WATER-SOLUBLE, MODIFIED AMINO ACID DERIVATIVES FOR TREATMENT OF NEUROLOGICAL DISEASES, AND SELECTED PSYCHIATRIC DISORDERS

Abstract

Water-soluble analogs of compounds intended for the treatment of neurological diseases, epilepsy, neuropathic pain and migraine, and psychiatric disorders, including anxiety and depression, especially suitable for the preparation of oral or parenteral drug forms, are disclosed.

##STR00001##

Claims

1. Compound of formula (I): ##STR00007## wherein: X represents hydrogen or N(CH.sub.3).sub.2, Y represents CH.sub.2 or C═O, R represents hydrogen or a halogen atom, preferably F, wherein, when Y is C═O, then X represents N(CH.sub.3).sub.2, or its optical isomers, mixtures thereof, and pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein it is selected from the group consisting of: N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide, N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide, N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide.

3. The compound according to claim 1, wherein, it is selected from the group consisting of: N-benzyl-2-(3-(dimethylamino)2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide.

4. The compound according to claim 1, wherein it is in a form of pharmaceutically acceptable salt, selected from: hydrochloride, sulfate, methanesulfonate, toluenesulfonate, succinate, fumarate, or lactate.

5. The compound according to claim 1, wherein it is selected from the group consisting of: (2R)-N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide, (2S)-N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide, (2R,S)-N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide, (2R)-N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide, (2S)-N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide, (2R,S)-N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide hydrochloride, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide hydrochloride, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide hydrochloride, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide hydrochloride, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide hydrochloride, (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide hydrochloride, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide metanesulfonate, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide metanesulfonate, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide metanesulfonate, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide toluenesulfonate, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide toluenesulfonate, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide toluenesulfonate, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide lactate, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide lactate, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide lactate, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide sulfate, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide sulfate, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide sulfate, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide succinate, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide succinate, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide succinate, (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide fumarate, (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide fumarate, (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide fumarate, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide methanesulfonate, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide methanesulfonate, (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide methanesulfonate, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide toluenesulfonate, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide toluenesulfonate, p1 (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide toluenesulfonate, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide lactate, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide lactate, (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide lactate, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide sulfate, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide sulfate, (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide sulfate, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide succinate, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide succinate, (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide succinate, (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide fumarate, (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide fumarate, and (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide fumarate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0075] The invention relates to water-soluble derivatives of 2-(2-oxopyrrolidin-1-yl)propanamide or (3-dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide.

[0076] The compounds were designed as close structural analogs of the compounds disclosed previously and known in the state of art (FIG. 1), and the main chemical modifications relies on the removal of one carbonyl group, leading to pyrrolidin-2-one derivatives (compounds 3 and 4) or on introduction of the dimethylamine moiety at the 3-position of the pyrrolidine-2,5-dione ring (compounds 5 and 6). Due to the presence of the said amino group, it is possible to transform the compounds into water-soluble and pharmaceutically acceptable salts, including hydrochlorides, sulfates, methanesulfonates, toluenesulfonates, succinates, fumarates, lactates, etc., by application of methods known in the art.

[0077] According to the invention, compounds of formula 3-6 can be prepared in a multi-step process, starting from commercially available, Tert-butoxycarbonyl (Boc) protected D,L-alanine (in the case of the racemic (R,S) mixtures), D-alanine (in the case of the compounds with the absolute R-configuration in the propanamide moiety), or L-alanine (in the case of the enantiomers with the absolute S-configuration in the propanamide moiety). Alternatively, the R- and S-enantiomers can by prepared by separation of suitable racemic mixtures, using the separation methods known in the art.

[0078] The first step of the synthesis consists of condensation of benzylamine or 2-fluorobenzylamine with Boc protected alanine, having the desired configuration of the asymmetric center, to give the intermediate of formula II. Next, removing of the Boc protected group leads to the starting primary amine of general formula III. The steps i i ii are common for the compound 3-6. In case of synthesis of pyrrolidin-2-one derivatives 3 and 4, the primary amine III is acylated using 4-chlorobutanoic acid chloride to yield the derivative IV. Next, compound IV is cyclized in the presence of base, e.g. sodium hydride, to give the desired products 3 and 4. Alternatively, instead of 4-chlorobutanoic acid chloride, 4-bromo or 4-iodobutanoic acid chlorides could be used. The synthesis of compounds 3 and 4 is shown in Scheme 1.

##STR00005##

[0079] In the case of salt derivatives 5, 6, the amine III is condensed with maleic anhydride to give monounsaturated amido acid V, which is next cyclized to maleimide derivative VI. Addition reaction of dimethylamine to the double bond of the compound VI, results in formation of tertiary amine, which next can be transformed into its water soluble salts, using the methods known in the art. Pharmaceutically acceptable salts include, among others, hydrochlorides, sulfates, methanesulfonates, toluenesulfonates, succinates, fumarates, lactates, etc. As examples, compounds 5 and 6 were obtained in the form of all the aforementioned salts. The subsequent steps of the synthesis of compounds 5 and 6 are demonstrated in Scheme 2.

##STR00006##

[0080] An advantageous feature of the compounds 3-6, in comparison to their chemical prototypes 1 and 2 is good water solubility, which may result in better pharmacokinetics, particularly in better pharmaceutical availability, better absorption from the gastrointestinal tract, and higher bioavailability. In addition, good solubility in water facilitates preparation of an appropriate oral form of the drug, and enable parenteral administration of the preparation, which is especially desirable in emergency situations, when a quick therapeutic effect is needed, e.g. to stop an epileptic seizure. Therefore, derivatives 3-6 should be regarded as close analogs of the lead compounds 1 and 2, but having more favorable physical and biopharmaceutical properties, i.e. better water solubility. Table 1 summarizes the results of the water solubility studies, per gram of compound at 25° C. The studies were performed for racemic mixtures (R,S), as well as for individual R- or S-enantiomers.

TABLE-US-00001 TABLE 1 Results of water solubility test, at 25° C., per 1 gram of compound. The volume of water required for dissolution of 1 g of the Compound substance at 25° C. (mL) .sup.a Matching term.sup.b (2R,S)-1 >100.sup.c .sub.  Slightly soluble (2R)-1 >100.sup.c .sub.  Slightly soluble (2S)-1 >100.sup.c .sub.  Slightly soluble (2R,S)-2 >100.sup.c .sub.  Slightly soluble (2R)-2 >100.sup.c .sub.  Slightly soluble (2S)-2 >100.sup.c .sub.  Slightly soluble (2R,S)-3 25 Soluble (2R)-3 25 Soluble (2S)-3 25 Soluble (2R,S)-4 30 Soluble (2R)-4 30 Soluble (2S)-4 30 Soluble (2R,S)-5 × HCl <1 Very soluble (2R)-5 × HCl <1 Very soluble (2S)-5 × HCl <1 Very soluble (2R,S)-6 × HCl <1 Very soluble (2R)-6 × HCl <1 Very soluble (2S)-6 × HCl <1 Very soluble .sup.a The studies were performed in accordance with the guidelines described in the European Pharmacopoeia 10.0 and the Polish Pharmacopoeia XII. .sup.bTerminology in accordance with the European Pharmacopoeia 10.0 and the Polish Pharmacopoeia XII. .sup.cMaximum volume of the used water-100 mL.

[0081] The obtained results indicate that the compounds disclosed in this application are classified as substances that are soluble (3, 4) or easily soluble (5, 6) in water, while the starting compounds (1 and 2), according to the accepted classification, rank as substances that are at least hardly soluble. It should be emphasized, that the better solubility in water is particularly surprising and not obvious in the case of pyrrolidin-2-one derivatives (3, 4) vs. pyrrolidine-2,5-dione derivatives (1, 2). The physicochemical data calculated using the SwissADME program (Daina et al. Sci. Rep. 2017, 7, 42717) indicate lower lipophilicity and, at the same time, greater polar surface area of the molecule for succinimide derivatives (1, 2), which suggests their potentially better solubility in water. Experimental data revealed the opposite effect, i.e. a much better water solubility for pyrrolidin-2-one derivatives (3, 4). Table 2 summarizes the values of lipophilicity parameters (log P.sub.o/w) and total polar surface area (tPSA) for racemic mixtures of pyrrolidine-2,5-dione derivatives—(2R,S)-1, (2R,S)-2 vs. pyrrolidin-2-one derivatives—(2R,S)-3 and (2R,S)-4.

TABLE-US-00002 TABLE 2 Comparison of lipophilicity parameters (log P.sub.o/w) and total polar surface area (tPSA) for racemic mixtures of pyrrolidine-2,5- dione derivatives (2R,S)-1, (2R,S)-2) and pyrrolidin-2- one derivatives (2R,S)-3 and (2R,S)-4). Physicochemical parameter.sup.a Compound Log P.sub.o/w.sup.b tPSA [Å.sup.2].sup.c (2R,S)-1 1.11 66.48 (2R,S)-2 1.42 66.48 (2R,S)-3 1.44 49.41 (2R,S)-4 1.76 49.41 .sup.aThe calculations were made with the use of the computer program SwissADME (Daina et al. Sci. Rep. 2017, 7, 42717). .sup.bLog P.sub.o/w—logarithm of the n-octanol/water partition coefficient. .sup.ctPSA—total polar surface area of the molecule.

[0082] Examples of realization of the invention are presented below.

EXAMPLE 1

Preparation of Compounds According to the Invention

[0083] Analytical Methods:

[0084] The .sup.1H NMR and .sup.13C NMR spectra were recorded using JEOL-500 spectrometer (JEOL USA, Inc. MA, USA), at 500 MHz and 126 MHz, respectively. Chemical shifts are given in δ (ppm) values relative to TMS δ=0 (.sup.1H) as internal standard. J values are expressed in Hertz (Hz). Deuterated chloroform (CDCl.sub.3) or deuterated dimethylsulfoxide (DMSO-d6) were used as solvents. The following signal abbreviations were used in the spectra description: s (singlet), br. s (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet). The UPLC/MS analysis system consisted of a Waters ACQUITY® UPLC® instrument (Waters Corporation, Milford, Mass., USA) coupled to a Waters TQD mass spectrometer operating in electrospray ionization (ESI) mode. Chromatographic separations were carried out using the Acquity UPLC BEH C18 column of dimensions 2.1×100 mm and grain diameter of 1.7 μm. The column was kept at 40° C., and eluted with a gradient from 95% to 0% of eluent A over 10 min, with a flow of 0.3 ml/min. Eluent A: water/formic acid (0.1%, v/v); eluent B: acetonitrile/formic acid (0.1%, v/v). The chromatograms were recorded using a Waters eλ PDA detector. Spectra were analyzed in the range of 200-700 nm with a resolution of 1.2 nm, and a sampling rate of 20 points/s. The enantiomeric purity was determined by chiral HPLC analysis using a Shimadzu Prominence and LC-2030C SD Plus apparatus, (Shimadzu Corporation, Kyoto, Japan) equipped with an Amylose-C chiral column (250×4.6 mm). The analysis was performed under the following conditions: column temperature: 20° C., mixture of eluents: hexane/i-PrOH=85/15 (v/v), flow: 0.7 mL/min, detection at λ=209 nm. For intermediates VI, the analyses were performed under the following conditions: column temperature—33° C., mixture of hexane/i-PrOH/TFA eluents=93.4/6.4/0.2 (v/v/v), flow: 0.75 mL/min, detection at λ=206 nm. Thin layer chromatography (TLC) was performed on aluminum plates coated with silica gel 60 F.sub.254 (Macherey-Nagel, Düren, Germany) using developing systems having the following composition: DCM:MeOH (9:0.3; v/v), DCM:MeOH (9:0.5; v/v). Spot detection—UV light (λ=254 nm). The melting points (mp) were determined using open capillaries and Büchi 353 apparatus (Büchi Labortechnik, Flawil, Switzerland). Names of the compounds described below and illustrating embodiments of the invention, were generated using the ChemBioDraw Ultra 12.0 program.

[0085] The preparation of the compounds according to the invention is described in the Examples below. The presented syntheses were not optimized in terms of yield, amount of the reagents used, and the final form of the obtained compounds.

[0086] Abbreviations used: AcOEt—ethyl acetate, DCM—dichloromethane, DCC—N,N′-dicyclohexylcarbodiimide, Et.sub.2O—diethyl ether, HCl—hydrochloric acid, HMDS—hexamethyldisilazane, MeOH—methanol, NaCl—sodium chloride, NaH—sodium hydride, NH.sub.4OH—ammonium hydroxide, Na.sub.2SO.sub.4—sodium sulfate, TFA—trifluoroacetic acid, TEA—triethylamine, ZnCl.sub.2—zinc chloride.

EXAMPLES OF SYNTHESIS, PHYSICOCHEMICAL AND SPECTRAL DATA OF INTERMEDIATES (II-IV), ACCORDING TO SCHEME 1)

Intermediate II (Wherein R═H): Tert-butyl-(R)-(1-benzylamino)-1-oxopropan-2-yl)carbamate

[0087] 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, next benzylamine (2.89 g, 27 mmol, 1 eq) was added dropwise, and the reaction was continued at room temperature for 4 h. Afterwards, DCM was distilled off, and the intermediate II was purified by column chromatography using DCM:MeOH (9:0.3; v/v) as eluent. The intermediate was obtained as a light oil. Yield 91% (6.95 g); TLC: R.sub.f=0.43 (DCM:MeOH (9:0.3; v/v)); C.sub.15H.sub.22N.sub.2O.sub.3 (278.35), monoisotopic mass: 278.16. UPLC (purity 100%): t.sub.R=5.44 min. (M+H).sup.+ 279.3.

Intermediate III (Wherein R═H): (R)-2-amino-N-benzylpropanamide

[0088] TFA (10 mL) was added to a solution of tert-butyl-(R)-(1-(benzylamino)-1-oxopropan-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 a 25% NH.sub.4OH solution, and the mixture was extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, and next DCM was evaporated to dryness. (R)-2-amino-N-benzylpropanamide (III) was obtained as a light oil. Yield: 89% (3.9 g); TLC: R.sub.f=0.21 (DCM:MeOH (9:0.5; v/v)); C.sub.10H.sub.14N.sub.2O (178.24), monoisotopic mass: 178.11. UPLC (purity 96.8%): t.sub.R=2.11 min. (M+H).sup.+ 179.2.

Intermediate IV (Wherein R═H) (R)-N-(1-(benzylamino)-1-oxopropan-2-yl)-4-chlorobutanamide 4-Chlorobutanoic 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-benzylpropanamide (III) (0.50 g, 2.8 mmol, 1 eq) in DCM (20 mL), and the mixture was stirred for 0.5 hour. Next, DCM was evaporated to dryness. The intermediate IV was purified by column chromatography using (DCM:MeOH (9:0.5; v/v) eluent system. The intermediate IV was obtained as a light oil. Yield: 82% (0.65 g); TLC: R.SUB.f.=0.53 (DCM:MeOH (9:0.5; v/v)); C.SUB.14.H.SUB.19.ClN.SUB.2.O.SUB.2 .(282.77), monoisotopic mass: 282.11. UPLC (purity 97.8%): t.SUB.R.=4.52 min. (M+H).SUP.+ 283.2.

[0089] Synthesis, Physicochemical and Spectral Data of the Final Compounds (2R)-3, (2S)-3, (2R,S)-3, and (2R)-4, (2S)-4, (2R,S)-4

Compound (2R)-3 (Wherein R═H): (2R)-N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide

[0090] NaH (0.106 g, 4.4 mmol, 2 eq) was added to a solution of (R)-N-(1-(benzylamino)-1-oxopropan-2-yl)-4-chlorobutanamide (0.63 g, 2.2 mmol, 1 eq) (IV, wherein R═H) in anhydrous THF. The reaction mixture was stirred for 4 hours, and next concentrated under reduced pressure. The oily residue was dissolved in 0.1 M HCl (50 mL) and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, and evaporated to dryness. The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 86% (0.47 g); mp 96.7-97.5° C.; Chiral HPLC>99% ee (t.sub.R=10.623 min); TLC: R.sub.f=0.42 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.18N.sub.2O.sub.2 (246.31), Monoisotope mass: 264.13. UPLC (purity: >99.9%): t.sub.R=3.92 min, (M+H).sup.+ 247.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.36 (d, J=7.2 Hz, 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, 2.2 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 13.8, 18.1, 31.1, 43.5, 43.8, 50.3, 127.5, 127.6, 128.7, 138.3, 170.6, 175.8.

Compound (2S)-3 (Wherein R═H): (2S)-N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide

[0091] The compound was obtained analogously to the compound (2R)-3, using (S)-N-(1-(benzylamino)-1-oxopropan-2-yl)-4-chlorobutanamide (0.63 g, 2.2 mmol, 1 eq) (IV, wherein R═H) and NaH (0.106 g, 4.4 mmol, 2 eq). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 79% (0.43 g); mp 96.4-97.2° C.; Chiral HPLC>99% ee (t.sub.R=14.215 min); TLC: R.sub.f=0.41 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.18N.sub.2O.sub.2 (246.31), monoisotope mass: 264.13. UPLC (purity: >99.9%): t.sub.R=3.90 min, (M+H).sup.+ 247.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.35 (d, J=7.2 Hz, 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, 2.2 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 13.8, 18.1, 31.1, 43.5, 43.8, 50.3, 127.5, 127.6, 128.7, 138.3, 170.6, 175.8.

Compound (2R,S)-3 (Wherein R═H): (2R,S)-N-benzyl-2-(2-oxopyrrolidin-1-yl)propanamide

[0092] The compound was obtained analogously to the compound (2R)-3, using (R,S)-N-(1-(benzylamino)-1-oxopropan-2-yl)-4-chlorobutanamide (0.63 g, 2.2 mmol, 1 eq) (IV, wherein R═H) and NaH (0.106 g, 4.4 mmol, 2 eq). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 88% (0.48 g); mp 78.1-78.6° C.; TLC: R.sub.f=0.41 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.18N.sub.2O.sub.2 (246.31), monoisotope mass: 264.13. UPLC (purity: >99.9%): t.sub.R=3.91 min, (M+H).sup.+ 247.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.36 (d, J=7.2 Hz, 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, 2.2 Hz, 2H), 4.70 (q, J=7.2 Hz, 1H), 6.76 (br. s, 1H), 7.19-7.22 (m, 2H), 7.23-7.25 (m, 1H), 7.27-7.31 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 13.8, 18.1, 31.1, 43.5, 43.8, 50.3, 127.5, 127.6, 128.7, 138.3, 170.6, 175.8.

Compound (2R)-4 (Wherein R═F): (2R)-N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide

[0093] The compound was obtained analogously to the compound (2R)-3, using (R)-4-chloro-N-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)butanamide (0,57 g, 1.9 mmol, 1 eq) (IV, wherein R═F) and NaH (0.091 g, 3.8 mmol, 2 eq). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. The compound was obtained as a white solid. Yield: 88% (0.44 g); mp 92.5-93.1° C.; Chiral HPLC>99% ee (t.sub.R=8.959 min); TLC: R.sub.f=0.39 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.17FN.sub.2O.sub.2 (264.30), monoisotope mass: 264.13. UPLC (purity: >99.9%): t.sub.R=4.04 min, (M+H).sup.+ 265.9. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.34 (d, J=7.2 Hz, 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, 5.7 Hz, 1H), 4.47 (dd, J=15.0, 6.2 Hz, 1H), 4.64-4.75 (m, 1H), 4.69 (d, J=7.2 Hz, 1H), 6.69 (br. s, 1H), 7.01 (t, J=9.1 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 7.21-7.27 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 13.7, 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.

Compound (2S)-4 (Wherein R═F): (2S)-N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide

[0094] The compound was obtained analogously to the compound (2R)-3, using (S)-4-chloro-N-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)butanamide (0.57 g, 1.9 mmol, 1 eq) (IV, wherein R═F) and NaH (0.091 g, 3.8 mmol, 2 eq). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. The compound was obtained as a white solid. Yield: 78% (0.39 g); mp 92.1-93.8° C.; Chiral HPLC>99% ee (t.sub.R=13.313 min); TLC: R.sub.f=0.40 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.17FN.sub.2O.sub.2 (264.30), monoisotope mass: 264.13. UPLC (purity: >99.9%): t.sub.R=4.03 min, (M+H).sup.+ 265.9. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.35 (d, J=7.2 Hz, 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, 5.7 Hz, 1H), 4.46 (dd, J=15.0, 6.2 Hz, 1H), 4.64-4.75 (m, 1H), 4.69 (d, J=7.2 Hz, 1H), 6.68 (br. s, 1H), 7.02 (t, J=9.1 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 7.21-7.27 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 13.7, 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.

Związek (2R,S)-4 (Wherein R═F): (2R,S)-N-(2-fluorobenzyl)-2-(2-oxopyrrolidin-1-yl)propanamide

[0095] The compound was obtained analogously to the compound (2R)-3, using (R,S)-4-chloro-N-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)butanamide (0.57 g, 1.9 mmol, 1 eq) (IV, wherein R═F) and NaH (0.091 g, 3.8 mmol, 2 eq). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. The compound was obtained as a white solid. Yield: 82% (0.41 g); mp 75.4-76.9° C.; TLC: R.sub.f=0.41 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.17FN.sub.2O.sub.2 (264.30), monoisotope mass: 264.13. UPLC (purity: >99.9%): t.sub.R=4.03 min, (M+H).sup.+ 265.9. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.34 (d, J=7.2 Hz, 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, 5.7 Hz, 1H), 4.47 (dd, J=15.0, 6.2 Hz, 1H), 4.63-4.76 (m, 1H), 4.70 (d, J=7.2 Hz, 1H), 6.69 (br. s, 1H), 7.01 (t, J=9.1 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 7.19-7.28 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 13.7, 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.

EXAMPLES OF SYNTHESIS, PHYSICOCHEMICAL AND SPECTRAL DATA OF INTERMEDIATES V AND VI, ACCORDING TO SCHEME 2

Intermediate V (Wherein R═H) (R)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid

[0096] Maleic anhydride (0.33 g, 3.4 mmol, 1 eq) was added to a solution of (R)-2-amino-N-benzylpropanamide (0.6 g, 3.4 mmol, 1 eq) (III) in AcOEt (40 mL), and the mixture was stirred for 30 min. Next, AcOEt was evaporated to dryness. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 98% (0.91 g); TLC: R.sub.f=0.28 (DCM:MeOH (9:0.1; v/v)); C.sub.14H.sub.16N.sub.2O.sub.4 (276.29), monoisotopic mass: 276.11. UPLC (>99.9% purity): t.sub.R=3.72 min. (M+H).sup.+ 278.2.

Intermediate VI (Wherein R═H) (R)-N-benzyl-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide

[0097] ZnCl.sub.2 (0.39 g, 10 mmol, 1 eq) was added to a suspension of (R)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid (0.80 g, 2.9 mmol, 1 eq) (V, wherein R═H) in dry benzene (20 mL), and the mixture was stirred, and heated to 80° C. Next, a solution of HMDS (0.70 g, 0.91 mL, 4.35 mmol, 1.5 eq) in dry benzene (8 mL) was added dropwise, during 30 minutes. The reaction was stirred at reflux for 24 hours, and next was 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 Na.sub.2SO.sub.4, and evaporated to dryness. The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 80% (0.60 g); mp 98.3-98.8° C.; Chiral HPLC>99% ee (t.sub.R=50.631 min); TLC: R.sub.f=0.34 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.14N.sub.2O.sub.3 (258.28), monoisotopic mass: 258.10. UPLC (purity 100%): t.sub.R=4.41 min. (M+H).sup.+ 259.2.

Intermediate VI (Wherein R═H) (S)-N-benzyl-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide

[0098] The compound was obtained analogously to the compound (R)-VI (wherein R═H) using (S)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid (0.80 g, 2.9 mmol, 1 eq) (V, wherein R═H), ZnCl.sub.2 (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 DCM:MeOH (9:0.5; v/v) solvent system. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 83% (0.62 g); mp 97.9-98.6° C.; Chiral HPLC >99% ee (t.sub.R=52.970 min); TLC: R.sub.f=0.34 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.14N.sub.2O.sub.3 (258.28), monoisotopic mass: 258.10. UPLC (purity 100%): t.sub.R=4.40 min. (M+H).sup.+ 259.2.

Intermediate VI (Wherein R═H) (R,S)-N-benzyl-2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)propanamide

[0099] The compound was obtained analogously to the compound (R)-VI (wherein R═H) using (R,S)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid (0.80 g, 2.9 mmol, 1 eq) (V, wherein R═H), ZnCl.sub.2 (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 DCM:MeOH (9:0.5; v/v) solvent system. After washing with Et.sub.2O, the compound was obtained as a white solid. Yield: 74% (0.55 g); mp 85.5-86.7° C.; TLC: R.sub.f=0.34 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.14N.sub.2O.sub.3 (258.28), monoisotopic mass: 258.10. UPLC (purity 100%): t.sub.R=4.39 min. (M+H).sup.+ 259.2.

Intermediate VI (Wherein R═F) (R)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-fluorobenzyl)propanamide

[0100] The compound was obtained analogously to the compound (R)-VI (wherein R═H) using (R)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid (0.85 g, 2.9 mmol, 1 eq) (V, wherein R═F), ZnCl.sub.2 (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 DCM:MeOH (9:0.5; v/v) solvent system. The compound was obtained as a whitewhite oil. Yield: 82% (0.65 g); Chiral HPLC>99% ee (t.sub.R=35.607 min); TLC: R.sub.f=0.75 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.13FN.sub.2O.sub.3 (276.27), monoisotopic mass: 276.09. UPLC (purity 99.6%): t.sub.R=4.55 min. (M+H).sup.+ 277.2.

Intermediate VI (Wherein R═F) (S)-2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)-N-(2-fluorobenzyl)propanamide

[0101] The compound was obtained analogously to the compound (R)-VI (wherein R═H) using (S)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid (0.85 g, 2.9 mmol, 1 eq) (V, wherein R═F), ZnCl.sub.2 (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 DCM:MeOH (9:0.5; v/v) solvent system. The compound was obtained as a whitewhite oil. Yield: 84% (0.67 g); Chiral HPLC>99% ee (t.sub.R=38.845 min); TLC: R.sub.f=0.75 (DCM:MeOH (9: 0.5; v/v)); C.sub.14H.sub.13FN.sub.2O.sub.3 (276.27), monoisotopic mass: 276.09. UPLC (purity 99.5%): t.sub.R=4.55 min. (M+H).sup.+ 277.1.

Intermediate VI (Wherein R═F) (R,S)-2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)-N-(2-fluorobenzyl)propanamide

[0102] The compound was obtained analogously to the compound (R)-VI (wherein R═H) using (R,S)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobut-2-ene acid (0.85 g, 2.9 mmol, 1 eq) (V, wherein R═F), ZnCl.sub.2 (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 DCM:MeOH (9:0.5; v/v) solvent system. The compound was obtained as a whitewhite oil. Yield: 77% (0.61 g); TLC: R.sub.f=0.75 (DCM:MeOH (9:0.5; v/v)); C.sub.14H.sub.13FN.sub.2O.sub.3 (276.27), monoisotopic mass: 276.09. UPLC (purity 99.8%): t.sub.R=4.56 min. (M+H).sup.+ 277.2.

Synthesis, Physicochemical and Spectral Data of the Final Compounds (2R)-5, (2S)-5, (2R,S)-5 i (2R)-6, (2S)-6, (2R,S)-6

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide hydrochloride

[0103] 2 M solution of dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF was added to a solution of (R)-N-benzyl-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide (0.60 g, 2.3 mmol, 1 eq, VI wherein R═H) in dry benzene (30 mL). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. Next, the compound was converted into its hydrochloride salt, by treating the compound with 2M methanolic hydrochloric acid. The product was obtained as a whitewhite solid. Yield: 88% (0.62 g); mp 115.8-116.9° C.; TLC: R.sub.f=0.36 (DCM:MeOH (9:0.5; v/v)); C.sub.16H.sub.22ClN.sub.3O.sub.3 (339.82), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.79 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.52 (d, J=7.2 Hz, 3H), 2.78 (s, 6H), 2.85 (br. s, 3H), 4.34 (d, J=6.0 Hz, 2H), 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide hydrochloride

[0104] The compound was obtained analogously to the compound (2R)-5.2 M solution of dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF was added to a solution of (S)-N-benzyl-2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)propanamide (0.60 g, 2.3 mmol, 1 eq, VI wherein R═H) in dry benzene (30 mL). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. Next, the compound was converted into its hydrochloride salt, by treating the compound with 2M methanolic hydrochloric acid. The product was obtained as a whitewhite solid. Yield: 83% (0.58 g); mp 115.4-116.7° C.; TLC: R.sub.f=0.37 (DCM:MeOH (9:0.5; v/v)); C.sub.16H.sub.22ClN.sub.3O.sub.3 (339.82), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.78 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.53 (d, J=7.2 Hz, 3H), 2.79 (s, 6H), 2.84 (br. s, 3H), 4.35 (d, J=6.0 Hz, 2H), 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide hydrochloride

[0105] The compound was obtained analogously to the compound (2R)-5.2 M solution of dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF was added to a solution of (R,S)-N-benzyl-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamide (0.60 g, 2.3 mmol, 1 eq, VI wherein R═H) in dry benzene (30 mL). The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. Next, the compound was converted into its hydrochloride salt, by treating the compound with 2M methanolic hydrochloric acid. The product was obtained as a whitewhite solid. Yield: 86% (0.60 g); mp 97.2-98.5° C.; TLC: R.sub.f=0.38 (DCM:MeOH (9:0.5; v/v)); C.sub.16H.sub.22ClN.sub.3O.sub.3 (339.82), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.79 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.54 (d, J=7.2 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide hydrochloride

[0106] The compound was obtained analogously to the compound (2R)-5, but using (R)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-fluorobenzyl)propanamide (0.64 g, 2. mmol, 1 eq, VI, wherein R═F), and 2 M solution of dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF. The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. Next, the compound was converted into its hydrochloride salt, by treating the compound with 2M methanolic hydrochloric acid. The product was obtained as a whitewhite solid. Yield: 85% (0.63 g); mp 118.4-119.6° C.; TLC: R.sub.f=0.45 (DCM:MeOH (9:0.5; v/v)); C.sub.16H.sub.21ClFN.sub.3O.sub.3 (357.81), monoisotope mass: 321.15. UPLC (purity: 99.9%): t.sub.R=2.91 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.52 (dd, J=11.5, 7.5 Hz, 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, 2.2 Hz, 1H), 7.26-7.33 (m, 1H), 7.61 (br. s, 1H), 7.8 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 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, 129.1, 129.2, 129.8, 130.0, 159.8, 161.7, 167.9, 168.0, 171.4.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide hydrochloride

[0107] The compound was obtained analogously to the compound (2R)-5, but using (S)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-fluorobenzyl)propanamide (0.64 g, 2. mmol, 1 eq, VI, wherein R═F), and 2 M solution of dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF. The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. Next, the compound was converted into its hydrochloride salt, by treating the compound with 2M methanolic hydrochloric acid. The product was obtained as a whitewhite solid. Yield: 89% (0.65 g); mp 118.5-119.8° C.; TLC: R.sub.f=0.46 (DCM:MeOH (9:0.5; v/v)); C.sub.16H.sub.21CIFN.sub.3O.sub.3 (357.81), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.92 min, (M+H)+322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.53 (dd, J=11.5, 7.3 Hz, 3H), 2.93 (s, 6H), 3.07-3.35 (m, 3H), 4.38-4.43 (m, 2H), 4.77 (dd, J=15.2, 7.5 Hz, 1H), 6.97 (t, J=8.8 Hz, 1H), 7.03-7.11 (m, 1H), 7.19 (dd, J=4.8, 2.3 Hz, 1H), 7.27-7.33 (m, 1H), 7.57 (br. s, 1H), 7.78 (br. s 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 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, 129.1, 129.2, 129.8, 130.0, 159.8, 161.7, 167.9, 168.0, 171.4.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide hydrochloride

[0108] The compound was obtained analogously to the compound (2R)-5, but using (R,S)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-fluorobenzyl)propanamide (0.64 g, 2. mmol, 1 eq, VI, wherein R═F), and 2 M solution of dimethylamine (0.105 g, 2.3 mmol, 1 eq) in THF. The crude product was purified by column chromatography using DCM:MeOH (9:0.5; v/v) solvent system. Next, the compound was converted into its hydrochloride salt, by treating the compound with 2M methanolic hydrochloric acid. The product was obtained as a whitewhite solid. Yield: 75% (0.54 g); mp 104.2-105.7° C.; TLC: R.sub.f=0.47 (DCM:MeOH (9:0.5; v/v)); C.sub.16H.sub.21CIFN.sub.3O.sub.3 (357.81), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.90 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.53 (dd, J=11.0, 7.5 Hz, 3H), 2.93 (s, 6H), 2.99 (br.s, 3H), 4.38-4.43 (m, 2H), 4.78 (dd, J=15.5, 7.5 Hz, 1H), 6.97 (t, J=8.9 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 7.18-7.21 (m, 1H), 7.27-7.33 (m, 1H), 7.57 (br.s, 1H), 7.76 (br. s 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Preparation and Physicochemical Data of Other Salts, i.e. Sulfate, Methanesulfonate, Toluenesulfonate, Succinate, Fumarate or Lactate, of Compounds (2R)-5, (2S)-5, (2R,S)-5, (2R)-6, (2S)-6 or (2R,S) According to the Invention

[0109] All salts were prepared following routine synthetic procedure. The procedure consisted of dissolving of 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 addition of a suitable acid, i.e. 1 eq of methanesulfonic, toluenesulfonic or lactic acid, or 0.5 eq of concentrated sulfuric, succinic or fumaric acid. The mixture was stirred for 15 minutes at room temperature, and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether, to give the appropriate salt as a white powder.

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide methanesulfonate

[0110] White solid; mp 116.4-117.2° C.; C.sub.17H.sub.25N.sub.3O.sub.6S (399.46), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.83 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.57 (dd, J=7.3, 4.2 Hz, 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, 7.5 Hz, 2H), 7.20-7.24 (m, 3H), 7.25-7.33 (m, 3H), 7.44 (br.s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 14.2, 31.2, 32.1, 32.2, 41.7, 42.1, 43.6, 44.5, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide methanesulfonate

[0111] White solid; mp 116.1-116.9° C.; C.sub.17H.sub.25N.sub.3O.sub.6S (399.46), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.80 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.58 (dd, J=7.3, 4.2 Hz, 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, 7.5 Hz, 2H), 7.20-7.25 (m, 3H), 7.26-7.32 (m, 3H), 7.44 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 14.2, 31.2, 32.1, 32.2, 41.7, 42.1, 43.6, 44.5, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide methanesulfonate

[0112] White solid; mp 102.2-102.8° C.; C.sub.17H.sub.25N.sub.3O.sub.6S (399.46), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.82 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.56 (dd, J=7.3, 4.2 Hz, 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, 7.5 Hz, 2H), 7.21-7.25 (m, 3H), 7.26-7.34 (m, 3H), 7.45 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl3) δ 14.1, 14.2, 31.2, 32.1, 32.2, 41.7, 42.1, 43.6, 44.5, 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.

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide toluenesulfonate

[0113] White solid; mp 116.8-117.4° C.; C.sub.23H.sub.29N.sub.3O.sub.6S (475.56), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.82 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.47-1.50 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide toluenesulfonate

[0114] White solid; mp 116.2-117.1° C.; C.sub.23H.sub.29N.sub.3O.sub.6S (475.56), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.82 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.48-1.51 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide toluenesulfonate

[0115] White solid; mp 101.2-101.9° C.; C.sub.23H.sub.29N.sub.3O.sub.6S (475.56), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.81 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.48-1.51 (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). .sup.13C NMR (126 MHz, CDCI.sub.3) δ 14.2, 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.

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide lactate

[0116] White solid; mp 116.2-116.9° C.; C.sub.13H.sub.27N.sub.3O.sub.6 (393.44), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.76 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.40-1.43 (m, 6H), 2.55 (d, J=9.2 Hz, 6H), 2.84 (dd, J=17.3, 5.3 Hz, 1H), 2.90-3.00 (m, 1H), 3.95 (ddd, J=11.7, 8.9, 5.4, Hz, 1H), 4.26 (q, J=7.0 Hz, 2H), 4.40-4.52 (m, 2H), 4.83 (dd, J=11.2, 7.5 Hz, 1H), 5.32 (br. s, 2H), 6.44 (br. s, 1H), 7.26-7.32 (m, 3H), 7.33-7.35 (m, 2H). .sup.13C NMR (126 MHz, CDCI.sub.3) δ 14.1, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide lactate

[0117] White solid; mp 115.7-116.4° C.; C.sub.13H.sub.27N.sub.3O.sub.6 (393.44), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.76 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.41-1.43 (m, 6H), 2.56 (d, J=9.2 Hz, 6H), 2.84 (dd, J=17.3, 5.3 Hz, 1H), 2.91-3.00 (m, 1H), 3.94 (ddd, J=11.7, 8.9, 5.4 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.39-4.51 (m, 2H), 4.82 (dd, J=11.2, 7.5 Hz, 1H), 5.33 (br. s, 2H), 6.44 (br. s, 1H), 7.26-7.30 (m, 3H), 7.31-7.34 (m, 2H). .sup.13C NMR (126 MHz, CDCI.sub.3) δ 14.1, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide lactate

[0118] White solid; mp 100.2-101.1° C.; C.sub.13H.sub.27N.sub.3O.sub.6 (393.44), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.76 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.42 (s, 6H), 2.56 (d, J=9.2 Hz, 6H), 2.85 (dd, J=17.3,5.3 Hz, 1H), 2.91-3.00 (m, 1H), 3.96 (ddd, J=11.7, 8.9, 5.4 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.40-4.53 (m, 2H), 4.82 (dd, J=11.2, 7.5 Hz, 1H), 5.31 (br. s, 2H), 6.44 (br. s, 1H), 7.26-7.31 (m, 3H), 7.33-7.36 (m, 2H). .sup.13C NMR (126 MHz, CDCI.sub.3) δ 14.1, 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.

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide sulfate

[0119] White solid; mp 117.1-117.9° C.; C.sub.32H.sub.44N.sub.6O.sub.13S (704.80), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.76 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, DMSO-d6) δ 1.49 (dd, J=10.0, 7.2 Hz, 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, 6.0 Hz, 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). .sup.13C NMR (126 MHz, CDCI.sub.3) δ 14.1, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide sulfate

[0120] White solid; 116.8-117.5° C.; C.sub.32H.sub.44N.sub.6O.sub.10S (704.80), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.76 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, DMSO-d6) δ 1.48 (dd, J=10.0, 7.2 Hz, 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, 6.0 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide sulfate

[0121] White solid; mp 102.7-103.5° C.; C.sub.32H.sub.44N.sub.6O.sub.10S (704.80), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.76 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, DMSO-d6) δ 1.49 (dd, J=10.0, 7.2 Hz, 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, 6.0 Hz, 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) .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide succinate

[0122] White solid; mp 116.8-117.5° C.; C.sub.36H.sub.48N.sub.6O.sub.10 (724.81), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.82 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCI.sub.3) δ 1.48-1.50 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide succinate

[0123] White solid; mp 115.9-116.6° C.; C.sub.36H.sub.48N.sub.6O.sub.10 (724.81), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.82 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.47-1.50 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide succinate

[0124] White solid; mp 101.8-102.5° C.; C.sub.36H.sub.48N.sub.6O.sub.10 (724.81), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.82 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.47-1.51 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2R)-5: (2R)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide fumarate

[0125] White solid; mp 116.4-117.1° C.; C.sub.36H.sub.46N.sub.6O.sub.10 (722.80), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.81 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.48-1.51 (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). .sup.13C NMR (126 MHz, CDCI.sub.3) δ 14.1, 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.

Compound (2S)-5: (2S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide fumarate

[0126] White solid; mp 115.9-116.6° C.; C.sub.36H.sub.46N.sub.6O.sub.10 (722.80), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.81 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.47-1.50 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R,S)-5: (2R,S)-N-benzyl-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)propanamide fumarate

[0127] White solid; mp 102.1-102.8° C.; C.sub.36H.sub.46N.sub.6O.sub.10 (722.80), monoisotope mass: 303.16. UPLC (purity: >99.9%): t.sub.R=2.81 min, (M+H).sup.+ 304.2. .sup.1H NMR (500 MHz, CDCI.sub.3) δ 1.47-1.51 (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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide methanesulfonate

[0128] White solid: mp 119.1-119.9° C.; C.sub.17H.sub.24FN.sub.3O.sub.6S (417.45), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.87 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.53 (dd, J=11.5, 7.5 Hz, 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, 7.3 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 16.2, 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.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide methanesulfonate

[0129] White solid: mp 118.7-119.4° C.; C.sub.17H.sub.24FN.sub.3O.sub.6S (417.45), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.87 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCI.sub.3) δ 1.52 (dd, J=11.5, 7.5 Hz, 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, 7.3 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 16.1, 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.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide methanesulfonate

[0130] White solid: mp 105.3-106.1° C.; C.sub.17H.sub.24FN.sub.3O.sub.6S (417.45), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.87 min, (M+H)+322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.54 (dd, J=11.5, 7.50 Hz, 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, 7.3 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 16.1, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide toluenesulfonate

[0131] White solid: mp 120.2-120.9° C.; C.sub.23H.sub.28FN.sub.3O.sub.6S (493.55), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sup.R=2.93 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.52 (dd, J=11.5, 7.5 Hz, 3H), 2.34 (s, 3H), 2.94 (s, 6H), 3.08-3.36 (m, 2H), 4.38-4.44 (m, 2H), 4.76 (dd, J=15.0, 7.3 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 15.2, 21.3, 31.0, 32.2, 32.4, 37.5, 50.0, 50.1, 60.9, 61.2, 115.2, 115.3, 115.4, 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.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide toluenesulfonate

[0132] White solid: mp 119.5-120.3° C.; C.sub.23H.sub.28FN.sub.3O.sub.6S (493.55), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.91 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.53 (dd, J=11.5, 7.5 Hz, 3H), 2.33 (s, 3H), 2.94 (s, 6H), 3.08-3.37 (m, 2H), 4.37-4.49 (m, 2H), 4.77 (dd, J=15.0, 7.3 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 15.2, 21.4, 31.0, 32.2, 32.4, 37.5, 50.0, 50.1, 60.8, 61.2, 115.1, 115.3, 115.4, 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.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide toluenesulfonate

[0133] White solid: mp 106.7-107.5° C.; C.sub.23H.sub.28FN.sub.3O.sub.6S (493.55), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.93 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.53 (dd, J=11.5, 7.5 Hz, 3H), 2.33 (s, 3H), 2.94 (s, 6H), 3.08-3.37 (m, 2H), 4.37-4.49 (m, 2H), 4.77 (dd, J=15.0, 7.3 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 15.2, 21.4, 31.0, 32.2, 32.4, 37.5, 50.0, 50.1, 60.8, 61.2, 115.1, 115.3, 115.4, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide lactate

[0134] White solid: mp 118.8-119.4° C.; C.sub.19H.sub.26FN.sub.3O.sub.6 (411.43), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.89 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.42-1.45 (m, 3H), 2.89 (s, 6H), 3.04-3.36 (m, 3H), 4.38-4.44 (m, 2H), 4.82 (dd, J=12.0, 7.5 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide lactate

[0135] White solid: mp 118.1-118.8° C.; C.sub.19H.sub.26FN.sub.3O.sub.6 (411.43), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.90 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.41-1.44 (m, 3H), 2.88 (s, 6H), 3.02-3.37 (m, 3H), 4.38-4.44 (m, 2H), 4.82 (dd, J=12.0, 7.5 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.3, 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.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide lactate

[0136] White solid: mp 104.9-105.6° C.; C.sub.19H.sub.26FN.sub.3O.sub.6 (411.43), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.87 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.41-1.44 (m, 3H), 2.87 (s, 6H), 3.04-3.35 (m, 3H), 4.37-4.48 (m, 2H), 4.83 (dd, J=12.0, 7.5 Hz, 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). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.3, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide sulfate

[0137] White solid: mp 119.4-120.2° C.; C.sub.32H.sub.42F.sub.2N.sub.6O.sub.13S (740.78), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.89 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, DMSO-d6) δ 1.46 (dd, J=12.6, 7.2 Hz, 3H), 2.64 (s, 6H), 2.90-3.00 (m, 2H), 3.06 (td, J=17.8, 5.0 Hz, 1H), 4.27 (t, J=5.2 Hz, 2H), 4.39-4.47 (m, 1H), 4.65 (dd, J=7.3, 2.7 Hz, 1H), 7.09-7.15 (m, 2H), 7.21-7.31 (m, 2H), 8.42-8.47 (m, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 31.0, 32.2, 32.4, 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.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide sulfate

[0138] White solid: mp 119.1-119.8° C.; C.sub.32H.sub.42F.sub.2N.sub.6O.sub.13S (740.78), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.90 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, DMSO-d6) δ 1.48 (dd, J=12.6, 7.2 Hz, 3H), 2.65 (s, 6H), 2.91-3.03 (m, 2H), 3.06-3.13 (m, 1H), 4.26 (t, J=5.2 Hz, 2H), 4.38-4.46 (m, 1H), 4.64 (dd, J=7.3, 2.7 Hz, 1H), 7.08-7.16 (m, 2H), 7.21-7.30 (m, 2H), 8.42-8.45 (m, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 31.0, 32.2, 32.4, 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.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide sulfate

[0139] White solid: mp 104.9-105.8° C.; C.sub.32H.sub.42F.sub.2N.sub.6O.sub.13S (740.78), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.91 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, DMSO-d6) δ 1.45 (dd, J=12.6, 7.2 Hz, 3H), 2.64 (s, 6H), 2.90-3.00 (m, 2H), 3.06 (td, J=17.8, 5.0 Hz, 1H), 4.27 (t, J=5.2 Hz, 2H), 4.38-4.47 (m, 1H), 4.67 (dd, J=7.3, 2.7 Hz, 1H), 7.10-7.16 (m, 2H), 7.22-7.32 (m, 2H), 8.40-8.46 (m, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 31.0, 32.2, 32.4, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide succinate

[0140] White solid: mp 119.6-120.4° C.; C.sub.36H.sub.46F.sub.2N.sub.6O.sub.13 (760.79), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sup.R=2.93 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.45-1.51 (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, 7.3 Hz, 1H), 6.82-7.12 (m, 2H), 7.18-7.35 (m, 1H), 7.43-7.59 (m, 1H), 8.08 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.2, 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.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide succinate

[0141] White solid: mp 118.8-119.4° C.; C.sub.36H.sub.46F.sub.2N.sub.6O.sub.10 (760.79), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.92 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.44-1.50 (m, 3H), 2.32-2.45 (m, 2H), 2.51-2.74 (m, 2H), 2.97 (s, 6H), 3.02-3.35 (m, 3H), 4.31-4.42 (m, 2H), 4.81 (dd, J=11.0, 7.3 Hz, 1H), 6.85-7.36 (m, 3H), 7.41-7.59 (m, 1H), 8.09 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide succinate

[0142] White solid: mp 106.1-106.7° C.; C.sub.36H.sub.46F.sub.2N.sub.6O.sub.13 (760.79), monoisotope mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.93 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.44-1.50 (m, 3H), 2.32-2.49 (m, 2H), 2.52-2.73 (m, 2H), 2.96 (s, 6H), 3.02-3.34 (m, 3H), 4.31-4.41 (m, 2H), 4.82 (dd, J=11.0, 7.3 Hz, 1H), 6.85-7.37 (m, 3H), 7.41-7.58 (m, 1H), 8.07 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 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.

Compound (2R)-6: (2R)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide fumarate

[0143] White solid: mp 118.3-119.1° C.; C.sub.36H.sub.44F.sub.2N.sub.6O.sub.10 (758.78), Monoisotopic mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.91 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.42-1.49 (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, 7.5 Hz, 1H), 6.97 (t, J=9, 5 Hz, 1H), 7.02-7.35 (m, 3H), 7.44-7.59 (m, 1H), 7.95 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 14.2, 31.0, 32.2, 32.4, 37.5, 50.0, 50.1, 60.9, 61.2, 115.2, 115.3, 115.4, 124.3, 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.

Compound (2S)-6: (2S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide fumarate

[0144] White solid: mp 118.1-118.8° C.; C.sub.36H.sub.44F.sub.2N.sub.6O.sub.10 (758.78), monoisotopic mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.92 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.41-1.47 (m, 3H), 2.96 (s, 6H), 3.07-3.29 (m, 2H), 3.41-3.53 (m, 2H), 4.51-4.64 (m, 2H), 4.77 (dd, J=14.5, 7.5 Hz, 1H), 6.91-6.98 (m, 1H), 7.05-7.39 (m, 3H), 7.46-7.63 (m, 1H), 7.99 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 14.2, 31.1, 32.2, 32.4, 37.5, 50.0, 50.1, 60.9, 61.2, 115.2, 115.3, 115.4, 124.2, 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.

Compound (2R,S)-6: (2R,S)-2-(3-(dimethylamino)-2,5-dioxopyrrolidin-1-yl)-N-(2-fluorobenzyl)propanamide fumarate

[0145] White solid: mp 104.7-105.4° C.; C.sub.36H.sub.44F.sub.2N.sub.6O.sub.10 (758.78), monoisotopic mass: 321.15. UPLC (purity: >99.9%): t.sub.R=2.90 min, (M+H).sup.+ 322.2. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.43-1.49 (m, 3H), 2.98 (s, 6H), 3.05-3.27 (m, 2H), 3.47-3.59 (m, 2H), 4.52-4.68 (m, 2H), 4.78 (dd, J=14.5, 7.5 Hz, 1H), 6.91-6.97 (m, 1H), 6.99-7.33 (m, 3H), 7.41-7.58 (m, 1H), 8.02 (br. s, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 14.1, 14.2, 31.1, 32.2, 32.4, 37.5, 50.0, 50.1, 60.9, 61.3, 115.2, 115.3, 115.5, 124.2, 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.

EXAMPLE 2

Biological Activity of the Compounds According to the Invention

[0146] Anticonvulsant Activity Studies

[0147] The studies were carried out on male white Swiss mice (CD-1) weighing 18-26 g. All procedures were performed in accordance with the applicable Polish and international guidelines for the ethics of animal research, after obtaining of the appropriate institutional consent. Substances (2R,S)-3, (2R)-3, (2S)-3, (2R,S)-4, (2R)-4, (2S)-4 and monohydrochlorides (2R,S)-5, (2R)-5, (2S)-5, (2R,S)-6, (2R)-6, (2S)-6 were administered intraperitoneally (ip), after dissolution in a mixture of DMSO, PEG-400, water for injection (10/40/50, v/v/v), as a single injections of 10 mL/kg volume, 30 minutes prior to the test. Screening tests were performed in groups consisted of 4 mice. All tests were performed according to the procedures described in the specialist literature: maximal electroshock test (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 (6 Hz, 32 mA) (Barton et al. Epilepsy Res. 2001, 47, 217-227; Wojda et al. Epilepsy Res. 2009, 86, 163-174); subcutaneous pentylenetetrazole test (scPTZ) (Ferreri et al. Pharmacol. Biochem. Behav. 2004, 77, 85-94). Results of the performed tests are presented in Table 3.

TABLE-US-00003 TABLE 3 Results of the screening tests at dose of 100 mg/kg, for compounds covered by formula (I), and their chemical insoluble in water prototypes (2R,S)-1, (2R)-1, (2S)-1, (2R,S)-2, (2R)-2, (2S)-2, which were disclosed in the Polish patent application P.429656. Test* Compound MES 6 Hz (32 mA) scPTZ (2R,S)-3 3/4 4/4 2/4 (2R)-3 4/4 4/4 3/4 (2S)-3 2/4 2/4 2/4 (2R,S)-4 3/4 3/4 2/4 (2R)-4 4/4 4/4 3/4 (2S)-4 2/4 2/4 2/4 (2R,S)-5 × HCl 3/4 4/4 2/4 (2R)-5 × HCl 3/4 4/4 3/4 (2S)-5 × HCl 2/4 3/4 2/4 (2R,S)-6 × HCl 3/4 4/4 2/4 (2R)-6 × HCl 3/4 4/4 3/4 (2S)-6 × HCl 2/4 3/4 2/4 (2R,S)-1.sup.# 3/4 3/4 2/4 (2R)-1.sup.# 3/4 4/4 3/4 (2S)-1.sup.# 1/4 4/4 2/4 (2R,S)-2.sup.# 3/4 3/4 3/4 (2R)-2.sup.# 4/4 4/4 3/4 (2S)-2.sup.# 2/4 2/4 2/4 *Tests carried out at the time point of 0.5 h in mice after intraperitoneal administration. The data indicate the number of mice protected in a given seizure model/number of mice tested; MES—maximal electroshock test; 6 Hz (32 mA)—psychomotor seizure test of convulsions induced by a low frequency current (6 Hz) and intensity of 32 mA; scPTZ test—convulsions induced by subcutaneous administration of pentetrazole. .sup.#Substances disclosed in the Polish patent application P.429656.

[0148] The obtained 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 monohydrochlorides (2R,S)-5, (2R)-5, (2S)-5, (2R,S)-6, (2R)-6, (2S)-6, described by the general formula (I), have broad anticonvulsant activity in various animal models of epileptic seizures, i.e. in the maximal electroshock test (MES), the pentetrazole subcutaneous seizure test (scPTZ), and the 6 Hz (32 mA) model, protecting 25-100% of the animals tested (Table 3). These models are recognized as the most important and widely used pharmacological tests allowing the identification of candidates for new antiepileptic drugs. Substances exhibiting protective activity in the aforementioned seizure models, can therefore be potentially effective in various types of human epilepsy; including tonic-clonic seizures with or without secondary generalization, generalized absence seizures, myoclonic seizures, partial seizures, and drug-resistant epilepsy. An advantageous feature of the compounds of formula (I) is that they are effective in all of the aforementioned seizure tests, i.e. MES, scPTZ and 6 Hz (32 mA). Advantageously, the disclosed broad spectrum of protective activity in the in vivo studies, confirms the possibility of using the compounds of the invention in monotherapy of various forms of epilepsy in humans, instead of polytherapy, which currently is the primary pharmacotherapeutic method used in epilepsy. The screening data shown in Table 3 indicates potent anticonvulsant activity of the R-enantiomers, i.e. compounds (2R)-3, (2R)-4, (2R)-5 i (2R)-6. In majority of cases, these compounds provided 100% protection in all models of epileptic seizures used. Therefore, the R-absolute configuration of the chiral carbon atom in the propanamide moiety seems to be preferential for anticonvulsant activity of compounds tested herein. Another advantage of the compounds of formula (I), especially substances obtained in the form of salts (e.g. monohydrochlorides), i.e. (2R,S)-5, (2R), (2S)-5, (2R,S)-6, (2R)-6, (2S)-6, results from their very good solubility in water. Due to the solubility, the preparations could be administered intravenously, in order to obtain a rapid effect of the treatment. This is crucial in situations requiring immediate intervention to stop seizures, including, e.g status epilpepticus, which is considered as a life-threatening situation. In addition to the improved solubility and the resulting advantages in medical applications, the compounds constituting the subject of this application, and the general structure of which is represented by formula (I), unexpectedly, despite significant chemical modifications relying on the removal of one of the carbonyl groups in the pyrrolidine-2,5-dione ring, or introducing the dimethylamine fragment into the aforementioned core structure, what lead to significant changes in geometry and polarity of the molecules, have almost identical or potent anticonvulsant activity as their chemical prototypes (2R,S)-1, (2R)-1, (2S)-1, (2R,S)-2, (2R)-2, (2S)-2, which were disclosed in the application Polish patent P.429656 (Table 3). Additionally, unexpectedly, new pyrrolidin-2-one derivatives, i.e. (2R,S)-3, (2R)-3, (2S)-3, (2R,S)-4, (2R)-4, and (2S)-4 exhibit protective activity in the MES and scPTZ tests unlike to model AED—levetiracetam with structure based on the same heterocyclic ring, but which remains inactive in the aforementioned models of epileptic seizures. Moreover, the introduction of a sterically big dimethylamine fragment at the 3-position of the pyrrolidine-2,5-dione ring, unexpectedly does not lead to a significant decrease in biological activity, at least in the case of 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 of close analogs of the present compounds, resulted in decrease in anticonvulsant effect, as it was proved in our earlier research (Kamiński, et al. Bioorg. Med. Chem. 2015, 23, 2548-2561).