IMIDAZOPYRIDINE DERIVATIVES AND THEIR SALTS

Abstract

Claim 1: A compound characterized by formula (1), wherein R¹ represents phenyl that is optionally substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl, cyclopropyl, F₂HC-, FH₂C-, F₃C-; R² represents hydrogen, methyl; R³ represents hydrogen, fluorine.

Description

26727 IMIDAZOPYRIDINE DERIVATIVES AND THEIR USE AS A MEDICINE The present invention relates to novel imidazopyridines of the general Formula A processes for their preparation, pharmaceutical compositions containing them, and their use in treatments, particularly in the treatment or prevention of conditions related to 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. 80: 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 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 there are multiple subtypes of NMDA receptors, which contain different NR2(AD) subunits (Paoletti et al., 2013 Νφ.^jOl^W^P^A^iN^ás1. Page i of 48 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; 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 NAMs also demonstrated antidepressant efficacy in early-stage clinical trials (Preskorn et al. 2008. J Clin Psychopharmacol 70:58). Preclinical studies using NR2B NAM and applying various strains of transgenic mice demonstrated that NR2B-containing NMDA receptors are involved in the positive effect of ketamine in, for example, forced swim tests (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). NR2B NAMs described to date have demonstrated disadvantages with respect to their receptor pharmacology and / or other drug properties that have limited potential use in human drug treatment (Taylor et al. 2006, Clin Pharmacokinet. 45:989; Addy et al. 2009 J of Clinical Pharmacology 49:856). In WO2016 / 29146, the compounds of the Formula (!) are disclosed R^Z~jfR2hT H (l). which are methionyl-tRNA synthetase (MetRS) inhibitors useful as antibiotics. Formula (I) in WO2016 / 29146 includes specific effects 1734, 1744, 1745, 1757, 1758, 1785, and 1790, which exhibit a benzimidazole or imidazopyridine substructure. It was surprisingly discovered that the compounds of the present invention are potent negative allosteric modulators of NR2B (see Table 1), whereas specific examples 1734, 1744, 1745, 1757, 1758, 1785 and 1790 of WO2016 / 29146 show considerably deficient allosteric modulation of the NR2B ion channel or no activity at all (see Table 2). Furthermore, the compounds of the present invention show good membrane permeability and low to moderate in vitro effluvium (see Table 3 for IF-2019-01493 03 8-APN-ANP#INPÍ) Page 2 of 48 MDCK assay of MDR1 (p-GP), and Table 4 for the MDCK assay of BCRP). Therefore, the compounds of the present invention are expected to show 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: apparent permeability coefficients (PE) of compounds across MDCK-MDR1 cell monolayers are measured (pH 7.4, 37 °C) in the apical-to-basal (AB) and basal-to-apical (BA) transport directions. AB permeability (PEAB) represents drug uptake from the blood into the brain, and BA permeability (PEBA) represents drug efflux from the brain back into the blood via passive permeability and active transport mechanisms mediated by efflux and uptake transporters expressed in MDCK-MDR1 cells, predominantly by overexpressed human MDR1.Identical or similar permeabilities in both transport directions indicate passive permeability, points of vector permeability to additional active transport mechanisms. A higher PEBA than PEAB (PEBA / PEAB >5) indicates the involvement of MDR1-mediated active effluvium, which may be related to the goal of achieving sufficient brain exposure. Therefore, this assay provides important support for selecting applicable compounds for further in vivo testing. High permeability not limited by effluvium across the blood-brain barrier is a favorable characteristic for compounds used in drugs that act primarily in the CNS. Similar concepts apply to BCRP MDCK assays and their interpretation; consequently, to ensure high permeability across the blood-brain barrier, minimizing effluent (effluent <5) in both MDR1 and BCRP transport is highly preferred. Furthermore, the compounds of the present invention are metabolically stable in human liver microsomes (see Table 5, 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 selection and / or design of IF-2019-01493 03 8-APN-ANP#INPI Page 3 of 48. 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 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 may allow for lower and less frequent dosing in patients. Therefore, enhanced stability in human liver microsomes is a favorable characteristic for compounds used in drug formulations. Consequently, the compounds of the present invention should be more viable for use in humans. Therefore, the objective technical problem is to provide powerful negative allosteric modulators of NR2B. The present invention provides novel imidazopyridines of Formula A A where R1 represents phenyl that is optionally substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl, cyclopropyl, F2HC-, FH2C-, F3C-; R2 represents hydrogen, methyl; R3 represents hydrogen, fluorine; or one of those salts, in particular, a salt acceptable from a pharmaceutical point of view. In one embodiment, in General Formula A, R1 has the same meaning as defined in any of the above embodiments, and R2 represents hydrogen; R3 represents fluorine. In one embodiment, in General Formula A, R1 has the same meaning as defined in any of the preceding embodiments, and R2 represents methyl; IF-2019-01493038-APN-ANP#INPI Page 4 of 48 R3 represents hydrogen. In one embodiment, in General Formula A, R1 has the same meaning as defined in any of the above embodiments, and R2 and R3 represent hydrogen. In one embodiment, in General Formula A, R2 and R3 have the same meaning as defined in any of the above embodiments, and R1 represents phenyl that is optionally substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, methyl, F2HC-. In one embodiment, in General Formula A, R2 and R3 have the same meaning as defined in any of the above embodiments, and R1 represents The present invention provides novel imidazopyridines of General Formula A that unexpectedly are potent negative allosteric modulators of NR2B. Another aspect of the invention relates to compounds according to the IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 5 of 48 Formula A as negative allosteric modulators of NR2B that have appropriate membrane permeability and low to moderate in vitro effluvium. Another aspect of the invention relates to the compounds according to Formula A as negative allosteric modulators of NR2B that have high metabolic stability in human liver microsomes. Another aspect of the invention relates to the compounds according to Formula A as negative allosteric modulators of NR2B having appropriate membrane permeability, low to moderate in vitro effluvium, 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. 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 schemes illustrate, 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 schemes, the abbreviated substituents may be as defined above. IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 6 of 48 Scheme 1 R3 R1 20-30% racemization observed S-enantiomer R-enantiomer IF-2019-01493 03 8-APN-ANP#INPI Page 7 of 48 Scheme 2 S enantiomer R enantiomer Alternatively, the synthesis according to schemes 1 and 2 can be carried out using 4-tert-butyl ester of racemic morpholin-2,4-dicarboxylic acid as the starting material. Both schemes 1 and 2 can be successfully used for the gram-scale synthesis of the final compounds from 40 mmol of the desired substituted morpholine (racemic or S-entantiomer; Examples 3b, 3d, 3e according to the Experiments Section), by using an excess of the desired substituted benzyl alcohol, DIPEA (3 equivalents), the required coupling agent, such as GDI, and DMF as the solvent. An alternative gram-scale synthesis can be carried out using the corresponding morpholine (racemic or S-enantiomer; 40 mmol), TEA (2.5 equivalents), a slight excess of imidoyl carbonate, and a 1 / 1 mixture of CH3CN / THF IF-2019-01493 03 8-APN-ANP#INPI Page 8 of 48 as a solvent. In schemes 1 and 2, all substituents R1, R2 and R3 have the meaning defined in General Formula A, all embodiments of the invention that refer directly to these and, specifically, the meaning defined in the claims. GENERAL DEFINITIONS Terms not specifically defined herein should have the meanings that would be given to them by people of mid-level skill level based on dissemination and context. In the event that a compound of the present invention is represented in the form of a chemical name as well 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. 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 explanatory memorandum and 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 varying proportions, of each of the enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers exist, and salts thereof, including pharmaceutically acceptable salts thereof. General Formula A Page 9 of 48 comprises tautomers A-1 and A-2: All compounds of the present invention exist in their tautomeric form A-1 and / or A-2. 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 the tissues of humans and animals 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, 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 that form a pharmaceutically acceptable salt with a parent compound containing an acidic portion include Na+, K+, Ca2+, Mg2+, 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 basic or acidic portion 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 base. Page 10 of 48 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 BCRP breast cancer resistant protein Dulbecco's Modified Eagle Medium DMEM FBS fetal bovine serum FLIPR fluorometric imaging plate reader HEK293 cell line derived from human embryonic kidney cells HEPES buffer of hydroxyethylpiperazinetanesulfonic acid MDCK canine kidney Madin-Darby MDR1 multidrug resistance protein 1 p-GP p-Glycoprotein In-vitro effect: Determination of in vitro pharmacological activity 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 stored until use at -150 °C. The cells were cultured in a culture medium (DMEM / F12, 10% FBS, 5 pg / ml Blasticidin, 150 pg / ml Zeozin, 500 pg / ml Geneticin). It is important that IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page ii of 48, the density should not exceed 80% confluence. 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 (BD 359324, 50,000 cells per well in 50 pl) 48 h before the assay in the induction medium. Preparation of the compound The test compounds were dissolved in 100% DMSO to a concentration of 10 mM, and in a first step, they were diluted in DMSO to a concentration of 5 mM, followed by dilution steps in 100% DMSO. The dilution factor and the number of dilution steps could be varied according to requirements. Generally, eight different concentrations were prepared by duplicate 1:5 dilutions. Other intermediate dilutions (1:37.5) of the substances were carried out with an aqueous test buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl, 10 mM HEPES, 10 mM glucose, pH 7.4) that yielded 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 assay buffer, leaving 10 µL of buffer in the cavities after washing. 10 µL of Ca loading buffer kit (AAT Bioquest) were added to the cells, and the plates were incubated with the lid on for 60 minutes. 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. Fluorescence (indicating an influx of calcium as a result of NR1 / NR2B ion channel activation) was read on the FLIPRtetra device for 60 seconds to monitor glutamate-induced effects. After 2 minutes, 20 μL of the compound or controls (rows 1-22) were carefully added to the assay buffer in the cavities. Fluorescence was read on the FLIPR tetra device for an additional 6 minutes to monitor the effects induced by the compound following agonist activation.The average of 2 measurements at 5 minutes and 5 minutes 10 seconds after the addition of the compound was calculated and reused for the calculations of IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ 12. Page 1 of 2 of 48 IC50. Each microtiter plate of the assay 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)Ab)+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 IC50 value are preferred. Table 1 In vitro affinity of the compounds of the present invention as obtained in the FLIPR test Example No. IC50 [nM] 1 409 2 83 4 228 6 475 8 404 9 293 10 156 11 55 12 73 13 122 14 121 15 93 16 104 17 76 18 54 19 128 24 748 25 477 26 78 27 95 28 42 31 132 IF-2019-01493 03 8-APN-ANP#INPI Page 13 of 48 Table 2 In vitro affinity of the nearest prior art compounds (examples 1734, 1744, 1745, 1757, 1758, 1785 and 1790 in WO2016 / 29146) as obtained in the same FLIPR assay as the compounds in Table 1 Example No. in WO2016 / 29146 IC50 [nM] 1734 >8885 1744 >8889 1745 >8898 1757 >8900 1758 >8884 1785 6200 1790 >8887 MDCK assay of MDR-1 (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 apical-abasal (AB) and basal-to-apical (BA) directions. MDCK-MDR1 cells (6 x 105 cells / cm2) were seeded on filters (Corning, Transwell, polycarbonate, 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, 4.17 mM NaHCO3, 1.19 mM Na2HPO4, 0.41 mM NaH2PO4, 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 basolateral donor site to measure AB or BA permeability, respectively. The receptor site contains 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 by HPLC-MS / MS. 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 Table 3. IF-2019-01493 03 8-APN-ANP#INPI Page 14 of 48 Table 3 Ex. Median Papp (ab) [10-6 cm / s] effluent ratio 1 61 0.9 2 31.5 1.7 6 44.4 1.48 8 39 1.6 9 49 1.16 10 37 1.6 11 32 1.4 12 46 0.9 13 35 1.3 14 38 1.1 15 59 1.2 16 41 1.2 17 40 1.3 18 37 1.3 19 42 1.6 26 32 2 27 65 1.2 28 42 1.1 31 18 1.8 The results of the experiment indicated above show that the compounds of the present invention are potent NR2B NAMs that have good membrane permeability and low to moderate in vitro effluvium. BCRP MDCK assay The apparent permeability coefficients (Papp) of the compounds through MDCK-BCRP monolayers (MDCKII cells transfected with human BCRP cDNA expression plasmid) were measured in the apical-abasal (AB) and basal-to-apical (BA) directions. MDCK-BCRP cells (6 x 105 cells / cm2) were seeded on filters (Corning, Transwell, polycarbonate, 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, 4.17 mM NaHCO3, 1.19 mM Na2HPO4, 0.41 mM NaH2PO4, 15 mM HEPES, 20 mL / L glucose, pH 7.4) enriched with 0.25% BSA to prepare the transport solutions (final concentration: 1 or 10 pM, final DMSO ≤ 0.5%). The transport solution was applied to the apical or basolateral donor site to measure AB or BA permeability, respectively. The recipient site contained HTP-4 buffer supplemented with 0.25% BSA. The ÍF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page i 5 of 48. Samples are collected at the beginning and end of the donor experiment and at various time intervals for up to 2 hours from the recipient site for concentration measurement by HPLC-MS / MS. 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 Table 4. Table 4 Ex- Papp (ab) mean [10-6 cm / s] efflux ratio 1 38 2.4 2 34 2.9 8 46 1.8 10 40 2.2 11 63 1 12 69 1 13 72 0.9 14 68 1.2 15 33 2.8 16 49 2.1 17 37 2.5 18 53 1.2 19 61 1.6 26 24 2.7 27 24 5.2 28 56 1.2 31 85 0.7 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 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 human), and the test compound at a final concentration of 1 µM. After a brief pre-incubation period at 37 °C, reactions were initiated by the addition of betanicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by solvent transfer at different time points. After centrifugation (10,000 g, 5 min), an aliquot of the supernatant was analyzed by LC-MS / MS 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 were IF-2019-01493 03 8-APN-ANP#INPI Page 16 of 48 shows in Table 5. Table 5 Ex. half-life -11 / 2 [min] of human liver microsomes 1 38 2 76 4 24 6 40 8 14 9 22 10 12 11 24 12 36 13 37 14 27 15 86 16 >130 17 >130 18 51 19 130 26 >130 27 130 28 >130 31 16 The present invention provides compounds according to Formula A that unexpectedly generate a favorable combination of the following key parameters: 1) negative allosteric modulation of NR2B, 2) favorable stability in human liver microsomes and 3) moderate to low in vitro effluence on MDR1 and BCRP 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. The appropriate tablets can be obtained, for example, by mixing a IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page i 7 of 48 compound of the present invention with known excipients, for example, inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants, and 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 Traynelis et al. (Traynelis 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 leads to 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) adjective and substance use-related disorders; (7) disease associated with symptoms of negative and positive valence. Based on their pharmacological effect, the compounds of the present 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 I disorder: symptoms of depression, hypomanic, manic, and combinations 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 that belong to neurotic disorders, IF-2019-01493 03 8-APN-ANP#INPI Page 18 of 48 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 syndrome and Rett 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 that include anhedonia, sustained threat and loss, suicidal ideation. As used herein, unless otherwise indicated, the terms “treat” and “treatment” 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. IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 9 of 48 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 on which the present invention focuses. 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, levomyinacipran, lithium, doxepin, and nortriptyline. The term “antidepressant” refers to any pharmacological 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 aripiprazole lauroxil. The term “antipsychotic” refers to any pharmacological 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, IF-2019-01493 03 8-APN-ANP#INPI Page 20 of 48 armodafinil, modafinil. The term “psychostimulant” refers to any pharmacological agent or drug that can be used to treat illnesses 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 nootropics selected 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 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 is used in addition to behavioral psychotherapy, TMS (transcranial magnetic stimulation), ECT (electroconvulsive therapy), and other treatments. EXPERIMENTS SECTION Abbreviations: ACN acetonitrile APCI atmospheric pressure chemical ionization Boc tert-butyloxycarbonyl CDI 1,1'-carbonylimidazole CO2 Carbon dioxide per day DCM dichloromethane DIPE diisopropyl ether DIPEA diisopropylethylamine DMF dimethylformamide ESI electrospray ionization (in MS) EtOAc ethyl acetate EtOH ethanol e.g. example h hour(s) HATU O-(7-azabenzotriazol-1-¡l)-N,N,N',N'-tetramethyluronium-hexafluorophosphate IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 2 of 48 HPLC high-performance liquid chromatography HPLC-MS combined high-performance liquid chromatography-mass spectrometry M molar (mol / L) MeOH methanol min minute(s) MS mass spectrometry MW molecular weight NH3 ammonia PSI pounds per square inch rt room temperature Rt retention time scCO2 supercritical CO2 solv solvent TBTU 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 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 δ chemical shift d doublet dd doublet of doublets dt doublet of triplets DMSO-c / 6 hexa-deutero-dimethyl sulfoxide H proton Hz Hertz (=1 / second) J coupling constant m multiplet ppm parts per million q quartet IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 22 of 48 s singlet t triplet td triplet of doublets General analytics All reactions were carried out using commercially available reagents and solvents. NMR spectra were 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 δ units. Selected data are reported as follows: chemical shift, multiplicity, coupling constants (J), and 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 LC quadrupole mass spectrometer coupled to an Agilent 6130 electrospray positive ionization system. Methods: HPLC-MS methods: Method 1 Method Name: Z003 S05 Device Description: Agilent 1200 with DA and MS detector Column: XBridge C18 3.0 x 30 mm_2.5 pm Column Manufacturer: Waters Description: Gradient / Solvent Time [min] % of Sol [Water 0.1% NH3] % of Sol [Acetonitrile] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 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 S03 Device description: Agilent 1200 with DA and MS detector Column: XBridge C18 3.0 x 30 mm_2.5 pm IF-2019-01493 03 8-APN-ANP#INPI Page 23 of 48 Method Name: Z011_S03 Column Producer: Waters Description: Gradient / Solvent Time [min] % of Sol [Water 0.1% NH3] % of Sol [Acetonitrile] Flow [ml / min] Temp [°C] Backpressure [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 Method 3 Method Name: 004_CA10 Device Description: Waters Acquity, QDa Detector Column: XBridge C18_3.0 x 30 mm 2.5 pm Column Manufacturer: Waters Description: Gradient / Solvent Time [min] % of Sol [Water 0.1% NH3] % of Sol [Acetonitrile] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0 Method 4 Method Name: Z018 S04 Device Description: Agilent 1200 with DA and MS detector Column: Sunfire C18_3.0 x 30 mm_2.5 pm Column Manufacturer: Waters Description: Gradient / Solvent Time [min] % of Sol [Water 0.1% TFA] % of Sol [Acetonitrile] Flow [ml / min] Temp [°C] Backpressure [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 Chiral analytical SFC methods: Method 5: l_C2_20_MeGH_NH3_001 IF-2019-01493 03 8-APN-ANP#INPI Page 24 of 48 Method name: l_C2_20_MEOH_NH3 001 Device description: from Agilent 1260 SFC with DAD and ELSD Column: Lux® Cellulose-2_4.6 x 250 mm 5 pm Column manufacturer: from Phenomenex Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [MEOH 20mM NH3] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 80.0 20.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0 Method 6: l_C4_20_MeOH_NH3_001 Method name: l_C4_20_MEOH_NH3_001 Device description: Agilent 1260 SFC with DAD and ELSD Column: Lux® Cellulose-4_4.6 x 250 mm 5 pm Column manufacturer: Phenomenex Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [MEOH 20mM NH3] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 80.0 20.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0 Method 7: l_C4_30_MEOH_NH3_001 Method name: l_C4_30_MEOH_NH3_001 Device description: Agilent 1260 SFC with DAD and ELSD Column: Lux® Cellulose-4_4.6 x 250 mm 5 pm Column manufacturer: Phenomenex Gradient / Solvent Time [min] % of So [scCO2] l% of Sol [MEOH 20mM NH3] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 70.0 3 0.0 4.0 40.0 2175.0 10.0 70.0 3 0.0 4.0 40.0 2175.0 Method 8: IJA_35_MEOH_NH3_001 Method name: l_IA_35_MEOH_NH3_001 IF-2019-01493 03 8-APN-ANP#INPI Page 25 of 48 Method name: IJA_35_MEOH_NH3_001 Device description: Agilent 1260 SFC with DAD and MS Column: Chiralpak® IA_4.6 x 250 mm_5 pm Column manufacturer: Daicel Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [MEOH 20mM NH3] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 65.0 35.0 4.0 40.0 2175.0 10.0 65.0 35.0 4.0 40.0 2175.0 Method 9: l_C4_30_ETOH_NH3_001 Method name: del l_C4_30_ETOH_NH3_001 Device description: del Agilent 1260 SFC with DAD and ELSD Column: Lux® Cellulose-4 4.6 x 250 mm_5 pm Column manufacturer: Phenomenex Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [20mM NH3 ETOH] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 70.0 30.0 4.0 40.0 2175.0 10.0 70.0 30.0_________ 4.0 40.0 2175.0 Method 10: l_IG_40_MEOH_NH3_001 Method name: IJG_40_MEOH_NH3_001 Device description: Agilent 1260 SFC with DAD and MS Column: Chiralpak®-IG_4.6 x 250 mm_5 pm Column manufacturer: Daicel Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [ETOH 20mM NH3] Flow [ml / min] Temp [°C] Backpressure [PSI] 0.0 60.0 40.0 4.0 40.0 2175.0 ___ 10.0 60.0 40.0 4.0 40.0 2175.0________ Method 11: l_SA_15_MEOH_NH3_001 Method name: del l_SA_15_MEOH_NH3_001 Device description: del Agilent 1260 SFC with DAD and MS IF-2019-01493 03 8-APN-ANP#INPI Page 26 of 48 Method name: del l_SA_15_MEOH_NH3_001 Column: CHIRAL ART® Amylose SA_4.6 x 250 mm_5 pm Column producer: YMC Gradient / Solvent Time [min] % of Sol [scCO2] % of Sol [20mM NH3 ETOH] Flow [ml / min] Temp [°C] Backpressure [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 Preparation of intermediaries: Example 1a N NH2 / °A 4-tert-butyl ester of S-morphol-2,4-dicarboxylic acid (10 g, 43.2 mmol) was dissolved in DMF (120 mL) and the temperature was reduced to 0 °C; TBTU was then added and the mixture was stirred for 15 min before the addition of TEA (12.05 mL) and 2,3-diamminopyridine (4.7 g; 43.2 mmol). The reaction mixture was stirred for 20 hours at room temperature before preparation: DMF was removed under reduced pressure, the crude was diluted with EtOAc (300 mL) and water (100 mL) and then filtered through a glass filter. The organic phase was separated and washed with a 5% aqueous solution of sodium bicarbonate (50 mL). The sodium bicarbonate solution was re-extracted with 100 ml of EtOAc, the organic phases were combined together and dried in Na2SO4. The residue obtained after solvent evaporation was purified by flash chromatography using EtOAc / MeOH / NH4OH (97 / 3 / 0.3). 11.5 g were obtained HPLC-MS; Method: Z011_S03; Rthimin] :0.82 _______ MS:323 (M+H)+________ Rt [min]: R-enantiomer 2.90; 4.7 % (Area)_______ Chiral SFC method to Rt: l_C2_20_MeOH_NH3_001.M Chiral SFC Rt method: l_C2_20_MeCH_NH3_001.M Rt [min]: S-enantiomer 3.38; 95.3 % (Area) Example 1b Example 1b was prepared in a manner analogous to Example 1a. Starting materials· 4-terbutyl ester of morpholine-2,4 dicarboxylic acid (550 mg, 2.4 mmol), 2,3 IF-2019-01493038-APN-ANP#INPI Page 27 of 48 diamino-5-fluoro-pyridine (340 mg; 2.7 mmol), TBTU (850 mg, 2.6 mmol) and TEA (1.0 mL, 7.2 mmol) in DMF (5 mL). Example 1a (11.5 g, 35.67 mmol) was dissolved in DMF (100 mL), CsF (7 g, 50 mmol) was added, and the reaction mixture was stirred for 28 hours at 100 °C. The temperature was then reduced to room temperature, and DMF was removed under reduced pressure. The crude was divided with EtOAc (250 mL) and water (50 mL), the organic phase was separated, and it was dried in Na₂SO₄. The crude obtained after solvent evaporation was purified by flash chromatography (DCM 95 / MeOH 5 / NH₄OH 0.5) to yield 5.2 g of the desired compound. HPLC-MS; Method: Z011_S03; Rt[min]: 0.77 MS:305 (M+H)+; 249 (M+H-lsobutene)*_______ Chiral SFC Rt method: l_C2_20_MeOH_NH3_001.M Rt [min]: S-enantiomer 2.83 ; 81.75 %___________ Chiral SFC method at Rt: l_C2_20_MeOH_NH3_001.M Rt [min]: R-enantiomer 3.63 min; 18.25%_______ SFC analysis indicated that a partial racemization was carried out (ee 63.5%), 5.2 g were subjected to a preparative chiral SFC chromatography. Preparatory conditions for CFS: Column Solvents: Lux®Cellulose-4 21.2x250 mm 5pm IF-2019-01493 03 8-APN-ANP#INPI Page 28 of 48 80% scCO2, 20 mM MeOH, 20% NH3, 150 bar backpressure regulator, 40°C temperature, 60 ml / min flow rate, 50 mg / ml sample concentration, MeOH sample solvent, 200 µL injection volume, 254 nM detector wavelength, Jasco Rockclaw 150 device Example 2b: 3.37 g were obtained after separation by preparative SFC N- n O HPLC-MS; Method: Z011_S03; Rt[min]: 0.76 MS: 305 (M+H)+; 249 (M+Hlsobutene)+ Chiral SFC method at Rt: |_C4_20_MeOH_NH3_001.M ___________________ Rt [min]: 2.30 1H RMN (400 MHz, DMSO-d6); δ ppm: 1,44 (s, 9 H); 3,04 (br s, 1 H); 3,17 (br s, 1 H); 3,68 (td, 1=11,43, 2,65 Hz, 1 H); 3,82 (br d, 1=13,39 Hz, 1 H); 3,94 - 4,08 (m, 1 H); 4,22 (br d, 1=12,88 Hz, 1 H); 4,76 (dd, 1=10,23, 2,91 Hz, 1 H); 7,22 (dd, 1=7,83, 4,80 Hz, 1 H); 7,93 (br d, 1=7,58 Hz, 1 H); 8,33 (dd, 1=4,80, 1,26 Hz, 1 H) Ejemplo 2c: Se obtuvieron 0,75 g después de la separación mediante SFC preparativa H ,°^O MS: 305 (M+H)+; 249 (M+H-lsobuteno)+ Rt [min]: 2,86 HPLC-MS; Método: Z011_S03; Rt[min]: 0,76 SFC quiral; Método: l_C4_2Q_MeOH_NH3_0Q1.M1H RMN (400 MHz, DMSO-cfe); δ ppm: 1,44 (s, 9 H); 3,04 (br s, 1 H); 3,17 (br s, 1 H); 3,68 (td, 1=11,43, 2,65 Hz, 1 H); 3,82 (br d, 1=13,39 Hz, 1 H); 3,94-4,08 (m, 1 H); 4,22 (br d, 1=12,88 Hz, 1 H); 4,76 (dd, 1=10,23, 2,91 Hz, 1 H); 7,22 (dd, 1=7,83, 4,80 Hz, 1 H); 7,93 (brd, 1=7,58 Hz, 1 H); 8,33 (dd, 1=4,80, 1,26 Hz, 1 H) IF-2019-01493 03 8-APN-ANP#INPI Page 29 of 48 Example 2d Example 1b (580 mg; 1.7 mmol) and K2CO3 (300 mg; 2.2 mmol) in 2-propanol (10 ml) were stirred at 80 °C for 6 h, at room temperature for 3 days and refluxed for 5 h. Then additional K2CO3 (300 mg; 2.2 mmol) was added and the mixture was refluxed for 16 h. After cooling to room temperature, ACN was added, and the mixture was filtered. The mother liquor was evaporated and the residue was purified by preparative HPLC (C-18 X-Bridge; 50 °C; H2O+0.15% ammonia : acetonitrile = 85:15 -> 65:35) to obtain 440 mg of the desired product. HPLC-MS; Method: Z018_S04; Rt[min]: 0.88 MS: 321 (MH)-; 267 (M+H-lsobutene)+ chiral CFS; Method: l_SA_15_MeOH_NH3_001 Rt : 1,82 min (39,5 %) y 2,48 min (60,5 %)1H RMN (400 MHz, DMSO-cfe); δ ppm: 1,44 (s, 9 H); 2,91 - 3,11 (m, 1 H); 3,12 - 3,24 (m 1 H); 3,67 (td, J=11,44, 2,72 Hz, 1 H); 3,81 (br d, J=13,31 Hz, 1 H); 4,00 (br d, J=10,90 Hz, 1 H); 4,21 (br d, J=12,55 Hz, 1 H); 4,75 (dd, J=10,27, 3,04 Hz, 1 H); 7,80 7,94 (m, 1 H); 8,33 (s, 1 H); 13,18 (brs, 1 H) ---------------Ejemplo 2e A mixture of 2,3-diamino-4-methyl-pyridine (85 mg; 0.69 mmol), [(tert-butoxy)carbonyl]morpholine-2-carboxylic acid (150 mg; 0.65 mmol), TBTU (220 mg, 0.69 mmol), and TEA (300 μΙ; 2.2 mmol) was stirred in DMF (2mL) at room temperature for 30 min. Acetic acid (2 ml) was then added and the mixture was stirred for 16 h at 100 C. After the addition of dioxane, it was lyophilized, the residue was absorbed in methanol, a few drops of concentrated ammonia were added, it was filtered and purified by preparative HPLC (C-18 X-Bridge; 50 °C; H2O+0.15% ammonia : acetonitrile = 82:18 -> 62:38) to obtain 120 mg (58%) of the desired product. ÍF-2019-01493 03 8-APN-ANP#INPÍ Page 30 of 48 Example 3b Example 2b (1.3 g; 4.27 mmol) was dissolved in DCM (20 mL) and the reaction mixture was cooled to 0 °C; HCl (5.34 mL; 4N solution in dioxane) was added and the temperature was raised to room temperature after 15 min. The reaction mixture was stirred for 15 hours; DCM was evaporated under reduced pressure at a temperature of 35 °C. 1.15 g of the desired product was obtained (Example 3b). HPLC-MS; Method: Z011_S03; Rt[min]: 0.18 Chiral SFC Method: I JA_35_MeQH_NH3_001M MS: 205 (M+H)+ Rt[min]: 3.82 3D example Example 3d was prepared analogously to Example 3b. Starting materials: Example 2d (440 mg, 1.4 mmol) and HCl (8 ml of 1N solution in dioxane) in dioxane (4 ml). Example 3e Example 2e (120 mg; 0.69 mmol) was mixed with hydrogen chloride in 'IF-2019-01493038-APN-ANPSINPI' Page 31 of 48 dioxane (4N; 10 ml) and the mixture was stirred at room temperature for 16h. The mixture was concentrated under vacuum and the residue (110 mg) was used without further purification. Example 4a A mixture of (4-fluorophenyl)methanol (3.0 g, 23.8 mmol) and N,N'-disuccinimidyl carbonate (6.1 g, 23.8 mmol) with 4-dimethylaminopyridine (1.1 g, 9.0 mmol) in DCM (30 mL) and acetonitrile (30 mL) was stirred for 16 h at room temperature. After adding more DCM, the mixture was extracted with water, hydrochloric acid (0.5 N), and aqueous Na₂CO₃ (1 N). The aqueous phases were extracted with DCM, and the organic phases were dried on MgSCU. After vacuum evaporation, the residue was stirred with diethyl ether and concentrated. The resulting solid was stirred again with diethyl ether, filtered, vacuum dried, and used without further purification. Amount obtained: 4.7 g HPLC-MS (Method ): Z018_S04 Rt[min]: 0.94 MS: 267 (M+H)*1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.81 (s, 4 H); 5.39 (s, 2 H); 7.27 (t, J=8.30 Hz, 2 H); 7.53 (t, J=6.46 Hz, 2 H)__________________ Example 4b Sample 4b was prepared analogously to Sample 4a. Starting materials: p -tolyl-methanol (10.0 g, 81.9 mmol), Ν,Ν'-disuccinimidyl carbonate (21,Og, 81.6 mmol), 4-dimethylaminopyridine (1.5 g, 12.3 mmol) in DCM (100 ml) with ACN (100 mmol). Page 32 of 481H NMR (400 MHz, DMSO-cfe); δ ppm: 2.32 (m, 3H); 2.80 (s, 4 H); 5.34 (s, 2 H); 7.24 (d, J=7.98 Hz, 2 H); 7.34 (d, J=8.11 Hz, 2 H) EXAMPLE EMPLOYMENT FORMS Example 1 (3-fluorophenyl)methanol (95.5 mg; 0.76 mmol) and CDI (123 mg; 0.76 mmol) were mixed together in DMF (3 mL); the reaction mixture was heated to 50°C for 30 minutes; then Example 3b (70 mg; 0.25 mmol) and DIPEA (0.13 mL; 0.76 mmol) were added sequentially and the reaction mixture was stirred for 17 hours at 50°C. The reaction mixture was cooled to room temperature and the residue was diluted with 1 mL of a MeOH / water (1 / 1) mixture before filtration and separation by semipreparative HPLC. 45 mg of the desired compound were obtained. Example 1 HPLC-MS; Method: Z003 S05; Rt[min]: 0.99 MS: 357 (M+H)+ chiral SFC; Method: 1 C4_30_MEQH_NH3_001__ Rt [min]: 2.60_________ 1H NMR (400 MHz, DMSO-cfe); δ ppm: 3.02 - 3.23 (m, 1H); 3.73 (td, J=11.37, 2.72 Hz, 1 H); 3.89 (br d, J=11.66 Hz, 1 H); 4.02 (brd, J=11.41 Hz, 1 H); 4.30 (br d, J=13.31 Hz, 1 H)· 4 84 (dd, J=10.01, 2.66 Hz, 1 H); 5.12 - 5.20 (m, 2H); 7.13 - 7.27 (m, 4H); 7.43 (td, J=7.98, 6.21 Hz, 1 H); 7.93 (br d, J=7.60 Hz, 1 H); 8.33 (dd, J=4.75, 1.20 Hz, 1 H); 13.01 (br s, 1 H)____________________________________________________________________________ Example 2 Example 2 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (4-fluorophenyl)methanol (82.3 ml; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude oil obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 50 mg IF-2019-01493 03 8-APN-ANP#INPI Page 33 of 48 _________________________Example 2_________________________________________ HPLC-MS:Method: Z003_S05; Rt[min]: 0.98 MS: 357 (M+H)+ Chiral SFC method: I C4,3o_EtOH_NH3_001 Rt [min]; 2.611H NMR (400 MHz, DMSO-cfe); δ ppm: 3.03 - 3.22 (m, 1H); 3.67 - 3.77 (m, 1H); 3.87 (brd, J=13.64 Hz, 1 H); 4.01 (brd, J=11.37 Hz, 1 H); 4.28 (brd, J=12.63 Hz, 1 H); 4.82 (dd, J=10.11, 2.78 Hz, 1 H); 5.09 - 5.16 (m, 2H); 7.17 - 7.24 (m, 3H); 7.47 (dd, J=8.46, 5.68 Hz, 2 H); 7.93 (br d, J=6.82 Hz, 1 H); 8.33 (d, J=3.79 Hz, 1 H); 12.99 (br s, 1 H) Example 4 Example 4 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (4-fluoro-2-methylphenyl)methanol (106 mg; 0.76 mmol); 1-T-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude oil obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 35 mg ________________F Ejemplo 4________________________________________________ HPLC-MS:Método: Z003_S05; Rt[min]: 1,04 MS: 371 (M+H)+ SFC quiral; Método: I C4L30_MeQH_NH3_001 Rt [min]: 2,581H RMN (400 MHz, DMSO-cfe); δ ppm: 2,34 (s, 3 H); 3,04 - 3,21 (m, 1 H); 3,71 (br t, J=10,39 Hz, 1 H); 3,85 (brd, J=13,31 Hz, 1 H); 4,01 (brd, J=11,15 Hz, 1 H); 4,25 (brs, 1 H); 4,81 (dd, J=10,08, 2,98 Hz, 1 H); 5,08 - 5,16 (m, 2 H); 6,98 - 7,11 (m, 2 H); 7,22 (dd, J=7,98, 4,82 Hz, 1 H); 7,39 (dd, J=8,36, 6,21 Hz, 1 H); 7,92 (br d, J=7,48 Hz, 1 H); 8,32 (dd, J=4,69, 1,14 Hz, 1 H); 13,00 (brs, 1 H)__ ÍF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Página 34 de 48 Ejemplo 5 A mixture of the product from Example 3e (50 mg; 0.17 mmol), Example 4a (50 mg; 0.19 mmol), and TEA (100 ml; 0.72 mmol) in THF (4 ml) and acetonitrile (4 ml) was heated to reflux and stirred at room temperature without further heating for 30 min. The mixture was concentrated under vacuum, and the residue was purified by Preparative HPLC to obtain 35.7 mg of the desired product. __________________2______Example 5__________________________________________ HPLC-MS (004_CA10): Rt[min]: 0.65 I MS: 371 (M+H)+1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.52 - 2.55 (m, 3H); 2.99 - 3.22 (m, 1H); 3.45 3.77 (m, 2H); 3.88 (br d, J=13.56 Hz, 1 H); 4.01 (br d, J=11.53 Hz, 1 H); 4.26 (br d, J=12 29 Hz 1 H); 4.79 (dd, J=10.20, 2.85 Hz, 1 H); 5.08 - 5.17 (m, 2H); 7.04 (dd, J=4.82, 0.63 Hz, 1 H); 7.20 (t, J=8.36 Hz, 2 H); 7.46 (t, J=6.13 Hz, 2 H); 8.18 (d, J=4.82 Hz, Ί H)__________________________ A sample of the product from Example 5 (34 mg) was separated by chiral chromatography (SFC) to gain access to Example 6. Preparation conditions: Column__________________________ Chiraloak® IG 10x250mm 5 pm______ Solvents: scCO2______________ 60 % __________ MeOH 20 mM NH3 40 %__ Backpressure regulator 120 bar__ Temperature_________________________ 40 °C _____________ Flow rate 10 ml / min__ Sample concentration 6 mg / ml__ Sample solvent MeOH:DCM 1:1 _________ Injection volume___________________ 300 pl _____________ Detector wavelength____________ 220 nm ___________ Device__ Mini Gram___________________________ Example 6 The following was obtained: 16 mg IF-2019-01493 03 8-APN-ANP#INPI Page 35 of 48 rExample 6 ____________________________ Chiral SFC Method: IG_40_MEOH_NH3_001 | Rt: 3.61 min1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.52 - 2.54 (m, 3H); 3.08 - 3.25 (m, 1H); 3.35 3.47 (m, 1H); 3.71 (br t, J=10.61 Hz, 1 H); 3.88 (br d, J=13.14 Hz, 1 H); 4.01 (br d, J=10.86 Hz, 1 H); 4.26 (br d, J=11.87 Hz, 1 H); 4.79 (br d, J=8.34 Hz, 1 H); 5.09 - 5.16 (m, 2H); 7.03 (d, J=4.80 Hz, 1 H); 7.20 (t, J=8.84 Hz, 2 H); 7.46 (dd, J=8.46, 5.68 Hz, 2 H); 8.18 (brd, J=4.04 Hz, 1 H); 12.98 (brs, 1 H)________________________________________ Example 8 Example 8 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), o-tolyl-methanol (92.6 mg; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 38 mg HPLC-MS: Method: Z003_S05; Rt[min]: 1.03__MS: 353 (M+H)+_________ Chiral SFC method: I C4_30_MeQH_NH3_001 Rt [min]: 3.14____________1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.32 (s, 3 H)¡ 3.03 - 3.22 (m, 1 H); 3.66 - 3.7( (m, 1 H); 3.87 (br d, J=13.56 Hz, 1 H); 4.01 (br d, 1=11.41 Hz, 1 H); 4.17 - 4.37 (m, ' H)·' 4 82 (dd, J=10.08, 2.98 Hz, 1 H); 5.15 (d, J=1.77 Hz, 2 H); 7.17 - 7.27 (m, 4 H) 7.34 (d, J=7.35 Hz, 1 H); 7.92 (br d, J=7.48 Hz, 1 H); 13.00 (brs, 1 H)____________________________________ Example 9 IF-2019-01493 03 8-APN-ANP#INPI Page 36 of 48 Example 9 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), m-tolyl-methanol (91.2 ml; 0.76 mmol); 1-T-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. 49 mg were obtained. <7 __________________________Example 9__________________________________________ HPLC-MS (Method): Z003_S05; Rt[min]: 1.04; MS:353 (M+H)+ Chiral SFC method: I C4_3Ó_MeOH_NH3_Q01 Rt[min]: 3.17 Ή NMR (400 MHz, DMSO-ó6); δ ppm: 2.30 - 2.40 (m, 3H); 3.00 - 3.22 (m, 1H); 3.41 3.76 (m, 1 H); 3.88 (br d, >13.56 Hz, 1 H); 4.02 (br d, >11.15 Hz, 1 H); 4.29 (br d, J=13.18 Hz, 1 H); 4.82 (dd, 1=10.14, 2.91 Hz, 1 H); 5.06 - 5.14 (m, 2H); 7.13 - 7.29 (m, 5H); 7.92 (brd, >7.48 Hz, 1 H); 8.32 (dd, >4.69, 1.14 Hz, 1 H); 13.00 (brs, 1 hour) Example 10 Example 10 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2-fluoro-6-methylphenyl)methanol (106 mg; 0.76 mmol); 1-T-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 25 mg v and NHF VA Example 10 HPLC-MS (Method): Z003 S05; Rt[min]: 1.03 MS: 371 (M+H)+ Chiral SFC Method: I C4 20 MeOH NH3 001 Rt[min]: 2.68 IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 37 of 481H NMR (400 MHz, DMSO-cfe); δ ppm: 2.40 (s, 3 H); 3.03 - 3.20 (m, 1H); 3.61 - 3.76 (m, 1H); 3.82 (br s, 1 H); 3.98 (br s, 1 H); 4.18 (br s, 1 H); 4.79 (br d, 7=7.86 Hz, 1 H); 5.17 - 5.23 (m, 2H); 7.03 - 7.12 (m, 2H); 7.21 (dd, J=1.92, 4.75 Hz, 1 H); 7.32 (td, 7=7.86, 6.21 Hz, 1 H); 7.92 (br d, 7=6.72 Hz, 1 H); 8.32 (br d, 7=4.06 Hz, 1 H); 12.98 (brs, 1 hour) Example 11 Example 11 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2-fluoro-4-methylphenyl)methanol (106 mg; 0.76 mmol); 1-T-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 49 mg HPLC-MS (Method): Z003_S05; Rt[min]: 1.06 MS: 371 (M+H£----Chiral SFC method: I C4_30_MeOH_NH3_001__Rt[min]: 2.89-------1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.25 - 2.34 (m, 3 H); 3.01 - 3.20 (ml H); 3.39 3 75 (m 1 H)· 3.76 - 3.91 (m, 1 H); 4.01 (br d, 7=9.76 Hz, 1 H); 5.19 (m, 2H); 7.00-7.12 (m, 2 H); 7.22 dd, 7=7.98, 4.69 Hz, 1 H); 7.37 (t, 7=7.86 Hz, 1 H); 7.92 (br d, 7-7.35 Hz, 1 H), 8.32 (dd, 7=4.63' 1.08 Hz, 1 H); 13.00 (br s, 1 H) Example 12 Example 12 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (3-fluoro-4-methylphenyl)methanol (106 mg; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. 38 mg were obtained. IF-20 i 9-0 i 493 03 8-APN-ANP#INPÍ Page 38 of 48 Example 12 HPLC-MS Method: Z003 S05; Rt[min]: 1.06 MS: 371 (M+H)+ ___ Chiral SFC method: I C4 30_MeOH_NH3_0Q1_____________ Rt[min]: 2.85 1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.23 (s, 3 H); 3.05 - 3.25 (m, 1H); 3.72 (td, J=11.31, 2.65 Hz, 1 H); 3.88 (br d, J=13.14 Hz, 1 H); 4.01 (br d, J=11.12 Hz, 1 H); 4.28 (br d' J=13.39 Hz, 1 H); 4.82 (dd, J=10.10, 2.78 Hz, 1 H); 5.06 - 5.15 (m, 2H); 7.12 7.31 (m, 4 H); 7.93 (brd, J=7.33 Hz, 1 H); 8.33 (d, J=3.54 Hz, 1 H); 12.99 (brs, 1 hour) Example 13 Example 13 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2-chloro-4-fluorophenyl)methanol (121.7 mg; 0.76 mmol); 1,1'-COI (123 mg; 0.76 mmol); DIPEA (0.13 mL; 0.76 mmol). Solvent: DMF (3 mL). The crude product obtained after preparation was purified by semipreparative HPLC. The following was obtained: 52 mg rExample 13_____________ HPLC-MS (Method): Z003_S05; Rt[min]: 1.06__MS: 391 (M+H)2-------Chiral SFC method: I C4_30_MeOH_NH3_0Q1__Rt[min]: 2.81----- —1H NMR (400 MHz, DMSO-cfe); δ ppm: 3.07 - 3.25 (m, 2 H); 3.67 - 3.78 (m, 1 H); 3.86 (brd J=13 14 Hz, 1 H); 4.01 (brd, J=11.12 Hz, 1 H); 4.26 (br d, J-13.39 Hz, 1 H); 4.83 dd J=9.98, 2.65 Hz, 1 H); 5.15 - 5.23 (m, 2 H); 7.20 - 7.29 (m, 2 H); 7.50 (dd, J=8 84, 2.53 Hz, 1 H); 7.61 (t, J=6.91 Hz, 1 H); 7.92 (br d, J=7.83 Hz, 1 H); 8.33 (d, J-3.54 Hz, IH); 13.01 (brs, 1 H)------------------------------------------Example 14 IF-2019-01493 03 8-APN-ANP#INPI Page 39 of 48 Example 14 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2-chloro-phenyl)-methanol (108 mg; 0.76 mmol); 1-T-CDI (123 mg; 0.76 mmol); DIPEA (0.13 mi; 0.76 mmol). Solvent: DMF (3 mi). The crude obtained after preparation was purified by semipreparative HPLC. Obtained: 54 mg HPLC-MS method: Z003_S05; Rt[min]: 1.04 MS: 373 (M +H)+ Chiral SFC method: I C4_30_MeOH_NH3_001________________ Rt[min]: 3,46________1H NMR (400 MHz, DMSO-cfe); δ ppm: 3.04 - 3.24 (m, 1 H); 3.73 (td, J=11.31, 2.47 Hz, 1 H); 3.89 (br d, J=13.18 Hz, 1 H); 4.02 (brd, J=11.41 Hz, 1 H); 4.29 (brd, J=13.05 Hz, 1 H); 4.84 (dd, J=10.08, 2.72 Hz, 1 H); 5.17 - 5.27 (m, 2 H); 7.22 (dd, J=7.98, 4.69 Hz, 1 H); 7.35 - 7.43 (m, 2 H); 7.46 - 7.58 (m, 2 H); 7.93 (br d, J=7.48 Hz, 1 H); 8.33 (dd, 7=4.63, 1.08 Hz, 1 H); 13.01 (prs, 1 Example 15 Example 15 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2,3-difluoro-phenyl)-methanol (85.2 pl mg; 0.76 mmol); 11'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 mi; 0.76 mmol). Solvent: DMF (3 mi). The crude oil obtained after preparation was purified by HPLC Page 40 of 48 Ή NMR (400 MHz, DMSO-c / 6); δ ppm: 3.04 - 3.23 (m, 1H); 3.72 (br t, 7=10.33 Hz, 1 H); 3.86 (brd, 7=13.56 Hz, 1 H); 4.01 (brd, 7=11.15 Hz, 1 H); 4.27 (brd, 7=12.42 Hz, 1 H); 4.83 (dd, 7=10.14, 2.79 Hz, 1 H); 5.19 - 5.29 (m, 2H); 7.20 - 7.47 (m, 4H); 7.93 (br d, 7=7.48 Hz, 1 H); 8.33 (dd, 7=4.63, 0.95 Hz, 1 H); 13.01 (brs, 1H) Example 16 Example 16 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2,6-difluorophenyl)methanol (84 µl; 0.76 mmol); 1-1'CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 56 mg NH HPLC-MS Method: Z003 S05; Rt[min]: 0.98 MS: 375 (M+H)+ ___ Chiral SFC method: I C4 30_MeQH_NH3_0Q1_______________ Rt[min]: 2.28__________ 1H NMR (400 MHz, DMSO-cfe); δ ppm: 3.10 (br s, 1 H); 3.17 - 3.26 (m, 1H); 3.70 (br s, 1 H); 3.85 (br s, 1 H); 4.00 (br s, 1 H); 4.21 (br s, 1 H); 4.79 (br d, 7=8.49 Hz, 1 H); 5.17 - 5.25 (m, 2H); 7.10 - 7.23 (m, 3H); 7.46 - 7.55 (m, 1H); 7.92 (br d, 7=6.72 Hz, 1 H); 8.32 (brd, 7=4.06 Hz, 1 H); 12.99 (brs, 1 hour) Example 17 Example 17 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), phenylmethanol (78 µL; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 mL; 0.76 mmol). Solvent: DMF (3 mL). The crude product obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 26 mg ÍF-20i9-0i493038-APN-ANP#INPi . . Page 4 of 48 íC^NH °A Ya Example 17 HPLC-MS Method: Z003 S05; Rt[min]: 0.97 MS: 339 (M+H)+ Chiral SFC Method: I C4 30 MeOH NH3_001_______________ Rt[min]: 3.10 1H NMR (400 MHz, DMSO-cfe); δ ppm: 3.03 - 3.24 (m, 1H); 3.72 (td, 1=11.37, 2.60 Hz, 1 H); 3.89 (br d, 1=13.31 Hz, 1 H); 4.02 (br d, 1=11.28 Hz, 1 H); 4.30 (br d, 1=12.93 Hz, 1 H); 4.82 (dd, 1=10.14, 3.04 Hz, 1 H); 5.10 - 5.19 (m, 2H); 7.22 (dd, 1=7.98, 4.82 Hz, 1 H); 7.31 - 7.42 (m, 5 H)¡ 7.93 (br d, Hz, 1 H); 8.33 (dd, 1=4.69, 1.27 Hz, 1 H); 13.01 (brs, 1H)__ Example 18 Example 18 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), p-tolyl-methanol (92.6 mg; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude oil obtained after preparation was purified by semi-preparative HPLC. 25 mg were obtained. Γ / _________________________Example 18____ HPLC-MS Method: Z003_S05; Rt [min]: 1.05 I MS: 353 (M+H)+__ Chiral SFC method: I C43o_EtQH_NH3_OO1 Rt[min]: 3.61_________1H NMR (400 MHz, DMSO-cfe); δ ppm: 2.28 - 2.33 (m, 3 H); 3.15 (br d, 1=12.13 Hz, 2 H); 3.65 - 3.77 (m, 1H); 3.87 (br d, 1=13.14 Hz, 1 H); 4.01 (br d, 1=10.61 Hz, 1 H); 4.28 (br d, 1=13.39 Hz, 1 H); 4.80 (dd, 1=10.23, 2.91 Hz, 1 H); 5.05 - 5.12 (m, 2H); 7.17 7.31 (m, 5H); 7.92 (brd, 1=7.58 Hz, 1 H); 8.32 (d, 1=3.54 Hz, 1 H)_ IF-2019-01493 03 8-APN-ANP#INPI Page 42 of 48 Example 19 Example 19 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2,4-difluorophenyl)methanol (84.6 ml; 0.76 mmol); 1-1'CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude oil obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 65 mg Example 19 HPLC-MS Method: Z003_S05; Rt[min]: 1.01 Chiral SFC Method: I C4_3Q_MeOH_NH3_001 MS: 375 (M+H) Rt[min]: 2.141H NMR (400 MHz, DMSO-cfe); δ ppm: 3.02 - 3.22 (m, 1H); 3.71 (br t, 7=10.48 Hz, 1 H); 3.84 (br d, 7=13.39 Hz, 1 H); 4.00 (br d, 7=11.37 Hz, 1 H); 4.25 (br d, 7=9.60 Hz, 1 H); 4.81 (dd, 7=10.11, 3.03 Hz, 1 H)¡ 5.11 - 5.21 (m, 2 H); 7.11 (td, 7=8.59, 2.02 Hz, 1 H); 7.19 - 7.32 (m, 2H); 7.52 - 7.64 (m, 1H); 7.92 (br d, 7=7.33 Hz, 1 H); 8.33 (d, 7=3.79 Hz, 1 H) 12.97 (br s, 1 H)____________ Example 24 Example 24 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (3,4-difluorophenyl)methanol (86.53 µL; 0.76 mmol); 1-1'CDI (123 mg; 0.76 mmol); DIPEA (0.13 mL; 0.76 mmol). Solvent: DMF (3 mL). The crude oil obtained after preparation was purified by semi-preparative HPLC. 56 mg i were obtained ÍF-2019-01493 03 8-APN-ANP#INPÍ ¿rO Page 43 of 48 Example 24 HPLC-MS Method: Z003_S05; Rt[min]: 1.01 Chiral SFC Method: I C4 30 EtOH NH3001 MS: 375 (M+H) Rt[min]: 2.371H NMR (400 MHz, DMSO-cfe); δ ppm: 3.05 - 3.25 (m, 1H); 3.73 (td, 7=11.34, 2.66 Hz, 1 H); 3.87 (br d, 7=12.67 Hz, 1 H); 4.01 (brd, 7=11.66 Hz, 1 H); 4.28 (brd, 7=13.18 Hz, 1 H); 4.83 (dd, 7=10.01, 2.91 Hz, 1 H); 5.07 - 5.17 (m, 2H); 7.19 - 7.31 (m, 2H); 7.40 7.54 (m, 2H); 7.93 (brd, 7=7.48 Hz, 1 H); 8.33 (dd, 7=4.69, 1.27 Hz, 1 H); 13.01 (brs, Example 25 Example 25 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (4-chloro-3-fluorophenyl)methanol (90.5 ml; 0.76 mmol); 11'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude product obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 39 mg θ' Example 25 ________________ HPLC-MS Method: Z003._S05; Rt[min]: 1.06 MS: 391(M+H)+ Chiral SFC method: I C43º_EtOH_NH3_OQ1 Rt[min]: 3.281H NMR (400 MHz, DMSO-cfe); δ ppm; 3.05 - 3.25 (m, 1 H); 3.42 (br s, 1 H); 3.73 (td, 7=11.25, 2.47 Hz, 1 H); 3.88 (br s, 1 H); 4.01 (br d, 7=11.53 Hz, 1 H); 4.28 (br d, 7=13.43 Hz, 1 H); 4.84 (br d, 7=7.86 Hz, 1 H); 5.10–5.20 (m, 2 H); 7.19–7.32 (m, 2H); 7.47 (d, 7=9.95 Hz, 1 H); 7.60 (t, 7=7.98 Hz, 1 H); 7.93 (br d, 7=7.35 Hz, 1 H); 8.33 (d, 7=3.80 Hz, 1 H); 13.01 (brs, 1H)__ IF-2019-01493 03 8-APN-ANP#INP Page 44 of Example 26 Example 26 was prepared in a manner analogous to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), [4-(difluoromethyl)phenyl]-methanol (79.9 mg; 0.76 mmol); 1-1′-CDI (123 mg; 0.76 mmol); PEAS (0.13 mi; 0.76 mmol). Solvent: DMF (3 mi). The crude obtained after preparation was purified by semipreparative HPLC. They obtained: 74 mg _________________________Example 26______________________ HPLC-MS Method: Z003_S05; Rt[min]: 0.99 MS: 389 (M+H)* Chiral SFC method: I C4j30_EtOH_NH3001 Rt[min]: 2.661H NMR (400 MHz, DMSO-cfe); δ ppm: 3.04 - 3.24 (m, 1 H); 3.63 - 3.85 (m, 1 H); 3.85 394 (m 1 H); 4.02 (broad, J=11.41 Hz, 1 H); 4.26 - 4.34 (m, 1 H); 4.84 (dd, J=10.01, 266 Hz 1 H); 5.16 - 5.25 (m, 2H); 7.03 (s, 1 H); 7.16 - 7.24 (m, 1 H); 7.33 - 7.60 (m, 4 H); 7.93 (brd, J=7.73 Hz, 1 H); 8.33 (dd, J=4.69, 1.39 Hz, 1 H); 13.01 (brs, 1H) Example 27 Example 27 was prepared in a manner analogous to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (2-fluoro-phenyl)-methanol (81.5 pl; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); PEAS (0.13 mi; 0.76 mmol). Solvent: DMF (3 mi). The crude oil obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 40 mg IF-2019-01493 03 8-APN-ANP#INPI Page 45 of 48 Example 27 HPLC-MS Method: Z003 S05; Rt[min]: 0.99 MS: 357 (M+H)+ Chiral SFC method: 1 C4_30_MeCH_NH3_001 Rt[min]: 2.66 1H NMR (400 MHz, DMSO-cfe) ¡ δ ppm: 3.01 - 3.21 (m, 1 H); 3.72 (br t, 1=10.39 Hz, 1 H); 3.86 (br d, 1=13.31 Hz, 1 H); 4.01 (br d, 1=10.52 Hz, 1 H); 4.27 (br d, 1=12.29 Hz, 1 H); 4.82 (dd, 1=10.14, 2.91 Hz, 1 H); 5.16 - 5.24 (m, 2H); 7.19 - 7.27 (m, 1H); 7.39 7.53 (m, 2 H); 7.93 (brd, 1=7.35 Hz, 1 H); 8.33 (d, 1=4.70 Hz, 1 H); 13.01 (brs, 1H) Example 28 Example 28 was prepared analogously to Example 1. Starting materials: Example 3b (70 mg; 0.25 mmol), (4-chlorophenyl)methanol (108 mg; 0.76 mmol); 1-1'-CDI (123 mg; 0.76 mmol); DIPEA (0.13 ml; 0.76 mmol). Solvent: DMF (3 ml). The crude oil obtained after preparation was purified by semi-preparative HPLC. The following was obtained: 44 mg _______________________Example 28______________________ HPLC-MS Method: Z003_S05; Rt[min]: 1.05 MS: 373 (M+H)* Chiral SFC method: I C43o_MeOH_NH3_OQ1 Rt[min]: 3.521H NMR (400 MHz, DMSO-cfe); δ ppm: 3.05 - 3.22 (m, 1H); 3.72 (td, 1=11.34, 2.66 Hz, 1 H); 3.87 (brd, 1=13.31 Hz, 1 H); 4.01 (brd, 1=11.28 Hz, 1 H); 4.28 (brd, 1=13.05 Hz, 1 H); 4.83 (dd, 1=10.01, 2.91 Hz, 1 H); 5.13 (d, 1=2.79 Hz, 2H); 7.22 (dd, 1=7.98, 4.69 Hz, 1 H); 7.44 (s, 4H); 7.93 (br d, 1=7.73 Hz, 1 H); 8.33 (dd, 1=4.69, 1.27 Hz, 1 H); 13.01 (brs, 1 H)____________________________________________ IF-2019-01493 03 8-APN-ANP#INPI Page 46 of 48 Example 30 A mixture of Example 3d (200 mg, 0.68 mmol), Example 4b (180 mg, 0.68 mmol) and TEA (300 μL, 2.2 mmol) in ACN (5 mL) was stirred at room temperature for 0.5 h. After adding aqueous ammonia (conc.) and evaporating, the residue was purified by preparative HPLC (C-18 X-Bridge; 50 °C; H2O+0.15% ammonia : acetonitrile = 80:20 -> 60:40) to obtain 225 mg of the desired product. F Example 30 | MS: 371 (M+H)+ HPLC-MS; Method: Z018_S04; Rt[min]: 0.97___1H NMR (400 MHz, DMSO-d6); δ ppm: 2.27 - 2.33 (m, 4H); 3.02 - 3.22 (m, 1H); 3.66 3 76 (m, 1 H); 3.86 (br d, J=13.89 Hz, 1 H); 4.01 (br d, J=10.86 Hz, 1 H); 4.27 (br d J=13 39 Hz, 1 H); 4.81 (dd, J=10.11, 3.03 Hz, 1 H); 5.05 - 5.12 (m, 2H); 7.15-7.30 (m 5 H) '7 86 (br d, J=8.34 Hz, 1 H); 8.33 (t, J=2.15 Hz, 1 H); 13.18 (br s, 1 H) A sample of the product from Example 30 (225mg) was separated by chiral chromatography (SFC) to gain access to Ex. 31. Preparation conditions: CHIRAL ART® Amvlose-SA Column_20 x 250 mm_5 pm Solvents: ___ scCO2 75% __ MeOH 20 mM of NH3 25% ______________ Backpressure regulator 150 bar__ Temperature________________ 40 °C ________________ Flow rate_____________ 60 ml / min__ Sample concentration 14 mg / ml__ Sample solvent MeOH'.DCM 2:1__ Injection volume________ 300 µL __ Detector wavelength 220 nm ___________ Device _____________ Sepiatec 1 Prep SFC 100____________________ Example 31 The following was obtained: 103 mg IF-2019-01493 03 8-APN-ANP#INPI Page 47 of 48 Chiral SFC method: l_SA_25_MeÓH_NH3_001 | Rt[min]: 3.531H NMR (400 MHz, DMSO-cfe); δ ppm: 2.28 - 2.33 (m, 4H); 3.01 - 3.20 (m, 1H); 3.66 3.76 (m, 1H); 3.81-3.96 (m, 1 H); 4.01 (br d, J=11.12 Hz, 1 H); 4.27 (br d, J=13.14 Hz, 1 H); 4.80 (dd, J=10.11, 3.03 Hz, 1 H); 5.04 - 5.13 (m, 2H); 7.18 (d, J=8.08 Hz, 2 H); 7.29 (d, J=7.83 Hz, 2 H); 7.86 (br d, J=7.33 Hz, 1 H); 8.33 (t, J=2.15 Hz, 1 H) IF-2019-01493038-APN-ANP#INPI Page 48 of 48 Argentine Republic - National Executive Branch 2019 - Year of Exports Additional Signature Sheet Graphic Report Number: IF-2019-01493 03 8-APN-ANP#INPI CITY OF BUENOS AIRES Wednesday, January 9, 2019 Reference: 20180103599 The document was imported by the GEDO system with a total of 48 page(s). Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=ELECTRONIC DOCUMENTARY MANAGEMENT - GDE, c=AR, o=MINISTRY OF MODERNIZATION, ou=SECRETARY OF ADMINISTRATIVE MODERNIZATION, serialNumber=CUIT 30715117564 Date: 2019.01.09 09:33:59 -03'00' Darío Julio Martin Mayares Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=GEST10N ELECTRONIC DOCUMENTARY - GDE, c=AR, o=MINISTRY OF MODERNIZATION, ou=SECRETARY OF ADMINISTRATIVE MODERNIZATION, serialNumber=CUIT 30715117564 Date: 2019.01.09 09:34:00 -03'00'

Claims

1. A compound, characterized in that it has Formula A: (FORMULA A) wherein R1 represents phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, methyl, ethyl, cyclopropyl, F2HC-, FH2C-, F3C-; R2 represents hydrogen, methyl; R3 represents hydrogen, fluorine. 17 Claims follow