KR102132847B1 - Compounds with high selectivity to tau aggregates, tau-targeting probe comprising the same, and preparation method thereof - Google Patents

Abstract

The present invention relates to a compound represented by the following Chemical Formula 1 useful for early diagnosis of degenerative brain diseases including dementia, prevention and treatment thereof, and a pharmaceutical composition comprising the same, which exhibits excellent binding strength to Tau aggregates.

Description

A compound having high selectivity to tau aggregates, a tau target probe comprising the same, and a method for manufacturing the same, and a method for preparing the same, and a preparation method thereof

The present invention relates to a compound having high selectivity to tau aggregates, a tau target probe comprising the same, and a method for manufacturing the same.

Alzheimer's disease (AD), which is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population, is characterized by progressive cognitive impairment, such as loss of memory, impaired executive function, behavioral symptoms, and loss of self-management ability. Symptoms can vary and other neurodegenerative diseases and signs and symptoms overlap. As a result, the accuracy of clinical diagnosis when judged by autopsy varies considerably.

Despite recent advances in related biomarkers for the diagnosis of AD, such as amyloid positron emission tomography (PET) contrast agents, the final diagnosis of AD is only possible with post-histological analysis of human brain samples. Post-mortem studies of the AD brain revealed two pathological features of the disease: (1) extracellular senile plaques (SPs) composed of Aβ peptides, and (2) a paired spiral of hyperphosphorylated tau protein Intracellular neurofibrillary tangles (NFTs) composed of filaments (PHFs).

Evidence of AD pathology can be obtained from cerebrospinal fluid (CSF) samples and brain imaging. The latter technique is non-invasive and can be used to identify patients at risk of developing AD before signs of cognitive impairment appear. In particular, PET is a sensitive imaging technique that enables in vivo and in-situ non-invasive visualization, characterization and quantification of physiological processes at the molecular level and has become a very powerful diagnostic tool.

Several PET probes have been developed for in vivo imaging of Aβ-plaques, of which four representative examples are compound 1 ([ ¹¹ C] PiB), compound 2 ([ ¹⁸ F] flute metamol, flutemetamol), compound 3a ([ ¹⁸ F] flobetapir, florbetapir) and compound 3b ([ ¹⁸ F] flobetaben, florbetaben) are shown in FIG. 1. The latter three have been approved for commercial use by regulatory agencies. However, the density of amyloid plaques is not correlated with the level of neurodegeneration or cognitive impairment in AD.

Unlike amyloid pathology, the density of NFTs and neocortical spread are very well associated with progressive neuronal degeneration and cognitive decline in AD patients, thus making PET imaging of NFTs a desirable biomarker of AD. In fact, a comparison of amyloid PET and Tau PET in a recently published PET imaging study reported that Tau PET signal has a higher correlation with cognitive ability and disease severity than Aβ imaging. While Aβ imaging provides an early indication of disease risk, brain amyloid scale is not correlated with disease severity. NFT imaging may not only detect early neurodegeneration prior to the onset of cognitive symptoms, but also predict disease progression. NFT imaging can help to describe the relationship between tau aggregate accumulation and the time from normal aging to AD, cognitive and structural changes in the brain. Tau agglutination imaging may help to study the regulation of disease following tau agglomeration.

In addition to being involved in Alzheimer's disease, Tau cohesiveness is tangle-only dementia (TD), neutrophil particle disease (AGD), progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), and Pick's disease , And other neurodegenerative diseases known as "Tau's disease," including anterior temporal lobe dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Therefore, Tau aggregate imaging may be useful in the diagnosis and study of these pathologies, and the currently developed Tau PET ligands are also likely to be important in early studies of other Tau diseases except Alzheimer's disease.

The development of small molecule PET imaging radioactive tracers for in vivo quantification of NFTs has been promoted by numerous academic and industrial groups. Recently, we have reviewed these efforts, as well as a number of challenges inherent in the discovery of suitable tau PET ligands. The high binding capacity for several recently discovered NFTs and selectivity for Aβ-plaques were selected and evaluated in early clinical studies (FIG. 2 ). Tohoku University announced the "THK compounds" series labeled with ¹⁸ F. Among them, compound 4 ([ ¹⁸ F] THK-5117) and compound 5 ([ ¹⁸ F] THK-5351) are widely evaluated. Current Avid / Lilly Siemens group (also known as ^[18 F] AV-1451, prior to the ^[18 F] T807) before the ^[18 F] 2 of ^18, known as T807 F- labeled compound, Compound 6 and Compound 7 ([ ¹⁸ F] AV-[ ¹⁸ F] T808). National Radiation Research Institute in Chiba (NIRS) has announced the compound 8 ^([11 C] PBB3) is also a compound series of 11 PBB cover (C labeled phenylbutadienylbenzothiazole) evaluated in human subjects. Very recently Merck & Co reported the discovery of a new Tau PET tracer 9 ([ ¹⁸ F] MK-6240) currently in clinical evaluation. Finally, Hoffmann-La Roche, in collaboration with Johns Hopkins University School of Medicine, reported in vitro and in vivo results with three potential Tau trackers [ ¹¹ C] RO6931643, [ ¹¹ C] RO6924963 and [ ¹⁸ F] RO6958948.

In all radiotracers, compound 6 has been the most extensively studied in AD patients. However, although Compound 6 is highly selective for Tau compared to Aβ, recent reports show it has a broad and high affinity target binding. Therefore, the signal-to-background ratio of early AD patients may not be optimal. In addition, Compound 6 has been reported to show rather slow removal from the human brain, which requires a long scanning time of 80 to 100 minutes, so the time-SUVR curve for 6 in the cerebral cortex is mild cognitive impairment (MCI) or AD It may not be flat within 100 minutes of the subject. Due to these limitations, more sensitive and selective Tau PET trackers are needed.

1. Khachaturian, Z. S. Diagnosis of Alzheimer's disease. Arch. Neurol. 1985, 42, 1097-1105 2. Citron, M. Alzheimer's disease: strategies for disease modification. Nat. Rev. Drug Discovery 2010, 9, 387-398 3.Nelson, P. T. et al., Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 2012, 71, 362-381 4. Delacourte, A. Diagnosis of Alzheimer's disease. Ann. Biol. Clin. 1998, 56, 133-142

Accordingly, it is an object of the present invention to provide a compound showing excellent selectivity to tau aggregates or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Another object of the present invention is to provide a pharmaceutical composition for early diagnosis, prevention or treatment of dementia containing the compound as an active ingredient.

Another object of the present invention is to provide a tau aggregate formation inhibitor containing the compound as an active ingredient.

In order to achieve the above object, the present invention provides a compound of the formula or a pharmaceutically acceptable salt thereof.

[Formula 1]

In addition, the present invention provides a precursor for the preparation of a compound or a pharmaceutically acceptable salt thereof according to various embodiments of the present invention having the structure of Formula 2 below.

[Formula 2]

In addition, the present invention provides a pharmaceutical composition for diagnosing, preventing or treating degenerative brain disease, comprising a compound according to various embodiments of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a method for preparing a compound or a pharmaceutically acceptable salt thereof according to various embodiments of the present invention.

According to various embodiments of the present invention, a compound of Formula 1 or a pharmaceutically acceptable salt thereof having high selectivity to tau aggregates has been provided. Since the compound according to the present invention shows high selectivity to tau aggregates compared to beta amyloid, it can be useful for early diagnosis, prevention or treatment of diseases related to tau aggregates including dementia.

1 shows the structure of a representative Aβ PET probe used in clinical practice.
2 shows the structure of a representative Tau PET tracer compound evaluated in clinical studies.
Figure 3 shows the fluorescence spectral profile of the six tau labeling material.
Figure 4 is a result of verifying the tau selectivity in the tau (MAPT-P301L) mice compared to normal mice (hippocampus CA3).
5 is a result of verifying the tau selectivity compared to the amyloid plaque of the tau-labeled compound.

Hereinafter, various aspects and various embodiments of the present invention will be described in more detail.

According to one aspect of the invention, a compound of the formula: or a pharmaceutically acceptable salt thereof is disclosed.

[Formula 1]

Wherein R ₁ - is H- or FR ₁ '-, and

Wherein -R ₁ '- is _{- (CH 2) L1 (CHOH} ) L2 (CH 2) L3 -, - (CH 2) m1 O (CH 2) m2-, - (CH 2) m1 O (CH 2) m2 O(CH ₂ ) _m3 -and -(CH ₂ ) _n1 -is selected,

L1 is 1 or 2, L2 is 0 or 1, and L3 is 1 or 2,

M1 is 2 or 3, m2 is 2 or 3, and m3 is 2 or 3,

N1 is an integer from 2 to 5,

또는

이고,Ar ₁ is

or

ego,

,

,

,

및

중에서 선택되며,Ar ₂ is

,

,

,

And

Is selected from

The R ₂ is selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ,

Wherein -R ₃ is _{-CH 3, CH 2 CH 3,} CH 2 CH 2 CH 3 , or selected from, or -R ₃ 'are -F,

Wherein -R ₃ '- is _{- (CH 2) p1 O (} CH 2) p2--, - (CH 2) p1 O (CH 2) p2 O (CH 2) p3 -, - (CH 2) p1 O ( CH ₂ ) _p2 O(CH ₂ ) _p3 O(CH ₂ ) _p4 -and -(CH ₂ ) _q1 -is selected,

P1 is 2 or 3, p2 is 2 or 3, p3 is 2 or 3, and p4 is 2 or 3,

Q1 is an integer from 2 to 5.

In one embodiment, the compound of Formula 1 has the structure of Formula 1a.

[Formula 1a]

The R ₁ , the Ar ₁ , the Ar ₂ , the R ₂ , and the R ₃ are as defined above.

In other embodiments, the -R ₁ '- is _{- (CH 2) (CHOH)} CH 2 -, - (CH 2) 2 O (CH 2) 2 O (CH 2) 2 - and - (CH _{2) 3} - is selected and, the R ₂ is H in the -R ₃ are 'is -F, the -R _3, -CH _3, or -R ₃ - is _{-CH 2 O (CH 2) 3} OCH 2 -, -(CH ₂ ) ₂ O(CH ₂ ) ₂ O(CH ₂ ) ₂ -and -(CH ₂ ) ₃ -.

In another embodiment, the compound of Formula 1 has a structure of any one of the following Formulas 1b to 1g.

[Formula 1b]

[Formula 1c]

[Formula 1d]

[Formula 1e]

[Formula 1f]

[Formula 1g]

Ar ₁ and Ar ₂ are as defined in claim 1.

In another embodiment, the compound of Formula 1 has a structure of any one of the following Formulas 1h to 1t.

[Formula 1h]

[Formula 1i]

[Formula 1j]

[Formula 1k]

[Formula 1l]

[Formula 1m]

[Formula 1o]

[Formula 1p]

[Formula 1q]

[Formula 1r]

[Formula 1s]

[Formula 1t]

.

.

In another embodiment, the F included in the compound according to various embodiments of the present invention or a pharmaceutically acceptable salt thereof is ¹⁹ F or ¹⁸ F.

Typically, the ¹⁸ F-labeled compound is a precursor containing a leaving group such as tosylate, mesylate, etc., and K in an organic solvent such as tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF). Reaction with [F-18]fluoride/kryptofix or tetrabutylammonium salt/potassium carbonate complex such as ¹⁸ F, Na ¹⁸ F, Cs ¹⁸ F and the resulting intermediate is deprotected with HCl or NaOH, by HPLC It can be synthesized by separating and purifying.

Another aspect of the present invention relates to a precursor for preparing a compound according to various embodiments of the present invention having a structure of the following formula.

[Formula 2]

Wherein R ₁ - is MEM- or TsO-R ₁ '- or MsO-R _1' -, and

Wherein -R ₁ '- is _{- (CH 2) (CHOH)} CH 2 -, - (CH 2) 2 O (CH 2) 2 O (CH 2) 2 - and - (CH _{2) 3} - is selected from,

또는

이고,Ar ₁ is

or

ego,

,

,

,

및

중에서 선택되며,Ar ₂ is

,

,

,

And

Is selected from

R ₂ is Boc,

Wherein -R ₃ is -CH ₃ or -R ₃ '-OTs or -R _3' -OMs,

Wherein -R ₃ '- are _{-CH 2 O (CH 2) 3} OCH 2 -, - (CH 2) 2 O (CH 2) 2 O (CH 2) 2 - and - (CH _{2) 3} - is selected from ,

The MEM means a 2-methoxyethoxymethyl group,

The TsO means a tosylate group, that is, p-toluenesulfonate,

The MsO means a mesylate group, that is, methanesulfonate,

The Boc protecting group means a tert-butyloxycarbonyl protecting group,

The THP means tetrahydropyranyl.

Another aspect of the present invention relates to a pharmaceutical composition for diagnosing, preventing or treating degenerative brain disease, comprising a compound according to various embodiments of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention comprises the step of administering to a human or animal a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as an active ingredient according to various embodiments of the present invention, diagnosis of degenerative brain disease , Prevention or treatment use or method.

Another aspect of the present invention relates to the diagnosis, prevention or treatment of degenerative brain disease of a compound or a pharmaceutically acceptable salt thereof according to various embodiments of the present invention.

Another aspect of the present invention relates to a method for preparing a compound of Formula 1a comprising the following steps.

[Formula 1a

(A) preparing a compound of formula 5 by reacting a compound of formula 3 with a compound of formula 4,

[Formula 3]

[Formula 4]

OHC-Ar ₂ -NHPr ₂

[Formula 5]

(B) preparing a compound of formula 7 by reacting the compound of formula 5 with the compound of formula 6,

[Formula 6]

Pr ₃ -R1'-Pr ₃

[Formula 7]

(C) preparing a compound of formula 9 by reacting the compound of formula 7 with a compound of formula 8,

[Formula 8]

Z-F

[Formula 9]

(D) preparing a compound of Formula 1a by performing a deprotection reaction on the compound of Formula 9.

In the above formula, Pr ₁ is MEM,

또는

이고,Ar ₁ is

or

ego,

,

,

,

및

중에서 선택되며,Ar ₂ is

,

,

,

And

Is selected from

R ₄ is ethyl,

Pr ₂ is Boc,

Wherein -R ₃ '- are _{-CH 2 O (CH 2) 3} OCH 2 -, - (CH 2) 2 O (CH 2) 2 O (CH 2) 2 - and - (CH _{2) 3} - is selected from ,

The Pr ₃ is TsO or MsO,

Z is selected from TBA, Na ⁺ , K ⁺ , Cs ⁺ ,

R ₁ is H,

R ₂ is H,

Wherein -R ₃ is -R ₃ '-F.

Here, the MEM means a 2-methoxyethoxymethyl group, the TsO means a tosylate group, the MsO means a mesylate group, and the Boc protecting group means a tert-butyloxycarbonyl protecting group, the THP means tetrahydropyranyl, and the TBA means tetra-n-butylammonium.

In one embodiment, step (A) may be performed in the presence of NaHMDS, and may be performed in a THF solvent.

In another embodiment, step (B) may be performed in the presence of NaH, and may be performed in a DMF solvent.

In another embodiment, step (C) may be performed in a THF solvent.

In another embodiment, step (D) may be performed using HCl in a MeOH solvent.

Another aspect of the present invention relates to a method for preparing a compound of Formula 1a comprising the following steps.

[Formula 1a]

(A) preparing a compound of Formula 12 by reacting a compound of Formula 3 with a compound of Formula 11,

[Formula 3]

[Formula 11]

OHC-Ar ₂ -N(CH ₃ )Pr ₂

[Formula 12]

(B) preparing a compound of Formula 1a by performing a deprotection reaction on the compound of Formula 12.

In the above formula, Pr ₁ is MEM,

또는

이고,Ar ₁ is

or

ego,

,

,

,

및

중에서 선택되며,Ar ₂ is

,

,

,

And

Is selected from

R ₄ is ethyl,

Pr ₂ is Boc,

R ₁ is H,

R ₂ is H,

R ₃ is CH ₃ .

At this time, the MEM means a 2-methoxyethoxymethyl group, and the Boc protecting group means a tert-butyloxycarbonyl protecting group.

In one embodiment, step (A) may be performed in the presence of NaHMDS, and may be performed in a THF solvent.

In another embodiment, step (B) may be performed using HCl in a MeOH solvent.

Hereinafter, the present invention will be described in more detail through examples and the like, but the scope and content of the present invention may be reduced or limited by the following examples. In addition, if it is based on the disclosure of the present invention including the following examples, it is obvious that a person skilled in the art can easily implement the present invention, in which experimental results are not specifically presented, and patents to which such modifications and corrections are attached Naturally, it is within the scope of the claims.

In addition, the experimental results presented below are only representative of experimental results of the examples and comparative examples, and the effects of various embodiments of the present invention, which are not explicitly presented below, will be described in detail in the corresponding parts.

Example

General way

Melting points were determined in open capillaries using an Opti Melting Melting Point Device (Stanford Research System, Inc.) and were not calibrated. NMR spectra were measured at 400 or 300 MHz ( ¹ H) and 100 MHz ( ¹³ C) using TMS as an internal standard. Chemical shifts (δ) are reported in parts per million (ppm) from tetramethylsilane (TMS). High resolution mass spectra were performed by LTQ Orbitrap (Thermo Electron Corporation). Analytical HPLC was performed using a Waters E2695 system equipped with a SunFireTM C18 colulmn (4.6 x 150 mm, 5 μm) column. HPLC data was recorded using the following method: H ₂ O/MeCN, 90/10 → 0/100 at 17 min, + 3 min equal volume, flow rate of 1.0 mL/min, λ = 254, 280 nm. The reaction was monitored by analytical thin layer chromatography (TLC) plate (Merck, Cat # 1.05715) and analyzed with 254 nm light. The reaction was purified by column chromatography using silica gel (Merck, Cat # 1.07734 & 1.09385). All chemicals and solvents are reagent grade and used as commercial raw materials without further purification. Reported yields are for purified products and have not been optimized. The compound was confirmed by TLC, ¹ H and ¹³ C NMR, HR-MS and elemental analysis. The analysis result is within ㅁ0.40% of the theoretical value. TLC, NMR and analytical data confirmed that the purity of the product was at least 95%.

Preparation Examples and Examples

2-amino-5-methoxybenzenethiol (2)

A mixture of 6-methoxybenzo[d]thiazol-2-amine (9 g, 50 mmol) and KOH (28 g, 500 mmol) in water (100 mL) was stirred at 110° C. overnight. After removing the scrap by filtration, the filtrate was neutralized with acetic acid (30% in water), and the precipitate was collected by filtration to give compound 2 as a pale yellow solid.

R _f =0.81 (MC/MeOH 10/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.83 (d, J = 2.96 Hz, 1Ar H ), 6.81 (d, J = 2.96 Hz, 1Ar H ), 6.72 (brs, N H ₂ ), 6.70 (s, Ar H ), 4.09 (brs, S H ), 3.63 (s, OC H ₃ ); MP: 81.6-82.8 ^o C.

2-(4-(bromomethyl)phenyl)-6-methoxybenzo[d]thiazole (3)

2-Aminothiophenol 2 (2.6 g, 16.75 mmol) and 4-bromomethylbenzoic acid (3.6 g, 16.75 mmol) were thoroughly mixed with trimethylsilyl polyphosphate (19 mL), followed by nitrogen atmosphere at 110° C. for 3 hours. Heated under. The reaction mixture was cooled to 60 °C, water (10 mL) was added, and then extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure to obtain a brown solid, which was purified by column chromatography (1: 4 EA / hexane) to give 3 as a colorless solid. Did.

R _f =0.74 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, Ar H ), 8.00 (s, Ar H ), 7.94 (d, J = 8.96 Hz, Ar H ), 7.50 (s, Ar H ), 7.48 (s, Ar H ), 7.34 (d, J = 8.24 Hz, Ar H ), 7.10 (dd, J = 8.96, 2.52 Hz, Ar H ), 4.53 (s, C H ₂ ), 3.89 (s, OC H ₃ )

2-(4-(bromomethyl)phenyl)benzo[ d ]thiazol-6-ol (4)

Dichloromethane (3.45 mL, 3.45 mmol) of 1 M BBr ₃ was added dropwise to a suspension of 3 (230 mg, 0.69 mmol) in dichloromethane (20 mL) dried at 0° C., and the reaction mixture was stirred at room temperature for 6 hours. While stirring. The mixture was quenched by dropwise addition of MeOH, the reaction mixture was poured into ammonia solution, the aqueous phase was separated, neutralized by addition of 1 N HCl and extracted with EA. The combined organic extracts were dried and the solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give compound 4 as a white solid.

R _f =0.54 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, Ar H ), 8.03 (s, Ar H ), 7.95 (d, J = 8.8 Hz, Ar H ), 7.54 (s, Ar H ), 7.52 ( s, Ar H ), 7.35 (d, J = 2.48 Hz, Ar H ), 7.03 (dd, J = 8.8, 2.52 Hz, Ar H ), 4.56 (s, C H ₂ )

2-(4-(bromomethyl)phenyl)-6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazole (5)

Hunig's base (0.13 mL, 0.75 mmol) was added to a stirred solution of compound 4 (160 mg, 0.5 mmol) in dichloromethane (20 mL) at room temperature, and the mixture was stirred for 30 minutes. To the mixture, MEM chloride (0.063 mL, 0.55 mmol) was added at room temperature and stirred for 6 hours. After adding water, extraction was performed with DCM tritium, and the solvent was removed under reduced pressure to obtain a yellow solid, which was purified by column chromatography (8: 1 hexane/EA) to give the title compound 5 as a white solid.

R _f =0.48 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, Ar H ), 7.86 (d, J =8.92 Hz, Ar H ), 7.51 (d, J =2.32 Hz, Ar H ), 7.41 (s, Ar H ), 7.39 (s, Ar H ), 7.11 (dd, J = 8.92, 2.36 Hz, Ar H ), 5.25 (s, OC H ₂ O), 4.53 (s, C H ₂ ), 3.78 (t, J = 4.44 Hz, OC H ₂ ), 3.50 (t, J = 4.72 Hz, OC H ₂ ), 3.30 (s, OC H ₃ )

diethyl (4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)benzyl)phosphonate (6)

A mixture of 5 ( 150 mg, 0.37 mmol) and triethyl phosphite (5 mL, excess) was heated at 160° C. for 3 hours. Excess triethyl phosphite was removed by vacuum distillation. The resulting solid was purified by column chromatography (EA) to give compound 6 as a light yellow solid.

R _f =0.42 (EA); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, Ar H ), 8.01 (s, Ar H ), 7.96 (d, J = 8.88 Hz, Ar H ), 7.63 (d, J = 2.32 Hz, Ar H ), 7.45 (d, J = 2.24 Hz, Ar H ), 7.43 (d, J = 2.24 Hz, Ar H ), 7.21 (dd, J = 8.88, 2.40 Hz, Ar H ), 5.37 (s, OC H ₂ O), 4.10-4.03 (m, 2OC H ₂ CH3), 3.89 (t, J = 4.48 Hz, OC H ₂ ), 3.61 (t, J = 3.08 Hz, OC H ₂ ), 3.41 (s, OC H ₃ ), 3.24 (d, J = 22 Hz, ArC H ₂ P), 1.29 (t, J = 7.04 Hz, 2CH ₂ C H ₃ )

tert -butyl (E) -(4-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)phenyl)carbamate (7a)

To a solution of phosphonate 6 (1 eq) dissolved in anhydrous THF, 1M NaHMDS in THF (1.1 eq) was added at 0 °C. The reaction mixture was stirred at 0° C. for 1 hour, then treated with a solution of aldehyde (1.1 eq.) dissolved in THF. The resulting solution was warmed to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure and the resulting liquid was extracted with EA and water. The combined organic layer was washed with brine and dried over MgSO ₄ . The crude product was purified by column chromatography (2:1 hexane/EA) to give the title compound 7a as a light yellow solid.

R _f =0.26 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, Ar H ), 7.95 (s, Ar H ), 7.87 (d, J = 8.88 Hz, Ar H ), 7.53 (m, 3Ar H ), 7.42 ( s, Ar H ), 7.40 (s, Ar H ), 7.32 (s, Ar H ), 7.30 (s, Ar H ), 7.13 (d, J = 2.4 Hz, Ar H ), 7.10 (d, J = 14.08 Hz, ArC H =CH), 6.97 (d, J = 16.28 Hz, ArCH=C H ), 6.47 (s, N H Boc), 5.28 (s, OC H ₂ O), 3.81 (t, J = 4.48 Hz , OC H ₂ ), 3.52 (t, J = 4.68 Hz, OC H ₂ ), 3.32 (s, OC H ₃ ), 1.46 (s, 3CC H ₃ )

tert- butyl ( E) -(5-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)pyridin-2-yl)carbamate (7b)

R _f =0.52 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, Ar H ), 8.06 (s, Ar H ), 8.04 (s, Ar H ), 7.98-7.94 (m, 2Ar H ), 7.89 (m, Ar H ), 7.62-7.59 (m, 3Ar H ), 7.19 (m, C H =CH), 7.10 (d, CH=C H , Ar H ), 5.35 (s, OC H ₂ O), 3.88 (t, C H ₂ O), 3.59 (t, J = 4.68 Hz, C H ₂ O), 3.39 (s, OC H ₃ ), 1.54 (s, 3CC H ₃ )

tert -butyl ( E )-(6-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)naphthalen-2-yl)carbamate (7c)

R _f =0.46 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00-7.94 (m, 2Ar H ), 7.92 (d, J = 8.88 Hz, 2Ar H ), 7.72 (s, Ar H ), 7.70-7.64 (m, 2Ar H , C H =CH), 7.57 (s, Ar H ), 7.55-7.53 (m, 2Ar H ), 7.31-7.27 (m, 2 Ar H ), 7.18-7.15 (m, Ar H , CH=C H ) , 6.83 (s, N H ), 5.31 (s, OC H ₂ O), 3.86 (t, OC H ₂ ), 3.58 (t, OC H ₂ ), 3.38 (s, OC H ₃ ), 1.55 (s, 3CC H ₃ )

tert- butyl ( E )-(4'-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)-[1,1'-biphenyl]-4-yl)carbamate (7d)

R _f =0.32 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, Ar H ), 8.04 (s, Ar H ), 7.97-7.94 (m, Ar H ), 7.66-7.56 (m, 9Ar H , C H = CH), 7.44 (d, J = 8.52 Hz, 2Ar H ), 7.23-7.18 (m, CH=C H , Ar H ), 5.35 (s, C H ₂ O), 3.88 (t, J = 4.44 Hz, OC H ₂ O), 3.59 (t, J = 4.76 Hz, Ar H ), 3.39 (s, OC H ₃ ), 1.54 (s, 3CC H ₃ )

( E )-5-(4-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)phenyl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (8a, precursor 1)

To a solution of compound 7a (105 mg, 0.197 mmol) in anhydrous DMF (2 mL) was added NaH (6 mg, 0.256 mmol) at 0 °C under nitrogen atmosphere for 1 hour. Then, the ditosylate compound (181 mg, 0.394 mmol) in dry DMF was added and stirred at room temperature for 3 hours. After it was poured into water, the reaction mixture was extracted with ethyl acetate, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexane/EA) to give compound 8a as a yellow solid.

R _f =0.09 (n-hexane/EtOAc 2/1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, Ar H ), 7.95 (s, Ar H ), 7.87 (d, J = 8.88 Hz, Ar H ), 7.72 (s, Ar H ), 7.69 ( s, Ar H ), 7.55-7.52 (m, 3Ar H ), 7.43 (s, Ar H ), 7.40 (s, Ar H ), 7.24 (s, Ar H ), 7.22 (s, Ar H ), 7.16 ( s, Ar H ), 7.13-7.09 (m, ArC H= C H ), 7.09 (s, Ar H ), 7.05 (s, Ar H ), 5.27 (s, OC H ₂ O), 4.06 (t, J = 4.68 Hz, OC H ₂ ), 3.80 (t, J = 4.77 Hz, NC H ₂ ), 3.73 (t, J = 6.00 Hz, OC H ₂ ), 3.59-3.50 (m, 3OC H ₂ ), 3.45 ( s, OC H ₃ ), 3.31 (s, OC H ₃ ), 2.34 (s, ArC H ₃ ), 1.37 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 819 (M+H) ⁺

( E )-5-(5-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)pyridin-2-yl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (8b, precursor 4)

R _f =0.29 (n-hexane/EtOAc 1/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 2.12 Hz, Ar H ), 8.06 (s, Ar H ), 8.04 (s, Ar H ), 7.95 (d, J = 8.88 Hz, Ar H ), 7.85-7.82 (dd, J = 8.76, 2.32 Hz, C H =CH), 7.79 (s, Ar H ), 7.77 (s, Ar H ), 7.67-7.61 (m, 4 Ar H ), 7.33 (s, Ar H ), 7.31 (s, Ar H ), 7.21-7.19 (dd, J = 8.92, 2.40 Hz, CH=C H ), 7.14 (d, J = 1.44 Hz, Ar H ), 5.35 (s , OC H ₂ O), 4.17 (t, J = 6.32 Hz, OC H ₂ ), 4.12 (t, J = 4.76 Hz, NC H ₂ ), 3.88 (t, J = 4.52 Hz, OC H ₂ ), 3.69 (t, J = 6.20 Hz, OC H ₂ ), 3.63-3.58 (m, 2OC H ₂ ), 3.53-3.49 (m, 2OC H ₂ ), 3.39 (s, OC H ₃ ), 2.42 (s, ArC H ₃ ), 1.52 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 820 (M+H) ⁺

( E )-5-(6-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)naphthalen-2-yl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4-methylbenzenesulfonate (8c)

R _f =0.15 (n-hexane/EtOAc 1/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, Ar H ), 8.05 (s, Ar H ), 7.86 (s, Ar H ), 7.77 (t, J = 8.04 Hz, 3 Ar H ), 7.66 (d, J = 8.32 Hz, 2Ar H ), 7.62 (d, J = 2.32 Hz, C H =CH), 7.38 (t, J = 3.80 Hz, Ar H ), 7.33 (d, J = 7.88 Hz, 4Ar H ), 7.27 (d, J = 8.04 Hz, 2Ar H ), 7.18 (dd, J = 8.88, 2.36 Hz, CH=C H ), 5.35 (s, OC H ₂ O), 4.14 (t, J = 4.68 Hz, OC H ₂ ), 4.10 (t, J = 4.92 Hz, NC H ₂ ), 3.91-3.87 (m, 2OC H ₂ ), 3.66-3.62 (m, 2OC H ₂ ), 3.61-3.57 (m, 2OC H ₂ ), 3.39 (s, OC H ₃ ), 2.44 (s, ArC H ₃ ), 1.45 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 869 (M+H) ⁺

( E )-5-(4'-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)-[1,1'-biphenyl]-4-yl)-2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 4 -methylbenzenesulfonate (8d)

R _f =0.25 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, Ar H ), 8.02 (s, Ar H ), 7.94 (d, J = 8.88 Hz, Ar H ), 7.77 (m, 2Ar H ), 7.62- 7.53 (m, 6Ar H ), 7.34-7.26 (m, 3Ar H , C H =CH), 7.21-7.18 (m, CH-C H , Ar H ), 5.33 (s, OC H ₂ O), 4.17-4.12 (t, J = 4.96 Hz, OC H ₂ ), 3.88-3.81 (m, NC H ₂ , OC H ₂ ), 3.72-3.56 (m, 5OC H ₂ ), 3.38 (s, OC H ₃ ), 2.44 (s, ArC H ₃ ), 1.46 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 895 (M+H) ⁺

tert -butyl ( E )-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)(4-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)phenyl)carbamate (9a)

To a solution of 8a (23 mg, 0.028 mmol) in anhydrous CH ₃ CN (5 mL) under a nitrogen atmosphere at 0° C. was added anhydrous 1M TBAF in THF (0.04 mL, 0.04 mmol). The solution was stirred at 90° C. for 10 minutes. After removing the solvent, the residue was purified by column chromatography to obtain 9a as a yellow solid.

R _f =0.36 (n-hexane/EtOAc 1/1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, Ar H ), 7.96 (s, Ar H ), 7.88 (d, J = 8.91 Hz, Ar H ), 7.55-7.52 (m, 3Ar H ), 7.44 (s, Ar H ), 7.41 (s, Ar H ), 7.22 (s, Ar H ), 7.14 (d, J = 2.34 Hz, C H= CH), 7.11 (d, J = 2.46 Hz, CH = C H ), 7.05 (s, Ar H ), 7.00 (s, Ar H ), 5.28 (s, OC H ₂ O), 4.56 (t, J = 3.96 Hz, C H ₂ F), 4.41 (t, J = 4.02 Hz, C H ₂ F), 3.81 (t, J = 4.35 Hz, OC H ₂ ), 3.78-3.68 (m, NC H ₂ ), 3.61-3.50 (m, 5OC H ₂ ), 3.32 (s, OC H ₃ ), 1.38 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 667 (M+H) ⁺

tert -butyl ( E )-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)(5-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)pyridin-2-yl)carbamate (9b)

R _f =0.29 (n-hexane/EtOAc 1/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 1.88 Hz, Ar H ), 8.06 (s, Ar H ), 8.04 (s, Ar H ), 7.95 (d, J = 8.88 Hz, Ar H ), 7.82 (dd, J = 8.72, 2.20 Hz, Ar H ), 7.67 (d, J = 8.64 Hz, Ar H ), 7.68-7.61 (m, 2Ar H , C H =CH), 7.19 (dd, J = 8.88, 2.32 Hz, CH=C H ), 7.13 (d, J = 3.28 Hz, Ar H ), 5.35 (s, OC H ₂ ), 4.60 (t, J = 4.08 Hz, C H ₂ F), 4.47 (t, J = 4.08 Hz, C H ₂ F), 4.20 (t, J = 6.28 Hz, OC H ₂ ), 3.88 (t, J = 4.48 Hz, OC H ₂ ), 3.73 (m, C H ₂ O, OC H ₂ ), 3.65-3.58 (m, C H ₂ O, 3OC H ₂ ), 3.39 (s, OC H ₃ ), 1.53 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 668 (M+H) ⁺

tert -butyl ( E )-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)(6-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)naphthalen-2-yl)carbamate (9c)

R _f =0.23 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, Ar H ), 8.05 (s, Ar H ), 7.96 (d, J = 8.88 Hz, Ar H ), 7.86 (s, Ar H ), 7.77 ( t, J = 7.84 Hz, 2Ar H ), 7.70 (s, Ar H ), 7.65 (d, J = 8.24 Hz, 2Ar H ), 7.61 (d, J = 2.20 Hz, C H = CH), 7.42-7.38 (m, 2Ar H ), 7.35 (s, Ar H ), 7.27 (s, Ar H ), 7.18 (dd, J = 8.92, 2.28 Hz, CH=C H ), 5.35 (s, OC H ₂ O), 4.57 (t, J = 4.08 Hz, FC H ₂ ), 4.45 (t, J = 4.04 Hz, FC H ₂ ), 3.92 (t, J = 5.84 Hz, OC H ₂ ), 3.88 (t, J = 4.40 Hz , NC H ₂ ), 3.73-3.66 (m, 2OC H ₂ ), 3.66-3.58 (m, 3OC H ₂ ), 3.39 (s, OC H ₃ ), 1.45 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 717 (M+H) ⁺

tert -butyl ( E )-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)(4'-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)-[1,1'-biphenyl]-4-yl)carbamate (9d)

R _f =0.17 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 8.88 Hz, 2Ar H ), 7.94 (d, J = 8.88 Hz, Ar H ), 7.65-7.57 (m, 9Ar H ), 7.37-7.23 (m, Ar H , C H =CH), 7.23-7.18 (m, CH=C H , 2Ar H ), 5.37 (s, OC H ₂ O), 4.60 (t, J = 3.96 Hz, C H ₂ F), 4.44 (t, J = 4.02 Hz, C H ₂ F), 3.89-3.82 (m, 2OC H ₂ ), 3.76 (m, NC H ₂ ), 3.69-3.57 (m, 5OC H ₂ ), 3.39 (s, OC H ₃ ) , 1.48 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 743 (M+H) ⁺

( E )-2-(4-(4-((2-(2-(2-fluoroethoxy)ethoxy)ethyl)amino)styryl)phenyl)benzo[ d ]thiazol-6-ol (10a, cold compound 1)

To a stirred solution of compound 9a (10 mg, 0.015 mmol) in MeOH (2 mL) was added concentrated HCl (1 mL) and stirred at 90° C. for 10 minutes. After removing the solvent, it was diluted with EA and neutralized with NH ₄ OH. The combined solution was extracted with EA and water, and the organic layer was purified by column chromatography (1: 1 hexane/EA) to obtain the target compound 10a as a yellow solid.

R _f =0.30 (n-hexane/EtOAc 1/1); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (brs, O H ), 7.97 (s, Ar H ), 7.94 (s, Ar H ), 7.83 (d, J = 8.79 Hz, Ar H ), 7.67 (s, Ar H ), 7.64 (s, Ar H ), 7.46-7.37 (m, 3Ar H ), 7.23 (d, J = 16.14 Hz, Ar H ), 7.06-6.97 (m, C H =C H ), 6.64 (s, Ar H ), 6.61 (s, Ar H ), 5.93 (brt, N H ), 4.60 (t, J = 4.02 Hz, C H ₂ F), 4.44 (t, J = 3.96 Hz, C H ₂ F), 3.71 (m, C H ₂ N), 3.62-3.57 (m, 4C H ₂ O), 3.25 (m, NHC H ₂ ); MS (ESI ⁺ , m/z): 479 (M+H) ⁺

( E )-2-(4-(2-(6-((2-(2-(2-fluoroethoxy)ethoxy)ethyl)amino)pyridin-3-yl)vinyl)phenyl)benzo[ d ]thiazol-6-ol (10b, cold compound 4)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.90 (s, O H ), 7.98-7.91 (m, 2Ar H ), 7.83 (d, J = 8.79 Hz, Ar H ), 7.67 (s, Ar H ), 7.64 (s, Ar H ), 7.50-7.40 (m, 2Ar H ), 7.26-7.23 (m, Ar H ), 7.01-6.97 (m, C H =CH), 6.87 (s, Ar H ), 6.50 (d, J = 3.51 Hz, C H =CH), 5.93 (brt, N H ), 4.60 (t, J = 4.02 Hz, C H ₂ F), 4.43 (t, J = 3.96 Hz, C H ₂ F), 3.57 (m, C H ₂ N), 3.62-3.57 (m, 4C H ₂ O), 3.27 (m, NHC H ₂ ); MS (ESI ⁺ , m/z): 480 (M+H) ⁺

( E )-2-(4-(2-(6-((2-(2-(2-fluoroethoxy)ethoxy)ethyl)amino)naphthalen-2-yl)vinyl)phenyl)benzo[ d ]thiazol-6-ol (10c)

R _f =0.21 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, Ar H ), 8.03 (s, Ar H ), 7.93 (d, J = 8.88 Hz, Ar H ), 7.85 (s, Ar H ), 7.77 ( t, J = 7.84 Hz, 2Ar H ), 7.70 (s, Ar H ), 7.65 (d, J = 8.24 Hz, 2Ar H ), 7.61 (d, J = 2.20 Hz, C H = CH), 7.40-7.35 (m, 2Ar H ), 7.33 (s, Ar H ), 7.27 (s, Ar H ), 7.18 (dd, J = 8.92, 2.28 Hz, CH=C H ), 4.57 (t, J = 4.08 Hz, FC H ₂ ), 4.45 (t, J = 4.04 Hz, FC H ₂ ), 3.92 (t, J = 5.84 Hz, OC H ₂ ), 3.88 (t, J = 4.40 Hz, NC H ₂ ), 3.73-3.66 ( m, OC H ₂ ), 3.66-3.58 (m, 2OC H ₂ ), 1.45 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 529 (M+H) ⁺

( E )-2-(4-(2-(4'-((2-(2-(2-fluoroethoxy)ethoxy)ethyl)amino)-[1,1'-biphenyl]-4-yl)vinyl)phenyl) benzo[ d ]thiazol-6-ol (10d)

R _f =0.15 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J = 8.88 Hz, 2Ar H ), 7.92 (d, J = 8.88 Hz, Ar H ), 7.65-7.55 (m, 9Ar H ), 7.37-7.21 (m, Ar H , C H =CH), 7.20-7.15 (m, CH=C H , 2Ar H ), 4.60 (t, J = 3.96 Hz, C H ₂ F), 4.44 (t, J = 4.02 Hz, C H ₂ F) , 3.89-3.82 (m, 2OC H ₂ ), 3.76 (m, NC H ₂ ), 3.64-3.59 (m, 3OC H ₂ ), 1.48 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 555 (M+H) ⁺

( E )-3-((tert-butoxycarbonyl)(4-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)phenyl)amino)propyl 4-methylbenzenesulfonate (11a, precursor 2)

R _f =0.22 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, Ar H ), 7.97 (s, Ar H ), 7.93 (d, J = 8.92 Hz, Ar H ), 7.68 (s, Ar H ), 7.66 ( s, Ar H ), 7.55-7.51 (m, 3Ar H ), 7.42 (s, Ar H ), 7.40 (s, Ar H ), 7.28 (s, Ar H ), 7.24 (s, Ar H ), 7.15- 7.13 (m, C H= C H ), 7.09-7.05 (m, 3Ar H ), 5.27 (s, OC H ₂ O), 4.00 (t, OC H ₂ ), 3.80 (NC H ₂ ), 3.63 (t , OC H ₂ ), 3.51 (t, OC H ₂ ), 2.37 (s, ArC H ₃ ), 1.86 (m, CH ₂ C H ₂ CH ₂ ), 1.35 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 745 (M+H) ⁺

( E )-3-(( tert -butoxycarbonyl)(5-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)pyridin-2-yl)amino)propyl 4-methylbenzenesulfonate (11b, precursor 5)

R _f =0.31 (n-hexane/EtOAc 1/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, Ar H ), 7.96 (m, 3Ar H ), 7.76-7.51 (m, 4Ar H ), 7.47 (m, 2Ar H ), 7.37 (s, Ar H ), 7.15-7.10 (m, Ar H, C H= C H ), 7.06 (s, Ar H ), 5.27 (s, OC H ₂ O), 4.00 (t, OC H ₂ ), 3.89 (NC H ₂ ), 3.63 (t, OC H ₂ ), 3.51 (t, OC H ₂ ), 2.37 (s, ArC H ₃ ), 1.86 (m, CH ₂ C H ₂ CH ₂ ), 1.35 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 746 (M+H) ⁺

tert -butyl ( E )-(3-fluoropropyl)(4-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)phenyl)carbamate (12a)

R _f =0.41 (n-hexane/EtOAc 2/1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, Ar H ), 7.96 (s, Ar H ), 7.55-7.51 (m, 3Ar H ), 7.45 (s, Ar H ), 7.43 (s, Ar H ), 7.15-7.10 (m, Ar H, C H= C H ), 7.06 (s, Ar H ), 5.28 (s, OC H ₂ O), 4.49 (t, J = 5.72 Hz, C H ₂ F ), 4.37 (t, J = 5.72 Hz, C H ₂ F), 3.81 (t, J = 4.28 Hz, OC H ₂ ), 3.74 (t, OC H ₂ ), 3.52 (t, OC H ₂ ), 3.32 (s, OCH ₃ ), 1.96-1.88 (m, CH ₂ C H ₂ CH ₂ ), 1.38 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 593 (M+H) ⁺

tert -butyl ( E )-(3-fluoropropyl)(5-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)pyridin-2-yl)carbamate (12b)

R _f =0.34 (n-hexane/EtOAc 1/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, Ar H ), 7.96 (s, Ar H ), 7.76-7.51 (m, 2Ar H ), 7.47 (s, Ar H ), 7.37 (s, Ar H ), 7.15-7.10 (m, Ar H, C H= C H ), 7.06 (s, Ar H ), 5.28 (s, OC H ₂ O), 4.49 (t, J = 5.72 Hz, C H ₂ F ), 4.37 (t, J = 5.72 Hz, C H ₂ F), 3.81 (t, J = 4.28 Hz, OC H ₂ ), 3.77 (t, OC H ₂ ), 3.54 (t, OC H ₂ ), 3.34 (s, OCH ₃ ), 2.00-1.89 (m, CH ₂ C H ₂ CH ₂ ), 1.38 (s, 3CC H ₃ ); MS (ESI ⁺ , m/z): 594 (M+H) ⁺

( E )-2-(4-(4-((3-fluoropropyl)amino)styryl)phenyl)benzo[ d ]thiazol-6-ol (13a, cold compound 2)

R _f =0.32 (n-hexane/EtOAc 2/1); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.92 (brs, O H ), 7.97 (s, Ar H ), 7.94 (s, Ar H ), 7.83 (d, J = 8.82 Hz, Ar H ), 7.67 (s, Ar H ), 7.64 (s, Ar H ), 7.41-7.38 (m, 3Ar H ), 7.26-7.21 (d, J = 16.17 Hz, Ar H )), 7.01-6.96 (m, C H =C H ), 6.61 (s, Ar H ), 6.59 (s, Ar H ), 6.01 (brt, N H ), 4.64 (t, C H ₂ F), 4.48 (t, C H ₂ F), 3.17 (t, NHC H ₂ ), 1.97-1.88 (m, CH ₂ C H ₂ CH ₂ ); MS (ESI ⁺ , m/z): 405 (M+H) ⁺

( E )-2-(4-(2-(6-((3-fluoropropyl)amino)pyridin-3-yl)vinyl)phenyl)benzo[ d ]thiazol-6-ol (13b, cold compound 5)

R _f =0.21 (n-hexane/EtOAc 1/2); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.93 (brs, O H ), 8.05-7.82 (m, 3Ar H ), 7.45 (s, Ar H ), 7.64 (s, Ar H ), 7.41-7.38 (m, 3Ar H ), 7.26-7.21 (d, J = 16.17 Hz, Ar H )), 7.01-6.96(m, C H =CH), 6.61 (s, CH=C H ), 6.55 (s, Ar H ), 4.65 (t, C H ₂ F), 4.44 (t, C H ₂ F), 3.17 (t, NHC H ₂ ), 1.99-1.88 (m, CH ₂ C H ₂ CH ₂ ); MS (ESI ⁺ , m/z): 406 (M+H) ⁺

tert -butyl ( E )-(4-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)phenyl)(methyl)carbamate (14a)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 2.00 Hz, Ar H ), 8.05 (s, Ar H ), 8.03 (s, Ar H ), 7.95 (d, J = 8.92, Ar H ), 7.85-7.82 (m, 2Ar H ), 7.74 (d, J = 8.72 Hz, Ar H ), 7.60 (s, Ar H ), 7.60 (s, Ar H ), 7.36 (m, CH=C H ) , 7.18-7.09 (m, 2Ar H , C H =CH), 3.90 (s, OC H ₃ ), 3.42 (s, NC H ₃ ), 1.53 (s, 3CC H ₃ )

tert -butyl (E) -(5-(4-(6-((2-methoxyethoxy)methoxy)benzo[ d ]thiazol-2-yl)styryl)pyridin-2-yl)(methyl)carbamate (14b)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, J = 2.00 Hz, Ar H ), 8.05 (s, Ar H ), 8.03 (s, Ar H ), 7.95 (d, J = 8.92, Ar H ), 7.85-7.82 (m, Ar H ), 7.74 (d, J = 8.72 Hz, Ar H ), 7.63 (s, Ar H ), 7.60 (s, Ar H ), 7.36 (m, CH=C H ) , 7.18-7.09 (m, 2Ar H , C H =CH), 3.90 (s, OC H ₃ ), 3.43 (s, NC H ₃ ), 1.55 (s, 3CC H ₃ )

( E )-2-(4-(4-(methylamino)styryl)phenyl)benzo[ d ]thiazol-6-ol (15a)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.85(s, OH), 7.95 (d, J = 8.4 Hz, 2 Ar H ), 7.82 (d, J = 8.5 Hz, Ar H ), 7.65 (d , J = 8.5 Hz, 2Ar H ), 7.40 (d, J = 2.1 Hz, C H =CH), 7.32 (d, J = 8.3 Hz, 2Ar H ), 7.21 (d, J = 16.3 Hz, Ar H ) , 6.97 (dd, J = 2.1 Hz, CH=C H ), 6.96 (d, J = 16.4 Hz, Ar H ), 6.55 (d, J = 8.4 Hz, 2Ar H ), 6.01 (m, N H ), 2.70 (d, J = 5.0 Hz, C H ₃ )

( E )-2-(4-(2-(6-(methylamino)pyridin-3-yl)vinyl)phenyl)benzo[ d ]thiazol-6-ol (15b)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, O H ), 8.05 (s, Ar H ), 8.15 (s, Ar H ), 8.00-7.94 (m, 3Ar H ), 7.92-7.67 (m, 2Ar H ), 7.42-7.09 (m, 2Ar H , CH=C H ), 7.00 (m, C H= CH), 2.86 (d, J = 4.20 Hz, NC H ₃ )

Diethyl 4-(5-(2,3-dihydroxypropoxy)benzo[d]thiazol-2-yl)benzylphosphonate (17)

Triethylamine (0.011 mL, 0.079 mmol) and glycidol (0.053 mL, 0.795 mmol) were added to a solution of diethyl 4-(5-hydroxybenzo[d]thiazol-2-yl)benzylphosphonate (16, 300 mg, 0.795 mmol) in ethanol. Did. The solution was stirred at 90 °C. After removing the solvent, the residue was purified by column chromatography to obtain diethyl 4-(5-(2,3-dihydroxypropoxy)benzo[d]thiazol-2-yl)benzylphosphonate (17).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 7.9 Hz, 2H), 7.92 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.41 (d , J = 2.3 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 9.0, 2.4 Hz, 1H), 4.18-4.09 (m, 4H), 4.04 (p, J = 7.1 Hz, 5H), 3.21 (d, J = 22.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 6H); MS (ESI+, m/z): 452 (M+H)+

3-((2-(4-((diethoxyphosphoryl)methyl)phenyl)benzo[d]thiazol-5-yl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate (18)

To a solution of compound 17 (320 mg, 0.709 mmol) in DCM (20 mL) under nitrogen atmosphere at 0 °C Triethylamine (0.148 mL, 1.063 mmol), 4-methylbenzene-1-sulfonyl chloride (149 mg, 0.780 mmol), DMAP (8.66 mg, 0.071 mmol) was added. Then stirred at room temperature for 3 hours. After it was poured into water, the reaction mixture was extracted with DCM, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain compound (18).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.44 (d , J = 2.3 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 2.6 Hz, 1H), 7.00 (dd, J = 8.9, 2.5 Hz, 1H), 4.25 (td, J = 11.2, 3.9 Hz, 4H), 4.06 (dd, J = 13.5, 5.8 Hz, 5H), 3.22 (d, J = 22.0 Hz, 2H), 2.40 (s, 3H), 1.27 (t, J=7.0 Hz, 6H); MS (ESI+, m/z): 606 (M+H)+

3-((2-(4-((diethoxyphosphoryl)methyl)phenyl)benzo[d]thiazol-5-yl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate (19)

To a solution of compound 18 (110 mg, 0.182 mmol) in DCM (20 mL) under nitrogen atmosphere, 3,4-dihydro-2H-pyran (0.166 mL, 1.816 mmol) and 4-methylbenzenesulfonic acid, water salt (51.8 mg, 0.272 mmol) was added in order. It was then stirred at room temperature for 5 minutes. Then, triethylamine (0.051 mL, 0.363 mmol) was added to the solution and stirred for an additional 5 minutes. Concentrated in vacuo and the residue was purified by column chromatography to give compound 19.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.76 (d , J = 6.1 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.29-7.24 (m, 3H), 6.99-6.94 (m, 1H) , 4.84-4.71 (m, 1H), 4.38-4.15 (m, 4H), 4.09-4.00 (m, 4H), 3.94-3.77 (m, 2H), 3.56-3.44 (m, 1H), 3.22 (d, J = 22.0 Hz, 2H), 2.38 (s, 3H), 1.82-1.63 (m, 2H), 1.57-1.38 (m, 4H), 1.27 (t, J = 7.0 Hz, 6H); MS (ESI+, m/z): 690 (M+H)+

(E)-3-((2-(4-(4-((tert-butoxycarbonyl)(methyl)amino)styryl)phenyl)benzo[d]thiazol-6-yl)oxy)-2-((tetrahydro- 2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate (20, precursor 3)

To a solution of compound 19 (1 eq) dissolved in anhydrous THF, 1M NaHMDS in THF (1.1 eq) was added at 0 °C. The reaction mixture was stirred at 0° C. for 1 hour, then treated with a solution of aldehyde (1.1 eq.) dissolved in THF. The resulting solution was warmed to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure and the resulting liquid was extracted with EA and water. The combined organic layer was washed with brine and dried over MgSO ₄ . The crude product was purified by column chromatography to give compound 20.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 7.5 Hz, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.77 (d , J = 6.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.32-7.23 (m, 5H), 7.20 (d, J = 16.2 Hz , 1H), 7.10 (d, J = 16.3 Hz, 1H), 6.99-6.94 (m, 1H), 4.85-4.71 (m, 1H), 4.39-4.00 (m, 4H), 3.95-3.72 (m, 2H ), 3.56-3.44 (m, 1H), 3.29 (s, 3H), 2.38 (s, 3H), 1.85-1.64 (m, 2H), 1.48 (s, 9H), 1.45-1.12 (m, 4H); MS (ESI+, m/z): 771 (M+H)+

(E)-3-((2-(4-(2-(6-((tert-butoxycarbonyl)(methyl)amino)pyridin-3-yl)vinyl)phenyl)benzo[d]thiazol-6-yl) oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-methylbenzenesulfonate (21, precursor 6)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 7.5 Hz, 2H), 7.92 (d, J = 8.9 Hz, 1H), 7.84 (dd , J = 8.8, 2.4 Hz, 1H), 7.77 (dt, J = 15.2, 7.6 Hz, 4H), 7.62 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 7.7, 2.5 Hz, 2H) , 7.14 (d, J = 6.2 Hz, 2H), 7.00-6.93 (m, 1H), 4.87-4.68 (m, 1H), 4.39-4.08 (m, 4H), 3.85 (ddd, J = 17.2, 16.4, 9.6 Hz, 2H), 3.60-3.46 (m, 1H), 3.44 (s, 3H), 2.38 (s, 3H), 1.83-1.62 (m, 6H), 1.55 (s, 9H); MS (ESI+, m/z): 772 (M+H)+

(E)-1-fluoro-3-((2-(4-(4-(methylamino)styryl)phenyl)benzo[d]thiazol-6-yl)oxy)propan-2-ol (22, cold compound 3 )

To a solution of compound 20 (10 mg, 0.013 mmol) in anhydrous THF (2 mL) under a nitrogen atmosphere at 0° C. was added anhydrous 1M TBAF in THF (0.026 mL, 0.026 mmol). The solution was stirred at 90° C. for 10 minutes. After removing the solvent, MeOH (2 mL) and concentrated HCl (1 mL) were added and stirred at 90° C. for 10 minutes. After removing the solvent, it was diluted with EA and neutralized with NH ₄ OH. The combined solution was extracted with EA and water, and the organic layer was purified by column chromatography to obtain the target compound 22.

¹ H NMR (400 MHz, DMSO) δ 7.99 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 16.4 Hz, 1H), 7.15 (dd, J = 8.9, 2.5 Hz, 1H), 7.00 (d, J = 16.4 Hz, 1H), 6.57 (d, J = 8.6 Hz, 2H), 4.58 (ddd, J = 14.4, 9.9, 5.2 Hz, 2H), 4.47 (ddd, J = 13.1, 9.5, 4.1 Hz, 2H ), 4.15-4.08 (m, 1H), 2.72 (s, 3H); MS (ESI+, m/z): 435 (M+H)+

(E)-1-fluoro-3-((2-(4-(2-(6-(methylamino)pyridin-3-yl)vinyl)phenyl)benzo[d]thiazol-6-yl)oxy)propan- 2-ol (23, cold compound 6)

¹ H NMR (400 MHz, DMSO) δ 8.12 (br s, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.9 Hz, 2H), 7.76 (d, J = 2.5 Hz , 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 16.7 Hz, 1H), 7.21 (d, J = 16.4 Hz, 1H), 7.17 (dd, J = 8.9, 2.6 Hz , 1H), 4.58 (ddd, J = 14.4, 9.9, 5.2 Hz, 2H), 4.47 (ddd, J = 13.1, 9.5, 4.1 Hz, 2H), 4.15-4.08 (m, 1H), 2.91 (s, 3H) ); MS (ESI+, m/z): 436 (M+H)+

¹⁸ Preparation of F-labeled compound

( E )-2-(4-(2-(6-((2-(2-(2-[ ¹⁸ F]fluoroethoxy)ethoxy)ethyl)amino)pyridin-3-yl)vinyl)phenyl)benzo[ d ] Preparation of thiazol-6-ol (27, hot compound 4)

Compound 8b (precursor 4) (1 mg, 1.2 μmol) was dissolved in THF (0.5 mL) and reacted with [F-18]TBAF (tetrabutylammoniumfluoride (50 mCi).The intermediate was reacted with 1 M HCl to deprotect and HPLC ( C18 semi Prep.HPLC column, water: EtOH = 80%: 20% (0 min) to water: EtOH = 0%: 100% (20 min)) to purify Compound 27 (Hot Compound 4) 10% ( EOB) was obtained within 90 minutes.

Preparation of hot compounds 1 to 3, 5 and 6

Compound 24 (hot compound 1) was prepared from compound 8a (precursor 1) in the same manner, compound 25 (hot compound 2) was prepared from compound 11a (precursor 2), and compound 26 (hot 3) from compound 20 (precursor 3). Compound 3) was prepared, compound 24 (hot compound 4) was prepared from compound 27 (precursor 4), and compound 29 (hot compound 6) was prepared from compound 21 (precursor 6), respectively.

(1) Hot compound 1

(2) Hot compound 2

(3) Hot compound 3

(4) Hot compound 5

(5) Hot compound 6

Test example

Compound to be tested

The following tests were performed on the following six compounds.

(1) Cold compound 1

(2) Cold compound 2

(3) Cold compound 3

(4) Cold compound 4

(5) Cold compound 5

(6) Cold compound 6

In vitro screening for selectivity analysis for tau and amyloid aggregates

(a) Induction of tau/amyloid aggregation

For induction of amyloid aggregation, the synthesized Abeta40 peptide was dissolved in PBS buffer at a concentration of 0.5 mg/mL to induce aggregation for 7 days at 37°C and 200 rpm shaking conditions. To induce aggregation of Tau protein, the concentration of Tau-K18 protein (0.5 mg/mL in PBS) isolated and purified from E. coli was combined with Heparin (0.1 mg/mL) and DTT (100 μM) at 37° C. and 200 rpm. Aggregation was induced for 7 days under shaking conditions.

(b) Measurement of labeling ability for tau and amyloid aggregate derivatives

Since the aggregation phenomenon of tau and amyloid appears only in the pathological environment, the reactivity of the aggregate and unaggregated tau protein and aggregated tau protein (aggregates) to confirm that the newly synthesized compound can label the tau aggregate protein Was compared and analyzed.

To confirm the labeling ability of the newly synthesized compounds for tau aggregate protein, 25 μL of 10 μM of the labeling substance diluted in PBS and 0.25 μg/mL of tau and amyloid pre-aggregate and aggregate diluted in PBS and 25 μL of 30 respectively After minute incubation, the fluorescence spectrum reaction was measured using a spectrophotometer (ThS/ PBB3 Ex: 430 nm, Em: 480-610) (compound1-6; Ex: 400 nm, Em: 450-600).

(c) Measurement of non-specific binding using Bovine Serum Albumin

To exclude non-specific binding of the compound to serum, reactivity between BSAs was tested through an in vitro assay. After incubation of 25 μL of 10 μM synthetic material in 25 μL of 0.25 mg/mL BSA for 30 minutes, the fluorescence spectrum reaction was measured using a spectrophotometer (ThS/ PBB3 Ex: 430 nm, Em: 480-610) (compound1- 6; Ex: 400 nm, Em: 450-600). The BSA response is intended to identify non-selective binding to other proteins in the blood when applied to the patient as an imaging agent.

(d) As a control for the experiment, PBB3 (Neuron, 79(6), 1094-1108) previously published as a tau selective marker was used together with ThS.

As a result of in vitro screening, it was confirmed that Cold No. 4 and Cold No. 5 had higher selectivity to Tau aggregates than amyloid aggregates. Cold No. 4 showed selectivity of 2.1 times, and Cold No. 5 showed selectivity of 2.6 times. Thioflavine S and PBB3 showed high BSA reactivity, whereas the selected compounds were found to have relatively low reactivity to BSA.

Table 1 below shows the results of comparing the tau/amyloid labeling ability of Compound 1-6.

Brain tissue staining results of 6 cold transgenic mice

(a) Tau transgenic mouse model (MAPT P301L)

The Tau transgenic mouse model exhibits Tau aggregation as it ages by having a P301L mutation in Tau. Experiments were conducted using brain tissue obtained from 8.5-month-old MAPTA transgenic mice.

(b) Amyloid transgenic mouse model (APP/PS1)

The amyloid mouse model shows amyloid aggregation as it ages by expressing the APP/PSEN1 gene. Experiments were conducted using 10-month-old APP/PSEN mice known to form amyloid plaques.

(c) brain tissue extraction

After the mice were over-anesthetized with 2% avertin, perfusion was performed through cardiac perfusion using physiological saline. After perfusion, tissue was fixed using 4% PFA and the brain was isolated. The extracted brain was further fixed in PFA and stored in a 30% sucrose solution for cryosection sample preparation. Subsequently, a cryosection mold was prepared using an OCT compound and brain tissue sections were obtained using a cryotome.

(d) brain tissue staining

After diluting the 10 mM compound dissolved in DMSO at 10 μM in physiological saline, brain tissue sections were stained overnight for about 12 hours and fluorescence images were confirmed (Ex: 460-490 nm, Em: 500-550). Brain tissue was stained with Hoechst (10 μM) for Nuclei counterstain (Ex: 360-400 nm, Em: 410-480).

(e) Fluorescence imaging

Fluorescence images were acquired using a 10X objective lens using an automated imaging device (Operetta), and the entire brain mapping was completed using an automatic stitch function.

Confirmation of affinity for amyloid plaques

Before confirming the affinity of Tau Tangle, the affinity for amyloid plaques was first confirmed. In this experiment, a fragment of an APP/PS1 mouse model generating amyloid plaque was used. Brain tissue sections of APP/PS1 mice 10 months old were stained overnight for about 12 hours, and then confirmed by fluorescence image.

As a result, amyloid plaques were observed by PBB3 and ThS, and among the test compounds, it was observed that Cold 4 and Cold 6 had lower affinity for amyloid plaques than other compounds.

Tau Tangle Affinity Check

Prior to confirming the tau tangle affinity, the tau transgenic mouse model to be used was confirmed using a tau tangle antibody, AT8, to confirm whether the tau transgenic mouse model expresses tau disease.

The fluorescence image was confirmed after staining the 8.5-month-old Tau transgenic mouse model and the 10-month-old wild type brain tissue section overnight for about 12 hours. In the wild type without tau disease, no fluorescence reaction was observed in six test compounds including PBB3 and ThS. However, in the transgenic mouse model, when stained using Cold 1, 4, 5, and 6, a fluorescence reaction was observed in the brain region identified by the Tau Tangle antibody.

Therefore, when considered in conjunction with the amyloid affinity experiment, it was found that Cold 4 and Cold 5 have low affinity for amyloid while high affinity for tau tangle. Based on Cold 4 and Cold 5, it is expected that tau target probes with high tau selectivity can be derived.

Claims (10)

Compounds of the formula: or pharmaceutically acceptable salts thereof:
[Formula 1a]

Wherein R ₁ - is H- or FR ₁ '-, and
Wherein -R ₁ '- is _{- (CH 2) L1 (CHOH} ) L2 (CH 2) L3 -, - (CH 2) m1 O (CH 2) m2-, and -(CH ₂ ) _m1 O(CH ₂ ) _m2 O(CH ₂ ) _m3 -is selected from,
L1 is 1 or 2, L2 is 1, and L3 is 1 or 2,
M1 is 2 or 3, m2 is 2 or 3, and m3 is 2 or 3,
Ar ₁ is

or

ego,
Ar ₂ is

And

Is selected from
The R ₂ is selected from H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ,
Wherein -R ₃ is _{-CH 3, CH 2 CH 3,} CH 2 CH 2 CH 3 , or selected from, or -R ₃ 'are -F,
R ₁ -is H- and at the same time -R ₃ is not any one selected from -CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ,
Wherein -R ₃ '- is _{- (CH 2) p1 O (} CH 2) p2--, - (CH 2) p1 O (CH 2) p2 O (CH 2) p3 -, - (CH 2) p1 O ( CH ₂ ) _p2 O(CH ₂ ) _p3 O(CH ₂ ) _p4 -and -(CH ₂ ) _q1 -is selected,
P1 is 2 or 3, p2 is 2 or 3, p3 is 2 or 3, and p4 is 2 or 3,
Q1 is an integer from 2 to 5. delete 2. The method of claim 1, wherein -R ₁ '- is _{- (CH 2) (CHOH)} CH 2 -, and _{- (CH 2) 2 O (} CH 2) 2 O (CH 2) 2 - is selected from,
R ₂ is H,
Wherein -R ₃ is -CH ₃ or -R ₃ '-F,
Wherein -R ₃ '- is _{- (CH 2) 2 O (} CH 2) 2 O (CH 2) 2 - and - (CH _{2) 3} -, or a pharmaceutically acceptable compound according to claim which is selected from among those available Salt of: According to claim 3, wherein the compound of Formula 1a is characterized in that it has a structure of any one of the following formula, the compound or a pharmaceutically acceptable salt thereof:
[Formula 1c]

[Formula 1d]

[Formula 1e]

[Formula 1f]

According to claim 1, wherein the compound of Formula 1a is characterized in that it has a structure of any one of the following formula, the compound or a pharmaceutically acceptable salt thereof:
[Formula 1p]

[Formula 1q]

[Formula 1r]

[Formula 1s]

The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein F is ¹⁹ F or ¹⁸ F. A precursor for preparing a compound of Formula 1 according to any one of claims 1, 3 to 5, having the structure of the formula:
[Formula 2]

Wherein R ₁ - is MEM- or TsO-R ₁ '- or MsO-R _1' -, and
Wherein -R ₁ '- is _{- (CH 2) L1 (CHOH} ) L2 (CH 2) L3 -, - (CH 2) m1 O (CH 2) m2-, and -(CH ₂ ) _m1 O(CH ₂ ) _m2 O(CH ₂ ) _m3 -is selected from,
L1 is 1 or 2, L2 is 1, and L3 is 1 or 2,
M1 is 2 or 3, m2 is 2 or 3, and m3 is 2 or 3,

Ar ₁ is

or

ego,
Ar ₂ is

And

Is selected from
R ₂ is Boc,
Wherein -R ₃ is -CH ₃ or -R ₃ '-OTs or -R _3' -OMs,
₃ wherein -R '- is _{- (CH 2) 2 O (} CH 2) 2 O (CH 2) 2 - is selected from - and - (CH _{2) 3}
The MEM means a 2-methoxyethoxymethyl group,
The TsO means a tosylate group,
The MsO means a mesylate group,
The Boc protecting group means a tert-butyloxycarbonyl protecting group. A pharmaceutical composition for the diagnosis, prevention or treatment of degenerative brain disease, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. Method of preparing a compound of Formula 1a comprising the following steps:
[Formula 1a]

(A) preparing a compound of formula 5 by reacting a compound of formula 3 with a compound of formula 4,
[Formula 3]

[Formula 4]
OHC-Ar ₂ -NHPr ₂
[Formula 5]

(B) preparing a compound of formula 7 by reacting the compound of formula 5 with the compound of formula 6,
[Formula 6]
Pr ₃ -R1'-Pr ₃
[Formula 7]

(C) preparing a compound of formula 9 by reacting the compound of formula 7 with a compound of formula 8,
[Formula 8]
ZF
[Formula 9]

(D) preparing a compound of Formula 1a by performing a deprotection reaction on the compound of Formula 9,
In the above formula, Pr ₁ is MEM,
Ar ₁ is

or

ego,
Ar ₂ is

And

Is selected from
R ₄ is ethyl,
Pr ₂ is Boc,
₃ wherein -R '- is _{- (CH 2) 2 O (} CH 2) 2 O (CH 2) 2 - is selected from - and - (CH _{2) 3}
The Pr ₃ is TsO or MsO,
Z is selected from TBA, Na ⁺ , K ⁺ , Cs ⁺ ,
R ₁ is H,
R ₂ is H,
Wherein -R ₃ is -R ₃ '-F,
The MEM means a 2-methoxyethoxymethyl group,
The TsO means a tosylate group,
The MsO means a mesylate group,
The Boc protecting group means a tert-butyloxycarbonyl protecting group,
The TBA means tetra-n-butylammonium. Method of preparing a compound of Formula 1a comprising the following steps:
[Formula 1a]

(A) preparing a compound of Formula 12 by reacting a compound of Formula 3 with a compound of Formula 11,
[Formula 3]

[Formula 11]
OHC-Ar ₂ -N(CH ₃ )Pr ₂
[Formula 12]

(B) preparing a compound of Formula 1a by performing a deprotection reaction on the compound of Formula 12,
In the above formula, Pr ₁ is MEM,
Ar ₁ is

or

ego,
Ar ₂ is

And

Is selected from
R ₄ is ethyl,
Pr ₂ is Boc,
R ₁ is H,
R ₂ is H
R ₃ is CH ₃ ,
The MEM means a 2-methoxyethoxymethyl group,
The Boc protecting group means a tert-butyloxycarbonyl protecting group.

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