EA042766B1 - 4-PYRAZINE-2-YLMETHYL-MORPHOLINE DERIVATIVES AND THEIR USE AS A MEDICINE - Google Patents

Description

The present invention relates to new 4-pyrazin-2-ylmethyl-morpholines of general formula A

methods for their preparation, pharmaceutical compositions which contain them, and their use in therapy, in particular for the treatment or prevention of conditions associated with NR2B negative allosteric modulating properties.

The compounds according to the invention according to the general formula A exhibit NR2B negative allosteric modulating properties.

In extensive studies over the past twenty years, N-methyl-D-aspartate (NMDA) receptors have been shown to play an important role in Alzheimer's disease, Parkinson's disease, dyskinesia, stroke, motor neuron disease, psychosis, epilepsy, anxiety, schizophrenia and pain. In recent years, the non-selective NMDA receptor antagonist ketamine (racemic as well as the S enantiomer), a drug used primarily for the initiation and maintenance of anesthesia, has been shown to be clinically effective in the treatment of major depressive disorder (MDD) at subanesthetic doses (Murrough and 2013, Am J Psychiatry 170: 1134; Singh et al 2016, Biol Psychiatry 80: 424). More specifically, ketamine exhibits a rapid onset of efficacy that lasts several days in MDD patients who do not respond well to standard drug therapy (Berman et al. 2000. Biol Psychiatry 47:351, Serafini et al. 2014. Curr. Neuropharmacol. 12: 444). However, non-selective NMDA receptor antagonists have many undesirable effects that limit their use. In particular, dissociative and psychogenic side effects are significant for non-selective NMDA receptor antagonists such as ketamine (Krystal et al. 1994. Arch. Gen. Psychiatry 51:199). In the early 1990s, the existence of different NMDA receptor subtypes was discovered that contain different NR2(A-D) subunits (Paoletti et al., 2013 Nat Rev. Neurosci 14:383). Recently, selective negative NR2B receptor NMDA receptor allosteric modulators (NR2B NAM) have received increased interest and have shown their potential for a wide range of clinical indications such as attention, emotion, mood and pain, as well as their involvement in various disorders in humans ( Mony et al., 2009. Br. J. Pharmacol 157:1301; Chaffey et al., Current Anaesthesia & Critical Care 19, 183). In particular, NR2B NAMs have also demonstrated the effectiveness of antidepressants in early clinical trials (Preskorn et al. 2008. J Clin Psychopharmacol 70:58). In preclinical studies using NR2B NAM as well as various strains of transgenic mice, NR2B containing NMDA receptors have been shown to mediate the beneficial effects of ketamine, for example in the forced swim test (Miller et al. 2014 eLife 3:e03581; Kiselycznyk et al. 2015, Behav Brain Res, 287:89). Moreover, selective NR2B NAMs have advantages over non-selective NMDA receptor antagonists such as ketamine due to significantly reduced dissociative and psychotomimetic side effects (Jimenez-Sanchez et al. 2014. Neuropsychopharmacology 39:2673). To date, NR2B NAMs have been described as having disadvantages with respect to their receptor pharmacology and/or other drug properties that have limited potential use for drug therapy in humans (Taylor, et al., 2006, Clin Pharmacokinet. 45: 989 ; Addy et al. 2009 J of Clinical Pharmacology 49:856)).

WO2015/130905 describes compounds of formula (I)

which are Nav1.6 inhibitors useful in the treatment of multiple sclerosis, polyneuritis, neuritis multiplex, amyotrophic lateral sclerosis, Alzheimer's disease or Parkinson's disease. WO2015/130905 describes specific examples 100, 105, 106 and 107 in which ring B corresponds to a meta-disubstituted phenyl ring.

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Example 100 Example 105 Example 106 Example 107

WO2015/130905 describes specific examples 100, 105, 106 and 107 which are weak Nav1.6 inhibitors (Nav 1.6 blockade for examples 100, 105 and 107 at 1-5 µM, and Nav 1.6 blockade for example 106 at >5 µM ).

The compounds of the present invention generally fall within formula (I) of WO2015/130905. The compounds of the present invention differ structurally from Examples 100, 105, 106 and 107 detailed in WO2015/130905 in that they contain a para-disubstituted pyrazinyl substructure instead of a meta-disubstituted phenyl ring.

Structural differences unexpectedly result in effective NR2B negative allosteric modulators (see Table 1), while specific examples 100, 105, 106 and 107 from WO2015/130905 do not show any activity on the NR1-NR2B ion channel (see Table 1). Table 2). In addition, the compounds of the present invention do not inhibit Nav 1.6 at concentrations where Specific Examples 100 and 105 of WO2015/130905 inhibit Nav 1.6 (5 μM; see Tables 3 and 4).

Moreover, the compounds of the present invention exhibit good membrane permeability and no efflux in vitro (see Table 5 for the MDCK assay of MDR1 (P-gp)). Therefore, it is believed that the compounds of the present invention exhibit favorable penetration into the brain, which is necessary for effective drugs for the treatment of diseases of the CNS. MDCK assays provide information regarding the ability of a compound to cross the blood-brain barrier. Permeability measurements through polarized, confluent monolayers of MDCK-MDR1 cells growing on permeable filter substrates were used as an in vitro absorption model: apparent permeability coefficients (PE) of compounds were measured through monolayers of MDCK-MDR1 cells (pH 7.4, 37°C) in the direction of transport from apical to basal (AB) and from basal to apical (BA). AV permeability (PEAV) is the absorption of a drug from the blood into the brain, and VA permeability (PEVA) is the efflux of a drug from the brain back into the blood through both mechanisms, passive permeability as well as active transport mechanisms mediated by efflux and uptake transporters , which are expressed on MDCK-MDR1 cells, primarily via overexpressed human MDR1. Identical or similar permeabilities in both directions of transport indicate passive permeability (PEBA/PEAB<1), vectorial permeability indicates additional active transport mechanisms. A higher PEBA compared to PEAV (PEBA/PEAV >5) indicates the involvement of an active efflux mediated by MDR1, which may be detrimental to achieve sufficient exposure in the brain. Thus, this assay provides valuable support for the selection of compounds suitable for further in vivo testing. High permeability, not limited by efflux, across the blood-brain barrier is a favorable characteristic for compounds intended to be used as drugs primarily acting in the CNS.

In addition, the compounds of the present invention are metabolically stable in human liver microsomes (see Table 6, metabolic stability). Thus, the compounds of the present invention are expected to have a favorable in vivo clearance and hence a desirable duration of action in humans.

Stability in human liver microsomes refers to the sensitivity of compounds to biotransformation in the context of selecting and/or designing drugs with favorable pharmacokinetic properties. The primary site of metabolism for many drugs is the liver. Human liver microsomes contain cytochrome P450 (CYP) and thus are a model system for studying drug metabolism in vitro. The increased stability in human liver microsomes is associated with several benefits, including increased bioavailability and a sufficient half-life, which may provide lower and less frequent dosing for patients. Thus, increased stability in human liver microsomes is a favorable characteristic for compounds intended for drug use.

Therefore, the compounds according to the present invention will be more competitive

- 2 042766 for use in humans.

Thus, it is an established technical challenge to provide effective and selective NR2B negative allosteric modulators.

The present invention provides novel 4-pyrazin-2-ylmethyl-morpholines of formula A

in which R ¹ represents methyl, ethyl, propyl, isopropyl, cyclopropyl, H3C-CH _{2 -CH} 2 -CH ₂ -, cyclobutyl;

R ² is phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl, cyclopropyl; or a salt thereof, in particular a pharmaceutically acceptable salt thereof.

In another embodiment, in general formula A, R ² has the same meaning as defined in any of the previous embodiments, and R ¹ is methyl, ethyl.

In another embodiment, in general formula A, R ¹ has the same meaning as defined in any of the preceding embodiments, and R ² is

The present invention provides novel 4-pyrazin-2-ylmethyl-morpholines of general formula A which are surprisingly potent and selective negative allosteric modulators of NR2B.

Another aspect of the invention relates to compounds according to formula A as potent and selective NR2B negative allosteric modulators having high membrane permeability and no efflux in vitro.

Another aspect of the invention relates to compounds according to formula A as effective and selective NR2B negative allosteric modulators having high tabolic stability in human liver microsomes.

Another aspect of the invention relates to compounds according to formula A as efficacious and selective NR2B negative allosteric modulators having high membrane permeability, no in vitro efflux and high metabolic stability in human liver microsomes.

Another aspect of the invention relates to pharmaceutical compositions containing at least one compound according to formula A, optionally together with one or more inert carriers and/or diluents.

A further aspect of the present invention relates to compounds according to formula A, for use in the prevention and/or treatment of disorders associated with NR2B negative allosteric modulators.

Another aspect of the invention relates to methods for the preparation of compounds according to the present invention.

Cooking.

The following scheme generally illustrates how the compounds according to the general formula A and the corresponding intermediates are prepared, by way of example. Abbreviated substituents may be defined as above unless the context of the scheme clearly dictates otherwise.

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Scheme 1

Scheme 1 illustrates the synthesis of pyrazine derivatives of the general formula A. The first step is the nucleophilic substitution of the substituted phenol derivative R2-OH and the methyl ester of 5-chloropyrazine-2-carboxylic acid; the ester group is reduced to the corresponding alcohol using NaBH4, then the hydroxy group is converted to a leaving group (eg mesylate).

The last step is nucleophilic displacement using mesylate and a slight excess of (S)-morpholine-2-carboxylic acid amide derived from the reaction of (8)-morpholine-2-carboxylic acid methyl ester with the corresponding amine R1-NH2. The synthesis approach described can also be used for gram scale synthesis using various purification techniques such as crystallization or column chromatography.

General definitions

Terms that are not specifically defined in this application should be understood in the meanings that they are understood by a person skilled in the art, taking into account the disclosure and context. The NR2B ion channel should be understood as an NMDA receptor containing an NR2B protein.

In the event that a compound of the present invention is presented as a chemical name as well as a formula, then the formula will take precedence in the event of any inconsistency. The symbol * can be used in subformulas to indicate a bond that connects to the nucleus of the molecule or to the substituent to which it is bonded, as defined.

The term substituted, as used in this application, means that any one or more hydrogens on the specified atom are replaced by a group selected from the specified groups, provided that the allowable numerical value of the valency of the specified atom is not exceeded, and that the substitution leads to the formation of a stable compound.

Stereochemistry.

Unless specifically stated otherwise, for the purposes of the description and claims of the appended claims, this chemical formula or name will cover rotamers, tautomers, and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereoisomers, E/Z isomers, etc.) and their racemates, as well as mixtures in various ratios of separate enantiomers, mixtures of diastereoisomers, or mixtures of any of the above forms, to which such isomers and enantiomers exist.

Salt.

The term pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions and/or dosage forms that are medically suitable for use in contact with human tissues, without undue toxicity, irritation, allergic response, or other problems or complications and are commensurate with a reasonable benefit/risk ratio.

As used herein, pharmaceutically acceptable salts refer to derivatives of the described compounds in which the parent compound forms a salt or complex with an acid or base. Examples of acids forming a pharmaceutically acceptable salt with the parent compound containing an alkaline component include mineral or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, or tartaric acid.

Examples of cations and bases forming a pharmaceutically acceptable salt with the parent compound containing an acidic component include Na ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ , NH ₄ ⁺ , L-arginine, 2,2'iminobisethanol, L-lysine, N-methyl-D-glucamine or tris(hydroxymethyl)aminomethane.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains an alkaline or acidic component using conventional chemical methods. In general, such salts may be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile or their mixture. Salts of other acids other than those mentioned above, which, for example, are suitable for purifying or isolating the compounds of the present invention (eg, trifluoroacetate salts) also form part of the invention.

Biological analyzes and data.

List of abbreviations.

DMEM - Dulbecco's Modified Eagle's Medium.

FBS - fetal bovine serum.

FLIPR is a fluorescence imaging plate reader spectrophotometer.

HEK293 is a cell line derived from human embryonic kidney cells.

HEPES - buffer based on hydroxyethyl piperazine ethane sulfonic acid.

IC ₅₀ - half maximum inhibitory concentration.

MDCK - Canine Kidney Madin-Darby Cells.

MDR1 is a multidrug resistance protein 1.

P-gp - p-Glycoprotein.

SOS is the standard error of the mean.

EGTA (ethylene glycol-bis(b-aminoethyl ether)-N,N,N',N'-tetraacetic acid), also known as egtazic acid.

In vitro influence.

Determination of pharmacological activity in vitro.

The activity of the compounds of the invention can be demonstrated using the following in vitro NMDA NR1/NR2B cell assays.

Method.

The human HEK293 cell line with tetracycline-induced expression of the NMDA NR1/NR2B receptor was used as a test system to evaluate the efficacy and activity of the compound. The cell line was obtained from ChanTest, catalog number CT6121. Compound activity was determined by measuring the effect of compounds on intracellular calcium concentration induced by glycine/glutamate agonism in the FLIPRtetra system (Molecular Devices).

Cell culture.

Cells were obtained as frozen cells in cryo vials and stored at -150° C. until use.

Cells were grown in cell culture (DMEM/F12, 10% FBS, 5 μg/ml Blasticidin, 150 μg/ml Zeocin, 500 μg/ml Geneticin). It is extremely important that the density should not exceed 80% confluence. For subculturing, cells were detached from the flasks using Versen. For the study, cells were detached, washed twice with induction medium (DMEM/F12 without glutamine, 10% FBS, 2 μg/ml Tetracycline, 2 mM Ketamine) and plated in 384-well amine-coated plates (Becton Dickinson, 50,000 cells per well in 50 µl) 48 hours before analysis in the induction medium.

Compound preparation.

Test compounds were dissolved in 100% DMSO at 10 mM and diluted in DMSO to 5 mM in a first step followed by serial dilution steps in 100% DMSO. The dilution ratio and the number of dilution steps can be changed according to needs. Typically, 8 different concentrations were prepared using 1:5 dilutions in duplicate, followed by intermediate dilutions (1:37.5) of substances in aqueous assay buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl ₂ , 10 mM HEPES, 10 mM Glucose, pH 7.4) resulting in a compound concentration 3 times the final test concentration and DMSO at 2.7% resulting in a 0.9% final DMSO concentration in the study.

FLIPR analysis.

On the day of the study, the cells were washed 3x with assay buffer (as described above), 10 µl of buffer remained in the wells after washing. 10 µl Ca loading kit buffer (AAT Bioquest; prepared from a kit containing the following components: Component A: Fluo-8 NW was dissolved in 200 µl DMSO and 20 µl of this solution was mixed with 10 ml buffer prepared from components B and C, Component B: 10x Pluronic® F127 Plus diluted 1:10 in component C, component C: HHBS (Hanks with 20 mM Hepes) was added to the cells and the plates were incubated with the lid for 60 min at room temperature 20 µl of assay buffer containing 60 μM glycine (20 μM final) and 3 μM glutamate (1 μM final) were added to column 1-23, column 24 received assay buffer without glycine/glutamate and was a negative unstimulated control. NR1/NR2B ion channel activation) on a FLIPRtetra device for 60 s to monitor glutamate-induced effects After 2 min, 20 µl dilutions of the compounds prepared as described above or controls (rows 1-22) were carefully added to the wells. Fluorescence was read on a FLIPR tetra device for an additional 6 min.

- 5 042766 for monitoring the effects induced by the compound after activation by agonists. The average value for 2 measurements at 5 min, 5 min 10 s after compound addition was calculated and subsequently used for IC ₅₀ calculations. Each microtiter plate for diluted compounds contained wells (in column 23 or 24) with DMSO controls instead of compounds as controls for glycine/glutamate-induced fluorescence (high controls) and wells with 1 μM reference NR2B NAM as low controls (compound 22; reference: Layton, Mark E et al., ACS Chemical Neuroscience 2011, 2(7), 352-362).

Data evaluation and calculation.

The reader output file contained the well number and measured mean fluorescence units. For data evaluation and calculations, low control measurements were taken as 0% control and high control measurements were taken as 100% control. IC ₅₀ values were calculated using the standard four parameter logistic model formula. Calculation:

[y=(ad)/(1+(x/c) ^b )+d], a=low value;

d=high value;

x=conc M;

c=IC50M;

b=tilt.

Preferred are NR2B negative allosteric modulators encompassed by the general structure A and exhibiting a low IC ₅₀ value.

Table 1

The NR2B affinity of the in vitro compounds of the present invention, . as obtained in FLIPR analysis

Example number IC50 [nM] 1 968 2 123 3 690 4 1200 5 110 6 87 7 1002 8 856 9 210 18 222 thirty 595 31 524 33 807 34 644 35 197 36 542

table 2

NR2B affinity in vitro closest analogues of the compounds (examples 100, 105, 106 and 107 in application WO2015/130905), as obtained in a similar FLIPR analysis for the compounds in table. 1

Example number in WO2015/130905 IC50 [nM] 100 >8887 105 >9261 106 >9255 107 >9257

Determination of Nav inhibition 1.6.

Equipment.

Electrophysiology platform IonWorks Quattro.

Compound tablet preparation.

Compounds were prepared in DMSO at 300x final assay concentrations of 1 and 5 μM.

The 300x DMSO stock solutions were transferred to assay plates, where 2 μl per well of each 300x stock solution was placed. All assay plates were stored at -80°C until the day of analysis.

On the day of analysis, suitable assay plates were thawed at room temperature, centrifuged, and 198 µl of external recording solution was added and mixed thoroughly.

This provided a 1:100 dilution. A further 1:3 dilution occurred when cells were added to the IonWorks Quattro electrophysiology platform, resulting in a total of 1:300 dilution.

In each assay plate, at least 8 wells were left for the vehicle control (0.3% DMSO) and at least 8 wells for each positive control specific to the cell line being tested. Positive controls were tested at maximum blocking and approximately IC ₅₀ concentration. Lidocaine was used as a positive control.

- 6 042766 concentrations of 30 and 1000 μM.

Solutions for registration of electrophysiological data.

The solutions for recording Nav1.6 currents were as follows:

external recording solution;

NaCl 137 mM;

KCl 4 mM;

MgCl ₂ 1 mM;

CaCl2 1.8 mM;

HEPES 10 mM;

Glucose 10 mM;

pH 7.3 (titrated with 10 M NaOH).

Internal recording solution:

CsF 90 mM;

CsCl 45 mM;

HEPES 10 mM;

EGTA 10 mM;

pH 7.3 (titrated with 1M CsOH).

Amphotericin B was used to obtain electrical access into the cells at a final concentration of 200 μg/ml in an internal recording solution.

Experimental protocols and data analysis.

Experimental protocol Nav1.6.

State dependent inhibition: sodium channels, when held at a depolarized potential or a long test pulse, the channels open and become inactivated and then remain inactivated until the membrane potential returns to hyperpolarized potentials when the inactivated channels recover from being inactivated in the closed state . An example is inhibition by Tetracaine, which is significantly stronger at a depolarized potential compared to a hyperpolarized potential. Nav1.6 data analysis.

Cells were kept at -120 mV. For complete inactivation of sodium channels (pulse 1), cells were pulsed to +0 mV for 2500 ms and returned back to -120 mV for 10 ms (for complete recovery from inactivation, however, channels to which drugs were bound , did not recover from inactivation) before going to +0 mV for 20 ms (pulse 2) as shown in FIG. 1.

Ion channel profiling data filters:

Data filter Platform Criteria Shutter quality IonWorks Quattro >30 MΩ Removing the shutter IonWorks Quattro <50% Shutter Removal (Shutter before Linking/Shutter after Linking) Current amplitude IonWorks Quattro >200 pA

Results of the control analysis.

In FIG. 2 provides exemplary positive control and vehicle control data associated with each cell line analyzed. The mean value is shown for each positive and negative control as a shaded symbol, with the total number of replicates of the individual wells shown next to the shaded symbol. Additionally, the individual data for each well is presented on the graph as open symbols, so fluctuations around the mean can be easily assessed. These data are provided to determine whether a compound will have ion channel activities compared to control data and provides an indication of assay variability and is therefore used to estimate the magnitude of a compound-specific effect that could be detected.

In FIG. 2 shows the control assays for the Nav1.6 IonWorks Quattro assay. Lidocaine, the reference compound for Nav1.6, inhibited evoked currents in a concentration- and application-dependent manner, as predicted.

To illustrate assay variability, both Example 106 of WO2015/130905 showing 14% inhibition of Nav 1.6 at 5 µM (normalized, see Table 3) and Example 7 of the present invention showing -15% inhibition of Nav 1.6 at 5 µM (normalized , see Table 4), respectively, are within the assay variability compared to control assay data, and thus do not show any significant inhibition of the Nav 1.6 channel at 5 μM.

In table. 3 and 4 show normalized percent inhibition of the Nav1.6 channel. Normalized data shows compound data normalized to vehicle control (0% inhibition) and maximum inhibition control (100% inhibition); maximum inhibition at Plc using 1000 μM lidocaine (not standardized) are in the range from 46.4% to

47.2% when performing experiments (see also Fig. 2. Results of the control analysis).

Table 3

Normalized in vitro Nav 1.6 inhibition of the closest analogues of the prior art (examples 100, 105, 106 and 107 in application WO2015/130905), as obtained in a similar electrophysiological analysis as for the compounds in table. 4 (concentrations: 1 and 5 μM)

Example number in WO2015/130905 Normalized other inhibition in % at 1 µM Normalized inhibition in % at 5 µM Percentage of SOS at 1 µM Percentage of SOS at 5 µM 100 2.2 37.8 6.2 8.4 105 18.2 68 2.6 4.1 106 -0.7 14 1.6 0.4 107 -8.5 13.1 3.9 2.8

Table 4 Normalized Nav 1.6 inhibition in vitro for compounds according to the present invention, as obtained in a similar electrophysiological analysis, as for compounds from the prior art in table. 3 (concentrations: 1 µM and 5 µM)

Example number Normalized inhibition in % at 1 µM Normalized inhibition in % at 5 µM Percentage of SOS at 1 µM Percentage SOS at 5 µM 1 -9 0.5 5.5 3.8 2 -4.4 -4.0 3.8 4.2 3 4.6 6.8 2.5 0.9 4 3.4 5 5.0 5.1 5 -3.9 3.7 1.9 2.2 6 5.6 0.2 2.1 2.7 7 -9 -15 5.4 1.6 8 3 1.1 5.1 4.2 9 0 4.6 0 3.8 18 -5 -10 4.3 3.7 thirty -13.4 -9.4 5.3 4.6 31 -5.8 -7 3.6 1.2 33 -10.5 -6.6 4.6 1.0

Preferred are NR2B negative allosteric modulators encompassed by the general structure A, which do not show any significant inhibition of Navi.6.

Compounds of the present invention did not show any significant inhibition of the Nav 1.6 channel at 1 and 5 μM, respectively (see Table 4 and Control Analysis Results), while examples 100 and 105 from WO2015/130905 showed 37.8 and 68 % inhibition of Nav 1.6 at 5 μM, respectively (see Table 3). Examples 106 and 107 of WO2015/130905 do not show any significant inhibition of the Nav 1.6 channel at 1 and 5 μM, respectively (i.e., inhibition is within assay variability, see Table 3 and Control Assay Results).

MDCK analysis of P-gp.

Apparent permeability coefficients (Papp) of compounds were measured through MDCK-MDR1 monolayers (MDCKII cells transfected with a plasmid expressing human MDR1 cDNA) in the apical to basal (AB) and basal to apical (BA) directions. MDCK-MDR1 cells (6x10 ⁵ cells/cm ² ) were seeded on filter elements (Coming, Transwell, polycarbonate, pore size 0.4 μm) and cultured for 9-10 days. Compounds dissolved in DMSO stock solution (1-20 mM) were diluted with HTP-4 aqueous buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO ₄ , 1.8 mM CaCl ₂ , 4.17 mM NaHCO ₃ , 1.19 mM Na ₂ HPO ₄ , 0.41 mM NaH ₂ PO ₄ , 15 mM HEPES, 20 mM glucose, pH 7.4) supplemented with 0.25% BSA, to prepare transport solutions (final concentration : 1 or 10 μM, final concentration of DMSO <0.5%). The transport solution was applied to the apical or basolateral donor side to measure A-B or B-A permeability, respectively. The receiving side contained HTP-4 buffer supplemented with 0.25% BSA. Samples were collected at the beginning and end of the experiment from the donor and at various time intervals up to 2 h also from the receiving side to measure concentrations using an HPLC-MS/MS (RapidFire High-throughput MS System (Agilent)) connected to a QTrap 6500 (AB Sciex ) or TSQ Vantage (Thermo Scientific)). The volumes of withdrawn intake samples were replaced with fresh intake solution. The efflux ratio was calculated by dividing the Papp (b-a) values by the Papp (a-b) values. The results are presented in table. 5.

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Table 5

Etc. Average Papp (a-b) [10-6 cm/s] REVA/PEAV efflux ratio 1 59 0.7 2 76 0.6 3 75 0.7 4 61 0.7 5 59 0.8 6 71 0.8 7 66 0.7 8 70 0.6 9 62 0.9 18 61 0.8 thirty 81 0.4 31 66 0.6 33 59 0.7

The experimental results presented above indicate that the compounds of the present invention are potent NR2B NAMs having high membrane permeability and no in vitro efflux, suggesting a very good ability to cross the blood-brain barrier.

metabolic stability.

The metabolic degradation of the test compound was examined at 37° C. with pooled human liver microsomes. A final incubation volume of 60 µl per time point contained TRIS buffer pH 7.6 at room temperature (0.1 M), magnesium chloride (5 mM aqueous solution), microsomal protein (1 mg/mL for humans) and test compound at final concentration 1 μM. After a short pre-incubation period at 37° C., reactions were initiated by adding betanicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and stopped by transferring an aliquot to acetonitrile at various time intervals. After centrifugation (10,000 g, 5 min), an aliquot of the supernatant was analyzed by HPLC-MS/MS as described above for P-gp MDCK analysis to quantify parent compound. The half-life was determined by the slope of the semi-log plot of the concentration versus time profile. The results are presented in table. 6.

The experimental results presented above indicate that the compounds of the present invention are potent NR2B NAMs with high stability in human liver microsomes.

The present invention provides compounds in accordance with formula A, which unexpectedly lead to a favorable combination of the following key parameters:

1) efficient and selective allosteric modulation of NR2B,

2) high stability in human liver microsomes, and

3) high permeability and no in vitro efflux in MDCK-MDR1 cell transporters.

Pharmaceutical composition.

Suitable formulations for administering the compounds of the present invention will be understood by those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalations, powders;

Suitable tablets can be prepared, for example, by mixing a compound of the present invention with known excipients, for example, inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.

- 9 042766 mi substances and pressing the resulting mixture with the formation of tablets.

Application for treatment / method of application.

Therapeutic applications of NR2B NAM in humans have been summarized in reviews by Traynelis et al. (Traynelis et al., Pharmacology Reviews, 2010, 62:405), Beinat et al. (Bernat et al., Current Medicinal Chemistry, 2010, 17:4166) and Mony et al. (Mony et al., British J. Pharmacology, 2009, 157:1301). The present invention relates to compounds that are useful in the treatment of psychiatric disorders, diseases and conditions in which negative allosteric modulation of NR2B has a therapeutic advantage:

(1) mood disorders and affective mood disorders;

(2) schizophrenia spectrum disorders;

(3) neurotic, stress-mediated and somatoform disorders, including anxiety disorders;

(4) developmental disorders;

(5) behavioral syndromes associated with physiological disorders and physical factors;

(6) substance use disorders and addictive disorders;

(7) disease associated with negative and positive valence symptoms;

(8) pain;

(9) cerebrovascular disease;

(10) episodic and paroxysmal disorders;

(11) neurodegenerative diseases.

In view of their pharmacological effect, the compounds of the present invention are suitable for use in the treatment of a disorder, disease or condition selected from the list including:

(1) treatment of mood disorders and mood affective disorders, including bipolar I disorder depressive, hypomanic, manic and mixed; bipolar disorder II; depressive disorders such as single episode or recurrent major depressive disorder, minor depressive disorder, postpartum onset depressive disorder, depressive disorders with psychotic symptoms; major depressive disorder with or without associated anxiety distress, mixed features, melancholic features, atypical features, psychotic features consistent with mood, psychotic features not consistent with mood, catatonia;

(2) treatment of mood disorders related to the schizophrenia spectrum and other psychotic disorders, including schizophrenia and schizoaffective disorder in association with negative and cognitive symptoms;

(3) treatment of disorders related to neurotic, stress-related and somatoform disorders, including anxiety disorders, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorders; obsessive-compulsive disorder; response to severe stress and adjustment disorders such as post-traumatic stress disorder; other neurotic disorders such as depersonalization-derealization syndrome;

(4) treatment of developmental disorders, including pervasive developmental disorders, including Asperger's syndrome and Rett's syndrome, autistic disorders, childhood autism and hyperactive disorder associated with mental retardation and stereotyped movements, specific motor developmental disorder, specific developmental learning disorder, lack of concentration of attention / hyperactivity syndrome;

(5) treatment of behavioral syndromes associated with physiological disorders and physical factors, including mental and behavioral disorders associated with the postpartum period, including postnatal and postpartum depression; eating disorders, including anorexia nervosa and bulimia nervosa and other impulse control disorders;

(6) treatment of substance use disorders and addictive disorders in which substance use disorders are induced by alcohol, cannabis, hallucinogen, stimulant, hypnotic, tobacco;

(7) treatment of disease associated with negative and positive valence symptoms, including anhedonia, delayed threat and loss, suicidal ideation;

(8) treatment of acute and chronic pain that is associated with neuropathy, such as diabetic neuropathy or polyneuropathy, physiological processes and physical disorders, including, for example, pain in the lumbosacral region, joint pain, diseases of the musculoskeletal system and connective tissue eg rheumatism, myalgia, nerve, nerve root and nerve plexus lesions eg phantom limb pain syndrome, carpal tunnel syndrome;

- 10 042766 (9) treatment of cerebrovascular diseases, for example, intracerebral or subarachnoid hemorrhage, ischemic stroke, stroke, occlusion and stenosis, cerebral atherosclerosis, cerebral amyloid angiopathy;

(10) treatment of episodic and paroxysmal disorders such as epilepsy;

(11) treatment of diseases that include forms of neurodegeneration such as stroke, Alzheimer's disease and Huntington's disease.

As used herein, unless specifically indicated otherwise, the terms treatment, treat will include monitoring and managing a human subject or human patient to combat a disease, condition, or disorder, and include administering a compound of the present invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate a disease, condition or disorder.

As used in this application, unless specifically stated otherwise, the term prevention will include:

(a) reduction in the frequency of one or more symptoms;

(b) reducing the severity of one or more symptoms;

(c) delaying or avoiding the development of additional symptoms; and/or (d) delaying or avoiding the development of the disorder or condition.

According to another aspect, the present invention provides a compound of formula A, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of the above conditions. According to another aspect, the present invention provides a compound of formula A according to any of the previous aspects, characterized in that the compound of formula A is used in addition to behavioral therapy, TMS (transcranial magnetic stimulation), ECT (electroconvulsive therapy) and other therapies.

Combined therapy.

The compounds of the present invention may be combined with other treatment options known to be used in the art for the treatment of any of the indications the treatment of which is the focus of the present invention. According to another aspect, the present invention provides a compound of formula A according to any of the previous aspects, characterized in that the compound of formula A is administered in addition to treatment with one or more antidepressants selected from the list including duloxetine, escitalopram, bupropion, venlafaxine , desvenlafaxine, sertraline, paroxetine, fluoxetine, vortioxetine, mirtazapine, citalopram, vilazodone, trazodone, amitriptyline, clomipramine, agomelatine, levomilnacipran, lithium, doxepin, nortriptyline. The term antidepressant will refer to any pharmaceutical agent or drug that can be used to treat depression or diseases associated with depressive symptoms.

According to another aspect, the present invention provides a compound of formula A according to any of the previous aspects, characterized in that the compound of formula A is administered in addition to treatment with one or more antipsychotics selected from the list including aripiprazole, paliperidone palmitate, lurasidone, quetiapine, risperidone, olanzapine, paliperidone, brexpiprazole, clozapine, asenapine, chlorpromazine, haloperidol, cariprazine, ziprasidone, amisulpride, iloperidone, fluphenazine, blonanserine, sripiprazole lauroxyl. The term antipsychotic will refer to any pharmaceutical agent or drug that can be used to treat diseases associated with psychotic or depressive symptoms.

According to another aspect, the present invention provides a compound of formula A according to any of the previous aspects, characterized in that the compound of formula A is administered in addition to treatment with one or more psychostimulants selected from the list including lisdexamfetamine, methylphenidate, amphetamine, dexamphetamineamine , dexmethylphenidate, armodafinil, modafinil. The term psychostimulant will refer to any pharmaceutical agent or drug that can be used to treat diseases such as mood disorders or impulse control disorders.

According to another aspect, the present invention provides a compound of formula A according to any of the previous aspects, characterized in that the compound of formula A is administered in addition to treatment with nootropics selected from the list including oxiracetam, piracetam, or the natural product St. John's wort. In accordance with another aspect, the present invention provides a compound of formula A, which is administered in addition to treatment with one or more antidepressants, antipsychotics, psychostimulants, nootropics or natural products in accordance with any of the previous aspects, characterized in that the combination of a compound of formula A and one or more antidepressants, neuroleptics, psychostimulants, nootropics or natural products are used in addition to behavioral therapy, TMS (transcranial magnetic stimulation), ECT (electroconvulsive therapy) and other therapies.

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Experimental section

Abbreviations:

ACN - acetonitrile;

APCI - atmospheric pressure chemical ionization;

Boc - tert-butyloxycarbonyl;

CDI - 1,1'-carbonyldiimidazole;

CO ₂ - carbon dioxide;

D - day;

DM - diode matrix;

DCM - dichloromethane;

DIPE - diisopropyl ether;

DIPEA - diisopropylethylamine;

DMF - dimethylformamide;

her. - enantiomeric excess;

ERI - electrospray ionization (in MS);

EtOAc - ethyl acetate;

EtOH - ethanol;

Etc. - an example;

h - hour(s);

HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

HPLC - high performance liquid chromatography;

HPLC-MS - coupled high performance liquid chromatography mass spectrometry;

M - molar (mol / l);

MeOH - methanol;

min - minute(s)

MS - mass spectrometry;

MW - molecular weight;

NH ₃ - ammonia;

PSI - pounds per sq. inch;

kt - room temperature;

Rt - retention time;

scCO ₂ - supercritical CO _2; rr - solvent;

TBTU - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;

TEA - triethylamine;

TFA - trifluoroacetic acid;

THF - tetrahydrofuran;

TLC - thin layer chromatography;

SCLC - supercritical liquid chromatography.

Abbreviations for spectral data:

1H-NMR - proton nuclear magnetic resonance;

br - wide;

δ - chemical shift;

d - doublet;

dd - doublet of doublets;

dt - doublet of triplets;

DMSO-d ₆ - hexa-deutero-dimethyl sulfoxide;

H is a proton;

Hz - Hertz (=1/s);

J is the interaction constant;

m is the multiplet, ppm;

q - quartet;

s - singlet;

t - triplet;

td - triplet of doublets.

General analytical data.

All reactions were carried out using industrial grade reagents and solvents. NMR spectra were recorded on a Broker AVANCE III HD 400 MHz instrument using TopSpin 3.2 p16 software. Chemical shifts were expressed as parts per million (ppm) downfield relative to internal standard trimethylsilane in 5 units. Selected data are presented as follows: chemical shift, multiplicity, interaction constants (J), integration. Analytical thin layer chromatography (TLC) was performed using Merck silica gel 12 042766 left 60 F254 plates. All compounds were visualized as single spots using shortwave UV light. Low resolution mass spectra were obtained using liquid chromatography/mass spectrometry (LCMS), which consisted of an Agilent 1100 series LC coupled to an Agilent 6130 quadrupole mass spectrometer (electrospray in positive ionization mode).

Methods.

HPLC-MS methods.

Method 1

Method name: Z003 S05

Agilent 1200 with DM and MS Detector XBridge C18 3.0 x 30 mm 2.5 µm Waters

Method 2

Instrument description: Column: Column manufacturer: Description:

Gradient/Thinner Time [min] 0.0 0.2 1.2 1.25 1.4 % Sol. [Water 0.1% _NH3 ] 95.0 95.0 o o o o o % Sol. [Acetonitrile] 5.0 5.0 100.0 100.0 100.0 Flow [ml/min] 2.2 2.2 2.2 s,o 3.0 Temp [°C] 60.0 60.0 60.0 60.0 60.0 Back pressure [psi] Method name: Z011 S03 Instrument Description: Agilent 1200 with DM and MS Detector Column: XBridge C18 3.0 x 30 mm 2.5 µm Manufacturer Waters columns: Description: Gradient/ % Sol. % Sol. Flow Temp [°C] Reverse Solvent [Water 0.1% [Acetonitrile] [ml/min] pressure Time [min] _NH3 ] [psi] oh oh 97.0 h, o 2.2 60.0 0.2 97.0 h, o 2.2 60.0 1.2 oh oh 100.0 2.2 60.0 1.25 0.0 100.0 h, o 60.0 1.4 oh oh 100.0 3.0 60.0

Method 3

Method name: Z017 S04 Description of the device: Agilent 1200 with DM and MS Detector column: Sunfire C18 3.0 x 30 mm 1.8 µm [Column manufacturer: waters (Description: Gradient/ Thinner Time [min] % Sol. [Water 0.1% TFA] % Sol. [Acetonitrile] Flow [ml/min] Temp [°C] Back pressure [PSI] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Analytical methods.

Chiral SLC: Method 4: I SA .20_IPA_NH ₃₀₀₁ .

Netod name: 1 SA 20 IPA NH ₃₀₀₁ Description of the device: Agilent 1260 SLC with DAD and MS Column: CHIRAL ART® Amylose SA_4.6 x 250 mm_5 µm Speaker manufacturer: YMC

Gradient/ Thinner Time [min] % Sol. [scCO2] % Sol. [ETOH 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] 0.0 85.0 15.0 4.0 40.0 2175.0 10.0 85.0 15.0 4.0 40.0 2175.0

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Method 5: I_IC_30_IPA_NH ₃ 001.

Netod name: l_IC_30_IPA_NH ₃ _ 001 Description of the device: Agilent 1260 SLC with DAD and MS Column: Chiralpak® IC 4.6 x 250 mm 5 µm Speaker manufacturer: Daicel

Gradient/Solvent Time [min] % Sol. [scCO2] % Sol. [MEON 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] 0.0 70.0 30.0 4.0 40.0 2175.0 10.0 7.0 30.0 4.0 40.0 2175.0

Preparative HPLC conditions for purification: Instrument: (Agilent 1100).

Eluents: Water - NH4OH 5% solution in water -CH ₃ CN;

Flow: 50 ml/min;

Temperature 60°C;

Speaker: XBridge C18.

Preparation of intermediate compounds.

Example 1a:

(8)-Morpholine-2-carboxylic acid methyl ester hydrochloride (35 g; 192.7 mmol) was co-mixed with 400 ml of 8 M methylamine in EtOH. The reaction mixture was stirred at room temperature for 60 hours. The solvent was removed under reduced pressure, THF (500 ml) and TEA (50 ml) were added and the reaction mixture was stirred at room temperature for 12 hours. A precipitate formed; the suspension was filtered through a glass filter and the filter solution was evaporated under reduced pressure. 23.5 g of the desired product is obtained as a solid.

Example 1b:

(S)-Morpholine-2-carboxylic acid methyl ester hydrochloride (5 g; 27.5 mmol) was co-mixed with 138 ml of 2M ethylamine in THF. The reaction mixture was stirred at room temperature for 60 hours. The solvent was removed under reduced pressure, THF (500 ml) and TEA (50 ml) were added and the reaction mixture was stirred at room temperature for 12 hours. A precipitate formed; the suspension was filtered through a glass filter and the filter solution was evaporated under reduced pressure. 4.3 g of the desired product is obtained as a solid.

Example 2a:

5-Chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol) and 4-fluorophenol (0.78 g; 6.95 mmol) were dissolved in DMSO (10 ml); K2CO3 (1.2 g; 8.69 mmol) was added and the reaction mixture was stirred 45 min at 60°C. The reaction mixture was poured into water (50 ml) and stirred for 15 min. The resulting precipitate was washed with water, 10% K2CO3 aqueous solution, and dried. 1.4 g of a solid was obtained.

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Example 2a: __________________

HPLC-MS; Method : Z01 l_S03;

Example 2b:

I MS: 249 (M+H)

Example 2b was synthesized analogously to example 2a.

Starting materials: methyl ester of 5-chloro-pyrazine-2-carboxylic acid (1 g; 5.79 mmol), 2fluoro-4-methyl phenol (0.75 ml; 6.95 mmol). 1.5 g of the desired compound is obtained as a solid.

Example 2b:_________________________________________________

HPLC-MS; Method : Z01 l_S03; _Rt [min] : 0.99 | MS: 263 (M+H)

Example 2c:

Example 2c was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 4-

Example 2d:

Example 2d was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 2,4-dimethyl phenol (0.83 ml; 6.95 mmol). 1.45 g of the desired compound is obtained as a solid.

Example 2d:_________________________________________________

HPLC-MS; Method : Z018_S04; R _t [min] : 1.02 | MS: 259 (M+H)

Example 2e:

Example 2e was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 4-chloro-2-fluorophenol (0.74 ml; 6.95 mmol). 1.55 g of the desired compound is obtained as a solid.

Example 2e: HPLC-MS (Z011_S03): RJmhh]: 1.01 MS: 283 and 285 (M+H) ⁺ ; Observed isotope distribution for 1 C1

- 15 042766

Example 2f:

Example 2f was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 2,4-difluorophenol (0.67 ml; 6.95 mmol). 1.50 g of the desired compound is obtained as a solid.

Example 2f:

HPLC-MS (Z01 l_S03): ^[min]: 0^5

2g example:

I MS: 267 (M+H)'

Example 2g was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 4-chloro-phenol (0.89 g; 6.95 mmol). 1.5 g of the desired compound is obtained as a solid.

Example 2h:

Example 2h was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 4fluoro-2-methyl phenol (0.88 g; 6.95 mmol). 1.5 g of the desired compound is obtained as a solid.

Example 2i:

Example 2h__________________________________________________________

HPLC-MS (Z011 S03): ^[min]: 0.97 | MS: 263 (M+H) ⁺

Example 2i was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 2fluorophenol (0.62 ml; 6.95 mmol). 1.22 g of the desired compound is obtained as a solid.

EExample 2i________________________________________________________________

HPLC-MS (Z01 l_S03): R _t [min]: 0.92 | MS: 249 (M+H) ⁺

2k example:

o _v o

Example 2k was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1 g; 5.79 mmol), 2-chlorophenol (0.71 ml; 6.95 mmol). 1.51 g of the desired compound is obtained as a solid.

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Example 2j:

Example 2j was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.00 g; 5.80 mmol), phenol (0.65 g; 6.95 mmol). 1.30 g of the desired compound is obtained as a solid.

Example 2j____________________________

HPLC-MS (Z017_S04): ^[min]: 0.92

Example 2:

I MS: 231 (M+H)'

Example 21 was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.00 g; 5.80 mmol), 2,6-difluorophenol (0.90 g; 6.95 mmol). 1.52 g of the desired compound is obtained as a solid.

Example 21____________________________

HPLC-MS (Z017_S04): ^[min]: 0.97

Example 2m:

I MS: 267 (M+H)'

Example 2m was synthesized analogously to example 2a.

Starting materials: 5-chloro-pyrazine-2-carboxylic acid methyl ester (320 mg; 1.85 mmol), 2-fluoro-6-methyl-phenol (257 mg; 2.04 mmol). 480 mg of the desired compound are obtained as a solid.

Example 2m____________________

HPLC-MS (Z017_S04): ^[min]: 1.00

Example 3 a:

| MS: 263 (M+H)

Example 2a (1.4 g; 5.64 mmol) was dissolved in MeOH (15 ml); NaBH ₄ (0.64 g; 16.9 mmol) was added and the reaction mixture was stirred 3 h at room temperature. Water was added to quench the reaction; then the reaction mixture was evaporated under reduced pressure and the residue was distributed between EtOAc (100 ml) and 10% aqueous solution of K ₂ CO ₃ (30 ml). The organic phase was dried over Na ₂ SO ₄ and the residue obtained after evaporation of the solvents was purified by flash chromatography (Eluent: gradient starting from gasoline ether/EtOAc 3/1 to gasoline ether/EtOAc 2/1). Received 0.8 g of the desired compound (oil).

- 17 042766

Example For_____________________________

HPLC-MS; Method : Z01 l S03; _Rt [min] : 0.80

I MC: 221 (M+H)

Example 3b:

Example 3b was prepared analogously to example 3a. Starting materials: example 2b (1.5 g; 5.72 mmol).

1 g of the desired compound was obtained.

Example 3b HPLC-MS; Method : Z011 S03; _Rt [min] : 0.88 MS: 235 (M+H) ⁺

Example 3c:

Example 3c was prepared analogously to example 3a. Starting materials: example 2c (1.35 g; 5.53 mmol). 0.95 g of the desired compound is obtained.

[Example Ze

HPLC-MS (Z01 l_S03): W[min]: 0.86 | MS: 217 (M+H) ⁺

3d example:

Example 3d was prepared analogously to example 3a. Starting materials: example 2d (1.45 g; 5.61 mmol). 0.83 g of the desired compound was obtained.

[Example 3d __________________________________________________________

HPLC-MS (Method ): Z01 l S03 R _t [min] : 0.91 | MS: 231 (M+H) ⁺

Example 3e:

Example 3e was prepared analogously to example 3a. Starting materials: example 2e (1.55 g; 5.48 mmol). 1.02 g of the desired compound was obtained.

Example 3f:

Example 3f was prepared analogously to example 3a. Starting materials: example 2f (1.50 g; 5.64 mmol). 1.04 g of the desired compound was obtained.

Example 3f HPLC-MS (Method ): Z011 S03 R _t [min] : 0.83 | MS: 239 (M+H) ⁺

3g example:

Example 3g was prepared analogously to example 3a. Starting materials: example 2g (1.5 g; 5.67 mmol).

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0.83 g of the desired compound was obtained.

Example 3g

HPLC-MS (Method ): Z01 l_S03 R _t [min] : 0.88

MS: 237 and 239 (M+H) ⁺ ; Observed isotope distribution for 1 C1

Example 3h:

Example 3h was prepared analogously to example 3a. Starting materials: example 2h (1.5 g; 5.72 mmol). 0.86 g of the desired compound was obtained.

Example 3h_____________________________

HPLC-MS (Method ): Z01 l_S03 R _t [min] : 0.86

Example 3i:

| MS: 235 (M+H)

Example 3i was prepared analogously to example 3a. Starting materials: example 2i (1.22 g; 4.92 mmol). 0.75 g of the desired compound is obtained.

Example 3i_______________________________

HPLC-MS (Method ): Z01 l_S03 R _t [min] : 0.8

Example 3k:

| MS: 221 (M+H)

3j example:

Example 3k was prepared analogously to example 3a. Starting materials: example 2k (1.51 g; 5.71 mmol). 0.85 g of the desired compound is obtained.

Example 3j was prepared analogously to example 3a. Starting materials: example 2k (1.30 g; 5.65 mmol). The crude material obtained after evaporation of the organic solvents was used as such in the following steps. 0.98 g of the desired compound was obtained (70% content).

Example 3j________________________________

HPLC-MS (Method ): Z017 S04 R _t [min] : 0.79

Example 3l:

| MS: 203 (M+H)'

Example 3l was prepared analogously to example 3a. Starting materials: example 2l (1.52 g; 5.71 mmol).

- 19 042766

The crude material obtained after evaporation of the organic solvents was used as such in the following steps. 1.30 g of the desired compound was obtained (85% content).

Example 31________________________________

HPLC-MS (Method ): Z017_S04 R _t [min] : 0.84

3m example:

I MS: 238 (M%

Example 3m was prepared analogously to example 3a. Starting materials: example 2m (480 mg; 1.83 mmol). The crude product after evaporation of the organic solvents was used as such in the following steps. 420 mg of the desired compound were obtained (85% content).

Example 3m___________________________

HPLC-MS (Method ): Z017_S04 R _t [min] : 0.87~

Example 4a:

I MS: 235 (M+H)

Example 3a (0.8 g; 3.63 mmol) was dissolved in 2-methyl-THF (Aldrich) (40 ml); TEA (0.76 ml; 5.45 mmol) was added dropwise followed by methanesulfonyl chloride (0.3 ml; 4 mmol). The mixture was stirred for 1.5 h at rt, then worked up. A 5% NaHCO ₃ solution in water was added to the reaction mixture, the phases were separated and dried over Na ₂ SO ₄ . The crude material obtained after evaporation of the organic solvents was used as such in the following steps. 1.05 g of the desired product was obtained.

Example 4a

HPLC-MS (Method ): Z017_S04

Example 4b:

| MS: 299 (M+H)

Example 4b was prepared analogously to example 4a. Starting material: Example 3b (1 g; 4.27 mmol). 1.3 g was obtained. The product was used as such in the next step.

Example 4b_____________________________

HPLC-MS (Method ): Z017_S04 R _t [min] : 0.99

Example 4c:

| MS: 313 (M+H)

Example 4c was prepared analogously to example 4a. Starting material: Example 3c (0.95 g; 4.39 mmol). 1.25 g was obtained. The product obtained after the work-up was used as such in the next step.

Example 4c_____________________________

HPLC-MS (Method ): Z017 S04 R _t [min] : 0.98 | MS: 295 (M+H)'

- 20 042766

Example 4d was prepared analogously to example 4a. Starting material: Example 3d (0.83 g; 3.61 mmol).

Received 1.1 g. The product obtained after the treatment was used as such in the next step.

Example 4d________________________________________________________

HPLC-MS (Method ): Z017_S04 R _t [min] : 1.02 | MS: 309 (M+H) ⁺

Example 4e:

Example 4d:

Example 4e was prepared analogously to example 4a. Starting material: example Ze (1.02 g; 4.0 mmol). 1.32 g was obtained. The workup product was used as such in the next step.

Example 4e HPLC-MS (Method ): Z017S04 R _t [min] : 1.01 MS: 333 and 335 (M+H) ⁺ ; Observed isotope distribution for 1 C1

Example 4f:

Example 4f was prepared analogously to example 4a. Starting material: Example 3f (1.04 g; 4.37 mmol). 1.35 g was obtained. The workup product was used as such in the next step.

Example 4f____________________________________________________________

HPLC-MS (Method ): Z017_S04 R _t [min] : 0.95 | MS: 317 (M+H) ⁺

4g example:

°~'S = O

O

IJ

Cl

Example 4g was prepared analogously to example 4a. Starting material: example 3g (0.83 g; 3.51 mmol).

Received 1.1 g. The product obtained after the treatment was used as such in the next step.

4g example HPLC-MS (Method ): Z017S04 R _t [min] : 0.99 MS: 315 and 317 (M+H) ⁺ ; Observed isotope distribution for 1 C1

Example 4h:

°-'S=O

Example 4h was prepared analogously to example 4a. Starting material: example 3h (0.86 g; 3.67 mmol). 1.12 g was obtained. The product obtained after the treatment was used as such in the next step.

diy.

Example 4h_____________________________

HPLC-MS (Method ): Z017 S04 R _t [min] : 0.97

Example 4i:

I MC: 313 (M+H)

Example 4i was prepared analogously to example 4a. Starting material: Example 3i (0.75 g; 3.41 mmol).

1.0 g was obtained. The product obtained after the work-up was used as such in the next step.

Example 4i_______________________________

HPLC-MS (Method ): Z017_S04 R _t [min] : 0.93

4k example:

I MC: 299 (M+H)'

Example 4j:

Example 4k was prepared analogously to example 4a. Starting material: example 3k (0.85 g; 3.59 mmol).

1.1 g was obtained. The workup product was used as such in the next step.

Example 4j was prepared analogously to example 4a. Starting material: Example 3k (0.98 g; 70% content; 3.39 mmol). The product obtained after the treatment was used as such in the next step. 1.35 g of the desired product was obtained (70% content).

Example 4j________________________________

HPLC-MS (Method ): Z017 S04 R _t [min] : 0.91

Example 4l:

I MC: 281 (M+H)

Example 4l was prepared analogously to example 4a. Starting material: Example 3l (1.30 g; 85% content; 4.64 mmol). The product obtained after the treatment was used as such in the next step. Received 1.70 g (content 85%).

Example 41_______________________________

HPLC-MS (Method ): Z017 S04 R _t [min] : 0.95

I MC: 317 (M+H)

- 22 042766

Example 4m was prepared analogously to example 4a. Starting material: example 3m (0.42 g; content

85%; 1.52 mmol). 0.55 g was obtained. The product obtained after the work-up was used as such in the next step.

Example 4m__________________________________________________

HPLC-MS (Method ): Z017S04 R _t [min] : 0.98 | MS: 313 (M+H) ⁺

Example 4m:

Illustrative Embodiments

Example 1

Example 4a (100 mg; 0.34 mmol) and example 1a (53.17 mg; 0.37 mmol) were dissolved in THF (5 ml); pyridine (0.08 ml; 1 mmol) was added and the reaction mixture was heated at 50° C. for 5 hours. The reaction mixture was cooled to rt, diluted with MeOH (3 ml) and filtered through a syringe filter. The resulting solution was purified by preparative HPLC. Received 53 mg of the desired compound.

Example 1 HPLC-MS; Method :Z011 S03; RJmhh] : 0.87 MS: 347 (M+H) ⁺ Chiral SKLC; Method: I_SA_20_IPA_NH ₃ _001 Rt [min]: 2.00; her. 100% Ή NMR (400 MHz, DMSO-O; δ ppm: 2.02 (m, 1 H); 2.17-2.24 (m, 1 H); 2.58 (t, 3 H); 2.66 - 2.71 (t, 1 N), 2.95 (t, 1 N), 3.54 - 3.69 (t, 3 N), 3.83 - 3.90 (t, 2 N); 7.27 (t, 4 H); 7.67 (t, 1 H); 8.19 (t, 1 H); 8.47 (t, 1 N).

Example 2

Example 2 was synthesized analogously to example 1.

Starting materials: example 4b (100 mg; 0.32 mmol) + example 1a (50.78 mg; 0.35 mmol). The crude material was purified by preparative HPLC. Received 105 mg of the desired compound.

Example 2_________________________________

HPLC-MS Method : Z011S03;; RJmhh]: 0.93

Chiral SLC method: I_SA_20_IPA_NH ₃ _001

MS: 361 (M+H)

Rt [min]; 1.96; her. 100% ^1H NMR (400 MHz, DMSO-b/b); δ ppm: 2.02 (m, 1 H); 2.16 - 2.24 (t, 1 N); 2.32 - 2.36 (t, 3 N); 2.57 (t, 3 H); 2.65 - 2.70 (t, 1 N); 2.94 (t, 1 H); 3.54 - 3.69 (t, 3 N); 3.83 - 3.90 (t, 2 N); 7.07 (t, 1 H); 7.21 (t, 1 H); 7.26 (t, 1 H); 7.67 (t, 1 H); 8.17 (t, 1 H); 8.55 (t, 1 N),

Example 3

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Example 3 was synthesized analogously to example 1.

Starting materials: example 4c (100 mg; 0.34 mmol) + example 1a (53.9 mg; 0.37 mmol). The crude material was purified by preparative HPLC. Received 80 mg of the desired compound.

Example 3 HPLC-MS: Method : Z011 S03; W[min]: 0.91 MS; 343 (M+H) ⁺ Chiral SKLC; Method: I_SA_20_IPA_NH ₃ _001 Rt [min]: 2.34; her. 99.59% Ή NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.02 (m, 1 H); 2.16 - 2.24 (m, 1 H); 2.30 - 2.34 (t, 3 N); 2.57 (t, 3 H); 2.68 (t, 1 H); 2.95 (t, 1 H); 3.54 - 3.68 (t, 3 N); 3.83 - 3.90 (t, 2 N); 7.06 - 7.10 (t, 2 N); 7.23 (t, 2 H); 7.63 - 7.70 (t, 1 N); 8.18 (t, 1 H); 8.43 (t, 1 N).

Example 4

Example 4 was synthesized analogously to example 1.

Starting materials: example 4d (100 mg; 0.32 mmol) + example 1a (51.4 mg; 0.36 mmol). The crude material was purified by preparative HPLC. Received 55 mg of the desired compound.

Example 4 HPLC-MS Z003 S05: R _t [min]: 1.14 MS: 357 (M+H)+ Chiral SKLC; Method: I_SA_20_IPA_NH ₃ _001 Rt [min]: 2.07; her. 94% Ή NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 1.99-2.07 (m, 4 H); 2.15 - 2.24 (m, 1 H); 2.26 - 2.32 (t, 3 N); 2.57 (t, 3 H); 2.68 (t, 1 H); 2.94 (t, 1 H); 3.54 - 3.67 (t, 3 N); 3.83 - 3.89 (t, 2 N); 6.97 - 7.06 (t, 2 N); 7.11 - 7.14 (t, 1 N); 7.67 (t, 1 H); 8.13 - 8.16 (t, 1 N); 8.44 (t, 1 N).

Example 5

Example 5 was synthesized analogously to example 1.

Starting materials: example 4e (100 mg; 0.30 mmol) + example 1a (47.66 mg; 0.33 mmol). The crude material was purified by preparative HPLC. 70 mg of the desired compound were obtained.

Example 5 HPLC-MS Z011_S03: R _t [min]: 10.96 MS: 381 and 383 (M+H) ⁺ ; Observed isotope distribution for 1 C1 Chiral SKLC; Method: I_SA_20_IPA_NH ₃ _001 Rt [min]: 2.27; her. 100% 'H NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.03 (m, 1 H); 2.21 (m, 1 H); 2.57 (w, 3 H); 2.65 - 2.70 (m, 1 H); 2.94 (t, 1 H); 3.54 - 3.70 (t, 3 N); 3.83 3.90 (t, 2 N); 7.37 (t, 1 H); 7.47 (t, 1 H); 7.63 - 7.69 (t, 2 N); 8.20 (d, d=1.31 Hz, 1 H); 8.61 (d, 7=1.33 Hz, 1 H).

Example 6

Example 6 was synthesized analogously to example 1.

Starting materials: example 4f (100 mg; 0.32 mmol) + example 1a (50.14 mg; 0.35 mmol). The crude material was purified by preparative HPLC. Received 81 mg of the desired compound.

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Example 6 HPLC-MS: Method: Z003 S05; _Rt [min]: 1.05 MS: 365 (M+H) ⁺ Chiral SKLC; Method: I SA 20 IP A NH ₃ 001 Rt [min]: 1.67; her. 100% 'H NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 1.99 - 2.07 (w, 1 H); 2.20 (t, 1 H); 2.57 (w, 3 H); 2.64 - 2.72 (w, 1 H); 2.94 (w, 1 H); 3.54 - 3.71 (t, 3 N); 3.83 - 3.90 (t, 2 N); 7.14 - 7.20 (t, 1 N); 7.44 - 7.52 (w, 2 H); 7.63 - 7.72 (t, 1 N); 8.19 (d, 7=1.37 Hz, 1 H); 8.60 (d, 7=1.35 Hz, 1 H).

Example 7

Example 7 was synthesized analogously to example 1.

Starting materials: example 4g (100 mg; 0.32 mmol) + example 1a (50.39 mg; 0.35 mmol). The crude material was purified by preparative HPLC. 97 mg of the desired compound were obtained.

Example 7 HPLC-MS (Method ): Z011_S03; _Rt [ _MHH ]: 0.93; MS: 363 and 365 (M+H) ⁺ ; Observed isotope distribution for 1 C1 Chiral SKLC; Method: I SA 20 IP A NH ₃ 001 _Rt [min]: 2.95; her. 100% P NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.02 (t, 1 N) 2.21 (t, 1 N) 2.57 (t, 3 N) 2.65 - 2.74 (br, 1 N) 2.96 ( t, 1 N) 3.54 - 3.70 (w, 3 N) 3.83 - 3.91 (w, 2 N) 7.24 - 7.29 (t, 2 N) 7.47 - 7, 51 (t, 2 N) 7.68 (t, 1 N) 8.21 (d, 7=1.35 Hz, 1 N) 8.50 (d, 7=1.35 Hz, 1 N)

Example 8

Example 8 was synthesized analogously to example 1.

Starting materials: example 4h (100 mg; 0.32 mmol) + example 1a (50.78 mg; 0.35 mmol). The crude material was purified by preparative HPLC. Received 60 mg of the desired compound.

Example 8 HPLC-MS (Method ): Z003 S05; _Rt [min] : 1.09 MS: 361 (M+H) ⁺ Chiral SLC method: I SA 20 IPA NH ₃ 001 _Rt [min]: 1.79 her. 100% 'H NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 1.99-2.06 (m, 1 H); 2.08 2.10 (t, 3 N); 2.16 - 2.25 (t, 1 N); 2.57 (d, 7=4.74 Hz, 3 H); 2.65 - 2.71 (w, 1 H); 2.95 (t, 1 H); 3.54 - 3.68 (w, 3 H); 3.83 - 3.90 (t, 2 N); 7.05 - 7.10 (w, 1 H); 7.16 - 7.22 (t, 2 N); 7.64 - 7.70 (t, 1 N); 8.16 (d, 7=1.33 Hz, 1 H); 8.49 (d, 7=1.32 Hz, 1 H).

Example 9

Example 9 was synthesized analogously to example 1.

Starting materials: example 4i (100 mg; 0.34 mmol) + example 1a (53.17 mg; 0.37 mmol). The crude material was purified by preparative HPLC. 49 mg of the desired compound were obtained.

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Example 9 HPLC-MS (Method ): Z003 S05; _Rt [min] : 1.03 MS: 347 (M+H) ⁺ Chiral SLC method: I_SA_20_IPA_NH ₃ _001 _Rt [min]: 1.84; her. 100% 'n NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.02 (w, 1 H); 2.20 (w, 1 H); 2.56 - 2.59 (t, 3 N); 2.65 - 2.70 (t, 1 N); 2.94 (t, 1 H); 3.54 - 3.70 (t, 3 N); 3.83 - 3.90 (t, 2 N); 7.25 - 7.43 (t, 4 N); 7.64 - 7.69 (t, 1 N); 8.19 (t, 1 H); 8.59 (t, 1 N).

Example 18.

Example 18 was synthesized analogously to example 1.

Starting materials: example 4k (100 mg; 0.32 mmol) + example 1a (50.78 mg; 0.35 mmol). The crude material was purified by preparative HPLC. Received 64 mg of the desired compound.

Example 18 HPLC-MS Method: Z003 S05; _Rt [min] : 1.07 MS: 363 and 365 (M+H) ⁺ ; Observed isotope distribution for 1 C1 Chiral SLC method: I_SA_20_IPA_NH ₃ _001 _Rt [min]: 2.38; her. 100% Ή NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.02 (w, 1 H); 2.21 (w, 1 H); 2.57-2.58 (w, 3 H); 2.64 - 2.71 (m, 1 H); 2.95 (m, 1 H); 3.54 - 3.70 (w, 3 H); 3.83 - 3.90 (w, 2 H); 7.30 - 7.36 (m, 1 H); 7.38 - 7.46 (t, 2 N); 7.59 - 7.63 (t, 1 N); 7.63 - 7.70 (t, 1 N); 8.18 (d, 7=1.33 Hz, 1 H); 8.57 (d, 7=1.34 Hz, 1 H).

Example 30.

Example 30 was synthesized analogously to example 1.

Starting materials: example 4f (100 mg; 0.32 mmol) and example 1b (60 mg; 0.38 mmol). The crude material was purified by preparative HPLC. Received 58 mg.

Example 30 HPLC-MS; Method: Z003 S05; RJmhh]: 1.10 MS: 379 (M+H) ⁺ Chiral SLC method: : I_SA_20_IPA_NH ₃ _001 _Rt [min]: 1.55; her. 100% Ή NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 0.98 (t, 7=7.18 Hz, 3 H); 2.02 (m, 1 H); 2.21 (t, 1 H); 2.65 - 2.70 (t, 1 N); 2.93 (t, 1 H); 3.04 - 3.11 (t, 2 N); 3.54 - 3.62 (t, 1 N); 3.64 - 3.68 (t, 2 N); 3.84 - 3.88 (t, 2 N); 7.14 - 7.20 (t, 1 N); 7.44 - 7.52 (t, 2 N); 7.69 (t, 1 H); 8.19 (br s, 1 H); 8.60 (t, 1 N).

Example 31.

Example 31 was synthesized analogously to example 1.

Starting materials: example 4b (100 mg; 0.32 mmol) and example 1b (60 mg; 0.38 mmol). The crude material was purified by preparative HPLC. Received 57 mg.

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Example 31 HPLC-MS; Method: Z011_S03; K _g [min]: 0.98 MS: 375 (M+H) ⁺ Chiral SLC method: : I_SA_20_IPA_NH ₃ _001 _Rt [min]: 1.83; her. 100% Ή NMR (400 MHz, DMSO-7b); δ ppm: 0.99 (t, 7=7.16 Hz, 3 H); 2.02 (t, 7=10.77 Hz, 1 H); 2.21 (w, 1 H); 2.32 - 2.36 (w, 3 H); 2.67 (m, 1 H); 2.93 (w, 1 H); 3.08 (m, 2 H); 3.54 - 3.69 (t, 3 N); 3.83 - 3.89 (m, 2 H); 7.07 (w, 1 H); 7.21 (w, 1 H); 7.26 (t, 7=8.17 Hz, 1 H); 7.69 (m, 1 H); 8.17 (m, 1 H); 8.55 (m, 1 n).

Example 33.

Example 33 was synthesized analogously to example 1.

Starting materials: example 4k (100 mg; 0.32 mmol) and example 1b (60 mg; 0.38 mmol). The crude material was purified by preparative HPLC. Received 37 mg.

Example 33 HPLC-MS; Method: Z003 S05; RJmhh]: 0.96 MS: 377 and 379 (M+H) ⁺ ' Isotope distribution observed for 1 C1 Chiral SLC method: : I_SA_20_IPA_NH ₃ _001 _Rt [min]: 2.16; her. 100% Ή NMR (400 MHz, DMS0-7 _b ); δ ppm: 0.99 (t, 7=7.18 Hz, 3 H); 2.02 (t, 7=10.76 Hz, 1 H); 2.21 (td, 7=11.31, 3.19 Hz, 1 H); 2.65 - 2.71 (w, 1 H); 2.94 (m, 1 H); 3.04 - 3.11 (t, 2 N); 3.54 - 3.70 (t, 3 N); 3.83 - 3.89 (t, 2 N); 7.30 7.46 (t, 3 N); 7.61 (dd, 7=7.96, 1.44 Hz, 1 H); 7.69 (t, 1 H); 8.18 (d, 7=1.33 Hz, 1 H); 8.57 (d, 7=1.32 Hz, 1 H).

Example 34.

Example 34 was synthesized analogously to example 1.

Starting materials: Example 4j (100 mg; 70% content; 0.25 mmol) and Example 1a (39.6 mg; 0.28 mmol). The crude material was purified by preparative HPLC. Received 71.0 mg of the desired product.

Example 34 HPLC-MS; Method: Z011 S03; RJmhh]: 0.85 MS: 329 (M+H) ⁺ Chiral SLC method: : I_SA_20_IPA_NH ₃ _001 _Rt [min]: 2.29; her. 100% Ή NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.03 (w, 1 H); 2.21 (m, 1 H); 2.58 (t, 3 H); 2.69 (t, 1 H); 2.96 (t, 1 H); 3.54 - 3.69 (t, 3 N); 3.83 - 3.91 (t, 2 N); 7.18 - 7.28 (t, 3 N); 7.44 (t, 2 H); 7.63 - 7.71 (t, 1 N); 8.20 (d, 7=1.37 Hz, 1 H); 8.46 (d, 7=1.35 Hz, 1 H).

Claims (19)

Example 35. Example 35 was synthesized analogously to example 1. Starting materials: example 4l (130 mg; 0.35 mmol) and example 1a (55.4 mg; 0.38 mmol). The crude material was purified by preparative HPLC. Received 71.0 mg of the desired product. Example 36. Example 36 was synthesized analogously to example 1. Starting materials: example 4m (130 mg; 0.42 mmol) and example 1a (66.0 mg; 0.46 mmol). The crude material was purified by preparative HPLC. Received 87.0 mg of the desired product. Example 36 HPLC-MS; Method: Z011 S03; ^[min]: 0.92 MS: 361 (M+H) ⁺ Chiral SLC method: : I_SA_20_IPA_NH ₃ _001 R _t [min]: 1.71; her. 100% Ή NMR (400 MHz, DMSO-7 ₆ ); δ ppm: 2.03 (m, 1 H); 2.15 - 2.22 (w, 4 H); 2.57 (w, 3 H); 2.62 - 2.75 (w, 1 H); 2.95 (w, 1 H); 3.52 - 3.61 (w, 1 H); 3.66 (s, 2 H); 3.80 - 3.93 (m, 2 H); 7.12 - 7.27 (t, 3 N); 7.62 - 7.74 (t, 1 N); 8.16 (d, 7=1.38 Hz, 1 H); 8.62 (d, 7=1.35 Hz, 1 H). CLAIM 1. Compound of formula A o \ R2 And in which R ¹ represents methyl, ethyl, propyl, isopropyl, cyclopropyl, H ₃ C-CH ₂ -CH ₂ -CH ₂ -, cyclobutyl; R ² is phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl, cyclopropyl. 2. Connection according to claim 1, where R ¹ is methyl, ethyl; R ² is - 28 042766 du όζά:σ· 3. The (S)-enantiomer according to claim 1 or 2, wherein the compound is selected from the group consisting of - 29 042766 6. (S)-Enantiomer according to one of claims 1-3, having the structure - 30 042766 7. (8)-Enantiomer according to one of claims 1-3, having the structure 8. (8)-Enantiomer according to one of claims 1-3, having the structure 9. (8)-Enantiomer according to one of claims 1-3, having the structure 10. (8)-Enantiomer according to one of claims 1-3, having the structure 11. (8)-Enantiomer according to one of claims 1-3, having the structure -31 042766 13. (8)-Enantiomer according to one of claims 1-3, having the structure 14. A pharmaceutically acceptable salt of a compound according to one of claims 1-13. 15. The use of a compound according to one of claims 1 to 13 or a pharmaceutically acceptable salt according to and. 14 as a medicine. 16. The use of a compound according to one of claims 1 to 13 or a pharmaceutically acceptable salt according to and. 14 for the treatment and/or prevention of bipolar I disorder depressive, hypomanic, manic and mixed forms; bipolar disorder II; depressive disorders; major depressive disorder with or without comorbid anxiety distress, mixed features, melancholic features, atypical features, psychotic features consistent with mood, psychotic features not consistent with mood, catatonia. 17. The use of a compound according to one of claims 1 to 13 or a pharmaceutically acceptable salt according to and. 14 for the treatment and/or prevention of single episode or recurrent major depressive disorder, minor depressive disorder, postpartum onset depressive disorder, depressive disorders with psychotic symptoms. 18. Use according to one of claims 15 to 17, characterized in that the compound is administered in addition to treatment with another antidepressant. 19. Use according to one of claims 15 to 17, characterized in that the compound is administered in addition to behavioral therapy. 20. The use of a compound according to one of claims 1 to 13 or a pharmaceutically acceptable salt according to and. 14 for the treatment of acute and chronic pain that is associated with neuropathy, physiological processes and physical disorders, diseases of the musculoskeletal system and connective tissue, lesions of the nerves, nerve roots and lesions of the nerve plexuses. 21. The use of a compound according to one of claims 1 to 13 or a pharmaceutically acceptable salt according to and. 14 for the treatment of diabetic neuropathy, polyneuropathy, lumbosacral pain, joint pain, rheumatism, myalgia, phantom limb pain syndrome, carpal tunnel syndrome. 22. A pharmaceutical composition containing a compound according to one of claims 1 to 13 or a pharmaceutically acceptable salt according to and. 14 in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.