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

Abstract

4-Pyrazin-2-ylmethyl-morpholines of the general formula (1), processes for their preparation, pharmaceutical compositions containing them and their use in treatments, particularly in the treatment or prevention of conditions that have a relation to the negative allosteric modulation properties of NR2B.

Description

26909 4-PYRAZ1N-2-YLMETHYL MORPHOL1NE DERIVATIVES AND THEIR USE AS MEDICINE The present invention relates to novel 4-pyrazin-2-ylmethyl-morphclines of the general Formula A A, processes for their preparation, pharmaceutical compositions containing them and their use in treatments, particularly in the treatment or prevention of conditions that have a relationship with the negative allosteric modulation properties of NR2B. The compounds of the invention according to General Formula A exhibit the negative allosteric modulation properties of NR2B. Extensive studies over the past 20 years have indicated that N-methyl-D-aspartate (NMDA) receptors play an important role in Alzheimer's disease, Parkinson's disease, dyskinesia, stroke, motor neuron disease, psychosis, epilepsy, anxiety, schizophrenia, and pain. Ketamine, a non-selective NMDA receptor antagonist (racemic, as is the S-enantiomer), a drug primarily used for the initiation and maintenance of anesthesia, has demonstrated clinical efficacy in recent years for the treatment of major depressive disorder (MDD) at subanesthetic doses (Murrough et al. 2013, Am J Psychiatry. 170: 1134; Singh et al. 2016, Biol Psychiatry. SO: 424). More specifically, ketamine produces a rapid onset of efficacy that lasts for several days in MDD patients who respond to standard drug treatments (Berman et al. 2000. Biol Psychiatry 47:351; Serafini et al. 2014. Curr. NeuropharmacoL 12:444). However, non-selective NMDA receptor antagonists have a range of undesirable effects that limit their application. In IF-2020-07221114-APN-ANP#INPI Page 1 of 53 In particular, dissociative and psychogenic side effects are prominent for non-selective NMDA receptor antagonists, such as ketamine (Krystal et al. 1994. Arch. Gen. Psychiatry 51:199). In the early 1990s, it was discovered that multiple NMDA receptor subtypes exist, containing different NR2(AD) subunits (Paoíetti et al., 2013 Nat Rev. Neurosci 14:383). More recently, selective NR2B subtype NMDA receptor negative allosteric modulators (NR2B NAMs) have generated interest and shown potential in a wide range of clinical indications, such as attention, emotion, mood, and pain; Furthermore, in addition to being involved in a number of different human disorders (Mony et al. 2009. Br. J. Pharmacol. 157:1301; Chaffey et al., Current Anaesthesia & Critical Care 19, 183). In particular, NR2B NAM also demonstrated antidepressant efficacy in the early stages of clinical trials (Preskorn et al. 2008).J Clin Psychopharmacology 70:58). Preclinical studies using NR2B NAMs and various transgenic mouse strains have shown that NR2B-containing NMDA receptors are involved in the positive effect of ketamine in, for example, the forced swim test (Miller et al., 2014 eLife 3:e03581; Kiselycznyk et al., 2015 Behav Brain Res, 287:89). Furthermore, 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). The NR2B NAMs described to date have shown disadvantages with respect to the pharmacology of their receptor and / or other drug properties that have a limited potential use in drug treatment for humans (Taylor, et al, 2006, Clin Pharmacokinet.45: 989; Addy et al. 2009 J of Clinical Pharmacology 49:856). The compounds of Formula (I) are disclosed in WO2015 / 130905 R2R3R4R3 Ααλ»rN ψ (R6)qAj^T, which are Nav1.6 inhibitors useful in the treatment of multiple sclerosis, polyneuritis, multiple neuritis, amyotrophic lateral sclerosis, Alzheimer's disease, or Parkinson's disease. Specific Examples IF-2020-07221114-APN-ANP#INPI are disclosed in WO2015 / 130905 Page 2 of 53 100, 105, 106 and 107 where ring B corresponds to a meta-dis-substituted phenyl ring. Example 100 Example 105 Example 106 Example 107 WO2015 / 130905 reports that Specific Examples 100, 105, 106 and 107 are weak Nav1.6 inhibitors (Nav 1.6 blockade of Examples 100, 105 and 107 at 1-5 μM, and Nav 1.6 blockade of Example 106 at >5 μM). The compounds of the present invention are generically included in Formula (i) of WO2015 / 130905. The compounds of the present invention differ structurally from Examples 100, 105, 106 and 107 explicitly disclosed in WO2015 / 130905 in that they contain a para-di-substituted pyrazinyl substructure instead of the meta-di-substituted phenyl ring. The structural differences unexpectedly result in potent negative allosteric modulators of NR2B (see Table 1), whereas Specific Examples 100, 105, 106, and 107 of WO2015 / 130905 exhibit no activity at the NR1-NR2B ion channel (see Table 2). Furthermore, the compounds of the present invention do not inhibit Nav 1.6 at the concentrations at which Specific Examples 100 and 105 of WO2015 / 130905 inhibit Nav 1.6 (5 pM; see Tables 3 and 4). Furthermore, the compounds of the present invention exhibit good membrane permeability and show no in vitro effluvium (see Table 5 for the MDCK assay of MDR1 (P-gp)). Therefore, it is anticipated that the compounds of the present invention will exhibit favorable penetration into the brain, which is required for effective CNS drugs. MDCK assays provide information on a compound's potential to cross the blood-brain barrier. Permeability measurements across polarized confluent MDCK-MDR1 cell monolayers, grown on permeable filter supports, are used as an in vitro absorption model: the apparent permeability coefficients (PE) of compounds across MDCK-MDR1 cell monolayers are measured (pH 7.4, IF-2020-07221114-APN-ANP#INPI Page 3 of 53 X) in the apical-to-basal (AS) and basal-to-apical (BA) transport directions. AB permeability (PEAS) represents drug uptake from the blood into the brain, and BA permeability (PESA) represents drug efflux from the brain back into the blood via passive permeability and active transport mechanisms mediated by efflux and uptake transporters expressed on MDCK-MDR1 cells, predominantly by overexpressed human MDR1. Identical or similar permeabilities in both transport directions indicate passive permeability (PEBA / PEAB ≥ 1), points of vectorial permeability to additional active transport mechanisms. A higher PEBA than PEAB (PEBA / PEAB > 5) indicates the involvement of MDR1-mediated active efflux, which may be aimed at achieving sufficient brain exposure.Therefore, this assay provides important support for selecting compounds suitable for further in vivo testing. High, non-effluent permeability across the blood-brain barrier is a favorable characteristic for compounds used in drugs that act primarily in the central nervous system. Furthermore, the compounds of the present invention are metabolically stable in human liver microsomes (see Table 6, Metabolic Stability). Therefore, it is anticipated that the compounds of the present invention will have favorable in vivo clearance and, consequently, the desired duration of action in humans. Stability in human liver microsomes refers to the susceptibility of compounds to biotransformation in the context of drug selection and / or design for favorable pharmacokinetic properties. The liver is the primary site of metabolism for many drugs. Human liver microsomes contain cytochrome P450 (CYP) and thus represent a model system for studying in vitro drug metabolism. Enhanced stability in human liver microsomes is associated with several advantages, including increased bioavailability and a suitable half-life, which can allow for lower and less frequent dosing in patients. Therefore, enhanced stability in human liver microsomes is a desirable characteristic for compounds used in drug formulation. Consequently, the compounds of the present invention should be more viable for use in humans. Therefore, the objective technical problem is to provide powerful and selective negative allosteric modulators of NR2B. IF-2020-07221114-APN-ANP#INPI Page 4 of 53 The present invention provides novel 4-pyrazin-2-methyl-morpholines of Formula A R2 where R1 represents methyl, ethyl, propyl, isopropyl, cyclopropyl, H3C-CH2-CH2CH2-, cyclobutyl; R2 represents phenyl that is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, cyclopropyl; or a salt of these, in particular, a pharmaceutically acceptable salt of these. In one embodiment, in General Formula A, R1 has the same meaning as defined in any of the above embodiments, and R1 represents methyl, ethyl. In one embodiment, in General Formula A, R1 has the same meaning as defined in any of the above embodiments, and R2 represents IF-2020-07221114-APN-ANP#INPI Page 5 of 53 The present invention provides novel 4'pyrazin-2-methyl-morpholines of General Formula A that unexpectedly are potent and selective negative allosteric modulators of NR2B. Another aspect of the invention relates to the compounds according to Formula A as potent and selective negative allosteric modulators of IMR2B that have high membrane permeability and do not exhibit in vitro effluent. Another aspect of the invention relates to compounds according to Formula A as potent and selective negative allosteric modulators of NR2B that have high metabolic stability in human liver microsomes. Another aspect of the invention relates to compounds according to Formula A as potent and selective negative allosteric modulators of NR2B that have high membrane permeability, exhibit no in vitro effluvium, and have 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. Another aspect of the present invention relates to compounds according to Formula A, for use in the prevention and / or treatment of disorders related to negative allosteric modulators of NR2B. Another aspect of the invention relates to manufacturing processes for the compounds of the present invention. Preparation The following scheme illustrates, by way of example, how to prepare the compounds according to General Formula A and the corresponding intermediate compounds. Unless otherwise defined in the context of the scheme, the abbreviated substituents may be as defined above. IF-2020-07221114-APN-ANP#INPI Page 6 of 53 Scheme 1 Scheme 1 illustrates the synthesis of pyrazine derivatives of General Formula A. The first step is a nucleophilic substitution of a substituted phenol derivative R2-OH and methyl ester of 5-chloro-pyrazine-2-carboxylic acid, wherein the ester group is reduced to the corresponding alcohol with NaBH4; then the hydroxy group is converted into a leaving group (e.g., mesioate). The last step is represented by a nucleophilic shift using the mesioate and a slight excess of an amide derivative of (S)-morpholin-2-carboxylic acid obtained by reacting the methyl ester of (S)-morpholin-2-carboxylic acid with the corresponding amine R1-NH2. The synthetic approach described can also be used for gram-scale synthesis by applying different purification techniques, such as crystallization or column chromatography. GENERAL DEFINITIONS Terms not specifically defined herein should have the meanings that people of mid-level expertise would give them based on dissemination and context. The NR2B ion channel should be understood as an NMDA receptor containing the NR2B protein. In the event that a compound of the present invention is represented in the form of a chemical name and as a formula, the formula shall prevail in case of discrepancy. An asterisk can be used in subformulas to indicate the bond that connects to the core molecule or to the substituent to which it is attached as defined. IF-2020-07221114-APN-ANP#INPI Page 7 of 53 As used herein, the term substituted means that one or more hydrogens of the designated atom are replaced by a selection from the indicated group, provided that the viable valency number of the designated atom is not exceeded and that the substitution results in a stable compound. Stereochemistry: Unless otherwise specified in the descriptive memorandum and the appended claims, a particular chemical formula or name encompasses rotamers, tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures, in different proportions, of each of the enantiomers, mixtures of diastereomers or mixtures of any of the foregoing forms in which such isomers and enantiomers exist. Salts: The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, according to acceptable medical judgment, suitable for use in contact with human tissues without causing excessive toxicity, irritation, allergic response or other problems or complications, and proportionate to a reasonable benefit / risk ratio. As used herein, the expression pharmaceutically acceptable salts refers to derivatives of disclosed compounds, wherein the parent compound forms a salt or a complex with an acid or a base. Examples of acids that form a pharmaceutically acceptable salt with a parent compound containing a basic portion include mineral or organic acids, including benzenesulfonic acid, benzoic acid, citric acid, ethanesulfamic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, melic acid, melodic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, or tartaric acid. Examples of cations and bases that form a pharmaceutically acceptable salt with a parent compound containing an acid portion include Na+, K+, Ca2+, Mg£, NH3, L-arginine, 2,2'-aminobisethanol, L-lysine, N-methyl-D-glucamine, or tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a portion IF-2020-07221114-APN-ANP#INPI Page 8 of 53 basic or acidic by conventional chemical methods. In general, such salts can be prepared by reacting the free acidic or basic 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, acetonitrile, or a mixture thereof. Salts of other acids not mentioned above, which, for example, are useful for purifying or isolating the compounds of the present invention (e.g., trifluoroacetate salts), also comprise a part of the invention. BIOLOGICAL ASSAYS AND DATA List of abbreviations Duibecco's modified Eagle medium DMEM FBS fetal bovine serum FLiPR fluorometric imaging plate reader HEK293 human embryonic kidney cell line derived from HEPES hydroxyethylpiperazinetan-sulfonium acid buffer IC50 mean maximum inhibitory concentration MDCK canine kidney Madín-Darby MDR1 multidrug resistance protein 1 P-gp glycoprotein P SEM standard error of the mean EGTA (ethylene glycol-bis(P-aminoethyl ether J-NNN'.N'-tetraacetic acid), also known as egtazic acid In-vitro effect. Determination of pharmacological action in vitro The activity of the compounds of the invention can be demonstrated by the following in vitro NMDA NR1 / NR2B cell assays: Method: A human HEK293 cell line with tetracycline-inducible expression of the NMDA receptor NR1 / NR2B was used as a test system for the compound's efficacy and potency. The cell line was obtained from ChanTest, Catalog #CT6121. The compound's activity was determined by measuring the effect of the compound on intracellular calcium concentration induced by glycine / glutamate agonism in a FLIPRtetra system (Molecular Devices). Cell culture: The cells were obtained as frozen cells in cryovials and IF-2020-07221114-APN-ANP#INPI Page 9 of 53 stored until use at -150eC, Cells were cultured in a culture medium (DMEM / F12, 10% FBS, 5 pg / ml Blasticidin, 150 pg / ml Zeozin, 500 µg / ml Geneticin). It is important that the density does not exceed 80% confluency. For subculture, cells were separated from the flasks using Versene. For the assay, cells were separated, washed twice with an induction medium (DMEM / F12 without glutamine, 10% FBS, 2 pg / ml Tetracycline, 2 mM Ketamine), and plated onto 384-well pure amine-coated plates (Becton Dickinson, 50,000 cells per well in 50 µL) 48 h before the assay in the induction medium. Preparation of the compound The test compounds were dissolved in 100% DIVISO to a concentration of 10 mM, and in a first step diluted in DMSO to a concentration of 5 mM, followed by dilution steps in 100% DMSO. The dilution factor and number of dilution steps can be varied according to requirements. Generally, different concentrations were prepared by duplicate 1:5 dilutions. Other intermediate dilutions (e.g., 1:37.5) of the substances were carried out with an aqueous test buffer (137 mM NaCl, 4 mM KCl, 1.3 mM CaCl2, 10 mM HEPES, 10 mM glucose, pH 7.4) that yields a compound concentration three times higher than the final test concentration, and 2.7% DMSO to obtain a final DMSO concentration of 0.9% in the assay. FLIPR Trial: On the day of the assay, the cells were washed 3x with the assay buffer (as described above), W µL of the buffer remaining in the cavities after washing. 10 µL of Ca kit loading buffer (AAT Bioquest; prepared from the kit containing the following components: Component A: Fluo-8 NW dissolved in 200 µL of DMSO and 20 µL of this solution were mixed with 10 µL of 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)) were added to the cells, and the plates were incubated with the lid on for 60 minutes at room temperature. 20 μL of assay buffer containing 60 μM of glycine (20 μM final) and 3 μM of glutamate (1 μM final) was added to column 1-23, column 24 was loaded with assay buffer without glycine / glutamate as a negative unstimulated control.The fluorescence was read (which indicated an influx of calcium as a result of IF-2020-07221114-APN-ANP#INPI. Page 10 of 53. Activation of the NR1 / NR2B ion channel was measured in the FLIPRtetra device for 60 seconds to monitor glutamate-induced effects. After 2 minutes, 20 μL of the compound dilution prepared as described above or controls (rows 1–22) in assay buffer were carefully added to the cavities. Fluorescence was measured in the FLIPRtetra device for an additional 6 minutes to monitor compound-induced effects following agonist activation. The average of two measurements taken at 5 minutes and 5 minutes 10 seconds after compound addition was calculated and reused for IC50 calculations.Each microtiter plate with dilution of the assay compound contained cavities (in column 23 or 24) with DMSO controls instead of compounds as controls for glycine / glutamate-induced fluorescence (high controls) and cavities with 1 μM of a 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's output file contains the number of cavities and the average fluorescence units measured. For data evaluation and calculation, the low control measurement was set to 0% control, and the high control measurement was set to 100% control. IC50 values ​​were calculated using the standard 4-parameter logistic regression formula. Calculation: [y=(ad) / ( 1 +{x / c)rtb)+d], a = low value, d = high value; x = cone M; c = IC50 M, b = slope. Negative allosteric modulators of NR2B covered with the general structure A and exhibiting a low IC5O value are preferred. Table 1 In vitro NR2B affinity of the compounds of the present invention as obtained in the FLIPR assay Example number IC50 [nM] 1 968 2 123 3 690 4 1200 5 110 6 87 7 1002 8 856 9 210 18 222 30 595 31 524 33 807 IF-2020-07221114-APN-ANP#INPI Page 11 of 53 1 Example number 1 IC50 [nM] 34 1 644 35 j 197 36 542 Table 2 In vitro NR2B affinity of the nearest prior art compounds (Examples 100, 105, 106 and 107 in WO2015 / 130905) as obtained in the same FLIPR assay as the compounds in Table 1 Example number in WQ2015 / 13Ó905 100 IC50 [nlUlj >8887 105 >9261 106 >9255 107 >9257 Determination of Nav 1.6 inhibition Equipment: lonWorks Quattro eledrophysiological platform Preparation of the composite plate The compounds were prepared in DMSO at 300x the final assay concentrations of 1 and 5 μM. The 300x DMSO stock solutions were transferred to test plates where 2 pt per cavity of each 390x stock solution were placed. All test plates were stored at -80°C until the day of the test. On the day of the test, the corresponding test plate was thawed at room temperature, centrifuged, and 198 μL of external recording solution was added and thoroughly mixed. This provided a 1:100 dilution. A further 1:3 dilution was carried out after addition to the cells on the ionWorks Quattro electrophysiological platform, providing a total dilution of 1:300. At least 8 wells were reserved in each assay plate for the vehicle control (0.3% DMSO) and at least 8 wells for each positive control specific to the cell line being evaluated. Positive controls were analyzed at maximum blockade and an approximate IC50 concentration. Lidocaine was used as a positive control at concentrations of 30 and 1000 μM. Electrophysiological recording solutions The solutions for recording the Nav1.6 currents were as shown below: External logging solution IF-2020-07221114-APN-ANP#INPI Page 12 of 53 NaCl 137 mM KCi 4 mM MgCl21 mM CaCI21.8 mM HEPES 10 tM GJucose 10 mM pH 7.3 (titrated with 10 Ml NaOH) Internal logging solution CsF 90 mM CsCI 45 mM HEPES 10 mM EGTA 10 mM pH 7.3 (titrated with 1 Nl CsOH) Amphotericin B was used to gain electrical access to the cell interior at a final concentration of 200 pg / ml in the internal recording solution. Experimental protocols and data analysis Nav1.6 Experimental Protocol State-dependent inhibition: By holding sodium channels at a depolarized potential or with long test pulses, the channels open and inactivate, remaining inactive until the membrane potential returns to hyperpolarized potentials, at which point the inactivated channels recover from inactivation into a closed state. An example is tetracaine inhibition, which is much stronger at depolarized potentials than at hyperpolarized potentials. Voitaje de i:on;jí'tJíj IF-2020-07221114-APN-ANP#INPI Page 13 of 53 Nav1.6 Data Analysis The cells were maintained at -120 mV. In order to fully inactivate the sodium channels (pulse 1), the cells were pulsed to +0 mV for 2500 ms and returned to -120 mV for 10 ms (to fully recover from inactivation, although channels that have drugs attached to them do not recover from inactivation) before returning to +0 mV for 20 ms (pulse 2). Ion Channel Profiler Data Filters Data Filter Platform Criteria Seal Quality lonWorks Quattro >30 MΩ Seal Drop lonWorks Quattro <50 % seal drop {seal before compounding / seal after compounding) Current Amplitude lonWorks Quattro >200 pA Test control results The positive and vehicle control data associated with each evaluated cell line are shown below as an example. The mean for each positive or negative control is shown as a solid symbol, with the total number of replicates for individual cavities provided next to the solid symbol. In addition, the individual data for each cavity are shown in the graph as open symbols, so that the variation from the mean value can be easily determined. This data is provided to help determine whether a compound exhibits ion channel activity relative to the control data and provides an indication of assay variability. Consequently, it is used to determine the effect size of a specific effect for a detectable compound. The following are the assay controls for the Nav1.6 lonWorks Quattro assay. Lidocaine, a reference compound for Nav1.6, inhibited evoked currents in a concentration- and use-dependent manner, as predicted. IF-2020-07221114-APN-ANP#INPI Page 14 of 53 R1 - pulse 1; P25 - pulse 25. A back / back value of 1.0 corresponds to 0% inhibition, and a back / back value of 0.0 corresponds to 100% inhibition. To illustrate assay variation, Example 106 of WO2015 / 130905, showing 14% inhibition of Nav 1.6 to 5 μM (normalized, see Table 3), and Example 7 of the present invention, showing -15% inhibition of Nav 1.6 to 5 μM (normalized, see Table 4), respectively, are within assay variation when compared to assay control data and, therefore, do not show any significant inhibition of the Nav 1.6 to 5 μM channel. Tables 3 and 4 show the normalized percentage inhibition of the Nav1.6 channel. The normalized data show the compound data normalized with respect to the vehicle control (0% inhibition) and the maximum inhibition control (100% inhibition); the maximum inhibition at P1 by 1000 μM lidocaine (unnormalized) ranged from 46.4% to 47.2% during the experiments. (See also the previous figure, Assay Control Results). IF-2020-07221114-APN-ANP#INPI Page 15 of 53 Table 3 In vitro inhibition of Nav 1.6 by the closest prior art compounds (Examples 100, 105, 106 and 107 in WO2015 / 130905) as obtained in the same electrophysiology assay as the compounds in Table 4 (concentrations: 1 μM and 5 μM). Example number in WO2D15 / 130905 Percent inhibition normalized to 1 μM Percent inhibition normalized to 5 μM Percent SEM at 1 μM Percent SEM at 5 μM 100 2.2 37.8 6.2 6.4 105 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 In vitro normalized inhibition of Nav 1.6 of the compounds of the present invention as obtained in the same electrophysiology assay as the compounds of the prior art in Table 3 (concentrations: 1 pM and 5 pM). Example Number Percent Inhibition Normalized to 1 μM Percent Inhibition Normalized to 5 μM Percent SEM at 1 μM Percent SEM 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 U__ 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 30 -13.4 -9.4 5.3 4.6 31 -5.8 -7 3.6 1.2 33 -10.5 -6.6 - 4.6 1.9 Negative allosteric modulators of NR2B included in the general structure A are preferred, as they do not exhibit any significant inhibition of Nav 1.6. The compounds of the present invention do not exhibit any significant inhibition of the Nav 1.6 channel at 1 and 5 μM, respectively (see Table 4 and Assay Control Results), whereas Examples 100 and 105 of WO2015 / 130905 exhibit 37.8% and 68% inhibition of Nav 1.6 at 5 μM, respectively (see Table 3). Examples 106 and W7 of WO2915 / 130905 do not exhibit any significant inhibition of the Nav 1.6 channel at 1 and 5 μM, respectively (i.e., the inhibition is within the assay variability, see Table 3 and Control Results of IF-2020-07221114-APN-ANP#INPI). Page 16 of 53 essay). MDCK assay of P-gp The apparent permeability coefficients (Papp) of the compounds through MDCK-MDR1 monolayers (MDCKII cells transfected with human MDR1 cDNA expression plasmid) were measured in the api-calcaba sal (AB) and basal-to-api cal (BA) directions. MDCK-MDR1 cells (6 x 10 cells / cm2) were seeded on filters (Corning, Transwell, poly carbon at o, 0.4 pm pore size) and cultured for 9 to 10 days. The compounds dissolved in DMSO stock solution (1–20 mM) were diluted with aqueous HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 14.17 mM NaHCO3, 1.19 mM Na2HPO4, 0.41 mM Na2HPO4, 15 mM HEPES, 20 mM glucose, pH 7.4) enriched with 0.25% BSA to prepare the transport solutions (final concentration: 1 or 10 μM, final DMSO 0.5%). The transport solution was applied to the apical or basal donor site to measure AB or BA permeability, respectively. The recipient site contained HTP-4 buffer supplemented with 0.25% BSA.Samples are collected from the donor site at the beginning and end of the experiment, and at various time intervals for up to 2 hours, also from the recipient site for concentration measurement using PLC-MS / MS (RapidFire high-performance MS system (Agilent) coupled to QTrap 6500 (AB Sciex) or TSQ Vantage (Thermo Scientific)). The analyzed recipient volumes are replaced with fresh recipient solution. The effluent ratio is calculated by dividing the Papp(ba) values ​​by the Papp(ab) values. The results are shown in the table. Table 5. Table 5 Example - Median Papp (ab) [10-6 cmZs] PEBA / PEAB effervescence 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 ___________ _ 30 81 0.4 ___________ 31 66 0.6 33 59__ _________ 0.7______ ____ IF-2020-07221114-APN-ANP#INPI Page 17 of 53 The results of the experiment indicated above show that the compounds of the present invention are potent NR2B MAMs that have high membrane permeability and do not exhibit in vitro effluent, which anticipates an excellent ability to cross the blood-brain barrier. Metabolic stability The metabolic degradation of the test compound was assessed at 37 °C using pooled human liver microsomes. The final incubation volume of 60 pL 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 human), and the test compound at a final concentration of 1 pM. After a brief pre-incubation period at 37 °C, reactions were initiated by the addition of betaniotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by transferring an aliquot in acetonitrile at different time points. After centrifugation (10,000 g, 5 min), an aliquot of the supernatant was analyzed by HPLC-MS / MS as previously described for the P-gp MDCK assay to determine the amount of the source compound.The half-life was determined using the slope of the semi-logarithmic plot of the concentration-time profile. The results are shown in Table 6. Table 6 Ex. Sem ¡vida - 11 ¡2 [m in] human liver microsomes 1 >130 ! 2 >130 3 >130 4 >130 5 >130 6 >130 7 >130 8 >130 9 >130 10 >130 30 >130 31 >130 33 >130 The results of the experiment indicated above show that the compounds of the present invention are potent NR2B NAMs that have high stability in human liver microsomes. The present invention provides computation Page 18 of 53 that unexpectedly generate a favorable combination of the following key parameters; 1) powerful and effective N R2 B negativ e aero m od ul, 2) high favorable stability in human liver microsomes and 3) high permeability and no in vitro effluvium in MDCK-MDR1 cell transporters. Pharmaceutical composition Suitable preparations for administering the compounds of the present invention will be obvious to persons of a mid-level skill and will include, for example, tablets, pills, capsules, suppositories, lozenges, solutions, syrups, elixirs, sachets, injectable products, inhalable products, powders, etc. The content of the pharmaceutically active compounds may vary in the range of 0.1 to 95% by weight, preferably from 5.0 to 90% by weight of the total composition. Suitable tablets can be obtained, 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, and by pressing the resulting mixture to form tablets. Use in treatment / method of use The therapeutic applications in humans of NR2B NAM were synthesized in reviews by Trayneís et al, (Trayneíis et al., Pharmacology Reviews, 2010, 62;405), Beinat et al. (Beinat 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 for treating psychiatric conditions, diseases, and disorders, where the negative allosteric modulation of NR2B confers a therapeutic benefit, including: (1) mood disorders and affective mood disorders; (2) schizophrenia spectrum disorders; (3) neurotic, stress-related, and somatoform disorders, including anxiety disorders; (4) psychological development disorders; (5) behavioral syndromes associated with physiological alterations and physical factors; (6) addictive and substance use disorders; (7) disease associated with symptoms of negative and positive valence; (8) pain; (9) cerebral diseases; (10) episodic and paroxysmal disorders; (11) neurodegenerative diseases. Based on their pharmacological effect, the compounds in this IF-2020-07221114-APN-ANP#INPI Page 19 of 53 invention are suitable for use in the treatment of a disease, condition or disorder selected from the list consisting of (1) treatment of mood disorders and affective mood disorders including bipolar disorder I: symptoms of depression, hypomanic, manic and combination of these symptoms; bipolar II disorder; depressive disorders such as a single depressive episode or recurrent major depressive disorder, minor depressive disorder, postpartum onset depressive disorder, depressive disorders with psychotic symptoms; major depressive disorder with or without concurrent anxious distress, mixed features, melancholic features, atypical features, mood-congruent psychotic features, mood-incongruent psychotic features, catatonia. (2) treatment of mood disorders belonging to the schizophrenia spectrum and other psychotic disorders including schizophrenia and schizoaffective disorder with associated cognitive and negative symptoms. (3) treatment of disorders belonging to neurotic, stress-related and somatoform disorders including anxiety disorders, general anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorders; obsessive-compulsive disorder; reaction to severe stress and adjustment disorders, such as post-traumatic stress disorder; other neurotic disorders such as depersonalization-derealization syndrome. (4) treatment of psychological development disorders including pervasive developmental disorders, including Asperger's syndrome and Reti's syndrome, autistic disorders, childhood autism and hyperactive disorder associated with mental retardation and stereotyped movements, specific developmental disorder of motor function, specific developmental disorders of school skills, attention deficit / hyperactivity disorder. (5) treatment of behavioral syndromes associated with physiological alterations and physical factors, including behavioral and mental disorders associated with the puerperium, including postnatal and postpartum depression; eating disorders, including anorexia nervosa and bulimia nervosa and other impulse control disorders. (6) treatment of adjective and substance use disorders, which are substance use disorders induced by alcohol, cannabis, hallucinogens, stimulants, hypnotics, tobacco. (7) treatment of diseases associated with symptoms of negative and positive valency IF-2020-07221114-APN-ANP#INPI Page 20 of 53 which include anhedonia, sustained threat and loss, suicidal ideation. (8) treatment of severe and chronic pain, which is related to neuropathy, for example, diabetic neuropathy or polyneuropathy, physiological processes and physical disorders including, for example, lower back pain, joint pain, diseases of the musculoskeletal system and connective tissue, for example, rheumatism, myalgia, disorders of the plexus, spinal nerve root and nerves, for example, phantom limb syndrome with pain, carpal tunnel syndrome, (9) treatment of cerebrovascular diseases, for example, intracerebral or subarachnoid hemorrhage, cerebral infarction, stroke, occlusion and stenosis, cerebral atherosclerosis, cerebral amyloid angiopathy. ¢10) treatment of episodic and paroxysmal disorders, for example, epilepsy, (11) treatment of diseases that include forms of neurodegeneration, for example, stroke, Alzheimer's disease and Huntington's disease. As used herein, unless otherwise indicated, the terms treat, “treatment1” include the handling and care of a human subject or human patient to combat a disease, condition or disorder and include the administration of a compound of the present invention to prevent the occurrence of symptoms or complications, alleviate symptoms or complications, or cure the disease, condition or disorder. As used herein, unless otherwise indicated, the term “prevention” includes (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delaying or preventing the development of additional symptoms; and / or (d) delaying or preventing the development of the disorder or condition. According to another aspect, the present invention provides a compound of Formula A or a salt thereof pharmaceutically acceptable for use in the treatment and / or prevention of the aforementioned conditions. According to another aspect, the present invention provides a compound of Formula A according to any of the above aspects, characterized in that the compound of Formula A is used in addition to behavioral psychotherapy, TMS (transcranial magnetic stimulation), ECT (electroconvulsive therapy), and other treatments. Joint treatment The compounds according to the present invention can be combined with other treatment options known for their use in the prior art in relation to the treatment of any of the indications in whose treatment IF-2020-07221114-APN-ANP#INPI Page 21 of 53 focuses on the present invention. According to another aspect, the present invention provides a compound of Formula A according to any of the foregoing aspects, characterized in that the compound of Formula A is administered in addition to treatment with one or more antidepressants selected from the list consisting of duloxetine, escitalopram, bupropion, venlafaxine, desvenlafaxine, sertraline, paroxetine, fluoxetine, vortioxetine, mirtazapine, citalopram, vilazodone, trazodone, amitriptyline, clomipramine, agomelatine, levomilnacypran, lithium, doxepin, and nortriptyline. The term antidepressant refers 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 foregoing aspects, characterized in that the compound of Formula A is administered in addition to treatment with one or more antipsychotics selected from the list consisting of aripiprazole, paliperidone palmitate, lurasidone, quetiapine, risperidone, olanzapine, paliperidone, brexpiprazole, clozapine, asenapine, chlorpromazine, haloperidol, cariprazine, ziprasidone, amisulpride, iloperidone, fluphenazine, blonanserin, and lauroxil. The term "antipsychotic" refers 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 foregoing aspects, characterized in that the compound of Formula A is administered in addition to treatment with one or more psychostimulants selected from the list consisting of lisdexamfetamine, methylphenidate, amphetamine, dexamphetamine, dexmethylphenidate, armodafinil, and modafinil. The term “psychostimulant” refers to any pharmaceutical agent or drug that can be used to treat conditions 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 above aspects characterized in that the compound of Formula A is administered in addition to treatment with other selected spikes from the list consisting of oxiracetam, piracetam, or the natural product St. John's wort. According to another aspect, the present invention provides a compound of Formula A that is administered in addition to treatment with one or more IF-2020-07221114-APN-ANP#INPI Page 22 of 53 antidepressants, antipsychotics, psychostimulants, nootropics or natural products, according to any of the above aspects characterized in that the combination of compound of Formula A and one or more antidepressants, antipsychotics, psychostimulants, nootropics or natural products are used in addition to behavioral psychotherapy, TMS {transcranial magnetic stimulation}, ECT (electroconvulsive therapy) and other treatments. EXPERIMENTS SECTION Abbreviations: AON acetonitrile APCI chemical ionization at atmospheric pressure Boc tert-butyloxycarbonyl GDI 1,1'-c carbonyldiimidazole CO2 carbon dioxide D day DA diode beam DCM dichloromethane DIRE diisopropyl ether DIPEA diisopropylethylamine DMF dimethylformamide enantiomeric excess ESI electrospray ionization (in MS) EtOAc ethyl acetate EtOH ethane Example h example hour(s) HATU 0- (7 -aza benzotriazol-1 - i I)- N,N,N',N'-tetramethiol i I uroni ohexafluorophosphate HPLC high-performance liquid chromatography HPLC-MS combined high-performance liquid chromatography-mass spectroscopy M molar (mol / !) MeOH methanol min minute(s) MIS mass spectrometry MW molecular weight IF-2020-07221114-APN-ANP#INPI Page 23 of 53 NH3 ammonia PSI Pounds per square inch rt room temperature Rt scCO2 retention time CO2 supercritical solvent TBTU tetrafluoroborate of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography SFC Supercritical fluid chromatography Abbreviations in spectral data: 1H- NMR Proton nuclear magnetic resonance br broad 5 chemical shift d doublet dd doublet of doublets dt doublet of triplets DMSO'ífs H he xa -de ute ro-d i met i I s ulf oxide o proton Hz Hertz (-1 / second) J coupling constant m multiplet ppm parts per million q quartet s singlet t triplets td multiplet of doublets General analytics. All reactions were carried out using commercially available reagents and solvents. The NMR spectrum was recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2 pl6 software. Chemical shifts are provided in parts per million (ppm) down from internal reference trimethylsilane in units. Selected data are reported as follows: IF-2020-07221114-APN-ANP#INPI Page 24 of 53 Chemical shift, multiplicity, coupling constants (J), integration. Analytical thin-layer chromatography (TLC) was performed using Merck silica gel 60 F254 plates. All compounds were visualized as single spots using short-wave UV light. Low-resolution mass spectra were obtained using a liquid chromatography-mass spectrometer (LCMS) consisting of an Agilent 1100 series quadrupole LC mass spectrometer coupled to an Agilent 6130 (electrospray positive ionization). Methods: HPLC-MS methods: Method 1 Method Name; Z003 S05 Device Description: Aqilent 1200 with DA and MIS detector Column: XBridge C13_3.0 x 30 mm_2.5 pm_________ Column Manufacturer: Waters Description; ___ Gradient / Solvent Time [min] % of Sol [Water 0.1% NHS] % of Sol [Nitrile Acetate] Flow [ml / min] Temp [°C] Backpressure [PS] p0 95.0 5.0 2.2 60.0 0.2 95.0 5.0 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________ Method 2 Method Name: Z011 SG3 Device Description: Agilent 1200 with DA and MS detector Column: XBridgeCIB 3.0 x 30 mm 2.5 pm Column Manufacturer: Waters Description: Gradient / Solvent Time [min] % of Sol [Water 0.1% NH3] % of Sol [Aceto nitrile] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 97.0 3.0 2.2 60.0 0.2 7.0 3.0 2.2 30.0 1.2 0.0 100.0 2.2 30.0 1.25 0.0 100.0 60.0 1.4 100.0 3.0 60.0 IF-2020-07221114-APN-ANP#INPI Page 25 of 53 Method 3 Method name: Z017 S04 Device description: Agüent 1200 with DA and MIS detector Column: Sunfire C18_3.0 x 30 mm_1.8 pm Column manufacturer: Waters Description: Gradient / Sol Vent Time [min] % of Sol [Water 0.1% TFA] % of Sol [Acetonitrile] Flow [ml / min] Temp [°C] Counter Pressure IP8L 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 I 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 □0.0 1.4 0.0 100.0 3.0__ 50.0 Chiral analytical SFC methods: Method 4: Ι_3Α„20^ΙΡΑ_ΝΗ,_001 Method Name:______ Description of the Agilent 1260 SFC ccn DAD and MS device:_______ Column: ^CHIRAL ART® Amylose SA_4.6 x 250 mm 5 pm dsYMC Producer [column:___________·___________________________ ___ Gradient / Sol vent e Time [min] % of Sol [scCO2] % of Sol [ETOH 20mM NHa] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 85.0 15.0 4.0 40.0 :2175.0 10.0 35.0 15.0 4.0 40.0 ________2175.0________ Method 5: I_1CJJOJPA_NH3_OO1 Method name: IJC_30JPANH3 001 Device description: Column: Agilent 1260 SFC with DAD and MS Chiralpak® IC 4.6 x 250 mm_5 pm Column manufacturer: Da ice I Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [MEOH 20mM NHa] Flow [ml / min] Temp [°C] [Backpressure ________FSI]__ 0.0 70.0 30.0 4.0 40.0 2175.0 10.0 7.0 30.0 4£_______ 40.0 2175.0_______ IF-2020-07221114-APN-ANP#INPI Page 26 of 53 Preparatory HPLC conditions for purification: Instrument: (Agilent 1100). Fluents: Water - 5% NH4OH solution in water - CH3CN; flow: 50 ml / min; temperature 60 °C; column: XBridge C18. Preparation of intermediaries: Example 1a EITHER Methyl ester of (S)-moffolin-2-carboxylic acid hydrochloride (35 g; 192.7 mmol) was mixed with 400 mL of a 3 M solution of 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 filtrate was evaporated under reduced pressure. 23.5 g of the desired product were obtained as a solid. Example 1a: Analytical data,___________________________________________ SFC~chiral method: l JC 30_IPA_NH3001.MI Rt [min): 3.72; ee 100% MS: 145 (M+H)* Example 1b Methyl ester of (S)-morpholim2-carboxylic acid hydrochloride (5 g; 27.5 mmol) was mixed with 138 mL of a 2 M solution of 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 filtrate was evaporated under reduced pressure. 4.3 g of the desired product were obtained as a solid. i Example 1b:_____________ ________________ ____„___________ j SFC method guirai: I JCJ3ÓJPA hJHa_001.M ' Rt [min]: 3.23; ee > 99 % I MS: 159 (M+Hf'~~ Example 2a IF-2020-07221114-APN-ANP#INPI Page 27 of 53 Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol) and 4-fluorophenol (0.78 g; 6.5 mmol) were dissolved in DMSO (10 mL); K₂CO₃ (1.2 g; 8.69 mmol) was added, and the reaction mixture was stirred for 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, a 10% aqueous K₂CO₃ solution, and dried. 1.4 g of solid were obtained. Example 2a:________________________ HPLC-MS; Method: ZO11 SQ3¡ RJminj: 0.92 | MS: 249 (M+H)* Example 2b Example 2b was synthesized in a manner analogous to Example 2a. Starting materials; Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol), 2-fluoro-4-methylphenol (0.75 ml; 6.95 mmol). 1.5 g of the desired compound were obtained as a solid. Example 2b:_____________________________________________ ______________________________ . ,_| HPLC-MS; Method: Z011 SQ3; Rjmin] : 0.99 | MS: 263 (M+H)* ~ ~! Example 2c IF-2020-07221114-APN-ANP#INPI Page 28 of 53 Example 2c was synthesized in a manner analogous to Example 2a. Starting materials: Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol), 4-methylphenol (0.73 ml; 6.95 mmol). 1.35 g of the desired compound were obtained as a solid. Example 2c: I HPLC-MS, Method: Z011 S03; Rt[min] : 0.97 ~· MS: 245 (M+H)+' j Example 2d Example 2d was synthesized in a manner analogous to Example 2a. Starting materials: Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol), 2,4-dlmethylphenol (0.83 ml; 6.95 mmol). 1.45 g of the desired compound were obtained as a solid. Example 2d: __________________________________ _______________ HPLC-MS; Method: 01S S04; Rt[min]: 1.02| MS: 259 (M+H)T Example 2e Example 2e was synthesized in a manner analogous to Example 2a. Starting materials; Methyl ester of acid Page 29 of 53 mmol), 4-cl gold-2-flu gold-fe no I ¢0.74 ml; 6.95 mmol). 1.55 g of the desired compound were obtained as a solid. Example 2e: ______ HPLC-MS (Z011_S03); Rt[min]: 1.01 I MS; 2S3 and 285 (M+H)+; an isotopic pattern was observed for 1 Ci __ Example 2f Example 2f was synthesized in a manner analogous to Example 2a. Starting materials: Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol), 2,4-difluorophenol (0.67 ml; 6.95 mmol). 1.50 g of the desired compound was obtained as a solid. Example 2f: _________________________ ______ HPLC-MS (Z011 S03): Rt[min]; 0.95 MS: 267 (M+Hf Example 2q Example 2g was synthesized in a manner analogous to Example 2a. Starting materials; Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol), 4-chloro-phenol (0.89 g; 6.95 mmol). 1.5 g of the desired compound were obtained as a solid. Example 2g________________________ MS: 265 and 267 (M+H)*; Η P LC -MS (Z011 _S 0 3}: Rt[mini: 0.99 isotopic pattern for 1 Ci Example 2h IF-2020-07221114-APN-ANP#INPI Page 30 of 53, Q Example 2h was synthesized in a manner analogous to Example 2a. Starting materials: Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 mmol), 4-fluoro-2-methylphenol (0.88 g; 6.95 mmol). 1.5 g of the desired compound was obtained as a solid. Example 2h_____________ _____________________ __ HPLC-MS (Z011 S03); RtfminJ: 0.97 I MS: 263(M+Hf Example 2i Example 2i was synthesized in a manner analogous to Example 2a. Starting materials: Methyl ester of 5-chloro-prazin-2-carboxylic acid (1 g; 5.79 mmol), 2-fluorophenol (0.62 ml; 6.95 mmol). 1.22 g of the desired compound were obtained as a solid. Example 2_______________________________________ ________________________ HPLC-MS (Z011, 503): Rjmin]: 0.92 | MS: 249 (M+H)* Example 2k Example 2k was synthesized in a manner analogous to Example 2a. Starting materials; Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1 g; 5.79 IF-2020-07221114-APN-ANP#INPI Page 31 of 53 mmol), 2-chlorophenol (0.71 ml; 6.95 mmol). 1.51 g of the desired compound were obtained as a solid. Example 2k ___ HPLOMS (Z011_S03): RJmin]: 0.97 MS: 265 and 267 (M+H)*: isotopic pattern observed for 1 OI__ Example 2! Example 2j was synthesized in a manner analogous to Example 2a. Starting materials; Methyl ester of 5-chloro-pyrazin-2-carboxylic acid (1.00 g; 5.80 mmol), phenol (0.65 g; 6.95 mmol). 1.30 g of the desired compound was obtained as a solid. Example 2j ______________________ ___________________ ____ HPLOMS (Z017 S04): RJminj: 0.92~ | MS: 231 (MW Example 2I Example 2l was synthesized in a manner analogous to Example 2a. Starting materials: 5-chloro-pyrazin-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 were obtained as a solid. IF-2020-07221114-APN-ANP#INPI Page 32 of 53 I Example 21________________1HPLC-MS (O17 SQ4): R, [min]: 0.97 ~ |~MS: 267 (M+H)+ Example 2m Example 2m was synthesized in an analogous manner to Example 2a. Starting materials: Methyl ester of 5-chloro-pyrazine-2'-carboxylic acid (320 mg) 1.85 mmol), 2-fluoro-6-methylphenol (257 mg; 2.04 mmol). 480 mg of the desired compound were obtained as a solid. Example 2m________ ___________ HPLC-MS (Z017 S04): Rt[min]: 1.00 ] MS: 263 (M+Hf Example 3a Example 2a (1.4 g; 5.64 mmol) was dissolved in MeOH (15 mL); NaBH4 (0.64 g; 16.9 mmol) was added, and the reaction mixture was stirred for 3 hours at room temperature. Water was added to inactivate the reaction; the reaction mixture was then evaporated under reduced pressure, and the residue was divided between EtOAc (106 mL) and a 10% aqueous K2CO3 solution (30 mL). The organic phase was dried in Na2SO4, and the residue obtained after solvent evaporation was purified by flash chromatography (eluent: petroleum ether / EtOAc 3 / 1 to petroleum ether / EtOAc 2 / 1 gradient). 0.8 g of the desired compound (oil) was obtained. Example 3a_______________________ HPLC-MS; Method: Z011 S03; R¡[min]: 0.801MS: 221 (M+H)* _ Example 3b IF-2020-07221114-APN-ANP#INPI Page 33 of 53 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 IMS: 235 (M+H)4 Example 3c Example 3c was prepared analogously to Example 3a. Starting materials: Example 2c (1.35 g and 5.53 mmol). 0.95 g of the desired compound was obtained. Example 3c HPLC-MS7Z011 S03): Rt[ml]: 0.86 ' I MS: 217 (M+H)4 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): Z011 .S03 RJrnin]: 0.91 ' |~MS: 231 (M+H)+ Example 3e IF-2020-07221114-APN-ANP#INPI Page 34 of 53 Example 3e was prepared analogously to Example 3a. Starting materials: Example 2e (1.55 g; 5.43 mmol). 1.02 g of the desired compound were obtained. Example 3e ________________ HPLC-MS {Method): Z011_S03 RJmin]: 0.91 MS: 255 and 257 (M+H)\ an isotopic pattern was observed for 1 Cl__ 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 were obtained. Example 3f__________________________ _ ____________Z! HPLC-MS (Method): Z011 S03 R. [minj : 0.33 ' I MS: 239 (M+H)+, Example 3q Example 3g was prepared analogously to Example 3a. Starting materials: Example 2g (1.5 g; 5.67 mmol). 0.33 g of the desired compound was obtained. Example 3g___________ MS: 237 and 239 (M+H)'; it HPLC-MS (Method): Z011_S03 Rtjmin]: 0.83 observed isotopic pattern -ANP#INPI Page 35 of 53 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 were obtained. Example 3h_____________________ _____________________ ___________________ HPLOMS (Method): Z011 S03 Rt[mln] : 0.86 Π MS; 235 (M+H)+ Example 31 Example 31 was prepared analogously to Example 3a. Starting materials: Example 21 (1.22 g; 4.92 mmol). 0.75 g of the desired compound was obtained. Example 3a______________________________ , _____________ HPLC-MS (Method); Z011 S03 R,[min]; 0.8 ' I MS?221 (M+H)* Example 3k 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 was obtained. Example 3k__________________ HPLC-MS (Method); Z011_S03 Rt(min]; 0.85 MS: 237 and 239 (M+H)4; IF-2020-072Ü1 M^ÍTOlRp#^ F Page 36 of 53 Example 3j HO isotopic for 1 Cl Example 3j was prepared analogously to Example 3a. Starting materials: Example 2k (1.30 g; 5.65 mmol). The crude obtained after evaporation of the organic solvents was used as such in the following steps. 0.98 g of the desired compound (70% content) was obtained. Example 3j ____________________ | HPLC-MS ('Method): Z017_S04 Rt[min]': 0.79 | MS: 203 (M Example 3I Example 3I was prepared analogously to Example 3a. Starting materials: Example 2I (1.52 g; 5.71 mmol). The crude obtained after evaporation of the organic solvents was used as such in the following steps. 1.30 g of the desired compound (85% content) was obtained. Example 3I___________________ __________________ HPLC-MS (Method): Z017_S04 Rj[min): 0.84__f MS: 238 (Μ V Example, 3m IF-2020-07221114-APN-ANP#INPI Page 37 of 53 HO 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 Rt[min] : 0.87| MS: 235 (M+Hf Example 4a 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 hours at room temperature before preparation. A 5% solution of NaHCO₃ in water was added to the reaction mixture, the phases were separated, and dried on Na₂S₅SC₅. The crude product obtained after evaporation of the organic solvents was used as is in the subsequent steps. 1.05 g of the desired product were obtained. Example 4a_______________________ ____ HPLC-MS (Method): Z017 S04 Rt[min] : 0.93 | MS; 299 (M+H)1 Example 4b IF-2020-07221114-APN-ANP#INPI 3S Page 38 of 53 Example 4b was prepared analogously to Example 4a. Starting material: Example 3b (1 g; 4.27 mmol). 1.3 g were obtained. The product was used as is in the next step. Example 4b___________________________ HPLC-MS (Method); Z017~S04 R. [min] : 0.99 I MS: 313'(M+Hf Example 4c 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 preparation was used as such in the next step. Example 4c__________ HPLC-MS(Method): Z017_S04 Rj [mini: 0.93 ________ IMS-295(M+Hf Example 4d IF-2020-07221114-APN-ANP#INPI Page 39 of 53 Example 4d was prepared analogously to Example 4a. Starting material: Example 3d (0.83 g ≤ 3.61 mmol). 1.1 g was obtained. The product obtained after preparation was used as such in the next step. ! Example~4d__________ ______________ i HPLC-MS (Method): Z017 S04 RJmin]: 1.02| MS: 309 (M+H) Example 4e Example 4e was prepared analogously to Example 4a. Starting material: Example 3e (1.02 g; 4.0 mmol). 1.32 g was obtained. The product obtained after preparation was used as such in the next step. Example 4e _________________ HPLC-MS (Method): Z017„S04 RT[min]: 1.01 MS: 333 and 335 (M+H)4¡ an isotopic pattern was observed for 1 Cl 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 product obtained after preparation was used as such in the next step. Example 4f __________________ HPLC-MS (Method): Z017 S04 RJmin]: 0.95 [ MS: 317 (M+H)* Example 4g IF-2020-07221114-APN-ANP#INPI Page 40 of 53 Example 4g ​​was prepared analogously to Example 4a. Starting material; Example 3g (0.03 g; 3.51 mmol). 1.1 g were obtained. The product obtained after preparation was used as such in the next step. Example 4g____ HPLC-MS (Method): Z017_S04 Rt[min]; 0.99 MS: 315 and 317 (M+H)+; isotopic pattern observed for 1 Cl Example 4h Example 4h was prepared analogously to Example 4a. Starting material: Example 3h (0.86 g; 3.67 mmol). 1.12 g were obtained. The product obtained after preparation was used as such in the next step. Example 4h_______________________________________ HPLC-MS (Method): Z017 S04 Rt[min] : 0.97 | MS: 313 (M+H)+, Example 4I IF-2020-07221114-APN-ANP#INPI Page 41 of 53 °'S=O Example 41 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 preparation was used as such in the next step. Example 4!__________ HPLC-MS (Method): Z017 S04 Rt[min]: 0.93 | MS: 299 (M+H)4 Example 4k Example 4k was prepared analogously to Example 4a. Starting material: Example 3k (0.85 g: 3.59 mmol). 1.1 g were obtained. The product obtained after preparation was used as a starter in the next step. Example 4k HPLC-MS (Method): Z017_S04 Rjminl: 0.97 MS: 315 and 317 {M+H)4; isotopic pattern observed for 1 Cl__ Example 4! IF-2020-07221114-APN-ANP#INPI Page 42 of 53 Example 4j was prepared analogously to Example 4a. Starting material: Example 3k (0.98 g; 70% content; 3.39 mmol). The product obtained after preparation was used as is in the next step. 1.35 g of the desired product (70% content) was obtained. Eg enripio 4j_______ | HPLC-MS (Method): Z017 S04 Rt|min]: 0.91| MS: 281 (M+H)4 Example 4I. Example 4I was prepared analogously to Example 4a. Starting material: Example 31 (1.30 g; 85% content; 4.64 mmol). The product obtained after preparation was used as a starter in the next step. 1.70 g (85% content) was obtained. Example 4I _______________________________ ______________________ __________ HPLC-MS (Method): Z017 S04 Rj [min]: 0.95 MS:317(M+Hf . Example 4m IF-2020-07221114-APN-ANP#INPI Page 43 of 53 Example 4m was prepared analogously to Example 4a. Starting material: Example 3m (0.42 g; 85% content; 1.52 mmol). 0.55 g was obtained. The product obtained after preparation was used as is in the next step. Example 4m ___________________ _________________ ___________________ HPLC-MS (Method): Z017..S04 Rt[min] : 0.98| MS: 313 (m7|)4 EXAMPLE WAYS TO IMPLEMENT 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 room temperature, diluted with MeOH (3 mL), and filtered using a syringe filter. The resulting solution was purified by preparative HPLC. 53 mg of the desired compound were obtained. MS: 347 (M+H)T Rt [min]; 2.00; ee 100% Example 1______________________________ HPLC-MS; method:Z011 S03 ¡Rt[min]: 0.87 chiral CFS; Method: I_SA_2QJPA_NH3J)O1 TTrMN'{400 MHz, DMSO-cQ; δppm: 2.02 (m, 1H); 2.17 - 2.24 (m, 1H); 2.58 (m, 3 H); 2.66 - 2.71 (m, 1H); 2.95 (m, 1H); 3.54 - 3.69 (m, 3H); 3.83 - 3.90 (m, 2H); 7.27 (mr4 H); 7.67 (m, 1H); 8.19 (m, 1H); 8.47 (m, 1 H). __ Example 2 IF-2020-07221114-APN-ANP#INPI Page 44 of 53 Example 2 was synthesized in a manner analogous to Example 1. Starting materials: Example 4b (100 mg; 0.32 mmol) + Example 1a (50.78 mg; 0.35 mmol). The crude was purified by preparative HPLC. 105 mg of the desired compound were obtained. Example plp_2___ _____ H PLC-MS: Method: Z011_S03: Rt[min]: 0.93 MS: 361. (M+H)*____________ SFCquiral Method: I SA 20JPA_NH. 0Q1 Rt~[person]; 1.96; ee 100 %1H NMR (400 MHz, DMSO-tfG)¡ or ppm: 2.02 (m, 1 H); 2.16 - 2.24 (m, 1 H); 2.32 - 2.36 (m, 3 H); 2.57 (m, 3 H); 2.65 - 2.70 (mr1 H); 2.94 (m, 1 H); 3.54 - 3.69 (m, 3 H); 3,S3 3.90 (m,2H); 7.07 (m, 1 H); 7.21 (m, 1 H); 7.26 (m, 1 H); 7.67 (m, 1 H); 8.17 (m, 1 H); 8.55 (m, 1 H). __________________________ ________________________ Example 3 Example 3 was synthesized in an analogous manner to Example 1. Starting Materials: Example 4c (100 mg; 0.34 mmol) + Example 1a (53.9 mg: 0.37 mmol). The crude was purified by preparative HPLC. 80 mg of the desired compound was obtained. Example 3_________ _________________ _______________ HPLC-MS: Method: Z011_S03; RJminl: 0.91 MS: 343 (M+H)+ SFC qurral; Method; l_SA_20_IPA_NH3_001 Rt[min]: 2.34; yes 99.59% 'TÍRMN (400 MHz, DMSO-dB); 5ppm: 2.02 (m, 1H); 2.16 - 2.24 (m, 1H); 2.30 - 2.34 (m, 3H); 2.57 (m, 3H); 2.68 (m, 1H); 2.95 (m, 1 H)¡ 3.54 - 3.68 (m, 3 H); 3.83 - 3.90 (m, 2H); 7.06 - 7.10 (m, 2H); 7.23 (m, 2 H)¡ 7.63 - 7.70 (m, 1 H); 8.18 (m, 1H); 8.43 (m, 1 H), ________________ _______________________________ _________ IF-2020-07221114-APN-ANP#INPI Page 45 of 53 Example 4 Example 4 was synthesized in a manner analogous to Example 1. Starting materials: Example 4d (100 mg; 0.32 mmol) + Example 1a (51.4 mg; 0.36 mmol). The crude was purified by preparative HPLC. 55 mg of the desired compound were obtained. Example 4_______________________ HPLC-MS Z003 S05: Rt[min]: 1.14 chiral CFS; Method: l_SA_20_IPA_NH^_001 MS: 357 (M+H}+ Rt[min]: 2.07; ee 94 %1H NMR (400 MHz, DMSOdj; 5 ppm: 1.99 - 2.07 (m, 4 H); 2.15 - 2.24 (m, 1 H); 2.26 2.32 (m, 3 H); 2.57 (m, 3 H); 2.6S (m, 1 H); 2.94 (m, 1 H) 3.54 - 3.67 (m, 3 H); 3.83 (m, 2 H); 6.97 - 7.06 (m, 2 H); Example 5 Example 5 was synthesized in a manner analogous to Example 1. Starting materials; Example 4e (100 mg; 0.30 mmol) + Example 1a (47.66 mg; 0.33 mmol). The crude was purified by preparative HPLC. 70 mg of the desired compound were obtained. HPLC-MS Z01VS03: RJmin]; 10.96 MS: 381 and 383 an isotopic pattern was observed for 1 Cl________ _______ chiral SFC; _____ Method: Rt [min]: 2.27;__________ ________________ IF-2020-07221114-APN-ANP#INPI Page 46 of 53 í_SA_20_IPA__NH5_001 ee 100 %____________ _____________1H RMhí^OO MHz. DMSO-Ós); δ ppm: 2.03 (m''l H); 2.21 (m, 1H); 2.57 (m, 3H); 2.65 - 2.70 (m, 1H); 2.94 (m, 1H); 3.54 - 3.70 (m, 3H); 3.83 - 3.90 (m, 2H); 7.37 (m, 1H); ' 7.47 (m, 1 H); 7.63 - 7.69 (m, 2H); 8.20 (d. .31 Hz, 1 H); 8.61 (d, J=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 was purified by preparative HPLC. 81 mg of the desired compound were obtained. Example 6 ___ H PLC-MS: Method: ZQ03_S05; Rt[min]:1.05 MS: 365 (M+Hf chiral CFS; Method: l_SA_20_IPA_NH3_001 eVTüO1H NMR (400 MHz, DMSO-d5); δ ppm: 1.99-2.07 (m, 1H): 2.20 (m, 1H); 2.57 (m, 3H); 2.64 - 2.72 (m, 1H); 2.94 (m, 1H); 3.54 - 3.71 (m, 3H); 3.83 - 3.90 (m, 2H); 7.14 7.20 (m, 1 H): 7.44 - 7.52 (m. 2 H); 7.63 - 7.72 (m, 1H); 8.19 (d, J=1.37 Hz:1 H); 8.60 (d. J=1.35 Hz, 1 H)._____________________ _____________________ ________________________ Example 7 Example 7 was synthesized in a manner analogous to Example 1. Starting materials: Example 4g ​​(100 mg; 0.32 mmol) + Example 1a (50.39 mg; 0.35 mmol). The crude was purified by preparative HPLC. 97 mg of the desired compound were obtained. IF-2020-07221114-APN-ANP#INPI Page 47 of 53 Example 7 HPLC-MS (Method): Z011_S03; Rt[min): 0.93; MS: 363 and 365 (M+H)'; was observed Isotopic pattern for 1 Cl chiral SFC, Method: I_SA_20JPA_NHÍ_001 RL(min]:2.95: ee 100 % ήΗ NMR (400 MHz, DMSO-d6)¡ δ ppm; 2.02 (m, 1 2.74 (m, 1 H) 2.96 (m, 1 H) 3.54 - 3.70 (m, 3 H) 3 H) 7.47-7.51 (m. 2 H) 7.68 (m, 1 H) 8.21 (d, >1.3 rl) 2.21 (m, 1 H) 2.57 (m, 3 H) 2.65 .03 - 3.91 (m, 2). H) 7.24 - 7.29 (m, 25 Hz, 1 H) 8.50 (d, >1.35 Hz, 1 H) Example 8 Example 8 was synthesized in an analogous manner to Example 1. Starting Materials: Example 4h (100 mg; 0.32 mmol) + Example 1a (50.73 mg; 0.35 mmol). The crude was purified by preparative HPLC. 60 mg of the desired compound was obtained. Example 8__________ ___ HPLC-MS (Methods): ZÓ03 S05; Rt[min]: 1.09 Key SFC method: l_SA_2C'JRA_NH3_001 MS: 361 (M+Hf Ri[minj: 1.79 yes, 100% Ή NMR (400 MHz, DMSO-ds) ¡ δ ppm: 1.99 - 2.06 (m, 1 H); 2.08 - 2.10 (m, 3H); 2.16 2.25 (m, 1H); 2.57 (d, >4.74 Hz, 3 H); 2.65 - 2.71 (m, 1 H)¡ 2.95 (m. 1 H); 3.54 - 3.68 (m, 3 H): 3.63 - 3.90 (m, 2 H); 7.05-7.10 (m, 1 H); 7.16-7.22 (m, 2H); 7.64-7.70 (m, H); 8.16 (d, >1.33 Hz, 1 H); 6.49 (d, >1.32 Hz. 1 H) Example 9 Example 9 was synthesized in a manner analogous to Example 1. Starting materials: Example 4¡ (100 mg;* 1 Page 48 of 53 0.37 mmol). The crude was purified by preparative HPLG. 49 mg of the desired compound were obtained. Example I) ' HPLC-MS (Method): Z003 S05; Rt[min]: 1.03 MS: 347 (M+H)+ ¡ Chiral SFC method: l_SA_20_IPA_NHj_p01 Ri [min): 1.84; ee 100% 1H NMR (400 MHz, DMSO-d3); Ó ppm: 2.02 (m. 1 H); 2.20 (m, 1H); 2.56 - 2.59 (m, 3H); 2.65 - 2.70 (m, 1H); 2.94 (m, 1H); 3.54 - 3.70 (m, 3H); 3,S3 - 3.90 (m, 2H); 7.25 7.43 (m, 4H); 7.64 - 7.69 (m, 1H); 8.19 (m, 1H); 8.59 (m, 1H). Example 1B Example 18 was synthesized in a manner analogous to Example 1. Starting materials: Example 4k (100 mg, 0.32 mmol) + Example 1a (50.78 mg; 0.35 mmol). The crude was purified by preparative HPLG. 64 mg of the desired compound were obtained. Example 18 ________________________ HPLC-MS Method: Z003_S05; Rt[minJ: 1.07 I MS: 363 and 365 (M+H)'; isotopic pattern observed for 1 CI i Rt[min]: 2.38; Chiral SFG method: l_SAj20_IPA_NHa_0011H NMR (400 MHz, DMSÓ-dc): δ ppm: 2.02 (m, 1^2.21 (m, 1 H); 2.57-2.58¼ 3 H); 2.64 - 2.71 (m, 1H); 2.95 (m, 1H); 3.54 - 3.70 (m, 3H); 3.83 - 3.90 (m, 2H); 7.30 7.36 (m, 1 H); 7.38 - 7.46 (m, 2H); 7.59 - 7.63 (m. 1 H); 7.63 - 7.70 (m, 1H); 8.18 (d, >1.33 Hz, 1 H): 8.57 (d, >1.34 Hz, 1 H). Example 30 IF-2020-07221114-APN-ANP#INPI Page 49 of 53 Example 30 was synthesized in a manner analogous to Example 1. Starting materials: Example 4f (100 mg; 0.32 mmol) and Example 1b (60 mg; 0.38 mmol). The crude was purified by preparative HPLC. 58 mg were obtained. Example 3Q________________ _______________________________ HPLC-MS; Method: Z003_S05; Rt[min]: 1.10 Í' MS: 370 {M+H)4___ Chiral SFC method: : l_SA_20JPA_NH3_001!Rt[mlnJ: 1.55; ee 100% _____1H NMR (400 MHz, DMSO-d6); δ ppm; Ó.93 (t, J=7.18 Hz, 3 H); 2.02 (m, 1H); 2.21 (m, 1H); 2.65 - 2.70 (m, 1 H), 2.93 (m, 1 H); 3.04 - 3.11 (m, 2H); 3.54 - 3.62 (m, 1H); 3.64 - 3.68 (m, 2H); 3.84 - 3.08 (m. 2 H); 7.14 - 7.20 (m, 1H); 7.44 - 7.52 (m, 2H); 7.69 (m, 1H); 3.19 (brs, 1H); 8.60 (m, 1 H). Example 31 Example 31 was synthesized in a manner analogous to Example 1. Starting materials: Example 4b (100 mg; 0.32 mmol) and Example 1b (60 mg; 0.38 mmol). The crude was purified by preparative HPLC. 57 mg were obtained. Example 31_________ ______________ HPLC-MS; Method; 011_SQ3; Rt[min]; 0.98 | MS; 375 (M+H)4 Chiral SFC method:: I ,SA_2OJPA_NH3001 ' Rt[min]; Ϊ.83; ee 100 % “NMRTI (400 MHz, DMSO-í / e); & ppm: 0.99 (t, J=7.16 Hz, 3H); 2.02 (t, J= 10.77 Hz, 1 H); 2.21 (m, 1 H) ¡ 2.32 - 2.36 (m, 3 H); 2.67 (m, 1 H) ¡ 2.93 (m, 1 H); 3.08 (m, 2 H) ¡ 3.54 - 3.69 (m, 3 H); H); 7.69 (m, 1H); 8.17 {m, 1 H); 8.55 (m, 1 H). IF-2020-07221114-APN-ANP#INPI Page 50 of 53 Example 33 Example 33 was synthesized in an analogous manner to Example 1. Starting Materials: Example 4k (100 mg; 0.32 mmol) and Example 1b (60 mg; 0.38 mmol). The crude was purified by preparative HPLC. 37 mg were obtained. Example 33______________________ HPLC-MS: Method: Z003_S05: RL[min]: 0.96 MS; 377 and 379 (M+Hf; isotopic pattern observed for 1 Cl Quinal SFC method: : LSA_20JPA_NHa_001 Rt[min]: 2.16; ee 100%1H NMR (400 MHz, DMSO-de); δ ppm: 0.99 (t, ^7.18 Hz, 3 H); 2.02 (t, J=10.76 Hz, 1 H); 2.21 (td, J=11.31, 3.19 Hz, 1 H); 2.65 - 2.71 (m, 1H); 2.94 (m, 1H); 3.04 - 3.11 (m, 2H); 3.54 - 3.70 (m, 3 H); 3.83 - 3.89 (m, 2H); 7.30 - 7.46 (m, 3H); 7.61 (dd, J=7.96, 1.44Hz, 1H); 7.69 (m, 1 H>; 8.18 (d, J=1.33 Hz, 1 H); 8.57 (d, J=1.32 Hz, 1 H). Example 34 Example 34 was synthesized in a manner analogous 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 was purified by preparative HPLC. 71.0 mg of the desired product were obtained. Example 34_______.__ I HPLC-MS; Method: Z011„S03; Rjmin]: 0.85 jWM^WlhDl-APN-ANPtfTNPT Page 51 of 53 Chiral SFC method: : l_SA_20_IPA_NH32001 I Rt[minj: 2.29; yes 100% '^HRMN (400 MHz, DMSO-dfi); δ ppm: 2.03 (day, Ί H); 2.21 (m, 1 H); 2.58 (m, 3A); 2.69 (m, 1 H); 2.96 (m, 1 H); 3.54 - 3.69 (m, 3 H); 3.83 - 3.91 (m, 2 H}¡ 7.18 - 7.28 (m, 3 H); 7.44 (m, 2 H); 7.63 - 7.71 (m, 1 H); 8.20 (d. J=1.37 Hz, 1 H); 8.46 (d, J=1.35 Hz, 1 H). Example 35 Example 35 was synthesized in an analogous manner to Example 1 . Starting materials: Example 4I (130 mg; 0.35 mmol) and Example 1a (55.4 mg; 0.38 mmol). The crude was purified by preparative HPLC. 71.0 mg of the desired product was obtained. Example 35 ___________________ HPLC-MS ¡ Method: Z003 _S05; R, [min]; 1.06 MS: 365 (M+Hf _____ Chiral SFC method:': ¡_SA_20JPA_NH3_001 ~ | RJoninj: 1.63Í~ee 100%nH NMR (400 MHz, DMSQ-day); δ ppm: 2.04 (m, 1 H); 2.21 (m, 1 H); 2.57 (m, 3 H); 2.63 - 2.71 (m, 1 H); 2.94 (m, 1H); 3.57 (m, 1H); 3.68 (s, 2H); 3.82 - 3.91 (m, 2H); 7.28 7.44 (m. 3 H); 7.60 - 7.74 (m, 1H); 8.21 (d, J=1.37 Hz, 1 H); 8.71 (d, J=1.35 Hz, 1 H). Example 36 Example 36 was synthesized in a manner analogous to Example 1. IF-2020-07221114-APN-ANP#INPI Page 52 of 53 Starting materials: Example 4m (130 mg; 0.42 mmol) and Example 1a (66.0 mg; 0.46 mmol). The crude was purified by preparative HPLC. 37.0 mg of the desired product were obtained. Example 36 _________________________________________ HPLC-MS ; Method: Z011 S03; Rt[min]: 0.92 MS: 361 (M+H)+ SFC quinal method; : Ι_5Α_20_ΙΡΑ„ΝΗ,_001 Ri[min]: 1.71; ee 100% 1H NMR (400 MHz, DMSQ-d6); or ppm; 2.03 (m, 1 H) ¡ 2.15 - 2.22 (m, 4 H); 2.57 (m, 3 H) ¡ 2.62 - 2.75 (m, 1 H); 2.95 (m, 1 H); 3.52 - 3.61 (m, 1 H); 8.16 (d, J=1.38 Hz, 1H); 8.62 (d, J=1.35 Hz, 1 H). ____ IF-2020-07221114-APN-ANP#INPI Page 53 of 53 Argentine Republic - National Executive Branch 2020 - Year of General Manuel Belgrano Additional Signature Sheet Graphic Report Number: IF-2020-07221114-APN-ANP#INPI CITY OF BUENOS AIRES Saturday, February 1, 2020 Reference: 20190102937 The document was imported by the GEDO system with a total of 53 page(s). Digitally signed by GESTION DOCUMENTAL ELECTRONICA- GDE Date: 2020.02.01 03:08:40 -03:00 Mariela Flavia Gonnet Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by DOCUMENTAL MANAGEMENT ELECTRONICS-GDE Date: 2020.02.01 03:08:16-03:00

Claims

1. A compound characterized by Formula A (FORMULA A) wherein R1 represents methyl, ethyl, propyl, isopropyl, cyclopropyl, H3C-CH2-CH2-CH2-, cyclobutyl; R2 represents phenyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, cyclopropyl. Nine claims follow.