Deuterated functional derivatives of α-alanine, particularly for treating neurological disorders

Abstract

Disclosed is a group of compounds that are modified alanine derivatives whose structures are designed based on bioisosteric and selective replacement of hydrogen atoms with deuterium, particularly for treating neurological disorders.

Description

[Technical field]

[0001] The present invention relates to compounds that, from a structural point of view, are modified (functionalized) derivatives of alanine, whose structure is designed on the basis of the bioisosteric and selective replacement of the hydrogen atom by its stable isotope, deuterium. These compounds are intended in particular for the treatment of neurological diseases, in particular epilepsy and neuropathic pain, and are characterized by clearly more favorable pharmacokinetic properties in mice compared to the parent molecule substituted with a hydrogen atom, i.e. a significantly longer biological half-life (t ) in plasma and brain. 0.5 ), are eliminated from the body more slowly, and have a distinctly more favorable absorption profile (bioavailability) from the site of administration (peritoneum or gastrointestinal tract). Thus, the selected deuterated derivatives that are the object of the present invention can be used as active ingredients of pharmaceutical preparations, in particular for the treatment of neurological disorders. The more favorable pharmacokinetic profile of the disclosed deuterated compounds compared to analogs containing hydrogen in their structure makes these compounds potentially more promising candidates for preclinical and clinical development. [Background technology]

[0002] Previous studies carried out with a series of functionalized amino acid derivatives revealed particularly favorable pharmacological properties and above-average safety margins for compounds with the R configuration of the stereocenter, in which the central fragment of the molecule is formed by D(R)-alanine, whose amino groups are incorporated into a pyrrolidine-2,5-dione ring and the carboxyl moiety is converted into a benzylamide moiety (preferably with an unsubstituted aromatic ring or a fluorine atom in position 2). These compounds are disclosed in patent application No. 429656, PCT / PL2020 / 050028 and patent No. PL240297, and their structures are shown in FIG. 1.

[0003] The presented compounds show a broad spectrum of anticonvulsant activity in animal models of seizures, which was confirmed in tests in mice and rats. Compound 1 is also shown to be effective in mouse models of neuropathic pain and depression and anxiety, as well as to have neuroprotective and neurotrophic effects in vitro. The unique features of compounds 1 and 2 are their minimal effect on mouse motor coordination in the rotarod test, their lack of sedative effect in locomotor activity tests on mice, their lack of interaction with CYP3A4 and CYP2D9 isoforms of cytochrome P-450, and their very high metabolic stability in human microsomes. Considering the above facts, the disclosed substances, especially compound 1, are promising candidates for drugs used in the treatment of various types of epilepsy (including drug-resistant epilepsy), affective diseases / disorders, i.e. epilepsy accompanied by depression and anxiety, neuropathic pain, neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.).

[0004] Despite the highly promising pharmacological properties, the applicability of the substances is hampered by their relatively short biological half-lives (t ) after intraperitoneal (ip) administration in mice, which for compound 1 are approximately 47 min (20 mg / kg dose) and 56 min (40 mg / kg dose) in serum and 57 min (20 mg / kg dose) and 75 min (40 mg / kg dose) in brain. 0.5 ) is slightly decreased by 100 mg / kg. For compound 2, these values ​​were 34 min (20 mg / kg dose) and 33 min (40 mg / kg dose) in serum and 34 min (20 mg / kg dose) and 38 min (40 mg / kg dose) in brain (see Tables 1-4). These results may force a person to administer the substance several times a day. As a result, the above administration regimen, i.e., multiple applications of the drug during the day, may contribute to non-compliance or reduced compliance of patients to the planned drug therapy, leading to reduced treatment efficacy. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above facts, the technical problem solved by the present invention is to provide a compound having more favorable pharmacokinetic parameters, in particular a longer plasma and brain biological half-life (t 0.5 The object of the present invention is to provide analogues of compounds 1 and 2, in particular compound 1, as disclosed in patent application No. 429656, PCT / PL2020 / 050028 and patent PL240297, which are characterized by the above-mentioned formula (I) and still have potent and broad anticonvulsant activity similar to that of the parent molecules 1 and 2 in tests performed in vivo (in mice). [Means for solving the problem]

[0006] The object of the present invention is to provide a deuterated derivative of N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide according to the general formula (I):

[0007] [ka] (In the formula, A is hydrogen or deuterium, and at least one A is deuterium; B is hydrogen or deuterium; X is hydrogen, deuterium or fluorine; Y is hydrogen or deuterium. It is.

[0008] Preferably, X is hydrogen or fluorine, particularly preferably fluorine.

[0009] Preferably, each A is deuterium.

[0010] Particularly preferably, when each A is deuterium, each B and X is also deuterium.

[0011] Preferably, each Y is deuterium.

[0012] In a preferred embodiment, the object of the present invention is to (R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide (compound d4-(R)-1, A=D, B=H, X=H, Y=H), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide (compound d9-(R)-2, A=D, B=D, X=D, Y=H), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(2-fluorobenzyl)propanamide (compound d4-(R)-4, A=D, B=H, X=F, Y=H), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide (compound d6-(R)-5, A=D, B=H, X=H, Y=D), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide (compound d 11 -(R)-6:A=D, B=D, X=D, Y=D), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide (compound d6-(R)-7, A=D, B=H, X=F, Y=D), (S)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide (compound d4-(S)-1, A=D, B=H, X=H, Y=H), (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide (compound d9-(S)-2, A=D, B=D, X=D, Y=H), (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(2-fluorobenzyl)propanamide (compound d4-(S)-4, A=D, B=H, X=F, Y=H), (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide (compound d6-(S)-5, A=D, B=H, X=H, Y=D), (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide (compound d 11 -(S)-6, A=D, B=D, X=D, Y=D), (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide (compound d6-(S)-7, A=D, B=H, X=F, Y=D), (R,S)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide (compound d4-(R,S)-1, A=D, B=H, X=H, Y=H), (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide (compound d9-(R,S)-2, A=D, B=D, X=D, Y=H), (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(2-fluorobenzyl)propanamide (compound d4-(R,S)-4, A=D, B=H, X=F, Y=H), (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide (compound d6-(R,S)-5, A=D, B=H, X=H, Y=D), (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide (compound d 11 -(R,S)-6, A=D, B=D, X=D, Y=D), (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide (compound d6-(R,S)-7, A=D, B=H, X=F, Y=D) The deuterated N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide derivative is selected from the group consisting of

[0013] These compounds are shown in the following scheme:

[0014] [ka]

[0015] Particularly preferably, the compounds according to the invention are N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide derivatives having the R configuration of the stereocenter at C-2 in the general formula (I) and in particular also containing deuterium in position A: (R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide (compound d4-(R)-1, A=D, B=H, X=H, Y=H), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide (compound d9-(R)-2, A=D, B=D, X=D, Y=H), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(2-fluorobenzyl)propanamide (compound d4-(R)-4, A=D, B=H, X=F, Y=H), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide (compound d6-(R)-5, A=D, B=H, X=H, Y=D), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide (compound d 11 -(R)-6:A=D, B=D, X=D, Y=D), (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide (compound d6-(R)-7, A=D, B=H, X=F, Y=D) is selected from the group consisting of:

[0016] Pharmacokinetic studies carried out in mice after intraperitoneal (ip) administration showed that the compounds according to the invention d4-(R)-1, containing 4 deuterium atoms in the imide ring (A=D), d9-(R)-2, containing 9 deuterium atoms including 4 in the imide ring and 5 in the aromatic ring (A=D, B=D, X=D), d6-(R)-5, having 6 deuterium atoms in the succinimide and methylene bridges (A=D, Y=D), and d6-(R)-6, having 11 deuterium atoms (A=D, B=D, X=D, Y=D), were synthesized according to the invention. 11 -(R)-6 exhibits significantly longer (approximately 1.5- to 3-fold) biological half-lives (t 0.5 ) (Tables 1-4), both doses, i.e., 20 and 40 mg / kg, were characterized by a much slower elimination from both the serum and brain of the test animals. In all cases, t 0.5 The values ​​were above the minimum desired value of 80 min. By incorporating various numbers of deuterium atoms into the structure, t 0.5 Similar highly beneficial effects in prolonging t were observed for compounds d4-(R)-4 and d6-(R)-7, which are bioisosteres of the parent compound 2. In particular, in terms of activity in the central nervous system, t 0.5 The effect of prolonging the t (approximately four-fold) was particularly striking in the brains of the test animals. A similar degree of t was observed in the negative examples, d5-(R)-3, which contains five deuterium atoms in the aromatic ring, and d3-(R)-8, which contains three deuterium atoms in the lateral methyl groups, although not trivially. 0.5 No extension of the time was observed. The structures of compounds d5-(R)-3 and d3-(R)-8 are shown in Figure 2.

[0017] The results obtained show, in particular, that selective deuteration of the pyrrolidine-2,5-dione ring, i.e., the incorporation of four deuterium atoms instead of four hydrogen atoms [position A of general formula (I)] significantly reduces the biological half-life (t 0.5) extension. Similarly, a favorable but slightly weaker effect was observed in the case of the incorporation of deuterium into the methylene bridge [Y position of general formula (I)]. Considering the fact that both the parent compound 1 (FIG. 1) and the deuterated analogue d4-(R)-1 described by formula (I) according to the invention are also characterized by an excellent metabolic stability in mouse microsomes in vitro, and the results obtained show that these substances are not metabolized to the imide fragment (see FIG. 19), it is possible to conclude that selective deuterium substitution in the pyrrolidine-2,5-dione ring allows the t 0.5 The effect of this on the elongation of t is even more non-obvious. This is caused by the selective incorporation of deuterium into the pyrrolidine-2,5-dione ring. 0.5 It may be suggested that the extension of the keto-enol tautomerization time may possibly result in a reduction in phase II metabolic conversion, i.e., coupling reactions (e.g., with glucuronic acid, glycine, etc.), inhibition of extrahepatic metabolism, or a reduction in the excretion of unchanged drug from the body. The reduction in said phase II metabolic conversion may hypothetically be the result of inhibiting the keto-enol tautomerization characteristic of imide derivatives by eliminating a "mobile" hydrogen atom, which prevents the in vivo formation of the enol form susceptible to coupling reactions (Valadbeigi, Y.; Farrokhpour, H. Struct. Chem. 2015, 26, 539-545). It is noteworthy that blocking the keto-enol tautomerization by the use of hydrogen / deuterium bioisosteric substitution has not been described in the literature so far and does not seem to be possible even when at least one hydrogen atom remains in the ring [i.e., when at least one A=H in general formula (I)].

[0018] Unexpectedly, the deuterated analogs of parent compound 1, i.e., d4-(R)-1 and d9-(R)-2 according to the present invention, showed significantly higher absorption after intraperitoneal administration, as well as a significantly higher AUC inf It is characterized by better penetration into the brain as evidenced by an increase in parameters; namely, a 1.4-3.2-fold increase in plasma and a 1.7-2.6-fold increase in brain. Non-trivially, the derivatives d6-(R)-5 and d 11-(R)-6, AUC inf A significant increase in AUC was observed in the brain at both doses and in plasma at only the 40 mg / kg dose. inf It should be emphasized that a spectacular 4.4-5.3-fold (plasma) and 7.5-7.9-fold (brain) increase in AUC was evident for the deuterated analogues of compound 2, namely d4-(R)-4 and d6-(R)-7. Similar increases in AUC in the plasma and brain of the test animals were not observed for d5-(R)-3, which was significantly higher than the AUC determined at a dose of 40 mg / kg. inf was lower in plasma and only slightly higher in mouse brain compared to parent compound 1. Nearly identical AUC inf The AUC values ​​were obtained (summarized in Tables 1–4). inf value-based data).

[0019] A further object of the invention are compounds according to the invention as defined above for use in medicine, in particular for the treatment or prevention of neurological diseases, epilepsy, neurological pain, migraine, depression, anxiety, neurodegenerative diseases or neuropathic pain. Preferably, the neurodegenerative disease is Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis.

[0020] In order to better explain the nature of the present invention, the description is exemplified by the following drawings. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows the structures of compounds 1 and 2 of the prior art (Patent Application No. 429656, PCT / PL2020 / 050028 and Patent No. PL240297). [Diagram 2] FIG. 1 shows structures of compounds d5-(R)-3 and d3-(R)-8, which are not embodiments of the present invention but are comparative examples that do not demonstrate the technical effects obtained according to the present invention. [Diagram 3]FIG. 1 shows concentrations of parent compound 1 and deuterated derivatives d4-(R)-1, d9-(R)-2, d6-(R)-5 and d11-(R)-6 in mouse serum as a function of time following ip administration at a dose of 20 mg / kg (n=3-4). [Figure 4] Figure 1 shows the concentrations of parent compound 1 and deuterated derivatives d4-(R)-1, d9-(R)-2, d5-(R)-3, d6-(R)-5 and d11-(R)-6 in mouse serum as a function of time after ip administration at a dose of 40 mg / kg (n=3-4). Compound d3-(R)-8, which has an identical profile to 1 and d5-(R)-3, is not shown in the figure. [Diagram 5] FIG. 1 shows concentrations of parent compound 1 and deuterated derivatives d4-(R)-1, d9-(R)-2, d6-(R)-5 and d11-(R)-6 in mouse brain as a function of time following ip administration at a dose of 20 mg / kg (n=3-4). [Figure 6] Figure 1 shows the concentrations of parent compound 1 and deuterated derivatives d4-(R)-1, d9-(R)-2, d5-(R)-3, d6-(R)-5 and d11-(R)-6 in mouse brain as a function of time after ip administration at a dose of 40 mg / kg (n=3-4). Compound d3-(R)-8, which has an identical profile to 1 and d5-(R)-3, is not shown in the figure. [Figure 7] FIG. 1 shows the concentrations of parent compound 2 and deuterated derivatives d4-(R)-4 and d6-(R)-7 in mouse serum as a function of time following ip administration at a dose of 20 mg / kg (n=4). [Figure 8] FIG. 1 shows the concentrations of parent compound 2 and deuterated derivatives d4-(R)-4 and d6-(R)-7 in mouse serum as a function of time following ip administration at a dose of 40 mg / kg (n=4). [Figure 9] FIG. 1 shows concentrations of parent compound 2 and deuterated derivatives d4-(R)-4 and d6-(R)-7 in mouse brain as a function of time following ip administration at a dose of 20 mg / kg (n=4). [Figure 10]FIG. 1 shows concentrations of parent compound 2 and deuterated derivatives d4-(R)-4 and d6-(R)-7 in mouse brain as a function of time following ip administration at a dose of 40 mg / kg (n=4). [Figure 11] FIG. 1 shows the concentrations of parent compound 2 and deuterated derivative d6-(R)-7 in mouse serum as a function of time after intragastric (po) administration at a dose of 40 mg / kg (n=4). [Figure 12] FIG. 1 shows concentrations of parent compound 2 and deuterated derivative d6-(R)-7 in mouse brain as a function of time following intragastric (po) administration at a dose of 40 mg / kg (n=4). [Figure 13] Figure 1 shows the effect of test compound 1 and deuterated derivatives d4-(R)-1, d9-(R)-2 on the latency of the first episode of clonic seizures in the scPTZ test. Results are presented as mean ± SEM (6 mice per group). Statistical analysis: one-way analysis of variance (ANOVA), followed by Dunnett's post-hoc test: *p<0.05, **p<0.01. [Figure 14] Figure 1 shows the antinociceptive activity of compound d4-(R)-1 in phase I and phase II of the formalin test. Results are presented as paw licking time in phase I of the test (0-5 min after formalin injection) and in phase II of the test (15-30 min after formalin injection). Values ​​represent the mean ± SEM for groups of 8-10 animals. Statistically significant differences compared to the control group (Veh) that received vehicle alone (1% aqueous solution of Tween 80). One-way analysis of variance (ANOVA) followed by Dunnett's post-hoc test: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 15]Figure 1 shows the antinociceptive activity of compound d4-(R)-1 in the capsaicin test, where the results are shown as paw licking time in the 5 min period after capsaicin injection. Values ​​represent the mean ± SEM for groups of 8-10 animals; statistically significant difference compared to the control group (Veh) that received vehicle alone (1% aqueous solution of Tween 80) - one-way analysis of variance (ANOVA), followed by Dunnett's post-hoc test: ****p<0.0001. [Figure 16] Figure 1 shows the antinociceptive activity of compound d4-(R)-1 in an oxaliplatin-induced neuropathic pain model. Results represent pain thresholds according to mechanical allodynia in the von Frey test 30 min after compound administration. Values ​​represent the mean ± SEM for groups of 8-10 animals; statistically significant differences compared to the group receiving oxaliplatin alone, one-way repeated measures analysis of variance (ANOVA), followed by Dunnett's post-hoc test: *p<0.05, **p<0.01, ***p<0.001. Statistically significant differences compared to the group of healthy animals: ^p<0.05, ^^p<0.01, ^^^p<0.001 (one-way repeated measures analysis of variance (ANOVA), followed by Dunnett's post-hoc test). [Figure 17] Figure 2 shows the antinociceptive activity of compound d4-(R)-1 in a streptozotocin-induced model of painful diabetic neuropathy. Results represent pain thresholds in response to mechanical allodynia in the von Frey test 30 min after compound administration. The control group (0) received vehicle (1% aqueous solution of Tween 80). Values ​​represent the mean ± SEM for groups of 8-10 animals. Statistically significant differences compared to the group receiving STZ alone: ​​*p<0.05, ***p<0.001, ****p<0.0001 (one-way repeated measures analysis of variance (ANOVA) followed by Bonferroni's post hoc test). Statistically significant differences compared to the control group (one-way ANOVA followed by Dunnett's post hoc test): ^p<0.05, ^^p<0.01. [Figure 18]Figure 1 shows the effect of compound d4-(R)-1 on the locomotor activity of animals. Results show the number of infrared beam breaks during a 30 min measurement. Values ​​represent the mean ± SEM for groups of 8-10 animals. Statistically significant difference compared to the control group (one-way repeated measures analysis of variance (ANOVA) followed by Dunnett's post-hoc test): **p<0.01. Veh-Tween 80 1% in water. [Figure 19A] FIG. 1 shows the UPLC spectrum of parent compound 1 after incubation with MLM for 120 min. [Figure 19B] FIG. 1 shows the UPLC spectrum of deuterated analog d4-(R)-1 after incubation with MLM for 120 min. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present invention has demonstrated a much longer biological half-life (t 0.5 )-disclosed are analogs of lead compounds 1 and 2 (Figure 1) that are characterized by greater than 80 minutes in plasma and brain, better brain penetration (AUC), and similar or more potent anticonvulsant activity. The disclosed compounds were designed using hydrogen / deuterium bioisosteric substitutions, and three or two sites of deuterium incorporation into the parent molecules 1 and 2, respectively, were proposed in the chemical studies carried out. Deuterium incorporation included the following fragments of the structure according to formula (I); (i) pyrrolidine-2,5-dione ring (substitution at A position); (ii) methylene moiety (substitution at Y position); (iii) benzylamine aromatic ring (substitution at B and X positions). In the chemical studies carried out, a deuterated analog of compound 1 was also synthesized, in whose structure three deuterium atoms were incorporated in place of hydrogen atoms of the lateral methyl groups (see compound d3-(R)-8 in Figure 2).

[0023] The compounds of formula (I) have a chiral center, and the scope of the present invention includes, in particular, the enantiomers with the R configuration, which may be recognized as bioisosteres of compounds 1 and 2 disclosed in patent applications P.429656, PCT / PL2020 / 050028, and patent PL240297. These compounds can be obtained by using appropriate isomeric forms of the starting materials (amino acid derivatives) or can be separated after preparation of the final compounds according to known separation methods.

[0024] Chemical Testing: The compounds of formula (I) according to the present invention can be obtained according to a four-step procedure using commercially available reagents as starting materials, namely the tert-butoxycarbonyl (Boc) derivative of alanine with the desired absolute configuration (R, S or R,S), benzylamine (or its deuterated derivatives - d2-benzylamine, d5-benzylamine or d7-benzylamine) or 2-fluorobenzylamine (or its deuterated derivatives - d2-2-fluorobenzylamine) and succinic anhydride (or its deuterated analogue - d4-succinic anhydride). The synthesis procedure and exemplary reaction conditions are shown in Scheme 1. In the first step, the condensation reaction of benzylamine or 2-fluorobenzylamine (or their respective deuterated derivatives) with alanine with the appropriate absolute configuration (R, S or R,S) protected with a tert-butoxycarbonyl group results in an intermediate of formula (IV), which is then deprotected to form a compound of formula (III). In the next step, the compound of formula (III) is used in a condensation reaction with an appropriate succinic anhydride (or d4-succinic anhydride) to give the amide-acid compound of formula (II), which is then cyclized to form the compound of general formula (I).

[0025] The intermediates and final compounds were obtained in good yields (>82%). The pseudomolecular ion masses of the intermediates and final products were determined by LC / MS. The structure of the final compound was: 1 H NMR and 13The purity of the final compound was determined by UPLC and was greater than 99% for the final product. The enantiomeric purity was confirmed by chiral HPLC and was greater than 99% ee.

[0026] Pharmacokinetic studies: As can be seen from the pharmacokinetic data in Tables 1-4, the non-deuterium parent compounds 1 and 2 exhibited non-linear pharmacokinetics over the dose range tested, as evidenced by the disproportionate increase in area under the curve (a two-fold increase in dose was associated with a significant increase in the AUC for compound 1 in serum and brain of animals, respectively). inf and for compound 2, AUC inf In the case of the deuterated derivative d4-(R)-1 according to the invention, increasing the dose resulted in a 4.1-fold and 2.4-fold increase in AUC inf A disproportionate 2.8-fold increase in the ratio was observed, but only in serum, which may indicate saturation of the elimination process of this compound. Other derivatives, which are preferred embodiments of the invention, containing various numbers of deuterium atoms in the structure, are characterized by nonlinear pharmacokinetics in the dose range tested, with a doubling of the dose resulting in a significant increase in the AUC in serum. inf and a 1.7-fold (d4-(R)-4), 2.3-fold (d6-(R)-5), and 1.8-fold (d6-(R)-7) increase in AUC inf 2.5 times (d6-(R)-5) and 5.2 times (d 11 In contrast to the above data, compound d9-(R)-2 according to the present invention showed a linear pharmacokinetic process (area ratio of 1.9 after doubling the dose in both mouse serum and brain). 11 A similar linearity was observed for -(R)-6 (area ratio of 2.0 after doubling the dose). Surprisingly, for the analogs containing a fluorine atom in their structure, i.e. d4-(R)-4 and d6-(R)-7, doubling the dose significantly increased the AUC inf The value increased slightly (1.1 times) or decreased.

[0027] Interestingly, the d5-(R)-3 derivative, which contains five deuterium atoms only in the aromatic ring, and the compound d3-(R)-8, which has a -CD3 group instead of the -CH3 group of the parent compound 1, were characterized by similar concentration-time profiles in the serum and brain of the tested animals, as well as similar values ​​of pharmacokinetic parameters, compared to the parent substance 1 (Tables 2 and 4). For these derivatives, the test was carried out only at a dose of 40 mg / kg. Thus, compounds d5-(R)-3 and d3-(R)-8 can be considered as negative examples, where the incorporation of deuterium atoms did not result in an improvement of the pharmacokinetic profile of compound 1. All derivatives, i.e. d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11 d-(R)-6, and d-(R)-7 showed significantly longer biological half-lives (t 0.5 Compounds d4-(R)-1, d9-(R)-2, d6-(R)-5, and d 11 For -(R)-6, this was compared to 1 and the counterexamples -d5-(R)-3 and d3-(R)-8, which showed a significant reduction in t in plasma and brain. 0.5 The deuterated analogs of starting compound 2, i.e., d4-(R)-4 and d6-(R)-7, showed at least a 2.6-fold increase in plasma and at least a 2.5-fold increase in brain. 0.5 A clearly more pronounced prolongation of AUC in the brain was observed. Interestingly, and non-obviously, in a preferred embodiment, the incorporation of deuterium into molecule 1 significantly increased the AUC inf The parameters were increased, but the C max The deuterated derivatives, which are the object of a particularly preferred embodiment of the present invention, namely d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11-(R)-6, and d6-(R)-7 are also characterized by significantly longer mean residence times (MRTs), i.e., serum (>133 min) and brain (>148 min), compared to the parent molecules 1 and 2, and the counterexamples d5-(R)-3 and d3-(R)-8.

[0028] A similar beneficial isotope effect of deuterium incorporation into the molecule was observed for compound d6-(R)-7 administered intragastrically (po) to mice at a dose of 40 mg / kg. Comparison of the profiles and pharmacokinetic parameters obtained for d6-(R)-7 versus parent compound 2 (see Table 5, Figures 11 and 12) demonstrated a significantly superior availability (AUC inf ), showing slightly higher plasma and brain concentrations and longer mean residence times.

[0029] FIG. 3 shows the concentrations of test compounds 1, d4-(R)-1, d9-(R)-2, d6-(R)-5 and d 11 4 shows the concentration-time profiles of the test compounds, d4-(R)-1, d9-(R)-2, d5-(R)-3, d6-(R)-5 and d-(R)-6 in mouse serum after administration (ip) at a dose of 40 mg / kg. 11 FIG. 5 shows the concentration-time profiles of test compounds 1, d4-(R)-1, d9-(R)-2, d6-(R)-5 and d-(R)-6 in mouse brain after administration (ip) at a dose of 20 mg / kg. 11 FIG. 6 shows the concentration-time profiles of test compounds 1, d4-(R)-1, d9-(R)-2, d5-(R)-3, d6-(R)-5 and d-(R)-6 in mouse brain after administration (ip) at a dose of 40 mg / kg. 11FIG. 7 shows the concentration-time profiles of test compounds 2, d4-(R)-4 and d6-(R)-7 in mouse serum after administration (ip) at a dose of 20 mg / kg; FIG. 8 shows the concentration-time profiles of test compounds 2, d4-(R)-4 and d6-(R)-7 in mouse serum after administration (ip) at a dose of 40 mg / kg; and FIG. 9 shows the concentration-time profiles of test compounds 2, d4-(R)-4 and d6-(R)-7 in mouse brain after administration (ip) at a dose of 20 mg / kg. 10 shows the concentration-time profiles of test compound 2, d4-(R)-4 and d6-(R)-7 in mouse brain after administration (ip) at a dose of 40 mg / kg; FIG. 11 shows the concentration-time profiles of test compound 2 and d6-(R)-7 in mouse plasma after administration (po) at a dose of 40 mg / kg; and FIG. 12 shows the concentration-time profiles of test compound 2 and d6-(R)-7 in mouse brain after administration (po) at a dose of 40 mg / kg.

[0030] From a chemical point of view, it is noteworthy that the same apparently beneficial isotopic effect of incorporating four deuterium atoms into the pyrrolidine-2,5-dione ring was not observed in the case of compound d4-(R)-KA-104, which is a deuterated analogue of compound (R)-6 disclosed in patent application No. 428485 and PCT / PL2020 / 050001. It should be noted that the deuterated imide fragment in d4-(R)-KA-104 is similar to that observed in the compounds disclosed in the present application, which are examples of preferred embodiments of the present invention. Pharmacokinetic studies performed on both of the above substances, i.e., (R)-6 and d4-(R)-KA-104, showed that d4-(R)-KA104, administered intraperitoneally to mice at a dose of 40 mg / kg, exhibited a slightly longer biological half-life (t 0.5 ) and mean residence time (MRT), as well as slightly higher bioavailability (AUC infThe chemical structures of the parent molecule, i.e., (R)-6, the deuterated analog d4-(R)-KA-104, and the pharmacokinetic study data are presented in Table 6.

[0031] [Table 1]

[0032] [Table 2]

[0033] [Table 3]

[0034] [Table 4]

[0035] [Table 5]

[0036] [Table 6]

[0037] The methodology section describes the synthesis procedure and physicochemical data of the newly obtained derivative d4-(R)-KA-104, not previously disclosed. This compound, which is a selectively deuterated analogue of compound (R)-6, disclosed in patent application No. 428485 and PCT / PL2020 / 050001, is also an object of the present invention.

[0038] Anticonvulsant activity: Another object of the present invention is to provide compounds described by formula (I), in particular the preferred embodiments of the present invention d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d7-(R)-8, d9-(R)-9, d10-(R)-11, d11-(R)-12, d12-(R)-13, d13-(R)-14, d14-(R)-15, d15-(R)-16, d16-(R)-17, d17-(R)-18, d18-(R)-19, d19-(R)-20, d19-(R)-21, d19-(R)-22, d19-(R)-23, d19-(R)-24, d19-(R)-25, d19-(R)-30, d19-(R)-41, d19-(R)-52, d19-(R)-60, d19-(R)-70, d19-(R)-81, d19-(R)-91, d19-(R)-102, d19-(R)-113, d19-(R)-121, d19-(R)-134, d19-(R)-141, d19-(R)-152, d19-(R)-161, d19-(R)-172, d19-(R)-181, d19-(R)-193, d19-(R)-194, d19-(R)-195, d19-( 11 -(R)-6, and d6-(R)-7. The deuterated compounds according to the present invention, as well as their hydrogen bioisosteres disclosed in patent application No. 429656, PCT / PL2020 / 050028 and patent PL240297, show anticonvulsant activity in a wide range of animal models and can be used as active ingredients in various drug forms for treating epilepsy. Based on the biological data for the individual stereoisomers of parent compounds 1 and 2 disclosed in patent application No. 429656, PCT / PL2020 / 050028 and patent PL240297, the S-enantiomers and racemic mixtures (R,S) of the deuterium-containing compounds disclosed in this application can be expected to have a broad range of anticonvulsant activity, but weaker than the R-eutomer.

[0039] Compounds d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11-(R)-6, and d6-(R)-7 show a broad spectrum of anticonvulsant activity, i.e., they are effective in the maximal electroshock seizure test (MES), the 6Hz (32mA and 44mA) seizure test, and the subcutaneous (subsutaneous) pentylenetetrazole seizure test (scPTZ, which discloses data for compounds d4-(R)-1 and d9-(R)-2) when administered intraperitoneally to mice (Table 6). Substances with such a pharmacological profile could potentially be effective in a broad range of human seizures, i.e., tonic-clonic seizures with or without secondary generalization, myoclonic seizures, generalized absence seizures, focal onset seizures, and drug-resistant epilepsy. At 0.5 hours after intraperitoneal administration, all deuterium-containing derivatives were effective in the MES, 6Hz (32mA), and 6Hz (44mA) tests / models. Compounds d4-(R)-1 and d9-(R)-2 were also effective in the scPTZ test, with potency comparable to that observed with the parent substance 1. Surprisingly, in a preferred embodiment of the invention, compared to the parent compounds 1 and 2, the deuterated derivatives are characterized by stronger activity in the MES test, which is one of the most important animal models of seizures that are always used to identify new antiepileptic drug candidates (Castel-Branco, MM et al. Methods Find. Exp. Clin. Pharmacol. 2009, 31, 101-106). In addition, the deuterated compounds d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11 d6-(R)-6, and d6-(R)-7 were effective in all seizure assays / models at an additional time point 2 hours after ip administration, whereas the parent molecules 1 (especially) and 2 were less active or inactive in this time interval. This suggests that the incorporation of deuterium, especially in the pyrrolidine-2,5-dione ring (position A, Formula I) but also in the methylene bridge (position Y, Formula I) has a positive effect on the pharmacokinetic profile and biological half-life (t 0.5), thus proving beyond doubt the prolongation of effective anticonvulsant protection of the deuterated compounds compared to the parent substances 1 and 2. PK / PD analysis of the obtained pharmacokinetic profiles in conjunction with data from seizure tests / models shows that the most favorable PK / PD properties are provided, in particular, by compounds d4-(R)-4 and d6-(R)-7, which are deuterated derivatives of compound 2. Of particular note is the fact that all the disclosed compounds, in particular d4-(R)-4 and d6-(R)-7, have a strong protective effect in the 6 Hz (44 mA) test, which is considered one of the most important animal models for identifying potentially effective substances for the treatment of drug-resistant epilepsy (Metcalf, C. et al. Epilepsia 2017, 1073-1084; Barton, M. E. et al. Epilepsy Res. 2001, 47, 217-227). Moreover, the nearly identical physicochemical properties of hydrogen and deuterium, as well as the anticonvulsant activity, suggest that the bioisosteric substitutions applied herein at least maintain the antidepressant, anxiolytic, analgesic, neuroprotective, and neurotrophic activity of the parent molecule 1 disclosed in patent application No. 429656, PCT / PL2020 / 050028, and patent PL240297. Considering the above facts, it is also suggested that the disclosed deuterium-containing derivatives have the same mechanism of action as their chemical precursors 1 and 2, i.e., they are positive and selective allosteric regulators of the EAAT2 glutamate transporter (Abram, M. et al. J. Med. Chem. 2022, 65, 11703-11725).It is noteworthy that according to literature data, compounds that directly or indirectly increase EAAT2 activity by increasing its expression on glial cells are promising candidates for treating neurological (including neurodegenerative) and psychiatric diseases, i.e. amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, neuropathic pain, anxiety, depression, ischemic stroke, epilepsy, etc. (Fontana, ACKJNeurochem. 2015, 134, 982-1007; Pajarillo, E. et al. Neuropharmacology 2019, 161, 107559; Rosenblum, LT; Trotti, D. Adv. Neurobiol. 2017, 16, 117-136; John, CS et al. Neuropsychopharmacology 2015, 40, 1700-1708; Zaitsev, AV et al. CNS Drugs 2020, 34, 1089~1103; Green, JL et al. Biochem. Pharmacol. 2021, 193, 114786; Temmermand, R. et al. Pharmacol. Res. 2022, 185, 106492).

[0040] Equally importantly, d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11 All compounds, d6-(R)-6, d6-(R)-7, and d7-(R)-8, showed significantly greater activity in a given seizure test / model than valproic acid (VPA, Table 6), a model antiepileptic drug with a wide range of therapeutic indications including treatment of generalized seizures (myoclonic, tonic-clonic, atonic, absence), focal onset seizures (simple or complex, secondarily generalized), Lennox-Gastaut syndrome, manic episodes in bipolar disorder, and migraine.

[0041] Figure 13 shows the effect of selected compounds, namely d4-(R)-1 and d9-(R)-2, on the latency of the first episode of clonic seizures in the scPTZ test. Compounds d4-(R)-1 and d9-(R)-2 dose-dependently increased the latency of the first onset of clonic seizures compared to the control group. Statistically significant results were obtained for compound d4-(R)-1 at doses of 40 and 60 mg / kg (prolonged latency: from 740±212.5 seconds to 1399±207.5 seconds, p<0.05 and 1789±11.2 seconds, p<0.01, respectively), and compound d9-(R)-2 at doses of 60 mg / kg (from 740±212.5 seconds to 1632±167.8 seconds, p<0.05). The parent compound 1 statistically significantly increased the latency at doses of 40 and 60 mg / kg (740±212.5 to 1568±150.9 sec, p<0.05 and 1467±210.8 sec, p<0.05, respectively). Unlike compounds d4-(R)-1 and d9-(R)-2, the effect observed with the parent derivative 1 was not dose-dependent.

[0042] [Table 7]

[0043] Antinociceptive activity: Compound d4-(R)-1, which is a particularly preferred embodiment of the present invention, exhibits, in addition to anticonvulsant activity, antinociceptive activity in several pain tests / models, namely, formalin-induced tonic pain test, capsaicin-induced pain test and models of neuropathic pain, namely, oxaliplatin (OXPT)-induced peripheral neuropathy and streptozotocin (STZ)-induced diabetic neuropathy models.

[0044] Evaluation of analgesic activity in the formalin test Pain was induced chemically by intraplantar injection of a 2.5% formalin solution in mice at a constant volume of 20 μL. Mice were placed in separate transparent observation chambers for 30 min. The measured values ​​were the total licking and biting time of the formalin-treated paw. Nociceptive responses were counted in two time intervals: 0-5 min after formalin injection (phase I of the test - acute pain) and 15-30 min after its administration (phase II of the test - inflammatory pain). The observed inhibition of the nociceptive response - a reduction in the time to lick and bite the paw, was interpreted as an analgesic effect of the test compound.

[0045] In the formalin test, intraperitoneally administered d4-(R)-1 showed potent analgesic activity in both phases of the test (Figure 14). The mean nociceptive response in the control group was 66.72 ± 6.56 s and 191.40 ± 20.46 s in the first and second phases of the test, respectively. All tested doses of compound d4-(R)-1 reduced the nociceptive response in the first phase of the formalin test to 46.80% (30 mg / kg dose), 49.85% (60 mg / kg dose), 64.40% (90 mg / kg dose), and 39.68% (120 mg / kg dose) of baseline (i.e., control), with statistically significant effects observed at three doses - 30, 60, and 120 mg / kg. In the second phase of the study, which addressed tonic inflammatory pain, compound d4-(R)-1 reduced the nociceptive response to 46.04% (at a dose of 30 mg / kg), 56.06% (at a dose of 60 mg / kg), 43.36% (at a dose of 90 mg / kg), and 30.24% (at a dose of 120 mg / kg) of baseline (i.e., control). Based on the results obtained, ED 50 The dose was calculated (the dose that reduces the nociceptive response by 50%). ED 50 The values ​​were 97.9 mg / kg (Phase I) and 71.5 mg / kg (Phase II), respectively.

[0046] Evaluation of analgesic activity in capsaicin-induced pain models This test assessed the licking and / or biting time of the hind paw following intraplantar injection of 1.6 μg of capsaicin in a constant volume of 20 μL. Observations were performed for 5 min after capsaicin administration. Inhibition of the nociceptive response - reduction in paw licking and biting time was a measure of the antinociceptive activity of the test compounds.

[0047] The nociceptive response in the control group was 66.50 ± 3.94 seconds. All doses of compound d4-(R)-1 administered intraperitoneally reduced the nociceptive response to 31.77% (30 mg / kg dose), 38.72% (60 mg / kg dose), and 10.90% (90 mg / kg dose) of the initial value (i.e., control), respectively. The ED 50 The value was 17.5 mg / kg (Figure 15).

[0048] Oxaliplatin (OXPT)-induced peripheral neuropathy model - von Frey study A single dose of OXPT resulted in a reduction in the pain threshold in animals in response to mechanical stimulation, as measured by the von Frey method (Frey instrument / fiber, Bioseb, France). Responses were observed before administration and 3 hours (early phase) and 7 days (late phase) after OXPT administration.

[0049] The average force (pain threshold) that elicited a paw withdrawal reaction in healthy mice (i.e., before OXPT administration) was 5.15±0.24 g (first group), 6.16±0.26 g (second group), and 6.37±0.40 g (third group). In the first group, a significant decrease in pain threshold was observed 3 hours after OXPT administration to 3.97±0.23 g (77.1% of baseline). Administration of d4-(R)-1 at a dose of 30 mg / kg increased the pain threshold to 5.73±0.40 g (111.3% of baseline). Seven days after OXPT administration, the pain threshold was 4.46 ± 0.20 g (86.6% of baseline), and d4-(R)-1 at a dose of 30 mg / kg increased the pain threshold to 6.38 ± 0.50 g (123.9% of baseline). In the second group, a significant decrease in the pain threshold to 3.93 ± 0.40 g (63.8% of baseline) was observed 3 hours after OXPT administration. Administration of 60 mg / kg d4-(R)-1 led to an increase in the pain threshold to 5.33 ± 0.427 g (86.5% of baseline). Seven days after OXPT administration, the pain threshold was 3.57 ± 0.31 g (57.9% of baseline), and d4-(R)-1 at a dose of 60 mg / kg increased the pain threshold to 7.34 ± 0.42 g (119.2% of baseline). In the third group, a significant decrease in the pain threshold was observed 3 hours after OXPT administration to 3.30 ± 0.27 g (51.2% of baseline). Administration of d4-(R)-1 at a dose of 90 mg / kg increased the pain threshold to 7.23 ± 0.42 g (113.5% of baseline). Seven days after OXPT administration, the pain threshold was 4.78 ± 0.34 g (75.0% of baseline), and d4-(R)-1 at 90 mg / kg increased the pain threshold to 7.04 ± 0.31 g (110.5 g of baseline) (Figure 16).

[0050] Streptozotocin-induced diabetic neuropathic pain model - von Frey test A single dose of streptozotocin resulted in the development of hyperglycemia (plasma glucose concentrations above 300 mg / dlL) and a decrease in the animals' pain threshold in response to mechanical stimulation (mechanical allodynia, von Frey test). Responses were tested 3 weeks after streptozotocin injection. Compound d4-(R)-1, administered intraperitoneally at doses of 30, 60, and 90 mg / kg, produced a statistically significant and dose-dependent increase in the pain threshold compared to measurements made before administration of the compound. Importantly, d4-(R)-1 completely eliminated the symptoms of developing sensory neuropathy at all doses.

[0051] The average force (pain threshold) that elicited a paw withdrawal response in the group of healthy mice (before STZ administration) was 5.89 ± 0.20 g. In the first group, a slight decrease in pain threshold was observed 3 weeks after STZ administration to 5.22 ± 0.45 g (88.6% of baseline). Administration of d4-(R)-1 at a dose of 30 mg / kg resulted in an increase in pain threshold to 6.86 ± 0.54 g (115.4% of baseline). In the second group, a significant decrease in pain threshold was observed 3 weeks after STZ administration to 4.53 ± 0.45 g (76.9% of baseline). Administration of d4-(R)-1 at a dose of 60 mg / kg resulted in an increase in pain threshold to 8.64 ± 0.72 g (146.6% of baseline). In the third group, a significant decrease in pain threshold was observed to 4.99±0.29 g (84.7% of baseline) 3 weeks after administration of STZ. Administration of d4-(R)-1 at a dose of 90 mg / kg resulted in an increase in pain threshold to 9.40±0.61 g (159.6% of baseline) (FIG. 17).

[0052] Due to the fact that the other derivatives containing deuterium atoms in their structures, like d4-(R)-1, are close analogues (bioisomers) of the compound d4-(R)-1, which showed potent anticonvulsant activity in in vivo studies, these substances are also expected to have potent and broad-spectrum antinociceptive activity resulting from the bioisosteric H / D substitutions, like d4-(R)-1.

[0053] Effects on locomotor activity of animals The effect of d4-(R)-1 on locomotor activity was also tested to evaluate its potential sedative properties. Strong sedative activity is an undesirable property that can lead to erroneous or inconclusive interpretation of antinociceptive test results. For this purpose, the number of ray crossings in the cage was counted in each group of animals during a 30-minute observation. The number of ray crossings for mice treated with vehicle (i.e., 1% aqueous Tween 80) was 1678.0 ± 150.0. This was significantly reduced after administration of the compound at a dose of 30 mg / kg only, to a value corresponding to 46.90% of the initial value. Administration of d4-(R)-1 at doses of 60 mg / kg, 90 mg / kg, and 120 mg / kg resulted in an increase in locomotor activity to 106.30%, 115.73%, and 118.95% of baseline, respectively, although these results were not statistically significant (Figure 18). Thus, the disclosed data demonstrate that d4-(R)-1 has no sedative effect and the results obtained in pain models are reliable and clearly demonstrate the antinociceptive potential of this compound.

[0054] In vitro metabolic stability The metabolic stability of the deuterated compound d4-(R)-1, which is an example of a particularly preferred embodiment of the present invention, and the parent molecule, i.e. 1, was tested in vitro by incubation with mouse liver microsomes (MLM) in the presence of NADPH as a cofactor for 120 minutes. Based on the UPLC chromatograms obtained from the reaction mixtures, no metabolites appeared in both cases, proving the very high metabolic stability of both test substances (Figure 19). Compounds 1 and 2 and their deuterated analogues d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11 -(R)-6, and d6-(R)-7 have similar high metabolic stability after 120 min incubation with human liver microsomes (HLM).

[0055] The excellent metabolic stability of the deuterated compound d4-(R)-1 and the parent molecule 1 in MLMs is consistent with the beneficial isotope effects (i.e., t0.5 The improvement in pharmacokinetic parameters, including prolongation, proves to be completely non-obvious in view of the results obtained from the in vitro metabolic stability studies.

[0056] methodology chemical research Analysis method Proton nuclear magnetic resonance ( 1 H NMR) and carbon nuclear magnetic resonance ( 13 C NMR spectra were recorded at 500 MHz and 126 MHz, respectively, using a JEOL-50 spectrometer (JEOL USA, Inc., Massachusetts, USA). Chemical shifts are given in δ (ppm) values ​​relative to TMS δ = 0 (1H) as internal standard. J values ​​are expressed in Hertz (Hz). Deuterated chloroform (CDCl3) was used as the solvent. The following signal abbreviations were used in the description of the spectra: br s (broad singlet), d (doublet), dd (doublet of doublets), t (triplet), td (triplet of doublets), q (quartet), qd (quartet of doublets), m (multiplet). The UPLC / MS analysis system consisted of a Waters ACQUITY® UPLC® instrument (Waters Corporation, Milford, Massachusetts, USA) coupled to a Waters TQD mass spectrometer operated in electrospray ionization (ESI) mode. Chromatographic separation was performed using an Acquity UPLC BEH C18 column with dimensions 2.1 x 100 mm and particle size 1.7 μm. The column was maintained at 40 °C and the flow rate was 0.3 mL min -1The mixture was eluted with a gradient from 95% to 0% of eluent A over 10 min at a flow rate of 100 rpm. Eluent A: water / formic acid (0.1% v / v); Eluent B: acetonitrile / formic acid 0.1%, v / v). Chromatograms were recorded using a PDA Waters eλ detector. Spectra were analyzed in the range 200-700 nm with a resolution of 1.2 nm and a sampling speed of 20 points / s. Thin-layer chromatography (TLC) was performed on a silica gel 60 F column with a development system with the following composition: DCM:MeOH (9:0.3; v / v), DCM:MeOH (9:0.5; v / v), spot detection-UV light (λ=254 nm). 254 The melting points (mp) were determined using an open capillary on a Buchi 353 apparatus (Buchi Labortechnik, Flawil, Switzerland). Compounds d4-(R)-1, d9-(R)-2, d5-(R)-3, d4-(R)-4, d6-(R)-5, d 11 -(R)-6, d6-(R)-7, d4-(S)-1, d9-(S)-2, d5-(S)-3, d4-(S)-4, d6-(S)-5, d 11 The enantiomeric purity for -(S)-6, d6-(S)-7 was determined by chiral HPLC spectrum analysis using a Shimadzu Prominence i lc 2030c+ instrument (Shimadzu Corporation, Kyoto, Japan) equipped with an Amylose-C chiral column (250 x 4.6 mm). The analysis was carried out 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. Chemical names of compounds representing exemplary embodiments of the present invention were created using the ChemBioDraw Ultra 12.0 program. The presented syntheses of intermediates and final products were not optimized in terms of yields, amounts of reagents used, and final form of the compounds obtained. Methods to obtain parent compounds 1 and 2 are disclosed in patent application No. 429656, PCT / PL2020 / 050028 and patent PL240297. Abbreviations used: AcOEt - Ethyl acetate DCC-N,N'-dicyclohexylcarbodiimide DCM - Dichloromethane Et2O - Diethyl Ether HCl - Hydrochloric Acid HMDS-Hexamethyldisilazane MeOH - Methanol NaCl - Sodium Chloride NH4OH- Ammonium hydroxide Na2SO4 - Sodium sulfate TFA - Trifluoroacetic acid ZnCl2 - Zinc chloride

[0057] Examples of synthesis and physicochemical and spectral data of intermediate products (II, III and IV according to Scheme 1):

[0058] [ka] EXAMPLES

[0059] Intermediate (R)-IV (B=H, X=H, Y=H); tert-butyl (R)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate Boc-D-alanine (5.0 g, 27 mmol, 1 equiv.) was dissolved in 20 mL of dichloromethane (DCM), then DCC (6.81 g, 1.2 equiv.) was added, followed by dropwise addition of benzylamine (2.95 g, 1 equiv.) after 30 min. The reaction was allowed to continue with stirring at room temperature for 4 h. After this time, the DCM was evaporated to dryness. The intermediate was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 91% (6.95 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 22N2O3(278.35), monoisotopic mass: 279.16. UPLC (purity >99%): t R = 5.44 min. (M+H) + 279.3. EXAMPLES

[0060] Intermediate (R)-IV (B=D, X=D, Y=H); tert-butyl (R)-(1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d5 (3.09 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 92% (7.08 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 17 D5N2O3(283.38), monoisotopic mass: 284.19. UPLC (purity >99%): t R = 5.41 min. (M+H) + 284.1. EXAMPLES

[0061] Intermediate (R)-IV (B=H, X=F, Y=H); tert-butyl (R)-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D-alanine (5.0 g, 27 mmol, 1 equiv.), DCC (6.81 g, 1.2 equiv.) and 2-fluorobenzylamine (3.31 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 93% (7.28 g); TLC: R f = 0.45 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 21 FN2O3(296.34), monoisotopic mass: 297.15. UPLC (purity >99%): t R = 5.54 min. (M+H) + 297.2. EXAMPLES

[0062] Intermediate (R)-IV (B=H, X=H, Y=D); tert-butyl (R)-(1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d2 (3.01 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 93% (7.18 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H20D2N2O3(280.36), monoisotopic mass: 281.18. UPLC (purity >99%): t R = 5.43 min. (M+H) + 281.2. EXAMPLES

[0063] Intermediate (R)-IV (B=D, X=D, Y=D); tert-butyl (R)-(1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d7 (3.15 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 94% (7.39 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 15 D7N2O3(285.39), monoisotopic mass: 286.21. UPLC (purity >99%): t R = 5.42 min. (M+H) + 286.3. EXAMPLES

[0064] Intermediate (R)-IV (B=H, X=F, Y=D); tert-butyl (R)-(1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and 2-fluorobenzylamine-d2 (3.36 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 93% (7.33 g); TLC: R f = 0.45 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 19 D2FN2O3(298.35), monoisotopic mass: 299.17. UPLC (purity >99%): t R = 5.53 min. (M+H) + 299.2. EXAMPLES

[0065] Intermediate (S)-IV (B=H, X=H, Y=H); tert-butyl (S)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-L-alanine (5.0 g, 27 mmol, 1 equiv.), DCC (6.81 g, 1.2 equiv.) and benzylamine (2.95 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 90% (6.86 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 22 N2O3(278.35), monoisotopic mass: 279.16. UPLC (purity >99%): t R = 5.43 min. (M+H) + 279.3. EXAMPLES

[0066] Intermediate (S)-IV (B=D, X=D, Y=H); tert-butyl (S)-(1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d5 (3.09 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 90% (6.92 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 17 D5N2O3(283.38), monoisotopic mass: 284.19. UPLC (purity >99%): tR = 5.40 min. (M+H) + 284.2. EXAMPLES

[0067] Intermediate (S)-IV (B=H, X=F, Y=H); tert-butyl (S)-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-L-alanine (5.0 g, 27 mmol, 1 equiv.), DCC (6.81 g, 1.2 equiv.) and 2-fluorobenzylamine (3.31 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 92% (7.20 g); TLC: R f = 0.45 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 21 FN2O3(296.34), monoisotopic mass: 297.15. UPLC (purity >99%): t R = 5.55 min. (M+H) + 297.2. EXAMPLES

[0068] Intermediate (S)-IV (B=H, X=H, Y=D); tert-butyl (S)-(1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-L-alanine (5.0 g, 27 mmol, 1 equiv.), DCC (6.81 g, 1.2 equiv.) and benzylamine-d2 (3.01 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 91% (7.03 g); TLC: R f= 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 20 D2N2O3(280.36), monoisotopic mass: 281.18. UPLC (purity >99%): t R = 5.43 min. (M+H) + 281.1. EXAMPLES

[0069] Intermediate (S)-IV (B=D, X=D, Y=D); tert-butyl (S)-(1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d7 (3.15 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 91% (7.14 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 15 D7N2O3(285.39), monoisotopic mass: 286.21. UPLC (purity >99%): t R = 5.42 min. (M+H) + 286.3. EXAMPLES

[0070] Intermediate (S)-IV (B=H, X=F, Y=D); tert-butyl (S)-(1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and 2-fluorobenzylamine-d2 (3.36 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 89% (7.01 g); TLC: R f = 0.45 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 19 D2FN2O3(298.35), monoisotopic mass: 299.17. UPLC (purity >99%): t R = 5.53 min. (M+H) + 299.3. EXAMPLES

[0071] Intermediate (R,S)-IV (B=H, X=H, Y=H); tert-butyl (R,S)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D,L-alanine (5.0 g, 27 mmol, 1 equiv.), DCC (6.81 g, 1.2 equiv.) and benzylamine (2.95 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 93% (7.16 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 22 N2O3(278.35), monoisotopic mass: 279.16. UPLC (purity >99%): t R = 5.42 min. (M+H) + 279.1. EXAMPLES

[0072] Intermediate (R,S)-IV (B=D, X=D, Y=H); tert-butyl (R,S)-(1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D,L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d5 (3.09 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 89% (6.85 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 17 D5N2O3(283.38), monoisotopic mass: 284.19. UPLC (purity >99%): t R = 5.43 min. (M+H) + 284.2. EXAMPLES

[0073] Intermediate (R,S)-IV (B=H, X=F, Y=H); tert-butyl (R,S)-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)carbamate Compound was obtained using a procedure similar to that described above. Boc-D,L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and 2-fluorobenzylamine (3.31 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. Compound was obtained as mp 111-115° C. Yield: 90% (7.05 g); TLC: R f = 0.45 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 21FN2O3(296.34), monoisotopic mass: 297.15. UPLC (>99% purity): t R = 5.56 min. (M+H) + 297.1. EXAMPLES

[0074] Intermediate (R,S)-IV (B=H, X=H, Y=D); tert-butyl (R,S)-(1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D,L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d2 (3.01 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 92% (7.10 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 20 D2N2O3(280.36), monoisotopic mass: 281.18. UPLC (purity >99%): t R = 5.43 min. (M+H) + 281.2. EXAMPLES

[0075] Intermediate (R,S)-IV (B=D, X=D, Y=D); tert-Butyl (R,S)-(1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D,L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and benzylamine-d7 (3.15 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 91% (7.15 g); TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 15 D7N2O3(285.39), monoisotopic mass: 286.21. UPLC (purity >99%): t R = 5.41 min. (M+H) + 286.3. EXAMPLES

[0076] Intermediate (R,S)-IV (B=H, X=F, Y=D); tert-butyl (R,S)-(1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)carbamate The compound was obtained using a procedure similar to that described above. Boc-D,L-alanine (5.0 g, 27 mmol, 1 equiv.) and DCC (6.81 g, 1.2 equiv.) and 2-fluorobenzylamine-d2 (3.36 g, 1 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. The compound was obtained as a clear, colorless oil. Yield: 90% (7.09 g); TLC: R f = 0.45 (DCM : MeOH (9 : 0.3; v / v)); C 15 H 19 D2FN2O3(298.35), monoisotopic mass: 299.17. UPLC (purity >99%): t R = 5.54 min. (M+H) + 299.2. EXAMPLES

[0077] Intermediate (R)-III (B=H, X=H, Y=H); (R)-2-amino-N-benzylpropanamide 10 mL of TFA was added to a solution of tert-butyl-(R)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (6.95 g, 25 mmol, 1 equiv.) in DCM (100 mL), the mixture was stirred for 2 h, then neutralized with 25% NH4OH solution, and then extracted with DCM (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4 and then evaporated to dryness. The compound was obtained as a clear, colorless 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), monoisotopic mass: 179.11. UPLC (purity 96.8%): t R = 2.11 min. (M+H) + 179.2. EXAMPLES

[0078] Intermediate (R)-III (B=D, X=D, Y=H); (R)-2-amino-N-((phenyl-d5)methyl)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R)-(1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)carbamate (7.08 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 94% (4.3 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H9D5N2O (183.27), monoisotopic mass: 184.14. UPLC (purity 96.3%): t R = 2.16 min. (M+H) + 184.1. EXAMPLES

[0079] Intermediate (R)-III (B=H, X=F, Y=H); (R)-2-amino-N-(2-fluorobenzyl)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R)-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)carbamate (7.08 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 92% (4.4 g); TLC: R f = 0.23 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 13 FN2O (196.23), monoisotopic mass: 197.10. UPLC (purity 97.4%): t R = 2.29 min. (M+H) + 197.2. EXAMPLES

[0080] Intermediate (R)-III (B=H, X=H, Y=D); (R)-2-amino-N-(phenylmethyl-d2)propanamide The compound was obtained using a similar procedure to that described above. tert-Butyl (R)-(1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)carbamate (7.01 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 95% (4.3 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 12 D2N2O (180.25), monoisotopic mass: 181.12. UPLC (purity >99%): t R = 2.12 min. (M+H) + 181.3. EXAMPLES

[0081] Intermediate (R)-III (B=D, X=D, Y=D); (R)-2-amino-N-((phenyl-d5)methyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R)-(1-oxo-1-(((phenylmethyl-d5)methyl-d2)amino)propan-2-yl)carbamate (7.13 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 95% (4.4 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H7D7N2O (185.28), monoisotopic mass: 186.15. UPLC (purity >99%): t R = 2.14 min. (M+H) + 186.2. EXAMPLES

[0082] Intermediate (R)-III (B=H, X=F, Y=D); (R)-2-amino-N-((2-fluorophenyl)methyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R)-(1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)carbamate (6.86 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a colorless, clear oil. Yield: 95% (4.3 g); TLC: R f = 0.23 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 11 D2FN2O (198.24), monoisotopic mass: 199.11. UPLC (purity >99%): t R = 2.28 min. (M+H) + 199.2. EXAMPLES

[0083] Intermediate (S)-III (B=H, X=H, Y=H); (S)-2-amino-N-benzylpropanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (S)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (6.50 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 87% (3.67 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 14 N2O (178.24), monoisotopic mass: 179.11. UPLC (purity 96.8%): t R = 2.12 min. (M+H) + 179.2. EXAMPLES

[0084] Intermediate (S)-III (B=D, X=D, Y=H); (S)-2-amino-N-((phenyl-d5)methyl)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (S)-(1-oxo-(((phenyl-d5)methyl)amino)propan-2-yl)carbamate (6.51 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 95% (4.0 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H9D5N2O (183.27), monoisotopic mass: 184.14. UPLC (purity 96.3%): t R = 2.15 min. (M+H) + 184.2. EXAMPLES

[0085] Intermediate (S)-III (B=H, X=F, Y=H); (S)-2-amino-N-(2-fluorobenzyl)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (S)-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)carbamate (6.82 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 93% (4.3 g); TLC: R f = 0.23 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 13 FN2O (196.23), monoisotopic mass: 197.10. UPLC (purity 98.2%): t R = 2.30 min. (M+H) + 197.1. EXAMPLES

[0086] Intermediate (S)-III (B=H, X=H, Y=D); (S)-2-amino-N-(phenylmethyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (S)-(1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)carbamate (7.01 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 94% (4.2 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 12 D2N2O (180.25), monoisotopic mass: 181.12. UPLC (purity >99%): t R = 2.13 min. (M+H) + 181.2. EXAMPLES

[0087] Intermediate (S)-III (B=D, X=D, Y=D); (S)-2-amino-N-((phenyl-d5)methyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (S)-(1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)carbamate (7.13 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 91% (4.2 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H7D7N2O (185.28), monoisotopic mass: 186.15. UPLC (purity >99%): t R = 2.14 min. (M+H) + 186.1. EXAMPLES

[0088] Intermediate (S)-III (B=H, X=F, Y=D); (S)-2-amino-N-((2-fluorophenyl)methyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (S)-(1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)carbamate (6.86 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a colorless, clear oil. Yield: 93% (4.2 g); TLC: R f = 0.23 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 11 D2FN2O (198.24), monoisotopic mass: 199.11. UPLC (purity >99%): t R = 2.28 min. (M+H) + 199.2. EXAMPLES

[0089] Intermediate (R,S)-III (B=H, X=H, Y=H); (R,S)-2-amino-N-benzylpropanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R,S)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (6.50 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 96% (3.9 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 14 N2O (178.24), monoisotopic mass: 179.11. UPLC (purity 98.2%): t R = 2.12 min. (M+H) + 179.3. EXAMPLES

[0090] Intermediate (R,S)-III (B=D, X=D, Y=H); (R,S)-2-amino-N-((phenyl-d5)methyl)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R,S)-(1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)carbamate (6.51 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 93% (3.9 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H9D5N2O (183.27), monoisotopic mass: 184.14. UPLC (purity 96.3%): t R = 2.14 min. (M+H) + 184.2. EXAMPLES

[0091] Intermediate (R,S)-III (B=H, X=F, Y=H); (R,S)-2-amino-N-(2-fluorobenzyl)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R,S)-(1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)carbamate (6.82 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 94% (4.2 g); TLC: R f = 0.23 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 13 FN2O (196.23), monoisotopic mass: 197.10. UPLC (purity 98.2%): t R = 2.31 min. (M+H) + 197.1. EXAMPLES

[0092] Intermediate (R,S)-III (B=H, X=H, Y=D); (R,S)-2-amino-N-(phenylmethyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R,S)-(1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)carbamate (7.01 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 93% (4.2 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 12 D2N2O (180.25), monoisotopic mass: 181.12. UPLC (purity >99%): t R = 2.12 min. (M+H) + 181.2. EXAMPLES

[0093] Intermediate (R,S)-III (B=D, X=D, Y=D); (R,S)-2-amino-N-((phenyl-d5)methyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R,S)-(1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)carbamate (7.13 g, 25 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a clear, colorless oil. Yield: 94% (4.3 g); TLC: R f = 0.21 (DCM : MeOH (9 : 0.5; v / v)); C 10 H7D7N2O (185.28), monoisotopic mass: 186.15. UPLC (purity >99%): t R = 2.14 min. (M+H) + 186.2. EXAMPLES

[0094] Intermediate (R,S)-III (B=H, X=F, Y=D); (R,S)-2-amino-N-((2-fluorophenyl)methyl-d2)propanamide The compound was obtained using a procedure similar to that described above. tert-Butyl (R,S)-(1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)carbamate (6.86 g, 23 mmol, 1 eq.) and 10 mL of TFA were used in the reaction. The compound was obtained as a colorless, clear oil. Yield: 94% (4.3 g); TLC: R f = 0.23 (DCM : MeOH (9 : 0.5; v / v)); C 10 H 11 D2FN2O (198.24), monoisotopic mass: 199.11. UPLC (purity >99%): t R = 2.28 min. (M+H) + 199.2. EXAMPLES

[0095] Intermediate (R)-II (A=D, B=H, X=H, Y=H); (R)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 Succinic anhydride-2,2,3,3-d4 (2.18 g, 21 mmol, 1 equiv.) was added to a solution of (R)-2-amino-N-benzylpropanamide (3.9 g, 21 mmol, 1 equiv.) in ethyl acetate (50 mL) and the mixture was stirred for 30 min. After this time, the ethyl acetate was evaporated to dryness. After washing with diethyl ether (Et2O), the compound was obtained as a solid. White solid. Yield: 94% (5.81 g); mp 129.5-131.6 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 14 D4N2O4(282.33), monoisotopic mass: 283.15. UPLC (purity 91.2%): t R = 3.12 min. (M+H) + 283.4. EXAMPLES

[0096] Intermediate (R)-II (A=H, B=D, X=D, Y=H); (R)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid Compound was obtained using a procedure similar to that described above. A solution of (R)-2-amino-N-((phenyl-d5)methyl)propanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride (1.22 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 95% (3.20 g); mp 129.9-131.8 °C; TLC: Rf = 0.35 (DCM : MeOH (9 : 0.5; v / v)); C14H13D5N2O4 (283.34), monoisotopic mass: 284.15. UPLC (purity >99%): tR = 3.12 min. (M+H)+ 284.1. EXAMPLES

[0097] Intermediate (R)-II (A=D, B=D, X=D, Y=H); (R)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R)-2-amino-N-((phenyl-d5)methyl)propanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 96% (3.28 g); mp 129.7-131.3 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H9D9N2O4(287.36), monoisotopic mass: 288.18. UPLC (purity >99%): t R = 3.12 min. (M+H) + 288.2. EXAMPLES

[0098] Intermediate (R)-II (A=D, B=H, X=F, Y=H); (R)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R)-2-amino-N-(2-fluorobenzyl)propanamide (4.12 g, 21 mmol, 1 eq.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (2.18 g, 21 mmol, 1 eq.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 95% (5.99 g); mp 131.2-132.6 °C; TLC: R f = 0.36 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 13 D4FN2O4(300.32), monoisotopic mass: 301.14. UPLC (purity 95.70%): t R = 3.32 min. (M+H) + 301.2. EXAMPLES

[0099] Intermediate (R)-II (A=D, B=H, X=H, Y=D); (R)-4-oxo-4-((1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R)-2-amino-N-((phenyl-d2)methyl)propanamide (2.16 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 95% (3.23 g); mp 129.5-131.8 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 12 D6N2O4(284.34), monoisotopic mass: 285.16. UPLC (purity >99%): t R = 3.13 min. (M+H) + 285.2. EXAMPLES

[0100] Intermediate (R)-II (A=D, B=D, X=D, Y=D); (R)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R)-2-amino-N-((phenyl-d5)methyl-d2)propanamide (2.22 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 94% (3.26 g); mp 129.1-131.2 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H7D 11 N2O4(289.38), monoisotopic mass: 290.20. UPLC (purity >99%): t R = 3.12 min. (M+H) + 290.2. EXAMPLES

[0101] Intermediate (R)-II (A=D, B=H, X=F, Y=D); (R)-4-((1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R)-2-amino-N-((2-fluorophenyl)methyl-d2)propanamide (2.37 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 95% (3.44 g); mp 131.3-132.5 °C; TLC: Rf = 0.36 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 11 D6FN2O4(303.15), monoisotopic mass: 304.34. UPLC (purity >99%): t R = 3.34 min. (M+H) + 304.3. EXAMPLES

[0102] Intermediate (S)-II (A=D, B=H, X=H, Y=H); (S)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-benzylpropanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 92% (5.69 g); mp 129.3-131.9 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 14 D4N2O4(282.33), monoisotopic mass: 283.15. UPLC (purity 93.5%): t R = 3.13 min. (M+H) + 283.1. EXAMPLES

[0103] Intermediate (S)-II (A=H, B=D, X=D, Y=H); (S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid The compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-((phenyl-d5)methyl)propanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride (1.22 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 96% (3.23 g); mp 129.5-131.4 °C; TLC: R f = 0.35 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 13 D5N2O4(283.34), monoisotopic mass: 284.15. UPLC (purity >99%): t R = 3.11 min. (M+H) + 284.2. EXAMPLES

[0104] Intermediate (S)-II (A=D, B=D, X=D, Y=H); (S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-((phenyl-d5)methyl)propanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.22 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 95% (3.24 g); mp 129.5-131.2 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H9D9N2O4(287.36), monoisotopic mass: 288.18. UPLC (purity >99%): t R = 3.11 min. (M+H) + 288.2. EXAMPLES

[0105] Intermediate (S)-II (A=D, B=H, X=F, Y=H); (S)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-(2-fluorobenzyl)propanamide (4.12 g, 21 mmol, 1 eq.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (2.18 g, 21 mmol, 1 eq.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 93% (5.86 g); mp 131.5-132.4 °C; TLC: R f = 0.36 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 13 D4FN2O4(300.32), monoisotopic mass: 301.14. UPLC (purity 99.20%): t R = 3.31 min. (M+H) + 301.2. EXAMPLES

[0106] Intermediate (S)-II (A=D, B=H, X=H, Y=D); (S)-4-oxo-4-((1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-((phenyl-d2)methyl)propanamide (2.16 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 96% (3.26 g); mp 129.5-131.7 °C; TLC: R f= 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 12 D6N2O4(284.34), monoisotopic mass: 285.16. UPLC (purity >99%): t R = 3.12 min. (M+H) + 285.2. EXAMPLES

[0107] Intermediate (S)-II (A=D, B=D, X=D, Y=D); (S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 Compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-((phenyl-d5)methyl-d2)propanamide (2.22 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 93% (3.23 g); mp 129.1-131.4 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H7D 11 N2O4(289.38), monoisotopic mass: 290.20. UPLC (purity >99%): t R = 3.13 min. (M+H) + 290.1. EXAMPLES

[0108] Intermediate (S)-II (A=D, B=H, X=F, Y=D); (S)-4-((1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (S)-2-amino-N-((2-fluorophenyl)methyl-d2)propanamide (2.37 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 94% (3.40 g); mp 131.2-132.4 °C; TLC: R f = 0.36 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 11 D6FN2O4(303.15), monoisotopic mass: 304.34. UPLC (purity >99%): t R = 3.35 min. (M+H) + 304.2. EXAMPLES

[0109] Intermediate (R,S)-II (A=D, B=H, X=H, Y=H); (R,S)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-benzylpropanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 95% (3.22 g); mp 89.3-90.9 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 14 D4N2O4(282.33), monoisotopic mass: 283.15. UPLC (purity >99%): t R = 3.12 min. (M+H) + 283.2. EXAMPLES

[0110] Intermediate (R,S)-II (A=H, B=D, X=D, Y=H); (R,S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid Compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-((phenyl-d5)methyl)propanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride (1.22 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 97% (3.26 g); mp 89.4-91.4 °C; TLC: R f = 0.35 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 13 D5N2O4(283.34), monoisotopic mass: 284.15. UPLC (purity >99%): t R = 3.13 min. (M+H) + 284.2. EXAMPLES

[0111] Intermediate (R,S)-II (A=D, B=D, X=D, Y=H); (R,S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-((phenyl-d5)methyl)propanamide (2.18 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 92% (3.14 g); mp 89.1-90.6 °C; TLC: R f= 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H9D9N2O4(287.36), monoisotopic mass: 288.18. UPLC (purity >99%): t R = 3.12 min. (M+H) + 288.2. EXAMPLES

[0112] Intermediate (R,S)-II (A=D, B=H, X=F, Y=H); (R,S)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-(2-fluorobenzyl)propanamide (4.12 g, 21 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (2.18 g, 21 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 93% (5.84 g); mp 89.3-90.5 °C; TLC: R f = 0.36 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 13 D4FN2O4(300.32), monoisotopic mass: 301.14. UPLC (purity >99%): t R = 3.32 min. (M+H) + 301.2. EXAMPLES

[0113] Intermediate (R,S)-II (A=D, B=H, X=H, Y=D); (R,S)-4-oxo-4-((1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-((phenyl-d2)methyl)propanamide (2.16 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 94% (3.19 g); mp 89.1-90.6 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 12 D6N2O4(284.34), monoisotopic mass: 285.16. UPLC (purity >99%): t R = 3.12 min. (M+H) + 285.1. EXAMPLES

[0114] Intermediate (R,S)-II (A=D, B=D, X=D, Y=D); (R,S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 Compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-((phenyl-d5)methyl-d2)propanamide (2.22 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 95% (3.29 g); mp 89.4-90.7 °C; TLC: R f = 0.34 (DCM : MeOH (9 : 0.5; v / v)); C 14 H7D 11 N2O4(289.38), monoisotopic mass: 290.20. UPLC (purity >99%): t R = 3.13 min. (M+H) + 290.3. EXAMPLES

[0115] Intermediate (R,S)-II (A=D, B=H, X=F, Y=D); (R,S)-4-((1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 The compound was obtained using a procedure similar to that described above. A solution of (R,S)-2-amino-N-((2-fluorophenyl)methyl-d2)propanamide (2.37 g, 12 mmol, 1 equiv.) in ethyl acetate (50 mL) and succinic anhydride-2,2,3,3-d4 (1.26 g, 12 mmol, 1 equiv.) was used in the reaction. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 96% (3.47 g); mp 89.4-90.6 °C; TLC: R f = 0.36 (DCM : MeOH (9 : 0.5; v / v)); C 14 H 11 D6FN2O4(303.15), monoisotopic mass: 304.34. UPLC (purity >99%): t R = 3.33 min. (M+H) + 304.2.

[0116] Examples of synthesis and physicochemical and spectral data of final products according to formula (I): EXAMPLES

[0117] Compound d4-(R)-1 (A=D, B=H, X=H, Y=H); (R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide ZnCl2 (1.36 g, 10 mmol, 1 equiv.) was added to a suspension of (R)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (2.82 g, 10 mmol, 1 equiv.) in anhydrous 1,4-dioxane (100 mL) and the whole mixture was heated to 110° C. Then, a solution of HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) in anhydrous 1,4-dioxane (15 mL) was added dropwise over 30 min. The reaction was continued with stirring at reflux for about 24 h and then concentrated under reduced pressure. After evaporation of the solvent, the oily residue was dissolved in DCM and extracted with 0.1 M HCl (3×50 mL), water (3×50 mL) and saturated NaCl solution (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and then evaporated to dryness. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, the compound was obtained as a solid. White solid. Yield: 89% (2.34 g); mp 138.2-138.9°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 12 D4N2O3(264.32), monoisotopic mass: 265.14. UPLC (purity >99%): t R = 3.79 min. (M+H) + 265.2. Chiral HPLC > 99% ee (t R = 24.566 min). 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.2 Hz, 3H), 4.39 (d, J=5.7 Hz, 2H), 4.77 (q, J=7.2 Hz, 1H), 6.40 (br s, 1H), 7.22-7.26 (m, 3H), 7.29-7.32 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 28.3, 33.7, 49.8, 127.7, 128.8, 137.9, 168.6, 177.0. EXAMPLES

[0118] Compound d4-(S)-1 (A=D, B=H, X=H, Y=H); (S)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (2.87 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 87% (2.29 g); mp 137.9-138.8°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 12 D4N2O3(264.32), monoisotopic mass: 265.14. UPLC (purity >99%): t R = 3.76 min. (M+H) + 265.3. Chiral HPLC > 99% ee (t R = 26.484 min). 1 H NMR (500 MHz, CDCl3) δ 1.59 (d, J=7.5 Hz, 3H), 4.43 (d, J=5.7 Hz, 2H), 4.79 (q, J=7.4 Hz, 1H), 6.33 (br s, 1H), 7.24-7.28 (m, 3H), 7.31 (d, J=6.9 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 127.7, 128.8, 137.9, 168.6, 177.0. EXAMPLES

[0119] Compound d4-(R,S)-1 (A=D, B=H, X=H, Y=H); (R,S)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-((1-(benzylamino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (2.87 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 85% (2.23 g); mp 83.4-84.2°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 12 D4N2O3(264.32), monoisotopic mass: 265.14. UPLC (purity >99%): t R = 3.78 min. (M+H) + 265.2. 1 H NMR (500 MHz, CDCl3) δ 1.55-1.59 (m, 3H), 4.40 (d, J=5.4 Hz, 2H), 4.76 (qd, J=7.4, 1.7 Hz, 1H), 6.41 (br s, 1H), 7.22-7.27 (m, 3H), 7.29-7.33 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 129.4, 129.4, 130.2, 130.2, 168.8, 177.0. EXAMPLES

[0120] Compound d9-(R)-2 (A=D, B=D, X=D, Y=H); (2R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide Compound was obtained using a procedure similar to that described above. (R)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.87 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 85% (2.29 g); mp 139.3-140.7°C; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H7D9N2O3(269.35), monoisotopic mass: 270.17. UPLC (purity >99%): t R = 3.82 min, (M+H) + 270.1. Chiral HPLC > 99% ee (t R = 24.539 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.2 Hz, 3H), 4.43 (d, J=5.7 Hz, 2H), 4.79 (q, J=7.2 Hz, 1H), 6.31 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.6, 34.0, 43.8, 49.9, 127.1, 127.3, 128.3, 137.7, 168.6, 176.9. EXAMPLES

[0121] Compound d9-(S)-2 (A=D, B=D, X=D, Y=H); (2S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.87 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 84% (2.26 g); mp 138.9-140.2°C; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H7D9N2O3(269.35), monoisotopic mass: 270.17. UPLC (purity >99%): t R = 3.81 min, (M+H) + 270.2. Chiral HPLC > 99% ee (t R = 26.476 min). 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.2 Hz, 3H), 4.40 (d, J=5.7 Hz, 2H), 4.77 (q, J=7.5 Hz, 1H), 6.42 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 34.0, 43.8, 49.8, 127.3, 128.1, 128.3, 137.7, 168.7, 177.0. EXAMPLES

[0122] Compound d9-(R,S)-2 (A=D, B=D, X=D, Y=H); (2R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.87 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 87% (2.34 g); mp 84.1-85.5°C; TLC: R f = 0.4 (DCM : MeOH (9 : 0.3; v / v)); C 14 H7D9N2O3(269.35), monoisotopic mass: 270.17. UPLC (purity >99%): t R = 3.80 min, (M+H) + 270.1. 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.2 Hz, 3H), 4.40 (d, J=5.7 Hz, 2H), 4.77 (q, J=7.2 Hz, 1H), 6.40 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 34.0, 43.8, 49.8, 127.1, 127.3, 128.1, 137.7, 168.6, 177.0. EXAMPLES

[0123] Compound d5-(R)-3 (A=H, B=D, X=D, Y=H); (2R)-2-(2,5-dioxopyrrolidin-1-yl)-N-((phenyl-d5)methyl)propanamide Compound was obtained using a procedure similar to that described above. (R)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid (2.83 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 10 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 87% (2.30 g); mp 138.9-140.2°C; TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 11 D5N2O3(265.32), monoisotopic mass: 266.15. UPLC (purity >99%): t R = 3.80 min, (M+H) + 266.2. Chiral HPLC > 99% ee (t R = 24.447 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.2 Hz, 3H), 2.67-2.71 (m, 4H), 4.42 (d, J=5.4 Hz, 2H), 4.76-4.79 (m, 1H), 6.37 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.6, 34.0, 43.8, 49.9, 127.1, 127.3, 128.3, 137.7, 168.6, 176.9. EXAMPLES

[0124] Compound d5-(S)-3 (A=H, B=D, X=D, Y=H); (2S)-2-(2,5-dioxopyrrolidin-1-yl)-N-((phenyl-d5)methyl)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid (2.83 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 10 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 85% (2.25 g); mp 138.4-139.8°C; TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 11 D5N2O3(265.32), monoisotopic mass: 266.15. UPLC (purity >99%): t R = 3.81 min, (M+H) + 266.2. Chiral HPLC > 99% ee (t R = 26.484 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.2 Hz, 3H), 2.69 (s, 4H), 4.42 (d, J=5.7 Hz, 2H), 4.79 (q, J=7.5 Hz, 1H), 6.38 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 28.3, 34.0, 43.9, 49.8, 127.1, 128.1, 137.7, 168.7, 175.6. EXAMPLES

[0125] Compound d5-(R,S)-3 (A=H, B=D, X=D, Y=H); (2R,S)-2-(2,5-dioxopyrrolidin-1-yl)-N-((phenyl-d5)methyl)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl)amino)propan-2-yl)amino)butanoic acid (2.83 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 10 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 84% (2.22 g); mp 84.4-86.1°C; TLC: R f = 0.43 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 11 D5N2O3(265.32), monoisotopic mass: 266.15. UPLC (purity >99%): t R = 3.82 min, (M+H) + 266.2. 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.5 Hz, 3H), 2.68 (s, 4H), 4.40 (d, J=5.7 Hz, 2H), 4.77 (q, J=7.2 Hz, 1H), 6.42 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 28.3, 33.9, 43.8, 49.8, 127.1, 128.1, 137.7, 168.7, 177.0. EXAMPLES

[0126] Compound d4-(R)-4 (A=D, B=H, X=F, Y=H); (R)-N-(2-fluorobenzyl)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide Compound was obtained using a procedure similar to that described above. (R)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (3.00 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 84% (2.36 g); mp 157.2-157.3°C; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 11 D4FN2O3(282.31), monoisotopic mass: 283.13. UPLC (purity >99%): t R = 4.01 min, (M+H) + 283.2. Chiral HPLC > 99% ee (t R = 18.863 min). 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.3 Hz, 3H), 4.38-4.52 (m, 2H), 4.76 (q, J=7.3 Hz, 1H), 6.48 (br s, 1H), 6.98-7.04 (m, 1H), 7.08-7.11 (m, 1H), 7.20-7.24 (1H), 7.30-7.31 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 37.9, 38.0, 49.8 115.4, 124.5 (J=3.6 Hz), 124.8, 124.9, 129, 4 (J=8.5 Hz), 130.2 (J=4.2 Hz), 168.7, 177.0. EXAMPLES

[0127] Compound d4-(S)-4 (A=D, B=H, X=F, Y=H); (S)-N-(2-fluorobenzyl)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (3.00 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 86% (2.41 g); mp 157.4-157.8°C; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 11 D4FN2O3(282.31), monoisotopic mass: 283.13. UPLC (purity >99%): t R = 3.90 min, (M+H) + 283.3. Chiral HPLC > 99% ee (t R = 21.383 min). 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.5 Hz, 3H), 4.40-4.51 (m, 2H), 4.77 (q, J=7.5 Hz, 1H), 6.49 (br s, 1H), 7.01 (t, J=9.3 Hz, 1H), 7.09 (td, J=7.5, 0.9 Hz, 1H), 7.21-7.25 (m, 1H), 7.31 (td, J=7.6, 1.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 14.5, 37.9 (d, J=4.2 Hz), 49.8, 115.5, 124.5 (d, J=3.6 Hz), 124.8, 124.9, 129.4 (d, J=7.8 Hz), 130.2 (d, J=3.6 Hz), 168.7, 176.9. EXAMPLES

[0128] Compound d4-(R,S)-4 (A=D, B=H, X=F, Y=H); (R,S)-N-(2-fluorobenzyl)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-((1-((2-fluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (3.00 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 85% (2.38 g); mp 98.4-99.7℃; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 11 D4FN2O3(282.31), monoisotopic mass: 283.13. UPLC (purity >99%): t R = 3.95 min, (M+H) + 283.2. 1H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.5 Hz, 3H), 4.40-4.50 (m, 2H), 4.76 (q, J=7.2 Hz, 1H), 6.52 (br s, 1H), 6.98-7.03 (m, 1H), 7.08 (td, J=7.5, 1.0 Hz, 1H), 7.20-7.24 (m, 1H), 7.30 (td, J=7.6, 1.7 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 34.0, 37.9 (d, J=3.6 Hz), 49.8, 115.5, 124.5 (d, J=3.6 Hz), 129.4 (d, J=8.5 Hz), 130.2 (d, J=4.2 Hz), 168.8, 177.0. EXAMPLES

[0129] Compound d6-(R)-5 (A=D, B=H, X=H, Y=D); (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (R)-4-oxo-4-((1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.84 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 86% (2.28 g); mp 138.3-139.1°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 10 D6N2O3(266.33), monoisotopic mass: 267.15. UPLC (purity >99%): t R= 3.78 min (M+H) + 267.2. Chiral HPLC > 99% ee (t R = 23.945 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.5 Hz, 3H), 4.78 (q, J=7.5 Hz, 1H), 6.35 (br s, 1H), 7.22-7.28 (m, 3H), 7.30-7.33 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 14.6, 25.7, 34.0, 49.8, 127.8, 128.8, 137.8, 168.6, 177.0. EXAMPLES

[0130] Compound d6-(S)-5 (A=D, B=H, X=H, Y=D); (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-oxo-4-((1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.84 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 84% (2.23 g); mp 138.3-139.0°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 10 D6N2O3(266.33), monoisotopic mass: 267.15. UPLC (purity >99%): t R = 3.78 min (M+H) +267.2. Chiral HPLC > 99% ee (t R = 25.872 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.5 Hz, 3H), 4.78 (q, J=7.5 Hz, 1H), 6.35 (br s, 1H), 7.23-7.28 (m, 3H), 7.30-7.34 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 14.6, 25.7, 34.0, 49.8, 127.8, 128.8, 137.8, 168.6, 177.0. EXAMPLES

[0131] Compound d6-(R,S)-5(A=D, B=H, X=H, Y=D);)(R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-(phenylmethyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-oxo-4-((1-oxo-1-((phenylmethyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.84 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 82% (2.18 g); mp 84.5-86.2°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H 10 D6N2O3(266.33), monoisotopic mass: 267.15. UPLC (purity >99%): t R = 3.78 min (M+H) + 267.3. 1H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.2 Hz, 3H), 4.77 (q, J=7.5 Hz, 1H), 6.35 (br s, 1H), 7.23-7.27 (m, 3H), 7.30-7.33 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 127.5, 128.5, 137.7, 168.6, 177.0. EXAMPLES

[0132] Compound d6-(R)-7 (A=D, B=H, X=F, Y=D); (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (R)-4-((1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (3.03 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 84% (2.39 g); mp 157.2-157.7°C; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H9D6FN2O3(284.32), monoisotopic mass: 284.14. UPLC (purity >99%): t R = 3.98 min (M+H) + 285.2. Chiral HPLC > 99% ee (t R = 18.011 min). 1H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.2 Hz, 3H), 4.76 (q, J=7.3 Hz, 1H), 6.44 (br s, 1H) 7.01 (ddd, J=10.2, 8.2, 1.0 Hz, 1H), 7.09 (td, J=7.6, 1.2 Hz, 1H), 7.21-7.26 (m, 1H), 7.31 (td, J=7.6, 1.7 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 115.5, 124.5 (d, J=3.6 Hz), 129.4 (d, J=8.5 Hz), 130.2 (d, J=4.2 Hz), 168.8, 177.0. EXAMPLES

[0133] Compound d6-(S)-7 (A=D, B=H, X=F, Y=D); (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-((1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (3.03 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 86% (2.44 g); mp 157.3-157.7°C; TLC: R f = 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H9D6FN2O3(284.32), monoisotopic mass: 284.14. UPLC (purity >99%): t R= 3.98 min (M+H) + 285.2. Chiral HPLC > 99% ee (t R = 20.145 min). 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.2 Hz, 3H), 4.76 (q, J=7.3 Hz, 1H), 6.44 (br s, 1H) 7.01 (ddd, J=10.2, 8.2, 1.0 Hz, 1H), 7.09 (td, J=7.6, 1.2 Hz, 1H), 7.21-7.26 (m, 1H), 7.31 (td, J=7.6, 1.7 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 115.5, 124.5 (d, J=3.6 Hz), 129.4 (d, J=8.5 Hz), 130.2 (d, J=4.2 Hz), 168.8, 177.0. EXAMPLES

[0134] Compound d6-(R,S)-7 (A=D, B=H, X=F, Y=D); (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((2-fluorophenyl)methyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-((1-(((2-fluorophenyl)methyl-d2)amino)-1-oxopropan-2-yl)amino)-4-oxobutanoic acid-2,2,3,3-d4 (3.03 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 84% (2.35 g); mp 98.3-99.8℃; TLC: R f= 0.44 (DCM : MeOH (9 : 0.3; v / v)); C 14 H9D6FN2O3(284.32), monoisotopic mass: 284.14 UPLC (>99% purity): t R = 3.98 min (M+H) + 285.2. 1 H NMR (500 MHz, CDCl3) δ 1.57 (d, J=7.2 Hz, 3H), 4.76 (q, J=7.3 Hz, 1H), 6.44 (br s, 1H) 7.01 (ddd, J=10.2, 8.2, 1.0 Hz, 1H), 7.09 (td, J=7.6, 1.2 Hz, 1H), 7.22-7.26 (m, 1H), 7.31 (td, J=7.6, 1.7 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 115.5, 124.5 (d, J=3.6 Hz), 129.4 (d, J=8.5 Hz), 130.2 (d, J=4.2 Hz), 168.8, 177.0. EXAMPLES

[0135] compound d 11 -(R)-6 (A=D, B=D, X=D, Y=D); (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (R)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.89 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 83% (2.40 g); mp 138.1-139.0°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H5D 11 N2O3(271.36), monoisotopic mass: 271.19. UPLC (purity >99%): t R = 3.80 min (M+H) + 272.2. Chiral HPLC > 99% ee (t R = 24.017 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.5 Hz, 3H), 4.79 (q, J=7.5 Hz, 1H), 6.32 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 127.5, 128.5, 137.7, 168.6, 177.0. EXAMPLES

[0136] compound d 11 -(S)-6 (A=D, B=D, X=D, Y=D); (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.89 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 85% (2.45 g); mp 138.1-139.1°C; TLC: R f= 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H5D 11 N2O3(271.36), monoisotopic mass: 271.19. UPLC (purity >99%): t R = 3.80 min (M+H) + 272.2. Chiral HPLC > 99% ee (t R = 26.128 min). 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.5 Hz, 3H), 4.79 (q, J=7.5 Hz, 1H), 6.32 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 127.5, 128.5, 137.7, 168.6, 177.0. EXAMPLES

[0137] compound d 11 -(R,S)-6(A=D, B=D, X=D, Y=D);(R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d4)-N-((phenyl-d5)methyl-d2)propanamide Compound was obtained using a procedure similar to that described above. (R,S)-4-oxo-4-((1-oxo-1-(((phenyl-d5)methyl-d2)amino)propan-2-yl)amino)butanoic acid-2,2,3,3-d4 (2.89 g, 10 mmol, 1 equiv.) and ZnCl2 (1.36 g, 20 mmol, 1 equiv.), and HMDS (2.42 g, 3.14 mL, 15 mmol, 1.5 equiv.) were used in the reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) eluent system. After washing with Et2O, compound was obtained as a solid. White solid. Yield: 82% (2.37 g); mp 84.2-86.3°C; TLC: R f = 0.39 (DCM : MeOH (9 : 0.3; v / v)); C 14 H5D11 N2O3(271.36), monoisotopic mass: 271.19. UPLC (purity >99%): t R = 3.80 min (M+H) + 272.2. 1 H NMR (500 MHz, CDCl3) δ 1.58 (d, J=7.5 Hz, 3H), 4.79 (q, J=7.5 Hz, 1H), 6.32 (br s, 1H). 13 C NMR (126 MHz, CDCl3) δ 14.5, 25.7, 34.0, 49.8, 127.5, 128.5, 137.7, 168.6, 177.0.

[0138] Synthesis procedure of compound d4-(R)-KA-104 The title compound was prepared according to the synthetic procedures illustrated in Scheme 2.

[0139] [ka] EXAMPLES

[0140] Intermediate (R)-VII; tert-butyl (R)-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)carbamate. Boc-D-phenylglycine (1.25 g, 5 mmol, 1 equiv.) was dissolved in 20 mL of DCM, followed by the addition of DCC (1.55 g, 7.5 mmol, 1.5 equiv.) and, after 30 min, 1-(3-(trifluoromethyl)phenyl)piperazine (1.15 g, 5 mmol, 1 equiv.). The reaction was allowed to continue with stirring at room temperature for 4 h. After this, the DCM was evaporated to dryness. Intermediate (R)-VII was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) eluent system. Clear, colorless oil. Yield: 78% (1.81 g); TLC: R f = 0.62 (DCM : MeOH (9 : 0.5; v / v)); C24 H 28 F3N3O3(463.50), monoisotopic mass: 464.21. UPLC (purity >99%): t R = 8.40 min. (M+H) + 464.2. EXAMPLES

[0141] Intermediate (R)-VI; (R)-2-amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one 5 mL of TFA was added to a solution of tert-butyl (R)-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)carbamate ((R)-VI) (1.39 g, 3 mmol, 1 equiv.) in DCM (50 mL) and the mixture was stirred for 2 h. The reaction mixture was then neutralized with 25% NH4OH solution and then extracted with DCM (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4 and then evaporated to dryness. (R)-2-amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one was obtained as a yellow oil. Yellow oil. Yield: 95% (1.03 g); C 19 H 20 F3N3O (363.38). Monoisotopic mass: 364.16. UPLC (>99% purity): t R = 4.96 min. (M+H) + 364.3. EXAMPLES

[0142] Intermediate (R)-V; (R)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)amino)butanoic acid-2,2,3,3-d4 Succinic anhydride-2,2,3,3-d4 (0.28 g, 2.8 mmol, 1 equiv.) was added to a solution of (R)-2-amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one ((R)-VI) (1.02 g, 2.8 mmol, 1 equiv.) in AcOEt (50 mL) and the reaction mixture was stirred for 30 min. After this time, AcOEt was distilled to dryness. After washing with Et2O ether, the compound was obtained as a solid. White solid. Yield: 87% (1.13 g); C 23 H 20 D4F3N3O4(467.48), monoisotopic mass: 468.20. UPLC (purity >99%): t R = 6.40 min. (M+H) + 468.2. EXAMPLES

[0143] Compound d4-(R)-KA-104; (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)pyrrolidine-2,5-dione-3,3,4,4-d4 ZnCl2 (0.27 g, 2.0 mmol, 1 equiv.) was added to a suspension of (R)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)amino)butanoic acid-2,2,3,3-d4((R)-V) (0.93 g, 2.0 mmol, 1 equiv.) in anhydrous 1,4-dioxane (50 mL) and the mixture was heated to 110° C. Then, a solution of HMDS (0.48 g, 0.62 mL, 3.0 mmol, 1.5 equiv.) in anhydrous 1,4-dioxane (5 mL) was added dropwise over 30 min. The reaction was continued with stirring at reflux for approximately 24 h and then concentrated under reduced pressure. After evaporation of the solvent, the oily residue was dissolved in DCM and extracted with 0.1 M HCl (3 × 50 mL), water (3 × 50 mL) and saturated NaCl solution (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and then evaporated to dryness. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) eluent system. After washing with Et2O ether, the compound was obtained as a solid. White solid. Yield: 80% (0.71 g); mp 189.2-190.6°C; TLC: R f = 0.35 (DCM : MeOH (9 : 0.5; v / v)); C 23 H 18 D4F3N3O3(449.47), monoisotopic mass: 449.19. UPLC (purity: >99%): t R = 6.94 min, (M+H) + 449.3. 1 H NMR (500 MHz, CDCl3) δ 2.79 (br s, 2H), 3.02-3.18 (m, 2H), 3.24-3.41 (m, 4H), 6.11 (s, 1H), 6.97 (dd, J=8.3, 2.3 Hz, 1H), 7.01 (s, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.30-7.39 (m, 5H), 7.41-7.46 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 42.4, 45.6, 48.5, 48.7, 56.9, 67.2, 112.8 (d, J=3.4 Hz), 116.7 (d, J=3.4 Hz), 119.2, 124.1 (q, J=272.9 Hz), 128.7, 128.9, 129.7, 129.8, 130.9, 131.5 (q, J=32.2 Hz), 132.8, 150.8, 165.1, 176.4.

[0144] In vivo pharmacokinetic study in mice General information Experiments were performed with male albino mice (CD-1) weighing 27–32 g, provided by a certified animal facility. Mice were housed in a room providing 15 air changes per hour at a temperature of 22–24 °C and humidity of 50% (+ / - 10%), with a 12:12 h light / dark cycle. In addition, mice had access to food and water at all times. All procedures were performed in accordance with the applicable Polish and European guidelines on the ethics of research involving animals after obtaining the appropriate approvals. Deuterium-containing test compounds (d4-(R)-1, d9-(R)-2, d4-(R)-4, d6-(R)-5, d 11-(R)-6 and d6-(R)-7), as well as the parent hydrogen-containing derivatives 1 and 2 disclosed in patent application No. 429656, PCT / PL2020 / 050028 and patent PL240297, were dissolved in a mixture of DMSO, PEG400 and water for injection (1:4:5, v / v / v) and administered ip to mice at two doses of 20 and 40 mg / kg. Compounds d5-(R)-3, d3-(R)-8, (R)-KA-104, and d4-(R)-KA-104 were administered only at a dose of 40 mg / kg. Compounds 2 and d6-(R)-7 were also tested after intragastric administration at a dose of 40 mg / kg as a solution in a mixture of DMSO / PEG400 / water for injection (1:4:5, v / v / v). Mice were sacrificed by decapitation under deep isoflurane anesthesia at various time points for blood and brain collection, i.e., 5, 15 and 30 min, and 1, 2, 4, 6, 8, 12 and 24 h after administration of test compounds (n=3-4). Blood was allowed to clot for 20 min at room temperature and then centrifuged at 10,000×g (Eppendorf miniSpin centrifuge, Germany) for 5 min to obtain serum. The obtained biomaterials were stored at -70°C until analysis.

[0145] Analysis method The concentrations of the test compounds in mouse serum and brain homogenates were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS). The analysis was performed on a Sciex QTRAP 4500 triple quadrupole mass spectrometer coupled to an Exion LC AC HPLC (Danaher Corporation, USA). Chromatographic separation was performed on a Hypersil Gold™ C18 column (3 × 50 mm, 5 μm, Thermo Scientific, USA) using a mixture of acetonitrile and water + 0.1% formic acid as the mobile phase. The analysis was performed at 40 °C and optimal retention times were obtained using the gradients shown in Table 7. Valsartan was used as an internal standard. Positive ionization mode (ESI+) was used for maximum sensitivity. Ion path parameters were optimized by continuous infusion (7 μL / min) of a solution of the test compound directly into the mass spectrometer using a syringe pump. The optimal parameters of the ion source were the ion spray voltage set at 5500 V and the gas temperature set at 500 °C. Curtain gas pressure was set at 20 psi and collision gas was set at medium. Data were collected and integrated using Analyst 1.7 software. Calibration curves were prepared in the appropriate matrix (serum or brain homogenate) in the ranges of 0.001–5 μg / mL and 0.1–40 μg / mL for serum, and 0.004–20 μg / g and 0.4–80 μg / g for brain tissue. Calibration curves were constructed by weighted (1 / x·x) linear regression analysis. Calculated precision and accuracy values ​​were within the ranges recommended by FDA guidelines for validation of bioanalytical methods. No matrix effects were observed that could significantly affect the accuracy of the assay. The determined compounds were stable during the sample preparation process and under autosampler conditions.

[0146] [Table 8]

[0147] Preparation of standard solutions Stock solutions of test compounds were prepared in methanol at a concentration of 1 mg / mL. Working standard solutions with concentrations of 0.01; 0.1; 0.25; 0.5; 1; 2.5; 5; 10; 50; 100; 200 and 400 μg / mL were then prepared by serial dilution of the stock solutions (effective concentrations of calibration samples were 0.001, 0.01, 0.025, 0.05, 0.1, 0.25, 0.5, 1, 5, 10, 20 and 40 μg / mL). To prepare a calibration curve, 5 μL of working standard solution containing a specific concentration of test compound was added to 45 μL of appropriate matrix (serum or brain homogenate) and mixed for 10 seconds. Samples were then deproteinized with 0.1% formic acid in acetonitrile supplemented with internal standard (1:3 v / v), shaken for 10 min (IKA Vibrax VXR, Germany), and centrifuged at 8000 × g for 5 min (Eppendorf miniSpin centrifuge, Germany). Two calibration curves were prepared to determine the concentrations of the test compounds. For the calibration curves ranging from 0.001 to 5 μg / mL, the supernatants were directly transferred to chromatography vials. For the calibration curves ranging from 0.1 to 40 μg / mL, the supernatants were further diluted 10-fold with the deproteinization reagent and then transferred to chromatography vials.

[0148] Sample preparation Brains were homogenized in 1:4 (w / v) distilled water using a LabGen 125 tissue homogenizer (Cole Parmer, UK). Brain or serum homogenate samples (50 μL) were deproteinized with 0.1% formic acid in acetonitrile supplemented with internal standard (1:3 v / v). Samples were then shaken for 10 min (IKA Vibrax VXR, Germany) and centrifuged at 8000 × g for 5 min (Eppendorf miniSpin centrifuge, Germany). Supernatants were either transferred directly to chromatography vials or diluted 10-fold with deproteinization reagent. Serum samples with test compound concentrations >40 μg / mL before deproteinization were diluted in pure matrix. The autosampler temperature was set to 15 °C and 1 μL was injected into the analytical column.

[0149] Pharmacokinetic analysis Pharmacokinetic parameters were estimated using noncompartmental analysis. max ) and the time required to reach the maximum blood concentration - t max was evaluated directly from the concentration-time plots. The linear trapezoidal rule was used to calculate the area under the concentration-time curve (AUC 0-t ) and the area under the concentration-time curve plotted to infinity (AUC inf ) was calculated. The slope of the terminal phase of the concentration-time curve (λ z ) was calculated using linear regression in Excel (Microsoft Office). 0.5λz ) is related to the relationship: ln2 / λ z The distribution volume (V z / F) is dose / (λ z AUC 0-∞ ) and clearance (CL / F) is calculated using the equation: Dose / AUC 0-∞ In these equations, F is the fraction of the dose absorbed. The mean residence time (MRT) of a compound in the body is given by the equation: AUMC 0-∞ / AUC 0-∞ where AUMC is the area under the first moment curve.

[0150] Evaluation of anticonvulsant activity and effects on motor coordination in in vivo studies in mice General information Experiments were performed in male albino mice (CD-1) weighing 25-30 g, provided by a certified animal facility. All procedures were performed in accordance with the applicable Polish and European guidelines on ethics of research on animals after obtaining appropriate approvals. Substances were administered intraperitoneally after pre-dissolution in a mixture of DMSO, PEG400 and water for injections (1:4:5, v / v / v) as a single injection of 0.1 mL / 10 g bw, 30 min and 2 h before a given test. Initial screening was performed in groups of 4 mice. The mean effective dose (ED 50 ) and the neurotoxic dose (TD) in the rotarod test 50) was estimated based on results obtained in three to four mouse groups of six mice.

[0151] Maximal electroshock seizure test In the maximal electroshock seizure test (MES), seizures were induced by an electrical stimulus of 500 V, 25 mA with a duration of 0.2 seconds. Electrical pulses were generated using an electric shock generator (Rodent Shocker, Type 221, Hugo Sachs Elektronik, Germany) and delivered to the mice using electrodes placed in the ear pinna. The test was performed 30 min / 2 h after intraperitoneal administration of various doses of compounds. During the experiment, the number of mice that experienced a seizure episode in the form of hindlimb tonic extension was counted (Luszczki, JJ et al. Fundam. Clin. Pharmacol. 2008, 22, 69-74).

[0152] Psychomotor seizure test (6Hz test) In the psychomotor seizure test (6 Hz test), seizures were induced by electrical stimulation of 32 mA and / or 44 mA with a frequency of 6 pulses per second. Electrical pulses were generated using an electric shock generator (ECT unit 57800; Ugo Basile, Gemonio, Italy) and delivered to the animals using corneal electrodes. Before starting the test, the ocular surface was gently moistened with a local anesthetic solution (1% lidocaine solution). The test was performed 30 min / 2 h after intraperitoneal administration of various doses of the compound. Electrical stimulation was delivered continuously for 3 s, followed by observation of the mouse for 10 s. During the experiment, the number of mice with episodes of psychomotor convulsions was counted: motor inhibition, staggering, maintaining the sitting position, forelimb clonus, vibrissae twitching and tail lifting were observed (Leclercq, K.; Kaminski, RMEpilepsia 2015, 56, 310-318).

[0153] Subcutaneous (subsutaneous) pentylenetetrazole (scPTZ) seizure test In the subcutaneous (subsutaneous) pentylenetetrazol seizure test, mice received pentylenetetrazol at a dose of 100 mg / kg. Test compounds were administered 30 min and 2 h before the experiment. After PTZ administration, mice were placed individually in transparent cages and observed for a period of 30 min / 2 h. During the experiment, the number of mice with clonic seizures lasting at least 3 seconds accompanied by loss of balance was counted. In addition, the latency of the onset of the first clonic seizure was measured and compared with the control group (Ferreri, G. et al. Pharmacol. Biochem. Behav. 2004, 77, 859-894; Laczkowski, K. et al. J. Enzym Inhib. Med. Chem. 2016, 31, 1576-1582).

[0154] Effects on mouse coordination in the rotarod test The effect of the test compounds on motor coordination was evaluated in the rotarod test (May Commat, RR 0711 RotaRod, Turkey). On the day before the actual experiment, mice were trained for 3 min on a rod rotating at 10 revolutions per minute (rpm). Experiments were performed 30 min and 2 h after compound administration. The motor coordination of the mice was tested for 60 s at a speed of the rotarod: 10 rpm. The measure of neurotoxicity was the inability to stay on the rod for a given time (Luszczki, JJ et al. Eur. Neuropsychopharmacol. 2005, 6, 609-616).

[0155] statistical analysis ED with corresponding 95% confidence limits 50 (effective dose) and TD 50 The (toxic dose) values ​​were calculated based on the Litchfield-Wilcoxon method (Litchfield, JT; Wilcoxon, FJ Pharmacol. Exp. Ther. 1949, 96, 99-113). To perform a statistical evaluation of the results of the scPTZ test, one-way ANOVA analysis of variance followed by Dunnett's post hoc test was used. Values ​​were considered statistically significant when p<0.05.

[0156] Assessment of antinociceptive activity and effects on locomotor activity in in vivo studies in mice General information Experiments were performed in male albino mice (CD-1) weighing 25-30 g, provided by a certified animal facility. All procedures were performed in accordance with the applicable Polish and European guidelines on ethics of research on animals after obtaining appropriate approvals. Substances were administered intraperitoneally after suspension in 1% Tween 80 solution as a single injection of 0.1 mL / 10 g bw, 30 min before a given test.

[0157] Antinociceptive activity All tests / models were performed according to procedures described in the expert literature: formalin test (Beirith et al. Eur. J. Pharmacol. 1998, 345, 233-245), capsaicin-induced pain model (Mogilski et al. Pharmacol. Biochem. Behav. 2015, 133, 99-110), oxaliplatin-induced neuropathic pain model - von Frey test (Salat et al. Pharmacol. Biochem. Behav. 2014, 122, 173-181), streptozocin-induced diabetic neuropathic pain model - von Frey test (Salat et al. Neuropharmacology 2017, 125, 181-188; Tanabe et al. J. Pharmacol. Sci. 2008, 107, 213-220). Test groups consisted of 8-10 mice.

[0158] Locomotor activity test in mice The evaluation of the influence of the test compounds on the locomotor activity of mice (evaluation of sedative or activating effects) was carried out using cages with dimensions 40 x 40 x 31 cm (Activity Cage; Ugo Basile, Gemonio VA, Italy) according to the methodology described in the scientific literature (Mogilski et al. Inflamm. Res. 2017, 66, 79-95). The compounds were administered 30 min before the experiment. The number of beam crossings in each group was counted in 10 min intervals for the next 30 min. The test groups consisted of 10 mice.

[0159] Assessment of metabolic stability in mouse microsomes Metabolic stability evaluation was performed using mouse liver microsomes (MLM) and human liver microsomes (HLM) purchased from Sigma-Aldrich (St. Louis, MO, USA). Detailed methodology is described in the literature (Kaminski et al. J. Med. Chem. 2015, 58, 5274-5286). Reaction mixtures were prepared by mixing 50 mM test compound with mouse or human microsomes (1 mg / mL) in 10 mM TRIS-HCl buffer. The reaction mixtures were preincubated at 37 °C for 5 min. After the initial incubation, 50 μL of NADPH regenerating system (Promega, Madison, WI, USA) was added to initiate the reaction. The reaction mixtures were then incubated at 37 °C for 120 min. The reaction was completed by adding 200 μL of cold primary methanol. The mixture was then centrifuged at 14,000 g for 15 min and the supernatant was analyzed using a Waters ACQUITY™ TQD LC / MS system equipped with a TQ detector (Waters, Milford, USA). Each experiment was performed in triplicate.

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, A is hydrogen or deuterium, and at least one A is deuterium; B is hydrogen or deuterium; X is hydrogen, deuterium, or fluorine; Y is hydrogen or deuterium).

2. The compound of claim 1, wherein each A is deuterium.

3. (R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(phenylmethyl-d ２ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl-d ２ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((2-fluorophenyl)methyl-d ２ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(2-fluorobenzyl)propanamide, (S)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ ) propanamide, (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl) propanamide, (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(2-fluorobenzyl)propanamide, (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(phenylmethyl-d ２ ) propanamide, (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl-d ２ ) propanamide, (S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((2-fluorophenyl)methyl-d ２ ) propanamide, (R,S)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ ) propanamide, (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl) propanamide, (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(2-fluorobenzyl)propanamide, (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(phenylmethyl-d ２ ) propanamide, (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl-d ２ ) propanamide, (R,S)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((2-fluorophenyl)methyl-d ２ ) Propanamide 2. The compound according to claim 1, characterized in that it is selected from the group consisting of:

4. (R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(2-fluorobenzyl)propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-(phenylmethyl-d ２ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((phenyl-d ５ ) methyl-d ２ ) propanamide, (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d ４ )-N-((2-fluorophenyl)methyl-d ２ ) Propanamide 2. The compound according to claim 1, characterized in that it is selected from the group consisting of:

5. The compound of claim 1, wherein the compound is (R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d 4 )propanamide.

6. The compound of claim 1, wherein the compound is (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d 4 )-N-(phenylmethyl-d 2 )propanamide.

7. The compound of claim 1, wherein the compound is (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d 4 )-N-((phenyl-d 5 )methyl)propanamide.

8. The compound of claim 1, wherein the compound is (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d 4 )-N-((phenyl-d 5 )methyl-d 2 )propanamide.

9. The compound of claim 1, wherein the compound is (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d 4 )-N-(2-fluorobenzyl)propanamide.

10. The compound of claim 1, wherein the compound is (R)-2-(2,5-dioxopyrrolidin-1-yl-3,3,4,4-d 4 )-N-((2-fluorophenyl)methyl-d 2 )propanamide.

11. A medicament comprising a compound according to any one of claims 1 to 10.

12. A drug for use in the treatment or prevention of a neurological disease, in particular epilepsy, neuropathic pain, migraine or inflammatory pain or depression or anxiety or a neurodegenerative disease, comprising a compound according to any one of claims 1 to 10.

13. A medicament for use in the treatment or prevention of migraine or neuropathic pain, comprising a compound according to any one of claims 1 to 10.

14. The drug according to claim 12, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis.

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