Water-soluble, modified amino acid derivatives for the treatment of nervous system diseases and selected psychiatric disorders

Abstract

Disclosed are water-soluble analogs of compounds intended for the treatment of nervous system disorders (epilepsy, neuropathic pain and migraine) and psychiatric disorders (including anxiety and depression), which are especially useful for the preparation of oral or parenteral pharmaceutical forms.

Description

Technical Field

[0001] This invention relates to chemical compounds, and regarding their structure, these chemical compounds are water-soluble, modified amino acid derivatives.

[0002] The compounds disclosed in this application are close analogues of substances known in the art and are intended for the treatment of neurological disorders (epilepsy, neuropathic pain, and migraine) and mental disorders (e.g., anxiety and depression). Compared to their precursors, the compounds according to the invention are characterized by more favorable physical and biopharmaceutical properties, i.e., better water solubility, and therefore, they can be used as active substances in pharmaceutical formulations. The good water solubility of the disclosed compounds is beneficial for the development of both oral and parenteral dosage forms. Background Technology

[0003] Previous studies on pyrrolidine-2,5-dione derivatives as candidates for novel antiepileptic drugs have demonstrated that compounds with alanine as the central moiety possess particularly favorable pharmacological properties and high safety margins. Beneficial chemical modifications of the amino acid depend on incorporating the alanine amino group into the succinimide ring and partially substituting the carboxyl group of the title amino acid with benzylamine (Kamiński, et al. Bioorg. Med. Chem. 2015, 23, 2548-2561; Rapacz, et al. Naunyn Schmiedeberg's Arch. Pharmacol. 2017, 6, 567-579). Among these derivatives, compounds with unsubstituted or fluorine-substituted aromatic rings at the 2-position exhibit particularly favorable biological properties, with compounds having an absolute R-configuration showing the most potent activity (the substance disclosed in Polish patent application P.429656). Importantly, effective doses of this molecule increased spontaneous activity in mice, ruling out their sedative effect, one of the most common side effects of antiepileptic drugs currently used in pharmacological therapy. No stimulatory effects were observed in the S-enantiomer and racemic mixture (R,S). The known compounds exhibit broad protective activity in animal models of epileptic seizures, and their effectiveness in animal models of neuropathic pain, as well as models of depression and anxiety, has also been demonstrated in the R-enantiomer. The general structures of the disclosed compounds are illustrated below.

[0004]

[0005] Despite favorable biological data for the aforementioned substances, particularly compounds with absolute R-configurations of -(2R)-1 and (2R)-2, their unsatisfactory water solubility can lead to serious problems in further clinical development. It should be emphasized that water solubility is one of the most important physical properties of a drug candidate, especially in terms of absorption from the gastrointestinal tract, ease of preparation of appropriate drug formulations, and the possibility of parenteral (primarily intravenous) administration. Poor water solubility of the active ingredient is also a major cause of low drug and / or bioavailability after oral administration, often leading to the discontinuation of new drug candidate development in preclinical and clinical trials. Furthermore, literature data indicate that nearly 70% of drug candidates are poorly soluble in water (Khadka et al. J. Pharm. Sci. 2014, 9, 304-316). Importantly, in the case of substances with low water solubility, therapeutic concentrations in the blood after oral administration are often achieved by increasing the dose used. However, such solutions pose a risk of local gastrointestinal toxicity, systemic toxicity, and increased potential for drug interactions. Therefore, good water solubility has been identified as one of the key physical properties to consider when searching for and developing new drug candidates (Vo et al. Eur. J. Pharm. Biopharm. 2013, 85, 799-813; Kawabata et al. Int. J. Pharm. 2011, 420, 1-10). Basic methods for improving the solubility of substances in water include physical methods (e.g., reducing particle size through micronization, modifying crystal structures, forming eutectic mixtures or solid dispersions of drugs in carriers, etc.) and chemical methods, such as structural modifications aimed at increasing the polarity of compounds, salts, or prodrugs (e.g., reducing particle size through micronization, modifying crystal structures, forming eutectic mixtures or solid dispersions of drugs in carriers) and chemical methods, such as structural modifications aimed at increasing the polarity of compounds, salts, or prodrugs (e.g.,...). (Eur. J. Pharm. Biopharm. 2018, 126, 40-56; Jermain et al. Int. J. Pharm. 2018, 535, 379-392). In view of the above facts, the technical problem solved by the present invention is to provide substances that are close analogs to the lead compounds known in the prior art, particularly those having an R-configuration with a stereocenter in the amino acid moiety, but with more advantageous physical and biopharmaceutical properties, namely, good solubility in water. Due to slight structural modifications and satisfactory water solubility, the compounds according to the invention should exhibit similar biological properties to the parent compound. Furthermore, the improved water solubility will also be beneficial for the development of oral dosage forms and will enable the disclosed compounds to be administered parenterally (including intravenously). Summary of the Invention

[0006] This invention relates to compounds of general formula I:

[0007]

[0008] in:

[0009] X represents hydrogen or N(CH3)2.

[0010] Y represents CH2 or C=O.

[0011] R represents a hydrogen or halogen atom, preferably F.

[0012] Where Y is C=O, then X represents N(CH3)2.

[0013] Or its optical isomers, mixtures thereof, and pharmaceutically acceptable salts thereof.

[0014] Preferably, the compounds according to the invention are selected from the group consisting of:

[0015] N-Benzyl-2-(2-oxoylidene-1-yl)propionamide

[0016] N-(2-fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide,

[0017] N-Benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide

[0018] And 2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide.

[0019] More preferably, the compounds according to the invention are selected from the group consisting of: N-benzyl-2-(3-(dimethylamino)-2,5-dioxonylpyrrolidone-1-yl)propionamide and 2-(3-(dimethylamino)-2,5-dioxonylpyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide.

[0020] Preferably, the compounds according to the invention are in the form of pharmaceutically acceptable salts selected from: hydrochloride, sulfate, methanesulfonate, toluenesulfonate, succinate, fumarate, or lactate.

[0021] Preferably, the compounds according to the invention are selected from the group consisting of:

[0022] (2R)-N-benzyl-2-(2-oxomylidene-1-yl)propionamide,

[0023] (2S)-N-benzyl-2-(2-oxomylidene-1-yl)propionamide,

[0024] (2R,S)-N-benzyl-2-(2-oxomylidene-1-yl)propionamide

[0025] (2R)-N-(2-fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide,

[0026] (2S)-N-(2-fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide,

[0027] (2R,S)-N-(2-fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide,

[0028] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide hydrochloride,

[0029] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide hydrochloride

[0030] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide hydrochloride

[0031] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide hydrochloride,

[0032] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide hydrochloride,

[0033] (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide hydrochloride

[0034] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide methanesulfonate,

[0035] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide methanesulfonate,

[0036] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide methanesulfonate,

[0037] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide toluenesulfonate,

[0038] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide toluenesulfonate,

[0039] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide toluenesulfonate

[0040] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide lactate,

[0041] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide lactate,

[0042] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide lactate,

[0043] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide sulfate,

[0044] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide sulfate,

[0045] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide sulfate,

[0046] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide succinate,

[0047] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide succinate,

[0048] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide succinate,

[0049] (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide fumarate,

[0050] (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide fumarate,

[0051] (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide fumarate,

[0052] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide methanesulfonate,

[0053] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide methanesulfonate,

[0054] (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide methanesulfonate,

[0055] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide toluenesulfonate,

[0056] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide toluenesulfonate,

[0057] (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide toluenesulfonate,

[0058] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide lactate,

[0059] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide lactate,

[0060] (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide lactate,

[0061] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide sulfate,

[0062] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide sulfate,

[0063] (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide sulfate,

[0064] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide succinate,

[0065] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide succinate,

[0066] (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide succinate,

[0067] (2R)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide fumarate,

[0068] (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide fumarate, and

[0069] (2R,S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide fumarate.

[0070] In a preferred embodiment, the present invention relates to water-soluble derivatives of pyrrolidine-2-one or pyrrolidine-2,5-dione, selected from the following compounds: N-benzyl-2-(2-oxoylidene-1-yl)propionamide (3), N-(2-fluorobenzyl)-2-(2-oxoylidene-1-yl)propionamide (4), N-benzyl-2-(3-(dimethylamino)-2,5-dioxoylidene-1-yl)propionamide (5), and 2-(3-dimethylamino)-2,5-dioxoylidene-1-yl)-N-(2-fluorobenzyl)propionamide (6), the general structures of which are shown below:

[0071]

[0072] Because of the presence of a tertiary amino group at the 3-position of the imide ring, these derivatives form water-soluble salts in the structures of compounds 5 and 6. Pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, toluenesulfonates, succinates, fumarates, lactates, etc. These salts, as well as other pharmaceutically acceptable salt-like compositions, also constitute the subject matter of this invention. According to the solubility classifications proposed in European Pharmacopoeia 10.0 and Polish Pharmacopoeia XII, the compounds of the subject matter of this invention are classified as water-soluble substances (compounds 3 and 4) or readily soluble in water (compounds 5 and 6). The compounds of Formula I have a chiral center in the propionamide moiety, and therefore can exist as optical isomers and mixtures thereof. Such optical isomers and mixtures thereof in different ratios (including racemic mixtures) are within the scope of this invention. Detailed Implementation

[0073] This invention relates to water-soluble derivatives of 2-(2-oxoylidene-1-yl)propionamide or (3-dimethylamino)-2,5-dioxoylidene-1-yl)propionamide.

[0074] The compounds were designed as analogs of previously disclosed and known compounds in the art (Figure 1), and the main chemical modifications depended on the removal of a carbonyl group, resulting in pyrrolidine-2-one derivatives (compounds 3 and 4), or on the introduction of a dimethylamine moiety at the 3-position of the pyrrolidine-2,5-diketone ring (compounds 5 and 6). Due to the presence of the amino group, the compounds could be converted into water-soluble and pharmaceutically acceptable salts, including hydrochlorides, sulfates, methanesulfonates, toluenesulfonates, succinates, fumarates, lactates, etc., by applying methods known in the art.

[0075] According to the present invention, compounds of formulas 3-6 can be prepared by a multi-step process, starting from commercially available tert-butoxycarbonyl (Boc) protected D,L-alanine (in the case of racemic (R,S) mixtures), D-alanine (in the case of compounds having an absolute R-configuration in the propionamide moiety), or L-alanine (in the case of enantiomers having an absolute S-configuration in the propionamide moiety). Alternatively, the R- and S-enantiomers can be prepared by separating suitable racemic mixtures using separation methods known in the art.

[0076] The first step of the synthesis consists of the condensation of benzylamine or 2-fluorobenzylamine with Boc-protected alanine, having the desired asymmetric central configuration, yielding an intermediate of formula II. Removal of the Boc protecting group then results in the initial primary amine of general formula III. Steps ii are common for compounds 3-6. In the synthesis of pyrrolidine-2-one derivatives 3 and 4, primary amine III is acylated using 4-chlorobutyrate chloride to produce derivative IV. Compound IV is then cyclized in the presence of a base, such as sodium hydride, to give the desired products 3 and 4. Alternatively, 4-bromo or 4-iodobutyrate chloride can be used instead of 4-chlorobutyrate chloride. The synthesis of compounds 3 and 4 is shown in scheme 1.

[0077]

[0078] Scheme 1. Synthesis of compounds 3 and 4 according to the present invention.

[0079] In the cases of salt derivatives 5 and 6, amine III condenses with maleic anhydride to give monounsaturated ammonium acid V, which is then cyclized to maleimide derivative VI. The addition reaction of dimethylamine to the double bond of compound VI results in the formation of a tertiary amine, which can then be converted to its water-soluble salt using methods known in the art. Pharmaceutically acceptable salts include, in particular, hydrochlorides, sulfates, methanesulfonates, toluenesulfonates, succinates, fumarates, lactates, etc. As examples, compounds 5 and 6 are obtained in the form of all of the above salts. Subsequent steps in the synthesis of compounds 5 and 6 are shown in Scheme 2.

[0080]

[0081] Scheme 2. Synthesis of compounds 5 and 6 according to the present invention.

[0082] Compared to their chemical prototypes 1 and 2, compounds 3-6 exhibit advantageous characteristics of good water solubility, which leads to better pharmacokinetics, particularly better drug availability, better gastrointestinal absorption, and higher bioavailability. Furthermore, good water solubility facilitates the preparation of suitable oral formulations and enables parenteral administration, which is particularly desirable in emergency situations requiring rapid therapeutic effects, such as seizure cessation. Therefore, derivatives 3-6 should be considered close analogs of lead compounds 1 and 2, but with more favorable physical and biopharmaceutical properties, namely, better water solubility. Table 1 summarizes the results of water solubility studies per gram of the compounds at 25°C. Racemic mixtures (R, S) and individual R- or S-enantiomers were investigated.

[0083] Table 1. Results of water solubility test per gram of compound at 25℃.

[0084]

[0085] a The study was conducted in accordance with the guidelines set forth in the European Pharmacopoeia 10.0 and the Polish Pharmacopoeia XII.

[0086] b According to the terminology of the European Pharmacopoeia 10.0 and the Polish Pharmacopoeia XII.

[0087] c The maximum volume of water used is 100 mL.

[0088] The results obtained indicate that the compounds disclosed in this application are classified as water-soluble (3, 4) or readily soluble (5, 6), while the starting compounds (1 and 2) are listed as at least poorly soluble according to accepted classifications. It should be emphasized that the better solubility in water of the pyrrolidine-2-one derivatives (3, 4) compared to the pyrrolidine-2,5-dione derivatives (1, 2) is particularly surprising and not readily apparent. Physicochemical data calculated using the SwissADME program (Daina et al. Sci. Rep. 2017, 7, 42717) indicate that the succinimide derivatives (1, 2) have lower lipophilicity and simultaneously larger polar surface areas, suggesting potentially better solubility in water. Experimental data show the opposite effect, with the pyrrolidine-2-one derivatives (3, 4) exhibiting better water solubility. Table 2 summarizes the lipophilicity parameters (log P) of racemic mixtures of pyrrolidine-2,5-dione derivatives -(2R,S)-1 and (2R,S)-2 compared to those of pyrrolidine-2-one derivatives -(2R,S)-3 and (2R,S)-4. o / w The values ​​of ) and total polar surface area (tPSA).

[0089] Table 2. Lipophilic parameters (log P) of racemic mixtures of pyrrolidine-2,5-dione derivatives (2R,S)-1, (2R,S)-2) and pyrrolidine-2-dione derivatives (2R,S)-3 and (2R,S)-4 o / w Comparison of total polar surface area (tPSA) and total polar surface area (tPSA).

[0090]

[0091] a The calculations were performed using the computer program SwissADME (Daina et al. Sci. Rep. 2017, 7, 42717).

[0092] b Log P o / w - The logarithm of the octanol / water partition coefficient.

[0093] c tPSA - Total polar surface area of ​​the molecule.

[0094] The following presents embodiments for implementing the present invention.

[0095] Example 1. Preparation of the compound according to the present invention.

[0096] Analysis method:

[0097] Recordings were performed at 500 MHz and 126 MHz using a JEOL-500 spectrometer (JEOL USA, Inc., Massachusetts (MA), USA). 1 H NMR and 13 C NMR spectrum. Chemical shift relative to TMS δ = 0 ( 1 H) is given as the internal standard, with δ (ppm) values. J values ​​are expressed in Hertz (Hz). Deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) is used as the solvent. The following signal abbreviations are used in the spectral description: s (singleton), br.s (broad singleton), d (doublet), t (triplet), q (quartet), m (multiplex). The UPLC / MS analysis system was a Waters TQD mass spectrometer coupled with a Waters instrument operating in electrospray ionization (ESI) mode. The instrument (Waters Corporation, Milford, MA, USA) was used. Chromatographic separation was performed using an Acquity UPLC BEH C18 column with dimensions of 2.1 × 100 mm and a particle diameter of 1.7 μm. The column was maintained at 40 °C and eluted over 10 min with a gradient of 95% to 0% eluent A at a flow rate of 0.3 mL / min. Eluent A: water / formic acid (0.1%, v / v); eluent B: acetonitrile / formic acid (0.1%, v / v). Chromatograms were recorded using a Waters eλPDA detector. Spectra were analyzed in the range of 200–700 nm at a resolution of 1.2 nm and a sampling rate of 20 points / s. Enantiomer purity was determined by chiral HPLC using a Shimadzu Prominence LC-2030C SD Plus system (Shimadzu Corporation, Kyoto, Japan) equipped with an Amylose-C chiral column (250 × 4.6 mm). Analysis was performed under the following conditions: column temperature: 20 °C, eluent mixture: hexane / i-PrOH = 85 / 15 (v / v), flow rate: 0.7 mL / min, detection at λ = 209 nm. For intermediate VI, analysis was performed under the following conditions: column temperature: -33 °C, eluent mixture: hexane / i-PrOH / TFA = 93.4 / 6.4 / 0.2 (v / v / v), flow rate: 0.75 mL / min, detection at λ = 206 nm. Using a developing system with the following composition: DCM:MeOH (9:0.3; v / v) or DCM:MeOH (9:0.5; v / v), coated with silicone 60F 254Thin-layer chromatography (TLC) was performed on an aluminum plate (Macherey-Nagel, Düren, Germany). Spot detection was performed under UV light (λ = 254 nm). Melting points (mp) were determined using an open capillary and a Büchi 353 apparatus (Büchi Labortechnik, Flawil, Switzerland). The names of the compounds described below and illustrating embodiments of the invention were generated using the ChemBioDrawUltra 12.0 program.

[0098] The following examples describe the preparation of compounds according to the present invention. The presented synthesis is not optimized in terms of yield, amount of reagents used, and final form of the obtained compound.

[0099] Abbreviations used: AcOEt - ethyl acetate, DCM - dichloromethane, DCC - N,N'-dicyclohexylcarbodiimide, Et2O - diethyl ether, HCl - hydrochloric acid, HMDS - hexamethyldisilazane, MeOH - methanol, NaCl - sodium chloride, NaH - sodium hydride, NH4OH - ammonium hydroxide, Na2SO4 - sodium sulfate, TFA - trifluoroacetic acid, TEA - triethylamine, ZnCl2 - zinc chloride.

[0100] Examples of synthesis, physicochemical, and spectroscopic data for intermediates (II-IV) according to scheme 1):

[0101] Intermediate II (where R = H): tert-butyl-(R)-(1-benzylamino)-1-oxoylidene-2-yl)carbamate

[0102] Boc-D-alanine (5.1 g, 27 mmol, 1 eq) was dissolved in 20 mL of DCM, and DCC (6.68 g, 32.4 mmol, 1.2 eq) was added. The mixture was stirred for 30 min, and then benzylamine (2.89 g, 27 mmol, 1 eq) was added dropwise, and the reaction was continued at room temperature for 4 h. Afterward, the DCM was distilled off, and intermediate II was purified by column chromatography using DCM:MeOH (9:0.3; v / v) as the eluent. The intermediate was obtained as a light oil. Yield 91% (6.95 g); TLC: R f =0.43(DCM:MeOH(9:0.3;v / v)); C 15 H 22 N₂O₃ (278.35), single isotopic mass: 278.16. UPLC (100% purity): t R = 5.44 min. (M+H) + 279.3.

[0103] Intermediate III (where R = H): (R)-2-amino-N-benzylpropionamide

[0104] TFA (10 mL) was added to a solution of tert-butyl-(R)-(1-(benzylamino)-1-oxomylidene-2-yl)carbamate (6.95 g, 25 mmol, 1 eq) (II) in DCM (40 mL), and the mixture was stirred for 2 hours. The TFA was then neutralized with 25% NH4OH solution, and the mixture was extracted with DCM (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, and the DCM was then evaporated to dryness. (R)-2-amino-N-benzylpropionamide (III) was obtained as a light oil. Yield: 89% (3.9 g); TLC: R f =0.21(DCM:MeOH(9:0.5;v / v)); C 10 H 14 N₂O (178.24), single isotopic mass: 178.11. UPLC (purity 96.8%): t R = 2.11 min. (M+H) + 179.2.

[0105] Intermediate IV (where R = H): (R)-N-(1-(benzylamino)-1-oxoylide-2-yl)-4-chlorobutyramide

[0106] 4-Chlorobutyric acid chloride (0.59 g, 4.2 mmol, 1.5 eq) and TEA (0.85 g, 8.4 mmol, 3 eq) were added to a solution of (R)-2-amino-N-benzylpropionamide (III) (0.50 g, 2.8 mmol, 1 eq) in DCM (20 mL), and the mixture was stirred for 0.5 h. The DCM was then evaporated to dryness. Intermediate IV was purified by column chromatography using a (DCM:MeOH (9:0.5; v / v) elution system. Intermediate IV was obtained as a light oil. Yield: 82% (0.65 g); TLC: R f =0.53(DCM:MeOH(9:0.5;v / v)); C 14 H 19 ClN2O2 (282.77), single isotopic mass: 282.11. UPLC (purity 97.8%): t R = 4.52 min. (M+H) + 283.2.

[0107] Synthesis, physicochemical and spectroscopic data of the final compounds (2R)-3, (2S)-3, (2R,S)-3 and (2R)-4, (2S)-4, (2R,S)-4

[0108] Compound (2R)-3 (where R = H): (2R)-N-benzyl-2-(2-oxomylidene-1-yl)propionamide

[0109] NaH (0.106 g, 4.4 mmol, 2 eq) was added to a solution of (R)-N-(1-(benzylamino)-1-oxoylide-2-yl)-4-chlorobutyramide (0.63 g, 2.2 mmol, 1 eq) (IV, where R = H) in anhydrous THF. The reaction mixture was stirred for 4 hours and then concentrated under reduced pressure. The oily residue was dissolved in 0.1 M HCl (50 mL) and extracted with DCM (3 x 50 mL). The organic layer was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was given as a white solid after washing with Et₂O. Yield: 86% (0.47 g); mp 96.7–97.5 °C; chiral HPLC >99% ee(t) R =10.623min); TLC:R f =0.42(DCM:MeOH(9:0.5;v / v)); C 14 H 18 N₂O₂ (246.31), single isotopic mass: 264.13. UPLC (purity: >99.9%): t R = 3.92 min, (M+H) + 247.2. 1 H NMR(500MHz, CDCl3)δ1.36(d,J=7.2Hz,3H),1.95–1.99(m,2H),2.28–2.36(m,2H),3.36–3.43(m,2H),4.38(dd, J=5.9,2.2Hz,2H),4.65–4.74(m,1H),6.75(br.s,1H),7.19–7.22(m,2H),7.23–7.25(m,1H),7.27–7.31(m,2H). 13 C NMR (126MHz, CDCl3) δ13.8,18.1,31.1,43.5,43.8,50.3,127.5,127.6,128.7,138.3,170.6,175.8.

[0110] Compound (2S)-3 (where R = H): (2S)-N-benzyl-2-(2-oxoylidene-1-yl)propionamide

[0111] This compound was obtained similarly to compound (2R)-3 using (S)-N-(1-(benzylamino)-1-oxoylidene-2-yl)-4-chlorobutyramide (0.63 g, 2.2 mmol, 1 eq) (IV, where R = H) and NaH (0.106 g, 4.4 mmol, 2 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. After washing with Et2O, the compound was given as a white solid. Yield: 79% (0.43 g); mp 96.4–97.2 °C; chiral HPLC >99% ee(t) R =14.215min); TLC:R f =0.41(DCM:MeOH(9:0.5;v / v)); C 14 H 18 N₂O₂ (246.31), single isotopic mass: 264.13. UPLC (purity: >99.9%): t R = 3.90 min, (M+H) + 247.2. 1 H NMR(500MHz, CDCl3)δ1.35(d,J=7.2Hz,3H),1.94–1.99(m,2H),2.27–2.35(m,2H),3.37–3.41(m,2H),4.39(dd, J=5.9,2.2Hz,2H),4.65–4.74(m,1H),6.75(br.s,1H),7.20–7.23(m,2H),7.24–7.26(m,1H),7.27–7.32(m,2H). 13 C NMR (126MHz, CDCl3) δ13.8,18.1,31.1,43.5,43.8,50.3,127.5,127.6,128.7,138.3,170.6,175.8.

[0112] Compound (2R,S)-3 (where R = H): (2R,S)-N-benzyl-2-(2-oxomylidene-1-yl)propionamide

[0113] This compound was obtained similarly to compound (2R)-3 using (R,S)-N-(1-(benzylamino)-1-oxoylidene-2-yl)-4-chlorobutyramide (0.63 g, 2.2 mmol, 1 eq) (IV, where R = H) and NaH (0.106 g, 4.4 mmol, 2 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. After washing with Et2O, the compound was given as a white solid. Yield: 88% (0.48 g); mp 78.1–78.6 °C; TLC: R f =0.41(DCM:MeOH(9:0.5;v / v)); C 14 H 18 N₂O₂ (246.31), single isotopic mass: 264.13. UPLC (purity: >99.9%): t R = 3.91 min, (M+H) + 247.2. 1 H NMR (500MHz, CDCl3) δ1.36 (d, J=7.2Hz, 3H), 1.95–1.99 (m, 2H), 2.28–2.36 (m, 2H), 3.36–3.43 (m, 2H), 4.38 (dd, J= 5.9, 2.2Hz, 2H), 4.70 (q, J = 7.2Hz, 1H), 6.76 (br.s, 1H), 7.19–7.22 (m, 2H), 7.23–7.25 (m, 1H), 7.27–7.31 (m, 2H). 13 C NMR (126MHz, CDCl3) δ13.8,18.1,31.1,43.5,43.8,50.3,127.5,127.6,128.7,138.3,170.6,175.8.

[0114] Compound (2R)-4 (where R = F): (2R)-N-(2-fluorobenzyl)-2-(2-oxoylidene-1-yl)propionamide

[0115] This compound was obtained similarly to compound (2R)-3 using (R)-4-chloro-N-(1-((2-fluorobenzyl)amino)-1-oxoylidene-2-yl)-butyramide (0.57 g, 1.9 mmol, 1 eq) (IV, where R = F) and NaH (0.091 g, 3.8 mmol, 2 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was given as a white solid. Yield: 88% (0.44 g); mp 92.5–93.1 °C; chiral HPLC >99% ee(t) R=8.959min); TLC:R f =0.39(DCM:MeOH(9:0.5;v / v)); C14H 17 FN2O2 (264.30), single isotopic mass: 264.13. UPLC (purity: >99.9%): t R = 4.04 min, (M+H) + 265.9. 1 H NMR(500MHz, CDCl3)δ1.34(d,J=7.2Hz,3H),1.96–2.00(m,1H),2.27–2.44( m,2H),3.30–3.34(m,1H),3.39–3.42(m,1H),4.39(dd,J=14.9,5.7Hz,1H),4 .47(dd,J=15.0,6.2Hz,1H),4.64–4.75(m,1H),4.69(d,J=7.2Hz,1H),6.69 (br.s,1H),7.01(t,J=9.1Hz,1H),7.07(t,J=7.4Hz,1H),7.21–7.27(m,2H). 13 C NMR (126MHz, CDCl3) δ13.7,18.1,31.1,37.6,37.7,43.7,50.3,115.4,115.5,124 .3,124.3,125.1,125.3,129.3,129.4,130.0,130.1,160.0,162.0,170.6,175.8.

[0116] Compound (2S)-4 (where R = F): (2S)-N-(2-fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide

[0117] This compound was obtained similarly to compound (2R)-3 using (S)-4-chloro-N-(1-((2-fluorobenzyl)amino)-1-oxoylidene-2-yl)-butyramide (0.57 g, 1.9 mmol, 1 eq) (IV, where R = F) and NaH (0.091 g, 3.8 mmol, 2 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was given as a white solid. Yield: 78% (0.39 g); mp 92.1–93.8 °C; chiral HPLC >99% ee(t) R =13.313min); TLC:R f =0.40(DCM:MeOH(9:0.5;v / v)); C 14 H 17FN2O2 (264.30), single isotopic mass: 264.13. UPLC (purity: >99.9%): t R = 4.03 min, (M+H) + 265.9. 1 H NMR (500MHz, CDCl3) δ1.35 (d, J=7.2Hz, 3H), 1.95–2.00 (m, 1H), 2.26–2.45 ( m,2H),3.31–3.36(m,1H),3.38–3.43(m,1H),4.40(dd,J=14.9,5.7Hz,1H),4 .46(dd,J=15.0,6.2Hz,1H),4.64–4.75(m,1H),4.69(d,J=7.2Hz,1H),6.68 (br.s,1H),7.02(t,J=9.1Hz,1H),7.06(t,J=7.4Hz,1H),7.21–7.27(m,2H). 13 CNMR (126MHz, CDCl3) δ13.7,18.1,31.1,37.6,37.7,43.7,50.3,115.4,115.5,124 .3,124.3,125.1,125.3,129.3,129.4,130.0,130.1,160.0,162.0,170.6,175.8.

[0118] Compound (2R,S)-4 (where R = F): (2R,S)-N-(2-fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide

[0119] This compound was obtained similarly to compound (2R)-3 using (R,S)-4-chloro-N-(1-((2-fluorobenzyl)amino)-1-oxoylidene-2-yl)-butyramide (0.57 g, 1.9 mmol, 1 eq) (IV, where R = F) and NaH (0.091 g, 3.8 mmol, 2 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was given as a white solid. Yield: 82% (0.41 g); mp 75.4–76.9 °C; TLC: R f =0.41(DCM:MeOH(9:0.5;v / v)); C 14 H 17 FN2O2 (264.30), single isotopic mass: 264.13. UPLC (purity: >99.9%): t R = 4.03 min, (M+H) + 265.9. 1H NMR(500MHz, CDCl3)δ1.34(d,J=7.2Hz,3H),1.94–2.01(m,1H),2.24–2.45( m,2H),3.30–3.35(m,1H),3.38–3.44(m,1H),4.39(dd,J=14.9,5.7Hz,1H),4 .47(dd,J=15.0,6.2Hz,1H),4.63–4.76(m,1H),4.70(d,J=7.2Hz,1H),6.69 (br.s,1H),7.01(t,J=9.1Hz,1H),7.06(t,J=7.4Hz,1H),7.19–7.28(m,2H). 13 C NMR (126MHz, CDCl3) δ13.7,18.1,31.1,37.6,37.7,43.7,50.3,115.4,115.5,124 .3,124.3,125.1,125.3,129.3,129.4,130.1,130.2,160.0,162.1,170.6,175.8.

[0120] Examples of synthesis, physicochemical, and spectroscopic data for intermediates V and VI according to scheme 2:

[0121] Intermediate V (where R = H) (R)-4-((1-(benzylamino)-1-oxoylidene-2-yl)amino)-4-oxoylidene-2-enoic acid

[0122] Maleic anhydride (0.33 g, 3.4 mmol, 1 eq) was added to a solution of (R)-2-amino-N-benzylpropionamide (0.6 g, 3.4 mmol, 1 eq) (III) in AcOEt (40 mL), and the mixture was stirred for 30 min. The AcOEt was then evaporated to dryness. After washing with Et₂O, the compound was obtained as a white solid. Yield: 98% (0.91 g); TLC: R f =0.28(DCM:MeOH(9:0.1;v / v)); C 14 H 16 N₂O₄ (276.29), single isotopic mass: 276.11. UPLC (>99.9% purity): t R = 3.72 min. (M+H) + 278.2.

[0123] Intermediate VI (where R = H) (R)-N-benzyl-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)propionamide

[0124] ZnCl2 (0.39 g, 10 mmol, 1 eq) was added to a suspension of (R)-4-((1-(benzylamino)-1-oxomylidene-2-yl)amino)-4-oxomylidene-2-enoic acid (0.80 g, 2.9 mmol, 1 eq) (V, where R = H) in dried benzene (20 mL), and the mixture was stirred and heated to 80 °C. Then, a solution of HMDS (0.70 g, 0.91 mL, 4.35 mmol, 1.5 eq) in dried benzene (8 mL) was added dropwise over 30 minutes. The reaction was stirred under reflux for 24 hours and then concentrated under reduced pressure. The oily residue was dissolved in DCM and washed with 0.1 M HCl (3 × 50 mL), water (3 × 50 mL), and brine (3 × 50 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was given as a white solid after washing with Et₂O. Yield: 80% (0.60 g); mp 98.3–98.8 °C; chiral HPLC >99% ee(t) R =50.631min); TLC: R f =0.34(DCM:MeOH(9:0.5;v / v)); C 14 H 14 N₂O₃ (258.28), single isotopic mass: 258.10. UPLC (100% purity): t R = 4.41 min. (M+H) + 259.2.

[0125] Intermediate VI (where R = H) (S)-N-benzyl-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)propionamide

[0126] The compound was obtained similarly to compound (R)-VI (wherein, R=H) using (S)-4-((1-(benzylamino)-1-oxylidene-2-yl)amino)-4-oxylidene-2-enoic acid (0.80 g, 2.9 mmol, 1 eq) (V, where R=H), ZnCl2 (0.39 g, 10 mmol, 1 eq), and HMDS (0.70 g, 0.91 ml, 4.35 mmol, 1.5 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. After washing with Et2O, the compound was given as a white solid. Yield: 83% (0.62 g); mp 97.9–98.6 °C; chiral HPLC >99% ee(t) R =52.970min); TLC:R f=0.34(DCM:MeOH(9:0.5;v / v)); C 14 H 14 N₂O₃ (258.28), single isotopic mass: 258.10. UPLC (100% purity): t R = 4.40 min. (M+H) + 259.2.

[0127] Intermediate VI (where R = H)(R,S)-N-benzyl-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)propionamide

[0128] This compound was obtained similarly to compound (R)-VI (wherein, R=H) using (R,S)-4-((1-(benzylamino)-1-oxylidene-2-yl)amino)-4-oxylidene-2-enoic acid (0.80 g, 2.9 mmol, 1 eq) (V, where R=H), ZnCl2 (0.39 g, 10 mmol, 1 eq), and HMDS (0.70 g, 0.91 mL, 4.35 mmol, 1.5 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. After washing with Et2O, the compound was given as a white solid. Yield: 74% (0.55 g); mp 85.5–86.7 °C; TLC: R f =0.34(DCM:MeOH(9:0.5;v / v)); C 14 H 14 N₂O₃ (258.28), single isotopic mass: 258.10. UPLC (100% purity): t R = 4.39 min. (M+H) + 259.2.

[0129] Intermediate VI (where R = F) (R)-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)-N-(2-fluorobenzyl)propionamide

[0130] This compound was obtained similarly to compound (R)-VI (wherein, R = F) using (R)-4-((1-((2-fluorobenzyl)amino)-1-oxoylidene-2-yl)amino)-4-oxoylidene-2-enoic acid (0.85 g, 2.9 mmol, 1 eq) (V, where R = F), ZnCl2 (0.39 g, 10 mmol, 1 eq) and HMDS (0.70 g, 0.91 ml, 4.35 mmol, 1.5 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was obtained as a white oil. Yield: 82% (0.65 g); chiral HPLC >99% ee(t) R =35.607min); TLC:R f =0.75(DCM:MeOH(9:0.5;v / v)); C 14 H 13 FN2O3 (276.27), single isotopic mass: 276.09. UPLC (purity 99.6%): t R = 4.55 min. (M+H) + 277.2.

[0131] Intermediate VI (where R = F) (S)-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)-N-(2-fluorobenzyl)propionamide

[0132] This compound was obtained using (S)-4-((1-((2-fluorobenzyl)amino)-1-oxoylidene-2-yl)amino)-4-oxoylidene-2-enoic acid (0.85 g, 2.9 mmol, 1 eq) (V, where R = F), ZnCl2 (0.39 g, 10 mmol, 1 eq), and HMDS (0.70 g, 0.91 ml, 4.35 mmol, 1.5 eq) similarly to compound (R)-VI (where R = H). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was obtained as a white oil. Yield: 84% (0.67 g); chiral HPLC >99% ee(t) R =38.845min); TLC:R f =0.75(DCM:MeOH(9:0.5;v / v)); C 14 H 13 FN2O3 (276.27), single isotopic mass: 276.09. UPLC (purity 99.5%): t R = 4.55 min. (M+H) + 277.1.

[0133] Intermediate VI (where R = F) (R,S)-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)-N-(2-fluorobenzyl)propionamide

[0134] This compound was obtained similarly to compound (R)-VI (wherein, R = F) using (R,S)-4-((1-((2-fluorobenzyl)amino)-1-oxoylidene-2-yl)amino)-4-oxoylidene-2-enoic acid (0.85 g, 2.9 mmol, 1 eq) (V, where R = F), ZnCl2 (0.39 g, 10 mmol, 1 eq), and HMDS (0.70 g, 0.91 ml, 4.35 mmol, 1.5 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was given as a white oil. Yield: 77% (0.61 g); TLC: R f =0.75(DCM:MeOH(9:0.5;v / v)); C 14 H 13 FN2O3 (276.27), single isotopic mass: 276.09. UPLC (purity 99.8%): t R = 4.56 min. (M+H) + 277.2.

[0135] Synthesis, physicochemical and spectroscopic data of the final compounds (2R)-5, (2S)-5, (2R,S)-5i, (2R)-6, (2S)-6, and (2R,S)-6

[0136] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide hydrochloride

[0137] A solution of 2M dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF was added to a solution of (R)-N-benzyl-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)propionamide (0.60 g, 2.3 mmol, 1 eq, VI, where R = H) in dried benzene (30 mL). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was then converted to its hydrochloride salt by treatment with 2M methanol hydrochloric acid. The product was given as a white solid. Yield: 88% (0.62 g); mp 115.8–116.9 °C; TLC: R f =0.36(DCM:MeOH(9:0.5;v / v)); C 16 H 22ClN3O3 (339.82), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.79 min, (M+H) + 304.2. 1 HNMR(500MHz, CDCl3)δ1.52(d,J=7.2Hz,3H),2.78(s,6H),2.85(br.s,3H),4.34(d,J=6.0Hz,2 H),4.74–4.77(m,1H),7.18–7.24(m,2H),7.25–7.29(m,3H),7.59(br.s,1H),7.73(br.s,1H). 13 CNMR(126MHz, CDCl3)δ14.2,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61. 0,61.3,127.3,127.4,127.6,127.8,128.6,128.6,138.5,138.6,167.9,168.1,171.8.

[0138] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide hydrochloride

[0139] This compound was obtained similarly to compound (2R)-5. A solution of 2M dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF was added to a solution of (S)-N-benzyl-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)propionamide (0.60 g, 2.3 mmol, 1 eq, VI, where R = H) in dried benzene (30 mL). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was then converted to its hydrochloride salt by treatment with 2M methanol-hydrochloric acid. The product was given as a white solid. Yield: 83% (0.58 g); mp 115.4–116.7 °C; TLC: R f =0.37(DCM:MeOH(9:0.5;v / v)); C 16 H 22 ClN3O3 (339.82), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.78 min, (M+H) + 304.2. 1H NMR(500MHz, CDCl3) δ1.53(d,J=7.2Hz,3H),2.79(s,6H),2.84(br.s,3H),4.35(d,J=6.0Hz,2 H),4.73–4.79(m,1H),7.16–7.21(m,2H),7.27–7.31(m,3H),7.58(br.s,1H),7.74(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.2,32.1,32.2,41.7,42.1,43.6,49.8,50.0,61.1 ,61.2,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9.

[0140] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide hydrochloride

[0141] This compound was obtained similarly to compound (2R)-5. A solution of 2M dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF was added to a solution of (R,S)-N-benzyl-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)propionamide (0.60 g, 2.3 mmol, 1 eq, VI, where R = H) in dried benzene (30 mL). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was then converted to its hydrochloride salt by treatment with 2M methanol hydrochloric acid. The product was given as a white solid. Yield: 86% (0.60 g); mp 97.2–98.5 °C; TLC: R f =0.38(DCM:MeOH(9:0.5;v / v)); C 16 H 22 ClN3O3 (339.82), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.79 min, (M+H) + 304.2. 1H NMR(500MHz, CDCl3)δ1.54(d,J=7.2Hz,3H),2.80(s,6H),2.85(br.s,3H),4.28-4.38(m,2H) ,4.72–4.78(m,1H),7.15–7.22(m,2H),7.25–7.33(m,3H),7.59(br.s,1H),7.73(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.2,14.3,31.2,32.0,32.3,41.8,42.1,43.6,49.7,50.1,61.1 ,61.2,127.4,127.5,127.7,127.9,128.4,128.7,138.4,138.8,167.7,168.3,171.8.

[0142] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide hydrochloride

[0143] This compound was obtained similarly to compound (2R)-5 using (R)-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)-N-(2-fluorobenzyl)propionamide (0.64 g, 2.3 mmol, 1 eq, VI, where R = F) and 2M dimethylamine in THF (0.105 g, 2.3 mmol, 1 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was then converted to its hydrochloride salt by treatment with 2M methanol hydrochloric acid. The product was given as a white solid. Yield: 85% (0.63 g); mp 118.4–119.6 °C; TLC: R f =0.45(DCM:MeOH(9:0.5;v / v)); C 16 H 21 ClFN3O3 (357.81), single isotopic mass: 321.15. UPLC (purity: 99.9%): t R =2.91min, (M+H)+322.2. 1H NMR(500MHz, CDCl3)δ1.52(dd,J=11.5,7.5Hz,3H),2.94(s,6H),3.08-3.36(m,3H),4.38–4.44(m,2H),4.76(dd,J=15.0,7.30 Hz,1H),6.93–7.01(m,1H),7.03–7.10(m,1H),7.19(dd,J=4.7,2.2Hz,1H),7.26-7.33(m,1H),7.61(br.s,1H),7.8(br.s,1H). 13 CNMR (126MHz, CDCl3) δ14.2,31.0,32.2,32.4,37.5,50.0,50.0,60.9,61.2,115.2,1 15.3,115.3,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0144] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide hydrochloride

[0145] This compound was obtained similarly to compound (2R)-5 using a solution of (S)-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)-N-(2-fluorobenzyl)propionamide (0.64 g, 2.3 mmol, 1 eq, VI, where R = F) and 2M dimethylamine in THF (0.105 g, 2.3 mmol, 1 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was then converted to its hydrochloride salt by treatment with 2M methanol hydrochloric acid. The product was given as a white solid. Yield: 89% (0.65 g); mp 118.5–119.8 °C; TLC:R f =0.46(DCM:MeOH(9:0.5;v / v)); C 16 H 21 ClFN3O3 (357.81), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R =2.92min, (M+H)+322.2. 1H NMR (500MHz, CDCl3) δ1.53(dd,J=11.5,7.3Hz,3H),2.93(s,6H),3.07–3.35(m,3H),4.38–4.43(m,2H),4.77(dd,J=15.2,7.5Hz, 1H), 6.97(t,J=8.8Hz,1H),7.03–7.11(m,1H),7.19(dd,J=4.8,2.3Hz,1H),7.27–7.33(m,1H),7.57(br.s,1H),7.78(br.s,,1H). 13 C NMR (126MHz, CDCl3) δ14.2,31.0,32.2,32.4,37.5,50.0,50.0,60.9,61.2,115.2,1 15.3,115.3,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0146] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide hydrochloride

[0147] This compound was obtained similarly to compound (2R)-5 using a solution of (R,S)-2-(2,5-dioxonyl-2,5-dihydro-1H-pyrrolo-1-yl)-N-(2-fluorobenzyl)propionamide (0.64 g, 2.3 mmol, 1 eq, VI, where R = F) and 2M dimethylamine in THF (0.105 g, 2.3 mmol, 1 eq). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) solvent system. The compound was then converted to its hydrochloride salt by treatment with 2M methanol hydrochloric acid. The product was given as a white solid. Yield: 75% (0.54 g); mp 104.2–105.7 °C; TLC: R f =0.47(DCM:MeOH(9:0.5;v / v)); C 16 H 21 ClFN3O3 (357.81), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.90 min, (M+H) + 322.2. 1H NMR(500MHz, CDCl3)δ1.53(dd,J=11.0,7.5Hz,3H),2.93(s,6H),2.99(br.s,3H),4.38–4.43(m,2H),4.78(dd,J=15.5,7.5Hz ,1H),6.97(t,J=8.9Hz,1H),7.06(t,J=7.5Hz,1H),7.18–7.21(m,1H),7.27–7.33(m,1H),7.57(br.s,1H),7.76(br.s,,1H). 13 CNMR (126MHz, CDCl3) δ14.2,14.2,31.0,32.2,32.4,37.5,50.0,50.0,60.9,61.2,115.2,115. 3,115.3,124.3,125.2,129.1,129.1,129.2,129.8,130.0,159.7,161.7,167.9,168.0,171.3.

[0148] Preparation and physicochemical data of other salts of compounds (2R)-5, (2S)-5, (2R,S)-5, (2R)-6, (2S)-6 or (2R,S) according to the present invention, namely sulfates, methanesulfonates, toluenesulfonyl groups, succinates, fumarates or lactates.

[0149] All salts were prepared according to a standard synthetic procedure. The procedure consisted of dissolving 1 eq of compound (2R)-5, (2S)-5, (2R,S)-5, (2R)-6, (2S)-6, or (2R,S)-6 (as a free base) in anhydrous ethanol, and adding a suitable acid, namely 1 eq of methanesulfonic acid, toluenesulfonic acid, or lactic acid, or 0.5 eq of concentrated sulfuric acid, succinic acid, or fumaric acid. The mixture was stirred at room temperature for 15 minutes, and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether to obtain the suitable salt as a white powder.

[0150] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide methanesulfonate

[0151] White solid; mp 116.4–117.2℃; C 17 H 25 N3O6S (399.46), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.83 min, (M+H) + 304.2. 1H NMR(500MHz, CDCl3)δ1.57(dd,J=7.3,4.2Hz,3H),2.16(s,3H),2.67(s,6H),2.99–3.10(m,2H),4.29–4.38(m ,1H),4.38–4.55(m,1H),4.79(dd,J=15.2,7,5Hz,2H),7.20–7.24(m,3H),7.25–7.33(m,3H),7.44(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.2,32.1,32.2,41.7,42.1,43.6,44.5,49.8,50.0,6 1.1,61.2,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9.

[0152] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide methanesulfonate

[0153] White solid; mp 116.1–116.9℃; C 17 H 25 N3O6S(399,46), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.80 min, (M+H) + 304.2. 1 H NMR(500MHz, CDCl3)δ1.58(dd,J=7.3,4.2Hz,3H),2.15(s,3H),2.68(s,6H),2.99–3.12(m,2H),4.30–4.39(m ,1H),4.41–4.57(m,1H),4.78(dd,J=15.2,7.5Hz,2H),7.20–7.25(m,3H),7.26–7.32(m,3H),7.44(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.2,32.1,32.2,41.7,42.1,43.6,44.5,49.8,50.0,6 1.1,61.2,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9.

[0154] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide methanesulfonate

[0155] White solid; mp 102.2–102.8℃; C 17 H 25 N3O6S (399.46), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.82 min, (M+H) + 304.2. 1 H NMR(500MHz, CDCl3)δ1.56(dd,J=7.3,4.2Hz,3H),2.16(s,3H),2.67(s,6H),2.98–3.09(m,2H),4.28–4.39(m ,1H),4.40–4.58(m,1H),4.78(dd,J=15.2,7.5Hz,2H),7.21–7.25(m,3H),7.26–7.34(m,3H),7.45(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.2,32.1,32.2,41.7,42.1,43.6,44.5,49.8,50.0,6 1.1,61.2,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9.

[0156] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide toluenesulfonate

[0157] White solid; mp 116.8–117.4℃; C 23 H 29 N3O6S (475.56), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.82 min, (M+H) + 304.2. 1H NMR (500MHz, CDCl3) δ1.47–1.50(m,3H),2.34(s,3H),2.87–2.99(m,6H),3.08–3.36(m,2H),4.17–4.26(m,2H), 4.57–4.63(m,1H),4.73–4.75(m,1H),7.08–7.15(m,4H),7.17–7.24(m,3H),7.51–7.58(m,3H),7.68(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.2,14.2,31.0,32.1,32.2,21.3,41.8,42.1,43.6,49.9,50.0,61.0,61.3,127 .3,127.4,127.6,127.8,128.2,128.5,128.6,130.0,138.5,138.6,139.4,142.1,167.9,168.1,171.8.

[0158] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide toluenesulfonate

[0159] White solid; mp 116.2–117.1℃; C 23 H 29 N3O6S (475.56), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.82 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.48–1.51(m,3H),2.34(s,3H),2.87–2.98(m,6H),3.08–3.37(m,2H),4.18–4.27(m,2H), 4.57–4.62(m,1H),4.74–4.78(m,1H),7.07–7.13(m,4H),7.16–7.23(m,3H),7.50–7.58(m,3H),7.64(br.s,1H). 13C NMR (126MHz, CDCl3) δ14.2,14.2,31.0,32.1,32.2,21.3,41.8,42.1,43.6,49.9,50.0,61.0,61.3,127 .3,127.4,127.6,127.8,128.2,128.5,128.6,130.0,138.5,138.6,139.4,142.1,167.9,168.1,171.8.

[0160] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide toluenesulfonate

[0161] White solid; mp 101.2–101.9℃; C 23 H 29 N3O6S (475.56), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.81 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.48–1.51(m,3H),2.33(s,3H),2.87–2.97(m,6H),3.07–3.37(m,2H),4.18–4.26(m,2H), 4.56–4.61(m,1H),4.74–4.76(m,1H),7.08–7.13(m,4H),7.16–7.23(m,3H),7.50–7.58(m,3H),7.66(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.2,14.2,31.0,32.1,32.2,21.3,41.8,42.1,43.6,49.9,50.0,61.0,61.3,127 .3,127.4,127.6,127.8,128.2,128.5,128.6,130.0,138.5,138.6,139.4,142.1,167.9,168.1,171.8.

[0162] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide lactate

[0163] White solid; mp 116.2–116.9℃; C 19 H 27N3O6 (393.44), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.76 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.40–1.43(m,6H),2.55(d,J=9.2Hz,6H),2.84(dd,J=17.3,5.3Hz,1H),2.90–3.00(m,1H),3.95(ddd,J=11.7,8.9,5.4,Hz,1 H),4.26(q,J=7.0Hz,2H),4.40–4.52(m,2H),4.83(dd,J=11.2,7.5Hz,1H ),5.32(br.s,2H),6.44(br.s,1H),7.26–7.32(m,3H),7.33–7.35(m,2H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,19.4,31.2,32.1,32.2,41.7,42.1,43.6,49.8,50.0,61.1,61 .2,77.8,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9,176.9.

[0164] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide lactate

[0165] White solid; mp 115.7–116.4℃; C 19 H 27 N3O6 (393.44), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.76 min, (M+H) + 304.2. 1H NMR (500MHz, CDCl3) δ1.41–1.43(m,6H),2.56(d,J=9.2Hz,6H),2.84(dd,J=17.3,5.3Hz,1H),2.91–3.00(m,1H),3.94(ddd,J=11.7,8.9,5.4Hz,1H ),4.25(q,J=7.0Hz,2H),4.39–4.51(m,2H),4.82(dd,J=11.2,7.5Hz,1H) ,5.33(br.s,2H),6.44(br.s,1H),7.26–7.30(m,3H),7.31–7.34(m,2H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,19.4,31.2,32.1,32.2,41.7,42.1,43.6,49.8,50.0,61.1,61 .2,77.8,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9,176.9.

[0166] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide lactate

[0167] White solid; mp 100.2–101.1℃; C 19 H 27 N3O6 (393.44), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.76 min, (M+H) + 304.2. 1 H NMR(500MHz, CDCl3)δ1.42(s,6H),2.56(d,J=9.2Hz,6H),2.85(dd,J=17.3,5.3Hz,1H),2.91–3.00(m,1H),3.96(ddd,J=11.7,8.9,5.4Hz,1H), 4.25(q,J=7.0Hz,2H),4.40–4.53(m,2H),4.82(dd,J=11.2,7.5Hz,1H),5.31(br.s,2H),6.44(br.s,1H),7.26–7.31(m,3H),7.33–7.36(m,2H). 13C NMR (126MHz, CDCl3) δ14.1,14.2,19.4,31.2,32.1,32.2,41.7,42.1,43.6,49.8,50.0,61.1,61 .2,77.8,127.3,127.5,127.6,127.9,128.5,128.6,138.5,138.7,167.9,168.2,171.9,176.9.

[0168] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide sulfate

[0169] White solid; mp 117.1–117.9℃; C 32 H 44 N6O 10 S(704.80), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.76 min, (M+H) + 304.2. 1 H NMR(500MHz,DMSO-d6)δ1.49(dd,J=10.0,7.2Hz,3H),2.71–2.90(m,6H),2.96–3.13(m,2H),3.15–3.31(m,1H),4 .26(ddd,J=11.2,9.1,6.0Hz,3H),4.58–4.74(m,1H),7.15–7.24(m,3H),7.25–7.29(m,2H),10.46–10.79(m,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61.0 ,61.2,127.3,127.3,127.5,127.8,128.5,128.6,138.5,138.6,167.9,168.1,171.8.

[0170] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide sulfate

[0171] White solid; 116.8–117.5℃; C 32 H 44 N6O 10 S(704.80), single isotopic mass: 303.16. UPLC (purity: >99.9%): tR = 2.76 min, (M+H) + 304.2. 1 H NMR(500MHz,DMSO-d6)δ1.48(dd,J=10.0,7.2Hz,3H),2.70–2.91(m,6H),2.95–3.12(m,2H),3.14–3.30(m,1H),4 .25(ddd,J=11.2,9.1,6.0Hz,3H),4.58–4.74(m,1H),7.13–7.23(m,3H),7.24–7.28(m,2H),10.46–10.80(m,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61.0 ,61.2,127.3,127.3,127.5,127.8,128.5,128.6,138.5,138.6,167.9,168.1,171.8.

[0172] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide sulfate

[0173] White solid; mp 102.7–103.5℃; C 32 H 44 N6O 10 S(704.80), single isotopic mass: 303.16. UPLC (purity: >99.9%): t R = 2.76 min, (M+H) + 304.2. 1 H NMR(500MHz,DMSO-d6)δ1.49(dd,J=10.0,7.2Hz,3H),2.71–2.90(m,6H),2.96–3.13(m,2H),3.15–3.31(m,1H),4 .26(ddd,J=11.2,9.1,6.0Hz,3H),4.58–4.74(m,1H),7.15–7.24(m,3H),7.25–7.29(m,2H),10.46–10.79(m,1H) 13C NMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61.0 ,61.2,127.3,127.3,127.5,127.8,128.5,128.6,138.5,138.6,167.9,168.1,171.8.

[0174] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide succinate

[0175] White solid; mp 116.8–117.5℃; C 36 H 48 N6O 10 (724.81), single isotope mass: 303.16. UPLC (purity: >99.9%): t R = 2.82 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.48–1.50(m,3H),2.33–2.46(m,2H),2.50–2.68(m,2H),2.98(s,6H),3.10–3.38(m,2H), 4.15–4.26(m,2H),4.57–4.61(m,1H),4.72–4.75(m,1H),7.18–7.29(m,3H),7.49–7.62(m,2H),7.78(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.2,14.2,26.1 31.0,32.1,32.2,39.6,41.8,42.1,43.6,49.9,50.0,56.4,61.0,61.3,127 .3,127.4,127.6,127.8,128.5,128.6,138.5,138.6,167.9,168.1,171.8.

[0176] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide succinate

[0177] White solid; mp 115.9–116.6℃; C 36 H 48 N6O 10 (724.81), single isotope mass: 303.16. UPLC (purity: >99.9%): tR = 2.82 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.47–1.50(m,3H),2.32–2.47(m,2H),2.51–2.68(m,2H),2.97(s,6H),3.10–3.38(m,2H), 4.15–4.26(m,2H),4.56–4.62(m,1H),4.71–4.74(m,1H),7.19–7.27(m,3H),7.48–7.63(m,2H),7.79(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.2,14.2,26.1 31.0,32.1,32.2,39.6,41.8,42.1,43.6,49.9,50.0,56.4,61.0,61.3,127 .3,127.4,127.6,127.8,128.5,128.6,138.5,138.6,167.9,168.1,171.8.

[0178] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide succinate

[0179] White solid; mp 101.8–102.5℃; C 36 H 48 N6O 10 (724.81), single isotope mass: 303.16. UPLC (purity: >99.9%): t R = 2.82 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.47–1.51(m,3H),2.32–2.45(m,2H),2.51–2.68(m,2H),2.97(s,6H),3.11–3.37(m,2H), 4.16–4.25(m,2H),4.56–4.63(m,1H),4.71–4.78(m,1H),7.20–7.31(m,3H),7.49–7.63(m,2H),7.77(br.s,1H). 13C NMR (126MHz, CDCl3) δ14.2,14.3,26.1 31.0,32.1,32.2,39.6,41.8,42.1,43.6,49.9,50.0,56.4,61.0,61.3,127 .3,127.4,127.6,127.8,128.5,128.6,138.5,138.6,167.9,168.1,171.8.

[0180] Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide fumarate

[0181] White solid; mp 116.4–117.1℃; C 36 H 46 N6O 10 (722.80), single isotope mass: 303.16. UPLC (purity: >99.9%): t R = 2.81 min, (M+H) + 304.2. 1 H NMR(500MHz, CDCl3)δ1.48–1.51(m,3H),2.97(s,6H),3.10-3.39(m,2H),4.14–4.27(m,2H), 4.56–4.63(m,1H),4.71–4.74(m,1H),7.19–7.30(m,3H),7.48–7.65(m,4H),7.89(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61.0,61.2, 127.2,127.3,127.5,127.8,128.5,128.6,133.3,138.5,138.6,167.4,167.9,168.1,171.8.

[0182] Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide fumarate

[0183] White solid; mp 115.9–116.6℃; C 36 H 46 N6O 10 (722.80), single isotope mass: 303.16. UPLC (purity: >99.9%): t R= 2.81 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.47–1.50(m,3H),2.96(s,6H),3.11–3.38(m,2H),4.15–4,28(m,2H), 4.56–4.64(m,1H),4.70–4.72(m,1H),7.18–7.31(m,3H),7.47–7.64(m,4H),7.87(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61.0,61.2, 127.2,127.3,127.5,127.8,128.5,128.6,133.3,138.5,138.6,167.4,167.9,168.1,171.8.

[0184] Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide fumarate

[0185] White solid; mp 102.1–102.8℃; C 36 H 46 N6O 10 (722.80), single isotope mass: 303.16. UPLC (purity: >99.9%): t R = 2.81 min, (M+H) + 304.2. 1 H NMR (500MHz, CDCl3) δ1.47–1.51(m,3H),2.96(s,6H),3.10–3.38(m,2H),4.12–4.26(m,2H), 4.56–4.62(m,1H),4.70–4.73(m,1H),7.18–7.31(m,3H),7.48–7.66(m,4H),7.88(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.1,32.2,41.8,42.1,43.6,49.9,50.0,61.0,61.2, 127.2,127.3,127.5,127.8,128.5,128.6,133.3,138.5,138.6,167.4,167.9,168.1,171.8.

[0186] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide methanesulfonate

[0187] White solid: mp 119.1–119.9℃; C 17 H 24 FN3O6S (417.45), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.87 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.53 (dd, J = 11.5, 7.5Hz, 3H), 2.20 (s, 3H), 2.94 (s, 6H), 3.08–3.36 (m, 2H), 4.38–4.44 (m, 3H), 4. 76(dd,J=15.0,7.3Hz,1H),6.91–7.02(m,1H),7.03–7.10(m,1H),7.19–7.33(m,2H),7.61(br.s,1H),7.89(br.s,1H). 13 C NMR (126MHz, CDCl3) δ16.2,31.0,32.3,32.5,37.6,44.5,50.0,50.1,60.9,61.2,115.2 ,115.3,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0188] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide methanesulfonate

[0189] White solid: mp 118.7–119.4℃; C 17 H 24 FN3O6S (417.45), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.87 min, (M+H) + 322.2. 1H NMR (500MHz, CDCl3) δ1.52 (dd, J=11.5, 7.5Hz, 3H), 2.23 (s, 3H), 2.95 (s, 6H), 3.07–3.37 (m, 2H), 4.39–4.47 (m, 3H), 4. 77(dd,J=15.0,7.3Hz,1H),6.90–7.04(m,1H),7.05–7.13(m,1H),7.19–7.34(m,2H),7.61(br.s,1H),7.92(br.s,1H). 13 C NMR (126MHz, CDCl3) δ16.1,31.0,32.3,32.5,37.6,44.5,50.0,50.1,60.9,61.2,115.2 ,115.3,115.4,124.3,129.1,129.3,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0190] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide methanesulfonate

[0191] White solid: mp 105.3–106.1℃; C 17 H 24 FN3O6S (417.45), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R =2.87min, (M+H)+322.2. 1 H NMR(500MHz, CDCl3)δ1.54(dd,J=11.5,7.50Hz,3H),2.21(s,3H),2.96(s,6H),3.06–3.34(m,2H),4.38–4.46(m,3H),4 .78(dd,J=15.0,7.3Hz,1H),6.91–7.01(m,1H),7.03–7.11(m,1H),7.19–7.36(m,2H),7.60(br.s,1H),7.94(br.s,1H). 13 C NMR (126MHz, CDCl3) δ16.1,31.0,32.3,32.5,37.6,44.5,50.0,50.1,60.9,61.3,115.2 ,115.3,115.4,124.3,129.2,129.3,129.8,130.0,159.8,161.7,167.9,168.0,171.5.

[0192] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide toluenesulfonate

[0193] White solid: mp 120.2–120.9℃; C 23 H 28 FN3O6S (493.55), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.93 min, (M+H) + 322.2. 1 H NMR(500MHz, CDCl3)δ1.52(dd,J=11.5,7.5Hz,3H),2.34(s,3H),2.94(s,6H),3.08–3.36(m,2H),4.38–4.44(m,2H),4.7 6(dd,J=15.0,7.3Hz,1H),6.93–7.01(m,1H),7.03–7.10(m,1H),7.12–7.21(m,4H),7.26–7.48(m,4H),7.87(br.s,1H). 13 C NMR (126MHz, CDCl3) δ15.2,21.3,31.0,32.2,32.4,37.5,50.0,50.1,60.9,61.2,115.2,115.3,11 5.4,124.3,128.3,129.1,129.2,129.8,130.0,131.2,143.1,159.8,161.7,167.9,168.0,171.4.

[0194] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide toluenesulfonate

[0195] White solid: mp 119.5–120.3℃; C 23 H 28 FN3O6S (493.55), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.91 min, (M+H) + 322.2. 1H NMR(500MHz, CDCl3)δ1.53(dd,J=11.5,7.5Hz,3H),2.33(s,3H),2.94(s,6H),3.08–3.37(m,2H),4.37–4.49(m,2H),4.7 7(dd,J=15.0,7.3Hz,1H),6.90–7.02(m,1H),7.04–7.11(m,1H),7.14–7.24(m,4H),7.26–7.47(m,4H),7.88(br.s,1H). 13 C NMR (126MHz, CDCl3) δ15.2,21.4,31.0,32.2,32.4,37.5,50.0,50.1,60.8,61.2,115.1,115.3,11 5.4,124.2,128.3,129.1,129.2,129.8,130.0,131.2,143.1,159.8,161.7,167.9,168.0,171.4.

[0196] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide toluenesulfonate

[0197] White solid: mp 106.7–107.5℃; C 23 H 28 FN3O6S (493.55), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.93 min, (M+H) + 322.2. 1 H NMR(500MHz, CDCl3)δ1.53(dd,J=11.5,7.5Hz,3H),2.33(s,3H),2.94(s,6H),3.08–3.37(m,2H),4.37–4.49(m,2H),4.7 7(dd,J=15.0,7.3Hz,1H),6.90–7.02(m,1H),7.04–7.11(m,1H),7.14–7.24(m,4H),7.26–7.47(m,4H),7.88(br.s,1H). 13C NMR (126MHz, CDCl3) δ15.2,21.4,31.0,32.2,32.4,37.5,50.0,50.1,60.8,61.2,115.1,115.3,11 5.4,124.2,128.3,129.1,129.2,129.8,130.0,131.2,143.1,159.8,161.7,167.9,168.0,171.4.

[0198] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide lactate

[0199] White solid: mp 118.8–119.4℃; C 19 H 26 FN3O6 (411.43), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.89 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.42–1.45(m,3H),2.89(s,6H),3.04–3.36(m,3H),4.38–4.44(m,2H),4.82(dd,J=12.0,7.5Hz ,1H),5.38(br.s,1H),6.91–7.01(m,1H),7.03–7.11(m,1H),7.19–7.36(m,2H),7.38–7.46(m,2H),8.05(br.s,1H). 13 CNMR (126MHz, CDCl3) δ14.2,19.5,31.0,32.2,32.4,37.5,50.0,50.1,60.9,61.2,77.9,115.2 ,115.3,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4,178.7.

[0200] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide lactate

[0201] White solid: mp 118.1–118.8℃; C 19 H 26FN3O6 (411.43), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.90 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.41–1.44(m,3H),2.88(s,6H),3.02–3.37(m,3H),4.38–4.44(m,2H),4.82(dd,J=12 .0,7.5Hz,1H),5.40(br.s,1H),6.89–7.13(m,2H),7.18–7.35(m,2H),7.38–7.49(m,2H),8.07(br.s,1H). 13 CNMR (126MHz, CDCl3) δ14.3,19.5,31.0,32.1,32.4,37.5,50.0,50.1,60.9,61.2,77.9,115.2 ,115.3,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4,178.7.

[0202] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide lactate

[0203] White solid: mp 104.9–105.6℃; C 19 H 26 FN3O6 (411.43), single isotopic mass: 321.15. UPLC (purity: >99.9%): t R = 2.87 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.41–1.44(m,3H),2.87(s,6H),3.04–3.35(m,3H),4.37–4.48(m,2H),4.83(dd,J=12 .0,7.5Hz,1H),5.41(br.s,1H),6.85–7.14(m,2H),7.19–7.39(m,2H),7.42–7.51(m,2H),8.08(br.s,1H). 13CNMR (126MHz, CDCl3) δ14.3,19.5,31.0,32.1,32.4,37.6,50.0,50.1,60.9,61.2,77.9,115.2 ,115.3,115.4,124.3,129.1,129.3,129.8,130.0,159.8,161.7,167.9,168.0,171.4,178.7.

[0204] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide sulfate

[0205] White solid: mp 119.4–120.2℃; C 32 H 42 F2N6O 10 S(740.78), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.89 min, (M+H) + 322.2. 1 H NMR(500MHz,DMSO-d6)δ1.46(dd,J=12.6,7.2Hz,3H),2.64(s,6H),2.90-3.00(m,2H),3.06(td,J=17.8,5.0Hz,1H),4.27( t,J=5.2Hz,2H),4.39–4.47(m,1H),4.65(dd,J=7.3,2.7Hz,1H),7.09–7.15(m,2H),7.21–7.31(m,2H),8.42–8.47(m,1H). 13 C NMR (126MHz, CDCl3) δ14.2,31.0,32.2,32.4,37.5,50.0,50.1,60.9,61.2,115.2,1 15.3,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0206] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide sulfate

[0207] White solid: mp 119.1–119.8℃; C 32 H 42 F2N6O 10S(740.78), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.90 min, (M+H) + 322.2. 1 H NMR (500MHz, DMSO-d6) δ1.48 (dd, J=12.6, 7.2Hz, 3H), 2.65 (s, 6H), 2.91–3.03 (m, 2H), 3.06–3.13 (m, 1H), 4.26 (t, J= 5.2Hz,2H),4.38–4.46(m,1H),4.64(dd,J=7.3,2.7Hz,1H),7.08–7.16(m,2H),7.21–7.30(m,2H),8.42–8.45(m,1H). 13 C NMR (126MHz, CDCl3) δ14.2,31.0,32.2,32.4,37.5,50.0,50.1,60.9,61.2,115.2,1 15.3,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0208] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide sulfate

[0209] White solid: mp 104.9–105.8℃; C 32 H 42 F2N6O 10 S(740.78), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.91 min, (M+H) + 322.2. 1 H NMR(500MHz,DMSO-d6)δ1.45(dd,J=12.6,7.2Hz,3H),2.64(s,6H),2.90–3.00(m,2H),3.06(td,J=17.8,5.0Hz,1H),4.27( t,J=5.2Hz,2H),4.38–4.47(m,1H),4.67(dd,J=7.3,2.7Hz,1H),7.10–7.16(m,2H),7.22–7.32(m,2H),8.40–8.46(m,1H). 13C NMR (126MHz, CDCl3) δ14.2,31.0,32.2,32.4,37.5,50.0,50.1,60.9,61.2,115.2,1 15.3,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4.

[0210] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide succinate

[0211] White solid: mp 119.6–120.4℃; C 36 H 46 F2N6O 10 (760.79), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.93 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.45–1.51(m,3H),2.34–2.48(m,2H),2.52–2.71(m,2H),2.95(s,6H),3.05–3.31(m,3H),4.33– 4.45(m,2H),4.81(dd,J=11.0,7.3Hz,1H),6.82–7.12(m,2H),7.18–7.35(m,1H),7.43–7.59(m,1H),8.08(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.2,31.0,32.2,32.4,32.6,37.5,50.0,50.1,60.9,61.2,115.2,115.3 ,115.4,124.3,129.1,129.2,129.8,130.0,159.8,161.7,167.9,168.0,171.4,176.5,177.4.

[0212] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide succinate

[0213] White solid: mp 118.8–119.4℃; C 36 H 46 F2N6O 10(760.79), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.92 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.44–1.50(m,3H),2.32–2.45(m,2H),2.51–2.74(m,2H),2.97(s,6H),3.02–3.35(m,3 H),4.31–4.42(m,2H),4.81(dd,J=11.0,7.3Hz,1H),6.85–7.36(m,3H),7.41–7.59(m,1H),8.09(br.s,1H). 13 C NMR (126MHz, CDCl3) δ14.1,31.0,32.1,32.4,32.6,37.5,50.0,50.1,60.8,61.2,115.2,115.3 ,115.4,124.3,129.1,129.2,129.7,130.0,159.8,161.7,167.9,168.0,171.4,176.5,177.4.

[0214] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide succinate

[0215] White solid: mp 106.1–106.7℃; C 36 H 46 F2N6O 10 (760.79), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.93 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.44–1.50(m,3H),2.32–2.49(m,2H),2.52–2.73(m,2H),2.96(s,6H),3.02–3.34(m,3 H),4.31–4.41(m,2H),4.82(dd,J=11.0,7.3Hz,1H),6.85–7.37(m,3H),7.41–7.58(m,1H),8.07(br.s,1H). 13C NMR (126MHz, CDCl3) δ14.1,31.0,32.1,32.4,32.6,37.5,50.0,50.1,60.8,61.2,115.2,115.3 ,115.4,124.3,129.1,129.2,129.7,130.0,159.8,161.7,167.9,168.0,171.4,176.5,177.4.

[0216] Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)-N-(2-fluorobenzyl)propionamide fumarate

[0217] White solid: mp 118.3–119.1℃; C 36 H 44 F2N6O 10 (758.78), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.91 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.42–1.49(m,3H),2.97(s,6H),3.08–3.31(m,2H),3.42–3.58(m,2H),4.57–4.62(m,2H ), 4.78 (dd, J=14.5, 7.5Hz, 1H), 6.97 (t, J=9, 5Hz, 1H), 7.02–7.35 (m, 3H), 7.44–7.59 (m, 1H), 7.95 (br.s, 1H). 13 CNMR (126MHz, CDCl3) δ14.1,14.2,31.0,32.2,32.4,37.5,50.0,50.1,60.9,61.2,115.2,115.3,115.4,1 24.3,125.2,129.0,129.1,129.2,129.8,130.0,134.2,138.9,159.7,161.7,167.9,168.0,170.5,171.3.

[0218] Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide fumarate

[0219] White solid: mp 118.1–118.8℃; C 36 H 44 F2N6O 10(758.78), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.92 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.41–1.47(m,3H),2.96(s,6H),3.07–3.29(m,2H),3.41–3.53(m,2H),4.51–4.64(m,2 H),4.77(dd,J=14.5,7.5Hz,1H),6.91–6.98(m,1H),7.05–7.39(m,3H),7.46–7.63(m,1H),7.99(br.s,1H). 13 CNMR (126MHz, CDCl3) δ14.1,14.2,31.1,32.2,32.4,37.5,50.0,50.1,60.9,61.2,115.2,115.3,115.4,1 24.2,125.2,129.0,129.1,129.2,129.8,130.0,134.2,138.9,159.7,161.7,167.9,168.0,170.5,171.3.

[0220] Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)-N-(2-fluorobenzyl)propionamide fumarate

[0221] White solid: mp 104.7–105.4℃; C 36 H 44 F2N6O 10 (758.78), single isotope mass: 321.15. UPLC (purity: >99.9%): t R = 2.90 min, (M+H) + 322.2. 1 H NMR (500MHz, CDCl3) δ1.43–1.49(m,3H),2.98(s,6H),3.05–3.27(m,2H),3.47–3.59(m,2H),4.52–4.68(m,2 H),4.78(dd,J=14.5,7.5Hz,1H),6.91–6.97(m,1H),6.99–7.33(m,3H),7.41–7.58(m,1H),8.02(br.s,1H). 13CNMR (126MHz, CDCl3) δ14.1,14.2,31.1,32.2,32.4,37.5,50.0,50.1,60.9,61.3,115.2,115.3,115.5,1 24.2,125.1,129.0,129.1,129.2,129.8,130.0,134.2,138.7,159.7,161.7,167.9,168.0,170.5,171.3.

[0222] Example 2. Bioactivity of the compound according to the present invention

[0223] Anticonvulsant activity study

[0224] The study was conducted on male white Swiss mice (CD-1) weighing 18–26 g. All procedures were performed in accordance with applicable Polish and international animal research ethics guidelines, following appropriate institutional approval. Thirty minutes prior to testing, substances (2R,S)-3, (2R)-3, (2S)-3, (2R,S)-4, (2R)-4, (2S)-4 and monohydrochloride (2R,S)-5, (2R)-5, (2S)-5, (2R,S)-6, (2R)-6, (2S)-6 were administered intraperitoneally (ip) at a volume of 10 mL / kg, after being dissolved in a mixture of DMSO, PEG-400, and water for injection (10 / 40 / 50, v / v / v). Screening tests were performed in groups of four mice. All tests were performed according to the procedures described in the relevant literature: Maximum Electroconvulsive Therapy (MES) (Kamiński et al. Bioorg. Med. Chem. 2015, 23, 2548-2561; Castel-Branco et al. Pharmacol. 2009, 31, 101-106; Riban et al. Neurosci. 2002, 112, 101-111); Psychomotor Seizure Test (6Hz, 32mA) (Barton et al. Epilepsy Res. 2001, 47, 217-227; Wojda et al. Epilepsy Res. 2009, 86, 163-174); Subcutaneous Pentyltetrazole Test (scPTZ) (Ferreri et al. Pharmacol. Biochem. Behav. 2004, 77, 85-94). The results of the tests are presented in Table 3.

[0225] Table 3. Results of screening tests at a dose of 100 mg / kg for compounds covered by formula (I) and their water-insoluble chemical prototypes (2R,S)-1, (2R)-1, (2S)-1, (2R,S)-2, (2R)-2, and (2S)-2 disclosed in Polish patent application P.429656.

[0226]

[0227] *Tests were performed 0.5 h after intraperitoneal administration to mice. Data indicate the number of protected mice in a given seizure model / the number of mice tested; MES - maximum electroshock test; 6 Hz (32 mA) - psychomotor seizure test induced by a low-frequency current (6 Hz) and 32 mA intensity; scPTZ test - seizure induced by subcutaneous administration of pentylenetetrazol. # The substance disclosed in Polish patent application P.429656.

[0228] In vivo results in mice at a screening dose of 100 mg / kg (intraperitoneal administration) showed that compounds (2R,S)-3, (2R)-3, (2S)-3, (2R,S)-4, (2R)-4, (2S)-4, and monohydrochloride (2R,S)-5, (2R)-5, (2S)-5, (2R,S)-6, (2R)-6, (2S)-6 (described by general formula (I)) exhibited broad anticonvulsant activity in various animal models of seizures, protecting 25–100% of test animals in the maximal electroshock test (MES), pentylenetetrazole subcutaneous seizure test (scPTZ), and 6 Hz (32 mA) model (Table 3). These models are considered the most important and widely used pharmacological tests, allowing for the identification of new antiepileptic drug candidates. The substances that exhibit protective activity in the aforementioned seizure models are therefore potentially effective against various types of human epilepsy, including tonic-clonic seizures with or without secondary generalized seizures, generalized absence seizures, myoclonic seizures, partial seizures, and drug-resistant epilepsy. An advantageous feature of the compounds of formula (I) is their efficacy in all of the aforementioned seizure tests, namely MES, scPTZ, and 6Hz (32mA). Advantageously, the broad-spectrum protective activity in the disclosed in vivo studies confirms the possibility of using the compounds of the invention for monotherapy of various forms of epilepsy in humans, rather than polytherapy, which is currently the main drug treatment for epilepsy. The screening data shown in Table 3 demonstrate the potent anticonvulsant activity of the R-enantiomers, namely compounds (2R)-3, (2R)-4, (2R)-5, and (2R)-6. In most cases, these compounds provided 100% protection in all epileptic seizure models used. Therefore, the R-absolute configuration of the chiral carbon atom in the propionamide moiety appears to be preferred for the anticonvulsant activity of the compounds tested herein. Another advantage of compounds of formula (I), particularly those obtained in the form of salts (e.g., monohydrochlorides), namely (2R,S)-5, (2R), (2S)-5, (2R,S)-6, (2R)-6, and (2S)-6, is their very good solubility in water. Due to this solubility, the formulations can be administered intravenously for rapid therapeutic effect. This is crucial in cases requiring immediate intervention to stop seizures, including, for example, status epilepticus, which is considered a life-threatening condition.In addition to the improved solubility and resulting advantages in medical applications, the compounds constituting the subject of this application (and whose general structure is represented by formula (I)) unexpectedly possess, despite significant chemical modifications depending on the removal of a carbonyl group from the pyrrolidine-2,5-diketone ring or the introduction of a dimethylamine fragment into the aforementioned core structure, resulting in significant changes in the geometry and polarity of the molecule, almost identical or potent anticonvulsant activity to their chemical prototypes (2R,S)-1, (2R)-1, (2S)-1, (2R,S)-2, (2R)-2, and (2S)-2, which are disclosed in Polish patent application P.429656 (Table 3). Furthermore, surprisingly, the novel pyrrolidone-2-one derivatives, namely (2R,S)-3, (2R)-3, (2S)-3, (2R,S)-4, (2R)-4, and (2S)-4, exhibited protective activity in MES and scPTZ tests, unlike the AED-levetiracetam model with the same heterocyclic structure, but remained inactive in the aforementioned seizure model. Moreover, the introduction of a spatially large dimethylamine fragment at the 3-position of the pyrrolidone-2,5-dione ring unexpectedly did not lead to a significant reduction in biological activity, at least in the derivatives (2R,S)-5, (2R)-5, (2S)-5, (2R,S)-6, (2R)-6, and (2S)-6. It should be emphasized that the presence of one or two methyl groups at the 3-position in similar analogues of this compound leads to a reduction in anticonvulsant activity, as demonstrated in our earlier studies (Kamiński, et al. Bioorg. Med. Chem. 2015, 23, 2548-2561).

Claims

1. A compound of formula (I): ###0001### wherein: X represents hydrogen or N(CH3)2, Y represents CH2 or C=0, R represents hydrogen or a halogen atom, with the proviso that when Y is C=0, then X represents N(CH3)2, or a pharmaceutically acceptable salt thereof. (I) 2. The compound of claim 1, wherein: X represents N(CH3)2, Y represents CH2, and R represents hydrogen.

3. The compound of claim 1, wherein: X represents N(CH3)2, Y represents CH2, and R represents a halogen atom.

4. The compound of claim 1, wherein: X represents N(CH3)2, Y represents C=0, and R represents hydrogen.

5. The compound of claim 1, wherein: X represents N(CH3)2, Y represents C=0, and R represents a halogen atom.

6. The compound of claim 1, wherein: X represents N(CH3)2, Y represents CH2, and R represents F.

7. The compound of claim 1, wherein: X represents N(CH3)2, Y represents CH2, and R represents Cl. wherein said compound is 2R - enantiomers.

2. The compound of claim 1, wherein, 8. The compound of claim 1, wherein: X represents N(CH3)2, Y represents CH2, and R represents Br.

3. The compound of claim 1, wherein, 9. The compound of claim 1, wherein: X represents N(CH3)2, Y represents CH2, and R represents I. ( 2R )- N -Benzyl-2-(2-oxomylidene-1-yl)propionamide.

4. The compound of claim 1, wherein, 10. The compound of claim 1, wherein: X represents N(CH3)2, Y represents C=0, and R represents F. ( 2R )- N -(2-Fluorobenzyl)-2-(2-oxomylidene-1-yl)propionamide.

5. The compound of claim 1, wherein, 11. The compound of claim ( 2R )- N -Benzyl-2-(3-(dimethylamino)-2,5-dioxanepyrrolidone-1-yl)propionamide.

6. The compound of claim 1, wherein, ​ ( 2R )-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)- N -(2-fluorobenzyl)propanamide.

7. The compound according to any one of claims 1 to 6, wherein, ​ 8. The compound of claim 7, wherein, ​ ( 2R )- N -Benzyl-2-(3-(dimethylamino)-2,5-dioxylidene-1-yl)propionamide hydrochloride, and 2R )-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)- N -(2-fluorobenzyl)propanamide hydrochloride.​

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