Compounds for the treatment of alzheimer's disease and the method of obtaining these compounds

Abstract

The present invention relates to a method (100) of synthesizing novel multi-effective urea / thiourea compounds which provide simultaneous inhibition of cholinesterase (AChE) and monoamine oxidase (MAO) enzymes known to play roles in Alzheimer's disease (AD); can interact with Ap peptides and / or P amyloid plaque; provide neuroprotective effect by reducing oxidative damage; and to the synthesized compounds and the biological activities they exhibit.

Description

[0001] DESCRIPTION

[0002] COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND THE METHOD OF OBTAINING THESE COMPOUNDS

[0003] Technical Field

[0004] The present invention relates to a method of synthesizing novel multi-effective urea / thiourea compounds which provide simultaneous inhibition of cholinesterase (AChE) and monoamine oxidase (MAO) enzymes known to play roles in Alzheimer's disease (AD); can interact with Ap peptides and / or P amyloid plaque; provide neuroprotective effect by reducing oxidative damage; and to the synthesized compounds and the biological activities they exhibit.

[0005] Background of the Invention

[0006] Alzheimer's disease is a chronic, progressive, neurodegenerative disease that develops in various parts of the central nervous system due to irreversible loss of neurons and is characterized by a decrease in cognitive functions and is the most common type of dementia that has been known since ancient times (Berchtold and Cotman, 1998; Gilman, 1997). Although there are many hypotheses about the pathophysiology of the disease, the molecular basis thereof has not been fully clarified (Smith et al., 2007). The cholinergic system (Craig et al., 2011), beta amyloid (AP) protein (Hardy and Selkoe, 2002), tau protein, oxidative stress (Su et al., 2008), increase in MAO-B level (Bolea et al., 2011; Weinreb et al., 2011; Bautista- Aguilera et al., 2014), inflammation (Holmes 2013) and toxic metal ions (Greenough et al., 2013) are the main hypotheses explaining the causes of the development and progression of AD. The revelation that AD is a multifactorial disease and the fact that the drugs used in treatment are only intended to alleviate the symptoms of the disease cause the inability to provide palliative treatment options and strengthen multiple targeted drug development strategies in the treatment of AD. Within the scope of the main treatment approaches for the disease, increasing cholinergic functions (Bajda et al., 2013), inhibiting Ap aggregate formation (Mason et al., 2003), MAO-B inhibition (Bolea et al., 2011; Weinreb et al., 2011; Bautista- Aguilera et al., 2014), curing the oxidative damage caused by free radicals (Leuner et al., 2012), preventing inflammation in the brain (Shin et al., 2012) and other approaches can be listed as multiple target points.

[0007] With the imaging of the crystal structures of AChE, which is pointed out as a target in disease etiology, and of MAO enzymes, which are thought to be possibly involved in treatment (Ta§gi and Gokhan Kelekgi 2017; Sussman et al., 1991; Kryger et al., 2000), studies on this subject have also progressively increased (Barak et al., 2005; Ta§<?i and Gokhan Kelekgi 2017). Within this context, ladostigil, which was discovered as a result of the molecular modification of the AChE inhibitor rivastigmine with the MAO-B inhibitor rasagiline, is a molecule that has reached clinical investigations.

[0008] On the other hand, the fact that the molecules that will be designed as enzyme inhibitors are peptide-based has been a prominent point in recent years since they are in the protein structure of enzymes. However, the poor in vivo stability, insufficient pharmacokinetic properties and low bioavailability of peptide -based molecules limit their widespread use. For this reason, one of the most important studies carried out in order to improve the drug properties of peptide -based molecules is the use of organic carbamate and urea derivatives containing amide and heterocyclic structures with an isosteric approach. While carbamates are compounds with amide-ester hybrid properties, and ureas are compounds with double amide bonds, their molecules are resistant to aminopeptidases that metabolize peptide-based drugs. By virtue of these properties, urea and carbamate derivatives have taken an important role in medicinal chemistry (Ghosh and Brindisi, 2015). Furthermore, it is known that the fact that biological activity is linked to the three- dimensional structures of molecules and that the observation of pharmacological activity is related to the approach of the drug molecule to the relevant target such as drug-receptor, drug-enzyme, etc. and the good compatibility thereof. The fact that the stereochemistry of the drug molecule is as important as the proteins with which the drug interacts in the occurrence of the effect shows the importance of derivatives obtained as pure enantiomers and puts these compounds ahead of their racemic forms.

[0009] On the other hand, monoamine oxidase inhibitors (MAOIs) have been used for more than forty years for the treatment of depression, and it is known that hepatotoxicity, hypertensive crises and cumulative side effects occur when taken with tyramine-containing foods and other types of drugs, and therefore their clinical use has decreased and regressed, however, that interest in these drugs has increased again in recent years. The most important reason for this is that with the development in the fields of peptide chemistry and gene technology, information on the structure and function of the MAO enzyme has increased because it has been understood that there are at least two isozymes of MAO that are called MAO-A and MAO-B and exhibit structural differences. Thus, reversible, selective compounds that do not produce hypertensive effects as a result of interaction with tyramine- containing foods have started to replace nonselective and irreversible first- generation MAOI, and this group of drugs has become up-to-date again. During investigations, while MAO-A selective inhibitors have gained importance in the treatment of depression, MAO-B inhibitors have been introduced as promising drugs in Parkinson's and Alzheimer's diseases (Olanow, 1993; Sandler et al. 1993). During the studies carried out on the subject, it has been found that different heterocyclic compounds carrying nitrogen atoms play a key role in the design of reversible and selective MAO inhibitor compounds and that oxadiazoles, tetrazoles, l,3,4-oxadiazole-3(2H)-carboxamide derivatives, 3,4-dihydroquinoline-(lH)-2- ones, piperine derivatives and oxazolidinones exhibit potent, reversible and selective MAO-B inhibitory effects (Belleau and Moran, 1962; Kneubuehler et al. 1995; Wouters et al. 1992; Ooms et al. 2003; Frederick et al. 2004; Liv et al. 2007; Sunal et al. 2007; Ke and Qian, 2008; Silverman and Ding 1993; Erdem et al. 2014). Later it was realized that the common feature of this group of substrates and inhibitors is the presence of the amino or imino group that plays a role in the interaction of the enzyme with the active site thereof (Kneubuehler et al. 1993).

[0010] Some heterocyclic compounds that have been shown to have MAO-B inhibitory effects have emerged as third generation MAO inhibitors in the 1980s. These are selectively acting inhibitors that can be used in a wider dose range, do not lose their reversibility during chronic use and show minimum side effects. The fact that the N-substituted oxazolidinone derivatives (toloxatone, simoxatone and befloxatone) have high efficacy and their structural similarity to the urea / thiourea derivatives proposed for patent suggests that the proposed compound group may also exhibit a potent MAO inhibitory effect.

[0011] It is known that thiourea and urea derivatives of various different structures exhibit MAO, choline esterase inhibitory effects and antioxidant activity.

[0012] The difficulties of currently applied treatments for progressive diseases such as AD and Parkinson's disease (PD) in providing palliative treatment shows the importance of the development of novel drugs (Sterling et al, 2002). Therefore, in the context of the multifactorial etiology of AD, researchers have turned to multiple targets through a single molecule instead of a single molecule and a single target. The fact that there are not many compounds in this subject shows the gap in this field. Furthermore, the poor in vivo stability and the low bioavailability properties of peptide- structured ones among enzyme inhibitor drug molecules show that their pharmacokinetic properties are required to be improved. The fact that most of the existing compounds are racemic compounds is insufficient in explaining the drugreceptor and drug-target relationship. For this reason, in order to overcome the above-mentioned deficiencies, there is a need for a novel compound for the treatment of Alzheimer's disease and the method of development of this compound.

[0013] The United States patent document no. US2014357599, an application included in the state of the art, discloses a method for the treatment of Alzheimer's disease. In the said invention mentioned in the United States patent document no. US2014357599, it is believed that the novel compounds thereof are acting on the enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and that the downstream inhibition of NF-kB is the result of the lowering of cellular concentrations of nicotinamide adenine dinucleotide (NAD). The compounds of the invention is believed to be particularly useful for down-regulating NAD via inhibition of NAMPRT, and such compounds are therefore particularly useful for treating diseases in which activation of NF-KB is implicated. Such methods are useful in the treatment of a variety of diseases including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and CPOD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet induced skin damage; autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telangiectasia.

[0014] Summary of the Invention

[0015] The objective of the present invention is to obtain the novel multi-effective urea / thiourea compounds which provide simultaneous inhibition of cholinesterase and monoamine oxidase enzymes known to play roles in Alzheimer's disease; can interact with Ap peptides and / or p amyloid plaque; provide neuroprotective effect by reducing oxidative damage, and the biological efficacies they exhibit.

[0016] Another objective of the present invention is the synthesis of compounds by the method of synthesizing amide bond-containing urea / thiourea derivatives, which are advantageous compared to amide-structured peptide molecules with poor in vivo stability, insufficient pharmacokinetic properties and low bioavailability.

[0017] Detailed Description of the Invention

[0018] “Compounds for the Treatment of Alzheimer's Disease and The Method of Obtaining These Compounds” realized to fulfd the objectives of the present invention is shown in the figures attached, in which:

[0019] Figure 1 is a flowchart of the inventive method.

[0020] Figure 2 shows the urea / thiourea compound structures obtained by Formula

[0021] (I).

[0022] Figure 3 shows the urea / thiourea compound structures obtained by Formula

[0023] (II).

[0024] The present invention is urea / thiourea compounds which are used in the treatment of Alzheimer's and Parkinson's disease that are progressive diseases and in which only symptomatic improvement is possible; provide simultaneous inhibition of cholinesterase and monoamine oxidase enzymes known to play roles in Alzheimer's disease; prevent the Ap fibril formation; provide neuroprotective effect by reducing oxidative damage; exhibit antioxidant effect; have formula (I) and formula (II); comprise two groups of compounds as

[0025]

[0026] R S

[0027] Formula (I) 1 : Phenyl or naphthyl

[0028] 2: -O or -S

[0029] 3: o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m- chlorophenyl, p-chlorophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl

[0030] Formula (II) 1: o-methoxyphenyl, m- methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m- chlorophenyl, p-chlorophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, naphthyl 2: -O or -S. Urea / thiourea compounds of the inventive formula (I) are (7?)-l-(2- methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea, (S)-l-(2-methoxyphenyl)- 3-(l-(naphthalen-l-yl)ethyl)thiourea, (7?)-l-(2-methoxyphenyl)-3-(l-(naphthalen- l-yl)ethyl)urea, (S)-l-(2-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l- (3-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl), (S)-l-(3-methoxyphenyl)-3-(l- (naphthalen-l-yl)ethyl)thiourea, (7?)-l-(4-methoxyphenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (S)-l-(4-methoxyphenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (7?)-l-(4-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea, (5)-l-(4- methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(2-fluorophenyl)-3-(l- (naphthalen-l-yl)ethyl)thiourea, (S)-l-(2-fluorophenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (7?)-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea, (S)-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea, (7?)-l-(3- fluorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)urea, (5)- 1 -(3-fluorophenyl)-3-( 1 -

[0031] (naphthalen- 1 -yl)ethyl)urea, (R)- 1 -(4-fluorophenyl)-3-( 1 -(naphthalen- 1 - yl)ethyl)thiourea, (S)-l-(4-fluorophenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (R)- 1 -(4-fluorophenyl)-3-( 1 -(naphthalen- 1 -yl)ethyl)urea, (5)- 1 -(4-fluorophenyl)- 3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(3-chlorophenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (S)-l-(3-chlorophenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (R)- 1 -(3-chlorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)urea, (5)- 1 -(3-chlorophenyl)- 3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(4-chlorophenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (S)-l-(4-chlorophenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (R)- 1 -(4-chlorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)urea , (5)- 1 -(4-chlorophenyl)- 3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(2-methoxyphenyl)-3-(l- phenylethyl) thiourea, (5)- 1 -(2-methoxyphenyl)-3 -(1 -phenylethyl)thiourea, (R)- 1 - (2-fluorophenyl)-3-(l-phenylethyl)thiourea, (S)-l-(2-fluorophenyl)-3-(l- phenylethyl)thiourea, ( / ?)- l-(3-fluorophenyl)-3-(l-phenylethyl)thiourea, (5)-l-(3- fluorophenyl)-3 -(1 -phenylethyl)thiourea.

[0032] Urea / thiourea compounds of the inventive formula (II) are (7?)-l-(l- benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)thiourea, (S')-l-(l-benzylpyrrolidine- 3-yl)-3-(2-methoxyphenyl)thiourea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(3- methoxyphenyl)thiourea , (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3- methoxyphenyl)thiourea, ( / )- 1 -( l-benzylpyrrolidine-3-yl)-3-(4- methoxyphenyl)thiourea , ( )- l -( l -bcnzylpyrrolidinc-3-yl)-3-(4- methoxyphenyl)thiourea, ( / )- 1 -( l-benzylpyrrolidine-3-yl)-3-(2- methoxyphenyl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)urea,

[0033] (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)urea, (S)-l-(l- benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)urea, (7?)-l-(l -benzy lpyrrolidine-3 - yl)-3-(4-methoxyphenyl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4- methoxyphenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)thiourea,

[0034] (5)- 1 -( 1 -benzylpyrrolidine-3-yl)-3 -(2-fluorophenyl)thiourea, (7?)- 1 -( 1 - benzy Ipyrrolidine- 3 - y 1) - 3 - (3 -fluoropheny l)thiourea, (5)- 1 -( 1 -benzy Ipyrrolidine- 3 - yl)-3-(3-fluorophenyl)thiourea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4- fluorophenyl)thiourea, (5)- 1-(1 -benzy lpyrrolidine-3-yl)-3-(4- fluorophenyl)thiourea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)urea, (5)- 1 -( 1 -benzy lpyrrolidine-3-yl)-3 -(2-fluorophenyl)urea, (7?) - 1 - ( 1 - benzylpyrrolidine-3-yl)-3-(3-fluorophenyl)urea, (5)- 1-(1 -benzy lpyrrolidine-3 -y 1)- 3-(3-fluorophenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-fluorophenyl)urea, (5)- 1 -( 1 -benzy lpyrrolidine-3-yl)-3 -(4-fluorophenyl)urea, (7?) - 1 - ( 1 - benzylpyrrolidine-3-yl)-3-(2-chlorophenyl)thiourea, (S)-l-(l -benzy lpyrrolidine-3 - yl)-3-(2-chlorophenyl)thiourea, (R)- 1 -( 1 -benzylpyrrolidine-3-yl)-3-(3 chlorophenyl)thiourea, (5)- 1 -( 1 -benzy lpyrrolidine-3 -yl)-3-(3 chlorophenyl)thiourea, (7?)- 1 -( 1 -benzy lpyrrolidine-3 -yl)-3-(4 chlorophenyl)thiourea, (5)- 1 -( 1 -benzy lpyrrolidine-3 -yl)-3-(4 chloropheny l)thiourea, (7?) - 1 - ( 1 -benzy Ipyrrolidine- 3 -y 1) - 3 - (2-chloropheny l)urea, (5)- 1 -( 1 -benzy lpyrrolidine-3-yl)-3 -(2-chlorophenyl)urea, (7?)- 1 -( 1 - benzylpyrrolidine-3-yl)-3-(3-chlorophenyl)urea, (5)- 1-(1 -benzy lpyrrolidine-3 -y 1)- 3-(3-chlorophenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-chlorophenyl)urea, (5)- 1 -( 1 -benzy lpyrrolidine-3-yl)-3 -(4-chlorophenyl)urea, (7?)- 1 -( 1 - benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)thiourea, (S)-l-(l -benzy lpyrrolidine-3- yl)-3-(naphthalen- 1 -yl)thiourea, (R)- 1 -( 1 -benzylpyrrolidine-3-yl)-3-(naphthalen- 1 - yl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)urea.

[0035] Urea / thiourea compounds of formula (I) and (II) provide simultaneous inhibition of cholinesterase and monoamine oxidase enzymes known to play roles in Alzheimer's disease; prevent the Ap fibril formation; provide neuroprotective effect by reducing oxidative damage; and exhibits antioxidant effect. Urea / thiourea compounds of formula (I) and (II) are also used in the treatment of diseases involving dementia, depression, anxiety, cancer, bacterial infection, convulsions, HIV, diabetes and cognitive disorder. The inventive urea / thiourea compounds are pharmaceutical compositions comprising any compound of Formula (I) and (II). The inventive urea / thiourea compounds are medicaments comprising any compound of Formula (I) and (II).

[0036] The reaction performed for the urea / thiourea compounds obtained by Formula (I) is shown by equation (1) and the reaction performed for the urea / thiourea compounds obtained by Formula (II) is shown by equation (2): or phenyl

[0037] Y= O, S W= o-, m-, p-CH3; OCH3, F, Cl 39-78

[0038] (2) 100. Method

[0039] The method (100) used to synthesize the inventive urea / thiourea compounds comprises the steps of synthesizing urea / thiourea compounds by mixing (R / S) 1- phenyl(naphthyl)ethyl amine or (3 / ? / 3.S')- l-bcnzyl-3-aminopyrrolidinc and phenyl / naphthyl isocyanate (isothiocyanate) in dichloromethane (101); and purifying synthesized compounds (102).

[0040] In the step of synthesizing urea / thiourea compounds by mixing (R / S) 1- phenyl(naphthyl)ethyl amine or (3 / ? / 3.S')- l -bcnzyl-3-aminopyrrolidinc and phenyl / naphthyl isocyanate (isothiocyanate) in dichloromethane (101) of the inventive method (100), urea / thiourea derivative compounds are synthesized by mixing equivalent moles of (R / S) l-phenyl(naphthyl)ethyl amine or (3A73.S')-1 - benzyl- 3 -aminopyrrolidine and phenyl / naphthyl isothiocyanate in dichloromethane for 1-5 hours at room temperature.

[0041] In the step of purifying synthesized compounds (102) of the inventive method (100), the reaction is monitored by thin-layer chromatography when urea / thiourea compounds are being synthesized and the synthesized compounds are purified by crystallization from ethanol or precipitation from ethyl acetate / n-hexane mixture.

[0042] In the inventive method (100), molecular modeling is performed before the compounds are synthesized. For this purpose, the molecular docking method, which is the most widely used structure-based design method in rational drug design, was utilized. Docking calculations were carried out by AutodockVina (Trott and Olson, 2010) program. In preliminary studies carried out for the preparation of enzyme and ligand structures for docking, high-resolution x-ray crystal structures of MAO-A (PDB code: 2Z5X) and MAO-B (PDB code: 2XFN), human AChE (PDB code: 4M0E) enzymes required for docking were downloaded from the protein data bank in PDB format. After the ligands and water molecules present in the crystal structure in a complex state with the enzyme were deleted and enzyme was cleaned, the enzyme with empty active site was saved as pdb. This file was opened in AutodockTools (Morris et al., 2009) and the structure thereof was prepared for docking process and converted into pdbqt format. The most stable conformation was selected by performing conformation scanning of the compounds with Spartan 16 by semiempirical PM6 method (Stewart, 2007) and optimized by M06- 2X / 6-31G(d,p) method (Zhao and Truhlar 2008) in Gaussian09 program. Docking and preliminary evaluation were carried out by using the AutodockVina program (Trott and Olson, 2010) using the pdbqt files of the enzymes and ligands. Each enzyme was first docked with inhibitors in their crystal structures and the parameters that enable the correct docking pose (RMSD<2) to be obtained were determined. The ligands designed in the study were also docked by using the same parameters. Flexible docking was repeated at least 3 times for each ligand. As a result of the calculations, different conformations in which the ligand can bind to the enzyme and the Gibbs free binding energies (AG) and inhibition constants (Ki) belonging to each of them were obtained. For each ligand, the conformations that bind with the highest affinity were selected and the enzyme-ligand interactions and binding mechanism were examined with AutodockTools and Discovery Studio programs. In the conducted preliminary feasibility trials, it was found that all of the docked compounds exhibited the targeted inhibition effects. Most of the ligands have strong binding affinities to both MAO-B and AChE enzymes.

[0043] Furthermore, biological activity evaluations were carried out for the inventive urea / thiourea compounds. Firstly, the cholinesterase (AChE) inhibitory activity assay of the compounds was carried out. The inhibitory effects of the compounds on AChE and BuChE enzymes were assayed by using the Ellman method (Ellman et al., 1961). The method is based on the principle of reacting thiocholine released from acetylcholine or butyrylcholine by the effect of AChE and BuChE enzymes with DTNB reagent and measuring the absorbance of 5-thio-2-nitrobenzoate ion. Activity measurements were carried out at 250°C, by using 0.5 mM butyrylthiocholine or acetylthiocholine as substrate and in a 100 mM 3-(N- morpholino)-propanesulfonic acid (pH 8.0) medium comprising 0.125 mM DTNB. Reactions were initiated by the addition of enzyme and the absorbance increase at 412 nm was monitored on a Peltier equipped Shimadzu 1601 PC spectrophotometer. Donepezil was used as a reference compound for comparison of the experimental findings (Eyer et al., 2003).

[0044] The inhibitory activity assay of the compounds on human MAO isoforms was carried out. The activity of human MAO isoforms was assayed by using p-tyramine as substrate. The inhibitory effects of the synthesized compounds on hMAO isoforms were examined by using recombinant human MAO-A and -B (hMAO-A and -B) isoforms. MAO activity was assayed with Amplex Red MAO assay kit (Molecular Probes, USA). First, the specific enzyme activities of commercial isoforms were assayed. The MAO activity assay method to be used allows continuous measurement (kinetics) of MAO activity. H2O2 formation catalyzed by MAO isoforms was detected by using 10-acetyl-3,7-dihydroxyphenoxazine (Amplex®-Red reagent) which can form fluorescent resorufin by reacting with H2O2 in the presence of non-fluorescent, highly sensitive horseradish peroxidase. The resorufin formed as a result of the reaction is stable. P-thyramine was used as substrate. Chlorgilin and pargyline, which are specific inhibitors of MAO-A and - B, were used for the activity assay of isoforms. Recombinant enzymes were diluted in reaction buffer (pH 7.4); specific inhibitors (chlorgilin and pargyline) were added to a 100 pL enzyme solution at a concentration of 0.5 mM and incubated at room temperature for 30 minutes. The positive control solution was prepared by dilution of a 20 mM H2O2 working solution with reaction buffer such that the final concentration was 10 pM. The negative control was the reaction buffer without H2O2. The reaction was initiated by adding a 100 pL Amplex Red reagent (400 / HRP / substrate working solution) to the wells containing sample and controls and the mixtures were incubated at room temperature for 30 minutes. Kinetic measurements were carried out by monitoring fluorescence at 530 nm excitation and 590 nm emission wavelengths. Selectivity index (SI) was calculated as (Ki)(MAO-A) / Ki(MAO-B). As the SI value decreases, the inhibitory effect of the compounds against the hMAO-A isoform increases; as the SI value increases, the inhibitory effect of the compounds against the hMAO-B isoform increases.

[0045] Kinetic studies were also carried out for the obtained compounds. The synthesized substances were dissolved in DMSO such that their maximum concentration was 1% and used in the appropriate concentration range (0.001 pM-5.00 mM). Selegiline (selective and irreversible MAO-B inhibitor), lazabemide (selective and reversible MAO-B inhibitor) and moclobemide (selective and reversible MAO-A inhibitor) were also used in DMSO in the appropriate concentration range (0.001 pM-5.00 mM). The type of inhibition was determined by Line weaver-Burk plotting and IC50 and Ki values were calculated. Protein content was assayed by SIGMA Total Protein kit, Micro TP0100 (Bradford, 1976).

[0046] Reversibility study was carried out for the obtained compounds. The reversibility of the inhibitory effects of the synthesized compounds on hMAO isoforms was assayed by dialysis method (Chimenti, 2010). Recombinant enzymes were prepared in potassium phosphate buffer (0.05 M, pH 7.4, 1% DMSO containing 5% sucrose) at a concentration 5 times their Ki values and incubated at 37°C for 15 minutes. Known inhibitors (selegiline, lazabemide, moclobemide) were also prepared by this method and incubated. These mixtures were then taken into dialysis bags of 25X16 mm; 12000 mol. weight and left to dialysis for 24 hours in dialysis buffer (100 mM potassium phosphate, pH 7.4, 5% sucrose) at 4°C; dialysis was repeated 2 times. The remaining MAO activity after dialysis was measured.

[0047] The interaction assay of the obtained compounds with beta amyloid fibrils was carried out. For the preparation of amyloid fibrils, a 500 pM Ap (1-40) peptide was dissolved in 0.02% cold ammonium solution and vortexed. 20pL out of lOOpL was taken for incubation for the preparation of fibrils. The rest was stored as fresh Ap (1-40) at -80°C. A 500 pM Ap (1-42) was dissolved in 0.02% cold ammonium solution and vortexed briefly. 20pL of the lOOpL was taken for incubation for the preparation of fibrils. The rest was stored as fresh Ap (1-42) at -80°C. For Ap (1- 40) fibril preparation, a 2400 pL reaction mixture was prepared with 50 pM fresh Ap (1-40), 100 mM NaCl, 50 mM phosphate buffer with pH 7.5. The formation of fibrils was detected by ThT fluorescence measurement. For Ap fibril inhibition, 50 pM of the prepared P amyloid fibril (1-40) or (1-42) was incubated with various concentrations of the synthesized compounds in 500 pL reaction medium containing 100 mM NaCl, 50 mM phosphate buffer pH=7.5 at 37°C. Then, the ThT fluorescence intensity was measured by taking samples at certain time points. The decrease in spectrum values showed that the fibril formation in the medium was inhibited by the compounds (Tanzi 2005, Kayed, 2003, Baysal et al., 2017).

[0048] In vitro antioxidant activity assay was carried out for the obtained compounds. DPPH free radical scavenging activity method used for this purpose is a method based on measuring the scavenging effects of antioxidants on DPPH (1,1-diphenyl- 2-picrylhydrazyl) radical, a stable organic nitrogen radical. According to the activity protocol, 4 mL of DPPH solution was added to the prepared test compound solutions. A 1 mL of ethanol was used as control. After incubation at room temperature in the dark for 30 minutes, their absorbance was measured at 517 nm. The absorbance values of the samples were evaluated against the control (Sanchez- Moreno et al., 1998). It is a method based on measuring the scavenging effects of antioxidants on DPPH (l,l-diphenyl-2-picrylhydrazyl) radical, a stable organic nitrogen radical. DPPH test was performed according to the method of Fukumoto and Mazza (Fukumoto and Mazza 2000) with some modifications as follows. The experiments were performed in 96-well microplates. DPPH was used as an indicator of free radical scavenging activity. The compounds were mixed at various concentrations (20 pL) with a 150 pM DPPH (180 pL) and incubated for 30 minutes at room temperature in the dark. Absorbance was measured at 520 nm by using a microplate reader. Radical scavenging activity was given as IC50. Trolox solution was used as standard. In DPPH experiment, the purple-colored DPPH solution is reduced to diphenylpicryl hydrazine, the yellow-colored product, upon adding compounds at different concentrations (Moniruzzaman et al., 2015). In the CUPRAC antioxidant assay method carried out for the compounds, the copper (II) ion reducing capacity of the compounds was assayed by using the CUPRAC test kit. This kit is based on the Apak method (Apak et al, 2004). By using Cu(II)- neocuproin (Nc) reagent, a chromogenic oxidant, the capacity of antioxidant- active compounds to reduce copper ion is measured. Trolox is used as a standard. Phenolic hydroxyls transform into quinone structures by the CUPRAC redox reaction, and the Cu(I)-Nc chelate formed as a result of this redox reaction gives maximum absorbance at 450 nm. The resulting color is the result of a load transfer in the metal— digand direction. The Cu(I)-Nc chelate complex has a more uniform tetrahedral structure and its molecular strain is reduced and stabilized compared to the Cu(II)-Nc complex. Since the stability constants of the 1:2 complexes given by Cu(I) and Cu(II) ions with the Nc ligand are respectively of the order of 1019 and 1012, the standard reduction potential of Cu(II)-Cu(I) increases from 0.17 V (in the presence of Nc) to about 0.60 V as a result of the selective stabilization of Cu(I) with respect to Cu(II), which enables the Cu(II)-Nc reagent to oxidize biologically important antioxidants and most polyphenolic compounds with efficacy. IC50 (50% inhibiting concentration) values are defined as the concentration of the substance that reduces 50% of the initial CUPRAC absorbance value of the system.

[0049] Inhibition %= 100 [ (A0 - A] / A0)]

[0050] Inhibition% is plotted against inhibitor concentration.

[0051] The superoxide anion scavenging capacity of the compounds was assayed by using Superoxide Anion Scavenging Capacity Assay Kit (BioSource Cat no: MBS9718966). In this colorimetric assay, superoxide anion is formed by a reaction catalyzed by xanthine oxidase (XO). 02 forms a water-soluble formazan compound by reacting with the tetrazolium salt WST-8 dye. This compound gives an absorbance at 450 nm. Cytotoxicity test (XTT analysis) was also performed for the compounds. The possible cytotoxic effects of the synthesized compounds were carried out through the assay of their effects on the proliferation of HepG2 cell line by using XTT based cell proliferation kit (Biological Industries, USA), and applying the protocol of the kit. The basis of the assay relies on the conversion of XTT compound (2,3-Bis(2- methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbox-anilide) of metabolically active cells into the orange-colored formazan and on the spectrophotometric measurement of this compound. Approximately 4x 104 -6x 104 cells were seeded in each well of 96-well cell culture plates with suitable growth medium. After the cells were treated in accordance with the plate design, they were incubated at 37°C in a CO2 incubator for 6, 12, 24, 48 hours. At the end of the incubation period, a 50 pL XTT solution was added per well and the cells were incubated again at 37°C for 2-4 hours. After incubation, the plate was read at 450 nm in a plate reader. Results were standardized by using control group values. XTT experiment was carried out as n=3 minimum.

[0052] In vitro blood brain barrier permeability test (PAMPA-BBB) was carried out for the inventive urea / thiourea compounds. In order for compounds / drugs designed for the central nervous system to reach their therapeutic targets, they must cross the blood brain barrier (BBB). The ability of some of the selected derivatives to cross the BBB was assayed by using PAMPA-BBB (Parallel artificial membrane blood brain barrier permeability test). Drugs (Testosterone, Verapamil, P-estradiol, Progesterone, Corticosterone, Piroxicam, Hydrocortisone, Lomefloxacin, Dopamine) used as standard in the method and porcine brain lipid (PBL) were supplied from SIGMA-ALDRICH (Germany); donor and acceptor microplates were supplied from Millipore (USA). In summary, compounds were dissolved in DMSO (100 mg / mL), diluted in PBS / EtOH (7:3) and added to donor plates. The acceptor plate was placed on top and incubated at 250°C for 16 hours. The donor plate was removed and the compound concentrations in the acceptor plate wells were measured in a UV plate reader (Di et al., 2003). The penetration ability of the compounds into the BBB was evaluated as follows:

[0053] CNS+ (very good BBB penetration): Pe (10-6 cm s-1) >4.00

[0054] CNS± (very poor BBB penetration): Pe (10-6 cm s-1) 4.00-2.00.

[0055] CNS- (poor BBB penetration): Pe (10-6 cm s-1) <2.00

[0056] By means of the said invention, it is enabled to design multi-targeted molecules with antioxidant effect which inhibits both ChE / MAO-B enzymes for the treatment of Alzheimer's and Parkinson's disease that are progressive diseases and in which only symptomatic improvement is possible, and which prevents Ap fibril formation; to make amide bond-containing urea / thiourea derivatives advantageous over amide- structured peptide molecules with poor in vivo stability, insufficient pharmacokinetic properties and low bioavailability; to demonstrate the efficacy of designed molecules at target points by molecular docking studies; to successfully synthesize urea and thiourea derivatives; to make the synthesis of molecules easy to apply; to make the synthesis of the synthesized urea / thiourea derivatives stereospecific; to explain the three-dimensional drug-receptor interaction structures with the separately obtained R / S enantiomers; and to have high efficacy compounds against enzymes at target points.

[0057] Spectral data of the inventive urea / thiourea compounds are as follows:

[0058] Compound 1R: R-l-(2-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0059] [a]26360 = (-) 440o (0.1 g / 100 mL acetone). Yield: 46%. Melting Point: 74-75 °C. 1HNMR (400 MHz, DMSO): 5 8.95 (s, 1H, NH), 8.54 (d, 1H, NH, J=7.2 Hz), 8.20 (d, 1H, Ar, J=8.2 Hz), 8.13 (d, 1H, Ar, J=8.0 Hz), 7.97 (d, 1H, Ar, J=8.0 Hz), 7.89 (d, 1H, Ar, J=8.0 Hz), 7.67-7.50 (m, 4H, Ar), 7.09-6.86 (m, 3H, Ar), 6.88 (t, 1H, CH, J=6.8 Hz), 3.76 (s, 3H, OCH3), 1.61 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 179.6, 151.0, 139.6, 133.8, 131.2, 129.0, 128.6, 128.3, 127.0,

[0060] 125.9, 125.6, 123.9, 123.0, 119.8, 111.74, 55.8, 48.7, 20.7 ppm. HRMS (TOF MS ES+): Calculated C20H20N20S: 337.1375; Found 337.1377.

[0061] Compound 2S: S-l-(2-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0062] [a]26360 = (+) 440o (0.1 g / 100 mL acetone). Yield: 49%. Melting Point: 74-75 °C. 1H NMR (400 MHz, DMSO 5 8.95 (s, 1H, NH), 8.54 (d, 1H, NH, J=7.2 Hz), 8.20 (d, 1H, Ar, J=8.2 Hz), 8.13 (d, 1H, Ar, J=8.0 Hz), 7.97 (d, 1H, Ar, J=8.0 Hz), 7.89 (d, 1H, Ar, J=8.0 Hz), 7.67-7.50 (m, 4H, Ar), 7.09-6.86 (m, 3H, Ar), 6.88 (t, 1H, CH, J=6.8 Hz), 3.76 (s, 3H, OCH3), 1.61 (d, 3H, CH3, J=6.8 Hz) ppm,13C NMR (100 MHz, DMSO): 5 179.6, 151.0, 139.6, 133.8, 131.2, 129.0, 128.6, 128.3, 127.0,

[0063] 125.9, 125.6, 123.9, 123.0, 119.8, 111.74, 55.8, 48.7, 20.7 ppm. HRMS (TOF MS ES+): Calculated C20H20N20S: 337.1375; Found 337.1377.

[0064] Compound 3R R-l-(2-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0065] [a]26360 = (-) 240o (0.1 g / 100 mL acetone). Yield: 74%. Melting Point: 212-214 °C. 1H NMR (400 MHz, DMSO): 5 8.17 (d, 1H, NH, J=8.0 Hz), 8.09 (dd, 1H, Ar, J=1.8 Hz,J=7.6 Hz), 8.00 (s, 1H, NH), 7,97 (d, 1H, Ar, J=8.0 Hz), 7.85 (d, 1H, Ar J=8.0 Hz), 7.64-43 (m, 5H, Ar), 6.95 (dd, 1H, Ar J=1.4 Hz, J=8.0 Hz), 6.88-6.79 (m, 2H, Ar), 5.63 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 3.82 (s, 3H, OCH3), 1.53 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 154.6, 147.5, 141.3, 133.8, 130.9, 129.7, 129.2, 127.7, 126.7, 125.9, 123.4, 120.5, 117.6, 111.2, 55.8,

[0066] 44.9, 22.5 ppm. HRMS (TOF MS ES+): Calculated C20H20N202: 321.1603; Found 321.1603.

[0067] Compound 46: S-l-(2-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0068] [a]26360 = (+) 240o (0.1 g / 100 mL acetone). Yield: 71%. Melting Point: 212-214 °C. 1H NMR (400 MHz, DMSO): 5 8.17 (d, 1H, NH, J=8.0 Hz), 8.09 (dd, 1H, Ar, J=1.8 Hz,J=7.6 Hz), 8.00 (s, 1H, NH), 7,97 (d, 1H, Ar, J=8.0 Hz), 7.85 (d, 1H, Ar J=8.0 Hz), 7.64-43 (m, 5H, Ar), 6.95 (dd, 1H, Ar J=1.4 Hz, J=8.0 Hz), 6.88-6.79 (m, 2H, Ar), 5.63 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 3.82 (s, 3H, OCH3), 1.53 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 154.6, 147.5, 141.3, 133.8, 130.9, 129.7, 129.2, 127.7, 126.7, 125.9, 123.4, 120.5, 117.6, 111.2, 55.8, 44.9, 22.5 ppm. HRMS (TOF MS ES+): Calculated C20H20N202: 321.1603; Found 321.1622.

[0069] Compound 5R: R-l-(3-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0070] [a]26360 = (-) 440o (0.1 g / 100 mL acetone). Yield: 88%. Melting Point: 152-153 °C. 1H NMR (400 MHz, DMSO): 5 9.48 (s, 1H, NH), 8.24 (d, 1H, NH, J=7.6 Hz), 8.20 (d, 1H, Ar, J=8.4 Hz), 7.97 (d, 1H, Ar, J=8.0 Hz), 7.88 (d, 1H, Ar, J=8.0 Hz), 7.62-7.16 (m, 6H, Ar), 6.92 (d, 1H, Ar, J=8.0 Hz), 6.62 (dd, 1H, Ar, J=2.2 Hz, J=8.0 Hz), 5.63 (t, 1H, CH, J=6.8 Hz), 3.56 (s, 3H, OCH3), 1.63 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 179.6, 159.8, 147.9, 139.3, 134.0, 131.3, 129.8, 129.0, 128.1, 126.8, 126.2, 125.9, 123.9, 123.5, 114.8, 109.9, 108.0, 55.4, 49.3, 20.6 ppm. HRMS (TOF MS ES+): Calculated C20H20N20S: 335.1218; Found 335.1215.

[0071] Compound 6S: S-l-(3-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0072] [a]26360 = (+) 440o (0.1 g / 100 mL acetone). Yield: 74%. Melting Point: 152-153 °C. 1H NMR (400 MHz, DMSO): 5 9.48 (s, 1H, NH), 8.24 (d, 1H, NH, J=7.6 Hz), 8.20 (d, 1H, Ar, J=8.4 Hz), 7.97 (d, 1H, Ar, J=8.0 Hz), 7.88 (d, 1H, Ar, J=8.0 Hz), 7.62-7.16 (m, 6H, Ar), 6.92 (d, 1H, Ar, J=8.0 Hz), 6.62 (dd, 1H, Ar, J=2.2 Hz, J=8.0 Hz), 5.63 (t, 1H, CH, J=6.8 Hz), 3.56 (s, 3H, OCH3), 1.63 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 179.6, 159.8, 147.9, 139.3, 134.0, 131.3, 129.8, 129.0, 128.1, 126.8, 126.2, 125.9, 123.9, 123.5, 114.8, 109.9, 108.0, 55.4, 49.3, 20.6 ppm. HRMS (TOF MS ES+): Calculated C20H20N20S: 335.1218; Found 335.1215.

[0073] Compound 7R: 7?-l-(4-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0074] [a]26360 = (-) 540o (0.1 g / 100 mL acetone). Yield: 67%. Melting Point: 137-138 °C. 1H NMR (400 MHz, DMSO): 5 9.25 (s, 1H, NH), 8.21 (d, 1H, NH, J=8.2 Hz), 7.99 (br, 1H, Ar), 7,97 (d, 1H, Ar, J=8.0 Hz), 7.87 (d, 1H, Ar, J=8.0 Hz), 7.65-7.42 (m, 4H, Ar), 7.29 (d, 2H, Ar, J=8.0 Hz), 6.87 (d, 2H, Ar, J=8.2 Hz), 6.29 (br, 1H, CH), 3.73 (s, 3H, OCH3), 1.61 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.4, 156.7, 139.8, 133.9, 132.5, 131.1, 129.1, 127.9, 126.1, 125.8, 123.8, 123.0, 114.1, 55.4, 49.3, 21.1 ppm. HRMS (TOF MS ES+): Calculated C20H20N20S: 335.1218; Found 335.1218.

[0075] Compound 85: 5-l-(4-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0076] [a]26360 = (+) 540o (0.1 g / 100 mL acetone). Yield: 86%. Melting Point: 137-138 °C. 1H NMR (400 MHz, DMSO): 5 9.25 (s, 1H, NH), 8.21 (d, 1H, NH, J=8.2 Hz), 7.99 (br, 1H, Ar), 7,97 (d, 1H, Ar, J=8.0 Hz), 7.87 (d, 1H, Ar, J=8.0 Hz), 7.65-7.42 (m, 4H, Ar), 7.29 (d, 2H, Ar, J=8.0 Hz), 6.87 (d, 2H, Ar, J=8.2 Hz), 6.29 (br, 1H, CH), 3.73 (s, 3H, OCH3), 1.61 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 5 180.4, 156.7, 139.8, 133.9, 132.5, 131.1, 129.1, 127.9, 126.1, 125.8, 123.8, 123.0, 114.1, 55.4, 49.3, 21.1 ppm. HRMS (TOF MS ES+): Calculated C20H20N20S: 335.1218; Found 335.1191.

[0077] Compound 9R: R-l-(4-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0078] [a]26360 = (-) 140o (0.1 g / 100 mL acetone). Yield: 82%. Melting Point: 226-227 °C. 1H NMR (400 MHz, DMSO): 5 8.21 (s, 1H, NH), 8.18 (d, 1H, Ar, J=8.4 Hz), 7.96 (d, 1H, Ar, J=7.8 Hz), 7,84 (d, 1H, J=8 Hz), 7.67-7.47 (m, 4H, Ar), 7.29 (d, 2H, Ar, J=8.4 Hz), 6.81 (d, 2H, NH, J=8.4 Hz), 6.66 (d, 1H, Ar, J=8.0 Hz), 5.64 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 3.69 (s, 3H, OCH3), 1.54 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 155.0, 154.2, 141.2, 134.0, 130.7, 128.9, 128.0, 126.6, 125.8, 123.26, 122.3, 119.7, 114.4, 55.4, 45.2, 22.7 ppm. HRMS (TOF MS ES+): Calculated C20H20N202: 321.1603; Found 321.1611.

[0079] Compound 10S: S- l-(4-methoxyphenyl)-3-(l -(naphthalen- 1 -yl)ethyl)urea

[0080] [a]26360 = (+) 140o (0.1 g / 100 mL acetone). Yield: 91%. Melting Point: 226-227 °C. 1H NMR (400 MHz, DMSO): 5 8.21 (s, 1H, NH), 8.18 (d, 1H, Ar, J=8.4 Hz), 7.96 (d, 1H, Ar, J=7.8 Hz), 7,84 (d, 1H, J=8 Hz), 7.67-7.47 (m, 4H, Ar), 7.29 (d, 2H, Ar, J=8.4 Hz), 6.81 (d, 2H, NH, J=8.4 Hz), 6.66 (d, 1H, Ar, J=8.0 Hz), 5.64 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 3.69 (s, 3H, OCH3), 1.54 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 155.0, 154.2, 141.2, 134.0, 130.7, 128.9, 128.0, 126.6, 125.8, 123.26, 122.3, 119.7, 114.4, 55.4, 45.2, 22.7 ppm. HRMS (TOF MS ES+): Calculated C20H20N202: 321.1603; Found 321.1610.

[0081] Compound 11R: R-l-(2-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea [a]26360 = (+) 40o (0.1 g / 100 mL acetone). Yield: 65%. Melting Point: 143-144 °C. 1H NMR (400 MHz, DMSO): 5 9.13 (s, 1H, NH), 8.50 (d, 1H, NH, J=6.0 Hz), 8.18 (d, 1H, Ar, J = 8.4 Hz), 7.97 (d, 1H, Ar, J=8.0 Hz), 7.89 (d, 2H, Ar, J=8.0 Hz), 7.68 - 7.05 (m, 7H, Ar), 6.26 (br, 1H, CH), 1.62 (d, 3H, CH3, J=6.8 Hz) ppm. 13C Compound 145: S-l-(2-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0082] [a]26360 = (+) 160o (0.1 g / 100 mL acetone). Yield: 88%. Melting Point: 195-197 °C. 1H NMR (400 MHz, DMSO): 5 8.32 (s, 1H, NH), 8.18-8.12 (m, 2H, Ar), 7.97 (d, 1H, Ar, J = 8.0 Hz), 7.85 (d, 1H, Ar, J = 8.0 Hz), 7.67 - 7.46 (m, 4H, Ar), 7.29 (d, 1H, NH J = 7.2 Hz), 7.18 (t, 1H, Ar, J=8.0 Hz ), 7.06 (t, lH,Ar, J=8.0 Hz ), 6.93- 6.89 (m, 1H, Ar) 5.64 (br, 1H, CH), 1.55 (d, 3H, CH3, J=6.8 Hz) ppm,13C NMR (100 MHz, DMSO): 5 5 154.4, 152.9, 150.7, 141.1, 133.7, 130.7, 129.2, 128.6, 127.7, 126.5, 125.9, 124.6, 123.6, 122.5, 122.0, 119.9, 115.3, 45.1, 22.7 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2O: 307.1247; Found 307.1195.

[0083] Compound 15R: R-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0084] [a]26360 = (-) 220o (0.1 g / 100 mL acetone). Yield: 43%. Melting Point: 69-72 °C. 1H NMR (400 MHz, DMSO): 5 9.55 (s, 1H, NH), 8.36 (d, 1H, NH, J = 7.6 Hz), 8.14 (d, 1H, Ar, J = 8.4 Hz), 7.94 (d, 1H, Ar, J=8.4 Hz), 7.85 (d, 1H, Ar, J = 8.4 Hz), 7.62 (d, 1H, Ar J = 11.6 Hz), 7.60 - 7.48 (m, 4H, Ar), 7.27 (td, 1H, Ar, J =6.8 Hz, J =8.2 Hz), 7.14 (dd, 1H, Ar, J = 8.4 Hz, J =1.1 Hz), 6.84 (dt, 1H, Ar, J = 8.4 Hz, J =0.8 Hz), 6.23 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 1.60 (d, 3H, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO) 5 179.7, 163.4, 160.9, 141.9 (d, J = 10.8 Hz), 139.5, 133.9, 131.1, 130.4 (d, J = 9.8 Hz), 129.2, 128.2, 126.9, 126.2, 126.0, 123.8, 123.4, 118.1, 110.4 (d, J = 20.7 Hz), 49.3, 20.9 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2S: 325.1175; Found 325.1175.

[0085] Compound 165: S-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0086] [a]26360 = (+) 220o (0.1 g / 100 mL acetone). Yield: 59%. Melting Point: 69-72 °C. 1H NMR (400 MHz, DMSO): 5 9.55 (s, 1H, NH), 8.36 (d, 1H, NH, J = 7.6 Hz), 8.14 (d, 1H, Ar, J = 8.4 Hz), 7.94 (d, 1H, Ar, J=8.4 Hz), 7.85 (d, 1H, Ar, J = 8.4 Hz), 7.62 (d, 1H, Ar J = 11.6 Hz), 7.60 - 7.48 (m, 4H, Ar), 7.27 (td, 1H, Ar, J =6.8 Hz, J =8.2 Hz), 7.14 (dd, 1H, Ar, J = 8.4 Hz, J =1.1 Hz), 6.84 (dt, 1H, Ar, J = 8.4 Hz, J =0.8 Hz), 6.23 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 1.60 (d, 3H, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO) 5 179.7, 163.4, 160.9, 141.9 (d, J = 10.8 Hz) , 139.5, 133.9, 131.1, 130.4 (d, J = 9.8 Hz), 129.2, 128.2, 126.9, 126.2, 126.0, 123.8, 123.4, 118.1, 110.4 (d, J = 20.7 Hz), 49.3, 20.9 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2S: 325.1175; Found 325.1218.

[0087] Compound 177?: 7?-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)

[0088] [a]26360 = (-) 60o (0.1 g / 100 mL acetone). Yield: 95%. Melting Point: 228-230 °C. 1H NMR (400 MHz, DMSO): 5 8.50 (s, 1H, NH), 8.13 (d, 1H, Ar, J=8.4 Hz), 7.93 (dd, 1H, Ar, J=1.6 Hz, J=8.0 Hz), 7.82 (d, 1H, Ar, J=8.0 Hz), 7.61-7.46 (m, 4H, Ar), 7.41 (td, 1H, Ar, J=2.4 Hz, J=8.0 Hz), 7.20 (td, 1H, Ar, J =7.0 Hz, J =8.2 Hz), 6.97 (ddd, 1H, Ar, J=0.8 Hz, J=2.8 Hz, J=8.2 Hz), 6.82 (d, 1H, NH, J=8.0 Hz), 6.66 (dt, 1H, J=2.4 Hz, J=8.0 Hz), 5.60 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 1.51 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 164.0, 161.7, 154.5, 142.7 (d, J = 11.5 Hz), 141.0, 133.9, 130.7, 130.6 (d, J = 10.0 Hz), 129.2, 127.8, 126.7, 126.1 (d, J = 13.7 Hz), 123.6, 122.6, 113.7 (d, J = 2.2 Hz), 107.8 (d, J = 21.1 Hz), 104.6 (d, J = 26.7 Hz), 45.4, 22.4. ppm. HRMS (TOF MS ES+): Calculated C19H17FN2O: 307.1247; Found 307.1247.

[0089] Compound 185: S-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0090] [a]26360 = (+) 60o (0.1 g / 100 mL acetone). Yield: 98%. Melting Point: 228-230 °C. 1H NMR (400 MHz, DMSO): 5 8.50 (s, 1H, NH), 8.13 (d, 1H, Ar, J=8.4 Hz), 7.93 (dd, 1H, Ar, J=1.6 Hz, J=8.0 Hz), 7.82 (d, 1H, Ar, J=8.0 Hz), 7.61-7.46 (m, 4H, Ar), 7.41 (td, 1H, Ar, J=2.4 Hz, J=8.0 Hz), 7.20 (td, 1H, Ar, J =7.0 Hz, J =8.2 Hz), 6.97 (ddd, 1H, Ar, J=0.8 Hz, J=2.8 Hz, J=8.2 Hz), 6.82 (d, 1H, NH J=8.0 Hz), 6.66 (dt, 1H, J=2.4 Hz, J=8.0 Hz), 5.60 (dq, 1H, CH, J=6.8 Hz, J=7.2 Hz), 1.51 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 164.0, 161.7, 154.5, 142.7 (d, J = 11.5 Hz), 141.0, 133.9, 130.7, 130.6 (d, J = 10.0 Hz), 129.2, 127.8, 126.7, 126.1 (d, J = 13.7 Hz), 123.6, 122.6, 113.7 (d, J = 2.2 Hz), 107.8 (d, J = 21.1 Hz), 104.6 (d, J = 26.7 Hz), 45.4, 22.4. ppm. HRMS (TOF MS ES+): Calculated C19H17FN2O: 307.1247; Found 307.1247.

[0091] Compound 19R : R- 1 -(4-fluorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)thiourea

[0092] [a]26360 = (-) 200o (0.1 g / 100 mL acetone). Yield: 51%. Melting Point: 80-83 °c. 1H NMR (400 MHz, DMSO): 5 9.40 (s, 1H, NH), 8.22 (d, 1H, NH, J = 7.2 Hz), 8.16 (d, 1H, Ar, J = 8.4 Hz), 7.94 (d, 1H, Ar J = 8.0 Hz), 7.84 (d, 1H, Ar, J = 8.0 Hz), 7.60 - 7.39 (m, 6H, Ar), 7.14 - 7.05 (m, 2H, Ar), 6.25 (br, 1H, CH), 1.59 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.4, 139.7, 136.3, 133.9, 131.1, 129.2, 128.1 , 126.8, 126.2, 126.0, 125.5, 123.9, 123.3, 115.6, 115.4,

[0093] 49.4, 21.1 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2S: 323.1018;

[0094] Found 323.1014.

[0095] Compound 205: S-l-(4-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0096] [a]26360 = (+) 200o (0.1 g / 100 mL acetone). Yield: 36%. Melting Point: 80-83 °c. 1H NMR (400 MHz, DMSO): 5 9.40 (s, 1H, NH), 8.22 (d, 1H, NH, J = 7.2 Hz), 8.16 (d, 1H, Ar, J = 8.4 Hz), 7.94 (d, 1H, Ar J = 8.0 Hz), 7.84 (d, 1H, Ar, J = 8.0 Hz), 7.60 - 7.39 (m, 6H, Ar), 7.14 - 7.05 (m, 2H, Ar), 6.25 (br, 1H, CH), 1.59 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.4, 139.7, 136.3, 133.9, 131.1, 129.2, 128.1 , 126.8, 126.2, 126.0, 125.5, 123.9, 123.3, 115.6, 115.4,

[0097] 49.4, 21.1 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2S: 323.1018;

[0098] Found 323.1015. Compound 217?: ?-l-(4-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0099] [a]26360 = (-) 80o (0.1 g / 100 mL acetone). Yield: 31%. Melting Point: 230-232 °C. 1H NMR (400 MHz, DMSO): 5 8.36 (s, 1H, NH), 8.12 (d, 1H, Ar, J=8.4 Hz), 7.92 (dd, 1H, Ar, J=1.6 Hz, J=8.0 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.61- 6.97 (m, 8H, Ar), 6.71 (d, 1H, NH, J=8.0 Hz), 5.60 (dq, 1H, CH, J=7.2 Hz, J=6.8 Hz), 1.51 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 158.5, 156.2, 154.8, 141.1, 137.1, 133.9, 130.7, 129.1, 127.7, 126.7, 126.0, 123.5, 122.5, 119.6, 119.6, 115.7, 115.5, 45.1, 22.6 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2O: 307.1247; Found 307.1269.

[0100] Compound 22S: S-l-(4-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0101] [a]26360 = (+) 80o (0.1 g / 100 mL acetone). Yield: 42%. Melting Point: 230-232 °C. 1H NMR (400 MHz, DMSO): 5 8.36 (s, 1H, NH), 8.12 (d, 1H, Ar, J=8.4 Hz), 7.92 (dd, 1H, Ar, J=1.6 Hz, J=8.0 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.61- 6.97 (m, 8H, Ar), 6.71 (d, 1H, NH, J=8.0 Hz), 5.60 (dq, 1H, CH, J=7.2 Hz, J=6.8 Hz), 1.51 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 5 158.5, 156.2, 154.8, 141.1, 137.1, 133.9, 130.7, 129.1, 127.7, 126.7, 126.0, 123.5, 122.5, 119.6, 119.6, 115.7, 115.5, 45.1, 22.6 ppm. HRMS (TOF MS ES+): Calculated C19H17FN2O: 307.1247; Found 307.1251.

[0102] Compound 23R 7?-l-(3-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea [a]26360 = (-) lOOo (0.1 g / 100 mL acetone). Yield: 27%. Melting Point: 96-98 °C. 1H NMR (400 MHz, DMSO): 5 9.51 (s, 1H, NH), 8.38 (d, 1H, NH J=7.6 Hz), 8.14 (d, 1H, Ar, J=8.4 Hz), 7.94 (d, 1H, Ar, J=8.0 Hz), 7.85 (d, 1H, Ar, J=8.0 Hz), 7.76 (s, 1H, Ar), 7.54-7.08 (m, 7H, Ar), 6.23 (dq, 1H, CH, J=6.8 Hz, J=6.4 Hz), 1.61 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 179.9, 141.7, 139.4, 133.9 133.0, 131.1, 130.5, 129.2, 128.2, 126.9, 126.2, 125.9, 123.8, 123.7, 123.4, 122.0, 121.0, 49.4, 20.9 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2S: 339.0723; Found 339.0702.

[0103] Compound 245: S-l-(3-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0104] [a]26360 = (+) lOOo (0.1 g / 100 mL acetone). Yield: 50%. Melting Point: 96-98 °C. 1H NMR (400 MHz, DMSO): 5 9.51 (s, 1H, NH), 8.38 (d, 1H, NH J=7.6 Hz), 8.14 (d, 1H, Ar, J=8.4 Hz), 7.94 (d, 1H, Ar, J=8.0 Hz), 7.85 (d, 1H, Ar, J=8.0 Hz), 7.76 (s, 1H, Ar), 7.54-7.08 (m, 7H, Ar), 6.23 (dq, 1H, CH, J=6.8 Hz, J=6.4 Hz), 1.61 (d, 3H, CH3, J=6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 179.9, 141.7, 139.4, 133.9 133.0, 131.1, 130.5, 129.2, 128.2, 126.9, 126.2, 125.9, 123.8, 123.7, 123.4, 122.0, 121.0, 49.4, 20.9 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2S: 339.0723; Found 339.0722.

[0105] Compound 257?: 7?-l-(3-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0106] [a]26360 = (+) 20o (0.1 g / 100 mL acetone). Yield: 92%. Melting Point: 254-256 °C. 1H NMR (400 MHz, DMSO) 5 8.57 (s, 1H, NH), 8.14 (d, 1H, Ar, J = 8.4 Hz), 7.93 (d, 1H, Ar, J = 7.2 Hz), 7.82 (d, 1H, Ar, J = 8.0 Hz), 7.64 (t, 1H, Ar, J = 2.0 Hz), 7.61 - 7.46 (m, 4H, Ar), 7.20 (t, 1H, Ar, J = 8.0 Hz), 7.13 (ddd, 1H, Ar, J = 1.0 Hz, J =2.0 Hz, J =8.2 Hz), 6.91 (ddd, 1H, Ar, J =1.0 Hz, J =2.0 Hz, J =8.0 Hz), 6.84 (d, 1H, NH, J = 7.6 Hz), 5.61 (dq, 1H, CH, J = 6.8 Hz, J = 7.2 Hz), 1.52 (d, 3H, CH3, J=7.2 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 154.5, 142.4, 141.0, 133.9, 133.6, 130.8, 129.2, 127.8, 126.7, 126.1, 125.9, 123.6, 122.6, 121.2, 117.31, 116.4, 45.2, 22.5 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2O: 323.0951; Found 323.0952.

[0107] Compound 26S: S-l-(3-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0108] [a]26360 = (-) 20o (0.1 g / 100 mL acetone).: Yield: 87%. Melting Point: 255-256 °C. 1H NMR (400 MHz, DMSO) 5 8.57 (s, 1H, NH), 8.14 (d, 1H, Ar, J = 8.4 Hz), 7.93 (d, 1H, Ar, J = 7.2 Hz), 7.82 (d, 1H, Ar, J = 8.0 Hz), 7.64 (t, 1H, Ar, J = 2.0 Hz), 7.61 - 7.46 (m, 4H, Ar), 7.20 (t, 1H, Ar, J = 8.0 Hz), 7.13 (ddd, 1H, Ar, J = 1.0 Hz, J =2.0 Hz, J =8.2 Hz), 6.91 (ddd, 1H, Ar, J =1.0 Hz, J =2.0 Hz, J =8.0 Hz), 6.84 (d, 1H, NH, J = 7.6 Hz), 5.61 (dq, 1H, CH, J = 6.8 Hz, J = 7.2 Hz), 1.52 (d, 3H, CH3, J=7.2 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 154.5, 142.4, 141.0, 133.9, 133.6, 130.8, 129.2, 127.8, 126.7, 126.1, 125.9, 123.6, 122.6, 121.2, 117.31, 116.4, 45.2, 22.5 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2O: 323.0951; Found 323.0953.

[0109] Compound 27 R: R-l-(4-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0110] [a]26360 = (-) 220o (0.1 g / 100 mL acetone). Yield: 78%. Melting Point: 70-73 °C. 1H NMR (400 MHz, DMSO) 5 9.49 (s, 1H, NH), 8.32 (d, 1H, NH J = 7.2 Hz), 8.18 (d, 1H, Ar J = 8.4 Hz), 7.97 (d, 1H, Ar, J = 8.0 Hz), 7.88 (d, 1H, Ar, J = 8.0 Hz), 7.62-7.52 (m, 6H, Ar), 7.33 (d, 2H, Ar, J = 8.4 Hz), 6.26 (br, 1H, CH), 1.62 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.0, 139.6, 139.1, 133.9, 131.1, 129.2, 128.7, 128.1, 128.0, 126.9, 126.2, 125.9, 124.5, 123.8, 123.4, 49.4, 21.0 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2S: 339.0723; Found 339.0724. Compound 285: S-l-(4-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea

[0111] [a]26360 = (+) 220o (0.1 g / 100 mL acetone). Yield: 90%. Melting Point: 70-73 °C. 1H NMR (400 MHz, DMSO) 5 9.49 (s, 1H, NH), 8.32 (d, 1H, NH J = 7.2 Hz), 8.18 (d, 1H, Ar J = 8.4 Hz), 7.97 (d, 1H, Ar, J = 8.0 Hz), 7.88 (d, 1H, Ar, J = 8.0 Hz), 7.62-7.52 (m, 6H, Ar), 7.33 (d, 2H, Ar, J = 8.4 Hz), 6.26 (br, 1H, CH), 1.62 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): ): 5 180.0, 139.6, 139.1, 133.9 , 131.1, 129.2, 128.7, 128.1, 128.0, 126.9, 126.2, 125.9, 124.5, 123.8, 123.4,

[0112] 49.4, 21.0 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2S: 339.0723;

[0113] Found 339.0720.

[0114] Compound 297?: 7?-l-(4-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0115] [a]26360 = (-) 20o (0.1 g / 100 mL acetone). Yield: 43%. Melting Point: 238-242 °C. 1H NMR (400 MHz, DMSO) 5 8.55 (s, 1H, NH), 8.16 (d, 1H, Ar, J = 8.4 Hz), 7.96 (d, 1H, Ar, J = 8.0 Hz), 7.84 (d, 1H, Ar, J = 8.0 Hz), 7.67 - 7.47 (m, 4H, Ar), 7.41 (d, 2H, Ar, J = 8.8 Hz), 7.25 (d, 2H, Ar, J = 8.8 Hz), 6.82 (d, 1H, NH, J = 8.0 Hz), 5.63 (dq, 1H, CH, J = 7.2, Hz, J = 6.8 Hz), 1.54 (d, 3H, CH3, J = 6.8 Hz). 13C NMR (100 MHz, DMSO): 5 154.6, 141.0, 139.7, 133.9, 130.7, 129.1, 128.9, 127.7, 126.7, 126.1, 125.9, 125.0, 123.5, 122.5, 119.5, 45.1, 22.6 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2O: 323.0951; Found 323.0978.

[0116] Compound 305: S-l-(4-chlorophenyl)-3-(l-(naphthalen-l-yl)ethyl)urea

[0117] [a]26360 = (+) 20o (0.1 g / 100 mL acetone). Yield: 46%. Melting Point: 238-242 °C. 1H NMR (400 MHz, DMSO) 5 8.55 (s, 1H, NH), 8.16 (d, 1H, Ar, J = 8.4 Hz), 7.96 (d, 1H, Ar, J = 8.0 Hz), 7.84 (d, 1H, Ar, J = 8.0 Hz), 7.67 - 7.47 (m, 4H, Ar), 7.41 (d, 2H, Ar, J = 8.8 Hz), 7.25 (d, 2H, Ar, J = 8.8 Hz), 6.82 (d, 1H, NH, J = 8.0 Hz), 5.63 (dq, 1H, CH, J = 7.2, Hz, J = 6.8 Hz), 1.54 (d, 3H, CH3, J = 6.8 Hz). 13C NMR (100 MHz, DMSO): 5 154.6, 141.0, 139.7, 133.9, 130.7, 129.1, 128.9, 127.7,

[0118] 126.7, 126.1, 125.9, 125.0, 123.5, 122.5, 119.5, 45.1, 22.6 ppm. HRMS (TOF MS ES+): Calculated C19H17C1N2O: 323.0951; Found 323.0959.

[0119] Compound 317?: 7?-l-(2-methoxyphenyl)-3-(l-phenylethyl)thiourea

[0120] [a]26360 = (-) 260o (0.1 g / 100 mL acetone). Yield: 73%. Melting Point: 106-108 °C. 1H NMR (400 MHz, DMSO) 5 8.96 (s, 1H, NH), 8.45 (d, 1H, Ar, J = 8.0 Hz), 8.02 (d, 1H, NH, J = 7.6 Hz), 7.51 - 6.99 (m, 7H, Ar), 6.89 (t, 1H, Ar, J = 7.6 Hz), 5.56 (br, 1H, CH), 3.81 (s, 3H, OCH3), 1.45 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.1, 151.5, 144.4, 129.2, 128.8, 128.3, 127.2, 127.1,

[0121] 126.7, 125.4, 125.1, 120.1, 111.6, 56.0, 53.0, 22.4 ppm. HRMS (TOF MS ES+): Calculated C16H18N2OS: 287.1218; Found 287.1219.

[0122] Compound 32S: S-l-(2-methoxyphenyl)-3-(l-phenylethyl)thiourea

[0123] [a]26360 = (+) 260o (0.1 g / 100 mL acetone). Yield: 65%. Melting Point: 106-108 °C. 1H NMR (400 MHz, DMSO) 5 8.96 (s, 1H, NH), 8.45 (d, 1H, Ar, J = 8.0 Hz), 8.02 (d, 1H, NH, J = 7.6 Hz), 7.51 - 6.99 (m, 7H, Ar), 6.89 (t, 1H, Ar, J = 7.6 Hz), 5.56 (br, 1H, CH), 3.81 (s, 3H, OCH3), 1.45 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.1, 151.5, 144.4, 129.2, 128.8, 128.3, 127.2, 127.1,

[0124] 126.7, 125.4, 125.1, 120.1, 111.6, 56.0, 53.0, 22.4 ppm. HRMS (TOF MS ES+): Calculated C16H18N2OS: 287.1218; Found 287.1218.

[0125] Compound 337?: 7?-l-(3-methoxyphenyl)-3-(l -phenylethyl)thiourea [a]26360 = (-) 300o (0.1 g / 100 mL acetone). Yield: 66%. Melting Point: 66-68 °C. 1H NMR (400 MHz, DMSO) 59.44 (s, 1H, NH), 8.15 (d, 1H, NH, J = 8.0 Hz), 7.41

[0126] - 7.13 (m, 7H, Ar), 6.93 (d, 1H, Ar J = 8.0 Hz), 6.63 (dd, 1H, Ar, J = 8.0 Hz, J =2.5 Hz,), 5.54 (dq, 1H, CH, J =6.8 Hz, J =7.2 Hz), 3.69 (s, 3H, OCH3), 1.45 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO) 5 179.9, 159.8, 144.3, 141.1, 129.7, 128.8, 127.3, 126.8, 115.1, 109.9, 108.6, 55.5, 53.1, 22.3 ppm. HRMS (TOF MS ES+): Calculated C16H18N2OS: 287.1218; Found 287.1226.

[0127] Compound 34S: S-l-(3-methoxyphenyl)-3-(l-phenylethyl)thiourea

[0128] [a]26360 = (+) 300o (0.1 g / 100 mL acetone). Yield: 73%. Melting Point: 66-68 °C. 1H NMR (400 MHz, DMSO) 59.44 (s, 1H, NH), 8.15 (d, 1H, NH, J = 8.0 Hz), 7.41

[0129] - 7.13 (m, 7H, Ar), 6.93 (d, 1H, Ar J = 8.0 Hz), 6.63 (dd, 1H, Ar, J = 8.0 Hz, J =2.5 Hz,), 5.54 (dq, 1H, CH, J =6.8 Hz, J =7.2 Hz), 3.69 (s, 3H, OCH3), 1.45 (d, 3H, CH3, J = 6.8 Hz) ppm.13C NMR (100 MHz, DMSO) 55 179.9, 159.8, 144.3, 141.1, 129.7, 128.8, 127.3, 126.8, 115.1, 109.9, 108.6, 55.5, 53.1, 22.3 ppm. HRMS (TOF MS ES+): Calculated C16H18N2OS: 287.1218; Found 287.1223.

[0130] Compound 35R: 7?-l-(2-fluorophenyl)-3-(l-phenylethyl)thiourea

[0131] [a]26360 = (-) 280o (0.1 g / 100 mL chloroform). Yield: 95%. Melting Point: 80-82 °C. 1H NMR (400 MHz, DMSO) 5 9.17 (s, 1H, NH), 8.42 (d, 1H, NH J = 6.4 Hz), 7.85 - 7.08 (m, 9H, Ar), 5.54 (br, 1H, CH), 1.47 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO) 5 181.0, 144.2, 128.8, 127.9, 127.7, 127.6, 127.5, 127.3 126.6, 124.3, 116.0, 53.3, 22.4 ppm. HRMS (TOF MS ES+): Calculated C15H15FN2S: 273.0862; Found 273.0864.

[0132] Compound 36S: S-l-(2-fluorophenyl)-3-(l-phenylethyl)thiourea [a]26360 = (+) 280o (0.1 g / 100 mL chloroform). Yield: 85%. Melting Point: 80-82 °C. 1H NMR (400 MHz, DMSO) 5 9.17 (s, 1H, NH), 8.42 (d, 1H, NH J = 6.4 Hz), 7.85 - 7.08 (m, 9H, Ar), 5.54 (br, 1H, CH), 1.47 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO) 5 181.0, 144.2, 128.8, 127.9, 127.7, 127.6, 127.5, 127.3 126.6, 124.3, 116.0, 53.3, 22.4 ppm. HRMS (TOF MS ES+): Calculated C15H15FN2S: 273.0862; Found 273.0862.

[0133] Compound 377?: 7?-l-(3-fluorophenyl)-3-(l-phenylethyl)thiourea

[0134] [a]26360 = (-) 90o (0.1 g / 100 mL acetone). Yield: 79%. Melting Point: 92-94 °C. 1H NMR (400 MHz, DMSO) 59.58 (s, 1H, NH), 8.30 (d, 1H, NH, J = 7.6 Hz), 7.61 (d, 1H, Ar, J = 11.2 Hz), 7.39 - 7.15 (m, 7H, Ar), 6.86 (td, 1H, Ar, J = 2.4 Hz, J = 8.0 Hz), 5.51 (br, 1H, CH), 1.45 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.0, 163.4, 160.9, 144.1, 142.0, 141.9, 130.4 (d, J = 9.6 Hz), 128.8, 127.3, 126.7, 118.2, 110.5 (d, J = 21.2 Hz), 109.1 (d, J = 21.2 Hz), 53.0, 22.3 ppm. HRMS (TOF MS ES+): Calculated C15H15FN2S: 273.0862; Found 273.0863.

[0135] Compound 385: S-l-(3-fluorophenyl)-3-(l-phenylethyl)thiourea

[0136] [a]26360 = (+) 90o (0.1 g / 100 mL acetone). Yield: 90%. Melting Point: 92-94 °C. 1H NMR (400 MHz, DMSO) 59.58 (s, 1H, NH), 8.30 (d, 1H, NH, J = 7.6 Hz), 7.61 (d, 1H, Ar, J = 11.2 Hz), 7.39 - 7.15 (m, 7H, Ar), 6.86 (td, 1H, Ar, J = 2.4 Hz, J = 8.0 Hz), 5.51 (br, 1H, CH), 1.45 (d, 3H, CH3, J = 6.8 Hz) ppm. 13C NMR (100 MHz, DMSO): 5 180.0, 163.4, 160.9, 144.1, 142.0, 141.9, 130.4 (d, J = 9.6 Hz), 128.8, 127.3, 126.7, 118.2, 110.5 (d, J = 21.2 Hz), 109.1 (d, J = 21.2 Hz), 53.0, 22.3 ppm. HRMS (TOF MS ES+): Calculated C15H15FN2S: 273.0862; Found 273.0868. Compound 397?: 7?-l-(l-benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)thiourea

[0137] [a]26360 = (-) 60o (0.1 g / 100 mL chloroform). Yield: 80%. Lipoid product. 1H NMR (400 MHz, DMSO) 5 8.90 (s, 1H, NH), 8.17 (d, 1H, Ar, J = 6.8 Hz), 8.00 (d, 1H, NH, J = 6.4 Hz), 7.40 - 7.19 (m, 5H, Ar), 7.13 - 6.81 (m, 3H, Ar), 4.67 (pyrrolidine CH in br, 1H, C-3), 3.80 (s, 3H OCH3), 3.35 (br, 2H, benzyl CH2), 2.73 (br, 1H, pyrrolidine proton), 2.64 (br, 1H, pyrrolidine proton), 2.50 (br, 1H, pyrrolidine proton), 2.33 - 2.20 (m, 2H, pyrrolidine protons), 1.62 (br, 1H, pyrrolidine proton) ppm, 13C NMR (100 MHz, DMSO) 5 180.4, 151.4, 140.2, 129.1, 128.7, 128.4, 127.4, 125.3, 120.1, 111.6, 60.4, 59.7, 56.0, 53.4, 52.8, 31.7 ppm. HRMS (TOF MS ES+): Calculated C19H23N3OS: 342.1640; Found 342.1640.

[0138] Compound 405: S-l-(l-benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)thiourea

[0139] [a]26360 = (+) 60o (0.1 g / 100 mL chloroform). Yield: 78%. Lipoid product. 1H NMR (400 MHz, DMSO) 5 8.90 (s, 1H, NH), 8.17 (d, 1H, Ar, J = 6.8 Hz), 8.00 (d, 1H, NH, J = 6.4 Hz), 7.40 - 7.19 (m, 5H, Ar), 7.13 - 6.81 (m, 3H, Ar), 4.67 (pyrrolidine CH in br, 1H, C-3), 3.80 (s, 3H OCH3), 3.35 (br, 2H, benzyl CH2), 2.73 (br, 1H, pyrrolidine proton), 2.64 (br, 1H, pyrrolidine proton), 2.50 (br, 1H, pyrrolidine proton), 2.33 - 2.20 (m, 2H, pyrrolidine protons), 1.62 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.4, 151.4, 140.2, 129.1, 128.7, 128.4, 127.4, 125.3, 120.1, 111.6, 60.4, 59.7, 56.0, 53.4, 52.8, 31.7 ppm. HRMS (TOF MS ES+): Calculated C19H23N3OS: 342.1640; Found 342.1642.

[0140] Compound 417?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)thiourea

[0141] [a]26360 = (-) 80o (0.1 g / 100 mL chloroform). Yield: 72%. Melting Point:54-56°C. 1H NMR (400 MHz, DMSO) 5 9.48 (br, 1H, NH), 7.87 (br, 1H, NH), 7.41 - 7.14 (m, 7H, Ar), 6.95 (d, 1H, Ar, J = 7.8 Hz), 6.67 (d, 1H, Ar, J = 7.8 Hz), 4.69 (pyrrolidine CH in br, 1H, C-3), 3.73 (s, 3H, OCH3), 3.60 (s, 2H, benzyl CH2 ), 2.72-2.64 (m, 2H, pyrrolidine protons), 2,51 ((br, 1H, pyrrolidine proton)) 2.36- 2.20 (m, 2H, pyrrolidine protons), 1.65 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.0, 159.7, 141.1, 139.2, 129.7, 129.0, 128.6, 127.3, 115.0, 109.7, 108.6, 60.2, 59.6, 55.5, 53.4, 52.7, 31.7 ppm. HRMS (TOF MS ES+): Calculated C19H23N3OS: 340.1484; Found 340.1478.

[0142] Compound 425: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)thiourea

[0143] [a]26360 = (+)80o (0.1 g / 100 mL chloroform). Yield: 87%. Melting Point:54-56°C. 1H NMR (400 MHz, DMSO) 5 9.48 (br, 1H, NH), 7.87 (br, 1H, NH), 7.41 - 7.14 (m, 7H, Ar), 6.95 (d, 1H, Ar, J = 7.8 Hz), 6.67 (d, 1H, Ar, J = 7.8 Hz), 4.69 (pyrrolidine CH in br, 1H, C-3), 3.73 (s, 3H, OCH3), 3.60 (s, 2H, benzyl CH2 ), 2.72-2.64 (m, 2H, pyrrolidine protons), 2,51 ((br, 1H, pyrrolidine proton)) 2.36- 2.20 (m, 2H, pyrrolidine protons), 1.65 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.0, 159.7, 141.1, 139.2, 129.7, 129.0, 128.6, 127.3, 115.0, 109.7, 108.6, 60.2, 59.6, 55.5, 53.4, 52.7, 31.7 ppm. HRMS (TOF MS ES+): Calculated C19H23N3OS: 340.1484; Found 340.1481.

[0144] Compound 437?: (J?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-methoxyphenyl)thiourea

[0145] [a]26360 = (-) lOOo (0.1 g / 100 mL chloroform). Yield: 91%. Melting Point:60- 62°C. 1H NMR (400 MHz, DMSO) 5 9.27 (br, 1H, NH), 7.60 (br, 1H, NH), 7.39 - 7.19 (m, 7H, Ar), 6.97 - 6.79 (m, 2H, Ar), 4.68 (pyrrolidine CH in br, 1H, C-3), 3.74 (s, 3H, 0CH3), 3.57 (ABq, 2H, benzyl CH2), 2.76 - 2.59 (m, 2H, pyrrolidine protons), 2.48 (m, 1H, pyrrolidine protons), 2.31 (q, 1H, pyrrolidine proton, J = 8.4 Hz), 2.16 (m, 1H, pyrrolidine proton), 1.59 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.6, 156.7, 139.4, 132.5, 128.9, 128.6, 127.3, 125.9, 114.1, 60.2, 59.6, 55.7, 53.5, 52.7, 31.7 ppm. HRMS (TOF MS ES+): Calculated C19H23N3OS: 340.1484; Found 340.1483.

[0146] Compound 445: (5')-l-(l-benzylpyrrolidine-3-yl)-3-(4-methoxyphenyl)thiourea

[0147] [a]26360 = (+) lOOo (0.1 g / 100 mL chloroform). Yield: 77%. Melting Point:60- 62°C. 1H NMR (400 MHz, DMSO) 5 9.27 (br, 1H, NH), 7.60 (br, 1H, NH), 7.39 - 7.19 (m, 7H, Ar), 6.97 - 6.79 (m, 2H, Ar), 4.68 (pyrrolidine CH in br, 1H, C-3), 3.74 (s, 3H, OCH3), 3.57 (ABq, 2H, benzyl CH2), 2.76 - 2.59 (m, 2H, pyrrolidine protons), 2.48 (m, 1H, pyrrolidine protons), 2.31 (q, 1H, pyrrolidine proton, J = 8.4 Hz), 2.16 (m, 1H, pyrrolidine proton), 1.59 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.6, 156.7, 139.4, 132.5, 128.9, 128.6, 127.3, 125.9, 114.1, 60.2, 59.6, 55.7, 53.5, 52.7, 31.7 ppm. HRMS (TOF MS ES+): Calculated C19H23N3OS: 340.1484; Found 340.1497.

[0148] Compound 457?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)urea

[0149] [a]26360 = (-) 20o (0.1 g / 100 mL acetone). Yield: 57%. Melting Point: 140- 142°C. 1H NMR (400 MHz, dmso) 5 8.07 (dd, 1H, Ar, J = 7.8, 1.8 Hz), 7.89 (s, 1H, NH), 7.38 - 7.22 (m, 5H, Ar), 7.09 (d, 1H, NH, J = 7.2 Hz), 6.98 - 6.78 (m, 3H, Ar), 4.12 (pyrrolidine CH in m, 1H, C-3), 3.84 (s, 3H, OCH3), 3.59 (ABq, 2H, benzyl CH2), 2.71 - 2.58 (m, 2H, pyrrolidine protons), 2.41 - 2.31 (m, 2H, pyrrolidine protons), 2.16 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 155.1, 147.6), 129.9, 129.0, 128.6, 127.3, 121.3, 120.9, 118.2, 110.9, 61.1, 59.8, 56.1, 52.8, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C19H23N3O2: 326.1869; Found 326.1851.

[0150] Compound 465: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)urea

[0151] [a]26360 = (+) 20o (0.1 g / 100 mL acetone). Yield: 53%. Melting Point: 140- 142°C. 1H NMR (400 MHz, dmso) 5 8.07 (dd, 1H, Ar, J = 7.8, 1.8 Hz), 7.89 (s, 1H, NH), 7.38 - 7.22 (m, 5H, Ar), 7.09 (d, 1H, NH, J = 7.2 Hz), 6.98 - 6.78 (m, 3H, Ar), 4.12 (pyrrolidine CH in m, 1H, C-3), 3.84 (s, 3H, OCH3), 3.59 (ABq, 2H, benzyl CH2), 2.71 - 2.58 (m, 2H, pyrrolidine protons), 2.41 - 2.31 (m, 2H, pyrrolidine protons), 2.16 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 155.1, 147.6), 129.9, 129.0, 128.6, 127.3, 121.3, 120.9, 118.2, 110.9, 61.1, 59.8, 56.1, 52.8, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C19H23N3O2: 326.1869; Found 326.1870.

[0152] Compound 47R: (R)-l-(l-benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)urea

[0153] [a]26360 = (-)l 20o (0.1 g / 100 mL acetone). Yield: 72%. Melting Point:69-71°C. 1H NMR (400 MHz, DMSO) 5 8.35 (s, 1H, NH), 7.38 - 7.20 (m, 5H, Ar), 7.16 - 7.03 (m, 2H, Ar), 6.80 (d, 1H, Ar, J = 8.2 Hz), 6.45 (dd, 1H, J = 8.2, 2.1 Hz), 6.30 (d, 1H, NH, J = 7.2 Hz), 4.11 (pyrrolidine CH in br, 1H, C-3), 3.69 (s, 3H, OCH3), 3.56 (ABq, 2H, benzyl CH2), 2.67 (td, 1H, pyrrolidine proton, J = 5.0 Hz, J = 8.4 Hz,), 2.57 (dd, 1H, pyrrolidine proton J = 12.5, 6.4 Hz), 2.42 - 2.26 (m, 2H, pyrrolidine protons), 2.15 (m, 1H), 1.50 (dt, J =8.0 Hz, J = 12.5, 1H) ppm. 13C NMR (100 MHz, DMSO) 5 160.1, 155.1, 142.1, 139.4, 129.8, 129.0, 128.6, 127.3, 110.3, 106.9, 103.7, 61.0, 59.8, 55.3, 52.7, 48.9, 32.5 ppm. HRMS (TOF MS ES+): Calculated C19H23N3O2: 326.1869; Found 326.1856. Compound 48S: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)urea

[0154] [a]26360 = (-)l 20o (0.1 g / 100 mL acetone). Yield: 79%. Melting Point:69-71°C. 1H NMR (400 MHz, DMSO) 5 8.35 (s, 1H, NH), 7.38 - 7.20 (m, 5H, Ar), 7.16 - 7.03 (m, 2H, Ar), 6.80 (d, 1H, Ar, J = 8.2 Hz), 6.45 (dd, 1H, J = 8.2, 2.1 Hz), 6.30 (d, 1H, NH, J = 7.2 Hz), 4.11 (pyrrolidine CH in br, 1H, C-3), 3.69 (s, 3H, OCH3), 3.56 (ABq, 2H, benzyl CH2), 2.67 (td, 1H, pyrrolidine proton, J = 5.0 Hz, J = 8.4 Hz,), 2.57 (dd, 1H, pyrrolidine proton J = 12.5, 6.4 Hz), 2.42 - 2.26 (m, 2H, pyrrolidine protons), 2.15 (m, 1H), 1.50 (dt, J =8.0 Hz, J = 12.5, 1H) ppm. 13C NMR (100 MHz, DMSO) 5 160.1, 155.1, 142.1, 139.4, 129.8, 129.0, 128.6, 127.3,

[0155] 110.3, 106.9, 103.7, 61.0, 59.8, 55.3, 52.7, 48.9, 32.5 ppm. HRMS (TOF MS ES+): Calculated C19H23N3O2: 326.1869; Found 326.1857.

[0156] Compound 497?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-methoxyphenyl)urea

[0157] [a]26360 = (-) 680 (0.1 g / 100 mL chloroform). Yield: 77%. Melting Point: 158- 160°C. 1H NMR (400 MHz, dmso) 5 8.13 (s, 1H, NH), 7.34 - 7.22 (m, 7H, Ar), 6.81 - 6.76 (m, 2H, Ar), 6.19 (d, J = 7.2 Hz, 1H, NH), 4.10 (pyrrolidine CH in m, 1H, C-3), 3.68 (s, 3H, OCH3), 3.57 (ABq, 2H, benzyl CH2), 2.66 (td, 1H, pyrrolidine proton, J = 5.0 Hz, J = 8.6 Hz), 2.58 (dd, 1H, pyrrolidine proton, J = 6.6 Hz, J = 9.4 Hz), 2.37-2.29 (m, 2H, pyrrolidine protons), 2.13 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5

[0158] 155.4, 154.3, 139.4), 134.0, 129.0, 128.6, 127.3, 119.7, 114.3, 61.1, 59.8, 55.6, 52.7, 49.9, 32.5 ppm. HRMS (TOF MS ES+): Calculated C19H23N3O2: 326.1869; Found 326.1869.

[0159] Compound 50S: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4-methoxyphenyl)urea

[0160] [a]26360 = (+) 68o (0.1 g / 100 mL chloroform). Yield: 82%. Melting Point: 158- 160°C. 1H NMR (400 MHz, dmso) 5 8.13 (s, 1H, NH), 7.34 - 7.22 (m, 7H, Ar), 6.81 - 6.76 (m, 2H, Ar), 6.19 (d, J = 7.2 Hz, 1H, NH), 4.10 (pyrrolidine CH in m, 1H, C-3), 3.68 (s, 3H, OCH3), 3.57 (ABq, 2H, benzyl CH2), 2.66 (td, 1H, pyrrolidine proton, J = 5.0 Hz, J = 8.6 Hz), 2.58 (dd, 1H, pyrrolidine proton, J = 6.6 Hz, J = 9.4 Hz), 2.37-2.29 (m, 2H, pyrrolidine protons), 2.13 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 155.4, 154.3, 139.4), 134.0, 129.0, 128.6, 127.3, 119.7, 114.3, 61.1, 59.8, 55.6, 52.7, 49.9, 32.5 ppm. HRMS (TOF MS ES+): Calculated C19H23N3O2: 326.1869;

[0161] Found 326.1872.

[0162] Compound 517?: (R)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)thiourea [a]26360 = (-) 16o (0.1 g / 100 mL acetone). Yield: 76%. Lipoid product. 1H NMR

[0163] (400 MHz, DMSO) 5 9.11 (s, 1H, NH), 8.12 (d, 1H, Ar, J = 6.4 Hz), 7.82 (s, 1H, NH), 7.37 - 7.06 (m, 8H, Ar), 4.65 (pyrrolidine CH in br, 1H, C-3), 3.29 (s, 2H, benzyl CH2), 2.72 - 2.62 (m, 2H, pyrrolidine protons), 2.50 (br, 1H, pyrrolidine proton), 2.39 - 2.11 (m, 2H pyrrolidine protons), 1.63 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 181.2, 154.6, 139.2, 129.1, 128.7, 127.7, 127.6, 127.4, 126.5, 124.4, 124.3, 116.0, 115.8, 60.3, 59.7, 53.7, 52.8, 31.7 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3S: 330.1440; Found 330.1443.

[0164] Compound 525: (5) - 1 - ( 1 -benzy Ipyrrolidine- 3 -y 1) - 3 -(2-fluoropheny l)thiourea

[0165] [a]26360 = (+) 16o (0.1 g / 100 mL acetone). Yield: 82%. Lipoid product. 1H NMR (400 MHz, DMSO) 5 9.11 (s, 1H, NH), 8.12 (d, 1H, Ar, J = 6.4 Hz), 7.82 (s, 1H, NH), 7.37 - 7.06 (m, 8H, Ar), 4.65 (pyrrolidine CH in br, 1H, C-3), 3.29 (s, 2H, benzyl CH2), 2.72 - 2.62 (m, 2H, pyrrolidine protons), 2.50 (br, 1H, pyrrolidine proton), 2.39 - 2.11 (m, 2H pyrrolidine protons), 1.63 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 181.2, 154.6, 139.2, 129.1, 128.7, 127.7, 127.6, 127.4, 126.5, 124.4, 124.3, 116.0, 115.8, 60.3, 59.7, 53.7, 52.8, 31.7 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3S: 330.1440; Found 330.1443.

[0166] Compound 53R (R)-l-(l-benzylpyrrolidine-3-yl)-3-(3-fluorophenyl)thiourea

[0167] [a]26360 = (-) 20o (0.1 g / 100 mL acetone). Yield: 61% Lipoid product. 1H NMR (400 MHz, DMSO) 5 9.63 (br, 1H, NH), 8.07 (d, 1H, NH, J = 4.4 Hz), 7.66 (d, 1H, Ar, J = 11.4 Hz), 7.39 - 7.21 (m, 6H, Ar), 7.17 (dd, 1H, Ar, J = 1.2 Hz, J = 8.2 Hz), 6.89 (td, 1H, Ar, J = 2.0 Hz, J =8.4 Hz), 4.68 (pyrrolidine CH in br, 1H, C-3), 3.60 (ABq, 2H, benzyl CH2), 2.80 - 2.60 (m, 2H, pyrrolidine protons), 2.54 (m, 1H, pyrrolidine proton), 2.35 (dd, 1H, pyrrolidine proton, J =8.0 Hz, J =15.6 Hz), 2.22 (m, 1H, pyrrolidine proton), 1.66 (br, 1H) ppm. 13C NMR (100 MHz, DMSO) 5 180.1, 163.4, 161.0, 142.0 (d, J = 10.8 Hz), 139.1, 130.4 (d, J = 9.4 Hz), 129.0, 128.6, 127.4, 118.1, 110.4 (d, J = 20.3 Hz), 109.2, 108. 9, 60.2, 59.6, 53.4, 52.7, 31.6 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3S: 330.1440; Found 330.1437.

[0168] Compound 54S: (5) - 1 - ( 1 -benzy Ipyrrolidine- 3 -y 1) - 3 -(3 -fluoropheny l)thiourea

[0169] [a]26360 = (+) 20o (0.1 g / 100 mL acetone). Yield: 58%. Lipoid product. 1H NMR (400 MHz, DMSO) 5 9.63 (br, 1H, NH), 8.07 (d, 1H, NH, J = 4.4 Hz), 7.66 (d, 1H, Ar, J = 11.4 Hz), 7.39 - 7.21 (m, 6H, Ar), 7.17 (dd, 1H, Ar, J = 1.2 Hz, J = 8.2 Hz), 6.89 (td, 1H, Ar, J = 2.0 Hz, J =8.4 Hz), 4.68 (pyrrolidine CH in br, 1H, C-3), 3.60 (ABq, 2H, benzyl CH2), 2.80 - 2.60 (m, 2H, pyrrolidine protons), 2.54 (m, 1H, pyrrolidine proton), 2.35 (dd, 1H, pyrrolidine proton, J =8.0 Hz, J =15.6 Hz), 2.22 (m, 1H, pyrrolidine proton), 1.66 (br, 1H) ppm. 13C NMR (100 MHz, DMSO) 5

[0170] 180.1, 163.4, 161.0, 142.0 (d, J = 10.8 Hz), 139.1, 130.4 (d, J = 9.4 Hz), 129.0, 128.6, 127.4, 118.1, 110.4 (d, J = 20.3 Hz), 109.2, 108. 9, 60.2, 59.6, 53.4, 52.7, 31.6 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3S: 330.1440; Found 330.1445.

[0171] Compound 55R: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-fluorophenyl)thiourea

[0172] [a]26360 = (-) 28o (0.1 g / 100 mL acetone). Yield: 59%. Melting Point: 79-81 °C. 1H NMR (400 MHz, DMSO) 5 9.41 (br, 1H, NH), 7.85 (br, 1H, NH), 7.46 - 7.04 (m, 9H, Ar), 4.66 (pyrrolidine CH in br, 1H, C-3), 3.58 (s, 2H, benzyl CH2), 2.68 (br, 2H, pyrrolidine protons), 2.49 (br, 1H, pyrrolidine proton), 2.33 (br, 1H, pyrrolidine proton), 2.20 (m, 1H, pyrrolidine proton), 1.59 (br, 1H, pyrrolidine proton) ppm,13C NMR (100 MHz, DMSO) 5 180.7, 160.3, 158.0, 139.2, 136.3,

[0173] 129.1, 128.7, 127.4, 125.6, 115.4 (d, J = 22.5 Hz), 60.3, 59.7, 53.4, 52.8, 31.7 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3S: 330.1440; Found 330.1445.

[0174] Compound 565: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4-fluorophenyl)thiourea

[0175] [a]26360 = (+) 28o (0.1 g / 100 mL acetone). Yield: 64%. Melting Point: 79-81 °C. 1H NMR (400 MHz, DMSO) 5 9.41 (br, 1H, NH), 7.85 (br, 1H, NH), 7.46 - 7.04 (m, 9H, Ar), 4.66 (pyrrolidine CH in br, 1H, C-3), 3.58 (s, 2H, benzyl CH2), 2.68 (br, 2H, pyrrolidine protons), 2.49 (br, 1H, pyrrolidine proton), 2.33 (br, 1H, pyrrolidine proton), 2.20 (m, 1H, pyrrolidine proton), 1.59 (br, 1H, pyrrolidine proton) ppm,13C NMR (100 MHz, DMSO) 5 180.7, 160.3, 158.0, 139.2, 136.3,

[0176] 129.1, 128.7, 127.4, 125.6, 115.4 (d, J = 22.5 Hz), 60.3, 59.7, 53.4, 52.8, 31.7 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3S: 330.1440; Found 330.1434. Compound 57 R: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)urea

[0177] [a]26360 = (+) 4o (0.1 g / 100 mL chloroform). Yield: 94%. Melting Point: 169-171 °C. 1H NMR (400 MHz, DMSO) 5 8.19 (d, 1H, NH, J = 2.4 Hz), 8.09 (dt, 1H, Ar, J = 1.8 Hz, J = 8.4 Hz,), 7.29 (d, 4H, Ar, J = 8.4 Hz), 7.23 (m, 1H, Ar), 7.14 (ddd,lH, Ar, J = 1,4 Hz, J = 8.2 Hz, J = 11.8 Hz), 7.03 (t, 1H, Ar J = 7.8 Hz), 6.88 (m, 1H, Ar), 6.84 (d, 1H, NH, J = 7.2 Hz), 4.10 (pyrrolidine CH in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.66 (td, 1H, pyrrolidine proton, J = 4,8 Hz, J = 8.6 Hz), 2.57 (dd, 1H, 1H, pyrrolidine proton, J = 6.4 Hz, J = 9.4 Hz,), 2.36 (dd, 1H, pyrrolidine proton, J = 3.8 Hz, J = 9.5,), 2.30 (q, 1H, pyrrolidine proton J =6.4 Hz), 2.15 (m, 1H, pyrrolidine proton), 1.47 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.7, 153.1, 139.4, 129.0, 128.8, 128.6, 127.3, 124.8 (, J = 13.6 Hz), 121.8 (d, J = 30.4 Hz), 120.3, 115.2, 115.0, 61.0, 59.8, 52.7, 49.0, 32.5 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3O: 314.1669; Found 314.1677.

[0178] Compound 585: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)urea

[0179] [a]26360 = (-) 4o (0.1 g / 100 mL chloroform). Yield: 96%. Melting Point: 169-171 °C. 1H NMR (400 MHz, DMSO) 5 8.19 (d, 1H, NH, J = 2.4 Hz), 8.09 (dt, 1H, Ar, J = 1.8 Hz, J = 8.4 Hz,), 7.29 (d, 4H, Ar, J = 8.4 Hz), 7.23 (m, 1H, Ar), 7.14 (ddd,lH, Ar, J = 1,4 Hz, J = 8.2 Hz, J = 11.8 Hz), 7.03 (t, 1H, Ar J = 7.8 Hz), 6.88 (m, 1H, Ar), 6.84 (d, 1H, NH, J = 7.2 Hz), 4.10 (pyrrolidine CH in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.66 (td, 1H, pyrrolidine proton, J = 4,8 Hz, J = 8.6 Hz), 2.57 (dd, 1H, 1H, pyrrolidine proton, J = 6.4 Hz, J = 9.4 Hz,), 2.36 (dd, 1H, pyrrolidine proton, J = 3.8 Hz, J = 9.5,), 2.30 (q, 1H, pyrrolidine proton J =6.4 Hz), 2.15 (m, 1H, pyrrolidine proton), 1.47 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.7, 153.1, 139.4, 129.0, 128.8, 128.6, 127.3, 124.8 (, J = 13.6 Hz), 121.8 (d, J = 30.4 Hz), 120.3, 115.2, 115.0, 61.0, 59.8, 52.7, 49.0, 32.5 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3O: 314.1669; Found 314.1677. Compound 59R: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(3-fluorophenyl)urea

[0180] [a]26360 = (-) 40o (0.1 g / 100 mL chloroform). Yield: 53%. Melting Point: 138-141 °C. 1H NMR (400 MHz, DMSO) 5 8.56 (s, 1H, NH), 7.41 (dt, 1H, Ar, J = 2.2 Hz J = 12.2 Hz), 7.33 - 7.16 (m, 6H, Ar), 6.96 (dd, 1H, Ar, J = 1.4 Hz, J = 8.2 Hz), 6.66 (td, 1H, Ar, J =2.4 Hz, J = 8.2Hz), 6.38 (d, 1H, NH, J = 7.4 Hz), 4.10 (pyrrolidine proton in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.66 (td, 1H, pyrrolidine proton, J = 8.6, 5.0 Hz,), 2.56 (dd, 1H, pyrrolidine proton, J =6.4 Hz, J = 9.4 Hz), 2.36 (dd, 1H, pyrrolidine proton, J = 3.8 Hz, J = 9.4 Hz), 2.30 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.14 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 164.1, 161.7, 154.9, 142.74 (d, J = 11.5 Hz), 139.4, 130.6 (d, J = 9.9 Hz), 129.0, 128.6, 127.3, 113.6 (d, J = 2.4 Hz), 107.7 (d, J = 21.3 Hz), 104.7, 104.4, 60.9, 59.7, 52.6, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3O: 314.1669; Found 314.1669.

[0181] Compound 60S: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3-fluorophenyl)urea

[0182] [a]26360 = (+) 40o (0.1 g / 100 mL chloroform). Yield: 24%. Melting Point: 138- 141 °C. 1H NMR (400 MHz, DMSO) 5 8.56 (s, 1H, NH), 7.41 (dt, 1H, Ar, J = 2.2 Hz J = 12.2 Hz), 7.33 - 7.16 (m, 6H, Ar), 6.96 (dd, 1H, Ar, J = 1.4 Hz, J = 8.2 Hz), 6.66 (td, 1H, Ar, J =2.4 Hz, J = 8.2Hz), 6.38 (d, 1H, NH, J = 7.4 Hz), 4.10 (pyrrolidine proton in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.66 (td, 1H, pyrrolidine proton, J = 8.6, 5.0 Hz,), 2.56 (dd, 1H, pyrrolidine proton, J =6.4 Hz, J = 9.4 Hz), 2.36 (dd, 1H, pyrrolidine proton, J = 3.8 Hz, J = 9.4 Hz), 2.30 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.14 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 164.1, 161.7, 154.9, 142.74 (d, J = 11.5 Hz), 139.4, 130.6 (d, J = 9.9 Hz), 129.0, 128.6, 127.3, 113.6 (d, J = 2.4 Hz), 107.7 (d, J = 21.3 Hz), 104.7, 104.4, 60.9, 59.7, 52.6, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3O: 314.1669; Found 314.1678.

[0183] Compound 617?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-fluorophenyl)urea

[0184] [a]26360 = (-) 40o (0.1 g / 100 mL chloroform). Yield: 73%. Melting Point: 151- 153°C. 1H NMR (400 MHz, DMSO) 5 8.40 (s, 1H, NH), 7.41 - 7.32 (m, 6H, Ar), 7.26 (br, 1H, NH), 7.04 (t, 2H Ar, J = 8.5 Hz) 6.32 (d, 1H, Ar, J = 7.2 Hz), 4.12 (pyrrolidine CH in br, 1H, C-3), 3.57 (ABq, 2H, Benzyl CH2), 2.74-2.58 (m, 2H, pyrrolidine protons), 2.39 - 2.31 (m, 2H, pyrrolidine protons), 2. 15 (br, 1H, pyrrolidine proton) 1.52 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 158.5, 156.1, 155.2, 139.0, 137.1, 129.1, 128.6, 127.4, 119.64, 119.6, 115.6, 115.4, 60.9, 59.7, 52.7, 48.9, 32.3 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3O: 314.1669; Found 314.1671.

[0185] Compound 625: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4-fluorophenyl)urea

[0186] [a]26360 = (+) 40o (0.1 g / 100 mL chloroform). Yield: 84%. Melting Point: 151- 153°C. 1H NMR (400 MHz, DMSO) 5 8.40 (s, 1H, NH), 7.41 - 7.32 (m, 6H, Ar), 7.26 (br, 1H, NH), 7.04 (t, 2H Ar, J = 8.5 Hz) 6.32 (d, 1H, Ar, J = 7.2 Hz), 4.12 (pyrrolidine CH in br, 1H, C-3), 3.57 (ABq, 2H, Benzyl CH2), 2.74-2.58 (m, 2H, pyrrolidine protons), 2.39 - 2.31 (m, 2H, pyrrolidine protons), 2. 15 (br, 1H, pyrrolidine proton) 1.52 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 158.5, 156.1, 155.2, 139.0, 137.1, 129.1, 128.6, 127.4, 119.64, 119.6, 115.6, 115.4, 60.9, 59.7, 52.7, 48.9, 32.3 ppm. HRMS (TOF MS ES+): Calculated C18H20FN3O: 314.1669; Found 314.1665.

[0187] Compound 637?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-chlorophenyl)thiourea

[0188] [a]26360 = (+) 12o (0.1 g / 100 mL acetone). Yield: 65%. Melting Point: 52-54 °C. 1H NMR (400 MHz, DMSO) 5 9.07 (br, 1H, NH), 8.27 (d, 1H, NH, J = 7.2 Hz), 7.79 (d, 1H, Ar, J = 6.4 Hz), 7.48 (dd, 1H, Ar, J = 1.2 Hz, J = 8.0 Hz), 7.39 - 7.14 (m, 7H, Ar), 4.69 (pyrrolidine proton in br, 1H, C-3), 3.62 (ABq, 2H, benzyl CH2), 2.75 (br, 1H, pyrrolidine proton), 2.67 (br, 1H, pyrrolidine proton), 2.57 (br, 1H, pyrrolidine proton), 2.35 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.24 (m, 2H, pyrrolidine proton), 1.66 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 181.2, 139.0, 136.7, 129.7, 129.0, 128.6, 127.4, 127.3, 126.9, 60.2, 59.6, 53.6, 52.8, 31.6 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3S: 346.1145; Found 346.1147.

[0189] Compound 645: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(2-chlorophenyl)thiourea

[0190] [a]26360 = (-) 12o (0.1 g / 100 mL acetone). Yield: 84%. Melting Point: 52-54 °C. 1H NMR (400 MHz, DMSO) 5 9.07 (br, 1H, NH), 8.27 (d, 1H, NH, J = 7.2 Hz), 7.79 (d, 1H, Ar, J = 6.4 Hz), 7.48 (dd, 1H, Ar, J = 1.2 Hz, J = 8.0 Hz), 7.39 - 7.14 (m, 7H, Ar), 4.69 (pyrrolidine proton in br, 1H, C-3), 3.62 (ABq, 2H, benzyl CH2), 2.75 (br, 1H, pyrrolidine proton), 2.67 (br, 1H, pyrrolidine proton), 2.57 (br, 1H, pyrrolidine proton), 2.35 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.24 (m, 2H, pyrrolidine proton), 1.66 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 181.2, 139.0, 136.7, 129.7, 129.0, 128.6, 127.4, 127.3, 126.9, 60.2, 59.6, 53.6, 52.8, 31.6 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3S: 346.1145; Found 346.1145.

[0191] Compound 65R: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(3-chlorophenyl)thiourea [a]26360 = (-) 28o (0.1 g / 100 mL acetone). Yield: 68%. Lipoid product. 1H NMR (400 MHz, DMSO) 5 9.55 (br, 1H, NH), 8.04 (br, 1H, NH), 7.78 (br, 1H, Ar), 7.34 - 7.19 (m, 7H), 7.09 (d, 1H, Ar, J = 6.4 Hz), 4.65 (pyrrolidine proton in br, 1H, C- 3), 3.58 (ABq, 2H, benzyl CH2), 2.72- 2.62 (m, 2H, pyrrolidine protons), 2.51 (br, 1H, pyrrolidine proton), 2.31 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.20 (m, 1H, pyrrolidine proton), 1.64 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.0, 141.7, 139.1, 132.9, 130.4, 129.0, 128.6, 127.3, 123.7, 122.1, 121.0, 60.2, 59.6, 53.5, 52.7, 31.6 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3S: 346.1145; Found 346.1149.

[0192] Compound 66S: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3-chlorophenyl)thiourea

[0193] [a]26360 = (+) 28o (0.1 g / 100 mL acetone). Yield: 65%. Lipoid product. 1H NMR (400 MHz, DMSO) 5 9.55 (br, 1H, NH), 8.04 (br, 1H, NH), 7.78 (br, 1H, Ar), 7.34 - 7.19 (m, 7H), 7.09 (d, 1H, Ar, J = 6.4 Hz), 4.65 (pyrrolidine proton in br, 1H, C- 3), 3.58 (ABq, 2H, benzyl CH2), 2.72- 2.62 (m, 2H, pyrrolidine protons), 2.51 (br, 1H, pyrrolidine proton), 2.31 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.20 (m, 1H, pyrrolidine proton), 1.64 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.0, 141.7, 139.1, 132.9, 130.4, 129.0, 128.6, 127.3, 123.7, 122.1, 121.0, 60.2, 59.6, 53.5, 52.7, 31.6 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3S: 346.1145; Found 346.1158.

[0194] Compound 67 R: (R)-l-(l -benzylpyrrolidine-3-yl)-3-(4-chlorophenyl)thiourea

[0195] [a]26360 = (-) 44o (0.1 g / 100 mL acetone). Yield: 82%. Melting Point: 87-89 °C. 1H NMR (400 MHz, DMSO) 5 9.45 (br, 1H, NH), 7.90 (br, 1H, NH), 7.46 (d, 2H, Ar, J = 8.4 Hz,), 7.32 - 7.17 (m, 7H, Ar), 4.61 (pyrrolidine proton in br, 1H, C-3), 3.53 (ABq, 2H, benzyl CH2), 2.72 - 2.51 (m, 3H, pyrrolidine protons), 2.28 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.15 (m, 1H, pyrrolidine proton), 1.59 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.3, 139.3, 139.1, 129.0, 128.7, 128.6, 127.9, 127.3, 124.5, 60.2, 59.7, 53.4, 52.7, 31.7 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3S: 346.1145; Found 346.1145.

[0196] Compound 685: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4-chlorophenyl)thiourea

[0197] [a]26360 = (+) 44o (0.1 g / 100 mL acetone). Yield: 72%. Melting Point: 87-89 °C. 1H NMR (400 MHz, DMSO) 5 9.45 (br, 1H, NH), 7.90 (br, 1H, NH), 7.46 (d, 2H, Ar, J = 8.4 Hz,), 7.32 - 7.17 (m, 7H, Ar), 4.61 (pyrrolidine proton in br, 1H, C-3), 3.53 (ABq, 2H, benzyl CH2), 2.72 - 2.51 (m, 3H, pyrrolidine protons), 2.28 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.15 (m, 1H, pyrrolidine proton), 1.59 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 180.3, 139.3, 139.1, 129.0, 128.7, 128.6, 127.9, 127.3, 124.5, 60.2, 59.7, 53.4, 52.7, 31.7 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3S: 346.1145; Found 346.1146.

[0198] Compound 69R (R)-l-(l -benzylpyrrolidine-3-yl)-3-(2-chlorophenyl)urea

[0199] [a]26360 = (-) 16o (0.1 g / 100 mL acetone). Yield: 62%. Melting Point: 158-161 °C. 1H NMR (400 MHz, DMSO) 5 8.12 (dd, 1H, Ar, J = 1.6 Hz, J = 8.4 Hz), 7.94 (br, 1H, NH), 7.36 (dd, 1H, Ar, J = 1.6 Hz, J = 8.0 Hz), 7.31 - 7.15 (m, 7H, Ar ve NH), 6.90 (dt, 1H, Ar, J = 1.6 Hz, J = 8.0 Hz), 4.10 (pyrrolidine proton in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.65 (dt, 1H, J = 4.4 Hz, J = 8.4 Hz, pyrrolidine proton), 2.59 (dd,lH, pyrrolidine proton, J = 6.4 Hz, J = 9.4 Hz), 2.37 (dd,lH, pyrrolidine proton, J = 3.8 Hz, J = 9.4 Hz), 2.31 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.15 (m, 1H, pyrrolidine proton), 1.48 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.7, 139.4, 137.1, 129.5, 129.0, 128.6, 127.8, 127.3, 122.7, 121.4, 120.9, 61.0, 59.8, 52.8, 49.0, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3O: 330.1373; Found 330.1389.

[0200] Compound 70S: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(2-chlorophenyl)urea

[0201] [a]26360 = (+) 16o (0.1 g / 100 mL acetone). Yield: 61%. Melting Point: 158-161 °C. 1H NMR (400 MHz, DMSO) 5 8.12 (dd, 1H, Ar, J = 1.6 Hz, J = 8.4 Hz), 7.94 (br, 1H, NH), 7.36 (dd, 1H, Ar, J = 1.6 Hz, J = 8.0 Hz), 7.31 - 7.15 (m, 7H, Ar ve NH), 6.90 (dt, 1H, Ar, J = 1.6 Hz, J = 8.0 Hz), 4.10 (pyrrolidine proton in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.65 (dt, 1H, J = 4.4 Hz, J = 8.4 Hz, pyrrolidine proton), 2.59 (dd,lH, pyrrolidine proton, J = 6.4 Hz, J = 9.4 Hz), 2.37 (dd,lH, pyrrolidine proton, J = 3.8 Hz, J = 9.4 Hz), 2.31 (q, 1H, pyrrolidine proton, J = 6.4 Hz), 2.15 (m, 1H, pyrrolidine proton), 1.48 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.7, 139.4, 137.1, 129.5, 129.0, 128.6, 127.8, 127.3, 122.7, 121.4, 120.9, 61.0, 59.8, 52.8, 49.0, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3O: 330.1373; Found 330.1373.

[0202] Compound 71R: (R)-l-(l-benzylpyrrolidine-3-yl)-3-(3-chlorophenyl)urea

[0203] [a]26360 = (+) 12o (0.1 g / 100 mL acetone). Yield: 85%. Melting Point: 114-116 °C. 1H NMR (400 MHz, dmso) 5 8.54 (s, 1H, NH), 7.63 (s, 1H, Ar), 7.32 - 7.08 (m, 7H), 6.90 (d, 1H, Ar, J = 8.0 Hz), 6.39 (d, 1H, NH, J = 7.2 Hz), 4.09 (pyrrolidine proton in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.66 (dd, 1H, pyrrolidine proton, J = 8.3 Hz, J = 13.3 Hz), 2.57 (t, 1H, pyrrolidine proton, J = 8.0 Hz), 2.36 (dd, 1H, pyrrolidine proton, J = 3.5 Hz, J = 9.4 Hz), 2.30 (q, 1H, pyrrolidine proton, J = 6.8 Hz), 2.13 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.8, 142.4, 139.4, 133.5, 130.7, 128.9, 128.6, 127.3, 121.0, 117.3, 116.3 60.9, 59.7, 52.6, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3O: 330.1373; Found 330.1370.

[0204] Compound 725: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3-chlorophenyl)urea

[0205] [a]26360 = (-) 12o (0.1 g / 100 mL acetone). Yield: 95%. Melting Point: 114-116 °C. 1H NMR (400 MHz, dmso) 5 8.54 (s, 1H, NH), 7.63 (s, 1H, Ar), 7.32 - 7.08 (m, 7H), 6.90 (d, 1H, Ar, J = 8.0 Hz), 6.39 (d, 1H, NH, J = 7.2 Hz), 4.09 (pyrrolidine proton in m, 1H, C-3), 3.56 (ABq, 2H, benzyl CH2), 2.66 (dd, 1H, pyrrolidine proton, J = 8.3 Hz, J = 13.3 Hz), 2.57 (t, 1H, pyrrolidine proton, J = 8.0 Hz), 2.36 (dd, 1H, pyrrolidine proton, J = 3.5 Hz, J = 9.4 Hz), 2.30 (q, 1H, pyrrolidine proton, J = 6.8 Hz), 2.13 (m, 1H, pyrrolidine proton), 1.49 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.8, 142.4, 139.4, 133.5, 130.7, 128.9, 128.6, 127.3, 121.0, 117.3, 116.3 60.9, 59.7, 52.6, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3O: 330.1373; Found 330.1373.

[0206] Compound 73R: (R)-l-(l-benzylpyrrolidine-3-yl)-3-(4-chlorophenyl)urea

[0207] [a]26360 = (+) 8o (0.1 g / 100 mL acetone). Yield: 50%. Melting Point: 151-153 °C. 1H NMR (400 MHz, DMSO) 5 8.50 (s, 1H, NH), 7.46 - 7.19 (m, 9H, Ar), 6.37 (d, 1H, NH, J = 7.2 Hz), 4.12 (br, 1H, pyrrolidine proton in m, 1H, C-3), 3.58 (ABq, 2H, benzyl CH2), 2.68 (dt, 1H, pyrrolidine proton J =5.2 Hz, J = 8.4 Hz), 2.57 (t, 1H, pyrrolidine proton, J = 8.0 Hz), 2.38 (dd, 1H, pyrrolidine proton, J = 3.5 Hz, J = 9.4 Hz), 2.33 (q, 1H, pyrrolidine proton, J = 6.8 Hz), 2.16 (m, 1H, pyrrolidine proton), 1.52 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.9, 139.8, 139.4, 129.0, 128.9, 128.6, 127.3, 124.9, 119.4, 60.9, 59.8, 52.7, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3O: 330.1373; Found 330.1374. Compound 745: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4-chlorophenyl)urea

[0208] [a]26360 = (-) 80 (0.1 g / 100 mL acetone). Yield: 68%. Melting Point: 151-153 °C. 1H NMR (400 MHz, DMSO) 5 8.50 (s, 1H, NH), 7.46 - 7.19 (m, 9H, Ar), 6.37 (d, 1H, NH, J = 7.2 Hz), 4.12 (br, 1H, pyrrolidine proton in m, 1H, C-3), 3.58 (ABq, 2H, benzyl CH2), 2.68 (dt, 1H, pyrrolidine proton J =5.2 Hz, J = 8.4 Hz), 2.57 (t, 1H, pyrrolidine proton, J = 8.0 Hz), 2.38 (dd, 1H, pyrrolidine proton, J = 3.5 Hz, J = 9.4 Hz), 2.33 (q, 1H, pyrrolidine proton, J = 6.8 Hz), 2.16 (m, 1H, pyrrolidine proton), 1.52 (m, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 154.9, 139.8, 139.4, 129.0, 128.9, 128.6, 127.3, 124.9, 119.4, 60.9, 59.8, 52.7, 48.9, 32.4 ppm. HRMS (TOF MS ES+): Calculated C18H20C1N3O: 330.1373; Found 330.1374.

[0209] Compound 757?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)thiourea

[0210] [a]26360 = (-) 60o (0.1 g / 100 mL acetone). Yield: 88%. Melting Point: 67-69 °C. 1H NMR (400 MHz, DMSO) 5 9.54 (br, 1H, NH), 7.99 - 7.11 (m, 13H, NH ve Ar), 4.73 (pyrrolidine proton in br, 1H, C-3), 3.57 (ABq, 2H, benzyl CH2), 2.59 (br, 3H, pyrrolidine protons), 2.32 (dd, dd, 1H, pyrrolidine proton, J = 8.2 Hz, J = 3.5 Hz), 2.15 (br, 1H, pyrrolidine proton), 1.58 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 181.9, 139.2, 135.1, 134.4, 130.1, 128.9, 128.7, 127.4, 126.8 126.6, 126.1, 125.3, 123.2, 60.1, 59.6, 53.9, 52.7, 31.6 ppm. HRMS (TOFMS ES+): Calculated C22H23N3S: 362.1691; Found 362.1691.

[0211] Compound 765: (S)-l-(l-benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)thiourea [a]26360 = (+) 60o (0.1 g / 100 mL acetone). Yield: 89%. Melting Point: 67-69 °C. 1H NMR (400 MHz, DMSO) 5 9.54 (br, 1H, NH), 7.99 - 7.11 (m, 13H, NH ve Ar), 4.73 (pyrrolidine proton in br, 1H, C-3), 3.57 (ABq, 2H, benzyl CH2), 2.59 (br, 3H, pyrrolidine protons), 2.32 (dd, dd, 1H, pyrrolidine proton, J = 8.2 Hz, J = 3.5 Hz), 2.15 (br, 1H, pyrrolidine proton), 1.58 (br, 1H, pyrrolidine proton) ppm. 13C NMR (100 MHz, DMSO) 5 181.9, 139.2, 135.1, 134.4, 130.1, 128.9, 128.7, 127.4, 126.8 126.6, 126.1, 125.3, 123.2, 60.1, 59.6, 53.9, 52.7, 31.6 ppm. HRMS (TOFMS ES+): Calculated C22H23N3S: 362.1691; Found 362.1691.

[0212] Compound 777?: (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)urea

[0213] [a]26360 = (-) 80o (0.1 g / 100 mL acetone). Yield: 52%. Melting Point: 181-183 °C. 1H NMR (400 MHz, DMSO) 5 8.48 (s, 1H, NH), 8.08 (d, 1H, Ar, J = 8.1 Hz), 8.02 (d, 1H, Ar, J = 7.5 Hz), 7.89 (d, 1H, Ar, J = 7.6 Hz), 7.59 - 7.22 (m, 9H, Ar), 6.85 (d, 1H, NH, J = 7.5 Hz), 4.20 (pyrrolidine proton in br, 1H, C-3), 3.59 (ABq, 2H, benzyl CH2), 2.79 - 2.59 (m, 2H, pyrrolidine protons), 2.46 (dd, 1H, pyrrolidine proton, J = 3.6 Hz, J = 9.5 Hz), 2.35 (q, 1H, pyrrolidine proton, J = 8.4 Hz), 2.1 (m, 1H, pyrrolidine proton), 1.57 (m, 1H, pyrrolidine proton) ppm.l3C NMR (100 MHz, DMSO) 5 155.5, 139.1, 135.5, 134.1, 129.1, 128.8, 128.6, 127.4, 126.3, 126.2, 125.9, 125.7, 122.4, 121.6, 116.6, 61.0, 59.7, 52.7, 49.1, 32.5 ppm. HRMS (TOF MS ES+): Calculated C22H23N3O: 346.1919; Found 346.1920.

[0214] Compound 78S: (5)- 1 -( 1 -benzylpyrrolidine-3-yl)-3-(naphthalen- 1 -yl)urea

[0215] [a]26360 = (+) 80o (0.1 g / 100 mL acetone). Yield: 79%. Melting Point: 181-183 °C. 1H NMR (400 MHz, DMSO) 5 8.48 (s, 1H, NH), 8.08 (d, 1H, Ar, J = 8.1 Hz), 8.02 (d, 1H, Ar, J = 7.5 Hz), 7.89 (d, 1H, Ar, J = 7.6 Hz), 7.59 - 7.22 (m, 9H, Ar), 6.85 (d, 1H, NH, J = 7.5 Hz), 4.20 (pyrrolidine proton in br, 1H, C-3), 3.59 (ABq, 2H, benzyl CH2), 2.79 - 2.59 (m, 2H, pyrrolidine protons), 2.46 (dd, 1H, pyrrolidine proton, J = 3.6 Hz, J = 9.5 Hz), 2.35 (q, 1H, pyrrolidine proton, J = 8.4 Hz), 2.1 (m, 1H, pyrrolidine proton), 1.57 (m, 1H, pyrrolidine proton) ppm.l3C NMR (100 MHz, DMSO) 5 155.5, 139.1, 135.5, 134.1, 129.1, 128.8, 128.6, 127.4, 126.3, 126.2, 125.9, 125.7, 122.4, 121.6, 116.6, 61.0, 59.7, 52.7, 49.1, 32.5 ppm.

[0216] HRMS (TOF MS ES+): Calculated C22H23N3O: 346.1919; Found 346.1919.

[0217] Within these basic concepts; it is possible to develop various embodiments of the inventive “Compounds For the Treatment of Alzheimer's Disease and The Method (100) of Obtaining These Compounds”; the invention cannot be limited to examples disclosed herein and it is essentially according to claims.

Claims

CLAIMS1. Urea / thiourea compounds which are used in the treatment of Alzheimer's and Parkinson's disease that are progressive diseases and in which only symptomatic improvement is possible; provide simultaneous inhibition of cholinesterase and monoamine oxidase enzymes known to play roles in Alzheimer's disease; prevent the Ap fibril formation; provide neuroprotective effect by reducing oxidative damage; exhibit antioxidant effect; have formula (I) and formula (II); and characterized by two groups of compounds asorR SFormula (I)1 : Phenyl or naphthyl 2: -O or -S3: o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m- chlorophenyl, p-chlorophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenylFormula (II)1: o-methoxyphenyl, m- methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m- chlorophenyl, p-chlorophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, naphthyl 2: -O or -S.

2. Urea / thiourea compounds according to Claim 1; characterized by the ( / )- 1 -(2- methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea, (S)-l-(2-methoxyphenyl)- 3-(l-(naphthalen-l-yl)ethyl)thiourea, (7?)-l-(2-methoxyphenyl)-3-(l-(naphthalen- l-yl)ethyl)urea, (S)-l-(2-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l- (3-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl), (S)-l-(3-methoxyphenyl)-3-(l- (naphthalen-l-yl)ethyl)thiourea, (7?)-l-(4-methoxyphenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (5)- l-(4-methoxyphenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (7?)-l-(4-methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea, (5)-l-(4- methoxyphenyl)-3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(2-fluorophenyl)-3-(l- (naphthalen-l-yl)ethyl)thiourea, (S)-l-(2-fluorophenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (7?)-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea, (S)-l-(3-fluorophenyl)-3-(l-(naphthalen-l-yl)ethyl)thiourea, (7?)-l-(3- fluorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)urea, (5)- 1 -(3-fluorophenyl)-3-( 1 -(naphthalen- 1 -yl)ethyl)urea, (R)- 1 -(4-fluorophenyl)-3-( 1 -(naphthalen- 1 - yl)ethyl)thiourea, (S)-l-(4-fluorophenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea,(R)- 1 -(4-fluorophenyl)-3-( 1 -(naphthalen- 1 -yl)ethyl)urea, (5)- 1 -(4-fluorophenyl)- 3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(3-chlorophenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (S)-l-(3-chlorophenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (R)- 1 -(3-chlorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)urea, (5)- 1 -(3-chlorophenyl)- 3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(4-chlorophenyl)-3-(l-(naphthalen-l- yl)ethyl)thiourea, (S)-l-(4-chlorophenyl)-3-(l -(naphthalen- l-yl)ethyl)thiourea, (R)- 1 -(4-chlorophenyl)-3 -( 1 -(naphthalen- 1 -yl)ethyl)urea , (5)- 1 -(4-chlorophenyl)- 3-(l-(naphthalen-l-yl)ethyl)urea, (7?)-l-(2-methoxyphenyl)-3-(l- phenylethyl) thiourea, (5)- 1 -(2-methoxyphenyl)-3 -(1 -phenylethyl)thiourea, (R)- 1 - (2-fluorophenyl)-3-(l-phenylethyl)thiourea, (S)-l-(2-fluorophenyl)-3-(l- phenylethyl)thiourea, (7?)- l-(3-fluorophenyl)-3-(l-phenylethyl)thiourea, (5)-l-(3- fluorophenyl)-3-(l-phenylethyl)thiourea belonging to the formula (I).

3. Urea / thiourea compounds according to Claim 1 or 2; characterized by the (7?)- 1 -( 1 -benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)thiourea, (5)- 1 -( 1 - benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)thiourea, (7?)-l -(1 -benzy Ipyrrolidine- 3-yl)-3-(3-methoxyphenyl)thiourea , (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3- methoxyphenyl)thiourea, (7?)- 1 -( l-benzylpyrrolidine-3-yl)-3-(4- methoxyphenyl)thiourea , (5')-l-(l-benzylpyrrolidine-3-yl)-3-(4- methoxyphenyl)thiourea, (7?)- 1 -( l-benzylpyrrolidine-3-yl)-3-(2- methoxyphenyl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(2-methoxyphenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)urea, (S)-l-(l- benzylpyrrolidine-3-yl)-3-(3-methoxyphenyl)urea, (7?)-l-(l -benzy lpyrrolidine-3- yl)-3-(4-methoxyphenyl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(4- methoxyphenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)thiourea, (5)- 1 -( 1 -benzylpyrrolidine-3-yl)-3 -(2-fluorophenyl)thiourea, (7?)- 1 -( 1 - benzy Ipyrrolidine- 3 - y 1) - 3 - (3 -fluoropheny l)thiourea, (5)- 1 -( 1 -benzy Ipyrrolidine- 3 - yl)-3-(3-fluorophenyl)thiourea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4- fluorophenyl)thiourea, (5)- 1-(1 -benzy Ipyrrolidine- 3 -y l)-3-(4- fluorophenyl)thiourea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(2-fluorophenyl)urea, (5)- 1 -( 1 -benzy lpyrrolidine-3-yl)-3 -(2-fluorophenyl)urea, (7?) - 1 - ( 1 -benzylpyrrolidine-3-yl)-3-(3-fluorophenyl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(3-fluorophenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-fluorophenyl)urea,(5)- 1 -( 1 -benzylpyrrolidine-3-yl)-3 -(4-fluorophenyl)urea, (7?)-l-(l- benzylpyrrolidine-3-yl)-3-(2-chlorophenyl)thiourea, (S)-l-(l -benzylpyrrolidine-3 - yl)-3-(2-chlorophenyl)thiourea, (R)- 1 -( 1 -benzylpyrrolidine-3-yl)-3-(3 chlorophenyl)thiourea, (5)- 1 -( 1 -benzylpyrrolidine-3 -yl)-3-(3 chlorophenyl)thiourea, (7?)- 1 -( 1 -benzylpyrrolidine-3 -yl)-3-(4 chlorophenyl)thiourea, (5)- 1 -( 1 -benzylpyrrolidine-3 -yl)-3-(4 chloropheny l)thiourea, (7?) - 1 - ( 1 -benzy Ipyrrolidine- 3 -y 1) - 3 - (2-chloropheny l)urea,(5)- 1 -( 1 -benzylpyrrolidine-3-yl)-3 -(2-chlorophenyl)urea, (7?)-l-(l- benzylpyrrolidine-3-yl)-3-(3-chlorophenyl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)- 3-(3-chlorophenyl)urea, (7?)-l-(l-benzylpyrrolidine-3-yl)-3-(4-chlorophenyl)urea, (5)- 1 -( 1 -benzylpyrrolidine-3-yl)-3 -(4-chlorophenyl)urea, (7?)- 1 -( 1 - benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)thiourea, ( )-l -( l -bcnzylpyrrolidinc-3- yl)-3-(naphthalen- 1 -yl)thiourea, (7?)- 1 -( 1 -benzylpyrrolidine-3-yl)-3-(naphthalen- 1 - yl)urea, (S)-l-(l-benzylpyrrolidine-3-yl)-3-(naphthalen-l-yl)urea belonging to the formula (II).

4. A pharmaceutical composition comprising at least one compound according to any one of the Claims 1 to 3.

5. A medicament comprising at least one compound according to any one of the Claims 1 to 3.

6. A compound according to any one of the preceding claims; which is used in the treatment of diseases involving dementia, depression, anxiety, cancer, bacterial infection, convulsions, HIV, diabetes and cognitive disorder.

7. A method (100) used for synthesizing urea / thiourea compounds according to any one of the preceding claims; characterized in that it comprises the steps ofsynthesizing urea / thiourea compounds by mixing (R / S) 1- phenyl(naphthyl)ethyl amine or (3 / / 3 )- l-bcnzyl-3-aininopyrrolidinc and phenyl / naphthyl isocyanate (isothiocyanate) in dichloromethane (101); and purifying synthesized compounds (102).

8. A method (100) according to Claim 1; characterized in that in step of synthesizing urea / thiourea compounds by mixing (R / S) l-phenyl(naphthyl)ethyl amine or (37? / 35')-l-benzyl-3-aminopyrrolidine and phenyl / naphthyl isocyanate (isothiocyanate) in dichloromethane (101), urea / thiourea derivative compounds are synthesized by mixing equivalent moles of (R / S) l-phenyl(naphthyl)ethyl amine or (37? / 35')-l-benzyl-3-aminopyrrolidine and phenyl / naphthyl isothiocyanate in dichloromethane for 1-5 hours at room temperature.

9. A method (100) according to Claim 1; characterized in that in step of purifying synthesized compounds (102), the reaction is monitored by thin-layer chromatography when urea / thiourea compounds are being synthesized and the synthesized compounds are purified by crystallization from ethanol or precipitation from ethyl acetate / n-hexane mixture.