyl)benzothiazol-2-yl]-1H-pyrazol-3-ylamine 26

-N N, /NH2 4-fluoro-N-[ 1-(6-methoxybenzothiazol-2-yl)-1 Η-pyrazol-3-yl]benzamide amide 27 h3c

3-cyano-4-fluoro-N-[l-(6-decyloxybenzothiazol-2-yl)-1Η-. Bizozol-3yl]benzamine 28

4-Fluoro-N-[ 1-(6-decyloxybenzothiazol-2-yl)-1Η-pyrazol-3-yl]-3-(trifluoromethyl)benzamide 29

H3C. 3-Amino-1-(6-methoxybenzothiazol-2-yl)-1H-pyrazole-4-furic acid 2-fluoroethyl ester 34 156931.doc -38- 201206485

H, C

N-[ 1-(5-Cyano-6-fluorobenzothiazol-2-yl)-1 H-. Bizozol-3-yl]acetamamine 35

1-(6-fluorothiazolo[5,4-15]pyridin-2-yl)-111-pyrazol-3-amine 36

L-[6-(2-[18F]fluoroethoxy)benzothiazol-2-yl]-lH-ηpyrazol-3-ylamine [18FJ-39 N n ^NH2

L-[6-(3-[18F]fluoropropoxy)benzothiazol-2-yl]-1Η-η-pyrazol-3-ylamine [18FJ-40

L-[6-([18F]fluoromethoxy)benzothiazol-2-yl]-1H-pyrazol-3-ylamine [18F]_41

18f,,o 2-(3-Aminopyrazol-1-yl)-6-[18F]fluoro-benzothiazole-5-carbonitrile [18F]-42

_(6-[18F]fluorothiazolo[5,4-b].pyridin-2-yl)-1Η-. Biazo-3-amine 156931.doc -39- 201206485 [18F]-43

9. A compound selected from the group consisting of: 1-(6-bromobenzothiazol-2-yl)-1Η-°bazol-3-ylamine 1

1-(6-iodobenzothiazol-2-yl)-111-pyrazol-3-ylamine 3

2 - (3 -Amino group ratio. Sit-1 -yl)-6-Nitrobenzopyrene. Sit-5 - 曱 guess 6

1-(6-Nitro-5-trifluoromethylbenzothiazol-2-yl)-1Η-indazol-3-ylamine 7

L· [2-(3-Amino-to-β-l-l-yl)-benzoindole. Sit 6-based] ° cephen-2-yl-pin 8

2-(3-Aminopyrazol-1-yl)-6-nitrobenzothiazole-5-furaldehyde 10 〇

I56931.doc • 40· 201206485 2-(3-Aminopyrazol-1-yl)-benzothiazole-6-olol 11

3-Amino-1-(6-hydroxybenzothiazol-2-yl)-1Η-pyrazole-4-furoate ethyl ester 12, ΝΗ, Ν Ν.

S

〇, /CH, 2- Benzene-4-sulfonic acid 2-[2-(3-amino-oxazol-1-yl)benzothiazole-6-yloxy]ethyl ester 18

3-Amino-1-{6-[2-(indolyl-4-sulfonyloxy)ethoxy]benzothiazol-2-yl}-1Η-pyrazole-4-carboxylic acid ethyl ester 19

0~CH, 3-[2-(3-Amino-oxazol-1-yl)benzothiazole-6-yloxy]propyl 3-nonyl-4-sulfonate 20-Ν Ν, /ΝΗ2,0 Benzene-4-sulfonic acid 3-[2-(3-amino-n-by-azosin-indoleyl)benzothiazole -6-yloxy]cyclobutyl ester 21 156931.doc •41 - 201206485 h3c

Nh2 toluene-4-supply acid 2-[2-(3-di-secondbutoxylamlylamine °°-1-yl) benzothiazole-6-yloxy]ethyl ester 22

N-[ 1-(6-Bromobenzothiazol-2-yl)-1Η-pyrazol-3-yl]acetamide 23

CH3

3-[2-(3-Aminocarbazole-1-yl)benzothiazol-6-yl]propyl ester of Br sulfanesulfonate 24

{4-[1-(6-Methoxybenzothiazol-2-yl)-1Η-»Bizozol-3-ylamine fluorenyl]-phenyl}diphenyl-indole 30

{4-[1-(6-Methoxybenzothiazol-2-yl)-1Η-. Bisazo-3-ylaminoindenyl]phenyl}thiophen-2-yl-indole 31 156931.doc -42- 201206485

{2-Cyano-4-[1-(6-decyloxybenzothiazol-2-yl)-1 Η-°Bizozol-3-ylaminoindenyl]-phenyl}tridecyl-ammonium 32

{4-[1-(6-Methoxybenzothiazol-2-yl)-1Η-°Bizozol-3-ylaminoindenyl]-2-di-denylmethyl-phenyl}trimethyl- Syria 33

1-(6-bromothiazolo[5,4-b]pyridin-2-yl)-1indole-pyrazole-3-amine 37

Nh2 1-(6-iodothiazolo[5,4-b]pyridin-2-yl)-1 Η-pyrazole-3-amine 38

Νη2 10. A compound selected from the group consisting of: l-[6-(2-[18F]fluoroethoxy)benzothiazol-2-yl]-1Η-η-pyrazol-3-ylamine [18FJ-39

L-[6-(3-[18F]fluoropropoxy)benzothiazol-2-yl]-1H-pyrazol-3-ylamine 156931.doc •43- 201206485 [18FJ-40

Pyrazol-3-ylamine 1 [6 ([F]fluorononyloxy) benzothiazol-2-yl] [18FJ-41 18f/, 〇

_5-phthalonitrile [18F]-42 2-(3-aminopyrazole "·yl)_6_[uF] fluorobenzothiazole

2_base)_1H-.比-3-amine 1_(6_[F]fluorothiazolo[5,4-b]. Bis-[18FJ-43 U. Compound of item 8] wherein F is not a group In some cases, F is defined as i8F. 12. The radiolabeled compound of the ", 1〇 or " is used as a compound for diagnostic imaging. 13. The compound of item 12, Used as a compound for diagnostic imaging of diseases selected from the group consisting of diseases including Alzheimer's disease, neurodegenerative disorders or amyloidosis. 14. Such as 1-4, 1〇 or Use of a radioactively labeled compound of the U-term thereof for the preparation of a pharmaceutical composition suitable for diagnostic imaging of a disease or a method for diagnosing a human ^ ^ ' 该 该 该 ' ' ' 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 44· 201206485 Symptoms, neurodegenerative disorders or halliac degeneration 15·--- or diagnostic composition, its group. Radioactively labeled compounds and pharmaceutically acceptable /4,1〇 or U. A pharmaceutical or diagnostic composition according to item 15, a carrier agent. The fragmentation method is selected from the group consisting of a disease involving Alzheimer's disease or A group of diseases in which powdery degeneration is caused. . . , , , , , , , , , , , , , , , , , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Suitable precursor molecule 18. The method of item 16, preferably, the method comprises reacting a chemical compound such as the ninth, _th, and the first phosphatase. A method for diagnosing a disease in a mammal selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder, or amyloidosis, such as a radiolabeled compound as described in (4) a composition of 16; imaging the mammal; and detecting a signal. 20. The method of claim 19, wherein the compound of item (4) is used. 21. The method of the method of 19 or 2G, wherein the effect of the therapy is monitored 22. A method of imaging an amyloid spot such as in a mammal, the method comprising administering to the mammal a compound such as a compound of item 4, 1 , n, 12 or 13, such as a combination of items 15 or 16. 23. imaging the mammal; and detecting signals. The method of item 22, wherein the compound used as the first item 1〇. 156931 .doc -45- 201206485 [Embodiment Abbreviation

Boc third butoxycarbonyl br wide signal (NMR data) Cl chemical ionization d double peak DAD diode array detector dd double doublet ddd double double doublet dt double triplet DMF condition from diterpene Indole DMSO Disulfoxide El Electron Ionization ELSD Evaporative Light Scattering Detector ESI Electrospray ionization EtOAc Ethyl acetate Fmoc Mercaptomethyloxycarbonyl Hal Halide HPLC High Pressure Liquid Chromatography GBq Gigabit Bequier ( Bequerel) K2.2.2 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexadecane K2CO3 potassium carbonate MBq million bequier MeCN acetonitrile MS Mass spectrometry analysis MTB decyl third butyl ether m multiple peaks me center multiple peaks NH4C1 vaporized ammonium 156931.doc -46- 201206485 spectrum-method: quadruple peak

Third butyl dimethyl oxalate

Extreme performance liquid chromatography

NMR jg_

PMB

RT

TBAF TBS_ THF_ THP_

UPLC Experimental 1-(6-Bromo-benzothiazol-2-yl)-1Η-pyrazol-3-ylamine 1

Under microwave heating 12 (2 ° gas _6_bromobenzothiazole (1.0 g, 4.02 mmol), 3-aminopyrazole (67 〇 mg, 8.05 mmol) and K2C03 (1.38 g, 10 mmoUMDMFG6 mL) The mixture was poured into water for 3 hours. The reaction mixture was poured into water and the mixture was washed with water and purified by chromatography to afford 470 mg (40%) of compound 1. H-NMR (400 MHz, CDC13 ): 6=8.19 (d, 1H), 7.92 (d, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 5.97 (d, 1H), 4.04 (br s, 2H) ppm. LC/ MS ES+ m/z 295.27 (M+l). 1_(6-fluoro-benzothiazol-2-yl)-1 -oxazol-3-ylamine 2

Nh2 Stirring 2-chloro-6-fluorobenzothiazole (200 mg '1'07 mmol) at 10 ° C 156931.doc -47 - 201206485 3-Amino &quot;Bizozole (178 mg, 2.14 mmol) And a mixture of K2C 〇 3 (885 mg, 6.40 mmol) in DMF (5 mL) The reaction mixture was poured into water and extracted with diethyl ether. The combined organics were washed with brine, dried over sodium sulfate < The residue was purified by chromatography on silica gel to afford 130 mg (52%) Compound 2. ^-NMR (300 MHz, DMSO-J6): 5 = 8.26 (d, 1H), 7.92 (dd, 1H), 7.77 (dd, 1H), 7.32 (ddd, 1H), 5.97 (d, 1H), 5.73 (br s, 2H) ppm. ESI-MS m/z 235 (M+l). 1-(6-iodobenzothiazol-2-yl)-1Η-pyrazol-3-ylamine 3

Stir 2-chloro-6-iodobenzothiazole (190 mg, 0.64 mmol), 3-aminopyrazole (53 mg, 1.0 mmol) and K2C03 (178 mg, 1. 〇mmol) at 120 ° C under microwave heating. The mixture in DMF (0.86 mL) was used for 20 minutes. Then add a 3-amino group. More than saliva (53 mg, 1.0 mmol) and K2C〇3 (356 mg, 2.0 mmol) and continued to stir for 1 hour under microwave conditions. The reaction mixture was poured into water, and the precipitate was filtered, washed with water and purified by chromatography on silica gel to afford 8.6 g (4%) Compound 3. !H NMR (300 MHz, DMSO-i/e) 6=5.76 (s, 2 Η), 5.97 (d, 1 Η), 7·55 (d, 1 Η), 7.73 (d, 1 Η), 8.26 (d, 1Η), 8.39 (s, 1Η) ppm. LC/MS ES+ m/z 343.08 (M+l). 2-(3-Amino-1H-0 than 吐-1-yl)-6-Gas-1,3-Benzene oxime _5_甲猜4

156931.doc -48- 201206485 Benzene-brewed chlorine (18.5 g' 132 mmol) was added to a solution of thiocyanate (12 g' 158 mmol) in acetone (350 mL) over 5 min and the mixture was refluxed for 15 min. 3-Bromo-4-fluoroaniline (25 g, 132 mmol) was added to the mixture at 4 (TC) and reflux was continued for 30 min. The hot solution was poured onto ice (4 mL) and the mixture was mixed for 5 min. The sediment was collected by filtration and washed with a 50 ° /. methanol solution (5 〇 mL). A 5% argon sodium hydride solution (1000 mL) was added to the precipitate and the suspension was stirred at 60 ° C for 2 hours. The mixture was cooled to room temperature and stored at room temperature for 3 days, during which time a precipitate formed, and the precipitate was collected by filtration, washed with water and dried under reduced pressure to give 22 2 g (67 〇 /.) 1-(3- Bromo-4-fluorophenyl)thiourea·, !H-NMR (300 MHz, DMSO-^6) 8 = 7.34 (dd, 1Η), 7.35 (ddd, 1H), 7.59 (br, 2H), 7.85 ( Dd,1H) 9.75 (br,1H) ppm. 1-(3-/odor-4-pyrene)thiourea (3.77 g' i5. i mmol) was dissolved in acetic acid (156 mL) and cooled to ht. Add bromine (3 63 g, 22 7 claws of acetic acid (69 mL) and heat the mixture to 1 1 after 15 minutes to keep it for 2 hours. Add sodium bisulfite solution and rapidly heat the mixture with vigorous stirring. 100 C 'The mixture loses bromine color during this period. The lower concentration of the mixture was suspended in aqueous ammonia and the basic mixture was extracted several times with dioxane. The organic extract was concentrated and dissolved in methanol (4 mL). Water (60 mL) was added and collected by filtration The precipitate formed was purified by chromatography (containing 12 to 50% ethyl acetate in hexane) to give 〇9〇g (23%) 5H扃-factor 3-茗# thiazol-2- Waste / 4 NMR (300 MHz, DMSO-〇?6) δ=7·57 (d,1H), 7.67 (s, 2H), 7.78 (d,1H) ppm. To 5·bromo-6- Fluorine-1,3-benzothiazol-2-amine (590 mg, 2.39 mmol) 156931.doc -49- 201206485 methyl"bibromide (3 mL) with copper cyanide (1) and heating the mixture to 200 C After cooling to room temperature, sodium bicarbonate solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated nh 4 ci solution and brine, dried over sodium sulfate and concentrated. (Chromatography of 2% to 40% ethyl acetate) and the residue was purified by trituration with methylene chloride to give 127 mg (25%) as a white solid. 300 MHz, DMSO-A) δ = 7.76 (d 1Η), 7.84 (s, 2Η), 7.93 (d, 2Η) ppm. To a solution of 2-amino-6-fluoro-1,3-benzothiazol-5-carbonitrile (2 g, 10.3 mmol) in acetonitrile (120 mL) was added EtOAc. Hey. Acetonitrile (1.6 g, 15.5 mmol) containing acetonitrile (1 〇〇 mL) was slowly added and the mixture was stirred for 3.5 hours. Ethyl acetate was added and the mixture was washed with a saturated NH.sub.4Cl solution, saturated sodium bicarbonate solution, brine and water. After evaporating the solvent, the residue was purified by chromatography (yield: hexanes to 5 hexanes of dioxane) to give 250 mg (ll%) as solids. -&lt;5-year-person 3·哀# ^ ψ^ : ·η NMR (300 MHz, DMSO-^6) 6=8.35 (d, 2Η), 8.67 (d, 1Η) ppm. DMF containing 2-gas-6-fluoro-1,3-benzothiazol-5-carbonitrile (75 mg, 0.35 mmol) was added to stirred potassium carbonate (97.5 mg, 0.70 mmol) and 1H-. The suspension of oxazol-3-amine (29.3 mg' 0.35 mmol) in DMF (0.47 mL) was heated to 80 C for 6.5 h. The mixture was poured into ice water and mixed for 10 minutes. The precipitate formed was collected by filtration and washed thoroughly with water. Wet-precipitate under ultrasonic irradiation in a mixture of methanol, acetic acid and a gas (1:1:1, 10 mL). After filtration, 19 mg (19%) of title compound 156931.doc -50- 201206485 Matter 4. NMR (400 MHz, DMSO-J6) 8 = 5.85 (s, 2 Η), 6.01 (d, 1 Η), 8.23-8.28 (m, 2 Η), 8.32 (d, 1H) ppm. ESI-MS m/ z 260 (M+l). L-[6_Ga-5-(trifluoromethyl)-1,3-benzene-salt-salt-2-yl]-111-»*--3-amine 5

F

Phenylhydrazine chloride (1.53 g, 10.8 mmol) was added to a solution of ammonium thiocyanate (0.94 g, 12.4 mmol) in acetone (17 mL) over 5 min and the mixture was refluxed for 15 min. Acetone (14 mL) containing 2-bromo-4-fluoro-5-(trifluoromethyl)aniline (2. g, 7.7 mmol) was added to the mixture at 40 ° C and reflux was continued for 9 min. The hot solution was poured onto ice (100 mL) and the mixture was stirred for 5 min until a precipitate formed, and the precipitate was collected by filtration and washed with 50% aqueous methanol (3 mL). A 5% sodium hydroxide solution (1 〇〇 mL) was added to the sump and the suspension was stirred at 6 ° C for 2 hours. The mixture was cooled to room temperature and extracted with diethyl ether and ethyl acetate. The combined organic extracts were washed with brine and concentrated under reduced pressure to give &lt;1&gt;&lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&& 5=7.45 (br., 2H), 7.96 (d, 1H), 8.01 (d, 1H), 9.42 (s, 1H) ppm. Adding carbonic acid (2.0 g to 1·[2_bromo-4-fluoro-5-(trifluoromethyl)phenyl]thiourea (1.0 g, 3.15 mmol) which was dried under high vacuum and flushed with argon 6.3 mmol), copper (i) (3 〇 mg, 〇 · 16 mmol), DL-proline (36 mg, 0.32 mmol) and DMSO (ll mL). Stir the mixture at room temperature, 156931.doc •51 · 201206485 During this period, add copper iodide (1) (30 mg, 0.16 mm〇i), DL-proline at 30, 60, 120 and 150 minutes. (36 mg, 0.32 mmol) and DMS oxime (5 mL). After 3 hours, the mixture was quenched with a saturated aqueous NH4CI mixture of ice water and stirred for 5 min and then basified with aqueous ammonia. The aqueous phase was extracted several times with dichlorohydrazine. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated evaporated evaporated. Μ f : !H NMR (400 MHz, DMSO-i/6) 5 = 7.53 (d, 1H), 7.76 (s, 2H), 7.88 (d, 1H) ppm. To 6-fluoro-5-(3) Fluoromethyl)-1,3-benzoindole _2_amine (220 §, 0.93 mmol) B (18 mL) was added with copper (11) (188 mg, 1.4 mmol) and the mixture was cooled. To 〇 ° C. Acetonitrile (9 mL) containing tributyl sulfoxide (丨 44 mg ' 1.4 mmol) was slowly added and the mixture was stirred at 0 ° C for 30 min and then at room temperature for 3.5 h. The mixture was diluted with ethyl acetate, washed with saturated NHCl solution, saturated sodium bicarbonate solution, brine and water. Evaporation yielded 100 mg (35%) 2-扃-(5-year--5-(three-year-old difference) )-人3-茗#thiazepine*· !H NMR (400 MHz, DMSO-i/6) 5 = 8.37 (d, 1H), 8.43 (d, 1H) ppm. Contains 2-gas-6-fluoro -5-(trimethylmethyl)-1,3-benzoate. Sodium (100 mg, 0.39 mmol) in DMF (3.2 mL) and acetonitrile (3.2 mL) were added to the mixed carbonate (81 mg) , 0.59 mmol) and 1H-0 to 0 all-3- (39 mg, 0.47 mmol) in a suspension of DMF (2.1 mL) and acetonitrile (2.1 mL) and heated to 70 ° C for 90 minutes. Add carbon 156931 after 15, 30, 45, 60 and 75 minutes. .doc -52- 201206485 Acid planer (81 mg '0.59 mmol). The mixture was poured into ice water and mixed for 1 min. The precipitate formed was collected by filtration and washed with water to give 55 mg (44%) of title compound. 5. 1U NMR (400 MHz, DMSO-c? 6) 5 = 5.84 (s, 2H), 6.01 (d,

1H), 8.09 (d, 1H), 8.24 (d, 1H) 8.25 (d, 1H) ppm 〇ESI-MS m/z 303 (M+l) o 2-(3-Amino-111-0 ratio spit -1-yl)-6-true*yl-1,3-1,3-benzopyrene _5-carbonitrile 6

Phenylhydrazine gas (6.4 mL, 54.9 mmol) was added to a solution of ammonium thiocyanate (5.0 g, 65.5 mmol) in acetone (174 mL) and the mixture was refluxed for 15 min. 1,5-Dibromo-4-mercaptoaniline (11.6 g, 39.2 mmol, C. Wang et al., 2003, 73, 2089-2095) was added to the mixture at 40 C and reflux was continued for 14 hours. . The hot solution was poured onto ice (2000 mL) and mixture was applied for 5 min to form a precipitate, and the precipitate was collected by filtration and washed with aqueous solution of EtOAc (100 mL). A 5% sodium hydroxide solution (400 mL) was added to the precipitate and the suspension was stirred at 60 ° C for 4 hours. The mixture was cooled to room temperature and passed. The filtrate was thoroughly extracted with a mixture of ethyl acetate and then a mixture of diethyl ether (50 °/.). The combined extracts were dried over sodium sulfate and evaporated <RTI ID=0.0></RTI> EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj s.,1 Η) 8.40 (br. s., 1 Η) 8.41 (s, 1 Η) 8.45 (s, 1 Η) 9.57 (br, 1H) ppm ο 156931.doc -53- 201206485 To the high vacuum Add cesium carbonate (5 32 g, 16 3 mmol), moth copper (1) to N(2,5-dibromo-4-ylphenyl)thiourea (2.9 g, 8.17 mmol) which was dried and flushed with argon. (77.8 mg '0.41 mmol), DL-proline (94 mg '0.82 mmol) and DMS0 (30 mL) » Mix the mixture at room temperature, repeating after 30, 60 and 90 minutes during this period Copper moth 0) (77 8 mg, 0.41 mmol), DL-proline (94 mg, 0.82 mmol) and DMSO (10 mL). After 2 hours, the mixture was quenched with a saturated aqueous H.sub.2Cl.sub.1 solution and stirred for 5 min and then basified with aqueous ammonia. The aqueous phase was extracted several times with a mixture of dioxane-nonanol (10:1). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporatedsssssssssssssssssssssss 6) δ = 7.65 (s, 1H) 8.29 (s, 2H) 8.51 (s, 1H) ppm. Add liquefied copper (ι·24 g) to B. (160 mL) containing 5-bromo-6-nitro-1,3-benzothiazol-2-amine (2.14 g, 8.35 mmol). 9.2 mmol) and cool the mixture to Ot:. A third butyl nitrite (丨.29 g, 12.5 mmol) in acetonitrile (52 mL) was slowly added and taken. (The mixture was stirred for 30 minutes and stirred at room temperature for another 2 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaCI solution, saturated sodium hydrogen carbonate solution, brine and water. After evaporation of solvent, residue was taken on silica gel. Purification by chromatography (70% dioxane in hexanes) afforded 1.28 g (52%) of 5- </ RTI> </ RTI> 扃 扃 ( ( ( 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻 噻, DMSO-t/6) 5 = 8.56 (s, 1H), 8.92 (s, 1H) ppm ° contains 5·&gt; odorous 2-chloro-6-nitro-1,3-benzo. 500 mg, 1.7 mmol) of DMF (14 mL) and acetonitrile (14 mL) were added to stirred cesium carbonate (353 156931.doc •54-201206485 mg, 2.56 mmol) and 1H-pyrazol-3-amine (170) Mg, 2.04 mmol) in a suspension of DMF (9 mL) and acetonitrile (9 mL) and warmed to 5 〇〇c for 30 min. then added a carbonated hammer (176 mg, 1.27 mmol) and continued at 5 〇 ° Stir for 60 minutes at C and stir for 90 minutes at 70 ° C. The mixture was poured into ice water and mixed for 10 minutes. The precipitate formed was collected by extraction with ethyl acetate. The organic phase was washed with brine under reduced pressure. Concentrated and chromatographed on silica gel (0 to 20% B) Purification of ethyl ester dichloromethane + 0.2 〇 / 〇 triethylamine), 300 mg (49% W5-涝-&lt;ί-break-eight-8-茗#thiazepine_2_po) ^-3- m ' *H NMR (300 MHz, DMSO-i/6) 5=5.98 (s, 2H), 6.05 (d, 1H), 8.18 (s, 1H), 8.28 (d, 1H), 8.84 (s, 1 H) ppm ° to 1 0 containing 1-(5-bromo-6-nitro-1,3-benzothiazol-2-yl)-1H-pyrazol-3-amine (200 mg, 0.59 mmol) Copper cyanide (1) (68 mg, 0.76 mmol) was added to ml 1,2-dimercaptoimidazole. The microwave vessel was closed and irradiated in a microwave reactor (CEM discover) at 100 ° C for 10 minutes at 120 ° C. The reaction mixture was further stirred for 3 hours. The reaction mixture was taken with EtOAc EtOAc (EtOAc) Dichloromethane (50 mL) was added and stirred. The precipitate formed was collected by filtration and purified on silica gel eluting with EtOAc (EtOAc: EtOAc 26 mg (13%) of title compound 6 »

!H NMR (400 MHz, DMSO-^6) 6 = 6.01 (br, 2 H) 6.09 (d, 1H) 8.33 (d, 1 H) 8.45 (s, 1 H) 9.23 (s, 1 H) ppm. ESI-MS m/z 287 (M+l). 156931.doc -55· 201206485 2-(3•Amino-1H-pyrazol-1-yl)·6-fluoro-1,3-benzothiazole-5-formaldehyde l〇

Add 1 to 2 toluene solution of diisobutylaluminum hydride (0.93 mL, 0·93 mmol) to 2-(3-amino-1Η-ΠΛ°-1-yl)-6-fluoro at -30 °C -1,3-Benzene ° plug. A solution of -5-indoleonitrile (40 mg, 0-1 54) in THF (mL) was taken and stirred for 3 h. Acetone (1 mL) was added and the mixture was quenched with saturated sodium tartrate. After extraction with ethyl acetate for several times, the organic phase was concentrated under reduced pressure and purified by chromatography eluting with EtOAc (EtOAc (EtOAc) Compound 10. !H-NMR (400 MHz, CDC13) δ=4.08 (br.5 2H), 6.00 (d, 1H), 7.61 (d, 1H), 8.21 (d, 1H), 8.25 (d, 1H), 10.41 ( s, 1H) ppm. LC/MS ES+ m/z 262.9 (M+l). 2-(3-Amino-pyrazol-1-yl)-benzothiazole-6-olol 11

Stir 2-gas-6-methoxybenzothiazole (500 mg, 2.5 mmol), 3-aminopyrazole (416 mg, 5.0 mmol) and K2C03 (1.38 g, 10 mmol) in DMF at 100 ° The mixture in (10 mL) was allowed to stand for 24 hours. The reaction mixture was poured into water and extracted with dioxane. The combined organic phases were washed with brine and dried over sodium sulfate to &lt; The residue was purified by chromatography to give 270 mg (yield: 440 / s) of 7-(^- sssssssssssssssssssssss =8.18 (d, 1Η), 7.62 (d I56931.doc -56- 201206485 1H), 7.55 (d, 1H), 7.00 (dd, 1H), 5.88 (d, 1H), 5.60 (br s, 2H), 3.77 (s,3H) ppm. ESI-MS m/z 247 (M+l). 1-(6-methoxy-benzothiazol-2-yl)-lH-»biazole-3-ylamine ( 179 mg, 0.73 mmol) was suspended in dichloromethane (η mL) and ΒΒγ3 (1 Μ in CH2C12, 11 mL, 11 mmol) was slowly added at 0 ° C. After 4 hours, sterol was slowly added and stirred. The mixture was concentrated for 1 min and then concentrated. The residue was crystallised eluted eluted eluted eluted eluted eluted -DMSO): 6=9.60 (s, 1H), 8.15 (d, 1H), 7.52 (d, 1H), 7.26 (d, 1H), 6.84 (dd, 1H), 5.86 (d, 1H), 5.57 ( Br s,2H) ppm.ESI-MS m/z 233 (M+l). 3-Amino-1-(6-hydroxy-benzothiazol-2-yl)-1Η-pyrazole-4_carboxylic acid Ester 12

Stir 3-ethyl-1H-pyrazole-4-furoate (73 〇 mg, 4 71 mmol), potassium carbonate (1·3 g, 9.42 mmol) and 2-gas 6-methoxybenzene at 50 °C And the mixture of thiophene (940 mg, 4.71 mmol) in DMF 'pour into water and extracting mmol with dioxane) in DMF (20 mL) 3 〇 small gas broth extract ° combined organic phase with brine Washed, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to afford 738 mg (49%) of 3- s. s. s&gt; iH), 7.78 (d, 1H), s' 2H), 4.37 (q, 2H), *Η-ΝΜΚ (300 MHz, CDC13): 5=8.69 (s, 7.33 (d, 1H), 7.10 ( Dd, 1H), 5.1 (br s 156931.doc •57- 201206485 3.92 (s, 3H), 1.41 (t, 3H) ppm. ESI-MS m/z 319 (Μ+l). 3 at 〇°C -Amino-1-(6-methoxybenzothiazol-2-yl)_1H_pyrazole_4_ethyl decanoate (50 mg '0_ 16 mmol) suspended in di-methane methane 〇 5 mL) Treated with tribromoborane (1 Μ in di- methane, 1.57 mL, 1.57 mmol). After dissolved and completely converted, 'add methanol and mix the reaction mixture for 10 min at room temperature' then evaporate the solvent in vacuo. The material was dissolved in decyl alcohol and concentrated twice more. The final residue was purified by chromatography on silica gel to afford 16.5 mg (34 ° / 〇) of compound 2a. ^-NMR (300 MHz, MeOD): δ = 8.60 ( s, 1Η), 7.62 (d, 1H), 7.23 (d, 1H), 6.94 (dd, 1H), 4.30 (q, 2H), 1.35 (t, 3H) ppm. ESI-MS m/z 305 (M +l), 303 (Ml). l-[6-(2-Gas-ethoxy)-benzoindole-2-yl]sal-3-ylamine 13

0XXV^NH2 2-(3-Amino-.pyridin-1-yl)-stupid and oxime-salt-6-alcohol 2 (50 mg, 0.22 mmol) dissolved in DMF (1 mL) with fluoro-2 - Iodoethane (45 mg, 0.26 mmol) and Cs2C03 (168 mg '0.52 mmol). After 24 hours at room temperature, the reaction mixture was poured into water and the precipitate was filtered, washed with water and dried to give 38 mg (63%) Compound 13. 'H-NMR (300 MHz, d6-DMSO): 5 = 8.18 (d, 1H), 7.63 (d, 1H), 7.60 (d, 1H), 7.04 (dd, 1H), 5.89 (d, 1H), 5.61 (br s, 2H), 4.80 (dd, 1H), 4.65 (dd, 1H), 4.30 (dd, 1H), 4.20 (dd, 1H) ppm. ESI-MS m/z 279 (M+l) o 3-Amino-l-[6-(2-fluoro-hexyloxy)-benzoxanthene·2·yl] 156931.doc ·58· 201206485 Formic acid Ethyl ester 14

Ch3 Stabilize 3-amino-1-(6-carbylbenzo[beta]-septyl-yl)-1 Η- at room temperature. 〇4- 曱 4-ethyl decanoate 12 (100 mg, 0.33 mmol), Cs2C 〇 3 (257 mg, 0.79 mmol) and fluoro-2-deethhin (69 mg '0.39 mmol) in DMF (2 mL) The mixture was taken for 1 hour. The reaction mixture was dissolved in ethyl acetate and water, followed by phase separation. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by chromatography on silica gel to afford 76 mg (66%). 'H-NMR (300 MHz, d6-DMSO): 6=8.61 (s, 1H), 7.73 (d, 1H), 7.66 (d, 1H), 7.11 (dd, 1H), 6.03 (br s, 2H) , 4.81 (dd, 1H), 4.65 (dd5 1H), 4.32 (dd, 1H), 4.22 (m, 4H), 1.27 (t, 3H) ppm. ESI-MS m/z 351.27 (M+l). 1-(6-fluoromethoxy-benzothiazol-2-yl)-1Η-pyrazol-3-ylamine 15

2-(3-Aminoguanidin-1 -yl)-benzoindole-6-ol 11 (50 mg, 0.22 mmol) was dissolved in DMF (1 mL) and NaH (10 mg) , 0.46 mmol '60%) for 1 hour. Bromofluorosilane (111 mg, 〇 99 111111〇1) was dissolved in DMF (1 mL) and added slowly. The reaction mixture was stirred at room temperature for 20 minutes and poured into water. The precipitate was filtered off, washed with water and purified by EtOAc EtOAc EtOAc EtOAc 'H-NMR (400 MHz, CDC13): 6 = 8.19 (d, 1H), 7.74 (d, 1H), 156931.doc •59· 201206485 7.52 (d,1H), 7.19 (dd,1H), 5.95 ( d, 1H), 4.04 (br s, 2H), 5.75 (d, 2H) ppm. LC/MS ES+ m/z 265.1 1 (M+l). L-[6-(3_Fluoropropoxy)-benzothiazole-2-yloxazol-3-ylamine 16

2-(3-Amino-pyrazol-1-yl)-benzothiazole-6-ol 11 (50 mg, 0.22 mmol) was dissolved in DMF (1 mL) eluted with Cs2C03 (168 mg, 0.52 mmol) 1- Desert-3-fluoropropanol (36.4 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 30 minutes and poured into water. The precipitate was filtered, washed with water and purified by silica gel chromatography eluting eluting eluting 'H-NMR (400 MHz, d6-DMSO): 8 = 8.18 (d, 1H), 7.62 (d, 1H), 7.58 (d, 1H), 7.01 (dd, 1H), 5.88 (d, 1H), 5.61 (br s, 2H), 4.59 (ddd, 2H), 4.09 (t, 2H), 2.09 (dddd, 2H) ppm. LC/MS ES+ m/z 293.08 (M+l). L-[6-(3-Fluoro-cyclobutoxy)-benzothiazole·2-yl]-1H-pyrazol-3-ylamine 17

3-[2-(3-Amino-pyrazol-1-yl)-benzothiazole·6-ylyl]-cyclobutyl ester 4?(35 mg, 0.077) is dissolved in THF (1 mL). TBAF (36 mg, 0.11 mmol) was added and the reaction mixture was stirred at 75 ° C for 5 h. The mixture was concentrated and the residue was purified by chromatography eluting eluting eluting !Η-ΝΜΚ (300 MHz, CDC13): 6 = 8.18 (d, 1H), 7.7〇 (dj 156931.doc •60- 201206485 1H), 7.16 (d, 1H), 6.96 (dd, 1H), 5.94 ( d, 1H), 4.86 (dddd, 1H), 4.28 (m, 1H), 4.00 (br s, 2H), 3.06 (m, 2H), 2.50 (m, 2H) ppm. LC/MS ES+ m/z 305.16 (M+l). Toluene·4-sulfonic acid 2-[2-(3-Amino-oxazol-1-yl)-benzothiazol-6-yloxy]-ethyl ester 18

2-(3-Amino-pyrazol-1-yl)-benzothiazole-6-ol 2 (50 mg '0.22 mmol) was dissolved in DMF (1 mL) using Cs2CO3 (105 mg &lt; Treatment with ethylene glycol-di-(p-nonyl phthalate) (399 mg, 1.08 mmol). The reaction mixture was stirred at 50 °C for 2 hours and poured into a saturated NH4Cl solution. The precipitate was filtered, washed with water and purified by chromatography eluting eluting ^-NMR (400 MHz, d6-DMSO): 6 = 8.18 (d, 1H), 7.75 (d, 2H), 7.59 (d, 1H), 7.46 (d, 1H), 7.42 (d, 2H), 6.89 (dd, 1H), 5.89 (d, 1H), 5.62 (br s, 2H), 4.32 (m, 2H), 4.17 (m, 2H), 2.36 (s, 3H) ppm. LC/MS ES+ m/z 43 1.35 (M+l). Toluene-4-sulfonic acid 3-[2-(3-amino-oxazol-1-yl)-benzothiazol-6-yloxypropylpropyl ester 20

2-(3-Amino-pyrazol-1-yl)-benzothiazole-6-ol 11 (50 mg, 0.22 156931.doc -61 · 201206485 mmol) dissolved in DMF (1 mL) using Cs2CO3 ( 105 mg, 0.32 mmol) and 1,3-propanediol-di-(p-toluene acid ester) (413 mg, 1.08 mmol). The reaction mixture was stirred at 50 ° C for 2 hours and poured into a saturated NH 4 C 1 solution. The precipitate was filtered off, washed with water and purified by chromatography on silica gel to afford 37 mg (3 8%) Compound 20. JH-NMR (300 MHz, CDC13): 5 = 8.18 (d, 1H), 7.75 (d, 2H), 7.67 (d, 1H), 7.22 (d, 2H), 7.12 (d, 1H), 6.88 (dd , 1H), 5.94 (d, 1H), 4.27 (t, 2H), 4.00 (br s, 2H), 3.99 (t, 2H), 2.33 (s, 3H), 2.14 (p, 2H) ppm. LC/MS ES+ m/z 445.20 (M+l). Toluene-4-sulfonic acid 3-[2-(3-amino-oxazol-1-yl)-benzothiazol-6-yloxy]-cyclobutyl ester 21

2-(3-Aminopyrazol-1-yl)-benzothiazole-6-ol 11 (120 mg, 0.52 mmol) was dissolved in DMF (3 mL) eluted with Cs2C03 (252_5, 0.77 mmol) Treatment with 3-cyclobutanediol bis(4-mercaptobenzenesulfonate) (205 mg, 0.52 mmol). The reaction mixture was stirred at 40 ° C for 11 hours and poured into a saturated NH 4 C 1 solution. The precipitate was filtered off, washed with water and purified by chromatography eluting eluting ^-NMR (400 MHz, CDC13): 6 = 8.17 (d, 1H), 7.80 (d, 2H), 7.67 (d, 1H), 7.36 (d, 2H), 7.05 (d, 1H), 6.88 (dd , 1H), 5.93 (d, 1H), 5.08 (m, 1H), 4.85 (m, 1H), 4.00 (br s, 2H), 2.67 (m, 2H), 2.56 (m, 2H), 2.46 (s , 3H) ppm. LC/MS ES+ m/z 156931.doc -62-201206485 457.17 (M+l) » Toluene-4-sulfonic acid 2-[2-(3-di-t-butoxycarbonylamino-pyrazolyl) -benzothiazole·6-yloxy]-ethyl ester 22

Benzene 4-sulfonic acid 2-[2-(3-amino.pyrazol-1-yl)benzothiazole-6-yloxy;| Ethyl ester 18 (100 mg, 0.23 mmol) dissolved in two gas In methane (3 mL). Boc2O (200 mg, 0.93 mmol), triethylamine (94 mg, 0.93 mmol) and DMAP (6 mg, 0.05 mmol) were added. The reaction mixture was stirred at 50 ° C for 4 hours and the volume was reduced. The residue was purified by chromatography on EtOAc (EtOAc) (EtOAc) (d, 1H), 7.34 (d, 2H), 7.17 (d, 1H), 6.95 (dd, 1H), 6.43 (d, 1H), 4.41 (t, 2H), 4.22 (t, 2H), 2.44 ( s, 3H), 1.48 (s, 18H) ppm. LC/MS ES+ m/z 63 1.38 (M+l). N-[l-(6----benzo-3-indenyl-3-yl)-ethanoamine 23

1-(6-Bromo-benzothiazol-2-yl)-1 Η-pyrazol-3-ylamine 1 (50 mg, 0.17 mmol) was dissolved in EtOAc (1 mL). Acetic acid needle (0.048 mL, 0.5 1 mmol) and DMAP (6 mg, 0.05 mmol) were added. The reaction mixture was mixed at room temperature for 156931.doc -63 - 201206485 for 20 hours and poured into a saturated NH4C1 solution. The precipitate was filtered, washed with water and purified by chromatography eluting elution ^-NMR (300 MHz, d6-DMSO): 5 = 10.98 (s, 1H), 8.51 (d, 1H), 8.32 (d, 1H), 7.77 (d, 1H), 7.62 (dd, 1H), 6.94 (d, 1H), 2.03 (s, 3H) ppm. LC/MS ES+ m/z 237.23 (M). 3-[2-(3-Amino-pyrazol-1-yl)-benzothiazol-6-yl]-propyl methanesulfonate 24

Allyl alcohol (62.52 pL, 0.92 mmol) was dissolved in THF (3 mL) at EtOAc. 9-BBN (5.52 mL, 2.76 mmol, 0.5 Μ in THF) was added slowly. The reaction mixture was stirred at room temperature for 17 hours. N-[1-(6-Bromo-benzothiazol-2-yl)-1Η-pyrazol-3-yl]-acetamide 23 (155 mg y 0.46 mmol) was suspended in DMF (2 mL). Pd(Ph3)4 (106 mg '0.092 mmol) and carbonic acid offload (0.8 mL, 2.4 mmol, 3 Μ in water) were added. The two reaction mixtures were brought together and stirred at 65 ° C for 4 hours. The solution was concentrated and the residue was crystallised eluted eluted eluted The residue was purified by chromatography on silica gel to give mg{59°A) N-{l-[6-(3-hydroxypropyl)benzothiazol-2-yl]-1H-port ratio -Base}-acetamide. ^-NMR (400 MHz, d6-DMSO): 8 = 10.96 (s, 1H), 8.50 (d, 1H), 7.84 (d, 1H), 7.74 (d, 1H), 7.31 (d, 1H), 6.91 (d, 1H), 4.47 (t, 1H), 3.39 (m, 2H), 2.70 (t, 2H), 2.03 (s, 3H), 1.73 (m, 2H) ppm. LC/MS ES+ m/z 217.16 (M+l). 156931.doc •64- 201206485 〇C-{1·[6-(3-hydroxy-propyl)benzothiazole^- 丨 丨 丨 3 3 3 - - - - - - - - - - - - - ( 〇38 mm〇i) was dissolved in dioxane (5 mL). Methane sulfonium chloride (〇 59 mL, 〇 % mm 〇 1) and triethylamine (0·21 mL, ι·52 mmol) were added. The reaction mixture was stirred at room temperature for 2 hrs, diluted with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by chromatography on EtOAc (EtOAc:EtOAc) ^-NMR (400 MHz, CDC13): 5 = 8.35 (d, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.64 (s, 1H), 7.31 (d, 1H), 7.07 (d , 1H), 4.26 (t, 1H), 3.01 (s, 2H), 2.88 (t, 2H), 2.21 (s, 3H), 2.14 (m, 2H) ppm. LC/MS ES+ m/z 395.18 (M+l). N-{l-[6-(3-fluoropropyl)-benzothiazol-2-yl]_iH-carbazol-3-yl}acetamidine 25

3-[2-(3-Amino-pyrazol-1-yl)-benzothiazol-6-yl]•propyl ester methanesulfonate 24 (80 mg' 0.2 mmol) was dissolved in THF (3 mL). TBAF (96 mg, 0.3 mmol) was added and the reaction mixture was stirred at 75 ° C for 5 hr and concentrated. The residue was purified by chromatography on silica gel to afford 30 mg (47%). ^-NMR (400 MHz, CDC13): 5 = 8.35 (d, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.64 (s, 1H), 7.31 (d, 1H), 7.07 (d , 1H), 4.48 (dt, 2H), 2.88 (t, 2H), 2.21 (s, 3H), 2.08 (m, 2H) ppm. LC/MS ES+ m/z 319.24 (M+l) 0 l-[6-(3-fluoro-propyl)-benzothiazol-2-yl]-1H-indazol-3-ylamine 26 156931.doc •65· 201206485

Ν-{1-[6-(3-Fluoropropyl)-benzothiazole·2_yl]· 1H_nbiazole _3_yl}acetamidamine 25 (30 mg, 0.09 mmol) in 0.5 M sodium hydroxide The ethanol solution (〇5 ml, 0.25 mmol) was stirred for 48 hours and then heated to 4 (rc was maintained for 8 hours (3 mL). The reaction mixture was neutralized and concentrated with 1 M hydrochloric acid. Purification gave 3.7 mg (14%) of compound 26. NMR (400 MHz, CDC13): 5 = 1.99-2.16 (m, 2 Η), 2.82- 2.92 (m, 2 H), 4.03 (br. s· , 2 H), 4·43 (t, 1 H), 4.55 (t, 1 H), 5.96 (d, 1 H), 7.29 (d, 5 H), 7.63 (d, 1 H), 7.74 (d , 1 H), 8.22 (d, 1 H) ppm. LC/MS ES+ m/z 277.19 (M+l) 〇4-Fluoro-N-[l-(6-methoxy-benzoxazole_2 _ )) azole _3_ base] _ benzamide 27

1-(6-decyloxy-benzo.ca. sit-2-yl)-1Η-° ratio. The _3_ylamine (145 mg, 0.59 mmol) was dissolved in pyridine (4 mL). 4-Fluorobenzoguanidine chloride (〇.097 mL, 〇·82 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes, followed by the addition of heptane (30 mL). After 10 minutes, the precipitate was filtered, washed with EtOAc (EtOAc) !H-NMR (400 MHz, d6-DMSO): 5 = 11.41 (s, 1H), 8.56 (d, 1H), 8.10 (dd, 2H), 7.75 (d, 1H), 7.65 (d, 1H), 7.33 (dd, 2H), 7.08 (m, 2H), 3.80 (s, 3H) ppm. ESI-MS m/z 369.19 (M+1)° 156931 .doc •66· 201206485 3-Amino-1-(6-methylindolyl- benzothiazol-2-yl)iH-pyrazole·4carboxylic acid 2_ Fluoro-ethyl ester 34

3_Amino-1-(6-methoxy-benzothiazol-2-yl)_m_indoleazole aspartate (150 mg '0_47 mmol) dissolved in ethanol (6 mL) with hydr Na (760 mg, 18.84 mmol) treatment. After stirring the suspension for 48 hours, 2N HCl was added until pH 3, the precipitate was filtered, washed with water and 6 mL cold dioxane / ethanol 1 / 1 and dried in vacuo to give 88 mg (65%) 3 蜃 _ _ ^_ methoxy-本本°°°°-2-yl)-1Η-α ratio. Formic acid a H-NMR (300 MHz, d6-DMSO): 8 = 8.55 (s, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.06 (dd, 1H), 5.99 (br s, 2H), 3.79 (s, 3H) ppm. ESI-MS m/z 291.21 (M+l). To 3-amino-1-(6-methoxy-benzoindole_2-yl)-1H-D ratio 〇-4-decanoic acid 13 (84 mg, 0.29 mmol), 2-fluoroethane (20 mg, 0.32 mmol) and a mixture of BOP (141 mg, 0.32 mmol) in DMF (5 mL). After stirring at 50 ° C for 30 hours, the mixture was concentrated and the residue was purified by chromatography to give 4 mg (4%) Compound 12. ^-NMR (300 MHz, d6-DMSO): 6 = 8.71 (s, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.12 (dd, 1H), 6.10 (br s, 2H), 4.83 (dd, 1H), 4.67 (dd, 1H), 4.53 (dd, 1H), 4.45 (dd, 1H), 3.84 (s, 3H) ppm. ESI-MS m/z 337.4 (M+l). 156931.doc -67 - 201206485 N-[1-(5-Cyano-6-fluorobenzothiazol-2-yl)_ih-pyrazol-3-yl]-acetamidine 35

DMF (0.15 ML) containing 2-gas-6-fluoro-1,3-propenyl-5-indole (5 mg, 0.24 mmol) was added to the certified carbonic acid (65 mg, 0.47) Methyl) and 3-ethyl-decylaminopyrazole (29.4 mg, 0.24 mmol) in a suspension in DMF (.32 mL). The mixture was poured into ice water and stirred for 10 minutes. The precipitate formed was collected by filtration and washed thoroughly with water: The residue was purified by chromatography (EtOAc EtOAc:EtOAc: 'H-NMR (400 MHz, DMSO-^6) 6=2.07 (s, 3 Η), 7.00 (d, 1 Η), 8.31 (d, 1 Η), 8.48 (d, 1 Η), 8.56 (d , 1 Η), 11.05 (s, 1 H) ppm. ESI-MS m/z 300 (M-l). 1-(6-fluorothiazolo[5,4-b]pyridin-2-yl)-lH-pyrazol-3-amine 36

Awkward brewing gas (5.8 mL, 50 mmol) was added to a solution of thiocyanate (4 35 g, 57 mmol) in acetone (79 mL) and the mixture was refluxed for 15 min. To a mixture of fluorene (52 mL) containing 6-fluoro-pyridin-3-amine (4.0 g, 35.7 mmol) at 40 C was added and the mixture was refluxed for 1.5 hours. The hot solution was poured onto ice water (4 mL) and mixture was allowed to stand for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% aqueous methanol (50 mL). A 5% sodium hydroxide solution (200 mL) was added to the precipitate at 60. (The suspension was stirred for 2.5 hours. Cooling 156931.doc •68·201206485 The mixture was allowed to reach room temperature and then extracted well with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate and evaporated under reduced pressure. 5 9 g of {9VA)l-(6-fluoropyridin-3-yl)thiourea were obtained. 丨H-NMR (400 MHz, DMSO-A) δ=7.15 (dd, 1H), 7.40 - 7.90 (br, 2H), 8.05 (ddd, 1H), 8.17 (dd, 1H), 9.82 (br. s., 1H) ppm. 1-(6-Fluoro&quot;Bitter-3-yl)thione (1·〇g' 5.8 mmol) was dissolved in acetic acid (56 mL) and added with water (1.21 g, 7.6 mmol) of acetic acid over 30 minutes. (57 mL). The mixture was heated to 1 ° C for 2 hours and solid sodium hydrogen sulfite was added. The mixture was poured into ice water and stirred vigorously for 5 minutes. Ammonia water was added and the basic mixture was extracted several times with diethyl ether and ethyl acetate. The combined organic extracts were washed successively with aq. EtOAc (aq.) and brine, dried over sodium sulfate, evaporated under reduced pressure, and chromatographed with EtOAc (0 to 100% ethyl acetate) Purification of ethyl acetate containing hydrazine to 20% methanol + 1% triethylamine followed to give Ί3 fluoropurine and [5,4-b] ° ratio -2-amine.· !H NMR (300 MHz, DMSO -i/6) 6=7.00 (dd, 1 Η), 7.77 (br. 2Η), 7.78 (dd, 1 Η) ppm. Adding vaporized copper (11) (66 mg, 0.49) to acetonitrile (6 mL) containing 6-fluoros &quot;sitting and [5,4-b]° bite 2-amine (55 mg, 0.33 mmol) (mmol) and the mixture was cooled to 0 °C. Acetonitrile (3 mL) containing butyl nitrite (58 μM, 0.49 mmol) was slowly added and the mixture was stirred for 3.5 hr. Ethyl acetate was added and the mixture was washed with saturated aq. NH4CI solution, sat. sodium bicarbonate and brine. Evaporate the solvent to give 74 bite: 156931.doc •69-201206485 !H NMR (400 MHz, DMSO-^e) 6=7.46 (dd, 1H), 8.60 (dd, 1H) ppm. Contains 2-gas-6-fluoro" plug. Sit and [5,4-b]e to bite (70 mg, 0.30 mmol) of DMF (2.5 mL) and acetonitrile (2.5 mL) to a stirred carbonated (62 mg '0.45 mmol) and 111-° ratio The suspension of 3-amine (29.6 mg, 0.36 mmol) in DMF (1.5 mL) EtOAc. Heat to 70 ° C for 2.5 hours (after adding additional portions of carbonic acid (60 mg, 0.44 mmol) after 15, 30, 45, 60 and 75 minutes), the mixture was poured into water (20 mL) Stir for 10 minutes. The aqueous layer was extracted with EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) -i/6) 8=5.84 (s, 2 Η), 6.00 (d, 1 H), 7.29 (dd, 1 H), 8.27 (d, 1H), 8.30 (dd, 1H) ppm. LC/MS ES+ m/z 235.9 (M+l). 1-(6-bromoindole sniffing [5,4-1&gt;]&quot; than bite_2-yl)-111-&quot; than salino-3-amine 37

Benzoic acid (1.9 mL, 16.7 mmol) was added to a solution of thiocyanate (1.45 g, 19.1 mmol) in acetone (21 mL) and the mixture was refluxed for 15 min. Acetone (26 mL) containing 3-amino-2,6-dibromopyridine (3.〇g, 11.9 mm〇l, Parlow, JJ; South, MS Tetrahedron 2003, 59, 7695-7702) at 40 °C ) was added to the mixture and reflux was continued for 15 hours. The hot solution was poured onto ice (100 mL) and the mixture was stirred for 5 min to form a precipitate 156931.doc • 70-201206485. The precipitate was collected by filtration and washed with a 5 〇 0 / 〇 aqueous solution (3 〇 mL). A 5% sodium hydroxide solution (1 〇〇 mL) was added to the sump and the suspension was mixed at 60 rpm for 2 hours. The mixture was cooled to room temperature over 7 hours with stirring and filtered. The filtrate was washed with diethyl ether and then extracted with ethyl acetate. The combined extracts were washed with brine &lt;~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (300 MHz, DMSO-^6) 5=7.69 (d, 1H), 8.01 (d, 1H), 9.40 (s,1H) ppm o 1_(2,6) dried under high vacuum and flushed with argon -Dibromopyridin-3-yl)thiourea (4.1 g '13.2 mmol) with cesium carbonate (8.59 g, 26.4 mmol), copper (1) (126 mg, 〇·66 mmol), DL- Proline (152 mg, 1.3 mmol) and DMSO (94 mL). The mixture was stirred at room temperature during which time copper iodide (1) (42 mg, 0.22 mmol), DL-proline (51 mg, 0.44 mmol) and DMSO (5) were repeatedly added after 30, 60 and 90 minutes. mL). After 2 hours, the mixture was quenched with a saturated NH.sub.4Cl solution ice water mixture and stirred for 5 min and then purified to pH 8 with aqueous ammonia. The aqueous phase was extracted several times with a two-gas methane-sterol mixture (10:1). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated The solid crude product was wet-milled with a mixture of hexane-di-methane (10:1) to give 1.6 g (5 1 %) (ί-虏 吆 吆 # [5,4-b]pyridin-2-amine·. !H NMR (400 MHz, DMSO-^6) 6 = 7.42 (d, 1H), 7.56 (d, 1H), 8.00 (s, 2H) ppm. To the mixture containing 6-bromo and [5,4-b] Add liquefied copper (11) (964 mg, 7.2 mmol) to acetonitrile (92 mL) of butyl-2-amine (li g, 4.8 mmol) and cool to mix 156931.doc -71 - 201206485 to 0° C. Slowly add butyl nitrite (739 mg, 72 mmol) in acetonitrile (46 mL) and stir the mixture at 〇 ° C for 3 且 and then at room temperature for further 4 hr. The ester was diluted, washed with saturated NI^C1 solution, saturated sodium bicarbonate solution, brine and water. Evaporation yielded 58 bromo-2- thiazolo[5,4_b]pyridine NMR (300 MHz, DMSO-^6) 5= 7.87 (d, 1 Η), 8.36 (d, 1 6-bromo-2-thiathiazolo[5,4_b]pyridine (58〇mg, 2.3 mm〇1) in DMF (14 mL) and acetonitrile (14 mL) Add to a suspension of the stirred carbonated (482 mg, 3.5 mmol) and 1H-pyrazole-3-amine (212 mg, 2.6 mmol) in DMF (9 mL) and EtOAc (9 mL) 7〇.〇Keep 4 At this time, an additional portion of cesium carbonate (241 mg, 1.7 mmol) was added after 15 '30, 45, 60, 75, 150, 165 and 180 minutes. The mixture was poured into ice water and stirred for 1 〇. The formed precipitate was collected by filtration and washed with water. The precipitate which was dried in vacuo was treated with di-methane for several times and filtered. A mixture of one of the gases was evaporated to give the title compound. 300 MHz, DMSO-(i6) 6=5.90 (s, 2H), 6.03 (d, 1H), 7.69 (d, 1H), 8.05 (d, 1H), 8.28 (d5 1H) ppm ° ESI-MS m/ z 266/268 (M+l) ° 1-(6-iodothiazolo[5,4-b]pyridin-2-yl)-ih-pyrazole-3-amine 38

Benzamidine chloride (284 mg, 2.0 mmol) was added to a solution of ammonium thiocyanate (176 mg 156931.doc -72 - 201206485 2.3 mmol) in acetone (3 mL) and the mixture was refluxed for 15 min. Acetone (2.7 mL) containing 3-amino-2,6-diiodopyridine (0.5 g, 1 45 mm 〇1) was added to the mixture at room temperature and stirring was continued for 3 hours. The solution was poured into ice water and the mixture was stirred for 5 minutes until a precipitate formed, and the precipitate was collected by filtration and washed with 50? A 5% sodium hydroxide solution (50 mL) was added to the sump and the suspension was stirred at room temperature for 2 hrs and filtered. The filtrate was washed with diethyl ether and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and evaporated The combined residue was purified by chromatography (yield: EtOAc to EtOAc: EtOAc (EtOAc) And [5,4_b]pyridinamine: H NMR (300 MHz, DMSO-c? 6) 5 = 7.36 (d, 1H), 7.60 (d, 1H), 7.94 (s, 2H) ppm. Add liquefied copper (h) (45 mg, 〇33 mmol) to acetonitrile (4 mL) containing 6-indole-[5,4-b]pyridine-2-amine (60 mg, 0.22 mmol) The mixture was cooled to Ot: ^ acetonitrile (2 mL) containing tributyl nitrite (33 mg, hexanes &lt (The mixture was stirred for 9 minutes and further stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with saturated NH4CI solution, saturated sodium hydrogen carbonate solution and brine. Sit and [5,4-b]. Bite.. ^NMR (400 MHz, DMSO-^) 5=8.03 (d, 1H), 8.11-8.13 (d, 1H) ppm 0 with 2-gas-6- Iodothiazolo[5,4_b]pyridine (52 mg, 〇18 mm〇1) i DMF (1.1 mL) and acetonitrile (ii mL) were added to the mixed carbonate (36 156931.doc -73- 201206485 mg, 0.26 mmol) and 1H-pyrazol-3-amine (16 mg, 019 mmol) in a suspension of DMF (0.6 mL) and acetonitrile (0.6 mL) and heated to 7 ° C for 1.2 h during this period An additional portion of carbonic acid (40 mg, 0.9 mmol) was added after 10, 20, 30, 40, 50 and 60 minutes. The mixture was poured into ice water and stirred for 10 minutes. The precipitate formed was collected by filtration and washed with water. The precipitate was purified by trituration with a methylene chloride and purified by preparative thin-layer chromatography (30% ethyl acetate, methane methane +1% triethylamine) to afford 10 mg of the title compound. ^-NMR (300 MHz, DMSO-J6) 8 = 5.90 (s, 2 H), 6.03 (d, 1H), 7.69 (d, 1H), 8·05 (d, 1H), 8.28 (d, 1H) ppm. LC/MS ES+ m/z 344.02 (M+l). L-{6-[2-[18F]fluoroethoxy]-1,3-benzothiazol-2-yl}-1Η-°bazol-3-amine [18F]-39

Γ8Π·39 nh2 ι.&gt;κ2·2·2/Κ2ανρ*ηΝ3Ρ MeCN; 120ec, 20 min 2.) 1MHCIt110°C, 5min-1 Capture [18F]fluoride with preconditioned QMA cartridge (Waters) GBq) » Dissolve the active substance using 1.5 mL Kryptofix solution (5 mg K222, 1 mg K2C03, 1.25 mL MeCN, 0.25 mL water) and remove the solvent at 120 ° C under mild nitrogen vapor and add MeCN (2 &gt;&lt; l mL) and evaporate as previously described. Precursor 22 (1.5 11^15〇41^〇]^80+1〇〇4[MeCN) was added and the resulting solution was stirred at 12 ° C for a minute. Aqueous hydrochloric acid (1 Μ '1 mL) was added to the mixture and stirred for a further 5 minutes under U (rc. 156931.doc -74 - 201206485 After the protecting group was cleaved, the solution was diluted with water to a total volume of about 20 mL and passed through the pre- Adjusted tC 18 plus cartridge (Waters). The cartridge was washed with water (10 mL) and lysed with 2 mL of MeCN to provide 1.125 GBq pre-purified product (19% decay correction) with 2.5 mL water (+0.1%) TFA) diluted and prepared by preparative HPLC (ACE 5 C18-HL; 250 x 10 mm; 5 μηι; Advanced Chromatography Technologies, A: water (+0.1% TFA); B: MeCN (+0.1% TFA) isocratic, 45 Purified by % B, 2 ml/min, tR = 9.5 min. The collected HPLC fractions were diluted with 50 mL of water and passed through a pre-conditioned tC18 plus cartridge. The cartridge was washed with 5 mL of water and dissolved with 2 mL of EtOH. 716 MBq of final product [18F]-39 (14%, decay corrected, radiochemical purity &gt; 98%) was provided after a total of 63 minutes of synthesis time. Analytical HPLC was used with non-radioactive F-19 fluoride standard 13 Co-shot to confirm product identity: ACE3-C18 50 mm&gt;&lt;4.6 mm; solvent gradient: 5% acetonitrile (start) -95% B in 7 minutes 0.1% trifluoroacetic acid, flow rate 2 ml/min, tR = 4.1 minutes. HPLC chromatogram of [18F]-39 is shown in Figure 2. l-{6-[3-[18F]fluoropropoxy ]-1,3-benzothiazol-2-yl}-1Η-indazol-3-amine [18F]-40

K2.2.2/K2〇〇3/[1BnNaF MeCN; 120eC, 20 min __^ reF]40 Capture aqueous [18F]fluoride (8.1 GBq) with QMA cartridge (Waters) and use 0.95 ml with 5 mg K2.2.2 MeCN+ 50 μM water containing 1 mg K2C〇3 was dissolved in the reaction vessel. The solvent was removed by heating at 120 ° C for 10 minutes under a stream of nitrogen. Anhydrous MeCN (1 ml) was added and evaporation was carried out as previously described. Add 156931.doc -75- 201206485 A solution of starting material 20 (2 mg) in 500 μM anhydrous MeCN. After heating at 120 ° C for 20 minutes, the crude reaction mixture was analyzed using analytical HPLC: ACE3-C18 50 mm x 4.6 mm; solvent gradient: 5% acetonitrile (starting) - 95% acetonitrile 0.1% trifluoride in 7 minutes Acetic acid, flow rate: 2 mL/min. The desired F-18 labeled product was confirmed by analytical HPLC (tR = 4.3 min) by co-firing with the corresponding non-radioactive F-19 fluoro standard. The crude product was purified by preparative HPLC: ACE 5-C 1 8-HL 250 mm x 10 mm; isocratic, 0.1% trifluoroacetic acid with 48% acetonitrile, flow rate: 4 ml/min; tR about 15 min. . The desired product [18F]-40 (500 MBq) was reconfirmed by analytical HPLC using a non-radioactive F-19 fluoro standard 16 (tR = 4.1 min). The collected HPLC fractions were diluted with 40 mL of water and fixed on a Sep-Pak Light C18 cartridge (Waters) which was washed with 5 mL of water and dissolved in 1 mL of ethanol to provide 471 MBq over a total of 60 minutes of synthesis time. 1000 μΐ EtOH of the product (1 1%, corrected for decay; radiochemical purity &gt; 97.5%). An HPLC chromatogram of [18F]-40 is shown in Figure 3. 1-{6-[[18卩]fluorodecyloxy]-1,3-benzothiazol-2-yl}-111-. Biazo-3-amine [18F]41 K^, KjC〇3, 18F MeCN, 130°C, 5min distillation

Aqueous []8F]fluoride (3 GBq) was captured with a QMA cartridge (Waters) and dissolved in a reaction vessel with a solution of 0.95 mL MeCN/2_7 mg K2C〇3 containing 15 mg K2.2.2. The 156931.doc -76-201206485 solvent was removed by heating at 140 ° C for 10 minutes under a stream of nitrogen. Anhydrous MeCN (1 mL) was added and evaporation was carried out as previously described. Adding dibromomethane (100 μL in 1000 μl anhydrous MeCN solution. After heating at 130 ° C for 5 minutes, the crude reaction mixture was cooled to room temperature. The ambience gas stream was bubbled through the reaction mixture. [18F]Bromo-Fluorine-purine was purified by distillation through several SepPak Silica Plus cartridges (Waters) and captured in 800 mL of DMSO in a 5 mL Weaton V vial. Type jjPLC analysis intermediate: ACE3-C18 50 mm x 4.6 mm; isocratic dissolution: starting with 0.1% trifluoroacetic acid containing ι〇〇/〇 acetonitrile for 5 minutes, flow rate: 2 mL/min; tR=l_3 In the second step, 3 mg "and 6 mg Cs2C03 were added sequentially and heated at 100 ° C for 20 minutes. The reaction mixture was diluted with 4 mL H2 〇 / MeCN (+0.1% TFA) 65:35 and finally by Preparative HpLC purification: ACE 5-C18-HL 250 mm x 10 mm; isocratic dissolution, 0. 1% difluoroacetic acid with 35% acetonitrile, flow rate: 4 mL/min; tR about 20 min. Product [18F]-41 (243 MBq) (tR = 3.9 min) and using analytical HPLC with non-radioactive F_19 fluoro standard 15 (tR = 3 8 min) Co-shot to reconfirm · ACE3-C18 50 mm&gt;&lt;4.6 mm; solvent gradient: 5% acetonitrile (starting) _95% acetonitrile in 1% trifluoroacetic acid in 7 minutes, flow rate: 2 ml/min. The HPLC fraction was diluted with 4 mL of water and fixed on a Sep-Pak light C18 cartridge (Waters) which was washed with 5 mL of water and dissolved in 1 mL of ethanol to provide 220 in a total of 11 minutes of synthesis time. The HPLC chromatogram of the MBq product (16%, decay corrected; radiochemical purity &gt; 99(6) of 1000 μί EtOH 〇[18F]41 is shown in Figure 4. 2-(3-Aminofluoro-u-benzopyrene Spit _5-甲猜156931.doc -77- 201206485 [18F]42

Aqueous [18F]fluoride (1.8 GBq) was captured with a QMA cartridge (Waters, Sep Pak Light QMA part number: WAT023525) and 1.5 mL K222/K2C03 solution (0.95 mL MeCN with 5 mg K222, 0.05 mg with 1 mg K2C03) The mL water) is dissolved into the reaction vessel. The solvent was removed by heating at 120 ° C for 1 minute under a stream of nitrogen. Anhydrous MeCN (1 mL) was added and the evaporation was carried out as previously described. A solution of precursor 6 (2.5 mg) in 500 μM of anhydrous DMF was added. After heating at 1800 ° C for 1 〇 minutes, the crude reaction mixture was cooled to room temperature and diluted with water to a total volume of 5 mL and purified by preparative HPLC: Sepserv UltraSep ES, Amid H RP18P 5 μιη, 25 0×8 mm; Isocratic dissolution, 10% acetonitrile + 70% acetonitrile 0.1% trifluoroacetic acid in 30 minutes, flow rate 3 111 [/ 11 ^ 11; 111 = 22 minutes. The collected HPLC fractions were diluted with 40 mL of water and fixed on a Sep-Pak light C18 cartridge (Waters, WAT 023501) which was washed with 5 mL of water and dissolved in 1 mL of ethanol to provide 220 MBq of product [18F]-42 ( tR = 3.9 min, RCP &gt; 99%) (20%, decay corrected), characterized and reconfirmed by analytical HPLC using non-radioactive F-19 Fluoride Standard 4 (tR = 3.7 min): ACE 3 C18 S/N-A56904, 5〇x4.6 mm ; 3 μηη, ACE-111-, A): water +0.1% TFA, Β) : MeCN+0.1% TFA, 0 to 7 minutes, 5 to 95% B; 7 to 7.10 minutes, 95 to 100% B; 7.1 to 9 minutes, 100°/. 8; 9 to 9_10 minutes, 100% 8 to 5% 8; 9.10 to 12 minutes 156931.doc -78 · 201206485 clock, 5% B; 2 mL/min. An HPLC chromatogram of [18F]-42 is shown in Figure 5. L-[6-[18F] Dun ° plug. Sit and [5,4-b] ° than bite-2-yl]-1H- ° ratio.坐-3-amine [18F]43

Aqueous [18F]fluoride (8.5 GBq) was captured with a QMA cartridge (Waters) and dissolved in a reactor with 1.5 mL of K222/K2CO3 solution (0.95 mL MeCN containing 5 mg K222, 0.05 mL water containing 1 mg K2C03). The solvent was removed by heating at 120 ° C for 10 minutes under a stream of nitrogen. Anhydrous MeCN (1 mL) was added and the evaporation was carried out as previously described. A solution of precursor 37 (5 mg) in 500 μί anhydrous DMSO was added. After heating at 180 ° C for 20 minutes, the crude reaction mixture was diluted with 4 mL water / MeCN (3: 1) and purified by preparative HPLC: ACE 5 C18 HL, 30% MeCN / 70% 0.1 Μ ammonium formate; Degree of dissolution, 4 mL / min; tR is about 20 minutes. The collected HPLC fractions were diluted with 40 mL of water and fixed on Sep-Pak tC18 plus short (Waters; part number: WAT036810), washed with 5 mL of water and dissolved in 1 mL of ethanol for a total of about 80 minutes of synthesis time. 1000 μΐ EtOH containing 650 MBq F-18 labeled product (radiochemical yield 13°/❶, decay corrected; &gt;99% HPLC) » Analysis of the desired F-18 labeled product using analytical HPLC [18F ]-43 (tR = 3.4 min): ACE3-C18 50 mm x 4_6 mm; solvent gradient: 5% acetonitrile (start) - 95% acetonitrile 0.1% trifluoroacetic acid in 7 min, flow rate: 2 mL/min, and Confirmation by analytical HPLC was performed by co-irradiation with the corresponding non-radioactive F-19 fluorine standard 36 (tR = 3.3 min). An HPLC chromatogram of 156931.doc -79-201206485 [18F]-43 is shown in Figure 6. Biological Data Examples The methods for preparing and labeling such compositions are more fully described in the following examples. The examples illustrate certain aspects and advantageous results of the above-described methods, which are presented by way of illustration and not limitation. Binding assay using human brain homogenate using a brain homogenate from AD patients in a 96-well plate (Greiner bi〇_one; Cat.: 651201; Cat. 06060130) for competitive assays using deuterated classifier protein ligands . The homogenate was prepared by homogenizing the gray matter and white matter-containing frontal cortex (Ultra_Turrax, set at 2, 30 sec, 24000 rpm) exfoliated from AD patients in phosphate buffered saline (PBS, pH 7.4). The homogenate at a concentration of 100 mg of wet tissue per ml was divided into 3 〇〇 μ1 aliquots and stored at -80 °C. Different concentrations of unlabeled test substance were incubated with 1 〇〇pg/ml homogenate and PB S, 〇. 1% BSA containing 10 nM hydrazine ligand at room temperature (final volume 200 μl) for 3 hours. . Subsequently, the binding mixture was filtered through a Whatman GF/B filter (wet with PBS, 0.1% BSA) using a Filtermate 196 collector (Packard). The filter was then washed twice with PBS, 〇.1 〇/0 BSA and 40 μ ΐ scintillant was added to each well, followed by measurement of bound radioactivity in a TopCount design (Perkin Elmer). Non-specific binding was assessed by adding an excess of non-radioactive reference ligand to the reaction mixture. Finally, IC5 depreciation is calculated by appropriate analysis of the software. 156931.doc • 80 · 201206485 Table 1: Binding Affinity of Compounds to Human AD Brain Homogen Compound ICS0 Human ADH ' fnMl 1 9 2 15 4 51 12 142 13 27 14 227 15 7 A 16 26 17 69 26 163 27 &gt; 400 34 367 36 57 _ Autoradiometric analysis This study used fresh cold-cold and stone-embedded frontal lobe slices from Alzheimer's disease dementia patients, frontotemporal dementia patients, and age-matched controls. Frozen sections of 18 μm thickness were cut on a cryostat (Leica, Germany) and cut into 6 μιη thickness paraffin sections on a slide microtome (Leica) and mounted on glass slides (Superfrost P1US, Fa Menzel, Braunschweig Germany). Make frozen sections at _2 〇. (: Attached to the slide for a few nights. Paraffin sections were removed using conventional histological methods. For binding studies, at room temperature in a moisture-containing incubator, sliced with 25 mM Hepes buffer (pH) 7.4) The test compound diluted to 1 〇Β (ΐ/μ1 of the mark ^18, 〇ι% BSA (each slide 2〇〇_3〇〇μι) was incubated for 15 hours. When performing the blocking experiment, Excess unlabeled test substance was added to the culture mixture. Miscellaneous 156931.doc -81 - 201206485 After the crossover, wash the sections 4 times with Hepes buffer, 0.1% BSA (or 2 times with 4〇0/ethanol) and finally dip 1 sec (2 times) in water (A. dest.). The air-dried section was exposed to an imaging plate and the signal was detected by a photoimager device (Fup BAS5000). 18F-39 18F- after AD brain slice after death Automatic radiography of 39 confirmed that the presence of Αβ spots was associated with specific binding. The results are shown in circle 7. 18F-40 Autoradiography of 18F-40 of AD brain slices after death confirmed that the presence of Αβ spots was associated with specific binding. In Figure 8. 18F-41 Autoradiography of 18F_41 of AD brain slices after death confirmed Αβ The presence of spots is associated with specific binding. The results are shown in Figure 9. Autoradiography of 18F-43 of AD brain sections after death confirmed that the presence of gossip spots was associated with specific binding. The results are shown in Figure 1. Biodistribution Biodistribution and excretion studies were performed in male NMRI mice (body weight approximately 30 g; 3 animals per time point). Animals were maintained under normal laboratory conditions, 22 ± 2 ° C and 12 Hour dark/light rhythm. Food and water free 156931.doc • 82 · 201206485 Access. During the adaptation phase of at least 3 days prior to the start of the study, the animal was clinically examined to determine that there were no abnormal clinical signs. Urine and feces were collected quantitatively at 2, 5, 30, 60, 240 minutes after intravenous injection (about 150 kBq) of l〇〇μΐ test compound. At the same time point 'decapitation by isoflurane anesthesia The animals were sacrificed, and the relevant organs and tissues were removed, and the radioactivity was measured using a gamma counter. When analyzing, the percentage of the injection dose decay correction per tissue weight (% ID/g±standard deviation) was calculated. Table 2 Brain absorption and brain clearance were expressed as % of injection dose per gram of tissue [% iD/g]. F-18 signal was detected 2 minutes and 3 minutes after administration of mouse compound. Favorable high brain absorption and rapid clearance in mouse brain. Brain absorption at 2 min. ί°/〇ID/εΙ Brain absorption at 30 minutes [% ID/el brain clearance [% min/g at 2 min]/ [30 minutes % iD/el 18F-39 5.14 2.45 2.1 18F-40 4.85 0.82 5.9 18F-41 3.91 1.59 2.6 18F-43 5.36 0.43 12.5 Tracer 18F-40 and 18F-43 show beneficially and quickly eliminated from the brain Non-specific radioactive signals. The above studies indicate that the compounds of formula I are useful as developing agents for amyloid-like spots. It penetrates the intact blood brain barrier and specifically binds to amyloid deposits. [Simple description of the diagram] 15693l.doc • 83 - 201206485 Figure 1: List of compounds prepared. Figure 2: HPLC chromatogram of compound [18F]-39. Figure 3: HPLC chromatogram of compound [18F]-40 compared to compound 16. Figure 4: HPLC chromatogram of [18F]MeBr and compound [18F]-41 compared to compound 15. Figure 5: HPLC chromatogram of compound [18F]-42 compared to compound 4. Figure 6: HPLC chromatogram of compound [18F]-43 compared to compound 36. Figure 7: Autoradiometric analysis of the combination of compound 18F-39 with brain sections from the cortex of Alzheimer's disease (AD) and controls without sputum beta spots (HC) (healthy controls). Blocking with specific signals with excess non-radioactive compounds. The arrow points to the spot specific signal. Figure 8: Autoradiometric analysis of the combination of compound 18F-40 with brain sections from the cortex of Alzheimer's disease (AD) and controls without sputum beta spots (HC) (healthy controls). Blocking with specific signals with excess non-radioactive compounds. The arrow points to the spot specific signal. Figure 9: Autoradiometric analysis of the combination of compound 18F-41 with brain sections from the cortex of Alzheimer's disease (AD) and controls without sputum beta spots (HC) (healthy controls). Blocking with specific signals with excess non-radioactive compounds. The arrow points to the spot specific signal. Figure 10: Autoradiometric analysis of the combination of compound 18F-43 with brain sections from the cortex of Alzheimer's disease (AD) and controls without sputum beta spots (HC) (healthy controls). Blocking with specific signals with excess non-radioactive compounds. The arrow points to the spot specific signal. 156931.doc -84·

Claims (1)

201206485 VII. Patent application scope: 1. A compound of formula I, R1 Wherein R1 is selected from the group consisting of Η, C(0)CH3, C(0)(CH2)nCH2X, c(o)cf3, C(0)0C(CH3)3, C(0)C6H4X, c (o) c6h3xz, c(o)heteroaryl, substituted c(0)heteroaryl; R2 is selected from the group consisting of hydrazine, CH3, (CH2)nCH3, (CH2)mCH2X, R1; R3 It is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3, C(0)0(CH2)mCH2X, C(0)NH2, C(0)NH(CH2) nCH3 'C(0)NH(CH2)mCH2X; R4 and Rs are independently selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH3, 0 (CH2)nCH2X, O-cyclobutyl-X, fluorenyl-cyclopentyl-X, fluorenyl-cyclohexyl-X, 0(CH2CH20)nCH2CH2X, SH, SCH3, S(CH2)nCH3, S(CH2)nCH2X, NH2, NHCH3 'N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X 'NCH3(CH2)mCH2X 'X ^ Z ; W is selected from CH or N; X is selected from the group consisting of F: , 18F, I, 125I, 123I; Z is selected from the group consisting of H, CF3, CN, C(0)H, C(0)CH3, C(0)0(CH2)nCH3; 156931.doc 201206485 m is defined as 1-4; and η is defined as 0-4; including all isomeric forms of δ hai compounds' includes Enantiomers and diastereomers as well as racemic mixtures, and any pharmaceutically acceptable salt, ester, guanamine, complex or prodrug thereof, wherein the formula contains only one X. 2. The compound of claim 1, wherein R1 is selected from the group consisting of: Η, C...) CH3, C(0)(CH2)nCH2X 'C(0)CF3 'C(0)OC(CH3)3 ^ C(0)C6H4X 'c(o)c6h3xz, c(o)heteroaryl, substituted c(〇)heteroaryl; R is selected from the group consisting of hydrazine, CH3, (CHJnCH:}, (CH2)mCH2X, R1; R3 is selected from the group consisting of Η, C(0)0H, C(〇)〇(CH2)nCH3, C(0)0(CH2)mCH2X, C(0)NH2 C(0)NH(CH2)nCH3, C(0)NH(CH2)mCH2X; R4 and Rs are independently selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3 , 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, 〇-cyclopentyl-X, 0(CH2CH20)nCH2CH2X, NH2, NHCH3, N(CH3)2, NH(CH2) „ CH3 'NH(CH2)mCH2X ^ NCH3(CH2)mCH2X, X, Z; W is selected from CH or N; X is selected from the group consisting of F, 18F, I, 125I, 123I; 156931.doc 201206485 Z Is selected from the group consisting of hydrazine, CF3, CN, C(0)H, C(0)CH3; m is defined as 1-3; and n is defined as 0-3; including all isomers of the compound Forms, including enantiomers and diastereomers And a racemic mixture, and any pharmaceutically acceptable salt, ester, guanamine, complex or prodrug thereof, wherein the formula contains only one X. 3. The compound of claim 1 or 2, wherein R1 It is selected from the group consisting of Η, C(0)CH3, C(0)(CH2)nCH2X, C(0)CF3, C(0)0C(CH3)3, C(0)C6H4X, C(0 C6H3XZ; R2 is selected from the group consisting of H, CH3, (CH2)nCH3, R1; R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3 , C(0)0(CH2)mCH2X; R4 and Rs are independently selected from the group consisting of H, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH2X, 0-cyclobutyl-X, 0 (CH2CH20)nCH2CH2X, X, Z; W is selected from CH or N; X is selected from the group consisting of F, 18F; Z is selected from the group consisting of Η, CF3, CN, C(〇)H m is defined as 1-2; 156931.doc 201206485 and η is defined as 0-2, including all isomeric forms of the compound, including enantiomers and diastereomers, as well as racemic mixtures, And any pharmaceutically acceptable salt, ester, guanamine, complex or prodrug thereof, wherein It contains an X. 4. A compound according to claim 1, 2 or 3 wherein X is 18F. 5. - a compound of formula I, R1 Wherein R1 is selected from the group consisting of Η, C(0)CH3, C(0)(CH2)nCH2X, C(0)CF3, C(0)OC(CH3)3, C(0)C6H4X, c(o)c6h3yz, c(o)c6h3xz, c(o)heteroaryl, substituted c(o)heteroaryl, c(o)och3, c(o)och2ch3, c(o)och2c6h5, ( :(0)0CH2CH=CH2, Fmoc, C(0)0CH2CH2Si(CH3)3, C(0)OCH2CCl3; R2 is selected from the group consisting of H, CH3, (CH2)nCH3, (CH2)mCH2X 'R1 R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3, C(0)0(CH2)mCH2X, C(0)NH2, C(0)NH( CH2)nCH3, C(0)NH(CH2)mCH2X; R4 and R5 are independently selected from the group consisting of H, CH3, 156931.doc 201206485 (CH2)nCH3, (CH2)nCH2X, 〇H, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, 〇-cyclobutyl_X, 〇_cyclopentyl_x, 〇_cyclohexyl_X, 0(CH2CH20)nCH2CH2X, SH, SCH3, S(CH2)nCH3 , S(CH2)nCH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, Y, Z; W is selected from CH or N; x It is selected from the group consisting of F, C1, Br, Gong, 〇s〇2CH3, 〇S02CF3, 〇S02C4F9, 〇s〇2c6H5 0S02C6H4CH3, 〇S02C6H4N02, 0S02C6H4Br, 0S02C6H2(CH(CH3)2)3, 〇so2c6h3(och3)2; γ is selected from the group consisting of N〇2, N+Me3, broad aryl, s+ aryl 2; The Z series is selected from the group consisting of Η, cf3, CN, C(0)H, C(〇)CH3, C(0)0(CH2)nCH3; m is defined as 1-4; and n is defined as 0-4; includes all isomeric forms of the compound, including enantiomers and diastereomers as well as racemic mixtures, and any pharmaceutically acceptable salts, esters, guanamines, complexes thereof Or a prodrug, wherein the formula contains only one X, and wherein the formula contains only one oxime. 6. The compound of claim 5, wherein R is selected from the group consisting of Η, c(0)CH3, 156931.doc r 201206485 C(0)(CH2)nCH2X, c(o)cf3, c(o)oc(ch3)3, c(o)c6h4x, c(o)c6h3yz, c(o)c6h3xz,c( o) c6h4y, c(o)heteroaryl, substituted c(o)heteroaryl, C(0)0CH2C6H5, C(0)0CH2CH=CH2, Fmoc; R2 is selected from the group consisting of: CH3, (CH2)nCH3, (CH2)mCH2X ' R1 ; R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3 'C(0)0(CH2)mCH2X 'C(0)NH2 'C(0)NH(CH2)nCH3, C(0)NH(CH2)mCH2X ; R4 and Rs are independently selected from the group consisting of: H, CH3, (CH2)nCH3, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH3, 0(CH2)nCH2X, O-cyclobutyl-X, O-cyclopentyl-X, 0(CH2CH20) nCH2CH2X, NH2, NHCH3, N(CH3)2, NH(CH2)nCH3, NH(CH2)mCH2X, NCH3(CH2)mCH2X, X, Y, Z; W is selected from CH or N; X is selected from the following composition Group: F, Cl, Br, I, 〇S02CH3, OSO2CF3 ' OSO2C4F9 ' OSO2C6H5 ' OSO2C6H4CH3 ' 0S02C6H4N02 , 0S02C6H4Br , 0S02C6H3 ( 0CH3 ) 2 ; Y is selected from the group consisting of N02, N+Me3, I+ aryl , s + aryl 2 ; Z series is selected from the group consisting of Η, CF3, CN, C(0)H, C(0)CH3; m is defined as 1-3; 156931.doc 201206485 and the definition of η 0-3; includes all isomeric forms of the compound, including enantiomers and diastereomers as well as racemic mixtures, and any pharmaceutically acceptable salts, esters, guanamines, complexes thereof Or prodrug, wherein the formula contains only one X, and wherein the formula contains only one hydrazine. 7. The compound of claim 5 or 6, wherein R1 is selected from the group consisting of hydrazine, C(0)CH3, C(0)(CH2)nCH2X, c(o)cf3, c(o)oc( Ch3)3, c(o)c6h4x, c(o)c6h3yz, c(o)c6h3xz, c(o)och3, C(0)0CH2CH3, C(0)0CH2C6H5, Fmoc; R2 is selected from the group consisting of :H, CH3, (CH2)nCH3, R1; R3 is selected from the group consisting of H, C(0)0H, C(0)0(CH2)nCH3, C(0)0(CH2)mCH2X; R4 and R5 are independently selected from the group consisting of H, (CH2)nCH2X, OH, OCH3, 0(CH2)nCH2X, Ο-cyclobutyl-X, 0(CH2CH20)nCH2CH2X, X, Y, Z; W is selected from CH or N; X is selected from the group consisting of F, CM, Br, I, OS02CH3, oso2cf3, oso2c4f9, oso2c6h5, oso2c6h4ch3; Y is selected from the group consisting of N〇2, N+ Me3, I+ aryl, S+ aryl 2; 156931.doc 201206485 z is selected from the group consisting of: 成, CF3, CN, C(0)H m is defined as 丨_2; and η is defined Is 〇_2, 'includes enantiomers and non-", guanamines, complexes or all isomeric forms of enantiomers including the compounds as well as a mixture, and any pharmaceutically acceptable salt prodrug thereof, wherein the formula comprises only one oxime, and wherein the formula comprises only Η@Υβ. a compound selected from the group consisting of machi; Η6 -Fluorobenzopyrene-Saltyl-2-yl)_ιη" than salivary 3FXr; ^irNHz 2^3-amino group. Ratio ° sitting small base) seven gas-benzothiazole·ylamine 2 5·carbonitrile 4 tri &amp;methylbenzopyrene wow_2_ Base)-lH-nbazolylamine 5^3·amine group °^ small base benzopyrene sniff 1-[6-(2·fluoroethoxy) benzoaldehyde 9 嗔 span-2-yl]-1Η_pyrazol-3-ylamine 13 156931.doc 201206485 / Ν, /ΝΗ 2 3 -Amino-1_[6-(2- gas ethoxy) benzoate. Sit -2_base]-111-. ratio. Take -4-ethyl citrate 14 . Lamp Κ 2 〇. 0 .CH. 1-[6-(Fluoromethoxy)benzothiazol-2-yl]-lH-η-pyrazol-3-ylamine 15 1-[6-(3-Fluoropropyl)benzothiazol-2-yl]-1Η-α-pyrazol-3-ylamine 16 2 l-[6-(3-fluorocyclobutoxy)benzothiazole- 2-based]-1H-. Bizol-3-ylamine 17 Ν-{1-[6-(3-propylpropyl)benzoindole α-yl-2-yl]-lH-ntba--3-yl}•Ethylamine 25 1-[6-(3-fluoropropyl) benzothiazol-2-yl]-lH-η-pyrazol-3-ylamine 26 4-Fluoro-N-[1-(6-methoxybenzothiazol-2-yl)-1Η-. Bizozol-3-yl]benzamide 27 156931.doc 201206485 h3c 3-cyano-4-fluoro-N-[l-(6-nonyloxybenzothiazol-2-yl)-1 H-indazol-3-yl]benzamide 9 C 4-Fluoro-N-[1-(6-decyloxybenzothiazol-2-yl)-1Η-. Biazo-3-yl]-3-(trifluoromethyl)benzamide 29 2-Amino-1-(6-methoxybenzothiazol-2-yl)-1Η-pyrazole-4-carboxylic acid 2-fluoroethyl ester 34 N-[l-(5-Akyl-6-gas benzo.sup.2-2-yl)-1Η-π ratio. Sit - !3-based] Ethylamine 35 1-(6-fluorothiazolo[5,4 ton]pyridin-2-yl)-111-pyrazol-3-amine 36 F', N s l-[6-(2-[18F]fluoroethoxy Benzothiazol-2-yl]-1H-pyrazol-3-ylamine 156931.doc -10· 201206485 [18F]-39 L-[6-(3-[18F]fluoropropoxy)benzothiazol-2-yl]-1Η-η-pyrazol-3-ylamine [18F]-40 ίΓ&quot;ν V 〜NH2 l-[6 -([18F]fluoromethoxy)benzothiazol-2-yl]-1H-pyrazol-3-ylamine [18FJ-41 2-(3-Amino.pyrazol-1-yl)-6-[18F]fluoro-benzothiazole-5-indolecarbonitrile [18F]-42 L-(6-[18F]fluorothiazolo[5,4-b]pyridin-2-yl)-1Η-pyrazol-3-amine [18FJ-43 9. A compound selected from the group consisting of: 1-(6-bromobenzothiazol-2-yl)-1 -pyrazol-3-ylamine 1 1-(6-iodobenzothiazol-2-yl)-111-pyrazol-3-ylamine 3 156931.doc • 11 - 201206485 2 - (3 -Amino group ° than 0 sitting 1 -yl)-6 · Stone Schottky benzo. Plug ° sit -5 - A guess 6 ΝΗ, 1-(6-nitro-5·trifluoromethylbenzothiazol-2-yl)-1Η-carbazole-3·ylamine 7 [2 - (3 -Amino. Ratio. Sit-1 -yl) - Benzo[J] σ -6 - yl] σ phene-2 - yl-pin 8 ζλ·ΧΧΗτΝΗ2 2-(3-Aminopyr Oxazol-1 -yl)-6-nitrobenzothiazole-5-carbaldehyde 10 〇 ΝΗ, 2-(3-Aminocarbazol-1-yl)-benzothiazole-6-olol 11 3-Amino-1-(6-hydroxybenzothiazol-2-yl)-1Η-pyrazole-4-furoate ethyl ester 12 〇, /CH, 156931.doc -12- 201206485 oxa-6-yloxytoluene-4-sulfonic acid 2·[2-(3-amino-pyrazole-indoleyl)benzothio]ethyl ester 18 H3c and η η sit 3- 3-amino-1-{6-[2·(indolyl-4-sulfonyloxy)ethoxy] stupid 2-yl} - 1 Η-° ratio. Sitting -4-carboxylic acid \^CH, toluene-4-continuation 3·[2_(3_amino"pyria +yl)benzoxyloxy]propyl ester 20 1 Toluene-4-producing acid 3_[2_(3_amino-0 ratio. sitting on a small base) benzon-s-sposatoyloxy]cyclobutyl ester 21 h3c, toluene-4-sulfonic acid 2_[2_(3_ Di-t-butoxycarbonylamino-based d-pyridyl-L-based benzothiazole-6-yloxy]ethyl ester 22 156931.doc -13· 201206485 N-[ 1-(6-bromobenzothiazol-2-yl)-1 Η-pyrazol-3-yl]acetamide 23 3-[2-(3-Amino-bisazol-1-yl)benzothiazole-6-yl]propyl sulfonate methanesulfonate 24 H3c, / /, 0 {4-[ 1-(6-decyloxybenzothiazol-2-yl)-1Η-oxazol-3-ylamine fluorenyl]-phenyl}diphenyl-salt 30 {4-[1-(6-Methoxybenzothiazol-2-yl)-1Η-pyrazol-3-ylaminemethyl hydrazino]phenyl}thiophen-2-yl-indole 31 {2-Cyano-4-[l-(6-methoxybenzothiazol-2-yl)-1Η-η-pyrazol-3-ylaminoindolyl]-phenyl}trimethyl-ammonium 32 156931.doc • 14· 201206485 {4-[1-(6-Methoxybenzothiazol-2-yl)-1H-pyrazol-3-ylaminoindolyl]-2-trifluoromethyl-phenyl}tridecyl-ammonium 33 1-(6-iodothiazolo[5,4 ton]pyridin-2-yl)-111-pyrazole-3-amine 38 10. A compound selected from the group consisting of: l-[6-(2-[18F]fluoroethoxy)benzothiazol-2-yl]-lH-ηpyrazol-3-ylamine [18F]-39 L-[6-(3-[18F]fluoropropoxy)benzothiazol-2-yl]-indole-n-bazol-3-ylamine [18FJ-40 l-[6-([18F]) Oxy)benzothiazol-2-yl]-1Η-η-pyrazol-3-ylamine 156931.doc -15- 201206485 [18F)-4i 42 Nh2 2-(3,aminopyrazol-1-yl)-6-[18F]fluorine-stupidated salic-carbonitrile [18F]- Nh2 HfF] fluorine sold saliva and [5,4-b]» than pyridine 1 base) _1H pyro-b 43 ,. 〇 11. 12. 13. 14. 15. The compound of claim 8, wherein when F is not When it is part of the _CF3_ group, 'F is defined as 18F. As requested, the 4 radioactively labeled compound of 4, 1 or &quot; is used as a compound for diagnostic imaging. The compound of claim 12, which is for use as a compound for diagnostic imaging of diseases selected from the group consisting of Alzheimer's disease, neurodegenerative disorders or amyloidosis. A pharmaceutical or diagnostic composition comprising a radiolabeled compound of F as claimed in claims 1 to 4, 1 or 18 and a pharmaceutically acceptable carrier. A method of preparing a 18F radiofluorinated compound according to claim 1 to 4, 1 or 11 wherein the method comprises reacting a suitable precursor molecule as claimed in claims 5 to 7 or 9 with a radioactive fluorinating agent. 156931.doc