CZ202135A3 - Dual active tacrine derivatives and their use - Google Patents

Abstract

The present solution provides new tacrine derivatives of general formula I, where n is 1, 2 or 3; R 1 is selected from -CH 3 ; -OCH3; -Br; -Cl; -F; phenoxy; 1-CH3-phenoxy; 1-OCH3-phenoxy; 2-OCH3-phenoxy; 3-CH3-phenoxy; 3-Cl-phenoxy; 3-C(CH 3 ) 3 -phenoxy; 3-C(O)-CH3-phenoxy; 2-CH3,4-CH3-phenoxy; and R 2 -H; -Cl; -Br; wherein - if R 2 is –Cl, then R 1 must be –Cl; - if R2 is -Br, R1 must be -Br; - if R1 is –OCH3 or phenoxy, n must not be 2, or their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their addition salts with acids. These compounds are effective drugs for the therapy of dementia and neurodegenerative diseases.

Description

Dually active tacrine derivatives and their use

Field of technology

The invention relates to new tacrine-based compounds as dually effective acetylcholinesterase inhibitors and Y-methyl-D-aspartate (NMDA) receptor antagonists, their preparation method and their therapeutic use.

Current state of the art

The so-called multi-target directed ligands (MTDLs) have recently appeared frequently in the scientific literature because they are compounds that are effective in the treatment of complex diseases due to their ability to interact with different targets suspected of disease pathogenesis at the same time . The underlying hypothesis is that multifactorial drugs will be more effective than single-target drugs. The MTDL strategy is a pharmacological tool to suppress diseases of a multifactorial nature and is mainly applied in the field of infectious diseases, oncological and neurological diseases. In the field of neurological diseases, these are mainly neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, vasculoma dementia, dementia with Lewy bodies or a combination thereof (RAMSAY, R.R., M.R. POPOVIC-NIKOLIC, K. NIKOLIC, E. ULIASSI AND M. L BOLOGNESI A perspective on multi-target drug discovery and design for complex diseases. Clinical and translational medicine, 2018, 7(1), 3).

The so-called the dual effect of drugs to inhibit acetylcholinesterase and at the same time the ability to antagonize NMDA receptors should, according to recommended procedures, be used in the therapy of dementia with Lewy bodies or in the therapy of dementia vasculature in combination with dementia with Lewy bodies and in combination with Parkinson's or Alzheimer's disease (NICE guideline, June 2018, Dementia). Thus, in these diseases, combinatory treatment using, for example, acetylcholinesterase inhibitors in combination with the NMDAR antagonist memantine is expedient, and the combination of these two effects into one treatment is a rational basis for the compatibility of both effects within one molecule. This is mainly due to the fact that disruption of both systems (cholinergic and glutamatergic neurotransmission) occurs simultaneously in the late stages, i.e. during the clinical manifestation of these diseases.

Alzheimer's disease (AD) is the most common form of dementia, which is characterized as a progressive neurodegenerative disease with a multifaceted pathogenesis. Symptoms of AD include severe memory impairment, impaired cognitive abilities, inability to perform daily activities, and loss of language skills. The etiology of AD is currently not fully explored, but the histopathological picture of the disease reflects the accumulation of extracellular insoluble deposits of amyloid β with the subsequent formation of neuritic plaques as well as the presence of intracellular neurofibrillar tangles, composed of hyperphosphorylated τ-protein in some areas of the brain, including the hippocampus. The most widely used hypothesis for the origin of AD is the cholinergic hypothesis, which assumes a reduced tone of the cholinergic system, other theories of the pathogenesis of AD include the hypothesis of the amyloid cascade, oxidative stress associated with the formation of free oxygen radicals or the presence of subclinical inflammation, which depict the interconnectedness and complexity of this disease.

Currently, the treatment of AD is based on inhibitors of the enzyme acetylcholinesterase (AChE, E.C. 3.1.1.7), which increase the level of acetylcholine at synapses and thereby facilitate the transmission of excitement. Currently, three AChE inhibitors are used in AD therapy, namely donepezil, galantamine and rivastigmine. They are used for mild to moderate stages of AD. As the first cholinesterase inhibitor for the treatment of AD, tacrine was approved in 1993, but its use was later abandoned due to its gastrointestinal side effects and hepatotoxicity. Furthermore, memantine, a non-competitive antagonist acting on N, is indicated for the treatment of moderate to severe stages of AD

- 1 CZ 2021 - 35 A3 methyl-D-aspartate receptors (NMDAR), which prevents glutamatergic excitotoxicity leading to neurodegeneration. However, their effectiveness is limited and short-lived.

The most frequently chosen strategy for the preparation of so-called MTDLs (ligands with a multifunctional character, from the English multi-target directed ligands) is the connection of two heterogeneous pharmacophores, where these pharmacophores are connected by a carbon chain ("linking" approach). However, this method leads to an increased molecular weight of the final compounds, reduced solubility and other inappropriate physicochemical properties of the resulting entity, as well as greater off-targeting and toxicity. Therefore, it is advantageous to search for a combination of different pharmacophores within one molecule (the so-called "merging" or "fusing" approach) (BENEK, O., J. KORBECNY AND O. SOUKUP A Perspective on Multi-target Drugs for Alzheimer's Disease. Trends in Pharmacological Sciences, 2020, 41(7), 433-445).

However, individual drugs with this so-called dual effect are not available on the market (with the exception of huperzine-A approved in China). However, this dual effect appears in the literature. A dual concept assuming inhibition of both AChE and NMDA receptors based on the mentioned "linking" approach was first presented by binding galantamine to memantine (SIMONI, E., S. DANIELE, G. BOTTEGONI, D. PIZZIRANI, M. L. TRINCAVELLI, L. GOLDONI, G TAROZZO, A. REGGIANI, C. MARTINI AND D. PIOMELLI Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease. Journal of medicinal chemistry, 2012, 55(22), 9708-9721; REGGIANI, A. Μ., E. SIMONI, R. CAPORASO, J. MEUNIER, E. KELLER, T. MAURICE, A. MINARINI, M. ROSINI AND A. CAVALLI In vivo characterization of ARN14140, a memantine/galantamine -based multi-target compound for Alzheimer's disease. Scientific Reports, 2016, 6(1), 1-11). Hybrids based on tacrine and memantine were also prepared (SPILOVSKA, K., J. KORBECNY, J. KRÁL, A. HOROVA, K. MUSILEK, O. SOUKUP, L. DRTINOVÁ, Z. GÁZOVÁ, K. SIPOSOVA AND K. KUCA 7Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer's Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies. In Molecules. 2013, vol. 2, p. 2397-2418; GAZOVA, Z., O. SOUKUP, V. SEPSOVA, K. SIPOSOVA, L. DRTINOVÁ, P. JOST, K. SPILOVSKA, J. KORABECNY, E. NEPOVIMOVA AND D. FEDUNOVA Multi-target-directed therapeutic potential of 7-methoxytacrine adamantylamine heterodimers in the Alzheimer's disease treatment. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2017, 1863(2), 607-619.) and later neuroprotective efficacy was confirmed in a laboratory rat model using NMDA-induced lesions for the hybrid 6-chlorotacrine-memantine memantine (KANIAKOVA, Μ., E NEPOVIMOVA, L. KLETECKOVA, K. SKRENKOVA, K. HOLUBOVA, Z. CHRIENOVA, V. HEPNAROVA, T. KUCERA, T. KOBRLOVA AND K. VALES Combination of memantine and 6-chlorotacrine as a novel multi-target compound against Alzheimer's disease. Current Alzheimer Research, 2019, 16(9), 821-833.). In China, this dual effect was observed with the approved drug for the treatment of Alzheimer's disease, huperzine-A. Despite great expectations, its dual-acting derivatives (ZHANG, J -M. AND G.-Y. HU Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartateinduced current in rat dissociated hippocampal neurons. Neuroscience, 2001, 105(3 ), 663-669.) together with bis-7-tacrine (bis-7-cognitin) (LIU, Y. W„ C. Y. LI, J. L. LUO, W. M. LI, H. J. FU, Y. Z. LAO, L. J. LIU, Y. P. PANG, D. C. CHANG, Z. W. LI, R. W. PEOPLES, Y X. AI AND Y. F. HAN Bis(7)-tacrine prevents glutamate-induced excitotoxicity more potently than memantine by selectively inhibiting NMDA receptors. Biochemical and Biophysical Research Communications, May 16 2008, 369(4) , 1007-1011.) never reached clinical trials.

Tacrine is a drug that was approved as a cholinesterase inhibitor due to its pro-cognitive effect for treatment in 1993, but its use was later abandoned due to its gastrointestinal side effects and hepatotoxicity. Thus, the further use of this molecule is connected with the demonstration of the safety of new molecules, especially the aspects of different metabolism, which will not lead to the formation of hepatotoxic intermediates (PATOČKA, J., D. JUN AND K. KUCA Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease. Current Drug Metabolism, May 2008, 9(4), 332-335.).

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The essence of the invention

The present invention solves the problems of the state of the art by presenting new dual-active derivatives with the ability to positively interfere with the deficient cholinergic system and simultaneously antagonize NMDA receptors. Application can thus be expected in the field of neurodegenerative diseases, specifically in the therapy of Alzheimer's disease, dementia with Lewy bodies or in the therapy of vasculoma dementia in combination with dementia with Lewy bodies and in the therapy of vasculoma dementia in combination with Parkinson's or Alzheimer's disease.

The subject of this invention are compounds derived from tacrine of general formula I

(I) where n is 1, 2 or 3,

R ¹ is selected from the group phenoxy; 1-CH-phenoxy: 1-OCTf-phenoxy: 2-OCH 3 -phenoxy; 3-CH3-phenoxy; 3-Cl-phenoxy; 3-C(CH 3 ) 3 -phenoxy; 3-C(O)-CH3-phenoxy; 2-CH3,4-CH3-phenoxy; and

R ² is -H;

wherein if R ¹ is phenoxy, n must not be 2.

The organic compounds of general formula I can be in the form of pharmaceutically acceptable salts with alkali metals, ammonia or amines, or addition salts with acids.

The compounds according to the present invention are preferably selected from the group of substances in Tables 1, 2 and 3.

The subject of the present invention are compounds of general formula I for use in inhibiting cholinesterases, in particular acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE), and simultaneous antagonistic action on NMDARs.

Further, the subject of this invention are compounds of general formula I for use as medicine.

More specifically, the subject of this invention are compounds of general formula I for the symptomatic treatment of dementia and neurodegenerative diseases, in particular selected from Alzheimer's disease, dementia with Lewy bodies or dementia vasculature in combination with dementia with Lewy bodies or dementia vasculature in combination with Parkinson's or Alzheimer's disease.

The subject of the invention is also a pharmaceutical preparation containing at least one compound of general formula I and at least one pharmaceutically acceptable carrier. Suitable carriers are especially fillers such as sugars, starches, carboxymethyl starch, cross-linked polyvinylpyrrolidine, alginic acid and its salts, solvents, binders, etc.

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Table 1:

Wi ^-¾. xi txx> w :¾ ·* x ' ' » ' Cw »x wsa, w In XXOX with ?x(Žxjá^šš^š^ SvX^Sj^ w Q*CCr> L\ XVů «Ák^»;4f^hs.. x ats® γ^Τ^Ύ^ΧνΛ ?4í...a^ * v ^řtóčjXA X x » x Λ i w "jXcOo MA£^jš$íís^ w SR 4.OXŮ0 w ?R _ν σχΦ w _what? X^Xůo

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Table 2:

C&h I

Strtíkiara .ďee&a&w I

S4” m7-(2-a^toy^ia®5xy^l,2 .0.

8^

H4S

W$hy<t<4ks^ c

40-^^lfe^>4 ₅ * _c 3;

Wáh¥fesktií&''§'-«asi®

M

X).

B42

WITH.,

m.

H

RH;

ΊΪ

RR:

RRg

7^4-dsfesŽsetjKý)-1 Λ&4yfXisy^ifaAOtí^

U44 ?4$ .23A

Wshydftstíxšdšs^áatia

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Table 3:

Naxěv^šžWffly úx </ 1 'ssis 05X0 (1¾ γ t 1 OS- 10 o'cio 2<3«!taieyWMW«lí» 1 ««am. IT j/ix) CAN ..A'OSj .Λ'ΤίΟ 2X'Cóo 1«(I Ι^ΜζΤ^ΜΜϊ»

Particularly preferred are compounds number: 1-56, III-56, 11-60, 1-61, 11-61, III-61.

For the preparation of substances, the method of preparing compounds of general formula I (Scheme 1-2) can be used.

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18: R - 1¾¾

19: R ::: 3-0(0¾¼

29: R = 3-0(05-0¾

21: R = 2-0¾. 4-CH·;

22: R = 1-0¾

23: R = 3-C(CH _with h

R = 3-0(0)-0¾

26: R =2-0¾. 4-CH ₃

s) r-hF 1 . il Λ X^- _NH2

26: R= 1-0¾

27: R = 3-0(0¾¼

28: R = 3-0(0)-0¾

29: R :=: 2-0¾. 4-CH ₃

Scheme 1. Synthesis of substituted 4-phenoxyaniline derivatives. Reaction conditions: i) 5 to 10 mol % CuBr; CS 2 CO 3 (2.0 eq.); 1-(2-pyridinyl)acetone (0.2 eq.); DMSO; 24 hours; 90°C; ii) MeOH/H 2 O (2:1); KOH (7.5 eq); microwave activation; 90 minutes; 160 °C.

26: R = 1-CH ₃ 35: n - 1

27: R = 3-C(ČH ₃ h 36; n = 2

28: R = 3-C(O)-CH ₃ 37: n-3

29: R « 2-CH ₃ 4-CH,

30: R = 1-H

31: R = I-OCH 3

32: R = 2-OCH 3

33: R = 3-CH ₃ : R = 3-Cl

Mil 38: R * Mil 39: R = 1-CH ₃

MU 40: R « 1-OCH,

Mile 41: R-2-00¾

Mil 42: R = 3-CH ₃

MU 43: R = 3-Cl

Miles 44; R = 3-C(CH ₃ ),

MU 45: R = 3-C(01-CK

Mil 46: R = 2-CH ₃ 4-CH ₃

MU 47: R - MU 48: R - 1-CH ₃

MU 49: R = 1-00¾

Mil 50: R = 2-OCH ₃

Mil 51: R-3-CH _s '

MU 52: R = 3-Cl

MU 53: R = 3-C(CHp·,

Mil 54: R = 3-C(O)-CH ₃

MU 55: R = 2-CH ₃ 4-CH ₃

MU 56: R = MU 57: R = 1-CH ₃ l-lll 58: R = 1-0CH ₃

MU 59: R = 2-OCH ₃ l-lll 60: R = 3-CH ₃ l-Ul 61: R - 3-Cl 1-lll 62: R = 3-C(CH.h I-IU 63: R = 3-C(O)-CH _with Mil 64: R = 2-CH ₃ 4-CH ₃

Scheme 2. Synthesis of substituted tacrine derivatives. Reaction conditions: i) para-toluenesulfonic acid monohydrate (PTSA; 0.01 eq); toluene; 24 hours; 150 °C; ii) diphenyl ether; 20 minutes; 220-240 °C; iii) POCl 3 (7.8 eq); 1 hour; 130 °C; iv) NH3 (gaseous); phenol (10 eq); 2 hours; 180°C.

Examples of implementation of the invention

The invention is described in the following cases, which are only illustrative and not limiting of the invention.

General chemical methods

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TLC was performed on aluminum plates covered with silica gel 60 F254 (Merck, Prague, Czech Republic). Column chromatography was performed at atmospheric pressure on silica gel 100 (particle size 0.063 to 0.200 mm, 70 to 230 mesh ASTM, Fluka, Prague, Czech Republic). Chemicals necessary for the synthesis were purchased from Sigma-Aldrich Co. LLC and Fluorochem Ltd. and were used without further purification. A CEM Explorer SP 12 S Class instrument was used for reactions performed under microwave activation conditions. A Dionex Ultimate 3000 LC-MS analytical system coupled with an Orbitrap Q Exactive Plus spectrometer (Thermo Fisher Scientific, Bremen, Germany) was used for mass spectrometry determination. The LC-MS system consists of a HHG-3400RS binary pump connected to a vacuum degasser. Also from the heated column compartment TCC-3000, autosampler WTS-3000 and ultraviolet detector VWD-3000. The quadrupole mass spectrometer was equipped with an electron spray ionization source and data were recorded in positive mode with the following parameters: spray voltage was 3.2 kV, capillary temperature was 350 °C, gas temperature was 300 °C. Ή and ¹³ C NMR spectra were determined at room temperature in deuterated dimethyl sulfoxide (DMSO-ó/6) on a Varian S500 NMR spectrometer (499.87 MHz for Ή and 125.71 MHz for ¹³ C) and a Bruker Avance III (600 MHz for Ti and 151 MHz for ¹³ C). Chemical shifts (<)) of protons in Ή NMR and carbons in ¹³ C NMR spectra are given in units of ppm. The reference standard for the shift in Ή NMR spectra was the central peak of DMSO-ria at δ = 2.50 ppm, the peak of CDCL at δ = 7.26 ppm, and the peak for methanol-0/4 at δ = 3.21 ppm. In the ¹³ C NMR spectra, the internal standard was the DMSO-ď peak at δ = 39.43 ppm, the CDCL peak at δ = 77.00 ppm and for methanol-dn the δ = 47.6 ppm peak. Interaction constants (J) are given in Hz. The spin multiplicity of signals in Ή NMR spectra is expressed as bs (broad singlet), s (singlet), d (doublet), dd (doublet of doublet), t (triplet) or m (multiplet).

Chemical shifts are given in ppm (parts per million, δ) with respect to the listed solvents.

Example 1 - procedure for the preparation of intermediates 22 to 25 and 26 to 29

The compounds were prepared according to Scheme 1. Commercially available starting compounds 18 to 21 (4.6 mmol; 1.0 eq), A-(4-hydroxyphenyl)acetamide (5.5 mmol ; 1.2 eq), CS 2 CO 3 (9.2 mmol; 2 eq), CuBr (510 mol%) and 1-(2-pyridinyl)acetone (0.2 eq). Anhydrous DMSO (5 mL) was then added. The reaction mixture was stirred for 24 h at 90 °C. After completion of the reaction time, the mixture was cooled to room temperature. Subsequently, ethyl acetate (EA) was added to the mixture and the resulting precipitate was filtered under reduced pressure through a frit. The filtrate was evaporated in vacuo and then extracted between DCM (3x50 mL) and water (100 mL). The organic fractions were combined, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography with mobile phase DCM/MeOH/25% aqueous NH3 solution (20:1:0.1) to give intermediates 22 to 25. Subsequently, these derivatives were placed in a microwave tube reactor and subjected to hydrolysis by reaction with KOH (27.3 mmol; 7.5 eq) in 5 mL MeOH/H 2 O (2:1). The reaction conditions were set at 160 °C at a maximum power of 150 W with a dynamic curve, for 90 min. After completion, the reaction mixture was immediately purified by flash chromatography with mobile phase DCM/MeOH/25% aqueous NH3 solution (9:1:0.1) to give products 26 to 29.

The characterization of the thus prepared structures (22 to 25 and 26 to 29) is given here:

N-[4-(2-methylphenoxy)phenyl]acetamide (22)

Yield: 79%. Orange viscous oil. Ή NMR (500 MHz, Chloroform-d): δ 7.46 (bs, 1H); 7.34 (d, J = 8.6 Hz, 2H); 7.17-7.13 (m, 1H); 7.10 - 7.04 (m, 1H); 7.00-6.94 (m, 1H); 6.80-6.74 (m, 3H); 2.15 (s, 3H); 2.07 (s, 3H). ¹³ C NMR (126 MHz, Chloroform-ti): δ 168.46; 154.71; 154.38; 132.64; 131.45; 129.73; 127.13; 123.88; 121.89; 119.30; 117.89; 24.37; 16,18; HRMS (ESU): [M ⁺ ]: calcd for Ci 5 HieNO ^{2 +} (m/z): 242.1176; found 242.1173

N-[4-(4-tert-butylphenoxy)phenyl]acetamide (23)

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Yield: 55%. Brown viscous oil. 'HNMR (500 MHz, Chloroform-d): δ - 7.34 (m, 2H); 7.31 (bs, 1H); 7.27-7.23 (m, 2H); 6.91-6.87 (m, 2H); 6.85-6.81 (m, 2H); 2.09 (s, 3H); 1.24 (s, 9H). ¹³ C NMR (126 MHz, Chloroform-d): δ 168.36; 154.99; 153.92; 146.03; 133.10; 126.54; 121.75; 119.32; 118.03; 34.30; 31.50; 24.42; HRMS (ESI ⁺ ): [M ⁺ ]: calcd for Ci ₈ H ₂₂ NO ₂ ⁺ (m/z): 284.1646; found 284.1642

A-[4-(4-acetylphenoxy)phenyl]acetamide (24)

Yield: 40%. Brown viscous oil. 'HNMR (500 MHz, Chloroform-d): δ - 7.83 (m, 2H); 7.74 (bs, 1H); 7.51-7.46 (m, 2H); 6.97-6.93 (m, 2H); 6.92-6.87 (m, 2H); 2.50 (s, 3H); 2.12 (s, 3H). ¹³ C NMR (126 MHz, Chloroform-d): δ 196.84; 168.52; 162.26; 151.44; 134.89; 131.76; 130.61; 121.71; 120.80; 116.92; 41.01; 30.16; 26.47; 24.44; HRMS (ESE): [M ⁺ ]: calcd for Ci ₆ Hi ₆ NO ₃ ⁺ (m/z): 270.1125; found 270.1122 /N-[4-(3,5-dimethylphenoxy)phenyl]acetamide (25)

Yield: 30%. Orange viscous oil. Ή NMR (500 MHz, Methanol-df. δ 7.41 - 7.36 (m, 2H); 6.82 - 6.77 (m, 2H); 6.63 - 6.61 (m, 1H); 6.47 - 6.42 (m, 2H); 2.55 (s, 3H); 2.15 - 2.13 (m, 6H). ¹³ C NMR (126 MHz, Methanol-d4): δ 170, 10; 157.60; 153.64; 139.39; 133.85; 124.37; 121.53; 118.84; 115.74; 39.04; 22.26; 19.97; HRMS (ESI ⁺ ): [M ⁺ ]: calcd for Ci6Hi ₈ NO ₂ ⁺ (m/z): 256.1332; found 256.1333

4-(2-Methylphenoxy)aniline (26)

Yield: 75%. Brown crystalline substance. Melting point: 122.5 to 123.4 °C. Ή NMR (500 MHz, Chloroform-d): δ 7.14 - 7.11 (m, 1H); 7.03-6.98 (m, 1H); 6.91-6.87 (m, 1H); 6.73-6.67 (m, 3H); 6.60-6.56 (m, 2H); 2.20 (s, 3H). ¹³ C NMR (126 MHz, Chloroform-d): δ 156.25; 149.78; 141.73; 131.20; 128.76; 126.88; 122.68; 119.80; 117.46; 116.44; 16.27; HRMS (ESI ⁺ ): [M ⁺ ]: calcd for Ci ₃ Hi ₄ NO ⁺ (m/z): 200.1070; found 200.1071

4-(4-tert-butylphenoxy)aniline (27)

Yield: 75%. Brown crystalline substance. Melting point: 127.5 to 128.4 °C. Ή NMR (500 MHz, Chloroform-d): δ 7.23 - 7.19 (m, 2H); 6.81-6.76 (m, 4H); 6.62-6.58 (m, 2H); 1.22 (s, 9H). ¹³ C NMR (126 MHz, Chloroform-d): δ 156.44; 149.14; 144.95; 142.16; 126.34; 120.96; 116.80; 116.41; 34.21; 31.55; HRMS (ESI ⁺ ): [M ⁺ ]: calcd for Ci ₆ H ₂₀ NO ⁺ (m/z): 242.1540; found 242.1535 l-[4-(4-aminophenoxy)phenyl]ethan-1-one (28)

Yield: 24%. Brown crystalline substance. Melting point: 147.5 to 149.0 °C. Ή NMR (500 MHz, Methanol-d ₄ ): δ 7.96 - 7.91 (m, 1H); 6.94-6.90 (m, 2H); 6.87-6.83 (m, 2H); 6.80-6.76 (m, 2H); 2.54 (s, 3H). ¹³ CNMR (126 MHz, Methanol-d4): δ 199.30; 165.14; 147.93; 146.28; 132.16; 131.82; 127.71; 122.58; 117.65; 117.01; 114.64; 26.44; HRMS (ESI ⁺ ): [M ⁺ ]: calcd for Ci 4 Hi ₃ NO ₂ ⁺ (m/z): 228.1020; found 228.1020

4-(3,5-dimethylphenoxy)aniline (29)

Yield: 67%. Brown crystalline substance. Melting point: 124.5 to 125.7 °C. Ή NMR (500 MHz, Methanol-d ₄ ): δ 6.68 - 6.64 (m, 2H); 6.64-6.60 (m, 2H); 6.54-6.51 (m, 1H); 6.38-6.35 (m, 2H); 2.10 (s, 6H). ¹³ CNMR (126 MHz, Methanol-d4): δ 159.03; 148.68; 143.36; 139.04; 123.31; 120.45; 116.39; 114.50; 20.01; HRMS (ESI ⁺ ): [M ⁺ ]: calcd for Ci 4 Hi ₆ NO ⁺ (m/z): 214.1227; found 214.1225.

Example 2 - procedure for the preparation of substituted phenoxytacrine derivatives 56 to 64

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1. Synthesis step

The compounds were prepared according to Scheme 2. Variously substituted 4-phenoxyanilines 26 to 29 (1.0 eq.) or commercially available derivatives 30 to 34 (1.0 eq.) were weighed into a 250 mL distillation flask. Next, 50 mL of toluene and 0.1 g of PTSA were added to the flask. Ethyl 2oxocycloalkanecarboxylate 35 to 37 (1.1 eq.) was added to the reaction mixture. The flask containing the mixture was placed in an oil bath and a Dean-Stark condenser attachment was attached to it. The cyclocondensation reaction took place for 24 h at a temperature of 150 °C. After completion of the reaction, the solvent was evaporated under vacuum and diphenyl ether (10.0 eq) was added to the reaction mixture. The reaction mixture was heated for 20 min at 220-240 °C in a metal block under a Dean-Stark reflux condenser. After completion of the reaction, the reaction mixture was cooled to room temperature, and then approximately 30 ml of heptane was added. The resulting precipitate was filtered under reduced pressure through a frit. The residue on the frit was washed three times with 20 mL of heptane. Intermediate (I-III) 38 to 46 was purified by flash chromatography using DCM/MeOH/25% aqueous NH 3 (20:1:0.1) mobile phase.

The following derivatives (I-III) 38 to 46 were prepared by this procedure, the characterization of which is given with the exception of 11-38 (compound 11-38 characterized only by melting point and HRMS; NMR not determined due to low solubility):

7-phenoxy-2,3-dihydro-1H-cyclopenta[n]quinolin-9(4EZ)-one (1-38)

Yield: 68%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.99 (bs, 1H); 7.57-7.50 (m, 2H); 7.43-7.35 (m, 3H); 7.18 - 7.13 (m, 1H); 7.05 - 7.01 (m, 2H); 2.96 (t, J = 7.6 Hz, 2H); 2.66 (t, J = 7.3 Hz, 2H); 2.06-1.96 (m, 2H). ¹³ C NMR (126 MHz, DMSO-rie): δ 173.59; 157.01; 154.07; 152.46; 136.67; 130.34; 126.22; 123.76; 123.52; 120.37; 119.14; 118.93; 112.00; 31.97; 27.75; 21.64; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci ₈ Hi ₆ NO ₂ ⁺ (m/z): 278.1176; found 278.1171.

7-(2-Methoxyphenoxy)-1H,2H,3H,4H,9H-cyclopenta[n]quinolin-9-one (1-40)

Yield: 35%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 12.01 (bs, 1H); 7.58-7.52 (m, 2H); 7.39-7.36 (m, 1H); 7.34-7.27 (m, 1H); 6.81-6.74 (m, 1H); 6.65-6.60 (m, 1H); 6.59-6.54 (m, 1H); 3.84 (s, 3H); 2.94 (t, J = 7.7 Hz, 2H); 2.64 (t, J = 7.3 Hz, 2H); 2.05 (p, J = 7.7 Hz, 2H). ¹³ C NMR (126 MHz, DMSO-1/6): δ 177.39; 155.48; 154.25; 153.78; 137.44; 131.12; 129.74; 127.55; 126.72; 125.86; 122.54; 120.35; 120.23; 119.05; 110.25; 33.21; 29.02; 22.92; 15.29; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci 9 Hi ₈ NO ₃ ⁺ (m/z): 308.1282; found 308.1282

7-(3-Methoxyphenoxy)-1H,2H,3H,4H,9H-cyclopenta[no]quinolin-9-one (1-41)

Yield: 7%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSO-rie): δ 12.01 (bs, 1H), 7.57 - 7.54 (m, 2H), 7.40 - 7.36 (m, 1H), 7.32 - 7.27 (m, 1H), 6.77 - 6.72 ( m, 1H), 6.63 - 6.60 (m, 1H), 6.59 - 6.54 (m, 1H), 3.74 (s, 3H), 2.98 (t, J= 7.7 Hz, 2H), 2.67 (t, J= 7.3 Hz , 2H), 2.04 (p, 7= 7.7 Hz, 2H). ¹³ C NMR (126 MHz, DMSO-76): Δ 173.80, 161.23, 158.56, 154.37, 152.51, 136.98, 131.06, 126.48, 123.85, 120.55, 119.42, 112.59, 111.03, 109.68, 105.22, 55.75 ; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci 9 Hi ₈ NO ₃ ⁺ (m/z): 308.1282; found 308.1281

7-(4-methylphenoxy)-1H,2H,3H,4H,9H-cyclopenta[n]quinolin-9-one (1-42)

Yield: 50%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ y. δ 11.94 (bs, 1H); 7.52 (d, 7=8.9 Hz, 1H); 7.45 (d, J= 2.8 Hz, 1H ); 7.35 (dd, J= 8.9; 2.9 Hz, 1H); 7.21 (d, J = 8.1 Hz, 2H); 6.96 - 6.92 (m, 2H) ; 2.96 (t, J = 7.6 Hz, 2H); 2.65 (t, J = 7.3 Hz, 2H); 2.30 (s, 3H); 2.06 - 1.97 ( m, 2H) ^.13 C NMR (126 MHz, DMSO-7 ₆ ): δ 173.47, 154.56, 153.87;

-10 CZ 2021 - 35 A3

153.12; 136.37; 133.09; 130.67; 126.12; 123.14; 120.16; 119.27; 119.01; 111.25; 31.96; 27.77; 21.62; 20.47; HRMS (EST): [M+H] ⁺ : calcd for Ci ₉ Hi ₈ NO ₂ ⁺ (m/z): 292.1333; found 292.1329

7-(4-Chlorophenoxy)-1H,2H,3H,4H,9H-cyclopenta[6]quinolin-9-one (1-43)

Yield: 19%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.99 (bs, 1H); 7.57-7.53 (m, 2H); 7.46-7.42 (m, 2H); 7.07 - 7.03 (m, 2H); 7.01-6.97 (m, 1H); 2.97 (t, J = 7.6 Hz, 2H); 2.66 (t, J = 7.3 Hz, 2H); 2.08-1.97 (m, 2H). ¹³ C NMR (126 MHz, DMSO-de): δ 173.47; 156.12; 154.17; 151.98; 136.95; 130.19; 127.47; 126.24; 123.54; 120.43; 119.27; 118.88; 112.56; 31.97; 27.72; 21.69; HRMS (ESE): [M+H] ⁺ : calcd for Ci ₈ Hi ₅ C1NO ₂ ⁺ (m/z): 312.0786; found 312.0781

7-(4-tert-butylphenoxy)-1H.2HAHAH.9H-cyclopenta[6]quinolin-9-one (1-44)

Yield: 27%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.99 (bs, 1H); 7.58-7.32 (m, 5H); 7.00-6.94 (m, 2H); 3.01-2.95 (m, 2H); 2.70-2.61 (m, 2H); 2.09-1.96 (m, 2H); 1.30 (s, 9H). ¹³ C NMR (126 MHz, DMSO-d6): δ 173.79; 154.82; 154.26; 153.16; 146.45; 136.74; 127.27; 126.46; 123.61; 121.21; 120.52; 119.33; 118.90; 115.32; 111.82; 34.56; 32.22; 31.73; 28.01; 21.90; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 22 H ₂₄ NO ₂ ⁺ (m/z): 334.1802; found 334.1801

7-(4-acetylphenoxy)-1H.2H3HAH.9H-cyclopenta[6]quinolin-9-one (1-45)

Yield: 33%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 12.07 (bs, 1H), 8.02 - 7.97 (m, 2H), 7.66 - 7.64 (m, 1H), 7.62 - 7.58 (m, 1H), 7.46 - 7.42 (m, 1H), 7.10 - 7.06 (m, 2H), 2.99 (t, J= 7.6 Hz, 2H) , 2.68 (t, J = 7.3 Hz, 2H), 2.55 (s, 3H), 2.09 - 2.01 (m, 2H). ¹³ CNMR(126 MHz, DMSO-de): δ 196.93, 173.75, 161.86, 154.60, 151.01, 137.65, 132.36, 131.25, 126.59, 124, 51, 120.88, 119.63, 117.81, 114.24, 32.27, 28.02, 27.04, 21.89; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ qHi ₈ NO 3 ⁺ (m/z): 318.1281; found 320.1281

7-(3,5-dimethylphenoxy)-1H.2HAHAH.9H-cyclopenta[6]quinolin-9-one (1-46)

Yield: 25%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.95 (bs, 1H); 7.48 (d, J = 8.9 Hz, 1H); 7.42 (d, δ=2.9 Hz, 1H); 7.28 (dd, J = 8.9; 2.9 Hz, 1H); 6.73 (s, 1H); 6.56 (d, J = 1.5 Hz, 2H); 2.91 (t, J = 7.7 Hz, 2H); 2.60 (t, J = 7.3 Hz, 2H); 2.18 (s, 6H); 2.00-1.92 (m, 2H). ¹³ C NMR (126 MHz, DMSO-1/ ₆ ): δ 173.79; 157.40; 154.29; 152.89; 139.91; 136.84; 126.49; 125.60; 123.81; 120.51; 119.35; 116.79; 112.40; 32.23; 28.02; 21.92; 21.35; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for (m/z): 306.1488; found 306.1489

7-phenoxy-1,2,3,4,9,10-hexahydroacridin-9-one (1-3 8)

Yield: 85%. A yellow crystalline substance. Melting point: > 300.0 °C. HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci ₉ Hi ₈ NO ₂ ⁺ (m/z): 292.1293; found 292.1324

7-(2-methylphenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-39)

Yield: 49%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.39 (bs, 1H); 7.55-7.48 (m, 1H); 7.39-7.31 (m, 2H); 7.28-7.21 (m, 2H); 7.17-7.10 (m, 1H); 6.95-6.89 (m, 1H); 2.74-2.65 (m, 2H); 2.42-2.34 (m, 2H); 2.17 (s, 3H); 1.79-1.62 (m, 4H). ¹³ CNMR (126 MHz, DMSO): δ 175.61; 154.51; 153.17; 146.98; 135.56; 132.12; 129.72; 128.04; 124.84; 124.48; 123.17; 120.20; 120.16; 115.28; 109.87; 27.57; 22.36; 22.19; 21.98; 16.29; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for (m/z): 306.1488; found 306.1489

7-(2-Methoxyphenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-40)

-11 CZ 2021 - 35 A3

Yield: 51%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.36 (bs, 1H); 7.52-7.44 (m, 1H); 7.36-7.29 (m, 1H); 7.28-7.16 (m, 3H); 7.11 - 7.04 (m, 1H); 7.03-6.96 (m, 1H); 3.72 (s, 3H); 2.73-2.65 (m, 2H); 2.43 - 2.32 (m, 2H); 1.81-1.61 (m, 4H). ¹³ C NMR (126 MHz, DMSO-d6): δ 175.63; 153.87; 151.90; 146.86; 144.18; 135.30; 126.19; 124.38; 122.51; 122.35; 121.66; 119.80; 115.13; 114.06; 108.63; 56.09; 27.56; 22.37; 22.19; 21.99; HRMS (EST): [M+H] ⁺ : calcd for C 2 o H ₂ o NO 3 ⁺ (m/z): 322.1438; found 322.1439

7-(3-Methoxyphenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-41)

Yield: 26%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.44 (bs, 1H); 7.54 (d,7=8.9 Hz, 1H); 7.51 (d,7=2.8 Hz, 1H); 7.37 (dd, 7=8.9; 2.9 Hz, 1H); 7.29 (t, 7 = 8.2 Hz, 1H); 6.76-6.72 (m, 1H); 6.61 (t, 7= 2.4 Hz, 1H); 6.58-6.54 (m, 1H); 3.74 (s, 3H); 2.73-2.65 (m, 2H); 2.46-2.38 (m, 2H); 1.80-1.65 (m, 4H). ¹³ C NMR (126 MHz, DMSO-Je): δ 175.67; 161.22; 158.62; 152.10; 147.18; 136.14; 131.03; 124.52; 124.28; 120.16; 115.42; 112.48; 11.95; 109.61; 105.15; 55.74; 27.59; 22.34; 22.18; 21.98; HRMS (EST): [M+H] ⁺ : calcd for C ₂ oH ₂ qNO ₃ ⁺ (m/z): 322.1438; found 322.1436

7-(4-methylphenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-42)

Yield: 43%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.40 (bs, 1H); 7.52-7.49 (m, 1H); 7.42-7.40 (m, 1H); 7.36-7.33 (m, 1H); 7.22-7.18 (m, 2H); 6.95-6.91 (m, 2H); 2.68 (t, 7= 6.3 Hz, 2H); 2.40 (t, 7= 6.2 Hz, 2H); 2.29 (s, 3H); 1.76-1.64 (m, 4H). ¹³ C NMR (126 MHz, DMSO-76): δ 175.41; 154.57; 152.76; 146.82; 135.57; 133.00; 130.62; 124.27; 123.66; 119.88; 119.17; 115.03; 111.11; 27.37; 22.15; 21.99; 21.74; 20.56; HRMS (EST): [M+H] ⁺ : calcd for C 2 oH ₂ qN0 ₂ ⁺ (m/z): 306.1489; found 306.1478

7-(4-Chlorophenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-43)

Yield: 91%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.44 (bs, 1H); 7.54 (d, 7= 8.9 Hz, 1H); 7.50 (d, 7= 2.9 Hz, 1H); 7.43 (d, 7= 8.3 Hz, 2H); 7.38 (dd, 7= 9.0; 3.0 Hz, 1H); 7.04 (d, 7= 8.4 Hz, 2H); 2.73-2.64 (m, 2H); 2.44-2.36 (m, 2H); 1.77-1.67 (m, 4H). ¹³ C NMR (126 MHz, DMSO-76): δ 175.39; 156.17; 151.64; 147.06; 136.00; 130.11; 127.47; 124.27; 124.04; 120.46; 120.08; 115.27; 112.46; 27.37; 22.09; 21.91; 21.75; HRMS (EST): [M+H] ⁺ : calcd for ^{Ci9Hi7ClNO2 +} ₍ m/z): 326.0943; found 326.0938

7-(4-tert-butylphenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-44)

Yield: 91%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.43 (bs, 1H); 7.55-7.51 (m, 1H); 7.45-7.44 (m, 1H); 7.43-7.39 (m, 2H); 7.38-7.35 (m, 1H); 6.98-6.94 (m, 2H); 2.70 (t, 7= 6.2 Hz, 2H); 2.41 (t, 7= 6.2 Hz, 2H); 1.79-1.72 (m, 2H); 1.72-1.65 (m, 2H); 1.29 (s, 9H). ¹³ CNMR (126 MHz, DMSO-76): δ 175.67; 154.8, 152.81; 147.12; 146.41; 135.8; 127.24; 124.49; 124.04; 120.13; 118.86; 115.35; 111.62; 34.54; 31.73; 27.58; 22.34; 22.18; 21.97; HRMS (EST): [M+H] ⁺ : calcd for C 23 H ₂₆ NO ₂ ⁺ (m/z): 348.1958; found 348,1960

7-(3,5-dimethylphenoxy)-1,2,3,4,9,10-hexahydroacridin-9-one (11-46)

Yield: 91%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.42 (bs, 1H); 7.55-7.49 (m, 1H); 7.48-7.42 (m, 1H); 7.37-7.32 (m, 1H); 6.83-6.75 (m, 1H); 6.66-6.59 (m, 2H); 2.73-2.66 (m, 2H); 2.44-2.37 (m, 2H); 2.25 (s, 6H); 1.80-1.64 (m, 4H). ¹³ C NMR (126 MHz, DMSO-76): δ 175.68; 157.44; 152.50; 147.14; 139.89; 135.98; 125.54; 124.52; 124.29; 120.12; 116.73; 115.37; 112.27; 108.39; 27.58; 22.35; 22.18; 21.98; 21.35; HRMS (EST): [M+H] ⁺ : calcd for C 2 i H ₂₂ NO ₂ ⁺ (m/z): 320.1646; found 320.1642

-12 CZ 2021 - 35 A3

2-phenoxy-5H,6H,7H^H,9H,1QH,11H-cyclohepta[6]quinolin-11-one (III-38)

Yield: 74%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSO-de): δ 11.49 (bs, 1H); 7.55 (d, J = 8.9 Hz, 1H); 7.48 (d, J = 2.9 Hz, 1H); 7.41-7.38 (m, 2H); 7.18 7.14 (m, 1H); 7.05 - 7.02 (m, 2H); 7.01-6.99 (m, 1H); 2.85-2.80 (m, 2H); 2.77-2.72 (m, 2H); 1.81-1.77 (m, 2H); 1.69-1.63 (m, 2H); 1.47-1.40 (m, 2H). ¹³ CNMR (126 MHz, DMSO-d6): δ 174.28; 157.02; 154.27; 147.51; 137.69; 133.84; 129.63; 12.55; 123.47; 122.06; 121.82; 118.94; 111.56; 32.04; 31.51; 26.59; 25.54; 24.63; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 2 oH ₂ oNO 2 ⁺ (m/z): 306.1489; found 306.1475

2-(2-Methoxyphenoxy)-5H,6H,7H,8H,9H,10H,11H-cyclohepta[6]quinolin-11-one (III-40)

Yield: 40%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.44 (bs, 1H); 7.53-7.48 (m, 1H); 7.35-7.31 (m, 1H); 7.27-7.18 (m, 3H); 7.10 - 7.07 (m, 1H); 7.04-6.98 (m, 1H); 3.73 (s, 3H); 2.84-2.78 (m, 2H); 2.78-2.69 (m, 2H); 1.80-1.78 (m, 2H); 1.71-1.62 (m, 2H); 1.45-1.41 (m, 2H). ¹³ C NMR (126 MHz, DMSO-d6): δ 174.44; 154.30; 153.00; 151.91; 144.10; 126.25; 124.74; 122.40; 122.30; 121.67; 120.17; 114.04; 109.15; 56.10; 34.00; 32.31; 27.69; 26.31; 23.53; HRMS (ESE): [M+H] ⁺ : calcd for C2iH ₂₂ NO ₃ ⁺ (m/z): 336.1595; found 336.1595

2-(3-Methoxyphenoxy)-5H,6H,7H,8H,9H,10H,11H-cyclohepta[6]quinolin-11-one (III-41)

Yield: 40%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.52 (bs, 1H); 7.57-7.54 (m, 1H); 7.53-7.52 (m, 1H); 7.40-7.36 (m, 1H); 7.32-7.26 (m, 1H); 6.76-6.73 (m, 1H); 6.63-6.61 (m, 1H); 6.58-6.55 (m, 1H); 3.74 (s, 3H); 2.85-2.79 (m, 2H); 2.78-2.72 (m, 2H); 1.84-1.75 (m, 2H); 1.71-1.63 (m, 2H); 1.47-1.40 (m, 2H). ¹³ C NMR (126 MHz, DMSO-d6): δ 174.51; 161.23; 158.57; 153.32; 152.58; 135.57; 131.03; 124.88; 124.09; 120.51; 120.47; 112.97; 111.01; 109.65; 105.23; 55.75; 34.02; 32.30; 27.65; 26,27; 23.54; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C2iH ₂₂ NO ₃ ⁺ (m/z): 336.1595; found 336.1594

2-(4-Methylphenoxy)-5H,6H,7H,8H,9H,10H,11H-cyclohepta[6]quinolin-1 1-one (III-42)

Yield: 74%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.47 (bs, 1H); 7.52 (d, J = 8.9 Hz, 1H); 7.42 (d, J = 2.8 Hz, 1H); 7.36-7.33 (m, 1H); 7.20 (d, J = 8.2 Hz, 2H); 6.95-6.92 (m, 2H); 2.83-2.79 (m, 2H); 2.76-2.71 (m, 2H); 2.30 (s, 3H); 1.80-1.75 (m, 2H); 1.67-1.62 (m, 2H); 1.45-1.39 (m, 2H). ¹³ CNMR (126 MHz, DMSO-d6): δ 174.28; 154.59; 153.27; 152.97; 134.94; 133.00; 130.62; 124.57; 123.49; 120.15; 120.12; 119.18; 111.67; 33.74; 32.00; 27.47; 26.02; 23.29; 20.44; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C2iH ₂₂ NO ₂ ⁺ (m/z): 320.1646; found 320.1634

2-(4-Chlorophenoxy)-5H,6H,7H,8H,9H,10H,11H-cyclohepta[6]quinolin-1 1-one (III-43)

Yield: 29%. Brown crystalline substance. Melting point: > 300.0 °C. Ή NMR (500 MHz, DMSOd ₆ ): δ 11.51 (bs, 1H); 7.55 (d, J = 8.9 Hz, 1H); 7.51 (d, J = 2.8 Hz, 1H); 7.45-7.41 (m, 2H); 7.40-7.36 (m, 1H); 7.07 - 7.03 (m, 2H); 2.85-2.80 (m, 2H); 2.77-2.72 (m, 2H); 1.82-1.75 (m, 2H); 1.69-1.61 (m, 2H); 1.46-1.39 (m, 2H). ¹³ CNMR (126 MHz, DMSO-d6): δ 174.19; 156.16; 153.14; 152.00; 135.54; 130.26; 130.17; 127.41; 124.67; 123.82; 120.49; 120.27; 112.99; 33.86; 32.03; 27.34; 26.00; 23.27; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C20Hi ₉ C1NO ₂ ⁺ (m/z): 340.1099; found 340.1089

2. Synthesis step

To the intermediate (I-III) 38 to 46 (1.0 eq) placed in a 250 mL flask was slowly added POCl ₃ (7.8 eq) under constant cooling (ice-water mixture). Subsequently, the reaction mixture was heated under

-13 CZ 2021 - 35 A3 reflux at 130 °C for 1 h. Residual POCE was vacuum distilled off and the distillation residue was diluted with 50 ml of DCM, poured onto a mixture containing ice and water in a volume of 150 ml, a concentrated aqueous solution of NH3 (25 %, 30 mL), and 3 * shaken in a separatory funnel with DCM (3 x 50 mL). The organic phases were combined, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure and the crude intermediate (I-III) 47 to 55 was purified by flash chromatography using a PE/EA (4:1) mobile phase.

The following derivatives (I-III) 47 to 55 were prepared by an analogous procedure, the characterization of which is given below:

9-chloro-7-phenoxy-1H,2H,3H-cyclopenta[b]quinoline (1-47)

Yield: 74%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform -dy. δ 8.00 (d, J = 9.1 Hz, 1H); 7.66 (d, J = 2.7 Hz, 1H); 7.44 - 7.36 (m, 3H); 7.19 - 7.15 (m, 1H); 7.11 - 7.07 (m, 2H); 3.22 (t, J= 7.7 Hz, 2H); 3, 15 (t, J = 7.5 Hz, 2H); 2.29 - 2.19 (m, 2H). ¹³ C NMR (126 MHz, Chloroformd): δ 166.29; 156.87; 155.53; 145.39; 136.58; 134.54; 130.82; 129.96; 126.37; 123.85; 122.56; 119.14; 110.23; 35.34; 30.58; 22, 77; HRMS (ESU): [M+H] ⁺ : calcd for Ci ₈ Hi ₅ C1NO ⁺ (m/z): 296.0837; found 296.0829

9-chloro-7-(2-methoxyphenoxy)-1H,2H,3H-cyclopenta[6]quinoline (1-49)

Yield: 74%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-d): δ 7.91 - 7.87 (m, 1H); 7.48-7.44 (m, 1H); 7.34-7.28 (m, 1H); 7.15-7.10 (m, 1H); 7.02-6.96 (m, 2H); 6.92-6.88 (m, 1H); 3.75 (s, 3H); 3.12 (t, J = 7.7 Hz, 2H); 3.05 (t, J = 7.5 Hz, 2H); 2.15 (p, J = 7.6 Hz, 2H). ¹³ C NMR (126 MHz, Chloroform-d): δ 165.71; 156.36; 151.51; 144.93; 144.45; 136.55; 134.40; 130.43; 126.31; 125.50; 121.51; 121.32; 121.29; 113.01; 108.13; 55.94; 35.28; 30.49; 22.73; HRMS (ESU): [M+H] ⁺ : calcd for CisHnClNOU (m/z): 32.0942; found 326.0943

9-Chloro-7-(3-methoxyphenoxy)-1H,2H,3H-cyclopenta[o]quinoline (1-50)

Yield: 75%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-d) δ 7.97 - 7.92 (m, 1H); 7.62-7.59 (m, 1H); 7.37-7.32 (m, 1H); 7.23-7.17 (m, 1H); 6.66-6.62 (m, 1H); 6.59-6.55 (m, 2H); 3.72 (s, 3H); 3.15 (t, J = 7.7 Hz, 2H); 3.08 (t, J = 7.5 Hz, 2H); 2.17 (p, J = 7.6 Hz, 2H). ¹³ CNMR (126 MHz, Chloroform-d) δ 166.24; 161.10; 158.01; 155.38; 145.16; 136.80; 134.62; 130.64; 130.35; 126.39; 122.75; 111.19; 110.61; 109.54; 105.13; 55.42; 35.30; 30; 50; 22.73; HRMS (ESI ): [M+H] ⁺ : calcd for Ci ₉ Hi ₇ C1NO2 ⁺ (m/z): 326.0942; found 326.0940

9-Chloro-7-(4-methylphenoxy)-1H,2H,3H-cyclopenta[o]quinoline (1-51)

Yield: 32%. Yellow viscous oil. Ή NMR (500 MHz, DMSO-d ₆ ): δ 7.97 (d, J = 9.1 Hz, 1H), 7.46 (dd, J = 9.1, 2.7 Hz, 1H), 7 .37 (d, J= 2.7 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.06 - 7.02 (m, 2H), 3.09 (t, J= 7 .7 Hz, 2H), 3.04 (t, J= 7.4 Hz, 2H), 2.32 (s, 3H), 2.18 - 2.08 (m, 2H), ¹³ C NMR (126 MHz, DMSO-de): δ 166.27, 156.15, 153.59, 144.74, 134.97, 134.62, 133.85, 131.19, 130.82, 125.56, 122, 17, 119.71, 107.94, 34.73, 30.18, 22.44, 20.50; HRMS (ESU): [M+H] ⁺ : calcd for Ci ₉ Hi ₇ C1NO ⁺ (m/z): 310.0994; found 310.0988

9-chloro-7-(4-chlorophenoxy)-1H,2H,3H-cyclopenta[b]quinoline (1-52)

Yield: 56%. Yellow viscous oil. Ή NMR (500 MHz, DMSO-d ₆ ): δ 8.03 (d, J = 9.0 Hz, 1H); 7.54-7.48 (m, 4H); 7.19 - 7.15 (m, 2H); 3.15 - 3.08 (m, 4H); 2.22-2.12 (m, 2H). ¹³ C NMR (126 MHz, DMSO-de): δ 166.89; 155.12; 145.14; 135.16; 134.97; 131.42; 130.37; 129.95, 128.22; 125.64; 122.51; 121.27; 109.33; 34.84; 30.23; 22.49; HRMS (ESU): [M+H] ⁺ : calcd for Ci ₈ Hi ₄ C1 ₂ NO ⁺ (m/z): 330.0447; found 330.0434

9-Chloro-7-(4-tert-butylphenoxy)-1H,2H,3H-cyclopenta[o]quinoline (1-53)

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Yield: 34%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.94 - 7.90 (m, 1H; 7.61 - 7.58 (m, 1H); 7.35 - 7.28 (m, 3H); 6 .95 - 6.91 (m, 2H); 3.15 (t, J= 7.7 Hz, 2H); 3.08 (t, J = 7.5 Hz, 2H); 2.21 - 2, 12 (m, 2H); 1.27 (s, 9H). ¹³ C NMR (126 MHz, Chloroform-d): δ 166.04; 155.85; 154.33; 146.74; 145.08; 136 .69; 134.53; 130.57; 126.77; 126.40; 122.51; 118.60; 110.16; 35.30; 34.40; 31.50; 30.50; 22.73 ; HRMS (EST): [M+H] ⁺ : calcd for C22H23 _C1NO ⁺ (m/z): 352.1463; found 352.1463

9-Chloro-7-(4-acetylphenoxy)-1H,2H,3H-cyclopenta[6]quinoline (1-54)

Yield: 45%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-d): δ 8.05 - 8.01 (m, 1H); 7.94-7.88 (m, 1H); 7.71-7.61 (m, 1H); 7.59-7.54 (m, 1H); 7.39-7.34 (m, 1H); 7.03-6.96 (m, 2H); 3.23-3.17 (m, 2H); 3.12 - 3.07 (m, 2H); 2.52 (s, 3H); 2.24-2.16 (m, 2H). ¹³ C NMR (126 MHz, Chloroform-dy. δ 196.72; 166.75; 161.32; 157.54; 154.05; 132.55; 130.76; 128.22; 126.51; 126, 50; 123.36; 118.55; 117.83; 110.90; 30.50; 26.51; 22.74; 22.72; HRMS (EST): [M+H] ⁺ : calcd for C2oHi7ClNO2 ⁺ (m/z): 338.0942; found 338.0940

9-Chloro-7-(3,5-dimethylphenoxy)-1H,2H,3H-cyclopenta[o]quinoline (1-55)

Yield: 63%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-d) δ 7.95 - 7.90 (m, 1H); 7.60-7.57 (m, 1H); 7.34-7.30 (m, 1H); 6.73-6.71 (m, 1H); 6.63-6.59 (m, 2H); 3.15 (t, J = 7.7 Hz, 2H); 3.07 (t, J = 7.5 Hz, 2H); 2.23 (s, 6H); 2.17 (p, J = 7.6 Hz, 2H). ¹³ C NMR (126 MHz, Chloroform-d): δ 166.00; 156.78; 155.80; 144.99; 139.82; 136.80; 134.54; 130.49; 126.41; 125.57; 122.77; 116.79; 110.38; 35.27; 30.50; 22.74; 21.34; HRMS (EST): [M+H] ⁺ : calcd for C ₂₀ Hi ₉ C 1 NO ⁺ (m/z): 324.1149; found 324.1147

9-chloro-7-phenoxy-1,2,3,4-tetrahydroacridine (11-47)

Yield: 95%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.95 (d, J= 9.1 Hz, 1H); 7.63 (d, J= 2.7 Hz, 1H); 7.40 (dd, J = 9.1; 2.7 Hz, 1H); 7.38 - 7.33 (m, 2H); 7.18 - 7.12 (m, 1H); 7.10 - 7.05 (m, 2H ); 3.14 - 3.03 (m, 2H); 2.99 - 2.89 (m, 2H); 1.97 - 1.83 (m, 4H). ¹³ C NMR (126 MHz, Chloroform- <7): δ 157.88; 156.62; 155.41; 143.42; 140.21; 130.58; 129.80; 129.11; 126.16; 123.69; 122.77; 119 .07; 109.87; 33.85; 27.42; 22.56; 22.48; HRMS (EST): [M+H] ⁺ : calcd for Ci ₉ Hi ₇ C1NO ⁺ (m/z): 311 .0891; found 311.0894

9-Chloro-7-(2-methylphenoxy)-1,2,3,4-tetrahydroacridine (11-48)

Yield: 86%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.89 - 7.85 (m, 1H); 7.39 - 7.36 (m, 1H); 7.31 - 7.26 (m, 1H); 7.24 - 7.20 (m, 1H); 7.16 - 7.11 (m, 1H); 7.07 - 7.03 (m, 1H); 6.92 - 6.88 (m, 1H ); 3.02 (t, J= 6.1 Hz, 2H); 2.90 (t, J= 6.2 Hz, 2H); 2.18 (s, 3H); 1.88 - 1.83 (m, 4H). ¹³ CNMR(126 MHz, Chloroform-1/): δ 157.63; 156.21; 154.02; 143.17; 140.36; 131.71; 130.60; 130.09 ; 129.27; 127.37; 126.40; 124.60; 122.07; 120.04; 107.92; 33.92; 27.59; 22.71; 22.64; 16.22; HRMS (EST): [M+H] ⁺ : calcd for C ₂₀ Hi ₉ C1NO ⁺ (m/z): 324.1150; found 324.1149

9-Chloro-7-(2-methoxyphenoxy)-1,2,3,4-tetrahydroacridine (11-49)

Yield: 86%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.87-7.84 (m, 1H); 7.45-7.42 (m, 1H); 7.33-7.29 (m, 1H); 7.14 - 7.09 (m, 1H); 7.01 - 6.95 (m, 2H); 6.93 - 6.87 (m, 1H); 3.74 (s, 3H); 3, 01 (t, J = 6.1 Hz, 2H); 2.89 (t, J = 6.2 Hz, 2H); 1.87 - 1.83 (m, 4H). ¹³ C NMR (126 MHz, Chloroform-dy. δ 157.57; 156.32; 151.50; 144.43; 143.19; 140.42; 130.31; 129.18; 126.32; 125.49; 121.83; 121 .50; 121.29; 113.01; 107.86; 55.94; 33.89; 27.58; 22.71; 22.64; HRMS (EST): [M+H] ⁺ : calcd for C ₂₀ Hi ₉ C1NO ₂ ⁺ (m/z): 340.1098 found 340.1099 9-chloro-7-(3-methoxyphenoxy)-1,2,3,4-tetrahydroacridine (11-50)

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Yield: 87%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.92-7.86 (m, 1H); 7.63-7.58 (m, 1H); 7.36-7.32 (m, 1H); 7.21-7.16 (m, 1H); 6.65-6.61 (m, 1H); 6.59-6.55 (m, 2H); 3.71 (s, 3H); 3, 04 (t, J= 6.2 Hz, 2H); 2.92 (t, J= 6.1 Hz, 2H); 1.89 - 1.85 (m, 4H). ¹³ C NMR (126 MHz, Chloroform-dy. δ 161.09; 158.14; 157.99; 155.32; 143.49; 140.60; 130.59; 130.34; 129.37; 126.36; 123.13; 111 .21; 110.40; 109.55; 105.12; 55.42; 33.94; 27.59; 22.68; 22.61; HRMS (EST): [M+H] ⁺ : calcd for C ₂ oHi ₉ C1N02 ⁺ (m/z): 340.1098; found 340.1095

9-Chloro-7-(4-methylphenoxy)-1,2,3,4-tetrahydroacridine (II-51)

Yield: 79%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-d): δ 7.94 (d, J = 9.1 Hz, 1H); 7.61 (d, δ=2.7 Hz, 1H); 7.40 (dd, J = 9.1; 2.7 Hz, 1H); 7.21-7.17 (m, 2H); 7.02-6.98 (m, 2H); 3.11 (t, J = 6.1 Hz, 2H); 2.99 (t, J = 6.2 Hz, 2H); 2.37 (s, 3H); 1.97-1.92 (m, 4H). ¹³ CNMR (126 MHz, Chloroform-dy. δ 157.88; 156.17; 154.24; 144.46; 140.36; 133.55, 130.61; 130.47; 129.25; 126.34 ; 122.67; 119.33; 109.21; 34.00; 27.59; 22.78; 22.64; 20.73; HRMS (ESE): [M+H] ⁺ : calculated for C ₂ oHigClNO ⁺ (m/z): 324.1150; found 324.1143

9-chloro-7-(4-chlorophenoxy)-1,2,3,4-tetrahydroacridine (Π-52)

Yield: 59%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.97 (d, J = 9.1 Hz, 1H); 7.63 (d, J = 2.7 Hz, 1H); 7.39 (dd, J = 9.1; 2.7 Hz, 1H); 7.36 - 7.32 (m, 2H); 7.04 - 7.00 (m, 2H); 3.11 (t, J= 6.2 Hz, 2H); 3.00 (t, J= 6.3 Hz, 2H); 1.97 - 1.93 (m, 4H). ¹³ C NMR (126 MHz, Chloroform-d): δ 158.41 ; 155.47; 155.12; 143.64; 140.47; 130.90; 129.95; 129.47; 128.98; 126.32; 122.71; 120.40; 110.27; 34 .00; 27.67; 22.62; 22.61; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci ₉ Hi ₆ C1 ₂ NO ⁺ (m/z): 344.0604; found 344 ,0602

7-(4-tert-butylphenoxy)-9-chloro-1,2,3,4-tetrahydroacridine (11-53)

Yield: 49%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.90-7.85 (m, 1H); 7.59-7.57 (m, 1H); 7.34-7.28 (m, 3H); 6.94 - 6.90 (m, 2H); 3.03 (t, J= 6.1 Hz, 2H); 2.91 (t, J = 6.2 Hz, 2H); 1.91 - 1 .82 (m, 4H); 1.26 (s, 9H). ¹³ C NMR (126 MHz, Chloroform-dy. δ 157.91; 155.80; 154.30; 146.72; 143.37; 140 .53; 130.50; 129.29; 126.76; 126.40; 122.94; 118.61; 109.93; 34.40; 33.93; 31.51; 27.59; 22.70 ; 22.63; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂₃ H ₂₅ C1NO ⁺ (m/z): 366.1619; found 366.1618

9-Chloro-7-(3,5-dimethylphenoxy)-1,2,3,4-tetrahydroacridine (11-55)

Yield: 83%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.91 (d, J = 9.1 Hz, 1H); 7.58 (d, J = 2.7 Hz, 1H); 7.32 (dd, J = 9.1; 2.7 Hz, 1H); 6.72 (d, J= 1.9 Hz, 1H); 6.63 - 6.60 (m, 2H); 3.05 (t, J = 6.1 Hz, 2H); 2.93 (t, J = 6.1 Hz, 2H); 2.23 (s, 6H); 1.91 - 1.84 (m, 4H). ¹³ C NMR ( 126 MHz, Chloroform-dy. δ 157.86; 156.74; 155.80; 139.81; 130.34; 129.32; 126.41; 125.58; 123.25; 116.81; 110, 14; 33.82; 27.58; 22.66; 22.61; 21.34; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ iH ₂ iC1NO ⁺ (m/z): 338 .1307; found 338.1304 1-chloro-2-phenoxy-6H,7H,8H,9H,10H-cyclohepta[o]quinoline (III-47)

Yield: 81%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.97 (d, J = 9.0 Hz, 1H); 7.68 (d, J = 2.7 Hz, 1H), 7.43 - 7.37 (m, 3H); 7.20 - 7.15 (m, 1H); 7.12 - 7.07 (m, 2H); 3.25 - 3.19 (m, 5H); 1.94 - 1 .86 (m, 3H); 1.86 - 1.78 (m, 2H); 1.78 - 1.71 (m, 2H). ¹³ C NMR (126 MHz, Chloroform-d): δ 163.49 ; 156.81; 155.72; 143.28; 138.77; 134.31; 130.95; 129.94; 126.51; 123.88; 122.61; 119.11; 111.20; 40 .12; 31.81; 30.44; 27.47; 26.92; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ oHigClNO ⁺ (m/z): 324.1150; found 324 ,1145

-chloro-2-(2-methoxyphenoxy)-6H,7H,8H,9H,10H-cyclohepta[b]quinoline (III-49)

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Yield: 77%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.81 - 7.76 (m, 1H); 7.41 - 7.39 (m, 1H); 7.26 - 7.21 (m, 1H); 7.07-7.02 (m, 1H); 6.95-6.90 (m, 2H); 6.86-6.80 (m, 1H); 3.68 (s, 3H); 3, 09 - 3.01 (m, 4H); 1.78 - 1.70 (m, 2H); 1.67 - 1.62 (m, 2H); 1.60 - 1.56 (m, 2H). ¹³ CNMR(126 MHz, Chloroform-í/): δ 162.98; 156.52; 151.52; 144.48; 142.87; 138.76; 134.26; 130.53; 126.45; 125 .48; 121.50; 121.41; 121.29; 113.01; 109.00; 55.96; 40.03; 31.84; 30.46; 27.46; 26.95; HRMS (ESU ): [M+H] ⁺ : calculated for C ₂ iH ₂ iC1NO ₂ ⁺ (m/z): 354.1255; found 354.1253

-chloro-2-(3-methoxyphenoxy)-6H,7H,8H,9H,10H-cyclohepta[b]quinoline (III-50)

Yield: 98%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform -dy. δ 7.93 - 7.87 (m, 1H); 7.63 - 7.61 (m, 1H); 7.35 - 7.31 (m, 1H); 7.20-7.15 (m, 1H); 6.65-6.61 (m, 1H); 6.59-6.55 (m, 2H); 3.71 (s, 3H); 3, 17 - 3.11 (m, 4H); 1.85 - 1.79 (m, 2H); 1.75 - 1.70 (m, 2H); 1.69 - 1.64 (m, 2H). ¹³ C NMR (126 MHz, Chloroform-1/): δ 163.53; 161.09; 158.06; 155.50; 143.22; 138.88; 134.43; 130.80; 130.34; 126.51; 122.77; 111.53; 111.18; 109.52; 105.09; 55.42; 40.05; 31.83; 30.47; 27.45; 26.92; HRMS ( ESU): [M+H] ⁺ : calcd for C ₂ iH ₂ iC1NO ₂ ⁺ (m/z): 354.1255; found 354.1255 1-chloro-2-(4-methylphenoxy)-6H,7H,8H ,9H,10H-Cyclohepta[o]quinoline (III-51)

Yield: 95%. Yellow viscous oil. Ή NMR (500 MHz, Chloroform-dy. δ 7.95 (d, J = 9.0 Hz, 1H); 7.64 (d, J = 2.7 Hz, 1H); 7.40 (dd, J = 9.1; 2.7 Hz, 1H); 7.19 (d, J= 8.2 Hz, 2H); 7.02 - 6.97 (m, 2H); 3.25 - 3.18 ( m, 4H); 2.38 (s, 3H); 1.92 - 1.88 (m, 2H); 1.84 - 1.78 (m, 2H); 1.75 - 1.73 (m, 2H) ^.13 CNMR (126 MHz, Chloroform-1/): δ 163.24; 156.37; 154.35; 143.04; 138.72; 134.33; 133.57; 130.75; 130. 44; 126.41; 122.37; 119.34; 110.49; 40.12; 31.84; 30.41; 27.46; 26.97; 20.84; HRMS (ESU): [M+ H] ⁺ : calculated for C ₂ iH ₂ iC1NO ⁺ (m/z): 338.1307; found 338.1301

-Chloro-2-(4-chloroquinoxy)-6/. 7//.8//. 9//. 107/-Cyclohepta[o]quinoline (III-52)

Yield: 24%. Yellow viscous oil. Ή NMR (500 MHz, DMSO-α/ ₆ ): δ 8.01 - 7.98 (m, 1H); 7.53-7.47 (m, 4H); 7.19 - 7.14 (m, 2H); 3.20-3.14 (m, 4H); 1.88-1.79 (m, 2H); 1.70-1.64 (m, 4H). ¹³ C NMR (126 MHz, DMSO-1/6): δ 163.72; 155.45; 155.29; 143.05; 137.42; 134.63; 131.57; 130.33; 12.28; 125.74; 122.82; 121.11; 110.25; 31.27; 29.94; 27.24; 26.61;HRMS (ESU): [M+H] ⁺ : calcd for C 2 oHisC _{1 2} NO ⁺ (m/z): 358.0760; found 358.0754

3. Synthesis step

Intermediate (I-III) 47 to 55 (1.0 eq) was transferred to a two-necked 100 mL flask, dissolved in phenol (10.0 eq) at 80 °C, then the temperature was raised to 180 °C. The reaction mixture was bubbled with NH 3 gas generated in situ. After amination was complete, the mixture was cooled to room temperature and extracted between 2MNaOH (100 mL) and DCM (3 x 100 mL). The organic phases were combined, dried over anhydrous Na ₂ SO 4 , and filtered. The filtrate was concentrated under reduced pressure and the reaction mixture was purified by flash chromatography using DCM/MeOH/25% aqueous NH 3 (9:1:0.1) as the mobile phase. Substituted derivatives (I-III) 56 to 64 were obtained as free bases in yields (7 to 68%).

This procedure gave (I-III) 56 to 64, the characterization of which is given below. For the purposes of biological determination, selected representatives were converted to hydrochloride salts.

7-phenoxy-1 //.2//.3//-cyclopenta|b]quinolin-9-amine (1-56)

Yield: 50%. Brown crystalline substance. Melting point: 157.2 to 158.1 °C. Ή NMR (500 MHz, DMSO-1/β): δ 14.66 (s, 1H); 8.71 (s, 1H); 8.24 - 8.12 (m, 1H); 8.00-7.95 (m, 1H); 7.56-7.52 (m, 1H); 7.40-7.36 (m, 2H); 7.16-7.12 (m, 1H); 7.03-7.00 (m, 2H); 3.16 - 3.12 (m, 2H); 2.83 (t, J = 7.4 Hz, 2H); 2.20-2.13 (m, 2H). ¹³ C NMR (126 MHz, DMSO-1/ ₆ ): δ 158.87; 157.42; 154.19;

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153.22; 135.55; 130.84; 126.03; 124.27; 122.49; 118.74; 117.43; 115.49; 112.72; 32.12; 28.47; 22.53; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci ₈ Hi ₇ N ₂ O ⁺ (m/z): 277.1336; found 277.1337

7-(2-Methoxyphenoxy)-1H,2H,3H-cyclopenta[6]quinolin-9-amine (1-58)

Yield: 21%. Brown crystalline substance. Melting point: 185.6 to 186.2 °C. Ή NMR (500 MHz, DMSO-1/β): δ 7.95 - 7.92 (m, 1H); 7.88-7.84 (m, 1H); 7.74 (bs, 2H); 7.35-7.31 (m, 1H); 7.24 7.17 (m, 2H); 7.08 - 7.03 (m, 1H); 7.01-6.96 (m, 1H); 3.74 (s, 3H); 2.93 (t, J = 5.9 Hz, 2H); 2.54 (t, 7=5.8 Hz, 2H); 1.87-1.78 (m, 4H). ¹³ C NMR (126 MHz, DMSO-1/6): δ 154.76; 153.06; 152.38; 151.47; 144.41; 136.20; 125.98; 123.89; 123.14; 121.63; 121.35; 116.81; 114.04; 109.33; 108.76; 56.11; 29.68; 23.43; 21.95; 21.59; HRMS (ESE): [M+H] ⁺ : calcd for Ci9Hi9N ₂ O ₂ ⁺ (m/z): 307.1442; found 307.1437

7-(3-Methoxyphenoxy)-1H,2H,3H-cyclopenta[6]quinolin-9-amine (1-59)

Yield: 37%. Brown crystalline substance. Melting point: 195.2 to 195.8 °C. Ή NMR (500 MHz, Methanol-14): δ 7.68 - 7.64 (m, 2H); 7.32-7.27 (m, 1H); 7.18 - 7.13 (m, 1H); 6.63-6.59 (m, 1H); 6.51-6.46 (m, 2H); 3.66 (s, 3H); 3.00 (t, J= 7.7 Hz, 2H); 2.82 (t, J = 7.4 Hz, 2H); 2.15 (p, J = 7.6 Hz, 2H). ¹³ C NMR (126 MHz, Methanol-1/4): δ 161.33; 158.64; 153.70; 149.70; 140.48; 130.10; 128.99; 125.34; 123.42; 119.06; 117.69; 114.63; 110.19; 108.76; 104.33; 54.45; 32.98; 27.24; 22.13; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci 9 Hi ₉ N ₂ O ₂ ⁺ (m/z): 307.1442; found 307.1434

7-(4-Methylphenoxy)-1H,2H,3H-cyclopenta[6]quinolin-9-amine hydrochloride (1-60)

Yield: 9%. Black crystalline substance. Melting point: 292.7 °C (compound decomposition). Ή NMR (500 MHz, DMSO-í/e): δ 7.92 (d, J = 2.6 Hz, 1H); 7.76 (d, J = 9.1 Hz, 1H), 7.32 (dd, J = 9.1, 2.6 Hz, 1H); 7.30 (s, 2H); 7.17-7.13 (m, 2H); 6.90-6.85 (m, 2H); 2.98 (t, J = 7.7 Hz, 2H); 2.79 (t, J = 7.3 Hz, 2H); 2.25 (s, 3H); 2.14 - 2.03. ¹³ C NMR (126 MHz, DMSO-1/6): δ 162.72; 155.67; 153.33; 149.57; 132.82; 130.91; 129.97; 126.74; 123.72; 118.49; 115.81; 114.76; 111.67; 33.63; 28.22; 22.75; 20.89; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci 9 Hi ₉ N ₂ O ⁺ (m/z): 291.1492; found 291.1512

7-(4-chlorophenoxy)-1 //.2//. 3 H -cyclopenta]quinolin-9-amine hydrochloride (1-61)

Yield: 36%. Brown crystalline substance. Melting point: 281.5 °C (compound decomposition). Ή NMR (500 MHz, DMSO-1/β): δ 7.86 (d, J= 2.7 Hz, 1H); 7.72 (d, J = 9.0 Hz, 1H); 7.42-7.38 (m, 2H); 7.25 (dd, J = 9.0; 2.7 Hz, 1H); 7.01-6.97 (m, 2H); 6.38 (s, 2H); 2.89 (t, J = 7.7 Hz, 2H); 2.80 (t, J = 7.3 Hz, 2H); 2.10 - 2.00 (m, 2H). ¹³ C NMR (126 MHz, DMSO-1/6): δ 166.29; 157.17; 150.93; 145.94; 145.93; 130.53; 129.97; 126.61; 121.79; 119.13; 118.37; 113.93; 111.54; 34.62; 27.87; 22.49; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for Ci8Hi ₆ C1N ₂ O ⁺ (m/z): 311.0946; found 311.0940

7-(4-tert-butylchlorophenoxy)-127,277,3/7-cyclopenta[6]quinoline-9-amine (1-62)

Yield: 15%. Brown crystalline substance. Melting point: 149.5 to 150.2 °C (compound decomposition). Ή NMR (500 MHz, Methanol-1/ ₄ ): δ 7.62 (d, J= 9.2 Hz, 1H); 7.55 (d, J = 2.6 Hz, 1H); 7.29-7.24 (m, 2H); 7.16 (dd, J = 9.1; 2.6 Hz, 1H); 6.84-6.80 (m, 2H); 2.90 (t, J = 7.7 Hz, 2H); 2.76 (t, J = 7.3 Hz, 2H); 2.07 (p, J = 7.6 Hz, 2H); 1.20 (s, 9H). ¹³ C NMR (126 MHz, Methanol-1/4): δ 164.63; 155.41; 153.43; 147.50; 145.88; 143.34; 128.99; 127.54; 126.36; 122.10; 118.07; 117.62; 114.80; 114.29; 109.42; 33.76; 30.53; 27.15; 22,23; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 22 H ₂₅ N ₂ O ⁺ (m/z): 333.1962; found 333.1961 1-[4-({9-amino-177,277,37/-cyclopenta[6]quinolin-7-yl}oxy)phenyl]ethan-1-one (1-63)

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Yield: 15%. Brown crystalline substance. Melting point: 162.5 to 166.8 °C. T1 NMR (500 MHz, DMSO-de): δ 7.96 (d, J = 2.7 Hz, 1H); 7.94-7.90 (m, 2H); 7.77-7.72 (m, 1H); 7.36-7.30 (m, 1H); 7.09-7.08 (m, 1H); 7.01-6.97 (m, 1H); 2.91 (t, J = 7.7 Hz, 2H); 2.76 (t, J = 7.3 Hz, 2H); 2.47 (s, 3H); 2.04 (p, J = 7.6 Hz, 2H). ¹³ C NMR (126 MHz, DMSO-d6): δ 19.91; 162.36; 157.79; 150.78; 148.01; 132.02; 131.26; 129.82; 128.94; 123.48; 119.24; 118.32; 117.09; 115.69; 114.57; 113.07; 34.23; 28.13; 27.03; 22.66; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 2 oHi 9 N ₂ O 2 ⁺ (m/z): 319.1442; found 319.1441

7-(3,5-dimethylphenoxy)-1H,2H,3H-cyclopenta[6]quinolin-9-amine (1-64)

Yield: 12%. Brown crystalline substance. Melting point: 141.2 to 142.5°C. Ή NMR (500 MHz, Methanol-14): δ 7.66 - 7.61 (m, 2H); 7.28-7.24 (m, 1H); 6.70-6.67 (m, 1H); 6.55-6.50 (m, 2H); 3.00 (t, J = 7.7 Hz, 2H); 2.80 (t, J = 7.4 Hz, 2H); 2.19-2.10 (m, 8H). ¹³ C NMR (126 MHz, Methanol-14): δ 162.00; 157.30; 154.27; 149.96; 139.72; 128.98; 124.92; 124.86; 123.45; 119.05; 117.62; 116.02; 114.80; 114.61; 109.83; 43.48; 32.82; 27.26; 22.10; 19.98; HRMS (ESE): [M+H] ⁺ : calcd for C ₂ qH ₂ iN ₂ O ⁺ (m/z): 305.1649; found 305.1645

7-(2-Methylphenoxy)-1,2,3,4-tetrahydroacridin-9-amine (Π-57)

Yield: 7%. Brown crystalline substance. Melting point: 205.8 to 206.3 °C. Ή NMR (500 MHz, DMSO-de): δ 6.85 - 6.78 (m, 1H); 6.70-6.65 (m, 1H); 6.42-6.38 (m, 2H); 6.33-6.26 (m, 1H); 6.23-6.16 (m, 1H); 6.01-5.97 (m, 1H); 2.02 (t, J = 6.1 Hz, 2H); 1.69 (t, J = 6.1 Hz, 2H); 1.37 (s, 3H); 1.08-0.96 (m, 4H). ¹³ C NMR (126 MHz, DMSO-d6): δ 153.87; 153.53; 153.47; 150.02; 138.48; 130.48; 128.55; 126.28; 124.91; 123.12; 121.59; 118.05; 116.33; 108.62; 106.57; 30.15; 22.18; 21.27; 21.06; 14.12; HRMS (ESI ⁺ ): [M ⁺ H] ⁺ : calcd for C20H2 _{iN2O +} (m/z): 305.1649; found 305.1649

7-(2-Methoxylphenoxy)-1,2,3,4-tetrahydroacridin-9-amine (11-58)

Yield: 21%. Brown crystalline substance. Melting point: 144.5 to 145.2 °C. Ή NMR (500 MHz, DMSO-de): δ 7.95 - 7.92 (m, 1H); 7.88-7.84 (m, 1H); 7.74 (bs, 1H); 7.35-7.31 (m, 1H); 7.24 7.17 (m, 2H); 7.08 - 7.03 (m, 1H); 7.01-6.96 (m, 1H); 3.74 (s, 3H); 2.93 (t, J = 5.9 Hz, 2H); 2.54 (t, J = 5.8 Hz, 2H); 1.87-1.78 (m, 4H). ¹¹³ C NMR (126 MHz, DMSO-d6): δ 154.76; 153.06; 152.38; 151.47; 144.41; 136.20; 125.98; 123.89; 123.14; 121.63; 121.35; 116.81; 114.04; 109.33; 108.76; 56.11; 29.68; 23.43; 21.95; 21.59; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 2 OH ₂ iN ₂ O ₂ ⁺ (m/z): 321.1598; found 321.1596

7-(3-Methoxylphenoxy)-1,2,3,4-tetrahydroacridin-9-amine (11-59)

Yield: 45%. Brown crystalline substance. Melting point: 152.7 to 153.6 °C. Ή NMR (500 MHz, DMSO-de) δ 8.05 (d, J= 2.6 Hz, 1H); 7.82 (d, J = 9.1 Hz, 1H); 7.41-7.37 (m, 1H); 7.27 (t, J = 8.2 Hz, 1H); 7.21 - 7.14 (m, 2H); 6.73-6.68 (m, 1H); 6.59 (t, J = 2.4 Hz, 1H); 6.55-6.51 (m, 1H); 3.73 (s, 3H); 2.89 (t, J = 5.9 Hz, 2H); 2.55 (t, J = 6.0 Hz, 2H); 1.87-1.78 (m, 4H). ¹³ C NMR (126 MHz, DMSO-de): δ 161.19; 159.20; 154.69; 152.18; 151.12; 139.97; 130.99; 126.90; 124.24; 117.31; 112.00; 110.03; 109.60; 109.20; 104.21; 55.74; 31.49; 23.72; 22.37; 22,22; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ qH ₂ iN ₂ O ₂ ⁺ (m/z): 321.1598; found 321.1593

7-(4-Methylphenoxy)-1,2,3,4-tetrahydroacridine-9-amine hydrochloride (11-60)

Yield: 13%. Brown crystalline substance. Melting point: 268.5 °C (compound decomposition). Ή NMR (500 MHz, DMSO-de): δ 7.86 (d, J= 2.5 Hz, 1H); 7.67-7.64 (m, 1H); 7.19 (s, 1H); 7.16 (d, J = 8.3 Hz, 2H); 6.89-6.85 (m, 2H); 6.34 (s, 2H); 2.82 (t, J = 6.0 Hz, 2H); 2.54 (t, J = 6.1 Hz, 2H); 2.27 (s, 3H); 1.83-1.78 (m, 4H). ¹³ C NMR (126 MHz, DMSO-d ₆ ): δ 156.49; 155.81; 151.66; 148.12; 143.27; 131.81; 130.44; 129.86; 122.00; 117.64; 117.61; 110.88; 109.36; 33.42; 23.81;

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22.72; 22.77; 20.9; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ oH 2 iN ₂ 0 ⁺ (m/z): 305.1649; found 305.1649

7-(4-Chlorophenoxy)-1,2,3,4-tetrahydroacridine-9-amine hydrochloride (11-61)

Yield: 58%. Brown crystalline substance. Melting point: 296.5 °C (compound decomposition). Ή NMR (500 MHz, DMSO-1/β): δ 7.90 (d, J= 2.6 Hz, 1H); 7.69 (d, J = 9.0 Hz, 1H); 7.42-7.37 (m, 2H); 7.27-7.23 (m, 1H); 7.01-6.97 (m, 2H); 6.35 (s, 2H); 2.82 (t, J = 6.0 Hz, 2H); 2.54 (t, J = 6.1 Hz, 2H); 1.86-1.75 (m, 4H). ¹³ C NMR (126 MHz, DMSO-1/6): δ 157.12; 156.94; 150.81; 148.15; 143.66; 130.21; 129.96; 126.63; 122.11; 119.28; 117.64; 111.34; 109.44; 33.41; 23.82; 22.84; 22.76; HRMS (ESE): [M ⁺ H] ⁺ : calcd for _{Ci9Hi8C1N2O +} (m/z): 325.1103; found 325.1097

7-(4-tert-butylphenoxy)-1,2,3,4-tetrahydroacridin-9-amine (11-62)

Yield: 36%. Brown crystalline substance. Melting point: 132.3 to 133.8 °C. Ή NMR (500 MHz, Methanol-^): δ 7.64 - 7.60 (m, 2H); 7.32-7.29 (m, 2H); 7.28-7.24 (m, 1H); 6.88-6.84 (m, 2H); 2.83 (t, J = 6.0 Hz, 2H); 2.50 (t, J = 6.1 Hz, 2H); 1.88-1.78 (m, 4H); 1.22 (s, 9H). ¹³ C NMR (126 MHz, Methanol-1/4): δ 155.03; 154.08; 154.05; 151.45; 146.28; 138.89; 128.98; 126.49; 125.11; 123.62; 117.85; 117.00; 114.79; 109.41; 109.14; 33.80; 30.61; 30.51; 22.92; 21.99; 21.73; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 23 H ₂₂ N ₂ O ⁺ (m/z): 347.2118; found 347.2114

7-(3,5-dimethylphenoxy)-1,2,3,4-tetrahydroacridin-9-amine (11-64)

Yield: 40%. Brown crystalline substance. Melting point: 155.2 to 156.4 °C. Ή NMR (500 MHz, DMSO-1/β): δ 7.91 (d, J= 2.6 Hz, 1H); 7.69 (d, J = 9.0 Hz, 1H); 7.23 (dd, J = 9.0; 2.6 Hz, 1H); 6.73 (s, 1H)); 6.57 (s, 2H); 2.84 (t, J = 6.0 Hz, 2H); 2.54 (t, J = 6.1 Hz, 2H); 2.22 (s, 5H); 1.86 1.77 (m, 4H). ¹³ C NMR (126 MHz, DMSO-1/6): δ 158.52; 156.51; 151.63; 148.84; 143.03; 139.67; 129.60; 124.71; 123.00; 117.86; 115.43; 111.77; 109.63; 33,34; 24.05; 22.91; 22.86; 21.40; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 2 i H ₂₃ N ₂ O ⁺ (m/z): 319.1805; found 319.1803

2-fcnoxy-6//.7//. 8//.9//. 10/-cyclohcpta|á|ch i noli η-11-amine hydrochloride (III-56)

Yield: 62%. White crystalline substance. Melting point: 292.8 °C (compound decomposition). Ή NMR (500 MHz, DMSO-rie): δ 7.90 (d, J = 2.6 Hz, 1H); 7.71 (d, J = 9.0 Hz, 1H); 7.38 - 7.33 (m, 2H), 7.24 (dd, J = 9.0; 2.5 Hz, 1H); 7.11 - 7.06 (m, 1H); 6.99-6.96 (m, 2H); 6.39 (s, 2H); 3.01-2.95 (m, 2H); 2.83-2.76 (m, 2H); 1.83-1.76 (m, 2H); 1.66-1.60 (m, 2H); 1.59-1.52 (m, 2H). ¹³ C NMR (126 MHz, DMSO-rie): δ 163.57; 158.59; 151.91, 147.47; 143.23; 130.49; 130.33; 123.15; 122.42; 118.98; 117.78; 114.96; 112.37; 39.26; 32.15; 28.14; 27.19; 25.87; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ qH ₂ iN ₂ O ⁺ (m/z): 305.1649; found 305.1643

2-(2-Methoxyphenoxy)-6//.7//.8//.9//. 10/-Cyclohcpta|b|quinoline-11-amine (III-58)

Yield: 23%. Brown crystalline substance. Melting point: 132.3 to 133.6 °C (compound decomposition). Ή NMR (500 MHz, DMSO-α/ ₆ ): δ 7.97 - 7.93 (m, 2H); 7.38-7.34 (m, 1H); 7.26-7.19 (m, 2H); 7.09-7.06 (m, 1H); 7.02-6.97 (m, 1H); 3.75 (s, 3H); 3.18 - 3.10 (m, 2H); 2.90-2.83 (m, 2H); 1.87 - 1;80 (m, 2H); 1.73-1.67 (m, 2H), 1.60-1.52 (m, 2H). ¹³ C NMR (126 MHz, 500 MHz, DMSO-rie): δ 158.24; 155.55; 152.83; 151.52; 144.14; 129.80; 126.19; 123.14; 121.67; 121.56; 119.21; 117.49; 115.70; 114.68; 114.07; 109.17; 56.13; 34.22; 31.47; 26.88; 26.05; 25.04; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C ₂ iH ₂₃ N ₂ O ₂ ⁺ (m/z): 335.1755; found 335.1755

2-(3-Methoxyphenoxy)-6//.7//.8//.9//. 10/-Cyclohcpta|b|quinoline-11-amine (III-59)

Yield: 23%. Brown crystalline substance. Melting point: 126.5 to 127.2 °C (compound decomposition). Ή NMR (500 MHz, DMSO-α/ ₆ ): δ 8.11 (d, J= 2.6 Hz, 1H); 7.97 (d, J = 9.1 Hz, 1H); 7.74 (bs, 1H); 7.53-7.48 (m, 1H); 7.32-7.27 (m, 1H); 6.76-6.72 (m, 1H); 6.64-6.60 (m, 1H); 6.58 - 6.53

-20 CZ 2021 - 35 A3 (m, 1H); 3.74 (s, 3H); 3.15 - 3.10 (m, 2H); 2.88-2.84 (m, 2H); 1.87-1.80 (m, 2H); 1.73-1.66 (m, 2H); 1.60-1.54 (m, 2H). ¹³ CNMR (126 MHz, DMSO-d6): δ 161.24; 159.52; 158.80; 153.48; 152.08; 131.09; 125.11; 124.74; 117.74; 114.90; 112.52; 110.32; 109.57; 104.54; 55.78; 49.06; 35.07; 31.56; 27.02; 26.20; 25.14; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C 2 i H 2 3 N ₂ O 2 ⁺ (m/z): 335.1755; found 335.1755

2-(4-Methylphenoxy)-6//.7//.8//.9//. 10//-cyclohcpta|b|quinoline-1 I-amine hydrochloric! (III-60)

Yield: 28%. Gray crystalline substance. Melting point: 310.7 °C (compound decomposition). 'HNMR (500 MHz, DMSO-de): δ 7.83 (d, J = 2.6 Hz, 1H); 7.67 (d, J = 9.1 Hz, 1H); 7.19 (dd, J = 9.0; 2.5 Hz, 1H); 7.15 (d, J = 8.3 Hz, 2H); 6.89-6.85 (m, 2H); 6.31 (s, 2H); 2.99-2.94 (m, 2H); 2.81-2.76 (m, 2H); 2.27 (s, 3H); 1.83-1.75 (m, 2H); 1.66-1.59 (m, 2H); 1.58-1.52 (m, 2H). ¹³ C NMR (126 MHz, DMSO-de): δ 163.15; 155.84; 152.17; 146.82; 143.05; 131.99; 130.46; 130.13; 121.72; 118.64; 117.79; 114.61; 111.37; 31.86; 27.89; 26.91; 25.52; 20.47; HRMS (ESI ⁺ ): [M+H] ⁺ : calcd for C2iH23N2O ⁺ (m/z): 319.1805; found 319.1798

2-(4-chlorophenoxy)-6//.7//.8//.9//. 10//-cyclohcpta|b|quinoline-1 I -amine hydrochloride (III-61)

Yield: 51%. Brown crystalline substance. Melting point: 298.5 °C (compound decomposition). Ή NMR (500 MHz, DMSO-de): δ 8.11 (d,7=2.5 Hz, 1H); 7.96 (d, δ=9.1 Hz, 1H); 7.61 (dd,7=9.1; 2.5 Hz, 1H); 7.46-7.42 (m, 2H); 7.08 - 7.05 (m, 2H); 3.12 - 3.09 (m, 2H); 2.86-2.82 (m, 2H); 1.83-1.79 (m, 2H); 1.71-1.66 (m, 2H); 1.57-1.50 (m, 2H). ¹³ C NMR (126 MHz, DMSO-d6): δ 157.95; 156.12; 154.49; 154.33; 133.91; 130.64; 128.37; 126.49; 122.67; 120.42; 117.37; 115.02; 112.34; 33.77; 31,32; 26.59; 25.86; 24.91; HRMS (ESI ⁺ ): [M ⁺ H] ⁺ : calcd for _{C20H20ClN2O +} (m/z): 339.1259; found 339.1254

Example 3: In vitro testing, inhibition of human enzymes AChE and BChE by compounds according to the invention

Selected representatives were investigated for their inhibitory potential against the human enzymes AChE (/7 AChE) and BChE (úBChE). The test results are shown in Table 4.

The in vitro activity of selected candidates was determined using the Ellman method according to a previously published protocol (POHANKA, M., D. JUN AND K. KUCA Improvement of acetylcholinesterase-based assay for organophosphates in way of identification by reactivators. Taianta, Oct 15 2008, 77 (1), 451-454

Table 4. Results of determination of inhibition of ΛAChE and ΛBChE for selected structures of the general formula

AND

compound AChE IC ₅₀ ± SEM (μΜ) ^a BChE IC ₅₀ ±SEM (pM) ^a SI ^b 1-56 6.42 ±0.15 2.93 ± 0.08 0.46 1-60 8.36 ±0.19 7.34 ± 0.20 0.88 1-61 5.07 ± 0.08 3.60 ±0.07 0.71 11-60 3.29 ± 0.08 1.95 ± 0.05 0.59 11-61 2.92 ± 0.09 3.32 ±0.11 1.14 III-56 5.36 ±0.10 1.40 ±0.05 0.26 III-60 3.79 ± 0.08 2.78 ±0.10 0.73 III-61 4.22 ±0.11 1.85 ± 0.06 0.44

^a The results shown are the average value of at least three experiments. ^b The selectivity index (SI) for /7AChE is expressed as the ratio ABChE ICWAAChE IC50.

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Example 4: In vitro testing, determination of inhibitory activity for GluN1/GluN2A and GluN1/GluN2B NMDAR subunit

The inhibitory activity of the tested compounds against NMDARs, specifically GluN1/GluN2A and GluN1/GluN2B, was tested using the "whole-cell patch clamp" technique on HEK293 cells expressing these NMDARs subunits according to a previously published protocol (KANIAKOVA, M., L. KLETECKOVA, K. LICHNEROVA, K. HOLUBOVA, K. SKRENKOVA, M. KOŘÍNEK, J. KRUSEK, T. SMEJKALOVA, J. KORBECNY, K. VALES, ίο O. SOUKUP AND M. HORAK 7-Methoxyderivative of tacrine is a 'foot-in- the-door'openchannel blocker of GluNl/GluN2 and GluNl/GluN3 NMDA receptors with neuroprotective activity in vivo. Neuropharmacology, 2018, 140, 217-232.). The inhibitory capacity was tested at a holding potential of -60 mV and at a holding potential of +40 mV.

Table 5. Results of affinity determinations for GluN1/GluN2A and GluN1/GluN2B NMDARs for selected structures of general formula I and tacrine reference compounds

compound GluN1/GluN2A (-60 mV) IC ₅₀ ±SEM(pM) GluN1/GluN2A (+40 mV) *ic ₅₀ ±sem GluN1/GluN2B (-60 mV) ic ₅₀ ±sem (μΜ) GluN1/GluN2B (+40 mV) *ic ₅₀ ±sem Takrin 9.1 + 0.5 *84.6+ 1.6 19.7+1.8 *168.8 + 9.3 1-56 6.92 + 0.86 *21.93+ 1.13 2.16 + 0.19 *2.04 ± 0.22 1-61 11.29 + 0.61 *17.07 + 1.56 9.37 + 1.11 *10.43 + 2.20 11-60 10.97 + 0.98 *30.56 + 2.37 4.53 ± 0.77 *4.82 + 0.73 11-61 12.33 ± 0.77 *19.00 + 2.07 5.47 ± 0.76 *5.85 + 0.93 III-56 5.85 ± 0.22 *28.28 + 1.12 1.64 + 0.15 *1.05 + 0.13 III-60 63.05 ± 14.66 — 18.84 + 2.67 *25.56 + 5.92 III-61 69.41 + 7.88 ___ 24.16 + 3.03 *31.32 + 5.51

Claims (6)

PATENT CLAIMS 1. Tacrine derivatives of general formula I (I) where n is 1, 2 or 3, R ¹ is selected from the group phenoxy; 1-CH-phenoxy: 1-OCFL-phenoxy; 2-OCH3-phenoxy; 3-CH3-phenoxy; 3-Cl-phenoxy; 3-C(CH 3 ) 3 -phenoxy; 3-C(O)-CH3-phenoxy; 2-CH3,4-CH3-phenoxy; and R ² is -H; wherein if R ¹ is phenoxy, n must not be 2, or their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their addition salts with acids. 2. Tacrine derivatives of general formula I according to claim 1 and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their addition salts with acids, for use as medicine. 3. Tacrine derivatives of the general formula I according to claim 1 and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their addition salts with acids, for use in the treatment of dementia or neurodegenerative disease by inhibiting cholinesterase and simultaneously acting antagonistically against NMDAR. 4. Tacrine derivatives of general formula I according to claim 1 and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their addition salts with acids, for use in the treatment of dementia or neurodegenerative diseases. 5. Tacrine derivatives of the general formula I according to claim 1 and their pharmaceutically acceptable salts with alkali metals, ammonia or amines, or their addition salts with acids for use in the treatment of Alzheimer's disease or dementia with Lewy bodies or in the therapy of dementia vasculature in combination with dementia with Lewy bodies or in the therapy of dementia vasculature in combination with Parkinson's or Alzheimer's disease. 6. Pharmaceutical preparation characterized in that it contains at least one tacrine derivative of general formula I according to claim 1 and at least one pharmaceutically acceptable carrier.