Phenylpiperazinamide derivatives modified with aliphatic amino acid fragments for the treatment of neurological diseases

Abstract

A group of chemical compounds, particularly for the treatment of neurological diseases, is disclosed, being phenylpiperazinamides modified with fragments of non-aromatic amino acids. (Formula I)

Description

[0001] t Phenylpiperazinamide derivatives modified with aliphatic amino acid fragments for the treatment of neurological diseases

[0002] The invention relates to chemical compounds which are structurally amide derivatives of bioisosterically substituted phenylpiperazines in which the acyl fragment is formed by aliphatic amino acid derivatives (a-alanine or 2-amino-3-m ethoxypropanoic acid [O-methyl serine]). In vivo pharmacological studies conducted in mice have shown that the disclosed substances have a stronger protective effect in the 6 Hz (44 mA) model, which is the basic animal model of human drug-resistant seizures, compared to substances with a similar chemical structure currently available in the art. The compounds of the present invention also act effectively in additional models of epileptic seizures; in particular in the maximal electroshock test (MES) as well as in the 6 Hz (32 mA) model. In the case of selected substances, a strong antinociceptive effect has also been proven in pain models (including in neuropathic pain). Therefore, the present invention discloses original compounds that can be used as active substances for medicinal formulations employed in particular in neurological diseases, i.e. epilepsy (preferably in drug-resistant epilepsy), neuropathic pain, and also taking into account the results obtained in inflammatory pain.

[0003] State of the art

[0004] The identification and development of new antiepileptic drug candidates is invariably based on the use of a broad panel of animal models of epileptic seizures. The most important of these include MES, 6 Hz (32 mA) and 6 Hz (44 mA) in which seizures are induced by an electrical stimulus and scPTZ in which seizures are induced chemically by the subcutaneous administration of pentylenetetrazol to the animals. It should be emphasized that due to the simplicity and ease of interpretation of the obtained results and good translation of the results from animals to humans, 6 Hz (44 mA) and MES tests are currently most commonly used in screening tests.

[0005] The 6 Hz (44 mA) model is currently the primary test used to identify candidates for the therapy of drug-resistant seizures. Therefore, it was implemented and is used as the first screening test by the American ETSP program (Epilepsy Therapy Screening Program of the National Institute of

[0006] Neurological Disorders and Stroke, NIH, Bethesda, MD, USA) which focuses on the development of new formulations effective in the treatment of drug-resistant epilepsy. Drug-resistant epilepsy remains a significant clinical problem because it affects 30-40% of epileptic patients. It is worth emphasizing that the 6 Hz (44 mA) model is also used to differentiate the anticonvulsant efficacy and thus the clinical usefulness of approved drugs and candidates for new antiepileptic drugs. Importantly, a number of antiepileptic drugs well-established in pharmacotherapy are inactive or exhibit significantly weaker activity in the 6 Hz model (44 mA) than in 6 Hz seizures using lower current intensity, i.e. 22 or 32 mA, which are considered to be animal equivalents of human focal seizures. Such a relationship has been observed for example for levetiracetam and valproic acid (Epilepsy Res. 2001, 47, 217-227 ). Therefore, the 6 Hz (44 mA) test is particularly useful for identifying candidates for new antiepileptic drugs intended for the treatment of drug-resistant seizures (Neurochem. Res. 2017, 42, 1894-1903).

[0007] The second model of epileptic seizures widely used in preclinical research is the MES test. In this test, anticonvulsant activity is demonstrated by compounds that block sodium conduction, e.g. lacosamide, phenytoin or carbamazepine; formulations whose mechanism of action is related to the enhancement of inhibitory GABAergic neurotransmission, e.g. phenobarbital, and drugs that inhibit excitatory glutamatergic neurotransmission (topiramate). The MES model is considered to be equivalent to generalized tonic-clonic seizures and partial seizures with or without secondary generalization in humans (Methods Find. Exp. Clin. Pharmacol. 2009, 31, 101-106). Taking the above facts into account, compounds that act effectively in the 6 Hz (44 mA) and MES models may be candidates for the therapy of various types of seizures, i.e. generalized tonic-clonic seizures, partial seizures with or without secondary generalization and, what is worth emphasizing, drug-resistant seizures, and also focal seizures in the case of activity in the 6 Hz (32 m) test.

[0008] Previous studies on the group of amide amino acid derivatives with a pyrrolidine-2, 5-dione core (or an acetamide fragment) have shown that a number of such compounds are active in various animal models of epileptic seizures (Eur. J. Med. Chem. 2011, 464634-4641, J. Med. Chem. 2015, 58, 5274-5286, Eur. J. Med. Chem. 2015, 102, 14-25, Bioorg. Med. Chem. 2016, 24, 1598-1607,

[0009] Bioorg. Med. Chem. 2016, 26, 2147-2151, Eur. J. Pharmacol. 2016, 781 239-249, J. Med. Chem. 2017, 60, 8565-8579, Arch. Pharm. Chem. Life Sci. 2017, 350, 1600368, Int. J. Mol. Sci. 2020, 21, 5750, ACS Chem. Neurosci. 2020, 11, 1996-2008, Epilepsia 2020, 61, 2119-2128, Int. J. Mol. Sci. 2021, 22, 13092; Bioorg. Chem. 2021, 109, 104751, Arch. Pharm. 2021, 354, 2000225, ChemMedChem 2021, 16, 1619-163, Cells 2022, 11, 1862). Among them, the most favorable pharmacological properties have been revealed by compounds in which the central fragment of the molecule is formed by phenylglycine, alanine and O-methyl serine (Fig. 1), i.e. KA-104, a pyrrolidine-2, 5-dione derivative containing a phenylglycine residue (ACS Chem. Neurosci. 2020, 11, 1996-2008, Epilepsia 2020, 61, 2119-2128); KA-11, a pyrrolidine-2, 5-dione derivative with anα- alanine fragment (J. Med. Chem. 2015, 58, 5274-5286); KA-93, a pyrrolidine-2, 5-dione derivative with an O-methyl-serine moiety (J. Med. Chem. 2017, 60, 8565-8579), and compounds in which succinimide was replaced by an acetamide group, including KJ-5, a phenylglycine derivative (Cells 2022, 11, 1862). As a result, the ED50values in the MES test for the α-alanine derivative (KA-11) and O-methyl serine (KA-93) were above 80 mg / kg, and in the 6 Hz (32 mA) test they were above 20 mg / kg (within 30 minutes after IP administration). Among the phenylglycine derivatives, at the same time point the strongest anticonvulsant activity in mice was observed for compound KA-104, ED50(MES) = 23.7 mg / kg, ED50(6 Hz, 32 mA) = 29.9 mg / kg, ED50(6 Hz, 44 mA) = 73.2 mg / kg, while substitution of the cyclic pyrrolidine-2, 5-dione fragment with an acyclic acetamide moiety led to a significant (4-fold) attenuation of protection in the MES test, ED50= 89.9 mg / kg and a slight decrease or increase in activity in the 6 Hz (32 mA) - EDso= 29.9 mg / kg and 6 Hz (44 mA) - EDso= 68.0 mg / kg models, respectively. It should be strongly emphasized that among the amino acid amide derivatives obtained so far, no combinations have been obtained that would be characterized by a strong protective effect in the 6 Hz (44 mA) model with required ED50values around or below 30 mg / kg and the MES model with ED50values around or preferably below 70 mg / kg in mice after intraperitoneal administration.

[0010] Technical problem

[0011] Taking the above facts into account, the technical problem solved by the present invention is to provide a new chemotype of compounds characterized by broad anticonvulsant activity that can be observed in animal models of epileptic seizures, i.e. MES, 6 Hz (32 mA) and 6 Hz (44 mA). In particular, these compounds should be characterized by a stronger protective effect in mice after intraperitoneal (IP) administration in the 6 Hz (44 mA) test, preferably effective doses (ED50) of about or preferably below 30 mg / kg and ED50values in the MES test of about or preferably below 70 mg / kg than substances with a similar chemical structure known in the art. In addition, these compounds should have antinociceptive effects in animal models of pain, including in particular in models of neuropathic pain. Compounds with such an activity profile in the in vivo studies may be candidates for drugs for the treatment of epilepsy (especially drug-resistant epilepsy) and pain of neurological or inflammatory origin.

[0012] Summary of the invention

[0013] The object of the invention is a compound selected from the derivatives of N-(1-oxo-1-(4- phenylpiperazin-1-yl)propan-2-yl)acetamide represented by the general formula (I): wherein:

[0014] A is hydrogen or deuterium,

[0015] B is hydrogen or deuterium,

[0016] X is hydrogen or deuterium,

[0017] R1is a trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or phenyl group,

[0018] R2is a methyl, ethyl or methoxymethylene group,

[0019] Preferably, the compound of the invention is selected from:

[0020] (R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0021] (Compound (R,S)-1, wherein A=H, B=H, X=H, R1=CF3, R2=CH3)

[0022] (R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0023] (Compound (R)-1, wherein A=H, B=H, X=H, R1=CF3, R2=CH3) (S)-N-( 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2-yl)acetamide

[0024] (Compound (S)-1, wherein A=H, B=H, X=H, R1=CF3, R2=CH3)

[0025] (R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide

[0026] (Compound d1-(R,S)-1, wherein A=H, B=H, X=D, R1=CF3, R2=CH3)

[0027] (R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide

[0028] (Compound d1-(R)-1, wherein A=H, B=H, X=D, R1=CF3, R2=CH3)

[0029] (S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide

[0030] (Compound d1-(S)-1, wherein A=H, B=H, X=D, R1=CF3, R2=CH3)

[0031] (R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-d3

[0032] (Compound d3- (R,S)-1, wherein A=D, B=H, X=H, R1=CF3, R2=CH3)

[0033] (R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3

[0034] (Compound d3- (R)-1, wherein A=D, B=H, X=H, R1=CF3, R2=CH3)

[0035] (S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3

[0036] (Compound d3- (S)-1, wherein A=D, B=H, X=H, R1=CF3, R2=CH3)

[0037] (R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-

[0038] 2,2,2-d3(Compound d4-(R,S)-1, wherein A=D, B=H, X=D, R1=CF3, R2=CH3)

[0039] (R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-

[0040] 2,2,2-d3(Compound d4-(R)-1, wherein A=D, B=H, X=D, R1=CF3, R2=CH3)

[0041] (S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-

[0042] 2,2,2-d3(Compound d4-(S)-1, wherein A=D, B=H, X=D, R1=CF3, R2=CH3)

[0043] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -y1-2,2, 3 ,3 , 5 , 5 , 6,6-d8)propan-

[0044] 2-yl)acetamide (Compound d9-(R,S)-1, wherein A=H, B=D, X=D, R1=CF3, R2=CH3)

[0045] (R)-N-(l -oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1 -y1-2,2, 3 ,3 ,5 ,5 ,6,6-d8)propan-2- yl)acetamide (Compound d9-(R)-1, wherein A=H, B=D, X=D, R1=CF3, R2=CH3)

[0046] (S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2- yl)acetamide (Compound d9- (S)-1, wherein A=H, B=D, X=D, R1=CF3, R2=CH3) (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)pheny1-4-d)piperazin- 1 -y1-2,2, 3 ,3 , 5 , 5 , 6,6-d8)propan-

[0047] 2-yl)acetamide-2,2,2-d3(Compound di2-(R,S)-1, wherein A=D, B=D, X=D, R1=CF3, R2=CH3)

[0048] (R)-N-(l -oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1 -y1-2,2, 3 ,3 ,5 ,5 ,6,6-d8)propan-2- yl)acetamide-2,2,2-d3(Compound di2-(R)-1, wherein A=D, B=D, X=D, R1=CF3, R2=CH3)

[0049] (S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2- yl)acetamide-2,2,2-d3(Compound di2- (S)-1, wherein A=D, B=D, X=D, R1=CF3, R2=CH3)

[0050] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2-yl)acetamide

[0051] (Compound (R,S)-2, wherein A=H, B=H, X=H, R1=OCF3, R2=CH3)

[0052] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0053] (Compound (R)-2, wherein A=H, B=H, X=H, R1=OCF3, R2=CH3)

[0054] (S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0055] (Compound (S)-2, wherein A=H, B=H, X=H, R1=OCF3, R2=CH3)

[0056] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2-yl)acetamide

[0057] (Compound d1-(R,A)-2, wherein A=H, B=H, X=D, R1=OCF3, R2=CH3)

[0058] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide

[0059] (Compound d1-(R)-2, wherein A=H, B=H, X=D, R1=OCF3, R2=CH3)

[0060] (S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide

[0061] (Compound d1- (S)-2, wherein A=H, B=H, X=D, R1=OCF3, R2=CH3)

[0062] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2-yl)acetamide-

[0063] 2.2.2-d3(Compound d3-(R,A)-2, wherein A=D, B=H, X=H, R1=OCF3, R2=CH3)

[0064] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2- d3(Compound d3- (R)-2, wherein A=D, B=H, X=H, R1=OCF3, R2=CH3)

[0065] (S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )phenyl)piperazin-1-yl)propan-2-yl)acetamide-2, 2, 2- d3(Compound d3- (S)-2, wherein A=D, B=H, X=H, R1=OCF3, R2=CH3)

[0066] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2-yl)acetamide-

[0067] 2.2.2-d3(Compound d4-(R,A)-2, wherein A=D, B=H, X=D, R1=OCF3, R2=CH3) (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide- 2,2,2-d3(Compound d4-(R)-2, wherein A=D, B=H, X=D, R1=OCF3, R2=CH3)

[0068] (S)-N-(1 -oxo-1 -(4-(3-(trifluorom ethoxy )pheny1-4-d)piperazin- 1 -yl)propan-2-yl)acetamide-

[0069] 2,2,2-d3(Compound d4- (S)-2, wherein A=D, B=H, X=D, R1=OCF3, R2=CH3)

[0070] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(piperazi n- 1 -y1-2,2, 3 , 3 , 5 , 5 , 6,6- d8(propan-2-yl (acetamide (Compound d9-(R,S)-2, wherein A=H, B=D, X=D, R1=OCF3, R2=CH3)

[0071] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-

[0072] 2-yl)acetamide (Compound d9-(R)-2, wherein A=H, B=D, X=D, R1=OCF3, R2=CH3)

[0073] (S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan- 2-yl)acetamide (Compound d9-(.S'(-2, wherein A=H, B=D, X=D, R1=OCF3, R2=CH3)

[0074] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2, 3 , 3 , 5 , 5 , 6,6- d8)propan-2-yl)acetamide-2,2,2-d3(Compound d12-(R,S)-2, wherein A=D, B=D, X=D, R1=OCF3, R2=CH3)

[0075] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan- 2-yl)acetamide-2,2,2-d3(Compound d12-(R)-2, wherein A=D, B=D, X=D, R1=OCF3, R2=CH3)

[0076] (S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan- 2-yl)acetamide-2,2,2-d3(Compound d12-(S)-2, wherein A=D, B=D, X=D, R1=OCF3, R2=CH3)

[0077] (R,S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0078] (Compound (R,S)-3, wherein A=H, B=H, X=H, R1=SCF3, R2=CH3)

[0079] (R)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0080] (Compound (R)-3, wherein A=H, B=H, X=H, R1=SCF3, R2=CH3)

[0081] (S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0082] (Compound (S)-3, wherein A=H, B=H, X=H, R1=SCF3, R2=CH3)

[0083] (R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)phenyl)piperazin- 1 -yl)butan-2-yl)acetamide

[0084] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R,S)-4, wherein A=H, B=H, X=H, R1=CF3, R2=CH2OCH3) (R)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R)-4. wherein A=H, B=H, X=H, R1=CF3, R2=CH2OCH3)

[0085] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (S)-4, wherein A=H, B=H, X=H, R1=CF3, R2=CH2OCH3)

[0086] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide (Compound d1-(R,S)-4, wherein A=H, B=H, X=D, R1=CF3, R2=CH2OCH3)

[0087] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(tri fl uorom ethyl Jphenyl -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide (Compound d1-(R)-4, wherein A=H, B=H, X=D, R1=CF3, R2=CH2OCH3)

[0088] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide (Compound d1-(S)-4, wherein A=H, B=H, X=D, R1=CF3, R2=CH2OCH3)

[0089] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(R,S)-4, wherein A=D, B=H, X=H, R1=CF3, R2=CH2OCH3)

[0090] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(R)-4, wherein A=D, B=H, X=H, R1=CF3, R2=CH2OCH3)

[0091] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(S)-4, wherein A=D, B=H, X=H, R1=CF3, R2=CH2OCH3)

[0092] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound dt-(R,S)-4, wherein A=D, B=H, X=D, R1=CF3, R2=CH2OCH3)

[0093] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(tri fl uorom ethyl Jphenyl -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound dt-(R,S)-4, wherein A=D, B=H, X=D, R1=CF3, R2=CH2OCH3)

[0094] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound (h-(R,S)-4, wherein A=D, B=H, X=D, R1=CF3, R2=CH2OCH3)

[0095] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -y1-

[0096] 2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide (Compound d9-(R,S)-4, wherein A=H, B=D, X=D,

[0097] R1=CF3, R2=CH2OCH3) (R)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide (Compound d9-(R)-4, wherein A=H, B=D, X=D, R1=CF3, R2=CH2OCH3)

[0098] (S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide (Compound d9- (S)-4, wherein A=H, B=D, X=D, R1=CF3,

[0099] R2=CH2OCH3)

[0100] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)pheny1-4-d)piperazin- 1 -y1- 2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide-2,2,2-d3(Compound d12-(R,S)-4, wherein A=D, B=D, X=D, R1=CF3, R2=CH2OCH3)

[0101] (R)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3(Compound d12-(R)-4, wherein A=D, B=D, X=D, R1=CF3, R2=CH2OCH3)

[0102] (S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3(Compound di2-(S)-4, wherein A=D, B=D, X=D, R1=CF3, R2=CH2OCH3)

[0103] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R,S)-5, wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0104] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R)-5, wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0105] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (S)-5, wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0106] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy Jpheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide (Compound d1-(R,S)-5, wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3)

[0107] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy Jphenyl -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide (Compound d1-(R)-5, wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3)

[0108] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy Jpheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide (Compound d1-(S)-5, wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3) (R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(R,S)-5, wherein A=D, B=H, X=H, R1=OCF3,

[0109] R2=CH2OCH3)

[0110] (R)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluorom ethoxy)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(R)-5, wherein A=D, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0111] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(S)-5, wherein A=D, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0112] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d4-(R,S)-5, wherein A=D, B=H, X=D, R1=OCF3,

[0113] R2=CH2OCH3)

[0114] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d4-(R,S)-5, wherein A=D, B=H, X=D, R1=OCF3,

[0115] R2=CH2OCH3)

[0116] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d4-(R,S)-5, wherein A=D, B=H, X=D, R1=OCF3,

[0117] R2=CH2OCH3)

[0118] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0119] 2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide (Compound &9-(R,S)-5, wherein A=H, B=D, X=D,

[0120] R1=OCF3, R2=CH2OCH3)

[0121] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0122] 2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide (Compound d9-(R)-5, wherein A=H, B=D, X=D,

[0123] R1=OCF3, R2=CH2OCH3)

[0124] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0125] 2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide (Compound d9-(S)-5, wherein A=H, B=D, X=D,

[0126] R1=OCF3, R2=CH2OCH3) (R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0127] 2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide-2,2,2-d3(Compound di2-(R,S)-5, wherein A=D, B=D,

[0128] X=D, R1=OCF3, R2=CH2OCH3)

[0129] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0130] 2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide-2,2,2-d3(Compound di2-(R)-5, wherein A=D, B=D,

[0131] X=D, R1=OCF3, R2=CH2OCH3)

[0132] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0133] 2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide-2,2,2-£ / 3(Compound di2-(S)-5, wherein A=D, B=D,

[0134] X=D, R1=OCF3, R2=CH2OCH3)

[0135] (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(thiotrifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R,S)-6, wherein A=H, B=H, X=H, R1=SCF3, R2=CH2OCH3)

[0136] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(thiotrifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R)-6, wherein A=H, B=H, X=H, R1=SCF3, R2=CH2OCH3)

[0137] (S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(thiotrifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (S)-6, wherein A=H, B=H, X=H, R1=SCF3, R2=CH2OCH3)

[0138] (R, 5)-N-(1-(4-([l,r-biphenyl]-3-yl)piperazin-1-yl)-3-m ethoxy- 1-oxopropan-2-yl)acetamide

[0139] (Compound (R,S)-7, wherein A=H, B=H, X=H, R1=C6H5, R2=CH2OCH3)

[0140] (R)-N-(l -(4-([ 1,1’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)acetamide

[0141] (Compound (R)-7, wherein A=H, B=H, X=H, R1=C6H5, R2=CH2OCH3)

[0142] (R, 5)-N-(1-(4-([l,r-biphenyl]-3-yl)piperazin-1-yl)-3-m ethoxy- 1-oxopropan-2-yl)acetamide

[0143] (Compound (R)-7, wherein A=H, B=H, X=H, R1=C6H5, R2=CH2OCH3)

[0144] (R, 5)-N-(1-(4-([l,r-biphenyl]-3-yl)piperazin-1-yl)-3-m ethoxy- 1-oxopropan-2-yl)acetamide-

[0145] 2.2.2-d3(Compound d3-(R,.S’(-7, wherein A=D, B=H, X=H, R1=C6H5, R2=CH2OCH3)

[0146] (R)-N-(l -(4-([ 1,1’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)acetamide-

[0147] 2.2.2-d3(Compound d3-(R)-7, wherein A=D, B=H, X=H, R1=C6H5, R2=CH2OCH3)

[0148] (S)-N-( 1 -(4-([ 1 , 1’ -biphenyl] -3 -yl)piperazin- 1 -y 1 )- 3 -methoxy- 1 -oxopropan-2-yl)acetamide-

[0149] 2.2.2-d3(Compound d3- (S)-7, wherein A=D, B=H, X=H, R1=C6H5, R2=CH2OCH3) (R, S)-N-(l -oxo- 1-(4-(3-(trifluorom ethoxy )phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0150] (Compound (R,S)-8, wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5)

[0151] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0152] (Compound (R)-8, wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5)

[0153] (S)-N-(l -oxo- 1-(4-(3 -(tri fluorom ethoxy )phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0154] (Compound (S)-8, wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5)

[0155] (R,S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2- d3(Compound d3-(R,.S')-8, wherein A=D, B=H, X=H, R1=OCF3, R2=C2Hs)

[0156] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2-d3(Compound d3-(R)-8, wherein A=D, B=H, X=H, R1=OCF3, R2=C2H5)

[0157] (S)-N-(l -oxo- 1-(4-(3 -(tri fluorom ethoxy )phenyl)piperazin-1-yl)butan-2-yl)acetamide-2, 2, 2-d3

[0158] (Compound d3-(S)-8, wherein A=D, B=H, X=H, R1=OCF3, R2=C2Hs)

[0159] (R,S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0160] (Compound (R,S)-9, wherein A=H, B=H, X=H, R1=SCF3, R2=C2H5)

[0161] (R)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0162] (Compound (R)-9, wherein A=H, B=H, X=H, R1=SCF3, R2=C2H5)

[0163] (S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0164] (Compound (S)-9, wherein A=H, B=H, X=H, R1=SCF3, R2=C2H5)

[0165] In a particularly preferred embodiment, the object of the invention is a compound selected from the group consisting of derivatives with the R configuration of the stereogenic center located at C- 2 and also containing the -OCF3group as R1in the general formula (I):

[0166] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0167] (Compound (R)-2, wherein A=H, B=H, X=H, R1=OCF3, R2=CH3)

[0168] (R)- / ' / -(! -oxo- l -(4-(3-(trifluoromethoxy)phenyl-4-d)piperazin- l -yl)propan-2-yl)acetamide

[0169] (Compound d1-(R)-2, wherein A=H, B=H, X=D, R1=OCF3, R2=CH3)

[0170] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2- d3(Compound d3-(R)-2, wherein A=D, B=H, X=H, R1=OCF3, R2=CH3) (R(-A-(1-oxo-1-(4-(3-(trifluoromethoxy(phenyl-4-d(piperazin-1-yl(propan-2-yl(acetamide- 2,2,2-d3(Compound d4-(R)-2, wherein A=D, B=H, X=D, R1=OCF3, R2=CH3)

[0171] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan- 2-yl)acetamide (Compound d9-(R)-2, wherein A=H, B=D, X=D, R1=OCF3, R2=CH3)

[0172] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan- 2-yl)acetamide-2,2,2-d3(Compound di2-(R)-2, wherein A=D, B=D, X=D, R1=OCF3, R2=CH3)

[0173] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethoxy)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide (Compound (R)-5, wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0174] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(tri fl uoromethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide (Compound d1-(R)-5, wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3)

[0175] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethoxy)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d3-(R)-5, wherein A=D, B=H, X=H, R1=OCF3, R2=CH2OCH3)

[0176] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(tri fl uoromethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3(Compound d4-(R)-5, wherein A=D, B=H, X=D, R1=OCF3, R2=CH2OCH3)

[0177] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(tri fl uoromethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0178] 2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide (Compound d9-(R)-5, wherein A=H, B=D, X=D,

[0179] R1=OCF3, R2=CH2OCH3)

[0180] (R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(tri fl uoromethoxy (phenyl -4-d(pi perazi n- 1 -y1-

[0181] 2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide-2,2,2-d3(Compound di2-(R)-5, wherein A=D, B=D, X=D, R1=OCF3, R2=CH2OCH3)

[0182] (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0183] (Compound (R)-8, wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5)

[0184] (A>(-IV-(1-oxo-1-(4-(3-(trifluoromethoxy(phenyl(piperazin-1-yl(butan-2-yl(acetamide-2,2,2-d3

[0185] (Compound d3-(R)-8, wherein A=D, B=H, X=H, R1=OCF3, R2=C2H5)

[0186] Another subject of the invention is a compound as defined above intended for use in pharmacy, especially for the treatment (or prevention) of neurological diseases, including epilepsy, neurological pain (including neuropathic pain) and inflammatory pain or migraine. Preferably, the compound of the invention is intended to induce an anticonvulsant or analgesic effect.

[0187] For a better understanding of the subject of the invention, it is explained in the attached figures and tables contained in the body of the application.

[0188] Figure 1 shows the structures and anticonvulsant activity of the compounds: KA-11 (designated as compound 11 in J. Med. Chem. 2015, 58, 5274-5286), KA-93 (designated as compound 32 in J. Med. Chem. 2017, 60, 8565-8579), KA- 104 (designated as compound 22 in ACS Chem. Neurosci. 2020, 11, 1996-2008, Epilepsia 2020, 61, 2119-2128), KJ-5 (designated as compound 53 in Cells 2022, 11, 1862).

[0189] Figure 2 shows the activity of compound ( / / )-! in an in vitro model of spontaneous discharges caused by kainic acid-induced status epilepticus in slices of the rat entorhinal cortex. Values represent means ± SD for: A - 7 sections (concentration of 80 μM) and B - 8 sections (concentration of 120 μM). Exposure time to the compound was 20 minutes. Statistical analysis: Student’s t-test for dependent samples: *p<0.05, **p<0.01 compared to control (DMSO).

[0190] Figure 3 shows the structure, anticonvulsant activity in the MES test, 6 Hz (32 / 44 mA) (S) and activity in the in vitro model of spontaneous discharges caused by kainic acid-induced status epilepticus in slices of rat entorhinal cortex for the negative example, (R)-KJ-28 (B, C). (R)-KJ-28 at a concentration of 80 μM (B) and 120 μM (C) does not affect the number and timing of spontaneous neuronal discharges. Values represent means ± SD for 8 sections (80 μM) and 10 sections (120 μM). Exposure time to the compound was 20 minutes. Statistical analysis: Student’s t-test for dependent samples: *p<0.05, **p<0.01 compared to control (DMSO).

[0191] Figure 4 shows the antinociceptive activity of compound (R,S)-2 in phase I and 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 means ± SEM for groups of 8-10 animals. The difference was statistically significant compared to the control group (0) which received the vehicle only (Tween 80, 1% aqueous solution). Statistical analysis: One-way ANOVA (Dunnett’s post-hoc test): **p<0.01, ****p<0.0001. Figure 5 shows the antinociceptive activity of compound (R,S)-2 in the capsaicin test, where the results are presented as paw licking time within 5 min after capsaicin injection. The test was conducted 30 minutes after compound administration. Values represent means ± SEM for groups of 8-10 animals. The difference was statistically significant compared to the control group (0) which received the vehicle only (Tween 80, 1% aqueous solution). Statistical analysis: One-way ANOVA (Dunnett’s post-hoc test): ***p<0.001, ****p<0.0001.

[0192] Figure 6 shows the antinociceptive activity of compound (R,S)-2 in the oxaliplatin-induced neuropathic pain (OXPT) model. The results represent the pain threshold for mechanical allodynia in the von Frey test 30 minutes after compound administration. Values represent means ± SEM for groups of 8-10 animals. Statistical analysis after OXPT administration compared to the control group (1% Tween 80 solution) - ANOVA with repeated measures (Dunnett’s post-hoc test):Λp < 0.05,ΛΛp<0.01ΛΛΛp<0.001. Statistical analysis after OXPT administration compared with the results after administration of oxaliplatin and the test compound (OXPT + (R,S)-2) - repeated measures ANOVA (Dunnett’s post-hoc test): *p<0.05, **p<0.01.

[0193] Figure 7 shows the antinociceptive activity of compound (R,S)-2 in the hyperglycemia-induced neuropathic pain model after streptozotocin (STZ) administration. The results represent the pain threshold for mechanical allodynia in the von Frey test 30 minutes after compound administration. The control group (0) was given the vehicle (1% aqueous Tween 80 solution). Values represent means ± SEM for groups of 8-10 animals. Statistical analysis after STZ administration compared to control group 0 (1% Tween 80 solution) - one-way ANOVA (Dunnett’s post-hoc test):Λp < 0.05,ΛΛΛp<0.001. Statistical analysis after STZ administration compared with the results after administration of STZ and the test compound (STZ + (R,S)-2) - repeated measures ANOVA (Bonferroni post-hoc test): **p < 0.01, ***p < 0.001.

[0194] Figure 8 shows the antinociceptive activity of compound (R)-5 in phase I and 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 means

[0195] ± SEM for groups of 8-10 animals. The difference was statistically significant compared to the control group (0) which received the vehicle only (Tween 80, 1% aqueous solution). Statistical analysis: One-way ANOVA (Dunnett’s post-hoc test): **p<0.01, ***p<0.001, ****p<0.0001.

[0196] Figure 9 shows the antinociceptive activity of compound (R)-5 in the capsaicin test, where the results are presented as paw licking time within 5 min after capsaicin injection. The test was conducted 30 minutes after compound administration. Values represent means ± SEM for groups of 8-10 animals. The difference was statistically significant compared to the control group (0) which received the vehicle only (Tween 80, 1% aqueous solution). Statistical analysis: One-way ANOVA (Dunnett’s post-hoc test): **p<0.01, ****p<0.0001.

[0197] Figure 10 shows the antinociceptive activity of compound (R)-5 in the oxaliplatin-induced neuropathic pain (OXPT) model. The results represent the pain threshold for mechanical allodynia in the von Frey test 30 minutes after compound administration. Values represent means ± SEM for groups of 8-10 animals. Statistical analysis after OXPT administration compared to the control group (1% Tween 80 solution) - ANOVA with repeated measures (Dunnett’s post-hoc test):Λp < 0.05,ΛΛp<0.01. Statistical analysis after OXPT administration compared with the results after administration of oxaliplatin and the test compound (OXPT + (S)-5) - repeated measures ANOVA (Dunnett’s post-hoc test): *p<0.05, **p<0.01, ***p<0.001.

[0198] Figure 11 shows the antinociceptive activity of compound (R)-5 in the hyperglycemia-induced neuropathic pain model after streptozotocin (STZ) administration. The results represent the pain threshold for mechanical allodynia in the von Frey test 30 minutes after compound administration. The control group (0) was given the vehicle (1% aqueous Tween 80 solution). Values represent means ± SEM for groups of 8-10 animals. Statistical analysis after STZ administration compared to control group 0 (1% Tween 80 solution) - one-way ANOVA (Dunnett’s post-hoc test):Λp < 0.05. Statistical analysis after STZ administration compared with the results after administration of STZ and the test compound (STZ + (S)-5) - repeated measures ANOVA (Bonferroni post-hoc test): ***p < 0.001.

[0199] Detailed description of the invention The present invention discloses original derivatives of N-(1-oxo-1-(4-phenylpiperazin-1- yl)propan-2-yl)acetamide with protective action in animal models of epileptic seizures, including primarily the 6 Hz [44 mA] model, the structures of which were designed based on bioisosteric substitutions consisting in: z) introduction in the R1position of a trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or phenyl substituent; ii) replacement of the methyl group with a methoxymethylene or ethylene group in the R2position and replacement of selected hydrogen atoms with deuterium, its stable isotope. The introduction of deuterium included the following fragments of the structure according to formula (I); z) an acetyl fragment (substitution A); it) a piperazine ring (substitution B); and / or (zzz) position 4 of the aromatic ring (substitution X). Positions B and X seem to be particularly liable to biotransformation based on our previously obtained in vitro data (ACS Chem. Neurosci. 2020, 77, 1996-2008, Cells 2022, 77, 186). It should be emphasized that the almost identical physicochemical properties of hydrogen and deuterium suggest that the applied bioisosteric substitution will allow at least to maintain the biological activity of the “hydrogen” parent compounds and to advantageously improve their pharmacokinetic properties, which is reflected in the literature on hydrogen-deuterium substitutions (J. Med. Chem. 2019, 62, 5276-5297).

[0200] Unexpected technical effect:

[0201] Unexpectedly, it turned out that, contrary to the suggestions resulting from the art, the presented compounds demonstrate an exceptionally beneficial protective effect in two different and clinically important animal models of epileptic seizures, i.e. 6 Hz (44 mA) and MES (Table 1 and 2). For these compounds, it was possible to obtain ED50values of about or < 30 mg / kg (6 Hz, 44 mA model) and ED50values < 70 mg / kg (MES model) in mice 30 minutes after intraperitoneal (IP) administration (Table 2). In the light of current knowledge, such a combination of activity seemed impossible to obtain in compounds of a similar chemotype. In particular, considering the biological data disclosed for the pyrrolidine-2, 5-dione derivative (compound KA-104, Fig. 1) in the publication (ACS Chem. Neurosci. 2020, 77, 1996-2008, Epilepsia 2020, 61, 2119-2128) and the results for the acetamide analog (compound KJ-5, Fig. 1, Cells 2022, 77, 1862), it should rather have been expected that the presence of the acetyl residue (instead of the pyrrolidine-2, 5-dione fragment) would cause significant weakening of activity in the MES test. Meanwhile, in the case of the presented compounds (see example (R,S)-1 and (R,S)-4) it was unexpectedly possible to obtain the opposite effect, i.e. these compounds are characterized by stronger protection in the MES test than their succinimide analogs KA-11 and KA-93, respectively (Fig. 1). It is worth emphasizing that a much more pronounced intensification of protection in the MES model was observed for the remaining examples, i.e. (R,S)-2, (R,S)-3, (R,S)-5, and (R,S)-6, as well as their eutomers R. Similarly surprisingly, taking into account the data found in the art, the disclosed compounds have significantly higher activity in the 6 Hz (44 mA) drug-resistant seizure model as compared to structurally similar imide analogs (compound KA- 104, Fig. 1) or acetylphenylglycine analogs (compound KJ-5, Fig. 1). The effect of enhanced activity in the 6 Hz (44 mA) model for the compounds disclosed in this application is not due to structure-biological activity relationships that have been revealed so far for structurally similar derivatives.

[0202] The compounds of formula (I) of the invention can be obtained in a multi-step procedure using commercially available reagents as starting materials, i.e. a tert-butoxycarbonyl (Boc) protected derivative ofα- alanine, O-m ethyl serine or 2-aminobutanoic acid of the desired absolute configuration (R, S, or R, S), 1-(3-(trifluoromethyl)phenyl)piperazine and deuterated phenylpiperazine derivatives (i.e. 1-(3-(trifluoromethyl)pheny1-4-d)piperazine, 1-(3- (trifluoromethoxy)phenyl-4-d)piperazine, 1 - (3-(trifluoromethyl)phenyl-4-d)piperazine-

[0203] 2,2,3,3,5,5,6,6-d8, 1-(3-(trifluoromethoxy)pheny1-4-d)piperazine-2,2,3,3,5,5,6,6-d8and acetic acid chloride or its deuterated derivative, acetic acid chloride-d3. Non-commercial phenylpiperazine derivatives (3-OCF3, 3-SCF3, 3-C6H5) were obtained according to the literature data (Cells 2022, 11, 186).

[0204] The synthetic procedure and example reaction conditions for the final compounds are illustrated in Scheme 1. In the first step, as a result of the condensation reaction of a commercially available or previously obtained phenylpiperazine (or a deuterated derivative thereof) with a Boc- protected amino acid derivative (Boc-a-alanine, Boc-O-methylserine or Boc-2-aminobutanoic acid) of the appropriate absolute configuration (R, or S, or R,S), an intermediate of formula (III) is obtained, which is then subjected to a deprotection reaction to form a compound of formula (II). In the next step, compound (II) is subjected to an acylation reaction with acetic acid chloride (or its deuterated derivative), resulting in compounds of general formula (I). The intermediates and final compounds were obtained in good yields (>84%). The masses of pseudomolecular ions of the intermediates and final products were determined by LC / MS. The structures of the final compounds were confirmed through the analysis of1H NMR and13C NMR spectra. The purity of the intermediates and final compounds was determined by UPLC and was >99% for the final products. Enantiomeric purity was confirmed using chiral HPLC or SFC and was >99% ee.

[0205] Scheme 1. Synthesis of compounds of formula (I) of the invention.

[0206] In vivo anticonvulsant activity

[0207] The compounds being examples of a preferred embodiment of the invention and representing all amino acid subgroups within the framework of the present invention (i.e. α- alanine, O- methylserine or 2-aminobutanoic acid derivatives) exhibit broad anticonvulsant activity, acting effectively in the MES test, which is invariably one of the most important animal models of epileptic seizures and is used to identify candidates for new antiepileptic drugs (Methods Find. Exp. Clin. Pharmacol. 2009, 31, 101-106), in six-hertz (6 Hz) seizures at an amperage of 32 mA (focal seizure model), and in particular in the 6 Hz (44 mA) model, which is used to test substances potentially effective in the therapy of drug -resistant epilepsy (Epilepsia 2017, 1073-1084; Epilepsy Res. 2001, 47, 217-227). Table 1 presents data from screening studies at a dose of 100 mg / kg following intraperitoneal (IP) administration in mice. Table 1. Anticonvulsant activity in mice after IP administration at a screening dose of 100 mg / kg.

[0208] The compounds were tested 30 minutes after intraperitoneal administration. Data represent the number of mice protected from seizures / number of mice tested. Formulation: suspension in 1% aqueous Tween 80 solution. a MES: maximum electroshock test. b 6 Hz (32 mA): test of seizures induced by low-frequency current (6 Hz) and an amperage of 32 mA. c 6 Hz (44 mA): test of seizures induced by low-frequency current (6 Hz) and an amperage of 44 mA.

[0209] Abbreviations: NT - not tested.

[0210] The disclosed screening data show that with the exception of compound (S)-1 in the 6 Hz (32 mA) test all the other derivatives protected 100% of the tested animals in all the epileptic seizure models used, and the fact of complete (100%) efficacy in the 6 Hz (44 mA) test is particularly noteworthy. It should be noted that substances characterized by such a pharmacological profile, i.e. inhibition of seizures in the MES and 6 Hz (32 / 44 mA) tests, may be potentially effective in a wide spectrum of epileptic seizures in humans, namely tonic-clonic seizures with or without secondary generalization, myoclonic seizures, partial temporal seizures and, in particular, in drugresistant epilepsy. The obtained screening results were confirmed in quantitative pharmacological studies in which effective doses (ED50) were determined in individual convulsive tests and toxic doses (TD50) in the chimney test which is a measure of acute neurotoxicity of the substance (i.e. disturbances in the motor coordination of animals). These data allowed the calculation of protective indices for individual derivatives and in individual models of epileptic seizures (PI = TD50 / ED50), and their high values in the 6 Hz (32 mA) model (PI > 2.7) and in the 6 Hz (44 mA) test (PI > 2.5) indicate good separation (PI > 2) of the effective and toxic dose for the compounds disclosed in the present invention. It is also worth emphasizing that the substances of formula (I) proved to be highly active in the MES test with ED50values of < 70 mg / kg and, above all, in the 6 Hz (44 mA) model with ED50values of about or < 30 mg / kg (except for (R)-1 and (R,S)-4), which was the technical problem to be solved by the present invention. The ED50, TD50and PI values in mice after IP administration are summarized in Table 2.

[0211] Table 2. Quantitative in vivo data - ED50, TD50parameter values and protective indices (PI). 3.6 (6 Hz, 4342mA) 2'3^MES^ Hz, 32 mA) 4.4 (6 Hz, 44 mA) Hz, 32 mA)

[0212] The compounds were tested 30 minutes after intraperitoneal administration. Data represent the number of mice protected from seizures / number of mice tested. Formulation: suspension in 1% aqueous Tween 80 solution. a MES: maximum electroshock test. b 6 Hz (32 mA): test of seizures induced by low-frequency current (6 Hz) and an amperage of

[0213] 32 mA. c 6 Hz (44 mA): test of seizures induced by low-frequency current (6 Hz) and an amperage of 44 mA. d Chimney test: a measure of acute neurotoxicity (i.e. impaired motor coordination). e Protection Index (PI) = TD50 / ED50(in individual models). f VPA (valproic acid): a reference antiepileptic drug with a broad spectrum of activity in preclinical studies. Proprietary data: J. Med. Chem. 2022, 65, 11703-11725. * TD50was determined in the rotating rod (rotarod) test. Abbreviations: NT - not tested.

[0214] Taking into account the in vivo data in the prior art concerning substances with a chemical structure similar to the compounds disclosed in this application, it can be stated that the substances of formula (I) are unexpectedly characterized by significantly increased activity in the 6 Hz (44 mA) seizure model: ED50< 31 mg / kg. It should also be emphasized that among the previously known phenylglycine derivatives (see Fig. 1), replacing the pyrrolidine ring (KA- 104) with an acetamide fragment (KJ-5) causes a significant decrease in activity in the MES test. Contrary to expectations resulting from the observed changes in the properties of known compounds, in the case of derivatives of formula (I) an identical structural modification unexpectedly causes an enhanced protective effect in the above-mentioned seizure model.

[0215] To conclude, the in vivo data obtained in three models of epileptic seizures confirm the usefulness of the compounds of formula (I) as active ingredients of formulations that may be used in epilepsy, in particular in drug-resistant epilepsy, which, according to epidemiological data, affects 30-40% of epileptic patients and which is invariably a serious clinical problem (Epilepsia 2010, 51, 1069-1077; JAMA Neurol. 2018, 75 (3), 279-286; CNS Drugs 2021, 35 (9), 935-963). Moreover, based on literature data (J. Med. Chem. 2019, 62, 5276-5297), it is suggested that due to the almost identical physicochemical properties of hydrogen and deuterium, the disclosed analogs containing deuterium atoms in their structures have at least similar anticonvulsant activity compared to the parent hydrogen-containing molecules. Equally importantly, the compounds that are preferred embodiments of the invention (Table 2) showed significantly higher activity in individual seizure tests / models than valproic acid (VP A), which is a model antiepileptic drug with a wide range of therapeutic indications, including generalized epileptic seizures (myoclonic seizures, tonic-clonic seizures, atonic seizures, absence seizures), partial epileptic seizures (simple or complex seizures, secondary generalized seizures), Lennox-Gastaut syndrome, treatment of manic episodes in bipolar disorder and migraine.

[0216] Activities in an in vitro model of kainic acid-induced discharges in rat hippocampal slices For compound (R)- 1, additional studies were performed in an in vitro model of spontaneous discharges induced by kainic acid in slices of the rat entorhinal cortex, which is another model to assess the potential usefulness of the substance in alleviating drug-resistant seizures (Neurochem Res. 2017, 42, 1904-1918). The obtained results show that (R)-1 administered at a concentration of 80 μM and 120 μM acts effectively and significantly reduces the number and time of spontaneous neuronal discharges in the title model (Fig. 2).

[0217] Due to the similar profile of anticonvulsant activity in the in vivo studies (Table 2), it is postulated that the remaining derivatives being bioisosteres of compound (R)-1 will also be active in this model of drug-resistant seizures. Importantly, the replacement of the D-alanine residuαe- with D-phenylglycine leads to the abolition of biological activity, and this effect was observed for a negative example, i.e. compound (R)-KJ-28 (Fig. 3). It should be emphasized that the present application discloses the aforementioned structure-activity relationship for the first time and this is a non-obvious effect, because (R)-1 and (R)-KJ-28 have a similar profile of anticonvulsant activity in the in vivo models, i.e. MES, 6 Hz (32 mA) and 6 Hz (44 mA).

[0218] In vivo analgesic activity

[0219] Compound (R,S)-2, an D-αal-anine derivative, being an example of a preferred embodiment of the invention, exhibits, in addition to anticonvulsant activity, antinociceptive activity in a number of pain tests / models, i.e. the formalin test of tonic pain, the capsaicin-induced pain test and neuropathic pain models, i.e. the model of peripheral neuropathy induced by the administration of a cytostatic drug (oxaliplatin, OXPT) and the model of diabetic neuropathy induced by the administration of streptozotocin (STZ).

[0220] Assessment of analgesic activity in the formalin test

[0221] Pain was induced chemically by injecting mice subfascially with 2.5% formalin solution in a constant volume of 20 pL. The animals were placed in separate transparent observation chambers for 30 minutes. The measured value was the total time of licking and biting of the paw into which the formalin solution was administered. Nociceptive reaction time was measured in two time intervals: 0-5 minutes after formalin injection (phase I of the test - acute pain) and 15-30 minutes after its administration (phase II of the test - inflammatory pain). The observed inhibition of the nociceptive response, i.e. decreased paw licking and biting time, was interpreted as an analgesic effect of the test compound.

[0222] In the formalin test, compound (R,S)-2 administered intraperitoneally showed clear analgesic activity in both phases of the test (Fig. 4). Compound (R,S)-2 at doses of 12.5, 25 and 50 mg / kg reduced nociceptive reaction time in phase I and II of the formalin test, with a statistically significant effect observed for two doses, 25 and 50 mg / kg. Based on the obtained results, the ED50dose (dose causing a 50% reduction in nociceptive reaction time) was calculated. ED50values were 34.3 mg / kg (phase I) and 22.0 mg / kg (phase II), respectively.

[0223] Assessment of analgesic activity in the capsaicin-induced pain model

[0224] This test assessed the time spent licking and / or biting a hind paw into which 1.6 pg of capsaicin was injected subfascially in a constant volume of 20 pL. Observation was conducted for 5 minutes after capsaicin administration. Inhibition of the nociceptive response, i.e. reduction of the time of paw licking and biting, was a measure of the antinociceptive activity of the test compound.

[0225] Compound (R,S)-2 administered intraperitoneally statistically significantly reduced the nociceptive reaction time at all doses, i.e. 12.5, 25 and 50 mg / kg. The ED50value for the compound was 27.5 mg / kg (Fig. 5).

[0226] Oxaliplatin-induced peripheral neuropathy model (OXPT) - von Frey test

[0227] A single administration of OXPT results in a reduction of the pain threshold in animals in response to a mechanical stimulus, as measured by the von Frey method (Frey instrument / fiber, Bioseb, France). The reaction was observed before administration and 3 hours (early phase) and 7 days after OXPT administration (late phase).

[0228] In the 25 mg / kg group, the value that elicited paw withdrawal response (pain threshold) in healthy mice (i.e. before OXPT administration) was 5.84±0.43 g (baseline value) (Fig. 6). OXPT administration resulted in a significant reduction of the pain threshold to 2.78±0.34 g (47.6% of the baseline value) and 3.39±0.36 g (58.0% of the baseline value) in the early and late phases of the model, respectively. A single administration of the test compound at a dose of 25 mg / kg (IP) significantly reversed the OXPT effect (i.e. caused an increase in the pain threshold value) in the early phase (to 99.5% of the baseline value) and in the late phase (to 58.1% of the baseline value). In the 50 mg / kg group, the initial value of 6.69±0.37 g (healthy mice) decreased after OXPT administration to 4.43±0.27 g (66.2% of the baseline value) and 4.57±0.52 g (68.3% of the baseline value) in the early and late phases of the model, respectively. A single administration of compound (R,S)-2 at a dose of 50 mg / kg (IP) increased the pain threshold in the early phase (to 85.4% of the baseline value) and completely abolished allodynia in the late phase (104.8% of the baseline value). In the 75 mg / kg group, the initial value of 6.17±0.56 g (healthy mice) decreased after OXPT administration to 2.93±0.45 g (47.5% of the initial value) and 3.61±0.28 g (58.5% of the initial value) in the early and late phases of the model, respectively. A single administration of compound (R,S)-2 at a dose of 75 mg / kg (IP) caused an increase in the pain threshold (to 121.5% of the baseline value) in the early phase. In the late phase, allodynia also significantly reversed to 91.3% of the baseline value.

[0229] Hyperglycemia-induced neuropathic pain model after single administration of streptozotocin (STZ) - von Frey test

[0230] A single administration of STZ resulted in the development of hyperglycemia (plasma glucose concentration exceeded 300 mg / dL) and a decrease in the pain threshold in animals in response to a mechanical stimulus (mechanical allodynia, von Frey test). The response was studied 3 weeks after STZ injection. Compound (R,S)-2 administered intraperitoneally at doses of 12.5, 25 and 50 mg / kg led to a statistically significant and dose-dependent increase in the pain threshold compared to the measurement performed before compound administration (Fig. 7).

[0231] A single administration of streptozotocin (STZ) at a dose of 200 mg / kg resulted in allodynia observed as a decrease in the pain threshold. In the 12.5 mg / kg group, the baseline value that elicited the paw withdrawal response (pain threshold) in healthy mice (i.e. before STZ administration) was 6.08±0.29 g and was reduced through STZ administration to 4.30±0.21 g (70.7% of the baseline value). Administration of compound (R,S)-2 at a dose of 12.5 mg / kg (IP) completely inhibited allodynia (100.0% of the baseline value). In the 25 mg / kg group, the baseline value of 6.08±0.29 g was reduced to 5.02±0.27 g (82.6% of the baseline value), and the administration of compound (R,S)-2 at a dose of 25 mg / kg (IP) increased the pain threshold to 7.69±0.41 g, which corresponds to 126.5% of the baseline value. In the 50 mg / kg group, as a result of STZ administration, a slight (statistically insignificant) reduction in the pain threshold to 5.35±0.27 (88.0% of the baseline value) was observed. Administration of (R,S)-2 at a dose of 50 mg / kg (IP) increased the pain threshold to 8.70±0.41 g, which corresponded to 143.1% of the baseline value.

[0232] Similar and strong antinociceptive activity was revealed by compound (S)-5, representing a series of (S)-2-amino-3-m ethoxypropanoic acid [O-D-m ethyl serine] derivatives, which was effective in all pain models, i.e. formalin test (Fig. 8), capsaicin-induced pain model (Fig. 9), OXPT-induced peripheral neuropathy model (Fig. 10) and hyperglycemia-induced neuropathic pain model after single STZ administration (Fig. 11).

[0233] Due to the fact that the remaining derivatives of formula (I) of the invention are bioisosteres of compound (R,S)-2, it should be expected that these substances, similarly to (R,S)-2, also have a strong and broad antinociceptive effect.

[0234] Analytical methods

[0235] Proton magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were recorded using a JEOL-500 spectrometer (JEOL USA, Inc. MA, USA), at 500 MHz and 126 MHz, respectively. Chemical shifts are given in 5 values (ppm) relative to TMS 5=0 (1H) as the internal standard. J values are expressed in hertz (Hz). Deuterated chloroform (CDCl3) was used as the solvent. The following signal abbreviations are used in the descriptions of spectra: s (singlet), br s (broad singlet), d (doublet), br d (Broad doublet), dd (doublet of doublets), ddd (double double of doubles), dt (doublet of triplets), t (triplet), td (triplet of doublets), q (quartet), quin (quintet), m (multiplet). The UPLC / MS analysis system consisted of a Waters ACQUITY® UPLC® instrument (Waters Corporation, Milford, MA, USA) coupled with a Waters TQD mass spectrometer operated in the electrospray ionization (ESI) mode. Chromatographic separation was performed using an Acquity UPLC BEH C18 column with dimensions of 2.1 x 100 mm and a particle diameter of 1.7 pm. The column was kept at 40°C and eluted with a gradient from 95% to 0% of eluent A in 10 min at a flow rate of 0.3 mL min'1. Eluent A: water / formic acid (0.1%, v / v); eluent B: acetonitrile / formic acid (0.1%, v / v). Chromatograms were recorded using a Waters eλ PDA detector. The spectra were analyzed in the range of 200-700 nm with a resolution of 1.2 nm and a sampling rate of 20 points / s. Thin-layer chromatography (TLC) was performed on aluminum plates coated with 60 F254silica gel (Macherey -Nagel, Duren, Germany), using developing systems with the following composition: DCM:MeOH (9:0.3; v / v), DCM:MeOH (9:0.5; v / v). Spot detection - UV light (k = 254 nm). Melting points (MP) were determined using open capillaries in a Buchi 353 apparatus (Buchi Labortechnik, Flawil, Switzerland). Enantiomeric purity was determined by chiral HPLC spectra analysis using a Shimadzu Prominence-i LC-2030C SD Plus instrument (Shimadzu Corporation, Kyoto, Japan) equipped with a chiral Amylose-C column (250 x 4.6 mm). The analysis was performed in the following conditions: column temperature: 20°C, eluent mixture: hexane / 2-propanol = 50 / 50 (v / v) for compounds where R2= CH3, hexane / 2-propanol = 80 / 20 (v / v) for compounds where R2= CH2OCH3and C2H5at a flow rate of 1.0 mL / min, detection at k = 210 nm. The examples of the preparation of intermediates and final products presented below have not been optimized in terms of yield, amount of reagents used or final form of the obtained compounds.

[0236] Abbreviations used:

[0237] DCM - dichloromethane

[0238] DCC - N,N'-dicyclohexylcarbodiimide

[0239] Et2O - diethyl ether

[0240] MeOH - methanol

[0241] NH4OH - ammonium hydroxide

[0242] Na2SO4- sodium sulfate

[0243] TFA - trifluoroacetic acid

[0244] Examples of the synthesis and physicochemical and spectral data of intermediates (II, III) according to Scheme 1): Example 1. Intermediate (R,S )-! 11 (where B=H, X=H, R1=CF3, R2=CH3); (R,S)-tert-butyl(l- oxo-1 -(4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl )propan-2-y I) carbamate

[0245] Boc-DL-alanine (1.0 g, 5.2 mmol, 1 eq) was dissolved in 20 mL DCM, subsequently DCC (1.3 g, 1.2 eq) was added, and after 30 min 1-(3-trifluoromethylphenyl)piperazine (1.2 g, 5.2 mmol, 1 eq) was added dropwise. The reaction was continued with stirring at room temperature for 4 hours. Thereafter, DCM was distilled to dryness. The intermediate product was purified by column chromatography in the eluent system of DCMMeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0246] Yield: 90% (1.91 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 7.89 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O3F3 = 402.20, exp. (M+H)+= 402.1.

[0247] Example 2. Intermediate (R)-III (wherein B=H, X=H, R1=CF3, R2=CH3); (R)-tert-butyl(l- oxo-1 -(4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl )propan-2-y I) carbamate

[0248] The compound was obtained using an analogous procedure as above. Boc-D-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifhioromethylphenyl)piperazine (1.2 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0249] Yield: 91% (1.93 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR=

[0250] 7.88 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O3F3 = 402.20, exp. (M+H)+= 402.1.

[0251] Example 3. Intermediate (S)-III (wherein B=H, X=H, R1=CF3, R2=CH3); (S)-tert-butyl(l- oxo-1 -(4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl )propan-2-y I) carbamate

[0252] The compound was obtained using an analogous procedure as above. Boc-L-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifhioromethylphenyl)piperazine (1.2 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0253] Yield: 90% (1.91 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR=

[0254] 7.89 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O3F3 = 402.20, exp. (M+H)+= 402.1. Example 4. Intermediate 11 (wherein B=H, X=H, R1=OCF3, R2=CH3); (R,S)-tert- butyl(l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0255] The compound was obtained using an analogous procedure as above. Boc-DL-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0256] Yield: 88% (1.94 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.02 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O4F3=418.19,exp. (M+H)+= 418.3.

[0257] Example 5. Intermediate (R)-III (wherein B=H, X=H, R1=OCF3, R2=CH3); (R)-tert-butyl(l- oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0258] The compound was obtained using an analogous procedure as above. Boc-D-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0259] Yield: 88% (1.94 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.04 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O4F3= 418.19, exp. (M+H)+= 418.4.

[0260] Example 6. Intermediate (S)-III (wherein B=H, X=H, R1=OCF3, R2=CH3); (S)-tert-butyl(l- oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0261] The compound was obtained using an analogous procedure as above. Boc-L-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0262] Yield: 91% (2.00 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.07 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O4F3= 418.19, exp. (M+H)+= 418.4.

[0263] Example 7. Intermediate (R,.S)-111 (wherein B=H, X=H, R1=SCF3, R2=CH3); (R,S)-tert- butyl(l-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate The compound was obtained using an analogous procedure as above. Boc-DL-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0264] Yield: 86% (1.96 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.53 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O3SF3= 434.17, exp. (M+H)+= 434.3.

[0265] Example 8. Intermediate (R)-III (wherein B=H, X=H, R1=SCF3, R2=CH3); (R)-tert-butyl(l- oxo-1 -(4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0266] The compound was obtained using an analogous procedure as above. Boc-D-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0267] Yield: 90% (2.06 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR=

[0268] 8.51 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O3SF3= 434.17, exp. (M+H)+= 434.3.

[0269] Example 9. Intermediate (S)-III (wherein B=H, X=H, R1=SCF3, R2=CH3); (S)-tert-butyl(l- oxo-1 -(4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0270] The compound was obtained using an analogous procedure as above. Boc-L-alanine (1.0 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0271] Yield: 88% (2.01 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR=

[0272] 8.52 min. LC-MS (ESI): calc. (M+H)+for C19H26N3O3SF3= 434.17, exp. (M+H)+= 434.3.

[0273] Example 10. Intermediate (R,.S)-111 (wherein B=H, X=H, R1=CF3, R2=CH2OCH3); (R,S)~ tert-butyl(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2- yl)carbamate The compound was obtained using an analogous procedure as above. Boc-DL-O-m ethyl serine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethylphenyl)piperazine (1.2 g,

[0274] 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0275] Yield: 91% (2.04 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.69 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4F3 = 432.21, exp. (M+H)+= 432.2.

[0276] Example 11. Intermediate (R)-III (wherein B=H, X=H, R1=CF3, R2=CH2OCH3); (R)-tert- butyl(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0277] The compound was obtained using an analogous procedure as above. Boc-D-O-methylserine (1.14 g, 5.2 mmol, 1 eq), DCC (1.31 g, 1.2 eq) and 1-(3-trifluoromethylphenyl)piperazine (1.2 g,

[0278] 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0279] Yield: 92% (2.06 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.68 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4F3 = 432.21, exp. (M+H)+= 432.2.

[0280] Example 12. Intermediate ( S)-III (wherein B=H, X=H, R1=CF3, R2=CH2OCH3); (S)-tert- butyl(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0281] The compound was obtained using an analogous procedure as above. Boc-L-O-m ethyl serine (1.14 g, 5.2 mmol, 1 eq), DCC (1.31 g, 1.2 eq) and 1-(3-trifluoromethylphenyl)piperazine (1.2 g,

[0282] 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0283] Yield: 90% (2.02 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.72 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4F3 = 432.21, exp. (M+H)+= 432.2. Example 13. Intermediate (R,S)-III (wherein B=H, X=H, R1=OCF3, R2=CH2OCH3); (R,S)~ tert-butyl(3-methoxy-1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2- yl)carbamate

[0284] The compound was obtained using an analogous procedure as above. Boc-DL-O-m ethyl serine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0285] Yield: 91% (2.12 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 9.14 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O5F3 = 448.20, exp. (M+H)+= 448.2.

[0286] Example 14. Intermediate (R)-III (wherein B=H, X=H, R1=OCF3, R2=CH2OCH3); (R)-tert- butyl(3-methoxy-1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0287] The compound was obtained using an analogous procedure as above. Boc-D-O-methylserine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0288] Yield: 89% (2.07 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 9.10 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O5F3 = 448.20, exp. (M+H)+= 448.2.

[0289] Example 15. Intermediate ( S)-III (wherein B=H, X=H, R1=OCF3, R2=CH2OCH3); (S)-tert- butyl(3-methoxy-1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate

[0290] The compound was obtained using an analogous procedure as above. Boc-L-methyl serine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil. Yield: 91% (2.12 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 9.12 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O5F3 = 448.20, exp. (M+H)+= 448.2.

[0291] Example 16. Intermediate (R,S)-III (wherein B=H, X=H, R1=SCF3, R2=CH2OCH3); (R,S)~ tert-butyl(3-methoxy-1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2- yl)carbamate

[0292] The compound was obtained using an analogous procedure as above. Boc-DL-O-m ethyl serine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0293] Yield: 90% (2.17 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 9.45 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4SF3 = 464.18, exp. (M+H)+= 464.2.

[0294] Example 17. Intermediate (R)-III (wherein B=H, X=H, R1=SCF3, R2=CH2OCH3); (R)-tert- butyl(3-methoxy-1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2- yl)carbamate

[0295] The compound was obtained using an analogous procedure as above. Boc-D-O-methylserine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0296] Yield: 92% (2.22 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 9.48 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4SF3 = 464.18, exp. (M+H)+= 464.2.

[0297] Example 18. Intermediate ( S)-III (wherein B=H, X=H, R1=SCF3, R2=CH2OCH3); (S)-tert- butyl(3-methoxy-1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2- yl)carbamate

[0298] The compound was obtained using an analogous procedure as above. Boc-L-O-m ethyl serine

[0299] (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0300] Yield: 93% (2.24 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 9.50 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4SF3 = 464.18, exp. (M+H)+= 464.2.

[0301] Example 19. Intermediate (R,S)-III (wherein B=H, X=H, R1=CeH5, R2=CH2OCH3); (R,S)~ tert-butyl(l-(4-([l,l ’-biphenyl] -3-yl)piperazin-1-yl)-3-methoxy-1-oxopropan-2-yl)carbamate

[0302] The compound was obtained using an analogous procedure as above. Boc-DL-O-m ethyl serine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-([l,l’-biphenyl]-3-yl)piperazine (1.24 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0303] Yield: 94% (2.15 g); TLC: Rf= 0.91 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 10.38 min. LC-MS (ESI): calc. (M+H)+for C25H33N3O4= 440.25, exp. (M+H)+= 440.3.

[0304] Example 20. Intermediate (R)-III (wherein B=H, X=H, R1=CeH5, R2=CH2OCH3); (R)-tert- butyl(l-(4-([l,l ’-biphenyl]-3-yl)piperazin-1-yl)-3-methoxy-1-oxopropan-2-yl)carbamate

[0305] The compound was obtained using an analogous procedure as above. Boc-D-O-methylserine (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-([l,l’-biphenyl]-3-yl)piperazine (1.24 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0306] Yield: 92% (2.11 g); TLC: Rf= 0.91 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 10.36 min. LC-MS (ESI): calc. (M+H)+for C25H33N3O4= 440.25, exp. (M+H)+= 440.3.

[0307] Example 21. Intermediate ( S)-III (wherein B=H, X=H, R1=C6H5, R2=CH2OCH3); (S)-tert- butyl(l-(4-([l,l ’-biphenyl]-3-yl)piperazin-1-yl)-3-methoxy-1-oxopropan-2-yl)carbamate

[0308] The compound was obtained using an analogous procedure as above. Boc-L-O-m ethyl serine

[0309] (1.14 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-([l,l’-biphenyl]-3-yl)piperazine (1.24 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0310] Yield: 93% (2.13 g); TLC: Rf= 0.91 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 10.36 min. LC-MS (ESI): calc. (M+H)+for C25H33N3O4= 440.25, exp. (M+H)+= 440.3.

[0311] Example 22. Intermediate (wherein B=H, X=H, R1=OCF3, R2=C2H5); (R,S)-tert- butyl(l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)carbamate The compound was obtained using an analogous procedure as above. Boc-DL-2-aminobutanoic acid (1.06 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0312] Yield: 92% (2.07 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.67 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4F3 = 432.21, exp. (M+H)+= 432.2.

[0313] Example 23. Intermediate (R)-III (wherein B=H, X=H, R1=OCF3, R2=C2H5); (R)-tert- butyl(l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)carbamate The compound was obtained using an analogous procedure as above. Boc-D-2-aminobutanoic acid (1.06 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0314] Yield: 93% (2.09 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.66 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4F3 = 432.21, exp. (M+H)+= 432.2.

[0315] Example 24. Intermediate (S)-III (wherein B=H, X=H, R1=OCF3, R2=C2H5); (S)-tert- butyl(l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)carbamate The compound was obtained using an analogous procedure as above. Boc-L-2-aminobutanoic acid

[0316] (1.06 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluoromethoxyphenyl)piperazine (1.28 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0317] Yield: 92% (2.07 g); TLC: Rf= 0.88 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.69 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O4F3 = 432.21, exp. (M+H)+= 432.2.

[0318] Example 25. Intermediate 11 (wherein B=H, X=H, R1=SCF3, R2=C2H5); (R,S)-tert- butyl(l-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-2-yl)carbamate

[0319] The compound was obtained using an analogous procedure as above. Boc-DL-2- aminobutanoic acid (1.06 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3- trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0320] Yield: 94% (2.19 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.88 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O3SF3 = 448.18, exp. (M+H)+= 448.2.

[0321] Example 26. Intermediate (R)-III (wherein B=H, X=H, R1=SCF3, R2=C2H5); (R)-tert- butyl(l-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-2-yl)carbamate

[0322] The compound was obtained using an analogous procedure as above. Boc-D-2-aminobutanoic acid (1.06 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0323] Yield: 92% (2.14 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.91 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O3SF3 = 448.18, exp. (M+H)+= 448.2.

[0324] Example 27. Intermediate (S)-III (wherein B=H, X=H, R1=SCF3, R2=C2H5); (S)-tert- butyl(l-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-2-yl)carbamate

[0325] The compound was obtained using an analogous procedure as above. Boc-L-2-aminobutanoic acid (1.06 g, 5.2 mmol, 1 eq), DCC (1.3 g, 1.2 eq) and 1-(3-trifluorothiomethylphenyl)piperazine (1.36 g, 5.2 mmol, 1 eq) were used in the reaction. The crude product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.3; v / v). The compound was obtained as a clear colorless oil.

[0326] Yield: 91% (2.12 g); TLC: Rf= 0.89 (DCM:MeOH (9:0.3; v / v)); UPLC (purity > 99%), tR= 8.91 min. LC-MS (ESI): calc. (M+H)+for C20H28N3O3SF3 = 448.18, exp. (M+H)+= 448.2.

[0327] Example 28. Intermediate (R,.S)-H (wherein B=H, X=H, R1=CF3, R2=CH3); (R,S)-2-amino-

[0328] 1-( 4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0329] To a solution of (R,S)-tert-butyl(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-

[0330] 2-yl)carbamate (1.81 g, 4.5 mmol, 1 eq, see Example 1) in DCM (20 mL) δ mL TFA was added and the mixture was stirred for 2 h. Subsequently, it was neutralized with 25% NH4OH solution and then extracted with DCM (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4and then evaporated to dryness. The compound was obtained as a clear colorless oil.

[0331] Yield: 97% (1.32 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 4.65 min. LC-MS (ESI): calc. (M+H)+for Ci4Hi8N3OF3= 302.14, exp. (M+H)+= 302.0.

[0332] Example 29. Intermediate (R)-II (wherein B=H, X=H, R1=CF3, R2=CH3); (R)-2-amino-1-(4- (3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0333] The compound was obtained using an analogous procedure as above. In the reaction, (R?)-tert- butyl(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.81 g, 4.5 mmol, 1 eq, Example 2) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0334] Yield: 96% (1.30 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 4.64 min. LC-MS (ESI): calc. (M+H)+for Ci4Hi8N3OF3= 302.14, exp. (M+H)+= 302.1.

[0335] Example 30. Intermediate ( S’)- 11 (wherein B=H, X=H, R1=CF3, R2=CH3); (S)-2-amino-1-(4- (3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0336] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.81 g, 4.5 mmol, 1 eq, Example 3) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0337] Yield: 97% (1.32 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 4.64 min. LC-MS (ESI): calc. (M+H)+for C14H18N3OF3 = 302.14, exp. (M+H)+= 302.1.

[0338] Example 31. Intermediate (wherein B=H, X=H, R1=OCF3, R2=CH3); (R,S)-2- amino-1-(4-( 3-( trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one

[0339] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-butyl(l -oxo- l -(4-(3-(trifluoromethoxy)phenyl)piperazin- l -yl)propan-2-yl)carbamate (1.88 g, 4.5 mmol, 1 eq, Example 4) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0340] Yield: 97% (1.36 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0341] 4.88 min. LC-MS (ESI): calc. (M+H)+for C14H18N3O2F3 = 318.13, exp. (M+H)+= 318.3.

[0342] Example 32. Intermediate (R)-II (wherein B=H, X=H, R1=OCF3, R2=CH3); (R)-2-amino-1- (4-(3-( trijluoromethoxyl)phenyl)piperazin-1-yl)propan-1-one

[0343] The compound was obtained using an analogous procedure as above. In the reaction, (Rftert- butyl(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.88 g, 4.5 mmol, 1 eq, Example 5) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0344] Yield: 97% (1.36 g); TLC: Rf= 0.28 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0345] 4.89 min. LC-MS (ESI): calc. (M+H)+for C14H18N3O2F3 = 318.13, exp. (M+H)+= 318.4.

[0346] Example 33. Intermediate ( S’)- 11 (wherein B=H, X=H, R1=OCF3, R2=CH3); (S)-2-amino-1- (4-(3-( trifluor omethoxy)phenyl)piperazin-1-yl)propan-1 -one

[0347] The compound was obtained using an analogous procedure as above. In the reaction, (Sftert- butyl(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.88 g, 4.5 mmol, 1 eq, Example 6) and 5 mL TFA were used. The compound was obtained as a clear colorless oil. Yield: 98% (1.40 g); TLC: Rf= 0.28 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 4.88 min. LC-MS (ESI): calc. (M+H)+for C14H18N3O2F3 = 318.13, exp. (M+H)+= 318.4.

[0348] Example 34. Intermediate (R,.$’)- 11 (wherein B=H, X=H, R1=SCF3, R2=CH3); (R,S)-2-amino- l-( 4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl )propan-1-one

[0349] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-butyl( l -oxo-1 -(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.96 g, 4.5 mmol, 1 eq, Example 7) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0350] Yield: 98% (1.47 g); TLC: Rf= 0.29 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0351] 5.18 min. LC-MS (ESI): calc. (M+H)+for CI4HI8N3OSF3= 334.12, exp. (M+H)+= 334.3.

[0352] Example 35. Intermediate (R)-II (wherein B=H, X=H, R1=SCF3, R2=CH3); (R)-2-amino-1- (4-(3-( thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0353] The compound was obtained using an analogous procedure as above. In the reaction, (R?)-tert- butyl(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.96 g, 4.5 mmol, 1 eq, Example 8) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0354] Yield: 97% (1.45 g); TLC: Rf= 0.29 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0355] 5.19 min. LC-MS (ESI): calc. (M+H)+for CI4HI8N3OSF3= 334.12, exp. (M+H)+= 334.3.

[0356] Example 36. Intermediate ( S’)- 11 (wherein B=H, X=H, R1=SCF3, R2=CH3); (S) -2 -amino- 1- (4-(3-( trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one

[0357] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl(1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)carbamate (1.96 g, 4.5 mmol, 1 eq, Example 9) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0358] Yield: 98% (1.47 g); TLC: Rf= 0.29 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 5.21 min. LC-MS (ESI): calc. (M+H)+for CI4HI8N3OSF3 = 334.12, exp. (M+H)+= 334.3. Example 37. Intermediate (R,S)-II (wherein B=H, X=H, R1=CF3, R2=CH2OCH3); (R,S)-2- amino-3-methoxy-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0359] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-buty 1 (3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)carbamate (1.94 g, 4.5 mmol, 1 eq, Example 10) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0360] Yield: 98% (1.46 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0361] 5.41 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2F3 = 332.15, exp. (M+H)+= 332.2.

[0362] Example 38. Intermediate (R)-II (wherein B=H, X=H, R1=CF3, R2=CH2OCH3); (R)-2- amino-3-methoxy-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0363] The compound was obtained using an analogous procedure as above. In the reaction, (R)-tert- butyl(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2-yl)carbamate (1.94 g, 4.5 mmol, 1 eq, Example 11) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0364] Yield: 97% (1.45 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0365] 5.42 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2F3 = 332.15, exp. (M+H)+= 332.2.

[0366] Example 39. Intermediate ( S’)- 11 (wherein B=H, X=H, R1=CF3, R2=CH2OCH3); (S)-2-amino- 3-methoxy-1-(4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one

[0367] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2-yl)carbamate (1.94 g, 4.5 mmol, 1 eq, Example 12) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0368] Yield: 96% (1.43 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 5.41 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2F3 = 332.15, exp. (M+H)+= 332.2.

[0369] Example 40. Intermediate (R,S)-II (wherein B=H, X=H, R1=OCF3, R2=CH2OCH3); (R,S)-2- amino-3-methoxy-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-buty 1 (3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)carbamate (2.01 g, 4.5 mmol, 1 eq, Example 13) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0370] Yield: 96% (1.50 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0371] 5.85 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O3F3 = 348.15, exp. (M+H)+= 348.2.

[0372] Example 41. Intermediate (R)-II (wherein B=H, X=H, R1=OCF3, R2=CH2OCH3); (R)-2- amino-3-methoxy-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one

[0373] The compound was obtained using an analogous procedure as above. In the reaction, (R)-tert- butyl(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy)phenyl)piperazin- 1 -yl)propan-2-yl)carbamate (2.01 g, 4.5 mmol, 1 eq, Example 14) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0374] Yield: 98% (1.53 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0375] 5.85 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O3F3 = 348.15, exp. (M+H)+= 348.2.

[0376] Example 42. Intermediate ( S)-II (wherein B=H, X=H, R1=OCF3, R2=CH2OCH3); (S)-2- amino-3-methoxy-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one

[0377] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy)phenyl)piperazin- 1 -yl)propan-2-yl)carbamate (2.01 g, 4.5 mmol, 1 eq, Example 15) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0378] Yield: 98% (1.53 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR=

[0379] 5.86 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O3F3 = 348.15, exp. (M+H)+= 348.2.

[0380] Example 43. Intermediate (R,S)-II (wherein B=H, X=H, R1=SCF3, R2=CH2OCH3); (R,S)-2- amino-3-methoxy-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one

[0381] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-butyl(3 -methoxy- 1-oxo- 1-(4-(3 -(tri fluorothiomethyl)phenyl)piperazin-1-yl)propan-2- yl)carbamate (2.09 g, 4.5 mmol, 1 eq, Example 16) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0382] Yield: 97% (1.59 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.12 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2SF3 = 364.13, exp. (M+H)+= 364.2.

[0383] Example 44. Intermediate (R)-II (wherein B=H, X=H, R1=SCF3, R2^EEOCH3); (R)-2- amino-3-methoxy-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one

[0384] The compound was obtained using an analogous procedure as above. In the reaction, (R)-tert- butyl(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorothiomethyl)phenyl)piperazin- 1 -yl)propan-2- yl)carbamate (2.09 g, 4.5 mmol, 1 eq, Example 17) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0385] Yield: 98% (1.61 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.12 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2SF3 = 364.13, exp. (M+H)+= 364.2.

[0386] Example 45. Intermediate ( S)-II (wherein B=H, X=H, R1=SCF3, R2KIH2OCH3); (S)-2- amino-3-methoxy-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one

[0387] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorothiomethyl)phenyl)piperazin- 1 -yl)propan-2- yl)carbamate (2.09 g, 4.5 mmol, 1 eq, Example 18) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0388] Yield: 96% (1.57 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.11 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2SF3 = 364.13, exp. (M+H)+= 364.2.

[0389] Example 46. Intermediate (R,S)-II (wherein B=H, X=H, R1=CeH5, R2KIH2OCH3); (R,S)-1- (4-([ 1, 1 ’-biphenyl ]-3-yl)piperazin-1-yl)-2-amino-3-methoxypropan-1-one

[0390] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)~ tert-butyl ( I -(4-([ 1 , 1 ’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)carbamate (1.98 g, 4.5 mmol, 1 eq, Example 19) and 5 mL TFA were used. The compound was obtained as a clear colorless oil. Yield: 98% (1.50 g); TLC: Rf= 0.22 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 7.57 min. LC-MS (ESI): calc. (M+H)+for C20H25N3O2 = 340.20, exp. (M+H)+= 340.2.

[0391] Example 47. Intermediate (R)-II (wherein B=H, X=H, R1=CeH5, R2=CH2OCH3); (R)-1-(4- ([ 1, 1 ’-biphenyl ]-3-yl)piperazin-1-yl)-2-amino-3-methoxypropan-1-one

[0392] The compound was obtained using an analogous procedure as above. In the reaction, (R)-tert- butyl( 1 -(4-([ 1 , 1 ’ -biphenyl] -3 -yl)piperazin- 1 -y 1 ) -3 -methoxy- 1 -oxopropan-2-yl)carb amate (1.98 g,

[0393] 4.5 mmol, 1 eq, Example 20) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0394] Yield: 96% (1.47 g); TLC: Rf= 0.22 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 7.61 min. LC-MS (ESI): calc. (M+H)+for C20H25N3O2 = 340.20, exp. (M+H)+= 340.2.

[0395] Example 48. Intermediate (S)-II (wherein B=H, X=H, R1=C6H5, R2=CH2OCH3); (S)-1-(4- ([ 1, 1 ’-biphenyl ]-3-yl)piperazin-1-yl)-2-amino-3-methoxypropan-1-one

[0396] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl( 1 -(4-([ 1 , 1 ’ -biphenyl] -3 -yl)piperazin- 1 -y 1 ) -3 -methoxy- 1 -oxopropan-2-yl)carb amate (1.98 g,

[0397] 4.5 mmol, 1 eq, Example 21) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0398] Yield: 97% (1.48 g); TLC: Rf= 0.22 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 7.60 min. LC-MS (ESI): calc. (M+H)+for C20H25N3O2 = 340.20, exp. (M+H)+= 340.2.

[0399] Example 49. Intermediate (R,S)-II (wherein B=H, X=H, R1=OCF3, R2=C2H5); (R,S)-2- amino-1-(4-( 3-( trifhioromethoxy)phenyl)piperazin-1-yl) butan-1-one

[0400] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-butyl(l -oxo- l -(4-(3-(trifluoromethoxy)phenyl)piperazin- l -yl)butan-2-yl)carbamate (1.94 g,

[0401] 4.5 mmol, 1 eq, Example 22) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0402] Yield: 98% (1.46 g); TLC: Rf= 0.23 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.45 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2F3 = 332.15, exp. (M+H)+= 332.2. Example 50. Intermediate (R)-II (wherein B=H, X=H, R1=OCF3, R2=C2H5); (R) -2 -amino- 1- (4-(3-( trifluor omethoxy)phenyl)piperazin-1-yl) butan-1-one

[0403] The compound was obtained using an analogous procedure as above. In the reaction, (Rftert- butyl(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)carbamate (1.94 g, 4.5 mmol, 1 eq, Example 23) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0404] Yield: 97% (1.45 g); TLC: Rf= 0.23 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.49 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2F3 = 332.15, exp. (M+H)+= 332.2.

[0405] Example 51. Intermediate ( S’)- 11 (wherein B=H, X=H, R1=OCF3, R2=C2H5); (S)-2-anrino-1- (4-(3-( trifluor omethoxy)phenyl)piperazin-1-yl) butan-1-one

[0406] The compound was obtained using an analogous procedure as above. In the reaction, (Sftert- butyl(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)carbamate (1.94 g, 4.5 mmol, 1 eq, Example 24) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0407] Yield: 97% (1.45 g); TLC: Rf= 0.22 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.49 min. LC-MS (ESI): calc. (M+H)+for C15H20N3O2F3 = 332.15, exp. (M+H)+= 332.2.

[0408] Example 52. Intermediate (R,S)-II (wherein B=H, X=H, R1=SCF3, R2= C2H5); (R,S)-2- amino-1-(4-( 3-( trifluorothiomethyl)phenyl)piperazin-1-yl) butan-1-one

[0409] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)- tert-butyl(l -oxo- l -(4-(3-(trifluorothiomethyl)phenyl)piperazin- l -yl)butan-2-yl)carbamate (2.01 g, 4.5 mmol, 1 eq, Example 25) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0410] Yield: 98% (1.53 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.73 min. LC-MS (ESI): calc. (M+H)+for C15H20N3OSF3 = 348.13, exp. (M+H)+= 348.2.

[0411] Example 53. Intermediate (R)-II (wherein B=H, X=H, R1=SCF3, R2= C2H5); (R)-2-amino- l-( 4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-1-one The compound was obtained using an analogous procedure as above. In the reaction, (R)-tert- butyl(1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-2-yl)carbamate (2.01 g, 4.5 mmol, 1 eq, Example 26) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0412] Yield: 96% (1.50 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.76 min. LC-MS (ESI): calc. (M+H)+for C15H20N3OSF3 = 348.13, exp. (M+H)+= 348.2.

[0413] Example 54. Intermediate ( S’)- 11 (wherein B=H, X=H, R1=SCF3, R2= C2H5); (S)-2-amino-1- (4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-1-one

[0414] The compound was obtained using an analogous procedure as above. In the reaction, (S)-tert- butyl(1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-2-yl)carbamate (2.01 g, 4.5 mmol, 1 eq, Example 27) and 5 mL TFA were used. The compound was obtained as a clear colorless oil.

[0415] Yield: 98% (1.53 g); TLC: Rf= 0.24 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.75 min. LC-MS (ESI): calc. (M+H)+for C15H20N3OSF3 = 348.13, exp. (M+H)+= 348.2.

[0416] Examples of the synthesis and physicochemical and spectral data of the final products of formula (I):

[0417] Example 55. Compound (R,S)-1 (wherein A=H, B=H, X=H, R1=CF3, R2=CH3); (R,S)-N-(1- oxo-1 -(4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl )propan-2-yl)acetamide

[0418] To a solution of (R,S)-2-amino-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.21 g, 4 mmol, 1 eq, Example 28) in DCM (20 ml) triethylamine (TEA) (12 mmol, 3 eq) was added. Subsequently, acetyl chloride (6 mmol, 1.5 eq) was added dropwise to this mixture while stirring at 0°C. After the acid chloride was added dropwise, the reaction was continued with stirring at room temperature for 2 hours and then concentrated under reduced pressure. The final product was purified by column chromatography in the eluent system of DCM:MeOH (9:0.5; v / v). The compound was obtained as a solid after washing with diethyl ether (Et2O).

[0419] White solid. Yield: 93% (1.28 g); MP 127.9-128.7°C; TLC: Rf= 0.5 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.39 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O2F3 = 344.15, exp. (M+H)+= 344.2.1H NMR (500 MHz, CDCl3) δ 1.33 (d, J=6.9 Hz, 3 H), 1.99 (s, 3 H), 3.05- 3.33 (m, 4 H), 3.61-3.68 (m, 1 H), 3.68-3.78 (m, 2 H), 3.80-3.89 (m, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H), 6.64 (br d, 7=7.5 Hz, 1 H), 7.05 (br d, 7=8.0 Hz, 1 H), 7.08-7.15 (m, 2 H), 7.36 (t, 7=8.0 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.3, 49.0, 49.3, 113.0 (br d, J=3.6 Hz), 117.1 (br d, J=3.6 Hz), 119.6, 124.2 (q, 7=272.0 Hz) 129.9, 131.7 (q, 7=31.4 Hz), 151.0, 169.4, 171.1.

[0420] Example 56. Compound (R)-1 (wherein A=H, B=H, X=H, R1=CF3, R2=CH3); (R)-N-(l-oxo- l-( 4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0421] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.21 g, 4 mmol, 1 eq, Example 29), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0422] White solid. Yield: 92% (1.26 g); MP 121.2-122.7°C; TLC: Rf= 0.5 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.40 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O2F3 = 344.15, exp. (M+H)+= 344.3. Chiral HPLC > 99% ee (tR= 4.529 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, 7=6.9 Hz, 3 H), 2.00 (s, 3 H), 3.15-3.29 (m, 4 H), 3.59-3.69 (m, 1 H), 3.70-3.77 (m, 2 H), 3.82-3.91 (m, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H), 6.59 (br d, 7=7.2 Hz, 1 H), 7.06 (dd, 7=8.3, 2.0 Hz, 1 H), 7.10 (s, 1 H), 7.13 (d, 7=7.7 Hz, 1 H), 7.37 (t, 7=7.9 Hz, 1 H).13C NMR (126 MHz, CDCl3) 5 19.3, 23.4, 42.0, 45.1, 45.3, 49.0, 49.3, 113.0 (br d, 7=4.2 Hz), 117.1 (br d, 7=3.6 Hz), 119.6, 124.3 (q, 7=272.0 Hz), 129.9, 131.8 (q, 7=31.4 Hz), 151.0, 169.4, 171.1.

[0423] Example 57. Compound (S)-1 (wherein A=H, B=H, X=H, R1=CF3, R2=CH3); (S)-N-(l-oxo- l-( 4-( 3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0424] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.21 g, 4 mmol, 1 eq, Example 30), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0425] White solid. Yield: 90% (1.23 g); MP 120.5-121.7°C; TLC: Rf= 0.51 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.41 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O2F3 = 344.15, exp. (M+H)+= 344.2. Chiral HPLC > 99% ee (tR= 7.831 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.6 Hz, 3 H), 2.00 (s, 3 H), 3.23 (br dd, J=6.9, 3.7 Hz, 4 H), 3.60-3.68 (m, 1 H), 3.69-3.77 (m, 2 H), 3.85 (ddd, 7=13.0, 6.4, 3.7 Hz, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H), 6.62 (br d, 7=7.5 Hz, 1 H), 7.05 (dd, 7=8.3, 2.3 Hz, 1 H), 7.10 (s, 1 H), 7.13 (d, 7=7.7 Hz, 1 H), 7.36 (t, 7=7.9 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.3, 49.0, 49.3, 113.0 (br d, 7=4.2 Hz), 117.1 (br d, 7=4.2 Hz), 119.6, 124.2 (q, 7=272.6 Hz), 129.9, 131.7 (q, 7=31.4 Hz), 151.0, 169.4, 171.1.

[0426] Example 58. Compound (R,S)-2 (wherein A=H, B=H, X=H, R1=OCF3, R2=CH3); (R,S)-N- (l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0427] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one (1.27 g, 4 mmol, 1 eq, Example 31), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0428] White solid. Yield: 94% (1.35 g); MP 123.6-124.4°C; TLC: Rf= 0.54 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.66 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O3F3 = 360.15, exp. (M+H)+= 360.3.1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.9 Hz, 3 H), 1.99 (s, 3 H), 3.11-3.25 (m, 4 H), 3.58-3.66 (m, 1 H), 3.67-3.75 (m, 2 H), 3.84 (dd, 7= 6.4, 3.4 Hz, 1 H), 4.92 (quin, 7=7.0 Hz, 1 H) δ.62 (br d, 7=7.5 Hz, 1 H), 6.70 (s, 1 H), 6.73 (br d, 7=8.0 Hz, 1 H), 6.80 (dd, 7=8.6, 2.3 Hz, 1 H), 7.24-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9,

[0429] 45.1, 45.2, 48.8, 49.2, 109.1, 112.4, 114.5, 120.5 (q, 7=257.1 Hz), 130.3, 150.4, 152.1, 169.4,

[0430] 171.1.

[0431] Example 59. Compound (R)-2 (wherein A=H, B=H, X=H, R1=OCF3, R2=CH3); (R)-N-(l- oxo-1 -(4-( 3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0432] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one (1.27 g, 4 mmol, 1 eq, Example 32), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0433] White solid. Yield: 91% (1.31 g); MP 121.1-122.4°C; TLC: Rf= 0.53 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.64 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O3F3 = 360.15, exp. (M+H)+= 360.3. Chiral HPLC > 99% ee (tR= 4.484 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.9 Hz, 3 H), 2.00 (s, 3 H), 3.10-3.25 (m, 4 H), 3.58-3.65 (m, 1 H), 3.67-3.74 (m, 2 H), 3.84 (dd, J= 6.4, 3.4 Hz, 1 H), 4.93 (quin, .7=7,0 Hz, 1 H) δ.62 (br d, J=7.5 Hz, 1 H), 6.71 (s, 1 H), 6.73 (br d, J=8.0 Hz, 1 H), 6.80 (dd, J=8.6, 2.3 Hz, 1 H), 7.25-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.4, 23.4, 42.0, 45.1, 45.2, 48.8, 49.2, 109.1, 112.3, 114.4, 120.5 (q, J=257.1 Hz), 130.4, 150.4, 152.2, 169.4, 171.1.

[0434] Example 60. Compound (S)-2 (wherein A=H, B=H, X=H, R1=OCF3, R2=CH3); (S)-N-(l-oxo- l-( 4-( 3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0435] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1-one (1.27 g, 4 mmol, 1 eq, Example 33), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0436] White solid. Yield: 93% (1.33 g); MP 117.2-118.4°C; TLC: Rf= 0.53 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.65 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O3F3 = 360.15, exp. (M+H)+= 360.3. Chiral HPLC > 99% ee (tR= 8.477 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.6 Hz, 3 H) 2.00 (s, 3 H) 3.15-3.33 (m, 4 H), 3.58-3.66 (m, 1 H), 3.67-3.78 (m, 2 H), 3.84 (dd, J= 6.4, 3.4 Hz, 1 H), 4.92 (quin, .7=7,0 Hz, 1 H) δ.62 (br d, J=7.5 Hz, 1 H), 6.70 (s, 1 H), 6.73 (br d, J=8.0 Hz, 1 H), 6.79 (dd, J=8.6, 2.3 Hz, 1 H), 7.24-7.32 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.4, 23.4, 42.0, 45.1, 45.2, 48.8, 49.2, 109.1, 112.3, 114.4, 120.5 (q, J=257.1 Hz), 130.4, 150.4, 152.2, 169.4, 171.1.

[0437] Example 61. Compound (R,S)-3 (wherein A=H, B=H, X=H, R1=SCF3, R2=CH3); (R,S)-N- ( 1 -oxo- 1-( 4-(3-(trifluorothiomethyl)phenyl )piperazin-1-yl)propan-2-yl)acetamide

[0438] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one (1.33 g, 4 mmol, 1 eq, Example 34), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0439] White solid. Yield: 93% (1.4 g); MP 110.9-111.7°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 98%), tR= 7.02 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O2SF3 = 376.13, exp. (M+H)+= 376.3.1H NMR (500 MHz, CDCl3) δ 1.33 (d, J=6.9 Hz, 3 H), 1.99 (s, 3

[0440] H), 3.13-3.27 (m, 4 H), 3.60-3.69 (m, 1 H), 3.67-3.76 (m, 2 H), 3.84 (dd, J=6.4, 3.7 Hz, 1 H), 4.92 (quin, 7=7.0 Hz, 1 H), 6.63 (br d, 7=7.5 Hz, 1 H), 7.00 (dd, 7=8.3, 2.4 Hz, 1 H), 7.11-7.19 (m, 2 H), 7.27-7.33 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.2, 48.9, 49.3, 118.8, 123.9, 125.4, 129.7 (q, 7=308.0 Hz), 128.0, 130.2, 151.4, 169.3, 171.1.

[0441] Example 62. Compound (R)-3 (wherein A=H, B=H, X=H, R1=SCF3, R2=CH3); (R)-N-(l- oxo-1 -(4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0442] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one (1.33 g, 4 mmol, 1 eq, Example 35), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0443] White solid. Yield: 92% (1.38 g); MP 118.3-119.9°C; TLC: Rf= 0.56 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 98%), tR= 7.04 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O2SF3 = 376.13, exp. (M+H)+= 376.1. Chiral HPLC > 99% ee (tR= 4.559 min).1H NMR (500 MHz, CDCl3)1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.6 Hz, 3 H), 2.00 (s, 3 H), 3.27-3.47 (m, 3 H), 3.56 (br t, J=9.Q Hz, 1 H), 3.87-3.97 (m, 1 H), 4.00-4.19, (m, 2 H), 4.30 (br d, 7=13.8 Hz, 1 H), 4.87 (quin, J=6.9 Hz, 1 H), 6.57 (br d, J=6.6 Hz, 1 H), 7.42-7.55 (m, 2 H), 7.65-7.76 (m, 2 H).13C NMR (126 MHz, CDCl3) δ 18.6, 23.2, 40.5 43.9, 45.0, 52.6, 52.7, 122.2, 129.4 (q, 7=308.6 Hz) 126.7, 131.1, 133.9, 146.2, 169.9 171.6.

[0444] Example 63. Compound (S)-3 (wherein A=H, B=H, X=H, R1=SCF3, R2=CH3); (S)-N-(l-oxo- l-( 4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl )propan-2-yl)acetamide

[0445] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1-one (1.33 g, 4 mmol, 1 eq, Example 36), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0446] White solid. Yield: 90% (1.35 g); MP 108.1-109.6°C; TLC: Rf= 0.56 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 98%), tR= 7.05 min. LC-MS (ESI): calc. (M+H)+for C16H20N3O2SF3 = 376.13, exp. (M+H)+= 376.2. Chiral HPLC > 99% ee (tR= 9.746 min).1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.9 Hz, 3 H), 1.98 (s, 3 H), 3.12-3.24 (m, 4 H), 3.59-3.66 (m, 1 H), 3.66-3.76 (m, 2 H), 3.83 (ddd, 7=13.2, 6.4, 3.6 Hz, 1 H), 4.92 (quin, 7=7.0 Hz, 1 H), 6.70 (br d, 7=6.3 Hz, 1 H), 6.99 (ddd, 7=8.4, 2.7, 0.7 Hz, 1 H), 7.12-7.17 (m, 2 H), 7.26-7.34 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.3, 41.9, 45.1, 45.2, 48.9, 49.3, 118.8, 123.9, 125.3, 128.0, 129.7 (q, 7=308.0 Hz) 130.2, 151.4, 169.4, 171.1.

[0447] Example 64. Compound (R,S)-4 (wherein A=H, B=H, X=H, R1=CF3, R2=CH2OCH3); (R,S)~ N-( 3 -methoxy- 1 -oxo- 1-( 4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0448] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-3 -methoxy- 1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1 -one (1.33 g, 4 mmol, 1 eq, Example 37), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0449] White solid. Yield: 88% (1.32 g); MP 139.7-140.7°C; TLC: Rf= 0.54 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.09 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3F3 = 374.16, exp. (M+H)+= 374.2.1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H,) 3.11-3.22 (m, 2 H), 3.24-3.35 (m, 5 H), 3.46 (dd, 7=8.9, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 5.0 Hz, 1 H), 3.66-3.76 (m, 2 H), 3.77-3.85 (m, 1 H), 3.88-3.97 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.57 (br d, 7=7.6 Hz, 1 H), 7.05 (dd, 7=8.3, 2.2 Hz, 1 H), 7.08-7.13 (m, 2 H), 7.36 (t, 7=8.0 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.2, 45.7, 48.6, 48.8, 49.4, 59.4, 73.1, 112.9 (q, 7=3.9 Hz) 116.9 (q, 7=3.90 Hz) 119.4 (d, 7=1.1 Hz), 124.2 (q, 7=272.6 Hz), 129.8, 131, (q, 7=31.9 Hz), 151.0, 169.0, 169.7.

[0450] Example 65. Compound (R)-4 (wherein A=H, B=H, X=H, R1=CF3, R2=CH2OCH3); (R)-N- (3 -methoxy- 1 -oxo- 1-( 4-( 3-(trifhioromethyl)phenyl )piperazin-1-yl)propan-2-yl)acetamide

[0451] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-3 -methoxy- 1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1 -one (1.33 g, 4 mmol, 1 eq, Example 38), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0452] White solid. Yield: 91% (1.37 g); MP 132.2-133.8°C; TLC: Rf= 0.55 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.10 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3F3 = 374.16, exp. (M+H)+= 374.2. Chiral HPLC > 99% ee (tR= 10.507 min).1H NMR (500 MHz, CDCl3) δ 2.01 (s, 3 H), 3.29-3.43 (m, 6 H), 3.44-3.57 (m, 2 H), 3.61 (dd, 7=8.9, 5.2 Hz, 1 H), 3.97-4.19 (m, 4 H), 5.05-5.15 (m, 1 H), 6.47 (br d, 7=6.9 Hz, 1 H), 7.44 (br d, 7=7.7 Hz, 1 H), 7.50-7.58 (m, 2 H), 7.66 (br d, 7=6.9 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.2, 42.2, 45.7, 48.6, 48.8, 49.4, 59.4, 73.1, 112.9 (q, 7=3.9 Hz) 116.9 (q, 7=3.9 Hz) 119.4, 124.2 (q, 7=272.6 Hz),

[0453] 129.8, 131, (q, 7=31.9 Hz), 151.0, 169.0, 169.8.

[0454] Example 66. Compound (S)-4 (wherein A=H, B=H, X=H, R1=CF3, R2=CH2OCH3); (S)-N-

[0455] (3-methoxy-1 -oxo-1 -( 4-( 3-(trifluoromethyl)phenyl )piperazin-1-yl)propan-2-yl)acetamide

[0456] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-3 -methoxy- 1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1 -one (1.33 g, 4 mmol, 1 eq, Example 39), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0457] White solid. Yield: 90% (1.35 g); MP 130.1-131.3°C; TLC: Rf= 0.54 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.09 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3F3 =

[0458] 374.16, exp. (M+H)+= 374.2. Chiral HPLC > 99% ee (tR= 13.557 min).1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H,) 3.12-3.22 (m, 2 H), 3.23-3.35 (m, 5 H), 3.46 (dd, 7=8.9, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 5.0 Hz, 1 H), 3.66-3.75 (m, 2 H), 3.77-3.85 (m, 1 H), 3.88-3.96 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.57 (br d, 7=7.6 Hz, 1 H), 7.05 (dd, 7=8.3, 2.2 Hz, 1 H), 7.09-7.14 (m, 2 H), 7.36 (t, 7=8.0 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.2, 45.7, 48.6, 48.8, 49.4, 59.4, 73.1, 112.9 (q, 7=3.9 Hz) 116.9 (q, 7=3.9 Hz) 119.4 (d, 7=1.1 Hz), 124.2 (q, 7=272.6 Hz), 129.8, 131, (q, 7=31.9 Hz), 151.0, 169.0, 169.7.

[0459] Example 67. Compound (R,S)-5 (wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3); (R,S)-N-( 3 -methoxy- 1 -oxo- l-( 4-( 3-( trifhioromethoxy)phenyl)piperazin-1-yl)propan-2- yl)acetamide

[0460] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-3 -methoxy- 1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1 -one (1.39 g, 4 mmol, 1 eq, Example 40), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0461] White solid. Yield: 89% (1.39 g); MP 134.2-135.6°C; TLC: Rf= 0.59 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.51 min. LC-MS (ESI): calc. (M+H)+for CI7H22N3O4F3=

[0462] 390.16, exp. (M+H)+= 390.2.1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.10-3.18 (m, 2 H), 3.21- 3.30 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.67-3.75 (m, 2 H), 3.76-3.85 (m, 1 H), 3.88-3.97 (m, 1 H), 5.14 (td, 7=7.7, 4.9 Hz, 1 H), 6.53 (br d, 7=7.73 Hz, 1 H), 6.66-6.76 (m, 2 H) δ.80 (dd, 7=8.4, 2.2 Hz, 1 H) 7.19 -7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.2, 45.6, 48.7 48.7, 49.3, 59.4, 73.2, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0463] Example 68. Compound (R)-5 (wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3); (R)-N-

[0464] (3-methoxy-1-oxo-1-( 4-( 3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0465] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-3 -methoxy- 1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1 -one (1.39 g, 4 mmol, 1 eq, Example 41), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0466] White solid. Yield: 85% (1.33 g); MP 130.6-131.8°C; TLC: Rf= 0.60 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.52 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O4F3 = 390.16, exp. (M+H)+= 390.2. Chiral HPLC > 99% ee (tR= 9.764 min).1H NMR (500 MHz, CDCl3) 6 2.00 (s, 3 H), 3.11-3.19 (m, 2 H), 3.22-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.64-3.75 (m, 2 H), 3.76-3.85 (m, 1 H), 3.86-3.96 (m, 1 H), 5.14 (td, 7=7.7, 4.9 Hz, 1 H), 6.53 (br d, 7=7.7 Hz, 1 H), 6.67-6.77 (m, 2 H) δ.80 (dd, 7=8.4, 2.2 Hz, 1 H) 7.21 -7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 23.4, 42.1, 45.6, 48.6, 48.7, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0467] Example 69. Compound (S)-5 (wherein A=H, B=H, X=H, R1=OCF3, R2=CH2OCH3); (S)-N- (3 -methoxy- 1 -oxo- l-( 4-( 3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0468] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-3 -methoxy- 1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-1 -one (1.39 g, 4 mmol, 1 eq, Example 42), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0469] White solid. Yield: 91% (1.42 g); MP 128.2-129.5°C; TLC: Rf= 0.59 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.52 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O4F3 = 390.16, exp. (M+H)+= 390.2. Chiral HPLC > 99% ee (tR= 13.727 min).1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.10-3.19 (m, 2 H), 3.21-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.65-3.75 (m, 2 H), 3.76-3.84 (m, 1 H), 3.87-3.97 (m, 1 H), 5.14 (td, 7=7.7, 4.9 Hz, 1 H), 6.53 (br d, 7=7.7 Hz, 1 H), 6.67-6.76 (m, 2 H) δ.80 (dd, 7=8.4, 2.2 Hz, 1 H) 7.2 -7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.1, 45.6, 48.6, 48.7, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0470] Example 70. Compound (R,S)-6 (wherein A=H, B=H, X=H, R1=SCF3, R2=CH2OCH3); (R,S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2- yl)acetamide

[0471] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-3 -methoxy- 1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1 -one (1.45 g, 4 mmol, 1 eq, Example 43), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0472] White solid. Yield: 87% (1.41 g); MP 141.7-142.8°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.89 min. LC-MS (ESI): calc. (M+H)+for Ci7H22N3O3SF3= 406.14, exp. (M+H)+= 406.2.1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.12-3.20 (m, 2 H), 3.21-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.67-3.75 (m, 2 H) 3.76-3.85 (m, 1 H), 3.87-3.96 (m, 1 H), 5.15 (td, 7=7.7, 4.9 Hz, 1 H), 6.55 (br d, 7=7.6 Hz, 1 H), 6.97-7.05 (m, 1 H), 7.12-7.19 (m, 2 H), 7.29 (t, 7=8.1 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.1, 45.7, 48.6, 48.8, 49.3 59.4, 73.2, 118.6, 123.8, 125.3 (d, 7=2.0 Hz), 127.8, 129.7 (q, 7=308.0 Hz), 130.2, 151.5, 169.0, 169.7.

[0473] Example 71. Compound (R)-6 (wherein A=H, B=H, X=H, R1=SCF3, R2=CH2OCH3); (R)-N- (3 -methoxy- 1 -oxo- l-( 4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0474] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-3 -methoxy- 1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1 -one (1.45 g, 4 mmol, 1 eq, Example 44), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0475] White solid. Yield: 92% (1.49 g); MP 137.2-138.6°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.88 min. LC-MS (ESI): calc. (M+H)+for CI7H22N3O3SF3= 406.14, exp. (M+H)+= 406.2. Chiral HPLC > 99% ee (tR= 10.388 min).1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.12-3.19 (m, 2 H), 3.22-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.66-3.75 (m, 2 H) 3.76-3.85 (m, 1 H), 3.87-3.96 (m, 1

[0476] H), 5.15 (td, 7=7.7, 4.9 Hz, 1 H), 6.55 (br d, 7=7.6 Hz, 1 H), 6.98-7.04 (m, 1 H), 7.13-7.18 (m, 2 H), 7.29 (t, 7=8.1 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.2, 45.7, 48.6, 48.8, 49.3 59.4, 73.2, 118.6, 123.8, 125.3 (d, 7=2.2 Hz), 127.8, 129.7 (q, 7=308.0 Hz), 130.2, 151.5, 169.0, 169.7.

[0477] Example 72. Compound (S)-6 (wherein A=H, B=H, X=H, R1=SCF3, R2=CH2OCH3); (S)-N- (3 -methoxy- 1 -oxo- l-( 4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide

[0478] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-3 -methoxy- 1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)propan-1 -one (1.45 g, 4 mmol, 1 eq, Example 45), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0479] White solid. Yield: 89% (1.44 g); MP 135.7-136.8°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.89 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3SF3 = 406.14, exp. (M+H)+= 406.2. Chiral HPLC > 99% ee (tR= 14.648 min).1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.11-3.19 (m, 2 H), 3.21-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.65-3.75 (m, 2 H) 3.76-3.84 (m, 1 H), 3.87-3.96 (m, 1 H), 5.15 (td, 7=7.7, 4.9 Hz, 1 H), 6.55 (br d, 7=7.6 Hz, 1 H), 6.98-7.04 (m, 1 H), 7.12-7.18 (m, 2 H), 7.29 (t, 7=8.1 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.1, 45.7, 48.6, 48.8, 49.3 59.4, 73.2, 118.6, 123.8, 125.3 (d, 7=2.0 Hz), 127.8, 129.7 (q, 7=308.0 Hz), 130.2, 151.5, 169.0, 169.7.

[0480] Example 73. Compound (R,S)-7 (wherein A=H, B=H, X=H, R1=C6H5, R2CH2OCH3); (R,S)- N-(l-(4-([l,l ’-biphenyl] -3-yl)piperazin-1-yl)-3-methoxy-1-oxopropan-2-yl)acetamide

[0481] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-1- (4-([l,l ’-biphenyl]-3-yl)piperazin-1-yl)-2-amino-3 -methoxypropan- 1 -one (1.36 g, 4 mmol, 1 eq, Example 46), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0482] White solid. Yield: 88% (1.35 g); MP 172.7-173.8°C; TLC: Rf= 0.68 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 8.11 min. LC-MS (ESI): calc. (M+H)+for C22H27N3O3 = 382.21, exp. (M+H)+= 382.3.1H NMR (500 MHz, CDCl3) δ 2.02 (s, 3 H), 3.34 (s, 3 H), 3.41-3.70 (m, 5 H), 3.72-3.84 (m, 1 H), 4.19-4.57 (m, 4 H), 5.06 (q, 7=6.6 Hz, 1 H), 6.54 (br d, 7=6.59 Hz, 1 H), 7.35-7.40 (m, 1 H), 7.42-7.47 (m, 2 H), 7.57 (br d, 7=7.5 Hz, 3 H), 7.68 (br d, 7=7.7 Hz, 1 H), 7.76 (br s, 1 H), 8.08 (br s, 1 H).13C NMR (126 MHz, CDCl3) δ 23.1, 39.7, 43.3, 48.7, 55.2, 59.4, 119.7, 120.1, 127.2, 128.6, 128.9, 129.2, 131.0, 138.8, 142.5, 144.1, 169.6, 170.4. Example 74. Compound (R)-7 (wherein A=H, B=H, X=H, R1=C6H5, R2CH2OCH3); (R)-N- (l-(4-([l,l ’-biphenyl] -3-yl)piperazin-1-yl)-3-methoxy-1-oxopropan-2-yl)acetamide

[0483] The compound was obtained using an analogous procedure as above. In the reaction, (R)- ! -(4- ([l,r-biphenyl]-3-yl)piperazin-1-yl)-2-amino-3-methoxypropan-1-one (1.36 g, 4 mmol, 1 eq, Example 47), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0484] White solid. Yield: 90% (1.38 g); MP 168.2-169.6°C; TLC: Rf= 0.67 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 8.13 min. LC-MS (ESI): calc. (M+H)+for C22H27N3O3 = 382.21, exp. (M+H)+= 382.3. Chiral HPLC > 99% ee (tR= 12.198 min).1H NMR (500 MHz, CDCl3) 8 2.01 (s, 3 H), 3.34 (s, 3 H), 3.43-3.58 (m, 4 H), 3.61 (dd, J=8.9, 5.4 Hz, 1 H), 3.71 (br s, 1 H), 4.10-4.55 (m, 4 H), 5.06 (q, J=6.6 Hz, 1 H), 6.54 (br d, J=6.6 Hz, 1 H), 7.35 -7.40 (m, 1 H), 7.41- 7.47 (m, 2 H), 7.50-7.59 (m, 3 H), 7.64 (br d, J=7.7 Hz, 1 H), 7.69 (br d, J=6.Q Hz, 1 H) δ.00 (br s, 1 H).13C NMR (126 MHz, CDCl3) δ 23.2, 39.9, 43.5, 48.6, 54.7, 59.4, 119.4,119.7, 127.2, 128.6, 129.2, 130.9, 139.0, 144.0, 169.5, 170.2.

[0485] Example 75. Compound (S)-7 (wherein A=H, B=H, X=H, R1=C6H5, R2CH2OCH3); (S)-N- (l-(4-([l,l ’-biphenyl] -3-yl)piperazin-1-yl)-3-methoxy-1-oxopropan-2-yl)acetamide

[0486] The compound was obtained using an analogous procedure as above. In the reaction, (S)-1-(4- ([l,r-biphenyl]-3-yl)piperazin-1-yl)-2-amino-3-methoxypropan-1-one (1.36 g, 4 mmol, 1 eq, Example 48), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0487] White solid. Yield: 87% (1.33 g); MP 166.7-167.9°C; TLC: Rf= 0.67 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 8.14 min. LC-MS (ESI): calc. (M+H)+for C22H27N3O3 = 382.21, exp. (M+H)+= 382.3. Chiral HPLC > 99% ee (tR= 16.488 min).1H NMR (500 MHz, CDCl3) 6 2.01 (s, 3 H), 3.33 (s, 3 H), 3.43-3.58 (m, 4 H), 3.61 (dd, J=8.9, 5.4 Hz, 1 H), 3.71 (br s, 1 H), 4.10-4.55 (m, 4 H), 5.06 (q, J=6.6 Hz, 1 H), 6.54 (br d, J=6.6 Hz, 1 H), 7.35 -7.40 (m, 1 H), 7.41- 7.47 (m, 2 H), 7.50-7.59 (m, 3 H), 7.64 (br d, J=7.7 Hz, 1 H), 7.69 (br d, J=6.Q Hz, 1 H) δ.00 (br s, 1 H).13C NMR (126 MHz, CDCl3) δ 23.2, 39.8, 43.5, 48.6, 54.9, 59.4, 119.6,119.9, 127.2, 128.6, 129.2, 130.9, 138.8, 144.0, 169.6, 170.2. Example 76. Compound (R,S)-8 (wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5); (R,S)-N- (l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0488] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-1-one (1.33 g, 4 mmol, 1 eq, Example 49), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0489] White solid. Yield: 91% (1.37 g); MP 137.2-138.5°C; TLC: Rf= 0.53 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.78 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3F3 = 374.16, exp. (M+H)+= 374.2.1H NMR (500 MHz, CDCl3) δ 0.91 (t, 7=7.5 Hz, 3 H), 1.58 (dt, 7=14.1, 7.2 Hz, 1 H), 1.81 (ddd, 7=13.9, 7.5, 5.4 Hz, 1 H), 2.00 (s, 3 H), 3.18 (dt, 7=16.4, 5.3 Hz, 4 H), 3.62-3.79 (m, 3 H), 3.79-3.87 (m, 1 H), 4.93 (td, 7=7.5, 5.4 Hz, 1 H), 6.53 (br d, 7=8.0 Hz, 1 H), 6.67-6.76 (m, 2 H), 6.80 (dd, 7=8.3, 2.3 Hz, 1 H), 7.25 (t, 7=8.2 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.37, 48.9, 49.3, 49.7, 109.1, 112.4, 114.5, 120.5 (q, 7=257.0 Hz), 130.3, 150.3, 152.1, 169.7, 170.4.

[0490] Example 77. Compound (R)-8 (wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5); (R)-N-(l- oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0491] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-1-one (1.33 g, 4 mmol, 1 eq, Example 50), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0492] White solid. Yield: 89% (1.34 g); MP 134.5-135.9°C; TLC: Rf= 0.52 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.78 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3F3 = 374.16, exp. (M+H)+= 374.2. Chiral HPLC > 99% ee (tR= 10.242 min).1H NMR (500 MHz, CDCl3) δ 0.91 (t, 7=7.5 Hz, 3 H), 1.59 (dt, 7=14.1, 7.2 Hz, 1 H), 1.72 -1.86 (m, 1 H), 2.00 (s, 3 H), 3.19 (dt, 7=16.3, 5.1 Hz, 4 H), 3.63-3.77 (m, 3 H), 3.79-3.90 (m, 1 H), 4.93 (td, 7=7.5, 5.4 Hz, 1 H), 6.50 (br d, 7=7.9 Hz, 1 H), 6.67-6.76 (m, 2 H), 6.80 (dd, 7=8.3, 2.2 Hz, 1 H) 7.22-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.4, 48.9, 49.3, 49.7, 109.1, 112.4, 114.5, 120.5 (q, 7=257.0 Hz), 130.3, 152.1, 169.8, 170.4. Example 78. Compound (S)-8 (wherein A=H, B=H, X=H, R1=OCF3, R2=C2H5); (S)-N-(l- oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0493] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-1-one (1.33 g, 4 mmol, 1 eq, Example 51), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0494] White solid. Yield: 88% (1.32 g); MP 133.2-134.6°C; TLC: Rf= 0.53 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 6.78 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O3F3 = 374.16, exp. (M+H)+= 374.2. Chiral HPLC > 99% ee (tR= 14.383 min).1H NMR (500 MHz, CDCl3) δ 0.91 (t, 7=7.5 HZ, 3 H), 1.59 (dt, 7=14.2, 7.2 Hz, 1 H), 1.78-1.84 (m, 1 H), 2.00 (s, 3 H), 3.12-3.25 (m, 4 H), 3.62-3.78 (m, 3 H), 3.79-3.88 (m, 1 H), 4.93 (td, 7=7.4, 5.4 Hz, 1 H), 6.49 (br d, 7=7.9 Hz, 1 H), 6.67-6.75 (m, 2 H), 6.80 (dd, 7=8.3, 2.0 Hz, 1 H), 7.20-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.4, 48.9, 49.3, 49.7, 109.1, 112.4, 114.5, 120.5 (q, 7=257.0 Hz) 130.3, 150.3 (d, 7=1.7 Hz) 152.1, 169.8, 170.4.

[0495] Example 79. Compound (R,S)-9 (wherein A=H, B=H, X=H, R1=SCF3, R2= C2H5); (R,S)-N- (l-oxo-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide

[0496] The compound was obtained using an analogous procedure as above. In the reaction, (R,S)-2- amino-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-1-one (1.39 g, 4 mmol, 1 eq, Example 52), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0497] White solid. Yield: 90% (1.40 g); MP 140.2-141.4°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 7.02 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O2SF3 = 390.14, exp. (M+H)+= 390.2. Chiral HPLC > 99% ee (tR= 10.435 min).1H NMR (500 MHz, CDCl3) δ 0.91 (t, 7=7.5 Hz, 3 H), 1.59 (dt, 7=14.2, 7.2 Hz, 1 H), 1.79-1.86 (m, 1 H), 2.01 (s, 3 H), 3.20 (dt, 7=16.4, 5.0 Hz, 4 H), 3.63-3.79 (m, 3 H), 3.80-3.88 (m, 1 H), 4.93 (td, 7=7.5, 5.4 Hz, 1 H), 6.50 (br d, 7=7.9 Hz, 1 H), 6.97-7.03 (m, 1 H), 7.12-7.19 (m, 2 H), 7.27-7.34 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.4, 49.0, 49.3, 49.7, 118.7, 123.9, 125.3 (q, 7=2.1 Hz), 129.7 (q, 7=308.0 Hz), 128.0, 130.2, 151.4, 169.8, 170.4. Example 80. Compound (R)-9 (wherein A=H, B=H, X=H, R1=SCF3, R2= C2H5); (R)-N-(l- oxo-1 -(4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl) butan-2-y I) acetamide

[0498] The compound was obtained using an analogous procedure as above. In the reaction, (R)-2- amino-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-1-one (1.39 g, 4 mmol, 1 eq, Example 53), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0499] White solid. Yield: 88% (1.37 g); MP 138.4-139.7°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 7.05 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O2SF3 = 390.14, exp. (M+H)+= 390.2. Chiral HPLC > 99% ee (tR= 10.435 min).1H NMR (500 MHz, CDCl3) δ 0.91 (t, .7=7.5 HZ, 3 H), 1.59 (dt, J=14.2, 7.2 Hz, 1 H), 1.79-1.86 (m, 1 H), 2.01 (s, 3 H), 3.20 (dt, .7=16.4, 5.0 Hz, 4 H), 3.63-3.79 (m, 3 H), 3.80-3.88 (m, 1 H), 4.93 (td, .7=7.5, 5.4 Hz, 1 H), 6.50 (br d, J=7.9 Hz, 1 H), 6.97-7.03 (m, 1 H), 7.12-7.19 (m, 2 H), 7.27-7.34 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.4, 49.0, 49.3, 49.7, 118.7, 123.9, 125.3 (q, .7=2.1 Hz), 129.7 (q, .7=308.0 Hz), 128.0, 130.2, 151.4, 169.8, 170.4.

[0500] Example 81. Compound (S)-9 (wherein A=H, B=H, X=H, R1=SCF3, R2= C2H5); (S)-N-(l- oxo-1 -(4-( 3-(trifluorothiomethyl)phenyl)piperazin-1-yl) butan-2-y I) acetamide

[0501] The compound was obtained using an analogous procedure as above. In the reaction, (S)-2- amino-1-(4-(3-(trifluorothiomethyl)phenyl)piperazin-1-yl)butan-1-one (1.39 g, 4 mmol, 1 eq, Example 54), TEA (12 mmol, 3 eq) and acetyl chloride (6 mmol, 1.5 eq) were used.

[0502] White solid. Yield: 91% (1.42 g); MP 137.8-138.8°C; TLC: Rf= 0.57 (DCM:MeOH (9:0.5; v / v)); UPLC (purity > 99%), tR= 7.04 min. LC-MS (ESI): calc. (M+H)+for C17H22N3O2SF3 = 390.14, exp. (M+H)+= 390.2. Chiral HPLC > 99% ee (tR= 12.342 min).1H NMR (500 MHz, CDCl3) δ 0.91 (t, .7=7.5 Hz, 3 H), 1.54-1.66 (m, 1 H), 1.76-1.90 (m, 2 H), 2.01 (s, 3 H), 3.20 (dt, .7=16.2, 5.0 Hz, 4 H), 3.63-3.78 (m, 3 H), 3.79-3.88 (m, 1 H), 4.93 (td, J=7.4, 5.6 Hz, 1 H), 6.49 (br d, .7=7.9 Hz, 1 H), 7.00 (dd, J=8.3, 2.3 Hz, 1 H) 7.12-7.19 (m, 2 H), 7.27-7.34 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.4, 49.0, 49.3, 49.7, 118.7, 123.9, 125.3 (q, .7=2.1 Hz), 129.7 (q, .7=308.1 Hz), 128.0, 130.2, 151.4, 169.8, 170.4. The chemical procedure for deuterated compounds was conducted analogously using commercially available reagents, i.e. the tert-butoxy carbonyl (Boc) protected derivative of alanine, 2-aminobutanoic acid or O-methyl serine with the desired absolute configuration (R, S, or R,S), deuterated phenylpiperazine derivatives (i.e. 1-(3-(trifluoromethyl)pheny1-4-7)piperazine, 1-(3- (trifluoromethoxy)phenyl-4-d)piperazine, 1-(3-(trifluoromethyl)pheny1-4-7)piperazine-

[0503] 2,2,3,3,5,5,6,6-78, 1-(3-(trifluoromethoxy)pheny1-4-7)piperazine-2,2,3,3,5,5,6,6-78) and acetic acid chloride or its deuterated derivative, d3-acetic acid chloride. For all final compounds obtained, the masses of pseudomolecular ions (exp. (M+H)+) were determined by LCMS and these values corresponded to the calculated values (calc. (M+H)+). Additionally, for selected derivatives, the structures of the final compounds were confirmed by the analysis of3H NMR and13C NMR spectra. Furthermore, enantiomeric purity was determined by the analysis of chiral SFC spectra using an Agilent 1260 Infinity II SFC instrument equipped with a Trefoil CEL2 chiral column with a length of 15 cm and a diameter of 2.1 mm. The analysis was performed in the following conditions: column temperature: 30°C, mixture of supercritical carbon dioxide and methanol 85 / 15 (v / v), analysis time: 5 minutes, in an isocratic mobile phase system at a flow rate of 0.7 ml / min, detection at X = 210 nm. Below are all the examples:

[0504] Example 82. Compound d1-(R,S)-1 (wherein A=H, B=H, X=D, R1=CF3, R2=CH3) (R,S)-N- (1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C16H19DN3O2F3 = 345.16, exp. (M+H)+= 345.2. UPLC (purity > 99%), tR= 6.32 min.1H NMR (500 MHz, CDCl3) δ 1.33 (d, J=6.9, Hz, 3 H), 1.99 (s, 3 H), 3.15-3.29 (m, 4 H), 3.60-3.68 (m, 1 H), 3.70-3.76 (m, 2 H), 3.80-3.88 (m, 1 H), 4.93 (quin, J=6.9 Hz, 1 H), 6.67 (d, 1 H, 7=7.3 Hz), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.10 (d, J=2.5 Hz, 1 H), 7.35 (d, 1 H, 7=8.3 Hz).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.2 (d, 7=17.1 Hz), 49.2 (d, 7=41.1 Hz) 113.0, (d, J=3.9 Hz), 119.6, 124.2 (q, 7=272.5 Hz), 129.7, 131.6 (d, 7=31.9 Hz), 150.9, 169.4, 171.1.

[0505] Example 83. Compound d1-(R)-1 (wherein A=H, B=H, X=D, R1=CF3, R2=CH3) (S)-N-(1- oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C16H19DN3O2F3 = 345.16, exp. (M+H)+= 345.2. UPLC (purity > 99%), tR= 6.32 min. Chiral SFC > 99% ee (tR= 3.81 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.9 Hz, 3 H), 1.99 (s, 3 H), 3.15-3.29 (m, 4 H), 3.60-3.68 (m, 1 H), 3.69-3.76 (m, 2 H), 3.80-3.89 (m, 1 H), 4.93 (quin, J=6.9 Hz, 1 H), 6.64 (d, 1 H, 7=7.3 Hz), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.10 (d, J=2.5 Hz, 1 H), 7.36 (d, J= 8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.2 (d, 7=17.1 Hz), 49.2 (d, 7=41.1 Hz) 113.0, (d, 7=3.9 Hz), 119.6, 124.2 (q, 7=272.5 Hz), 129.7, 131.6 (d, 7=31.9 Hz), 150.9, 169.4, 171.1.

[0506] Example 84. Compound d1- (S)-1 (wherein A=H, B=H, X=D, R1=CF3, R2=CH3) («$)-#-( 1-oxo-1 - (4-(3-(trifluoromethyl)phenyl-4-d)piperazin- l -yl)propan-2-yl)acetamide calc. (M+H)+for C16H19DN3O2F3 = 345.16, exp. (M+H)+= 345.2. UPLC (purity > 99%), tR= 6.41 min. Chiral SFC

[0507] > 99% ee (tR= 4.46 min).1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.9 Hz, 3 H,), 2.00 (s, 3 H), 3.14-3.27 (m, 4 H), 3.60-3.68 (m, 1 H), 3.69-3.74 (m, 2 H), 3.80-3.85 (m, 1 H), 4.93 (quin, 7= 6.9 Hz, 1 H), 6.66 (d, 7=7.1 Hz, 1 H), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.09 (d, 7=2.4 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 6 19.3, 23.4, 41.9, 44.2, 49.2 (d, 7=41.2 Hz) 113.0, 119.5, 124.2 (q, 7=272.5 Hz), 129.7, 131.6 (d, 7=31.9 Hz), 150.9, 169.4, 171.1.

[0508] Example 85. Compound d3-(R,S)-1 (wherein A=D, B=H, X=H, R1=CF3, R2=CH3); (R,S)-N- (1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H17D3N3O2F3 = 347.17, exp. (M+H)+= 347.2. UPLC (purity > 99%), tR= 6.33 min.1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.9 Hz, 3 H), 3.06-3.32 (m, 4 H), 3.60-3.67 (m, 1 H), 3.68-3.78 (m, 2 H), 3.80-3.89 (m, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H), 6.64 (br d, 7=7.5 Hz, 1 H), 7.05 (br d, 7=8.0 Hz, 1 H), 7.08-7.15 (m, 2 H), 7.36 (t, 7=8.0 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.3, 49.0, 49.3, 113.0 (br d, 7=3.6 Hz), 117.1 (br d, 7=3.6 Hz), 119.6, 124.2 (q, 7=272.0 Hz) 129.9, 131.7 (q, 7=31.4 Hz), 151.0, 169.4, 171.1.

[0509] Example 86. Compound d3-(R)-1 (wherein A=D, B=H, X=H, R1=CF3, R2=CH3); oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H17D3N3O2F3 = 347.17, exp. (M+H)+= 347.2. UPLC (purity > 99%), tR= 6.32 min. Chiral SFC > 99% ee (tR= 3.81 min).1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.9 Hz, 3 H), 3.15-

[0510] 3.31 (m, 4 H), 3.59-3.69 (m, 1 H), 3.71-3.77 (m, 2 H), 3.82-3.92 (m, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H), 6.59 (br d, 7=7.2 Hz, 1 H), 7.06 (dd, 7=8.3, 2.0 Hz, 1 H), 7.10 (s, 1 H), 7.13 (d, 7=7.7 Hz, 1 H), 7.37 (t, 7=7.9 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 42.0, 45.1, 45.3, 49.0, 49.3, 113.0 (br d, 7=4.2 Hz), 117.1 (br d, 7=3.6 Hz), 119.6, 124.3 (q, 7=272.0 Hz), 129.9, 131.8 (q, 7=31.4 Hz), 151.0, 169.4, 171.1.

[0511] Example 87. Compound d3- (S)-1 (wherein A=D, B=H, X=H, R1=CF3, R2=CH3); (S)-N-(1- oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H17D3N3O2F3 = 347.17, exp. (M+H)+= 347.2. UPLC (purity > 99%), tR= 6.43 min. Chiral SFC > 99% ee (tR= 4.51 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, 7=6.6 Hz, 3 H), 3.23 (br dd, 7=6.9, 3.7 Hz, 4 H), 3.59-3.68 (m, 1 H), 3.69-3.77 (m, 2 H), 3.85 (ddd, 7=13.0, 6.4, 3.7 Hz, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H), 6.62 (br d, 7=7.5 Hz, 1 H), 7.05 (dd, 7=8.3, 2.3 Hz, 1 H), 7.10 (s, 1 H), 7.13 (d, 7=7.7 Hz, 1 H), 7.36 (t, 7=7.9 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.3, 49.0, 49.3, 113.0 (br d, 7=4.2 Hz), 117.1 (br d, 7=4.2 Hz), 119.6, 124.2 (q, 7=272.6 Hz), 129.9, 131.7 (q, 7=31.4 Hz), 151.0, 169.4, 171.1.

[0512] Example 88. Compound d4-(R,S)-1 (wherein A=D, B=H, X=D, R1=CF3, R2=CH3) (R,S)-N- (1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H16D4N3O2F3 = 348.18, exp. (M+H)+348.2. UPLC (purity > 99%), tR= 6.32 min.1H NMR (500 MHz, CDCl3) δ1.34 (d, 7=6.9 Hz, 3 H), 3.14-3.27 (m, 4 H), 3.60-3.68 (m, 1 H), 3.69-3.76 (m, 2 H), 3.81-3.89 (m, 1 H), 4.93 (quin, 7=6.9 Hz, 1 H), 6.63 (d, 7=7.2 Hz, 1 H), 7.05 (dd, 7=8.3, 2.4 Hz, 1 H), 7.10 (d, 7=2.3 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 22.5, 41.9, 45.2, 45.4, , 49.2, 49.4, 113.0, 119.6, 124.2 (q, 7=272.6 Hz), 129.7, 131.6, (q, 7=32.0 Hz), 150.9, 169.4, 171.1.

[0513] Example 89. Compound d4-(R)-1 (wherein A=D, B=H, X=D, R1=CF3, R2=CH3) (R)-N-(l- oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H16D4N3O2F3 = 348.18, exp. (M+H)+= 348.2. UPLC (purity > 99%), tR= 6.32 min. Chiral SFC > 99% ee (tR= 3.79 min).1H NMR (500 MHz, CDCl3) δ1.34 (d, 7=6.9 Hz, 3 H), 3.16- 3.27 (m, 4 H), 3.60-3.68 (m, 1 H), 3.69-3.75 (m, 2 H), 3.81-3.87 (m, 1 H), 4.93 (quin, 7=6.9 Hz,

[0514] 1 H), 6.64 (d, 7=7.2 Hz, 1 H), 7.04 (dd, 7=8.3, 2.4 Hz, 1 H), 7.11 (d, 7=2.3 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 22.5, 41.9, 45.2, 45.4, 49.2, 49.5, 113.0, 119.6, 124.2 (q, .7=272,6 Hz), 129.7, 131.6, (q, 7=32.0 Hz), 151.0, 169.4, 171.1

[0515] Example 90. Compound d4- (S)-1 (wherein A=D, B=H, X=D, R1=CF3, R2=CH3) (S)-N-(1-oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H16D4N3O2F3 = 348.18, exp. (M+H)+= 348.2. UPLC (purity > 99%), tR= 6.62 min. Chiral SFC > 99% ee (tR= 4.44 min).1H NMR (500 MHz, CDCl3) δ 1.33 (d, J=6.9 Hz, 3 H), 3.12-3.28 (m, 4 H), 3.60-3.68 (m, 1 H), 3.69-3.76 (m, 2 H), 3.82-3.87 (m, 1 H), 4.93 (quin, J=6.9 Hz, 1 H), 6.66 (d, 7=7.2 Hz, 1 H), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.10 (d, 7=2.4 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 22.7, 41.9, 45.2 45.4, 49.2, 49.5, 113.0, 119.6, 124.2 (q, 7=272.4 Hz), 129.7, 131.6 (q, 7=31.9 Hz), 150.9, 169.4, 171.1.

[0516] Example 91. Compound d9-(R,S)-1 (wherein A=H, B=D, X=D, R1=CF3, R2=CH3) (R,S)-N- (1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide; calc. (M+H)+for C16H11D9N3O2F3 = 353.21, exp. (M+H)+= 353.3. UPLC (purity > 99%), tR= 6.30.1H NMR (500 MHz, DMSO-76) δ 1.12 (d, 7=6.9 Hz, 3 H), 1.78 (s, 3 H), 4.70 (quin, 7=7.0 Hz, 1 H), 7.13 (d, 7=2.3 Hz, 1 H), 7.18 (dd, 7=8.4, 2.5 Hz, 1 H), 7.39 (dd, 7=10.4, 6.5 Hz, 1 H), 8.17 (d, 7=7.7 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 18.3, 22.8, 44.7, 111.9 (d, 7=3.9 Hz), 119.7, 124.9 (q, 7=272.6), 131.6 (q, 7=31.9 Hz), 151.2, 169.4, 171.1.

[0517] Example 92. Compound d9-(R)-1 (wherein A=H, B=D, X=D, R1=CF3, R2=CH3) (R)-N-(l- oxo-1-(4-(3-(trifhroromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2- yl)acetamide; calc. (M+H)+for C16H11D9N3O2F3 = 353.21, exp. (M+H)+= 353.3. UPLC (purity > 99%), tR= 6.31. Chiral SFC > 99% ee (tR= 3.85 min).1H NMR (500 MHz, DMSO-76) 1.12 (d, 7=6.9 Hz, 3 H), 1.78 (s, 3 H), 4.70 (quin, 7=7.0 Hz, 1 H), 7.13 (d, 7=2.3 Hz, 1 H), 7.18 (dd, 7=8.4, 2.5 Hz, 1 H), 7.39 (dd, 7=10.4, 6.5 Hz, 1 H), 8.17 (d, 7=7.7 Hz, 1 H).13C NMR (126 MHz, DMSO- 76) δ 18.2, 22.8, 44.7, 111.8, 119.56, 124.9 (d, 7=272.5 Hz), 130.2, 131.6 (q, 7=31.9 Hz), 151.4, 169.6, 171.1.

[0518] Example 93. Compound d9- (S)-1 (wherein A=H, B=D, X=D, R1=CF3, R2=CH3) (S)-N-(1-oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2-yl)acetamide; calc. (M+H)+for C16H11D9N3O2F3 = 353.21, exp. (M+H)+= 353.3. UPLC (purity > 99%), tR= 6.28. Chiral SFC > 99% ee (tR= 4.44 min).1H NMR (500 MHz, DMSO-76) δ 1.12 (d, J=6.9 Hz, 3 H), 1.78 (s, 3 H), 4.70 (quin, 7=7.0 Hz, 1 H), 7.13 (d, J=2.3 Hz, 1 H), 7.18 (dd, 7=8.4, 2.5 Hz, 1 H), 7.39 (dd, 7=10.4, 6.5 Hz, 1 H), 8.17 (d, 7=7.7 Hz, 1 H).13C NMR (126 MHz, DMSO-76) 5 18.2, 22.8, 44.7, 111.9 (d, J=3.9 Hz), 119.7, 124.9 (q, 7=272.5), 131.6 (q, 7=31.9 Hz), 151.3, 169.4, 171.1.

[0519] Example 94. Compound di2-(R,S)-1 (wherein A=D, B=D, X=D, R1=CF3, R2=CH3) (R,S)-N- (1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C16H8D12N3O2F3 = 356.23, exp. (M+H)+= 356.3. UPLC (purity > 99%), tR= 6.27.1H NMR (500 MHz, CDCl3) δ 1.12 (d, 7=6.9 Hz, 3 H), 4.69 (quin, 7=7.0 Hz, 1 H), 7.13 (d, 7=2.5 Hz, 1 H), 7.18 (dd, 1 H, 7=8.4, 2.6 Hz), 7.35-7.40 (m, 1 H), 8.18 (d, 7=7.7 Hz, 1 H).13C NMR (126 MHz, CDCl3) 18.1, 22.3, 44.7, 111.7 (d, 7=3.8 Hz), 119.6, 124.9 (q, 7=272.6 Hz), 130.2, 130.5, 151.4, 169.7, 171.2.

[0520] Example 95. Compound di2-(R)-1 (wherein A=D, B=D, X=D, R1=CF3, R2=CH3) (R)-N-(l- oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C16H8D12N3O2F3 = 356.23, exp. (M+H)+= 356.3. UPLC (purity > 99%), tR= 6.27. Chiral SFC > 99% ee (tR= 3.76 min).1H NMR (500 MHz, CDCl3) 8 1.12 (d, 7=6.9 Hz, 3 H), 4.69 (quin, 7=7.0 Hz, 1 H), 7.13 (d, 7=2.5 Hz, 1 H), 7.18 (dd, 1 H, 7=8.4, 2.6 Hz), 7.34-7.41 (m, 1 H), 8.18 (d, 7=7.7 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 18.2, 22.3, 44.7, 111.7 (d, 7=3.8 Hz), 119.6, 124.9 (q, 7=272.6 Hz), 130.2, 130.5, 151.4, 169.7, 171.2.

[0521] Example 96. Compound di2- (S)-1, (wherein A=D, B=D, X=D, R1=CF3, R2=CH3) (S)-N-(1- oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C16H8D12N3O2F3 = 356.23, exp. (M+H)+= 356.3. UPLC (purity > 99%), tR= 6.28. Chiral SFC > 99% ee (tR= 4.38 min).1H NMR (500 MHz, CDCl3) 6 1.12 (d, 7=6.9 Hz, 3 H), 4.71 (quin, 7=7.0 Hz, 1 H), 7.13 (d, 7=2.4 Hz, 1 H), 7.16-7.22 (m, 1 H), 7.39 (d, 7=8.4 Hz, 1 H), 8.17 (d, 7=7.8 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 18.2, 44.7, 111.7 (d, 7=3.8 Hz), 119.6, 124.9 (q, 7=272.6 Hz), 130.2, 130.4, 151.4, 169.5, 171.1. Example 97. Compound d1-(R,A')-2 (wherein A=H, B=H, X=D, R1=OCF3, R2=CH3) (R,S)-N- (1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C16H19DN3O3F3 = 361.16, exp. (M+H)+= 361.2. UPLC (purity > 99%), tR= 6.58.1H NMR (500 MHz, CDCl3) δ 1.33 (d, J=6.9 Hz, 3 H), 2.00 (s, 3 H), 3.11-3.24 (m, 4 H), 3.59-3.65 (m, 1 H), 3.67-3.73 (m, 2 H), 3.84 (ddd, 7=13.1, 6.5, 3.6 Hz, 1 H), 4.92 (quin, J=6.9 Hz, 1 H), 6.63 (d, 7=6.8 Hz, 1 H), 6.70 (d, 7=1.8 Hz, 1 H), 6.81 (dd, 7=8.4, 2.4 Hz, 1 H), 7.24-7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.2, 49.0, 49.2, 109.1, 112.4, 114.5, 120.5 (q, 7=257.1 Hz), 130.2, 150.3, 152.1, 169.4, 171.1.

[0522] Example 98. Compound d1-(R)-2 (wherein A=H, B=H, X=D, R1=OCF3, R2=CH3) (R)-N-(l- oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C16H19DN3O3F3 = 361.16, exp. (M+H)+= 361.2. UPLC (purity > 99%), tR= 6.58. Chiral SFC

[0523] > 99% ee (tR= 3.23 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, 7=6.9 Hz, 3 H), 2.00 (s, 3 H), 3.14-3.24 (m, 4 H), 3.59-3.63 (m, 1 H), 3.67-3.75 (m, 2 H), 3.84 (ddd, 7=13.1, 6.5, 3.6 Hz, 1 H), 4.92 (quin, 7=6.9 Hz, 1 H), 6.63 (d, 7=6.8 Hz, 1 H), 6.70 (d, 7=1.8 Hz, 1 H), 6.81 (dd, 7=8.4, 2.4 Hz, 1 H), 7.24-7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.2, 48.9, 49.3, 109.1, 112.4, 114.5, 120.7 (q, 7=257.1 Hz), 130.1 150.3, 152.1, 169.4, 171.1.

[0524] Example 99. Compound d1- (S)-2 (wherein A=H, B=H, X=D, R1=OCF3, R2=CH3) (S)-N-(1- oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C16H19DN3O3F3 = 361.16, exp. (M+H)+= 361.2. UPLC (purity > 99%), tR= 6.57. Chiral SFC

[0525] > 99% ee (tR= 3.77 min).1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.9 Hz, 3 H), 2.00 (s, 3 H), 3.13-3.24 (m, 4 H), 3.57-3.66 (m, 1 H), 3.67-3.78 (m, 2 H), 3.84 (ddd, 7=13.1, 6.5, 3.6 Hz, 1 H), 4.92 (quin, 7=6.9 Hz, 1 H), 6.62 (d, 7=6.8 Hz, 1 H), 6.70 (d, 7=1.8 Hz, 1 H), 6.81 (dd, 7=8.4, 2.4 Hz, 1 H), 7.24-7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.2, 48.9, 49.2, 109.2, 112.4, 114.5, 120.6 (q, 7=257.1 Hz), 130.2 150.3, 152.1, 169.4, 171.1.

[0526] Example 100. Compound d3-(7?..S)-2 (wherein A=D, B=H, X=H, R1=OCF3, R2=CH3); (R,S)~ N-(l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-dy calc. (M+H)+for C16H17D3N3O3F3 = 363.17, exp. (M+H)+= 363.2. UPLC (purity > 99%), tR= 6.55.1H NMR (500 MHz, CDCl3) δ 1.34 (d, J=6.9 Hz, 3 H), 3.11-3.26 (m, 4 H), 3.58-3.66 (m, 1 H), 3.66- 3.75 (m, 2 H), 3.84 (dd, J=, 6.4, 3.4 Hz, 1 H), 4.92 (quin, 7=7.0 Hz, 1 H) δ.62 (br d, 7=7.5 Hz, 1 H), 6.70 (s, 1 H), 6.73 (br d, 7=8.0 Hz, 1 H), 6.80 (dd, 7=8.6, 2.3 Hz, 1 H), 7.23-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 41.9, 45.1, 45.2, 48.8, 49.2, 109.1, 112.4, 114.5, 120.5 (q, 7=257.1 Hz), 130.3, 150.4, 152.1, 169.4, 171.1.

[0527] Example 101. Compound d3-(R)-2 (wherein A=D, B=H, X=H, R1=OCF3, R2=CH3); (R)-N- (l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2-,2-d3\ calc. (M+H)+for C16H17D3N3O3F3 = 363.17, exp. (M+H)+= 363.2. UPLC (purity > 99%), tR= 6.55. Chiral SFC > 99% ee (tR= 3.24 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, 7=6.9 Hz, 3 H), 3.11- 3.25 (m, 4 H), 3.57-3.65 (m, 1 H), 3.67-3.74 (m, 2 H), 3.84 (dd, 7=6.4, 3.4 Hz, 1 H), 4.93 (quin, 7=7.0 Hz, 1 H) δ.62 (br d, 7=7.5 Hz, 1 H), 6.71 (s, 1 H), 6.73 (br d, 7=8.0 Hz, 1 H), 6.80 (dd, 7=8.6, 2.3 Hz, 1 H), 7.25-7.30 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.4, 23.4, 42.0, 45.1, 45.2, 48.8, 49.2, 109.1, 112.3, 114.4, 120.5 (q, 7=257.1 Hz), 130.4, 150.4, 152.2, 169.4, 171.1.

[0528] Example 102. Compound d3-(.S')-2 (wherein A=D, B=H, X=H, R1=OCF3, R2=CH3); (S)-N- (l-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3,' calc. (M+H)+for C16H17D3N3O3F3 = 363.17, exp. (M+H)+= 363.2. UPLC (purity > 99%), tR= 6.57. Chiral SFC > 99% ee (tR= 3.78 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, 7=6.6 Hz, 3 H), 3.21- 3.50 (m, 4 H) 3.81-4.02 (m, 3 H) 4.15 (br d, 7=12.9 Hz, 1 H) 4.88 (br t, 7=6.6 Hz, 1 H) δ.52 (br d, 7=6.0 Hz, 1 H) δ.99 (br d, 7=8.0 Hz, 1 H) 7.13 (br s, 1 H) 7.22-7.28 (m, 1 H) 7.35-7.43 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 23.4, 42.0, 45.1, 45.2, 48.8, 49.2, 109.1, 112.3, 114.4, 120.5 (q, 7=257.1 Hz), 130.4, 150.4, 152.2, 169.4, 171.1.

[0529] Example 103. Compound d4-(R,.S')-2 (wherein A=D, B=H, X=D, R1=OCF3, R2=CH3) (R,S)~ N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H16D4N3O3F3 = 364.17, exp. (M+H)+= 364.2. UPLC (purity > 99%), tR= 6.55.1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.8 Hz, 3 H), 3.12-3.24 (m, 4 H), 3.59-3.67 (m, 1 H), 3.68-3.75 (m, 2 H), 3.84 (ddd, 7= 12.7, 6.1, 3.6 Hz, 1 H), 4.93 (quin, J=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (dd, 7=8.4, 2.2 Hz, 1 H), 7.25-7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.2, 41.9, 45.1, 45.2, 48.8, 49.2, 109.1, 112.3 (d, 7=36.7 Hz) 114.5, 120.5 (q, 7=257.1 Hz), 130.3, 150.3, 152.1, 169.6, 171.1.

[0530] Example 104. Compound d4-(R)-2 (wherein A=D, B=H, X=D, R1=OCF3, R2=CH3) (R)-N-(l- oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H16D4N3O3F3 = 364.17, exp. (M+H)+= 364.2. UPLC (purity > 99%), tR= 6.55. Chiral SFC > 99% ee (tR= 3.23 min).1H NMR (500 MHz, CDCl3) δ 1.34 (d, 7=6.8 Hz, 3 H), 3.14-

[0531] 3.22 (m, 4 H), 3.59-3.67 (m, 1 H), 3.68-3.75 (m, 2 H), 3.84 (ddd, 7= 12.7, 6.1, 3.6 Hz, 1 H), 4.93 (quin, J=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (dd, 7=8.4, 2.2 Hz, 1 H), 7.24-

[0532] 7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.3, 41.9, 45.1, 45.3, 48.8, 49.1, 109.1, 112.3 (d, 7=36.7 Hz) 114.5, 120.9 (q, 7=257.1 Hz), 130.3, 150.3, 152.1, 169.6, 171.1.

[0533] Example 105. Compound d-i-GS')-2 (wherein A=D, B=H, X=D, R1=OCF3, R2=CH3) (S)-N-(1- oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C16H16D4N3O3F3 = 364.17, exp. (M+H)+= 364.2. UPLC (purity > 99%), tR= 6.57. Chiral SFC > 99% ee (tR= 3.72 min).1H NMR (500 MHz, CDCl3) δ 1.33 (d, 7=6.8 Hz, 3 H), 3.15-

[0534] 3.23 (m, 4 H), 3.54-3.65 (m, 1 H), 3.66-3.75 (m, 2 H), 3.84 (ddd, 7=12.7, 6.1, 3.6 Hz, 1 H), 4.93 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (dd, 7=8.4, 2.2 Hz, 1 H), 7.23-

[0535] 7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 19.4, 41.9, 45.1, 45.4, 48.9, 49.0, 109.1, 112.3 (d, 7=36.7 Hz) 114.5, 120.8 (q, 7=257.1 Hz), 130.2, 150.3, 152.1, 169.6, 171.1.

[0536] Example 106. Compound d9-(R,S)-2 (wherein A=H, B=D, X=D, R1=OCF3, R2=CH3) (R,S)~ N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide; calc. (M+H)+for C16H11D9N3O3F3 = 369.21, exp. (M+H)+= 369.3. UPLC (purity > 99%), tR= 6.57.1H NMR (500 MHz, DMSO-76) δ 1.34 (d, 7= 6.8 Hz, 3 H), 1.99 (s, 3 H), 4.93 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (dd, , 7=8.4, 2.2 Hz, 1 H), 7.24-

[0537] 7.28 (m, 1 H).13C NMR (126 MHz, DMSO-76) δ 19.4, 41.9, 45.1, 45.3, 48.9, 49.1, 109.1, 112.3 (d, 7=36.8 Hz) 114.5, 120.9 (q, 7=257.1 Hz), 130.2, 150.3, 152.1, 169.6, 171.1.

[0538] Example 107. Compound d9-(R)-2 (wherein A=H, B=D, X=D, R1=OCF3, R2=CH3) (R)-N-(l- oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide; calc. (M+H)+for C16H11D9N3O3F3 = 369.21, exp. (M+H)+= 369.3. UPLC (purity > 99%), tR= 6.58. Chiral SFC > 99% ee (tR= 3.23 min).1H NMR (500 MHz, DMSO-76) δ 1.34 (d, 7=6.8 Hz, 3 H), 2.00 (s, 3 H), 4.93 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (dd, 7=8.4, 2.2 Hz, 1 H), 7.24-7.28 (m, 1 H).13C NMR (126 MHz, DMSO-76) δ 19.4, 41.9,

[0539] 45.1, 45.3, 48.9, 49.3, 109.1, 112.3 (d, 7=36.8 Hz) 114.5, 120.7 (q, 7=257.1 Hz), 130.1, 150.3,

[0540] 152.1, 169.6, 171.1.

[0541] Example 108. Compound d9-(.S')-2 (wherein A=H, B=D, X=D, oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide; calc. (M+H)+for C16H11D9N3O3F3 = 369.21, exp. (M+H)+= 369.3. UPLC (purity > 99%), tR= 6.58. Chiral SFC > 99% ee (tR= 3.73 min).1H NMR (500 MHz, DMSO-76) δ 1.33 (d, 7=6.8 Hz, 3 H), 2.00 (s, 3 H), 4.93 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (dd, 7=8.4, 2.2 Hz, 1 H), 7.24-7.28 (m, 1 H).13C NMR (126 MHz, DMSO-76) δ 19.3, 41.9,

[0542] 45.1, 45.3, 48.9, 49.1, 109.1, 112.3 (d, 7=36.8 Hz) 114.5, 120.5 (q, 7=257.1 Hz), 130.1, 150.2,

[0543] 152.1, 169.6, 171.1.

[0544] Example 109. Compound di2-(R,S)-2 (wherein A=D, B=D, X=D, R1=OCF3, R2=CH3) (R,S)~ N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C16H8D12N3O3F3 = 372.22, exp. (M+H)+= 372.3. UPLC (purity > 99%), tR= 6.55.1H NMR (500 MHz, DMSO-76) δ 1.34 (d, 7= 6.8 Hz, 3 H), 4.93 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (d, 7=8.4, 1 H), 7.23-7.28 (m, 1 H).13C NMR (126 MHz, DMSO-76) δ 19.3, 41.9, 45.1, 45.3, 48.9, 49.3, 109.1, 112.3 (d, 7=36.8 Hz) 114.5, 120.8 (q, 7=257.1 Hz), 130.1, 150.3, 152.1, 169.6, 171.1.

[0545] Example 110. Compound di2-(R)-2 (wherein A=D, B=D, X=D, R1=OCF3, R2=CH3) (R)-N- (1 -oxo-1 -(4-(3-(tri fluoromethoxy )pheny1-4-7)piperazin-1-y1-2, 2, 3, 3, 5,5,6, 6-d8)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C16H8D12N3O3F3 = 372.22, exp. (M+H)+= 372.3. UPLC (purity > 99%), tR= 6.57. Chiral SFC > 99% ee (tR= 3.25 min).1H NMR (500 MHz, DMSO-76) 5 1.33 (d, 7= 6.8 Hz, 3 H), 4.94 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (d, 7=8.4, 1 H), 7.25-7.29 (m, 1 H).13C NMR (126 MHz, DMSO-76) δ 19.4, 41.9, 45.0, 45.3, 48.9,

[0546] 49.2, 109.1, 112.3 (d, 7=36.8 Hz) 114.5, 120.7 (q, 7=257.1 Hz), 130.1, 150.3, 152.1, 169.6, 171.1.

[0547] Example 111. Compound di2- (S)-2 (wherein A=D, B=D, X=D, R1=OCF3, R2=CH3) (S)-N-(l- oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6-78)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C16H8D12N3O3F3 = 372.22, exp. (M+H)+= 372.3. UPLC (purity > 99%), tR= 6.57. Chiral SFC > 99% ee (tR= 3.75 min).1H NMR (500 MHz, DMSO-76)

[0548] 5 1.34 (d, J= 6.8 Hz, 3 H), 4.93 (quin, 7=6.8 Hz, 1 H), 6.65 (d, 7=6.8 Hz, 1 H), 6.70 (s, 1 H), 6.81 (d, 7=8.4, 1 H), 7.23-7.28 (m, 1 H).13C NMR (126 MHz, DMSO-76) δ 19.3, 41.9, 45.1, 45.3, 48.9, 49.3, 109.1, 112.3 (d, 7=36.8 Hz) 114.5, 120.5 (q, 7=257.1 Hz), 130.2, 150.3, 152.1, 169.6, 171.1.

[0549] Example 112. Compound d1-(R,S)-4 (wherein A=H, B=H, X=D, R1=CF3, R2=CH2OCH3) (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-7)piperazin- 1 -yl)propan-2- yl)acetamide; calc. (M+H)+for C17H21DN3O3F3 = 375.17, exp. (M+H)+= 375.2. UPLC (purity > 99%), tR= 6.42.1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.12-3.29 (m, 4 H), 3.31 (s, 3 H), 3.43-3.49 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.66-3.74 (m, 2 H), 3.77-3.84 (m, 1 H), 3.87- 3.95 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.58 (d, 7=7.7 Hz, 1 H), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.09 (d, 7=2.1 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 41.8, 45.9, 48.6, 49.1, 49.3, 59.4, 73.1, 112.8, 119.4, 124.2 (q, 7=272.4 Hz), 129.7, 131.6 (q, 7=31.9 Hz), 151.0, 169.0, 169.7.

[0550] Example 113. Compound d1-(R)-4 (wherein A=H, B=H, X=D, R1=CF3, R2=CH2OCH3) (R)- N-(3 -methoxy- 1 -oxo- 1-(4-(3 -(tri fluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C17H21DN3O3F3 = 375.17, exp. (M+H)+= 375.2. UPLC (purity > 99%), tR= 6.46. Chiral SFC > 99% ee (tR= 3.77 min).1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.14-3.29 (m, 4 H), 3.31 (s, 3 H), 3.42-3.49 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.68-3.74 (m, 2 H), 3.77- 3.86 (m, 1 H), 3.87-3.95 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.58 (d, 7=7.7 Hz, 1 H), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.09 (d, 7=2.1 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3)

[0551] 6 23.4, 41.8, 45.9, 48.6, 49.2, 49.3, 59.4, 73.1, 112.8, 119.4, 124.2 (q, 7=272.4 Hz), 129.7, 131.7 (q, 7=32.0 Hz), 151.0, 169.0, 169.7. Example 114. Compound d1- (S)-4 (wherein A=H, B=H, X=D, R1=CF3, R2=CH2OCH3) («$)- N-(3 -methoxy- 1 -oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide; calc. (M+H)+for C17H21DN3O3F3 = 375.17, exp. (M+H)+= 375.2. UPLC (purity > 99%), tR= 6.62. Chiral SFC > 99% ee (tR= 4.52 min).1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3 H), 3.14-3.29 (m, 4 H), 3.31 (s, 3 H), 3.42-3.49 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.68-3.74 (m, 2 H), 3.77- 3.86 (m, 1 H), 3.87-3.95 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.58 (d, 7=7.7 Hz, 1 H), 7.05 (dd, 7=8.3, 2.5 Hz, 1 H), 7.09 (d, 7=2.1 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) 6 23.3, 41.8, 45.9, 48.6, 49.1, 49.3, 59.4, 73.1, 112.8, 119.4, 124.2 (q, 7=272.4 Hz), 129.7, 131.7 (q, 7=32.0 Hz), 151.0, 169.0, 169.7.

[0552] Example 115. Compound d3-(R,S)-4 (wherein A=D, B=H, X=H, R1=CF3, R2=CH2OCH3);

[0553] (R,S)-N-( 3 -methoxy- 1 -oxo- l-( 4-( 3-( trifluor omethyl)phenyl)piperazin- l-yl)propan-2- yl)acetamide-2,2,2-d3,- calc. (M+H)+for C17H19D3N3O3F3 = 377.18, exp. (M+H)+= 377.2. UPLC (purity > 99%), tR= 6.24.1H NMR (500 MHz, CDCl3) δ 3.12-3.22 (m, 2 H), 3.24-3.35 (m, 5 H),

[0554] 3.46 (dd, 7=8.9, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 5.0 Hz, 1 H), 3.66-3.77 (m, 2 H), 3.77-3.85 (m, 1 H), 3.87-3.97 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.57 (br d, 7=7.6 Hz, 1 H), 7.05 (dd, 7=8.3, 2.2 Hz, 1 H), 7.08-7.13 (m, 2 H), 7.36 (t, 7=8.0 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.4, 42.2, 45.7, 48.6, 48.8, 49.4, 59.4, 73.1, 112.9 (q, 7=3.9 Hz) 116.9 (q, 7=3.9 Hz) 119.4 (d, 7=1.1 Hz), 124.2 (q, 7=272.6 Hz), 129.8, 131.8 (q, 7=31.9 Hz), 151.0, 169.0, 169.7.

[0555] Example 116. Compound d3-(R)-4 (wherein A=D, B=H, X=H, R1=CF3, R2=CH2OCH3); (R)- N-( 3 -methoxy- 1 -oxo- 1-( 4-(3-(trijluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide- 2,2,2-d3, calc. (M+H)+for C17H19D3N3O3F3 = 377.18, exp. (M+H)+= 377.2. UPLC (purity > 99%), tR= 6.34. Chiral SFC > 99% ee (tR= 3.78 min).1H NMR (500 MHz, CDCl3) δ 3.30-3.43 (m, 6 H), 3.44-3.57 (m, 2 H), 3.61 (dd, 7=8.9, 5.2 Hz, 1 H), 3.98-4.19 (m, 4 H), 5.04-5.15 (m, 1 H),

[0556] 6.47 (br d, 7=6.9 Hz, 1 H), 7.44 (br d, 7=7.7 Hz, 1 H), 7.51-7.58 (m, 2 H), 7.66 (br d, 7=6.9 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.2, 45.7, 48.6, 48.8, 49.4, 59.4, 73.1, 112.9 (q, 7=3.9 Hz) 116.9 (q, 7=3.9 Hz) 119.4, 124.2 (q, 7=272.6 Hz), 129.8, 131.8 (q, 7=31.9 Hz), 151.0, 169.0, 169.8. Example 117. Compound d3- (S)-4 (wherein A=D, B=H, X=H, R1=CF3, R2=CH2OCH3); (S)- N-( 3 -methoxy- 1 -oxo- 1-( 4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-

[0557] 2.2.2-dr, calc. (M+H)+for C17H19D3N3O3F3 = 377.18, exp. (M+H)+= 377.2. UPLC (purity > 99%), tR= 6.38. Chiral SFC > 99% ee (tR= 4.52 min).1H NMR (500 MHz, CDCl3) δ 3.13-3.22 (m, 2 H), 3.23-3.36 (m, 5 H), 3.46 (dd, 7=8.9, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 5.0 Hz, 1 H), 3.66-3.75 (m, 2 H), 3.77-3.85 (m, 1 H), 3.88-3.97 (m, 1 H), 5.15 (td, 7=7.7, 5.0 Hz, 1 H), 6.57 (br d, 7=7.6 Hz, 1 H), 7.05 (dd, 7=8.3, 2.2 Hz, 1 H), 7.08-7.14 (m, 2 H), 7.36 (t, 7=8.0 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.2, 45.7, 48.6, 48.8, 49.4, 59.4, 73.1, 112.9 (q, 7=3.9 Hz) 116.9 (q, J=3.9 Hz) 119.4 (d, 7=1.1 Hz), 124.2 (q, 7=272.6 Hz), 129.8, 131.6 (q, 7=31.9 Hz), 151.0, 169.0, 169.7.

[0558] Example 118. Compound d4-(R,S)-4 (wherein A=D, B=H, X=D, R1=CF3, R2=CH2OCH3) (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-7)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C17H18D4N3O3F3 = 378.19, exp. (M+H)+= 378.2. UPLC (purity > 99%), tR= 6.67.1H NMR (500 MHz, CDCl3) δ 3.12-3.28 (m, 4 H), 3.32 (s, 3 H), 3.43- 3.48 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.66-3.74 (m, 2 H), 3.76-3.84 (m, 1 H), 3.87-3.95 (m, 1 H), 5.15 (td, 7=7.7, 4.9 Hz, 1 H), 6.58 (d, 7=7.1 Hz, 1 H), 7.05 (dd, 7=8.3, 2.4 Hz, 1 H), 7.09 (d, 7=2.4 Hz, 1 H), 7.35 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 22.6, 42.2, 45.9, 48.6, 49.1, 49.2, 59.4, 73.1, 112.9, 119.4, 124.2 (q, 7=272.5 Hz), 129.7, 131.6 (q, 7=31.9 Hz), 151.0, 169.0, 169.8.

[0559] Example 119. Compound d4-(R)-4 (wherein A=D, B=H, X=D, R1=CF3, R2=CH2OCH3) (R)- N-(3 -methoxy- 1 -oxo- 1-(4-(3 -(tri fluoromethyl)pheny1-4-7)piperazin-1-yl)propan-2-yl)acetamide-

[0560] 2.2.2-73; calc. (M+H)+for C17H18D4N3O3F3 = 378.19, exp. (M+H)+= 378.2. UPLC (purity > 99%), tR= 6.79. Chiral SFC > 99% ee (tR= 3.70 min).1H NMR (500 MHz, CDCl3) δ 3.14-3.28 (m, 4 H), 3.32 (s, 3 H), 3.44-3.48 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.66-3.74 (m, 2 H), 3.76-3.84 (m, 1 H), 3.86-3.95 (m, 1 H), 5.15 (td, 7=7.7, 4.9 Hz, 1 H), 6.58 (d, 7=7.1 Hz, 1 H), 7.04 (dd, 7=8.3, 2.4 Hz, 1 H), 7.09 (d, 7=2.4 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) 5 22.8, 42.3, 45.9, 48.6, 49.1, 49.2, 59.4, 73.1, 112.9, 119.4, 124.2 (q, 7=272.5 Hz), 129.7, 131.6 (q, 7=31.9 Hz), 151.1, 169.0, 169.8. Example 120. Compound d-i-GS')-4 (wherein A=D, B=H, X=D, R1=CF3, R2=CH2OCH3) («$)- N-(3 -methoxy- 1-oxo- 1-(4-(3 -(trifluorom ethyl)pheny1-4-7)piperazin- 1-yl)propan-2 -yl)acetamide- 2,2,2-73; calc. (M+H)+for C17H18D4N3O3F3 = 378.19, exp. (M+H)+= 378.2. UPLC (purity > 99%), tR= 6.79. Chiral SFC > 99% ee (tR= 4.44 min).1H NMR (500 MHz, CDCl3) δ 3.13-3.28 (m, 4 H), 3.32 (s, 3 H), 3.42-3.48 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.68-3.74 (m, 2 H), 3.76-3.84 (m, 1 H), 3.87-3.95 (m, 1 H), 5.15 (td, 7=7.7, 4.9 Hz, 1 H), 6.58 (d, 7=7.1 Hz, 1 H), 7.04 (dd, 7=8.3, 2.4 Hz, 1 H), 7.09 (d, 7=2.4 Hz, 1 H), 7.36 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) 6 22.9, 42.2, 45.9, 48.7, 49.1, 49.2, 59.4, 73.1, 112.9, 119.4, 124.2 (q, 7=272.5 Hz), 129.7, 131.6 (q, 7=31.9 Hz), 151.0, 169.0, 169.8.

[0561] Example 121. Compound d9-(R,S)-4 (wherein A=H, B=D, X=D, R1=CF3, R2=CH2OCH3) (R,5)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6- 7s)propan-2-yl)acetamide; calc. (M+H)+for C17H13D9N3O3F3 = 383.22, exp. (M+H)+= 383.3. UPLC (purity > 99%), tR= 6.36.1H NMR (500 MHz, DMSO-76) δ 1.79 (s, 3 H), 3.18 (s, 3 H), 3.36 (dd, 7=9.8, 6.7 Hz, 1 H), 3.46 (dd, 7=9.7, 6.5 Hz, 1 H), 4.88 (dd, 7=14.7, 6.6 Hz, 1 H), 7.13 (d, 7=2.2 Hz, 1 H), 7.18 (dd, 7=8.4, 2.6 Hz, 1 H), 7.38 (d, 7=8.4 Hz, 1 H), 8.24 (d, 7=8.2 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 22.7, 48.4, 58.9, 72.2, 111.8 (d, 7=3.9 Hz), 119.6, 124.9 (q, 7=272.5 Hz), 130.2, 131.6 (q, 7=31.9 Hz), 151.3, 168.8, 170.1.

[0562] Example 122. Compound d9-(R)-4 (wherein A=H, B=D, X=D, R1=CF3, R2=CH2OCH3) (R)- N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide; calc. (M+H)+for Ci7Hi3D9N3O3F3= 383.22, exp. (M+H)+= 383.3. UPLC (purity > 99%), tR= 6.38. Chiral SFC > 99% ee (tR= 3.70 min).1H NMR (500 MHz, DMSO- 76) δ 1.78 (s, 3 H), 3.18 (s, 3 H), 3.36 (dd, 7=9.8, 6.7 Hz, 1 H), 3.46 (dd, 7=9.7, 6.5 Hz, 1 H), 4.88 (dd, 7=14.7, 6.6 Hz, 1 H), 7.13 (d, 7=2.2 Hz, 1 H), 7.18 (dd, 7=8.4, 2.6 Hz, 1 H), 7.38 (d, 7=8.4 Hz, 1 H), 8.24 (d, 7=8.2 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 22.8, 48.4, 58.9, 72.3, 111.7 (d, 7=3.9 Hz), 119.6, 124.9 (q, 7=272.5 Hz), 130.2, 131.7 (q, 7=31.9 Hz), 151.3, 168.8, 170.1.

[0563] Example 123. Compound d9-GS')-4 (wherein A=H, B=D, X=D, R1=CF3, R2=CH2OCH3) (S)- N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide; calc. (M+H)+for C17H13D9N3O3F3 = 383.22, exp. (M+H)+= 383.3. UPLC (purity > 99%), tR= 6.42. Chiral SFC > 99% ee (tR= 4.47 min).1H NMR (500 MHz, DMSO- 76) δ 1.77 (s, 3 H), 3.18 (s, 3 H), 3.36 (dd, 7=9.8, 6.7 Hz, 1 H), 3.46 (dd, 7=9.7, 6.5 Hz, 1 H), 4.88 (dd, 7=14.7, 6.6 Hz, 1 H), 7.13 (d, 7=2.2 Hz, 1 H), 7.19 (dd, 7=8.4, 2.6 Hz, 1 H), 7.38 (d, 7=8.4 Hz, 1 H), 8.24 (d, 7=8.2 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 22.7, 48.4, 58.9, 72.2, 111.8 (d, 7=3.9 Hz), 119.6, 124.9 (q, 7=272.5 Hz), 130.2, 131.9 (q, 7=31.9 Hz), 151.3, 168.8, 170.1.

[0564] Example 124. Compound di2-(R,S)-4 (wherein A=D, B=D, X=D, R1=CF3, R2=CH2OCH3) (R,S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6- 7s)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+. for C17H10D12N3O3F3 = 386.24, exp. (M+H)+=

[0565] 386.3. UPLC (purity > 99%), tR= 6.37.1H NMR (500 MHz, DMSO-76) δ 3.19 (s, 3 H), 3.36 (dd, 7=9.7, 6.6 Hz, 1 H), 3.46 (dd, 7=9.7, 6.5 Hz, 1 H), 4.89 (dd, 7=14.8, 6.6 Hz, 1 H), 7.14 (d, 7= 2.3 Hz, 1 H), 7.18-7.22 (m, 1 H), 7.35-7.42 (m, 1 H), 8.24 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 22.7, 48.3, 55.3, 58.9, 72.2, 111.8 (d, 7=4.1 Hz) 119.6, 124.9 (q, 7=272.6 Hz), 130.2, 131.9 (q, 7=31.9 Hz), 151.3, 168.8, 170.0.

[0566] Example 125. Compound di2-(R)-4 (wherein A=D, B=D, X=D, R1=CF3, R2=CH2OCH3) (R)- N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6- 7s)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C17H10D12N3O3F3 = 386.24, exp. (M+H)+=

[0567] 386.3. UPLC (purity > 99%), tR= 6.39. Chiral SFC > 99% ee (tR= 3.74 min).1H NMR (500 MHz, DMSO-76) δ 3.18 (s, 3 H), 3.36 (dd, 7=9.7, 6.6 Hz, 1 H), 3.46 (dd, 7=9.7, 6.5 Hz, 1 H), 4.89 (dd, 7=14.8, 6.6 Hz, 1 H), 7.15 (d, 7=2.3 Hz, 1 H), 7.16-7.22 (m, 1 H), 7.35-7.42 (m, 1 H), 8.23 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 22.8, 48.4, 55.3, 58.9, 72.2, 111.8 (d, 7=4.1 Hz) 119.7, 124.9 (q, 7=272.6 Hz), 130.2, 131.9 (q, 7=31.9 Hz), 151.3, 168.8, 170.0.

[0568] Example 126. Compound di2- (S)-4 (wherein A=D, B=D, X=D, R1=CF3, R2=CH2OCH3) («$)- N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-7)piperazin-1-y1-2,2,3,3,5,5,6,6- 7s)propan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C17H10D12N3O3F3 = 386.24, exp. (M+H)+=

[0569] 386.3. UPLC (purity > 99%), tR= 6.39. Chiral SFC > 99% ee (tR= 4.47 min).1H NMR (500 MHz,

[0570] DMSO-76) δ 3.18 (s, 3 H), 3.36 (dd, 7=9.7, 6.6 Hz, 1 H), 3.46 (dd, 7=9.7, 6.5 Hz, 1 H), 4.89 (dd, 7=14.8, 6.6 Hz, 1 H), 7.15 (d, J= 2.3 Hz, 1 H), 7.16-7.22 (m, 1 H), 7.35-7.42 (m, 1 H), 8.23 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, DMSO-76) δ 22.7, 48.4, 55.3, 58.9, 72.2, 111.8 (d, 7=4.1 Hz) 119.7, 124.9 (q, 7=272.6 Hz), 130.2, 131.9 (q, J=31.9 Hz), 151.3, 168.8, 170.0.

[0571] Example 127. Compound d1-(R,5)-5 (wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3) (R,5)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide; calc. (M+H)+for CI7H2IDN3O4F3= 391.17, exp. (M+H)+= 391.2. UPLC (purity > 99%), tR= 7.51.1H NMR (500 MHz, CDC13) δ 2.00 (s, 3 H), 3.10-3.30 (m, 4 H), 3.32 (s, 3 H), 3.42-3.49 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.72-3.82 (m, 2 H), 3.83-3.90 (m, 1 H), 3.91- 3.99 (m, 1 H), 5.13 (dd, 7=12.5, 7.5 Hz, 1 H), 6.55 (d, 7=7.0 Hz, 1 H), 6.80 (s, 1 H), 6.92 (d, 7=7.7 Hz, 1 H), 7.28 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDC13) δ 23.3, 41.6, 45.5, 48.6, 49.6, 49.8, 59.8, 73.1, 109.5, 115.2, 120.6 (q, 7=257.0 Hz), 130.4, 150.3, 169.0, 169.8.

[0572] Example 128. Compound d1-(R)-5 (wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3) (R)- N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide; calc. (M+H)+for CI7H2IDN3O4F3= 391.17, exp. (M+H)+= 391.2. UPLC (purity > 99%), tR= 7.53. Chiral SFC > 99% ee (tR= 3.20 min).1H NMR (500 MHz, CDC13) δ 2.00 (s, 3 H), 3.10-3.30 (m, 4 H), 3.32 (s, 3 H), 3.42-3.49 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.72-3.82 (m, 2 H), 3.83-3.90 (m, 1 H), 3.91-3.99 (m, 1 H), 5.13 (dd, 7=12.5, 7.5 Hz, 1 H), 6.55 (d, 7=7.0 Hz, 1 H), 6.80 (s, 1 H), 6.92 (d, 7=7.7 Hz, 1 H), 7.28 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDC13) δ 23.4, 41.6, 45.7, 48.6, 49.7, 49.8, 59.8, 73.2, 109.5, 115.2, 120.6 (q, 7=257.0 Hz), 130.4, 150.3, 169.1, 169.8.

[0573] Example 129. Compound d1- (S)-5 (wherein A=H, B=H, X=D, R1=OCF3, R2=CH2OCH3) (S)- N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide; calc. (M+H)+for CI7H2IDN3O4F3= 391.17, exp. (M+H)+= 391.2. UPLC (purity > 99%), tR= 7.58. Chiral SFC > 99% ee (tR= 3.78 min).1H NMR (500 MHz, CDC13) δ 2.00 (s, 3 H), 3.10-3.28 (m, 4 H), 3.32 (s, 3 H), 3.42-3.49 (m, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.72-3.81 (m, 2 H), 3.83-3.90 (m, 1 H), 3.91-3.99 (m, 1 H), 5.13 (dd, 7=12.5, 7.5 Hz, 1 H), 6.55 (d, 7=7.0 Hz, 1 H), 6.80 (s, 1 H), 6.92 (d, 7=7.7 Hz, 1 H), 7.28 (d, 7=8.3 Hz, 1 H).13C NMR (126 MHz, CDCl3) δ 23.4, 41.6, 45.6, 48.6, 49.6, 49.9, 59.8, 73.1, 109.5, 115.3, 120.6 (q, 7=257.0 Hz), 130.4, 150.3, 169.0, 169.8.

[0574] Example 130. Compound d3-(R,A)-5 (wherein A=D, B=H, X=H, R1=OCF3, R2=CH2OCH3);

[0575] (R,S)-N-( 3 -methoxy- 1 -oxo- l-( 4-( 3-( trifluoromethoxy)phenyl)piperazin-1-yl)propan-2- yl)acetanride-2,2,2-d3; calc. (M+H)+for Ci7Hi9D3N3O4F3= 393.18, exp. (M+H)+= 393.2. UPLC (purity > 99%), tR= 7.32.1H NMR (500 MHz, CDCl3) δ 3.08-3.18 (m, 2 H), 3.21-3.32 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.67-3.75 (m, 2 H), 3.77-3.85 (m, 1 H), 3.88-3.97 (m, 1 H), 5.14 (td, 7=7.7, 4.9 Hz, 1 H), 6.53 (br d, J=2.7 Hz, 1 H), 6.66-6.76 (m, 2 H) δ.80 (dd, 7=8.4, 2.2 Hz, 1 H) 7.20-7.28 (m, 1 H).13C NMR (126 MHz, CDCl3) 5 23.3, 42.2, 45.6, 48.7 48.7, 49.3, 59.4, 73.2, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0576] Example 131. Compound d3-(R)-5 (wherein A=D, B=H, X=H, R1=OCF3, R2=CH2OCH3);

[0577] (R)-N-(3-methoxy-1-oxo-1-(4-(3-(trifhioromethoxy)phenyl)piperazin-1-yl)propan-2- yl)acetamide-2,2,2-d3; calc. (M+H)+for Ci7Hi9D3N3O4F3= 393.18, exp. (M+H)+= 393.2. UPLC (purity > 99%), tR= 7.24. Chiral SFC > 99% ee (tR= 3.24 min).1H NMR (500 MHz, CDCl3) 8 3.11-3.19 (m, 2 H), 3.21-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.64-3.75 (m, 2 H), 3.74-3.85 (m, 1 H), 3.87-3.96 (m, 1 H), 5.14 (td, 7=7.7, 4.9 Hz, 1 H), 6.53 (br d, 7=7.7 Hz, 1 H), 6.67-6.77 (m, 2 H) δ.80 (dd, 7=8.4, 2.2 Hz, 1 H) 7.21- 7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 23.4, 42.1, 45.6, 48.6, 48.7, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0578] Example 132. Compound d3-(S)-5 (wherein A=D, B=H, X=H, R1=OCF3, R2=CH2OCH3);

[0579] (S)-N-( 3 -methoxy- 1 -oxo- 1-( 4-( 3-( trifluor omethoxy)phenyl)piperazin- l-yl)pr opan-2-yl)acetamide- 2,2,2-d3; calc. (M+H)+for C17H19D3N3O4F3= 393.18, exp. (M+H)+= 393.2. UPLC (purity > 99%), tR= 7.19. Chiral SFC > 99% ee (tR= 3.80 min).1H NMR (500 MHz, CDCl3) δ 3.10-3.19 (m, 2 H), 3.21-3.29 (m, 2 H), 3.31 (s, 3 H), 3.46 (dd, 7=9.0, 7.7 Hz, 1 H), 3.59 (dd, 7=9.0, 4.9 Hz, 1 H), 3.65-3.75 (m, 2 H), 3.76-3.86 (m, 1 H), 3.87-3.97 (m, 1 H), 5.14 (td, 7=7.7, 4.9 Hz, 1 H), 6.53 (br d, 7=7.7 Hz, 1 H), 6.67-6.76 (m, 2 H) δ.80 (dd, 7=8.4, 2.2 Hz, 1 H) 7.23-7.30 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 42.1, 45.6, 48.6, 48.7, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0580] Example 133. Compound d4-(R,A)-5 (wherein A=D, B=H, X=D, R1=OCF3, R2=CH2OCH3) (R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for Ci7Hi8D4N3O4F3= 394.18, exp. (M+H)+= 394.2. UPLC (purity > 99%), tR= 7.52.1H NMR (500 MHz, CDCl3) δ 3.33 (s, 1 H), 3.36-3.42 (m, 1 H), 3.48- 3.53 (m, 3 H), 3.54 -3.62 (m, 3 H), 3.82 (ddd, 7=23.8, 9.5, 3.2 Hz, 1 H), 4.02 (m, 2 H), 5.11 (dd, 7=12.7, 7.4 Hz, 1 H), 6.54 (d, 7=7.6 Hz, 1 H), 6.75-6.88 (m, 1 H), 6.92 (dd, 7=8.3, 1.8 Hz, 1 H), 7.28 -7.31 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 24.5, 40.1, 44.1, 48.6, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0581] Example 134. Compound d4-(R)-5 (wherein A=D, B=H, X=D, R1=OCF3, R2=CH2OCH3) (R)- N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C17H18D4N3O4F3= 394.18, exp. (M+H)+= 394.2. UPLC (purity > 99%), tR= 7.42. Chiral SFC > 99% ee (tR= 3.20 min).1H NMR (500 MHz, CDCl3) 6

[0582] 3.33 (s, 1 H), 3.36-3.42 (m, 1 H), 3.48-3.53 (m, 3 H), 3.54-3.62 (m, 3 H), 3.82 (ddd, 7=23.8, 9.5, 3.2 Hz, 1 H), 4.02 (m, 2 H), 5.11 (dd, 7=12.7, 7.4 Hz, 1 H), 6.54 (d, 7=7.6 Hz, 1 H), 6.73-6.85 (m, 1H), 6.92 (dd, 7=8.3, 1.8 Hz, 1 H), 7.28-7.31 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 24.5, 40.1, 44.1, 48.6, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7.

[0583] Example 135. Compound d4-G$')-5 (wherein A=D, B=H, X=D, R1=OCF3, R2=CH2OCH3) (S)- N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )pheny 1 -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-73; calc. (M+H)+for C17H18D4N3O4F3= 394.18, exp. (M+H)+= 394.2. UPLC (purity > 99%), tR= 7.42. Chiral SFC > 99% ee (tR= 3.72 min).1H NMR (500 MHz, CDCl3) 6

[0584] 3.34 (s, 1 H), 3.35-3.42 (m, 1 H), 3.48-3.53 (m, 3 H), 3.54-3.62 (m, 3 H), 3.82 (ddd, 7=23.8, 9.5, 3.2 Hz, 1 H), 4.02 (m, 2 H), 5.11 (dd, 7=12.7, 7.4 Hz, 1 H), 6.54 (d, 7=7.6 Hz, 1 H), 6.75-6.88 (m, 1 H), 6.92 (dd, 7= 8.3, 1.8 Hz, 1 H), 7.28-7.31 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 24.5, 40.1, 44.1, 48.6, 49.3, 59.4, 73.2, 109.0, 112.2, 114.4, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.0, 169.7. Example 136. Compound d9-(R,S)-5 (wherein A=H, B=D, X=D, R1=OCF3, R2=CH2OCH3) (R,S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide; calc. (M+H)+for C17H13D9N3O4F3= 399.22, exp. (M+H)+= 399.3. UPLC (purity > 99%), tR= 7.34.

[0585] Example 137. Compound d9-(R)-5 (wherein A=H, B=D, X=D, R1=OCF3, R2=CH2OCH3) (R)- N-(3 -methoxy- 1 -oxo-1 -(4-(3-(tri fluoromethoxy )pheny1-4-d)piperazin-1-y1-2, 2, 3, 3, 5, 5,6,6- d8)propan-2-yl)acetamide; calc. (M+H)+for C17H13D9N3O4F3= 399.22, exp. (M+H)+= 399.3. UPLC (purity > 99%), tR= 7.44. Chiral SFC > 99% ee (tR= 3.22 min).

[0586] Example 138. Compound d9- (S)-5 (wherein A=H, B=D, X=D, R1=OCF3, R2=CH2OCH3) (S)- N-(3 -methoxy- 1 -oxo-1 -(4-(3-(tri fluoromethoxy )pheny1-4-d)piperazin-1-y1-2, 2, 3, 3, 5, 5,6,6- d8)propan-2-yl)acetamide; calc. (M+H)+for C17H13D9N3O4F3= 399.22, exp. (M+H)+= 399.3. UPLC (purity > 99%), tR= 7.46. Chiral SFC > 99% ee (tR= 3.74 min).

[0587] Example 139. Compound d12-(R,A)-5 (wherein A=D, B=D, X=D, R1=OCF3, R2=CH2OCH3) (R,S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3; calc. (M+H)+for CI?HIODI2N304F3= 402.23, exp. (M+H)+=

[0588] 402.3. UPLC (purity > 99%), tR= 7.46.

[0589] Example 140. Compound d12-(R)-5 (wherein A=D, B=D, X=D, R1=OCF3, R2=CH2OCH3) (R)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3; calc. (M+H)+for CI?HIODI2N304F3= 402.23, exp. (M+H)+=

[0590] 402.3. UPLC (purity > 99%), tR= 7.38. Chiral SFC > 99% ee (tR= 3.25 min).

[0591] Example 141. Compound di2- (S)-5 (wherein A=D, B=D, X=D, R1=OCF3, R2=CH2OCH3) (S)- N-(3 -methoxy- 1 -oxo-1 -(4-(3-(tri fluoromethoxy )pheny1-4-d)piperazin-1-y1-2, 2, 3, 3, 5, 5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3; calc. (M+H)+for CI?HIODI2N304F3= 402.23, exp. (M+H)+=

[0592] 402.3. UPLC (purity > 99%), tR= 7.34. Chiral SFC > 99% ee (tR= 3.80 min).

[0593] Example 142. Compound d3-(R,A)-7 (wherein A=D, B=H, X=H, R1=C6H5, R2=CH2OCH3) (R,S)-N-( 1 -(4-([ 1 , 1’ -biphenyl] -3 -yl)piperazin- 1 -y 1 )- 3 -methoxy- 1 -oxopropan-2-yl)acetamide- 2,2,2-d3- calc. (M+H)+for C22H24D3N3O3= 385.23, exp. (M+H)+= 384.3. UPLC (purity > 99%), tR= 8.64.1H NMR (500 MHz, CDCl3) δ 3.33 (s, 3 H), 3.42-3.70 (m, 5 H), 3.73-3.84 (m, 1 H), 4.19-4.58 (m, 4 H), 5.06 (q, J=6.6 Hz, 1 H), 6.54 (br d, J=6.59 Hz, 1 H), 7.35-7.40 (m, 1 H), 7.42- 7.47 (m, 2 H), 7.57 (br d, J=7.5 Hz, 3 H), 7.68 (br d, .7=7,7 Hz, 1 H), 7.76 (br s, 1 H), 8.08 (br s, 1 H).13C NMR (126 MHz, CDCl3) δ 23.2, 39.8, 43.3, 48.7, 55.2, 59.4, 119.8, 120.1, 127.2, 128.6, 128.9, 129.2, 131.0, 138.8, 142.5, 144.1, 169.6, 170.4.

[0594] Example 143. Compound d3-(R)-7 (wherein A=D, B=H, X=H, R1=C6H5, R2=CH2OCH3) (R)- N-(l -(4-([ 1 , 1 ’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)acetamide-2,2,2-d3; calc. (M+H)+for C22H24D3N3O3= 385.23, exp. (M+H)+= 384.3. UPLC (purity > 99%), tR= 8.54. Chiral SFC > 99% ee (tR= 3.52 min).1H NMR (500 MHz, CDCl3) δ 3.34 (s, 3 H), 3.42-3.70 (m, 5 H), 3.73-3.84 (m, 1 H), 4.20-4.58 (m, 4 H), 5.06 (q, J=6.6 Hz, 1 H), 6.54 (br d, J=6.59 Hz, 1 H),

[0595] 7.35-7.41 (m, 1 H), 7.43-7.47 (m, 2 H), 7.57 (br d, J=7.5 Hz, 3 H), 7.68 (br d, .7=7,7 Hz, 1 H), 7.76 (br s, 1 H), 8.08 (br s, 1 H).13C NMR (126 MHz, CDCl3) δ 23.3, 39.7, 43.3, 48.7, 55.2, 59.4, 119.7, 120.1, 127.3, 128.6, 128.9, 129.3, 131.0, 138.9, 142.5, 144.2, 169.6, 170.4.

[0596] Example 144. Compound d3- (S)-7 (wherein A=D, B=H, X=H, R1=C6H5, R2=CH2OCH3) (S)- N-( 1 -(4-([ 1 , 1 ’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)acetamide-2,2,2-d3; calc. (M+H)+for C22H24D3N3O3= 385.23, exp. (M+H)+= 384.3. UPLC (purity > 99%), tR= 8.63. Chiral SFC > 99% ee (tR= 4.45 min).1H NMR (500 MHz, CDCl3) δ 3.33 (s, 3 H), 3.42-3.70 (m, 5 H), 3.73-3.84 (m, 1 H), 4.19-4.58 (m, 4 H), 5.06 (q, J=6.6 Hz, 1 H), 6.54 (br d, J=6.59 Hz, 1 H),

[0597] 7.35-7.40 (m, 1 H), 7.42-7.47 (m, 2 H), 7.57 (br d, J=7.5 Hz, 3 H), 7.68 (br d, .7=7,7 Hz, 1 H), 7.76 (br s, 1 H), 8.08 (br s, 1 H).13C NMR (126 MHz, CDCl3) δ 23.2, 39.7, 43.3, 48.7, 55.2, 59.4, 119.7, 120.1, 127.2, 128.6, 128.9, 129.2, 131.0, 138.8, 142.5, 144.1, 169.6, 170.4.

[0598] Example 145. Compound d3-(R,S)-8 (wherein A=D, B=H, X=H, R1=OCF3, R2=C2Hs) (R,S)~ N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2-d3; calc. (M+H)+for CI7HI9D3N3O3F3= 374.16, exp. (M+H)+= 374.2. UPLC (purity > 99%), tR= 6.95.1H NMR (500 MHz, CDCl3) δ 0.91 (t, J=7.5 Hz, 3 H), 1.59 (dt, J=14.1, 7.2 Hz, 1 H), 1.72-1.86 (m, 1 H), 3.19 (dt, .7=16.3, 5.1 Hz, 4 H), 3.64-3.77 (m, 3 H), 3.79-3.97 (m, 1 H), 4.93 (td, .7=7.5, 5.4

[0599] Hz, 1 H), 6.50 (br d, J=7.9 Hz, 1 H), 6.67-6.76 (m, 2 H), 6.81 (dd, .7=8.3, 2.2 Hz, 1 H) 7.22-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.5, 23.4, 26.3, 41.9, 45.5, 48.9, 49.3, 49.7, 109.1, 112.4,

[0600] 114.6, 120.5 (q, 7=257.0 Hz), 130.3, 152.1, 169.9, 170.4.

[0601] Example 146. Compound d3-(R)-8 (wherein A=D, B=H, X=H, R1=OCF3, R2=C2Hs) (R)-N- (1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C17H19D3N3O3F3 = 374.16, exp. (M+H)+= 374.2. UPLC (purity > 99%), tR= 7.02. Chiral SFC > 99% ee (tR= 3.30 min^H NMR (500 MHz, CDCl3) δ 0.91 (t, 7=7.5 Hz, 3 H), 1.59 (dt, 7=14.1, 7.2 Hz, 1 H), 1.72-1.86 (m, 1 H), 3.19 (dt, 7=16.3, 5.1 Hz, 4 H), 3.63-3.77 (m, 3 H), 3.79-3.90 (m, 1 H), 4.93 (td, 7=7.5, 5.4 Hz, 1 H), 6.50 (br d, 7=7.9 Hz, 1 H), 6.67-6.76 (m, 2 H), 6.80 (dd, 7=8.3, 2.2 Hz, 1 H) 7.22-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.6, 23.3, 26.3, 41.9, 45.4, 48.9, 49.3, 49.7, 109.2, 112.4, 114.6, 120.6 (q, 7=257.0 Hz), 130.3, 152.1, 169.8, 170.4.

[0602] Example 147. Compound d3- (S)-8 (wherein A=D, B=H, X=H, R1=OCF3, R2=C2Hs) (S)-N-(1- oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2-73; calc. (M+H)+for C17H19D3N3O3F3 = 374.16, exp. (M+H)+= 374.2. UPLC (purity > 99%), tR= 6.94. Chiral SFC > 99% ee (tR= 3.94 min)7H NMR (500 MHz, CDCl3) δ 0.92 (t, 7=7.5 Hz, 3 H), 1.59 (dt, 7=14.1, 7.2 Hz, 1 H), 1.73-1.86 (m, 1 H), 3.19 (dt, 7=16.3, 5.1 Hz, 4 H), 3.62-3.77 (m, 3 H), 3.79-3.90 (m, 1 H), 4.93 (td, 7=7.5, 5.4 Hz, 1 H), 6.50 (br d, 7=7.9 Hz, 1 H), 6.67-6.76 (m, 2 H), 6.80 (dd, 7=8.3, 2.2 Hz, 1 H) 7.22-7.29 (m, 1 H).13C NMR (126 MHz, CDCl3) δ 9.3, 23.4, 26.3, 41.9, 45.5, 48.9, 49.4, 49.7, 109.2, 112.4, 114.5, 120.5 (q, 7=257.0 Hz), 130.3, 152.1, 169.8, 170.5.

[0603] Evaluation of anticonvulsant activity and effects on motor coordination in the in vivo studies on mice

[0604] General information

[0605] The studies were conducted on male white CD-I mice weighing 22-26 g from a certified breeding farm. All procedures were performed in accordance with applicable Polish and European guidelines on the ethics of animal research, after obtaining appropriate approvals. The substances were administered intraperitoneally suspended in 1% Tween 80 solution, as single injections of 0.1 mL / 10 g bw., 30 minutes before the given test. Initial screening studies were performed on groups of 4 mice. The average effective dose (ED50) in a given test and the neurotoxic dose in the chimney test (TD50) were estimated on the basis of the results obtained in 3-4 groups of 8 animals. The MES and 6 Hz models and the chimney test were conducted based on procedures described in the relevant literature (J. Med. Chem. 2015, 58, 5274 5286, Eur. The substance was administered intraperitoneally suspended in 1% Tween 80 solution, as single injections of 0.1 mL / 10 g bw., 30 minutes before the given test.

[0606] Statistical analysis ED50(effective dose) and TD50(toxic dose) values along with their corresponding 95% confidence intervals were calculated using the logarithmic method according to Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 1949, 96, 99-113). A value at a significance level of p < 0.05 was considered statistically significant.

[0607] Activities in an in vitro model of spontaneous discharges caused by kainic acid-induced status epilepticus in slices of the rat entorhinal cortex

[0608] The assessment of spontaneous discharges was performed on sections of the entorhinal cortex obtained from Sprague-Dawley rats according to the procedure described in the literature (Epilepsia 2018, 59, 2035-2048). Status epilepticus was previously induced in the rats by the administration of kainic acid (Epilepsia 2017, 58, 1054-1062). Compounds (P)- \ and (R)-KJ-28 were dissolved in DMSO. The compounds were tested at two concentrations of 80 μM and 100 μM. Measurement time was 60 minutes: 20 minutes, DMSO + artificial cerebrospinal fluid (control), 20 minutes, test substance dissolved in the DMSO / artificial cerebrospinal fluid mixture, and 20 minutes, artificial cerebrospinal fluid. The working concentration of DMSO in the test systems was 0.01%. Discharges were measured in a Scientifica Slicemaster apparatus (Scientifica Inc., Uckfield, UK).

[0609] Evaluation of antinociceptive activity in the in vivo studies in mice

[0610] The studies were conducted on male white CD-I mice from a certified breeding farm weighing 25-30 g. All procedures were performed in accordance with applicable Polish and European guidelines on the ethics of animal research, after obtaining appropriate approvals. All tests / models were performed based on procedures described in the relevant literature: formalin test (Eur. J. Pharmacol. 1998, 345, 233-245), capsaicin-induced pain model (Pharmacol. Biochem. Behav.

[0611] 2015, 133, 99-110), model of oxaliplatin-induced peripheral neuropathy - von Frey test (Pharmacol. Biochem. Behav. 2014, 122, 173-181), model of neuropathic pain induced by singledose hyperglycemia (Neuropharmacology 2017, 125, 181-188; J. Pharmacol. Sci. 2008, 107, 213- 220). The substance was administered intraperitoneally suspended in 1% Tween 80 solution, as single injections of 0.1 mL / 10 g bw., 30 minutes before the given test. The study groups consisted of 8-10 animals.

Claims

CLAIMS1. A compound of formula (I):wherein:A is hydrogen or deuterium,B is hydrogen or deuterium,X is hydrogen or deuteriumR1is a trifluoromethyl, trifluoromethoxy or trifluorothiomethyl groupR2is a methyl or methoxymethylene group.

2. The compound according to claim 1, characterized in that it is:(R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide,(R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide,(S)-N-( 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2-yl)acetamide,(R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide,-oxo- l -(4-(3-(trifluoromethyl)phenyl-4-d)piperazin- l -yl)propan-2-yl)acetamide,(S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide,(R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-d3,(R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3,(S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3,(R,S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-,2,2-d3,(R)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-,2,2-d3,CS')-Af-( l -oxo- l -(4-(3 -(trifl uoromethyl (phenyl -4-d)piperazin- l -yl (propan -2-yl (acetamide-2,2,2-d3,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)pheny1-4-d)piperazin- 1 -y1-2,2, 3 ,3 , 5 , 5 , 6,6-d8)propan- 2-yl)acetamide,(R)-N-(l -oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1 -y1-2,2, 3 ,3 ,5 ,5 ,6,6-6?8)propan-2- yl)acetamide,(S)-N-(1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2- yl)acetamide,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)pheny1-4-d)piperazin- 1 -y1-2,2, 3 ,3 , 5 , 5 , 6,6-d8)propan- 2-yl)acetamide-2,2,2-d3,(R)-N-(l -oxo- 1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1 -y1-2,2, 3 ,3 ,5 ,5 ,6,6-6?8)propan-2- yl)acetamide-2,2,2-d3,(S)-TV-(l -oxo-1 -(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1 -y1-2,2, 3, 3, 5,5,6, 6-d8)propan-2- yl)acetamide-2,2,2-d3,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2-yl)acetamide,(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide,(S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )phenyl)piperazin-1-yl)propan-2-yl)acetamide,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2-yl)acetamide,(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide,(S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2-yl)acetamide-2,2,2-d3,(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-6?3,(S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )phenyl)piperazin-1-yl)propan-2-yl)acetamide-2, 2, 2- 6?3,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2-yl)acetamide- 2,2,2-d3,(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3,(S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )pheny1-4-d)piperazin-1-yl)propan-2-yl)acetamide-2,2,2-d3,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2, 3 , 3 , 5 , 5 , 6,6- d8)propan-2-yl)acetamide,(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide,(S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan- 2-yl)acetamide,(R,S)-N-( 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2, 3 , 3 , 5 , 5 , 6,6- d8)propan-2-yl)acetamide-2,2,2-d3,(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide-2,2,2-d3,(S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide-2,2,2-d3,(R,S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide,(R)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide,(S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)propan-2-yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide,(R)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(tri fl uorom ethyl Jphenyl -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(tri fl uorom ethyl Jphenyl -4-d)pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -y1-2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide,(R)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide,(S)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluoromethyl)pheny1-4-d)piperazin- 1 -y1-2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide-2,2,2-d3,(R)-N-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl)pheny1-4-d)piperazin-1-y1-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3,CS'(-Af-(3-methoxy-1-oxo-1-(4-(3-(trifluoromethyl(phenyl-4-d(piperazin-l -yl-2,2,3,3,5,5,6,6- d8)propan-2-yl)acetamide-2,2,2-d3,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(R)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluorom ethoxy)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy )phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl(acetamide),(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl)piperazin- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -yl)propan-2- yl)acetamide-2,2,2-d3,(R,S)-N-(3 -methoxy- 1 -oxo- 1 - (4 - (3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide,(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide,(R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2.2.3.3.5.5.6.6-d8)propan-2-yl)acetamide-2,2,2-d3,(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide-2,2,2-d3,(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(trifluorom ethoxy (phenyl -4-d(pi perazi n- 1 -y1-2,2,3,3,5,5,6,6-d8)propan-2-yl)acetamide-2,2,2-d3,(R,S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(thiotrifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide,(R)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(thiotrifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide or(S)-N-(3 -methoxy- 1 -oxo- 1 -(4-(3 -(thiotrifluoromethyl)phenyl)piperazin- 1 -yl)propan-2- yl)acetamide.(R, 5)-N-(1-(4-([l,r-biphenyl]-3-yl)piperazin-1-yl)-3-m ethoxy- 1-oxopropan-2-yl)acetamide(R)-N-(l -(4-([ 1,1’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)acetamide(R, 5)-N-(1-(4-([l,r-biphenyl]-3-yl)piperazin-1-yl)-3-m ethoxy- 1-oxopropan-2-yl)acetamide(R, 5)-N-(1-(4-([l,r-biphenyl]-3-yl)piperazin-1-yl)-3-m ethoxy- 1-oxopropan-2-yl)acetamide-(R)-N-(l -(4-([ 1,1’ -biphenyl]-3 -yl)piperazin- 1 -y l)-3 -methoxy- 1 -oxopropan-2-yl)acetamide-(S)-N-( 1 -(4-([ 1 , 1’ -biphenyl] -3 -yl)piperazin- 1 -y 1 )- 3 -methoxy- 1 -oxopropan-2-yl)acetamide-(R, S)-N-(l -oxo- 1-(4-(3 -(trifluorom ethoxy )phenyl)piperazin-1-yl)butan-2-yl)acetamide(R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide(S)-N-(l -oxo- 1-(4-(3 -(tri fluorom ethoxy )phenyl)piperazin-1-yl)butan-2-yl)acetamide (R,S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2- (R)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2-(S)-N-(1-oxo-1-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-2-yl)acetamide-2,2,2- (R,S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide (R)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide(S)-N-(1-oxo-1-(4-(3-(thiotrifluoromethyl)phenyl)piperazin-1-yl)butan-2-yl)acetamide3. The compound as defined in claims 1-2 for the use in pharmacy.

4. The compound as defined in claims 1-2 for the use in the treatment or prevention of neurological diseases, preferably epilepsy, neurological pain, neuropathic pain, inflammatory pain or migraine.

5. The compound for use according to claim 3 or 4, wherein the compound is intended to induce an anti convulsive or analgesic effect.

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