WO2022161556A1

WO2022161556A1 - Tacrine derivatives possessing dual activity and their use

Info

Publication number: WO2022161556A1
Application number: PCT/CZ2022/050004
Authority: WO
Inventors: Ondrej SOUKUP; Jan KORABECNY; Martin Horak; Anna Misiachna; Karel Vales; Ladislav Vyklicky
Original assignee: Fakultni Nemocnice Hradec Kralove; Ustav Experimentalni Mediciny Av Cr, V. V. I.; Narodni Ustav Dusevniho Zdravi, P.O.; Fyziologicky Ustav Av Cr, V. V. I.
Priority date: 2021-01-26
Filing date: 2022-01-20
Publication date: 2022-08-04
Also published as: CZ309262B6; CZ202135A3

Abstract

The present invention provides compounds of general formula I, wherein n is 1, 2 or 3, R1 is selected from the group -CH3; –OCH3; -Br; -Cl; -F; phenoxy; 1-CH3-phenoxy; 1-OCH3-phenoxy; 2-OCH3-phenoxy; 3-CH3-phenoxy; 3-Cl-phenoxy; 3-C(CH3)3-phenoxy; 3-C(O)-CH3-phenoxy; and 2-CH3,4-CH3-phenoxy; and R2 is -H; -Cl; or -Br; with the proviso that - when R2 is –Cl, R1 must be -Cl; - when R2 is –Br, R1 must be –Br; - when R1 is –OCH3 or phenoxy, n is not 2, or a pharmaceutically acceptable salt thereof with alkali metal, ammonia or amine, or an addition salt thereof with acid. The compounds of formula I are effective medicaments for the treatment of dementia and neurodegenerative diseases.

Description

Tacrine derivatives possessing dual activity and their use Field of technology The present invention relates to novel tacrine-based compounds having dual activity, i.e., activity as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. The invention further relates to a process for preparation of these compounds and to their therapeutic use. State-of-the-Art Multi-target directed ligands (MTDLs) have recently appeared frequently in the scientific literature as they are effective in the treatment of complex diseases due to their ability to interact with various targets related to the disease pathogenesis simultaneously. The basic hypothesis is that multi-target directed drugs would be more effective than single-target directed drugs. The MTDL strategy is a pharmacological tool for the control of diseases of a multifactorial nature and is used mainly in the field of infectious diseases, oncological diseases or neurological diseases. In the field of neurological diseases, the main targets are neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies or their combinations (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). A so-called dual-target effect of drugs manifesting as acetylcholinesterase inhibition and the ability to antagonize NMDA receptors should find application in the treatment of dementia with Lewy bodies or in the treatment of vascular dementia in combination with Lewy bodies dementia or in combination with Parkinson's or Alzheimer's disease (NICE guideline, June 2018, Dementia). Thus, in such conditions, the combination therapy using acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine is justified. Combining these two activities into one medicament is a rational basis for the compatibility of both effects within a single molecule. This is mainly because disruption of both systems (cholinergic and glutamatergic neurotransmission) occurs simultaneously in the later stages, i.e., within the clinical manifestation of these diseases. In addition, such compounds might be useful in Alzheimer's disease (AD) treatment. AD is the most widespread form of dementia, which is characterized as a progressive neurodegenerative disease with multiple pathogenesis. AD symptoms include severe memory impairment, cognitive impairment, inability to perform daily activities, and loss of language skills. The etiology of AD is currently not fully understood, but the histopathological feature of the disease reflects the accumulation of extracellular insoluble amyloid β deposits with subsequent neuritic plaque formation as well as the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated τ-protein in some brain regions, including the hippocampus. The most commonly cited hypothesis of AD development is the cholinergic hypothesis, assuming a reduced tone of the cholinergic system. Other theories of AD pathogenesis include the amyloid cascade hypotheses, oxidative stress associated with the production of reactive oxygen species, or the presence of subclinical inflammation. Taken together, these processes reflect the complexity and interconnection of the causes and courses of AD. Currently, the AD treatment is based mainly on acetylcholinesterase (AChE, E.C. 3.1.1.7) enzyme inhibitors, which increase acetylcholine levels at synapses and thus facilitate neurotransmission. Three AChE inhibitors are currently used in the treatment of AD, namely donepezil, galantamine and rivastigmine, which are administered in mild to moderate stages of AD. Furthermore, memantine, a non-competitive NMDA receptor antagonist which prevents glutamatergic excitotoxicity leading to neurodegeneration, is indicated for the treatment of moderate to severe stages of AD. However, the effectiveness of the currently available treatments is limited and only temporarily effective. When it comes to the development of novel potential drugs, the most frequent strategy for the preparation of MTDLs (multi-target directed ligands) is to combine two heterogeneous pharmacophores, wherein these pharmacophores are linked 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, and greater off-targeting and toxicity. Therefore, it is advantageous to look for a combination of different pharmacophores within a single molecule ( via "merging" or "fusing" approach) (BENEK, O., J. KORABECNY AND O. SOUKUP A Perspective on Multi-target Drugs for Alzheimer's Disease. Trends in Pharmacological Sciences, 2020, 41(7), 433-445). No individual drug with this dual activity is available on the market (except for huperzine-A approved in China). However, the dual activity is widely discussed in the literature. The dual concept of inhibiting both AChE and NMDA receptors based on the "linking" approach was first introduced by the binding of 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. M., 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). Furthermore, tacrine- memantine hybrids were prepared (SPILOVSKA, K., J. KORABECNY, J. KRAL, A. HOROVA, K. MUSILEK, O. SOUKUP, L. DRTINOVA, Z. GAZOVA, K. SIPOSOVA AND K. KUCA. 7- Methoxytacrine-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. DRTINOVA, 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 on, neuroprotective efficacy was confirmed for 6-chlorotacrine-memantine in a rat model using NMDA-induced lesions (KANIAKOVA, M., 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 novel multi-target compound against Alzheimer's disease. Current Alzheimer Research, 2019, 16(9), 821-833). In China, dual activity has been observed in huperzine-A, an approved drug for the treatment of Alzheimer's disease. Despite high expectations, both its dual-acting derivatives and bis-7-tacrine (bis-7-cognitine) never reached the clinical trial stage (ZHANG, J.-M. AND G.-Y. HU Huperzine A, a nootropic alkaloid, inhibits NMDA- induced current in rat dissociated hippocampal neurons. Neuroscience, 2001, 105(3), 663-669; 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 162008, 369(4), 1007-1011). Tacrine is a drug that was approved in 1993 as a cholinesterase inhibitor due to its pro-cognitive effect, but its use was later abandoned due to its gastrointestinal side effects and hepatotoxicity. Thus, the further potential use of tacrine derivatives must necessarily be associated with demonstrating the safety of new molecules, for example, due to a different metabolism, which would not lead to hepatotoxic intermediates (PATOCKA, 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). Disclosure of the Invention The present invention overcomes the above prior art limitations by providing novel dually active derivatives with the ability to positively interfere with a deficient cholinergic system, while simultaneously antagonizing excitotoxicity mediated via NMDA receptors. Thus, these compounds are suitable for use in the field of neurodegenerative diseases, in particular in the treatment of Alzheimer's disease, Lewy body dementia or in the treatment of vascular dementia in combination with Lewy body dementia or in the treatment of vascular dementia in combination with the Parkinson's or the Alzheimer's disease. The object of this invention are compounds of formula I,

wherein n is 1, 2 or 3, R¹ is selected from the group -CH₃; –OCH₃; -Br; -Cl; -F; phenoxy; 1-CH₃-phenoxy; 1-OCH₃-phenoxy; 2-OCH₃-phenoxy; 3-CH₃-phenoxy; 3-Cl-phenoxy; 3-C(CH₃)₃-phenoxy; 3-C(O)-CH₃-phenoxy; and 2- CH₃,4-CH₃-phenoxy; and R² is -H; -Cl; or -Br; with the proviso that - when R² is –Cl, R¹ must be -Cl; - when R² is –Br, R¹ must be –Br; - when R¹ is –OCH₃ or phenoxy, n is not 2. The organic compounds of general formula I may be in the form of pharmaceutically acceptable salts with alkali metals, ammonia or amines, or in the form of addition salts with acids. Compounds of general formula I are preferably selected from the compounds listed in Tables 1, 2 and 3. Furthermore, a subject of the invention is the compounds of general formula I for use for inhibition of cholinesterases, particularly for inhibition of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE), and for simultaneous NMDA receptor antagonist activity. A further subject of the invention are compounds of general formula I for use as medicaments. More specifically, the invention includes compounds of general formula I for symptomatic treatment of dementia and/or neurodegenerative diseases, more preferably selected from Alzheimer's disease, dementia with Lewy bodies, vascular dementia in combination with Lewy bodies dementia and vascular dementia in combination with Parkinson's or Alzheimer's disease. Yet, a further subject of the invention is a pharmaceutical composition containing at least one compound of general formula I and at least one pharmaceutically acceptable carrier. Suitable carriers include fillers such as sugars, starches, carboxymethylated starch, crosslinked polyvinylpyrrolidone, alginic acid and salts thereof, solvents, binders, etc. Table 1:

Table 2:

Table 3:

Particularly preferred are compounds selected from: I-13, I-58, II-13, I-14, II-14, I-15, II-15,II-58, III- 15, I-56, III-58, III-56, II-60, I-61, II-61, III-61 and III-62 due to the dual effect on cholinesterases and NMDA recptors and/or high efficacy towards the target and/or its selectivity towards the studied target respectivelly. The compounds of general formula I may be prepared using the method shown in Schemes 1-3:

Scheme 1. Synthesis of substituted tacrine derivatives. Reaction conditions: i) Lewis acid (preferably AlCl₃ or ZnCl₂); microwave irradiation; 10 min; 150 °C.

Scheme 2. Synthesis of substituted 4-phenoxyaniline derivatives. Reaction conditions: i) 5-10 mol % CuBr; Cs₂CO₃ (2,0 eq.); 1-(2-pyridinyl)acetone (0,2 eq.); DMSO; 24 h; 90 °C; ii) MeOH/H₂O (2:1); KOH (7,5 eq); microwave irradiation; 90 min; 160 °C.

Scheme 3. Synthesis of substituted tacrine derivatives. Reaction conditions: i) para-toluenesulfonic acid monohydrate (PTSA; 0,01 eq); toluene; 24 h; 150 °C; ii) diphenyl ether; 20 min; 220-240 °C; iii) POCl₃ (7,8 eq); 1 h; 130°C; iv) NH₃ (gas); phenol (10 eq); 2 h; 180 °C. Brief description of drawings Fig.1. Prepulse inhibition model: administration of tested compounds (5 mg/kg) and MK-801 (0.3 mg/kg) Fig.2. Open field: co-administration of tested compounds (5 mg/kg) with MK-801 (0.2 mg/kg) Fig.3. Morris water maze: MK-801 model Fig.4. Morris water maze: scopolamine model Examples of carrying out the invention The invention is further described using the following examples, which are purely illustrative and should not be construed as limiting the invention. General chemical methods TLC was performed on 60 F254 silica gel coated aluminum plates (Merck, Prague, Czech Republic). Column chromatography was performed at atmospheric pressure on silica gel 100 (particle size 0.063 - 0.200 mm, 70 - 230 mesh ASTM, Fluka, Prague, Czech Republic). The chemicals for the syntheses were purchased from Sigma Aldrich Co. LLC and Fluorochem Ltd. and were used without further purification. A CEM Explorer SP 12 S Class apparatus was used for reactions performed with microwave activation. A Dionex Ultimate 3000 LC-MS analytical system combined with an Orbitrap Q Exactive Plus spectrometer (Thermo Fisher Scientific, Bremen, Germany) was used for mass spectrometry measurements. The LC-MS system consists of a binary pump HHG-3400RS, which is connected to a vacuum degasser, from a heated column compartment TCC-3000, autosampler WTS- 3000 and ultraviolet detector VWD-3000. Quadrupole mass spectrometer was equipped with an electron-spray ionization source and the 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. ¹H and ¹³C NMR spectra were measured at room temperature in deuterated dimethyl sulfoxide (DMSO- d₆) on a Varian S500 NMR spectrometer (499.87 MHz for ¹H and 125.71 MHz for ¹³C) and a Bruker Avance III spectrometer (600 MHz for ¹H and 151 MHz for ¹³C). Chemical shifts (δ) of protons in ¹H NMR and carbons in ¹³C NMR spectra are reported in ppm. The reference standard for the shifts in ¹H NMR spectra was the central DMSO-d₆ peak at δ = 2.50 ppm, the CDCl₃ peak at δ = 7.26 ppm and the methanol-d₄ peak at δ = 3.21 ppm. In the ¹³C NMR spectra, the internal standard was the DMSO-d₆ peak at δ = 39.43 ppm, the CDCl₃ peak at δ = 77.00 ppm and the methanol-d₄ peak at δ = 47.6 ppm. The interaction constants (J) are reported in Hz. The spin multiplicity of signals in the ¹H NMR spectra is expressed as bs (broad singlet), s (singlet), d (doublet), dd (doublet of doublets), t (triplet) or m (multiplet). Chemical shifts are reported in ppm (parts per million, δ) relative to the indicated solvents. Example 1 – Method for preparation of compounds of general formula I The compounds were prepared according to Scheme 1. Commercially available starting materials 1-7 (1.0 eq.) were combined with corresponding cyclic ketones 8-10 (2.0 mL) in a tube for a microwave reactor, under Lewis acid (2.0 eq.) catalysis. The reaction mixture was stirred in the microwave reactor for 10 min. at 150 °C. After cooling, 3 mL of 2M NaOH solution and 2 mL of DCM were successively added to the reaction mixture and the mixture was allowed to stir for 30 minutes at room temperature. Subsequently, the mixture was diluted with 20 mL of 2M NaOH solution and extracted three times with 20 mL of dichloromethane (DCM). The organic layers were combined and dried over anhydrous Na₂SO₄. The reaction mixture was purified by flash chromatography with mobile phase DCM/MeOH/25% aqueous NH₃ (9:1:0.1). The 7-substituted tacrine derivatives (I-III) 11-17 were obtained as free bases in the yield of 55-98%. The characterization of the derivatives (I-III) 11-17 is provided below (for biological testing, the compounds (I-III) 11-17 were converted to hydrochloride salts): 7‐methyl‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-11) Yield: 83 %. Brown crystalline substance. Melting point: 252 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): δ 8.04 (s, 1H); 7.64 (d, J = 8.5 Hz, 1H); 7.47 – 7.39 (m, 1H); 7.06 (bs, 2H); 2.96 (t, J = 7.7 Hz, 2H); 2.81 (t, J = 7.3 Hz, 2H); 2.44 (s, 3H); 2.08 (p, J = 7.6 Hz, 2H).¹³C NMR (126 MHz, DMSO- d₆): δ 163.06; 148.31; 143.37; 132.99; 131.37; 125.08; 121.73; 116.91; 113.89; 33.55; 27.82; 22.30; 21.29; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₅N₂ ⁺ (m/z): 199.1229; found 199.1229 7‐methoxy‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-12) Yield: 60 %. White crystalline substance. Melting point: 264 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): δ 7.59 (d, J = 9.1 Hz, 1H); 7.49 (d, J = 2.8 Hz, 1H); 7.14 (dd, J = 9.1; 2.7 Hz, 1H); 6.30 (bs, 2H); 3.85 (s, 3H); 2.86 (t, J = 7.7 Hz, 2H); 2.80 (t, J = 7.3 Hz, 2H); 2.10 – 1.99 (m, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 164.15; 155.28; 145.52; 144.07; 129.58; 119.44; 118.05; 113.64; 101.55; 55.67; 34.35; 27.79; 22.50; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₅ON₂ ⁺ (m/z): 215.1178; found 215.1175 7‐chloro‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-13) Yield: 82 %. Brown crystalline powder. Melting point: 266 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.25 (d, J = 2.4 Hz, 1H); 7,67 (d, J = 8.9 Hz, 1H); 7.47 (dd, J = 8.9; 2.3 Hz, 1H); 6.52 (bs, 2H); 2.88 (t, J = 7.7 Hz, 2H); 2,80 (t, J = 7.3 Hz, 2H); 2.10 – 1.97 (m, 2H).¹³C NMR (126 MHz, DMSO- d₆): δ 167.38; 147.27; 145.67; 130.47; 128.19; 127.18; 121.41; 118.55; 114.34; 34.68; 27.81; 22.33; HRMS (ESI⁺): [M⁺]: calculated for C₁₂H₁₂ClN₂ ⁺ (m/z): 219.0683; found 219.0680 7‐bromo‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-14) Yield: 77 %. Orange crystalline powder. Melting point: 247 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.39 (d, J = 1.9 Hz, 1H); 7.65 – 7.54 (m, 2H); 6.53 (bs, 2H); 2.87 (t, J = 7.7 Hz, 2H); 2.80 (t, J = 7.3 Hz, 2H); 2.14 – 1.95 (m, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 167.45; 147.45; 145.58; 130.77; 130.67; 124.58; 119.17; 115.48; 114.34; 34.71; 27.82; 22.31; HRMS (ESI⁺): [M⁺]: calculated for C₁₂H₁₂BrN₂ ⁺ (m/z): 263.0178; found 263.0175 7‐fluoro‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-15) Yield: 83 %. White crystalline powder. Melting point: 185 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 7.97 – 7.88 (m, 1H); 7.76 – 7.66 (m, 1H); 7.45 – 7.31 (m, 1H); 6.40 (bs, 2H); 2.88 (t, J = 7.7 Hz, 2H); 2,80 (t, J = 7.3 Hz, 2H); 2.05 (p, J = 7.5 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 166.46; 166.44; 159.10; 157.20; 145.86; 145.84; 130.84; 130.77; 118.05; 117.98; 117.35; 117.15; 113.97; 106.14; 105.96; 34.57; 27.78; 22.43; HRMS (ESI⁺): [M⁺]: calculated for C₁₂H₁₂FN₂ ⁺ (m/z): 203.0979; found 203.0975 5,7‐dichloro‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-16) Yield: 72 %. Brown crystalline powder. Melting point: 222 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.27 (d, J = 2.3 Hz, 1H); 7.75 (d, J = 2.2 Hz, 1H); 6.70 (bs, 2H); 2.93 (t, J = 7.7 Hz, 2H); 2.81 (t, J = 7.3 Hz, 2H); 2.13 – 2.02 (m, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 168.07; 146.26; 143.49; 133.27; 128.02; 126.22; 120.99; 119.31; 115.38; 34.97; 27.86; 22.23; HRMS (ESI⁺): [M⁺]: calculated for C₁₂H₁₁Cl₂N₂ ⁺ (m/z): 253.02938; found 253.02911 5,7‐dibromo‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-17) Yield: 82 %. Light orange crystalline powder. Melting point: 153 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.45 (d, J = 2.1 Hz, 1H); 8.01 (d, J = 2.1 Hz, 1H); 6.71 (bs, 2H); 2.93 (t, J = 7.7 Hz, 2H); 2.82 (t, J = 7.3 Hz, 2H); 2.06 (p, J = 7.6 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 168.38; 146.15; 144.42; 133.59; 125.12; 124.77; 119.79; 115.37; 114.56; 35.03; 27.87; 22.24; HRMS (ESI⁺): [M⁺]: calculated for C₁₂H₁₁Br₂N₂ ⁺ (m/z): 342.9263; found 342.9259 7-methyl-1,2,3,4-tetrahydroacridine-9-amine hydrochloride (II-11) Yield: 98 %. Brown crystalline powder. Melting point: 154 °C. ¹H NMR (500 MHz, Methanol-d₄): δ 7.81 (dd, J = 1.9, 1.0 Hz, 1H); 7.59 (d, J = 8.6 Hz, 1H); 7.40 (dd, J = 8.6; 1.8 Hz, 1H); 2.88 (t, J = 6.1 Hz, 2H); 2.58 (t, J = 6.2 Hz, 2H); 2.48 (s, 3H); 1.97 – 1.83 (m, 4H).¹³C NMR (126 MHz, Methanol-d₄): δ 156.99; 151.01; 144.28; 134.76; 132.35; 126.31; 121.47; 117.96; 110.54; 33.31; 24.51; 23.75; 23.63; 21.60; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₇N₂ ⁺ (m/z): 213.1386; found 213.1382 7‐chloro‐1,2,3,4‐tetrahydroacridine‐9‐amine hydrochloride (II-13) Yield: 66 %. Brown crystalline powder. Melting point: 247 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J = 2.3 Hz, 1H); 7.62 (d, J = 8.9 Hz, 1H); 7.46 (dd, J = 9.0; 2.3 Hz, 1H); 6.42 (bs, 2H); 2.80 (t, J = 6.0 Hz, 2H); 2.53 (t, J = 6.1 Hz, 2H); 1.91 – 1.69 (m, 4H).¹³C NMR (126 MHz, DMSO- d₆): δ 158.22; 147.66; 145.07; 130.30; 128.40; 127.11; 121.22; 117.92; 109.94; 33.73; 23.85; 22.70; 22.58; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₄ClN₂ ⁺ (m/z): 233.0840; found 233.0837 7-bromo-1,2,3,4-tetrahydroacridine-9-amine hydrochloride (II-14) Yield: 72 %. Light orange crystalline powder. Melting point: 247 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.42 (d, J = 1.8 Hz, 1H); 7.60 – 7.51 (m, 2H); 6.44 (bs, 2H), 2.80 (t, J = 6.0 Hz, 2H); 2.53 (t, J = 6.1 Hz, 2H); 1.86 – 1.74 (m, 4H).¹³C NMR (126 MHz, DMSO-d₆): δ 158.29; 147.61; 145.18; 130.98; 130.42; 124.43; 118.54; 115.44; 109.96; 33.71; 23.84; 22.67; 22.56; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₄BrN₂ ⁺ (m/z): 277.0334; found 277.0332 7‐fluoro‐1,2,3,4‐tetrahydroacridine‐9‐amine hydrochloride (II-15) Yield: 77 %. White crystalline powder. Melting point: 268 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.08 – 8.00 (m, 1H); 7.76 – 7.69 (m, 1H); 7.49 – 7.41 (m, 1H); 6.75 (bs, 2H); 2.83 (t, J = 5.9 Hz, 2H); 2.53 (t, J = 6.1 Hz, 2H); 1.85 – 1.75 (m, 4H).¹³C NMR (126 MHz, DMSO-d₆): δ 159.24; 157.33; 155.97; 149.41; 141.72; 128.92; 118.77; 118.57; 117.06; 109.49; 106.30; 106.12; 32.42; 23.64; 22.32; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₄FN₂ ⁺ (m/z): 217.1135; found 217.1134 5,7‐dichloro‐1,2,3,4‐tetrahydroacridine‐9‐amine hydrochloride (II-16) Yield: 86 %. Brown crystalline powder. Melting point: 193 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.30 (d, J = 2.3 Hz, 1H); 7.74 (d, J = 2.2 Hz, 1H); 6.60 (bs, 2H); 2.87 – 2.82 (m, 2H); 2.53 (t, J = 6.0 Hz, 2H); 1.85 – 1.76 (m, 4H).¹³C NMR (126 MHz, DMSO-d₆): δ 158.97; 148.31; 141.25; 133.08; 128.12; 126.06; 120.83; 118.54; 111.02; 33.97; 23.89; 22.58; 22.38; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₃Cl₂N₂ ⁺ (m/z): 267;0450; found 267;0448 5,7‐dibromo‐1,2,3,4‐tetrahydroacridine‐9‐amine hydrochloride (II-17) Yield: 55 %. Light orange crystalline powder. Melting point: 203 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.48 (d, J = 2.1 Hz, 2H); 7.99 (d, J = 2.0 Hz, 1H); 6.61 (bs, 3H); 2.86 – 2.80 (m, 2H); 2.55 – 2.51 (m, 2H); 1.84 – 1.78 (m, 4H).¹³C NMR (126 MHz, DMSO-d₆): δ 159.27; 148.21; 142.14; 133.66; 125.05; 124.66; 118.99; 114.39; 111.00; 34.01; 23.88; 22.57; 22.38; HRMS (ESI⁺): [M⁺]: calculated for C₁₃H₁₃Br₂N₂ ⁺ (m/z): 356.9419; found 356.9413 2-methyl-6H,7H,8H,9H,10H-cyclohepta[b]quinoline-11-amine hydrochloride (III-11) Yield: 81 %. Brown crystalline powder. Melting point: 103 °C.¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J = 1.7 Hz, 1H); 7.61 (d, J = 8.5 Hz, 1H); 7.40 (dd, J = 8.5; 1.8 Hz, 1H); 6.71 (bs, 2H), 3.04 – 2.95 (m, 2H); 2.83 – 2.76 (m, 2H); 2.44 (s, 3H); 1.79 (p, J = 6.3 Hz, 2H); 1.63 (p, J = 5.4 Hz, 2H); 1.55 (p, J = 5.6 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆) δ 161.79; 148.32; 142.30; 133.12; 130.90; 126.02; 121.68; 117.36; 114.29; 37.74; 31.64; 27.57; 26.56; 25.30; 21;41; HRMS (ESI⁺): [M⁺]: calculated for C₁₅H₁₉N₂ ⁺ (m/z): 227.1542; found 227.1539 2‐methoxy‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-12) Yield: 82 %. Yellowish crystalline powder. Melting point: 237 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆) δ 7.64 (d, J = 9.1 Hz, 1H); 7.56 (d, J = 2.7 Hz, 1H); 7.23 (dd, J = 9.1, 2.6 Hz, 1H); 6.75 (bs, 2H); 3.87 (s, 3H); 3.02 – 2.94 (m, 2H); 2.85 – 2.77 (m, 2H); 1.80 (p, J = 5.9 Hz, 2H); 1.63 (p, J = 5.4 Hz, 2H); 1.57 (p, J = 5.5 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆) δ 160.14; 156.15; 156.15; 148.24; 139.03; 127.41; 120.78; 117.96; 114.38; 102.09; 55.91; 37.46; 31.62; 27.51; 26.56; 25.35; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₇ON₂ ⁺ (m/z): 243.1491; found 243.1487 2‐chloro‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-13) Yield: 94 %. Brown crystalline powder. Melting point: 253 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (d, J = 2.4 Hz, 1H); 7.64 (d, J = 8.9 Hz, 1H); 7.47 (dd, J = 8.9; 2.3 Hz, 1H); 6.41 (bs, 2H); 3.01 – 2.91 (m, 2H); 2.84 – 2.73 (m, 2H); 1.78 (p, J = 5.8 Hz, 2H); 1.61 (p, J = 5.5 Hz, 2H); 1.54 (p, J = 5.5 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆) δ 164.83; 146.48; 144.89; 130.54; 128.25; 127.70; 121.62; 118.85; 115.11; 31.74; 27.76; 26.75; 25.50; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₆ClN₂ ⁺ (m/z): 247.0996; found 247.0995 2-bromo-6H,7H,8H,9H,10H-cyclohepta[b]quinoline-11-amine hydrochloride (III-14) Yield: 88 %. Orange crystalline powder. Melting point: 231 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆) δ 8.44 – 8.32 (m, 1H); 7.57 (d, J = 2.0 Hz, 2H); 6.42 (bs, 2H); 2.99 – 2.89 (m, 2H); 2.81 – 2.74 (m, 2H); 1.78 (p, J = 5.9 Hz, 2H); 1.61 (p, J = 5.5 Hz, 2H); 1.54 (p, J = 5.6 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆) δ 164.92; 146.38; 145.06; 130.82; 130.71; 124.78; 119.45; 116.03; 115.11; 31.73; 27.75; 26.71; 25.48; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₆BrN₂ ⁺ (m/z): 291.0491; found 291.0488 2‐fluoro‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-15) Yield: 98 %. White crystalline powder. Melting point: 269 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 – 7.89 (m, 1H); 7.71 – 7.64 (m, 1H); 7.41 – 7.33 (m, 1H); 6.30 (bs, 2H); 3.01 – 2.91 (m, 2H); 2.84 – 2.74 (m, 2H); 1.86 – 1.74 (m, 2H); 1.65 – 1.50 (m, 4H).¹³C NMR (126 MHz, DMSO- d₆) δ 160.45; 158.51; 158.05; 153.95; 153.92; 133.87; 122.53; 122.46; 122.15; 121.95; 116.82; 116.74; 114.75; 108.60; 108.40; 32.79; 31.04; 26.23; 25.47; 24.59; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₆FN₂ ⁺ (m/z): 231.1292; found 231.1287 2,4‐dichloro‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-16) Yield: 96 %. Brown crystalline powder. Melting point: 244 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.27 (d, J = 2.2 Hz, 1H); 7.75 (d, J = 2.2 Hz, 1H); 6.58 (bs, 2H); 3.05 – 2.96 (m, 2H); 2.84 – 2.75 (m, 2H); 1.85 – 1.74 (m, 2H); 1.66 – 1.58 (m, 2H); 1.58 – 1.51 (m, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 165.46; 147.13; 141.05; 133.35; 128.02; 126.71; 121.20; 119.52; 116.09; 39.48; 31.67; 27.52; 26.60; 25.49; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₅Cl₂N₂ ⁺ (m/z): 281.0608; found 281.0604 2,4‐dibromo‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-17) Yield: 65 %. Light orange crystalline powder. Melting point: 142 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): δ 8.45 (d, J = 2.1 Hz, 1H); 8.00 (d, J = 1.9 Hz, 1H); 6.60 (bs, 2H); 3.04 – 2.96 (m, 2H); 2.82 – 2.76 (m, 2H); 1.83 – 1.76 (m, 2H); 1.66 – 1.59 (m, 2H); 1.59 – 1.51 (m, 2H).¹³C NMR (126 MHz, DMSO-d₆): δ 165.73; 147.06; 141.93; 133.58; 125.26; 125.01; 119.95; 116.06; 115.08; 31.67; 27.53; 26.58; 25.50; HRMS (ESI⁺): [M⁺]: calculated for C₁₄H₁₅Br₂N₂ ⁺ (m/z): 370.9576; found 370.9570. Example 2 – Method for preparation of intermediates 22-25 and 26-29 The compounds were prepared according to Scheme 2. A 50 mL distillation flask filled with an inert argon atmosphere was charged with commercially available starting materials: compound 18-21 (4.6 mmol; 1.0 eq), N-(4-hydroxyphenyl)acetamide (5.5 mmol; 1.2 eq), Cs₂CO₃ (9.2 mmol; 2 eq), CuBr (5- 10 mol%) and 1-(2-pyridinyl) acetone (0.2 eq). Anhydrous DMSO (5 mL) was added. The reaction mixture was stirred at 90 °C for 24 h. After completion of the reaction, 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 sintered glass filter. The filtrate was evaporated in vacuo and extracted by DCM (3 × 50 mL) and water (100 mL). The organic fractions were combined, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography, with elution by DCM/MeOH/25% aqueous NH₃ (20:1:0.1) to give intermediates 22-25. These intermediates were placed in a microwave reactor tube and subjected to hydrolysis by reaction with KOH (27.3 mmol; 7.5 eq) in 5 mL of MeOH/H₂O (2:1). The reaction conditions were set at 160 °C at a maximum power of 150 W with a dynamic curve, for 90 min. Upon completion, the reaction mixture was immediately purified by flash chromatography with elution by DCM/MeOH/25% aqueous NH₃ (9:1:0.1) to give products 26-29. The characterization of the prepared compounds (22-25 and 26-29) is reported here: N‐[4‐(2‐methylphenoxy)phenyl]acetamide (22) Yield: 79 %. Orange viscous oil. ¹H 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M⁺]: calculated for C₁₅H₁₆NO₂ ⁺ (m/z): 242.1176; found 242.1173 N‐[4‐(4‐tert‐butylphenoxy)phenyl]acetamide (23) Yield: 55 %. Brown viscous oil. ¹H NMR (500 MHz, Chloroform-d): δ 7.38 – 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).¹³C 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⁺]: calculated for C₁₈H₂₂NO₂ ⁺ (m/z): 284.1646; found 284.1642 N‐[4‐(4‐acetylphenoxy)phenyl]acetamide (24) Yield: 40 %. Brown viscous oil. ¹H NMR (500 MHz, Chloroform-d): δ 7.87 – 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).¹³C 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 (ESI⁺): [M⁺]: calculated for C₁₆H₁₆NO₃ ⁺ (m/z): 270.1125; found 270.1122 N‐[4‐(3,5‐dimethylphenoxy)phenyl]acetamide (25) Yield: 30 %. Orange viscous oil.¹H NMR (500 MHz, Methanol-d₄): 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). ¹³C 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⁺]: calculated for C₁₆H₁₈NO₂ ⁺ (m/z): 256.1332; found 256.1333 4‐(2‐methylphenoxy)aniline (26) Yield: 75 %. Brown crystalline powder. Melting point: 122.5-123.4 °C. ¹H 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). ¹³C 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⁺]: calculated for C₁₃H₁₄NO⁺ (m/z): 200.1070; found 200.1071 4‐(4‐tert‐butylphenoxy)aniline (27) Yield: 75 %. Brown crystalline powder. Melting point: 127.5-128.4 °C. ¹H 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).¹³C 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⁺]: calculated for C₁₆H₂₀NO⁺ (m/z): 242.1540; found 242.1535 1‐[4‐(4‐aminphenoxy)phenyl]ethan‐1‐one (28) Yield: 24 %. Brown crystalline powder. Melting point: 147.5-149.0 °C.¹H NMR (500 MHz, Methanol- d₄): 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). ¹³C NMR (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⁺]: calculated for C₁₄H₁₃NO₂ ⁺ (m/z): 228.1020; found 228.1020 4‐(3,5‐dimethylphenoxy)aniline (29) Yield: 67 %. Brown crystalline powder. Melting point: 124.5-125.7 °C.¹H NMR (500 MHz, Methanol- d₄): 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). ¹³C NMR (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⁺]: calculated for C₁₄H₁₆NO⁺ (m/z): 214.1227; found 214.1225. Example 3 – Method for preparation of substituted phenoxytacrine derivatives 56-64 The first step of the synthesis The compounds were prepared according to Scheme 3. 4-Phenoxyanilines 26-29 with varying substitutions (1.0 eq.) or commercially available derivatives 30-34 (1.0 eq.) were weighed into a 250 mL distillation flask. 50 mL of toluene and 0.1 g of PTSA were then added to the flask. Ethyl 2- oxocycloalkanecarboxylate 35-37 (1.1 eq.) was added to the reaction mixture. The flask with the mixture was placed in an oil bath and fitted with a Dean-Stark reflux condenser. The cyclocondensation reaction was carried out at 150 °C for 24 h. After completion of the reaction, the solvent was evaporated in vacuo and diphenyl ether (10.0 eq) was added to the reaction mixture. The reaction mixture was heated at 220- 240 °C for 20 minutes 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 about 30 mL of heptane was added. The resulting precipitate was filtered under reduced pressure through the sintered glass. The residue on the sintered glass was washed three times with 20 mL of heptane. Intermediate (I-III) 38-46 was purified by flash chromatography using DCM/MeOH/25% aqueous NH₃ (20:1:0.1). The following derivatives (I-III) 38-46 were prepared by this process; their characterization is reported below, with the exception of II-38 (compound II-38 was characterized only by melting point and HRMS; NMR was not determined due to its low solubility): 7-phenoxy-2, 3-dihydro-1H-cyclopenta[b]quinolin-9(4H)-one (I-38) Yield: 68 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₁₈H₁₆NO₂ ⁺ (m/z): 278.1176; found 278.1171. 7‐(2‐methoxyphenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-40) Yield: 35 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₁₉H₁₈NO₃ ⁺ (m/z): 308.1282; found 308.1282 7‐(3‐methoxyphenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-41) Yield: 7 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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, J = 7.7 Hz, 2H).¹³C NMR (126 MHz, DMSO-d₆): 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, 32.23, 28.02, 21.90; HRMS (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₈NO₃ ⁺ (m/z): 308.1282; found 308.1281 7‐(4‐methylphenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-42) Yield: 50 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.94 (bs, 1H); 7.52 (d, J = 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).¹³C NMR (126 MHz, DMSO-d₆): δ 173.47; 154.56; 153.87; 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 (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₈NO₂ ⁺ (m/z): 292.1333; found 292.1329 7‐(4‐chlorophenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-43) Yield: 19 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₁₈H₁₅ClNO₂ ⁺ (m/z): 312.0786; found 312.0781 7‐(4‐tert‐butylphenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-44) Yield: 27 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C 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]⁺: calculated for C₂₂H₂₄NO₂ ⁺ (m/z): 334.1802; found 334.1801 7‐(4‐acetylphenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-45) Yield: 33 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₂₀H₁₈NO₃ ⁺ (m/z): 318.1281; found 320.1281 7‐(3,5‐dimethylphenoxy)‐1H,2H,3H,4H,9H‐cyclopenta[b]quinolin‐9‐one (I-46) Yield: 25 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.95 (bs, 1H); 7.48 (d, J = 8.9 Hz, 1H); 7.42 (d, J = 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). ¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₂₀H₂₀NO₂ ⁺ (m/z): 306.1488; found 306.1489 7-phenoxy-1,2,3,4,9,10-hexahydroacridin-9-one (I-38) Yield: 85 %. Yellow crystalline powder. Melting point: ˃ 300.0 °C. HRMS (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₈NO₂ ⁺ (m/z): 292.1293; found 292.1324 7‐(2‐methylphenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-39) Yield: 49 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (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]⁺: calculated for C₂₀H₂₀NO₂ ⁺ (m/z): 306.1488; found 306.1489 7‐(2‐methoxyphenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-40) Yield: 51 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₂₀NO₃ ⁺ (m/z): 322.1438; found 322.1439 7‐(3‐methoxyphenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-41) Yield: 26 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.44 (bs, 1H); 7.54 (d, J = 8.9 Hz, 1H); 7.51 (d, J = 2.8 Hz, 1H); 7.37 (dd, J = 8.9; 2.9 Hz, 1H); 7.29 (t, J = 8.2 Hz, 1H); 6.76 – 6.72 (m, 1H); 6.61 (t, J = 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). ¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₂₀NO₃ ⁺ (m/z): 322.1438; found 322.1436 7‐(4‐methylphenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-42) Yield: 43 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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, J = 6.3 Hz, 2H); 2.40 (t, J = 6.2 Hz, 2H); 2.29 (s, 3H); 1.76 – 1.64 (m, 4H).¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₂₀NO₂ ⁺ (m/z): 306.1489; found 306.1478 7‐(4‐chlorophenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-43) Yield: 91 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): δ 11.44 (bs, 1H); 7.54 (d, J = 8.9 Hz, 1H); 7.50 (d, J = 2.9 Hz, 1H); 7.43 (d, J = 8.3 Hz, 2H); 7.38 (dd, J = 9.0; 3.0 Hz, 1H); 7.04 (d, J = 8.4 Hz, 2H); 2.73 – 2.64 (m, 2H); 2.44 – 2.36 (m, 2H); 1.77 – 1.67 (m, 4H). ¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₇ClNO₂ ⁺ (m/z): 326.0943; found 326.0938 7‐(4‐tert‐butylphenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-44) Yield: 91 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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, J = 6.2 Hz, 2H); 2.41 (t, J = 6.2 Hz, 2H); 1.79 – 1.72 (m, 2H); 1.72 – 1.65 (m, 2H); 1.29 (s, 9H). ¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₂₃H₂₆NO₂ ⁺ (m/z): 348.1958; found 348.1960 7‐(3,5‐dimethylphenoxy)‐1,2,3,4,9,10‐hexahydroacridin‐9‐one (II-46) Yield: 91 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₂₁H₂₂NO₂ ⁺ (m/z): 320.1646; found 320.1642 2‐phenoxy‐5H,6H,7H,8H,9H,10H,11H‐cyclohepta[b]quinolin‐11‐one (III-38) Yield: 74 %. Brown crystalline powder. Melting point: ˃ 300.0 °C.¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (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]⁺: calculated for C₂₀H₂₀NO₂ ⁺ (m/z): 306.1489; found 306.1475 2‐(2‐methoxyphenoxy)‐5H,6H,7H,8H,9H,10H,11H‐cyclohepta[b]quinolin‐11‐one (III-40) Yield: 40 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C 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 (ESI⁺): [M+H]⁺: calculated for C₂₁H₂₂NO₃ ⁺ (m/z): 336.1595; found 336.1595 2‐(3‐methoxyphenoxy)‐5H,6H,7H,8H,9H,10H,11H‐cyclohepta[b]quinolin‐11‐one (III-41) Yield: 40 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C 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]⁺: calculated for C₂₁H₂₂NO₃ ⁺ (m/z): 336.1595; found 336.1594 2‐(4‐methylphenoxy)‐5H,6H,7H,8H,9H,10H,11H‐cyclohepta[b]quinolin‐11‐one (III-42) Yield: 74 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (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]⁺: calculated for C₂₁H₂₂NO₂ ⁺ (m/z): 320.1646; found 320.1634 2‐(4‐chlorophenoxy)‐5H,6H,7H,8H,9H,10H,11H‐cyclohepta[b]quinolin‐11‐one (III-43) Yield: 29 %. Brown crystalline powder. Melting point: ˃ 300.0 °C. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (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]⁺: calculated for C₂₀H₁₉ClNO₂ ⁺ (m/z): 340.1099; found 340.1089 The second step of the synthesis The intermediate (I-III) 38-46 (1.0 eq) was charged into a 250 mL flask. POCl₃ (7.8 eq) was added slowly and with constant cooling (ice-water mixture). The reaction mixture was heated under reflux at 130 °C for 1 h. The residual POCl₃ was distilled off in vacuo and the distillation residue was diluted with 50 mL DCM, poured onto a mixture containing 150 ml ice and water and concentrated aqueous NH₃ (25%, 30 mL), and shaken three times in a separatory funnel with DCM (3 × 50 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and the crude intermediate (I-III) 47-55 was purified by flash chromatography using PE/EA (4:1) mobile phase. The following derivatives (I-III) 47-55 were prepared by analogous procedures, the characterization of which is reported herein: 9‐chloro‐7‐phenoxy‐1H,2H,3H‐cyclopenta[b]quinoline (I-47) Yield: 74 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₁₈H₁₅ClNO⁺ (m/z): 296.0837; found 296.0829 9‐chloro‐7‐(2‐methoxyphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-49) Yield: 74 %. Yellow viscous oil.¹H 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). ¹³C 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 (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₇ClNO₂ ⁺ (m/z): 32.0942; found 326.0943 9‐chloro‐7‐(3‐methoxyphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-50) Yield: 75 %. Yellow viscous oil.¹H 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). ¹³C NMR (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]⁺: calculated for C₁₉H₁₇ClNO₂ ⁺ (m/z): 326.0942; found 326.0940 9‐chloro‐7‐(4‐methylphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-51) Yield: 32 %. Yellow viscous oil.¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₇ClNO⁺ (m/z): 310.0994; found 310.0988 9‐chloro‐7‐(4‐chlorophenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-52) Yield: 56 %. Yellow viscous oil. ¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₁₈H₁₄Cl₂NO⁺ (m/z): 330.0447; found 330.0434 9‐chloro‐7‐(4‐tert-butylphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-53) Yield: 34 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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).¹³C 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 (ESI⁺): [M+H]⁺: calculated for C₂₂H₂₃ClNO⁺ (m/z): 352.1463; found 352.1463 9‐chloro‐7‐(4‐acetylphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-54) Yield: 45 %. Yellow viscous oil.¹H 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).¹³C NMR (126 MHz, Chloroform- d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₇ClNO₂ ⁺ (m/z): 338.0942; found 338.0940 9‐chloro‐7‐(3,5‐dimethylphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline (I-55) Yield: 63%. Yellow viscous oil.¹H 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).¹³C 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₉ClNO⁺ (m/z): 324.1149; found 324.1147 9-chloro-7-phenoxy-1,2,3,4-tetrahydroacridine (II-47) Yield: 95%. Yellow viscous oil. ¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₇ClNO ⁺ (m/z): 311.0891; found 311.0894 9‐chloro‐7‐(2‐methylphenoxy)‐1,2,3,4‐tetrahydroacridine (II-48) Yield: 86%. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₉ClNO⁺ (m/z): 324.1150; found 324.1149 9‐chloro‐7‐(2‐methoxyphenoxy)‐1,2,3,4‐tetrahydroacridine (II-49) Yield: 86%. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₉ClNO₂ ⁺ (m/z): 340.1098; found 340.1099 9‐chloro‐7‐(3‐methoxyphenoxy)‐1,2,3,4‐tetrahydroacridine (II-50) Yield: 87%. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₉ClNO₂ ⁺ (m/z): 340.1098; found 340.1095 9‐chloro‐7‐(4‐methylphenoxy)‐1,2,3,4‐tetrahydroacridine (II-51) Yield: 79 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): δ 7.94 (d, J = 9.1 Hz, 1H); 7.61 (d, J = 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). ¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₉ClNO⁺ (m/z): 324.1150; found 324.1143 9‐chloro‐7‐(4‐chlorophenoxy)‐1,2,3,4‐tetrahydroacridine (II-52) Yield: 59 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C 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]⁺: calculated for C₁₉H₁₆Cl₂NO⁺ (m/z): 344.0604; found 344.0602 7‐(4‐tert‐butylphenoxy)‐9‐chloro‐1,2,3,4‐tetrahydroacridine (II-53) Yield: 49 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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]⁺: calculated for C₂₃H₂₅ClNO⁺ (m/z): 366.1619; found 366.1618 9‐chloro‐7‐(3,5‐dimethylphenoxy)‐1,2,3,4‐tetrahydroacridine (II-55) Yield: 83 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C NMR (126 MHz, Chloroform-d): 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]⁺: calculated for C₂₁H₂₁ClNO⁺ (m/z): 338.1307; found 338.1304 11‐chloro‐2‐phenoxy‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline (III-47) Yield: 81 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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). ¹³C 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]⁺: calculated for C₂₀H₁₉ClNO⁺ (m/z): 324.1150; found 324.1145 11‐chloro‐2‐(2‐methoxyphenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline (III-49) Yield: 77 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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).¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₁H₂₁ClNO₂ ⁺ (m/z): 354.1255; found 354.1253 11‐chloro‐2‐(3‐methoxyphenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline (III-50) Yield: 98 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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).¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₁H₂₁ClNO₂ ⁺ (m/z): 354.1255; found 354.1255 11‐chloro‐2‐(4‐methylphenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline (III-51) Yield: 95 %. Yellow viscous oil.¹H NMR (500 MHz, Chloroform-d): 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).¹³C NMR (126 MHz, Chloroform-d): 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 (ESI⁺): [M+H]⁺: calculated for C₂₁H₂₁ClNO⁺ (m/z): 338.1307; found 338.1301 11‐chloro‐2‐(4‐chlorophenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline (III-52) Yield: 24 %. Yellow viscous oil. ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₁₈Cl₂NO⁺ (m/z): 358.0760; found 358.0754 The third step of the synthesis The intermediate compound (I-III) 47-55 (1.0 eq) was charged into 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 NH₃ gas prepared in situ. After completion of the amination reaction, the mixture was cooled to room temperature and extracted between 2M NaOH (100 mL) and DCM (3 × 100 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the reaction mixture was purified by flash chromatography using DCM/MeOH/25% aqueous NH₃ (9:1:0.1) as mobile phase. Substituted derivatives (I-III) 56-64 were obtained as free bases in yields (7-68%). Compounds (I-III) 56-64 were obtained by this procedure, the characterization of which is reported below. For biological assays, selected representative compounds were converted to hydrochloride salts. 7‐phenoxy‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine (I-56) Yield: 50 %. Brown crystalline powder. Melting point: 157.2-158.1 °C. ¹H NMR (500 MHz, DMSO- d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): δ 158.87; 157.42; 154.19; 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]⁺: calculated for C₁₈H₁₇N₂O⁺ (m/z): 277.1336; found 277.1337 7‐(2‐methoxyphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine (I-58) Yield: 21 %. Brown crystalline powder. Melting point: 185.6-186.2 °C. ¹H NMR (500 MHz, DMSO- d₆): 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, J = 5.8 Hz, 2H); 1.87 – 1.78 (m, 4H).¹³C 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]⁺: calculated for C₁₉H₁₉N₂O₂ ⁺ (m/z): 307.1442; found 307.1437 7‐(3‐methoxyphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine (I-59) Yield: 37 %. Brown crystalline powder. Melting point: 195.2-195.8 °C.¹H NMR (500 MHz, Methanol- d₄): 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). ¹³C NMR (126 MHz, Methanol-d₄): 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]⁺: calculated for C₁₉H₁₉N₂O₂ ⁺ (m/z): 307.1442; found 307.1434 7‐(4‐methylphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-60) Yield: 9 %. Black crystalline powder. Melting point: 292.7 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): 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 – 2.03.¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₁₉H₁₉N₂O⁺ (m/z): 291.1492; found 291.1512 7‐(4‐chlorophenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine hydrochloride (I-61) Yield: 36 %. Brown crystalline powder. Melting point: 281.5 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): 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); 2.0 (t, J = 7.3 Hz, 2H); 2.10 – 2.00 (m, 2H).¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₁₈H₁₆ClN₂O⁺ (m/z): 311.0946; found 311.0940 7‐(4‐tert-butylchlorophenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine (I-62) Yield: 15 %. Brown crystalline powder. Melting point: 149.5-150.2 °C (decomposition).¹H NMR (500 MHz, Methanol-d₄): 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). ¹³C NMR (126 MHz, Methanol-d₄): 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]⁺: calculated for C₂₂H₂₅N₂O⁺ (m/z): 333.1962; found 333.1961 1‐[4‐({9‐amino‐1H,2H,3H‐cyclopenta[b]quinolin‐7‐yl}oxy)phenyl]ethan‐1‐one (I-63) Yield: 15 %. Brown crystalline powder. Melting point: 162.5-166.8 °C. ¹H NMR (500 MHz, DMSO- d₆): 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).¹³C 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]⁺: calculated for C₂₀H₁₉N₂O₂ ⁺ (m/z): 319.1442; found 319.1441 7‐(3,5‐dimethylphenoxy)‐1H,2H,3H‐cyclopenta[b]quinoline‐9‐amine (I-64) Yield: 12 %. Brown crystalline powder. Melting point: 141.2-142.5°C.¹H NMR (500 MHz, Methanol- d₄): 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).¹³C NMR (126 MHz, Methanol-d₄): 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 (ESI⁺): [M+H]⁺: calculated for C₂₀H₂₁N₂O⁺ (m/z): 305.1649; found 305.1645 7‐(2‐methylphenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine (II-57) Yield: 7 %. Brown crystalline powder. Melting point: 205.8-206.3 °C.¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C 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]⁺: calculated for C₂₀H₂₁N₂O⁺ (m/z): 305.1649; found 305.1649 7‐(2‐methoxyphenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine (II-58) Yield: 21 %. Brown crystalline powder. Melting point: 144.5-145.2 °C. ¹H NMR (500 MHz, DMSO- d₆): 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). ^{1 13}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]⁺: calculated for C₂₀H₂₁N₂O₂ ⁺ (m/z): 321,1598; found 321,1596 7‐(3‐methoxyphenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine (II-59) Yield: 45 %. Brown crystalline powder. Melting point: 152.7-153.6 °C. ¹H NMR (500 MHz, DMSO- d₆) 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).¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₂₀H₂₁N₂O₂ ⁺ (m/z): 321.1598; found 321.1593 7‐(4‐methylphenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine hydrochloride (II-60) Yield: 13 %. Brown crystalline powder. Melting point: 268.5 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (126 MHz, DMSO-d₆): 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; 22.72; 22.77; 20.9; HRMS (ESI⁺): [M+H]⁺: calculated for C₂₀H₂₁N₂O⁺ (m/z): 305.1649; found 305.1649 7‐(4‐chlorophenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine hydrochloride (II-61) Yield: 58 %. Brown crystalline powder. Melting point: 296.5 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): 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 (ESI⁺): [M+H]⁺: calculated for C₁₉H₁₈ClN₂O⁺ (m/z): 325.1103; found 325.1097 7‐(4‐tert‐butylphenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine (II-62) Yield: 36 %. Brown crystalline powder. Melting point: 132.3-133.8 °C.¹H NMR (500 MHz, Methanol- d₄): 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. Hz, 2H); 2.50 (t, J = 6.1 Hz, 2H); 1.88 – 1.78 (m, 4H); 1.22 (s, 9H).¹³C NMR (126 MHz, Methanol-d₄): 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]⁺: calculated for C₂₃H₂₇N₂O⁺ (m/z): 347.2118; found 347.2114 7‐(3,5‐dimethylphenoxy)‐1,2,3,4‐tetrahydroacridine‐9‐amine (II-64) Yield: 40 %. Brown crystalline powder. Melting point: 155.2-156.4°C. ¹H NMR (500 MHz, DMSO- d₆): 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). ¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₂₁H₂₃N₂O⁺ (m/z): 319.1805; found 319.1803 2‐phenoxy‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-56) Yield: 62 %. White crystalline powder. Melting point: 292.8 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO- d₆): 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]⁺: calculated for C₂₀H₂₁N₂O⁺ (m/z): 305.1649; found 305.1643 2‐(2‐methoxyphenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine (III-58) Yield: 23 %. Brown crystalline powder. Melting point: 132.3-133.6 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): 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). ¹³C NMR (126 MHz, 500 MHz, DMSO-d₆): 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]⁺: calculated for C₂₁H₂₃N₂O₂ ⁺ (m/z): 335.1755; found 335.1755 2‐(3‐methoxyphenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine (III-59) Yield: 23 %. Brown crystalline powder. Melting point: 126.5-127.2 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): 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 (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). ¹³C NMR (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]⁺: calculated for C₂₁H₂₃N₂O₂ ⁺ (m/z): 335.1755; found 335.1755 2‐(4‐methylphenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-60) Yield: 28 %. Grey crystalline powder. Melting point: 310.7 °C (decomposition). ¹H NMR (500 MHz, DMSO-d₆): 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).¹³C NMR (126 MHz, DMSO-d₆): 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]⁺: calculated for C₂₁H₂₃N₂O⁺ (m/z): 319.1805; found 319.1798 2‐(4‐chlorophenoxy)‐6H,7H,8H,9H,10H‐cyclohepta[b]quinoline‐11‐amine hydrochloride (III-61) Yield: 51 %. Brown crystalline powder. Melting point: 298.5 °C (decomposition).¹H NMR (500 MHz, DMSO-d₆): δ 8.11 (d, J = 2.5 Hz, 1H); 7.96 (d, J = 9.1 Hz, 1H); 7.61 (dd, J = 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).¹³C 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]⁺: calculated for C₂₀H₂₀ClN₂O⁺ (m/z): 339.1259; found 339.1254 Example 4: In vitro assay: inhibition of human AChE and BChE enzymes by the compounds of the invention Selected representative compounds were assayed for their inhibition potential against human AChE (hAChE) and BChE (hBChE) enzymes. The results are shown in Table 4. In vitro activity of the compounds was determined using Ellman method, following a previously published protocol (POHANKA, M., D. JUN AND K. KUCA Improvement of acetylcholinesterase- based assay for organophosphates in way of identification by reactivators. Talanta, Oct 152008, 77(1), 451-454). Table 4. hAChE and hBChE IC₅₀ values of inhibition by selected compounds of general formula I ^a

The reported values are the average of at least three experiments. ^b The selectivity index (SI) for hAChE is expressed as the ratio hBChE IC₅₀/hAChE IC₅₀. Example 5: In vitro assay: determination of inhibitory activity against the GluN1/GluN2A and GluN1/GluN2B subtypes of NMDA receptors The inhibitory activity of the tested compounds against NMDA receptors, specifically against GluN1/GluN2A and GluN1/GluN2B, was assayed using the whole-cell patch clamp technique on HEK293 cell line expressing these NMDAR subunits according to a previously published protocol (KANIAKOVA, M., L. KLETECKOVA, K. LICHNEROVA, K. HOLUBOVA, K. SKRENKOVA, M. KORINEK, J. KRUSEK, T. SMEJKALOVA, J. KORABECNY, K. VALES, O. SOUKUP AND M. HORAK 7-Methoxyderivative of tacrine is a 'foot-in-the-door'open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo. Neuropharmacology, 2018, 140, 217-232.). The inhibitory activity was tested at a holding potential -60mV and at a holding potential +40mV. Table 5. Values of inhibitory activity against GluN1/GluN2A and GluN1/GluN2B subtypes for selected compounds of general formula I and reference tacrine compound

Example 6: In vivo effects: the effect of the tested compounds on the animal behavioral models based on glutamatergic and cholinergic dysfunction Lack of serious behavioral adverse effects of the selected compounds I-14, II-14, I-13 and I-12, which generally limit the use of many NMDA receptor antagonists, has been demonstrated on the model of prepuplse inhibition (PPI) monitoring the startle reflex of the animals. It is known that the weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong reflex-eliciting stimulus (pulse). An inhibitory effect on the PPI is typical for the class of glutamatergic antagonists and relust in psychomimetic side effects. Figure 1 shows that compounds I-14, II-14, I-13 and I-12 do not exert any harmful effect on the prepulse inhibition as demonstrated by reference NMDA receptor antagonist MK-801. In addition, to confirm the bioavailability in the brain and to elucidate beneficial effects of the tested compounds on the animal models of glutamatergic and cholinergic dysfunction, following experiments were performed. Open field: The effect on MK-801-induced hyperlocomotion To assess the effect of the selected compounds I-14, II-14, I-13 and I-12 on the behavioral effect (hyperlocomotion) induced by the noncompetitive NMDA receptor antagonist MK-801, these compounds (at the doses of 5 mg/kg) were administered together with MK-801 (0.2 mg/kg, i.p.) to rats and open field test was performed. The effect of the compounds on spontaneous locomotor activity was assessed in a black plastic square arena (80 × 80 cm), located in a separate room with defined light conditions (80 lx). The rat was placed in the center of the arena and then recorded for 10 min by a camera placed above the arena, connected to tracking software (EthoVision 14, Noldus, Netherlands). The arena was thoroughly cleaned between the animals. The dependent variable was the distance moved by the animal. The results confirmed alleviation of the MK-801-induced hyperlocomotion after application of I-14, I- 12, II-14 and I-13 (Fig 2). Morris water maze To investigate precognitive effect of the compounds I-13 and I-12 were tested at the doses of 1 and 5 mg/kg/day in rat models of cognitive deficit in the Morris water maze. Two models were used: the model induced by MK-801 (0.1 mg/kg/day) and the model of cholinergic dysfunction induced by scopolamine (2 mg/kg/day). During the first four training days, the Morris water maze procedure was performed according to (E. NEPOVIMOVA, L. SVOBODOVA, R. DOLEZAL, V. HEPNAROVA, L. JUNOVA, D. JUN, J. KORABECNY, T. KUCERA, Z. GAZOVA, K. MOTYKOVA, J. KUBACKOVA, Z. BEDNARIKOVA, J. JANOCKOVA, C. JESUS, L. CORTES, J. PINA, D. ROSTOHAR, C. SERPA, O. SOUKUP, L. AITKEN, R.E. HUGHES, K. MUSILEK, L. MUCKOVA, P. JOST, M. CHVOJKOVA, K. VALES, M. VALIS, Z. CHRIENOVA, K. CHALUPOVA AND K. KUCA Tacrine – Benzothiazoles: Novel class of potential multitarget anti-Alzheimer´s drugs dealing with cholinergic, amyloid and mitochondrial systems. Bioorg. Chem., 2021, 107, 104596) and on the fifth day, reversal test was performed. The results of Morris water maze reversal test using MK-801-induced and scopolamine-induced animal model are depicted in Fig. 3 and 4, respectively. In the MK-801 model, the results of the reversal show dose-dependent beneficial effect of the compound I-12 (fig.3). In the scopolamine model, both studied compounds I-12 and I-13 showed beneficial effect on the scopolamine-induced amnesia even in the dose of 1mg/kg (Fig.4). Another advantage are the pharmacokinetic properties of the compounds i.e.accumulation in brain as withnessed by the Table 6 describing the level of the studied representatives I-12 and II-14 in the plasma and brain respectrivelly in the two time endpoinst (15^th and 60^th minute) after intraperitoneal application in the mice model. Table 6: In vivo availability of selected compounds in the plasma and brain (mice, dose 5mg/kg), i.p.)

Claims

CLAIMS 1. Compound of general formula I,

wherein n is 1, 2 or 3, R¹ is selected from the group -CH₃; –OCH₃; -Br; -Cl; -F; phenoxy; 1-CH₃-phenoxy; 1-OCH₃-phenoxy; 2-OCH₃-phenoxy; 3-CH₃-phenoxy; 3-Cl-phenoxy; 3-C(CH₃)₃-phenoxy; 3-C(O)-CH₃-phenoxy; and 2- CH₃,4-CH₃-phenoxy; and R² is -H; -Cl; or -Br; with the proviso that - when R² is –Cl, R¹ must be -Cl; - when R² is –Br, R¹ must be –Br; - when R¹ is –OCH₃ or phenoxy, n is not 2, or a pharmaceutically acceptable salt thereof with alkali metal, ammonia or amine, or an addition salt thereof with acid. 2. Compound of general formula I according to claim 1 or a pharmaceutically acceptable salt thereof with alkali metal, ammonia or amine, or an addition salt thereof with acid, for simultaneous use as inhibitors of cholinesterases and as NMDAR antagonists. 3. Compound of general formula I according to claim 1 or a pharmaceutically acceptable salt thereof with alkali metal, ammonia or amine, or an addition salt thereof with acid, for use as a medicament. 4. Compound of general formula I according to claim 1 or a pharmaceutically acceptable salt thereof with alkali metal, ammonia or amine, or an addition salt thereof with acid, for use in the treatment of dementia or a neurodegenerative disease. 5. Compound of general formula I according to claim 1 or a pharmaceutically acceptable salt thereof with alkali metal, ammonia or amine, or an addition salt thereof with acid for use in the treatment of Alzheimer's disease or dementia with Lewy bodies, or in the treatment of vascular dementia in combination with Lewy bodies dementia, or in the treatment of vascular dementia in combination with Parkinson's or Alzheimer's disease. 6. A pharmaceutical composition containing at least one compound of general formula I according to claim 1, and at least one pharmaceutically acceptable carrier.