Compounds capable of acting on s1r as well as on seh and uses thereof

Abstract

The present invention relates to the field of analgesia. Concretely, the present invention provides compounds and pharmaceutical compositions, as well as their use in the treatment or prevention of pain. More particularly the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment or prevention in an animal, including a human, of pain.

Description

[0001] Compounds capable of acting on S1R as well as on sEH and uses thereof.

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of medicine, particularly to the field of analgesia. Concretely, the present invention provides compounds and pharmaceutical compositions, as well as their use in the treatment or prevention of pain.

[0004] BACKGROUND OF THE INVENTION

[0005] The treatment of pain conditions is of great importance in medicine. There is currently a world- wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions is documented in the large number of scientific works that have appeared recently in the field of applied analgesics.

[0006] Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. (IASP Pain Terminology, https: / / www.iasp- pain.org / resources / terminology / ).

[0007] The IASP recommends using specific features to describe a patient's pain: (a) region of the body involved (e.g., abdomen, lower limbs), (b) system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal), (c) duration and pattern of occurrence, (d) intensity, and (e) cause.

[0008] Pain can be broadly divided into three classes: nociceptive, inflammatory, and neuropathic pain. Nociceptive pain corresponds to the sensation associated with the detection of noxious stimuli able to induce tissue damage, whereas inflammatory pain is associated with the milieu of factors released during tissue inflammation, and neuropathic pain triggers in response to the damage of the nervous system by either trauma or chemical insult (e.g., treatments with antineoplastics) (cf. Woolf, J Clin Invest., 2010, 120(11): 3742-3744).

[0009] Diseases such as rheumatoid arthritis have a clear predominant inflammatory component which contributes to the pain state. However, in other situations such as during the immediate postoperative period, there might also be an inflammatory component but there is also a powerful nociceptive pain component.

[0010] Neuropathic pain is a complex phenomenon with a marked contribution of central mechanisms. The intradermal injection of capsaicin decreases the mechanical pain threshold in the area surrounding the injection even when the area was not stimulated with capsaicin (the so-called area of secondary hypersensitivity). This decrease in the mechanical threshold can be attributed to central sensitization, which is a key feature of neuropathic pain, and in fact, this model is considered a surrogate model of neuropathic pain, since anti-neuropathic drugs show antiallodynic activity in this test in both humans and rodents (cf. Sanchez-Fernandez et al., Adv Exp Med Biol., 2017, 964:109-132).

[0011] Inadequate treatment of pain is widespread throughout surgical wards, intensive care units, and accident and emergency departments, in general practice, in the management of all forms of chronic pain including cancer pain, and in end-of-life care. This issue extends to all ages, from newborns to medically frail elderly.

[0012] Current analgesics (including opioids, nonsteroidal anti-inflammatory drugs [NSAIDs] and gabapentinoids) show limited efficacy in many pain conditions, or a number of side effects which limit their use. For instance, the analgesic effect of NSAIDs is limited and insufficient for the treatment of severe pain states, and they can induce gastrointestinal events or the impairment of renal function, among several other adverse effects (cf. Yaksh et al., FlOOOPrime Rep., 2015, 7, 56). Opioids can induce a much higher analgesic effect, but also constipation, respiratory depression, tolerance, emesis and physical dependence, among other adverse events (cf. Al-Hasani and Bruchas, Anesthesiology, 2011 , 115:1363-1381). Gabapentinoids are used in neuropathic pain patients, but induce dizziness, somnolence, peripheral edema, ataxia or gait disturbance and diarrhea (cf. Meng et al. , Minerva Anestesiol., 2014, 80(5): 556-67).

[0013] In an attempt to overcome limitations of the already known analgesics, researchers have focused the attention on other targets.

[0014] The sigma-1 receptor (S1 R) is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system (cf. Ruiz-Cantero et al., Pharmacol Res., 2021 , 163:105339). S1 R antagonists modify the chaperoning activity of S1 R by increasing opioid signalling and decreasing N-methyl-D-aspartate receptor (NMDAR) responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions. Furthermore, S1 R antagonists (in the absence of opioids) have been shown to exert antinociceptive effects in preclinical models of neuropathic pain induced by nerve trauma or chemical injury (e.g., the antineoplastic paclitaxel), and more recently in inflammatory pain. Although most studies attributed the analgesic properties of S1 R antagonists to their central actions, it is now known that peripheral S1 R also participates in their effects (cf. Ruiz-Cantero et al., 2021 , supra).

[0015] On the other hand, epoxyeicosatrienoic acids (EETs) are potent endogenous anti-inflammatory and anti-nociceptive mediators, but they are rapidly degraded by the soluble epoxide hydrolase (sEH) to the less active or inactive dihydroxyeicosatrienoic acids. In vitro and in vivo studies have demonstrated that the modulation of chronic inflammation and neuronal pain by EETs is inversely dependent on the extent of their hydrolysis by sEH. Thus, the use of sEH inhibitors (sEHIs) to maintain high in vivo levels of EETs is a promising pharmacological approach to treat pain and inflammation. Consequently, sEHIs are in development for the treatment of neuropathic pain in human patients. In addition to their use in humans, sEHIs may become suitable analgesics for use in veterinary medicine (cf. Hammock et al., J Med Chem., 2021 , 64(4): 1856-1872).

[0016] In spite of the efforts made, there is still the need of further therapeutic approaches to the appropriate management of the pain.

[0017] SUMMARY OF THE INVENTION

[0018] The inventors of the present invention have designed molecules of formula (I) that efficiently act on S1 R as well as on sEH. This dual effect is of particular relevance as it has been surprisingly found that the administration of a S1 R antagonist in combination with a soluble epoxide hydrolase inhibitor (sEHI) synergistically potentiates the separate analgesic effect of each one of the compounds.

[0019] In this sense, it is important to note that the combination of at least one S1 R antagonist and at least one sEHI shows clear synergistic effects in reducing pain, as demonstrated by the experimental data provided in Figures 1-4 of WO2024105225A1. Each figure emphasizes the enhanced antinociceptive and anti-allodynic effects when these two types of drugs are used together, compared to their individual effects.

[0020] In Figure 1 , the paw withdrawal latency test demonstrates that individually administered S1 R antagonists or sEHIs result in significant antiallodynic effect in capsaicin-treated mice. However, adding an S1 R agonist (PRE-084) or an epoxygenase inhibitor (MS-PPOH) significantly reverses the beneficial effects of the respective drug classes without cross- interfering. This indicates separate but complementary mechanisms of action. Thus, the sEHIs and the S1 R antagonists each operate through distinct pathways contributing individually to pain relief but potentially lacking full effectiveness when administered alone.

[0021] The evidence for synergism is particularly strong in Figures 2-4. In these figures, the administration of suboptimal doses of either class alone (sEHIs such as AS2586114, UB-SCG- 54, EC-5026 or S1 R antagonists such as BD-1063, NE-100, S1 RA) fails to achieve notable reductions in mechanical hypersensitivity induced by capsaicin. However, their combination remarkably potentiates the anti-allodynic effect, yielding significantly better results than expected from the additive effect of each drug alone. Specifically, Figure 2 illustrates clearly that combining AS2586114 with S1 R antagonists significantly reduces hypersensitivity compared to the negligible effect observed with either drug alone. This Figure also shows that the observed synergy is dependent on both mechanisms as the administration of either a S1 R agonist or an epoxygenase inhibitor, abolished the anti-allodynic effect. Similarly, Figure 3 confirms the same principle with another sEHI (UB-SCG-54), where synergy with S1 R antagonists leads to notable relief of sensory hypersensitivity in mice that had capsaicin- induced pain. The significant reduction in mechanical hypersensitivity is far superior to that observed with single treatments, clearly indicating a synergistic rather than merely additive interaction. Figure 4 further corroborates this finding, showing that EC-5026, another sEHI, when combined with the S1 R antagonist S1 RA, strongly suppresses capsaicin-induced mechanical hypersensitivity at doses that individually have minimal or no effect. Again, the combination outperforms the individual treatments, reinforcing the notion of synergism between these classes.

[0022] Overall, the synergistic interaction likely arises from simultaneous modulation of distinct but complementary biological pathways. The S1 R antagonists may inhibit mechanisms associated with sensory neuron excitability or glial activation, whereas sEHIs likely increase endogenous epoxy-fatty acid levels, promoting anti-inflammatory and analgesic actions. Hence, combining these agents not only enhances pain control but also reduces the required dose of each individual agent, potentially limiting adverse effects. In summary, these figures clearly demonstrate a synergistic benefit of combining S1 R antagonists and sEHIs in managing pain, supported by significantly enhanced effects observed in experimental models of pain compared to either agent administered alone.

[0023] The present invention provides novel molecules that simultaneously act as dual S1 R antagonists and sEHIs. This dual mechanism of action is supported by clear experimental evidence provided in Figures 1 to 4 of WO2024105225A1 , along with binding and inhibitory potency data derived from Table 1 and FIG. 5 of the present invention. All compounds described in the invention exhibit potent inhibitory activity towards soluble epoxide hydrolase (sEH), as demonstrated by IC50values below 100 nM. Such low IC50values clearly indicate a strong inhibitory effect, implying that these molecules effectively increase endogenous levels of analgesic epoxy-fatty acids, thus contributing substantially to the overall analgesic effect observed experimentally. Furthermore, all compounds evaluated in the invention exhibit significant binding affinity for the S1 R, evidenced by Ki values below 400 nM. These low Ki values indicate robust antagonistic action at the S1 R, further contributing to analgesic activity through modulation of receptor-mediated pathways implicated in sensory hypersensitivity and nociceptive signaling.

[0024] The synergy between S1 R antagonism and sEH inhibition is clearly supported by the data illustrated in Figures 1 to 4 of WO2024105225A1. As previously described, these figures collectively demonstrate that combining low doses of an S1 R antagonist and an sEHI produces substantially greater analgesic efficacy compared to each agent administered individually. Such synergistic interactions are due to simultaneous modulation of complementary pain signaling and inflammatory pathways, enhancing overall therapeutic efficacy. Thus, taken together, Figures 1-4 of WO2024105225A1 , in conjunction with the potency and affinity values reported in Table 1 and the data from FIG. 5 of the instant application, provide strong experimental evidence of the significant and synergistic analgesic effects achieved by the novel dual-action compounds described in the present invention. These dual-function molecules effectively harness two distinct analgesic mechanisms simultaneously, providing a therapeutically advantageous approach for pain management with increased efficacy and potentially reduced side-effect profiles.

[0025] As it can be derived from Table 1 , all the compounds of the invention have IC50 values below 100 nM, providing, at least, a significant inhibitory effect on sEH.

[0026] As it can be derived from Table 1 , all the evaluated compounds of the invention have Ki values below 400 nM, providing, at least, a significant binding effect on the S1 R.

[0027] In order to confirm that the effect of the compounds on S1 R was an antagonistic effect, a nanoluciferase binary technology test based on the ability of S1 R to heteromerize with the binding immunoglobulin protein (BiP) in living cells (cf. Morato et al., ACS Chem Neurosci., 2023, 14(11):2201-2207) was carried out. The results are provided in FIG. 1 and show that PRE-084, a well-known S1 R agonist, presents agonism towards S1 R, while haloperidol, a well stablished S1 R antagonist, and the compounds of the invention present antagonism towards S1 R.

[0028] As it has been discussed above, S1 R and sEH have been widely reported to be involved in pain as well as recognized targets in the inhibition of pain. Therefore, the data provided in Table 1 below support the suitability of the compounds of formula (I) as candidates in the treatment and prevention of pain. The above was further confirmed in an in vivo model of pain, in particular in a tactile allodynia model.

[0029] As it is shown below, the administration of the compound of the invention was able to induce an antiallodynic effect in the capsaicin-induced mechanical hypersensitivity (FIG. 2, 3, and 4). In addition, it was found that this effect was reversed when either PRE-084 (S1 R agonist) or MS-PPOH (a CYP450 epoxygenase inhibitor) were co-administered (FIG. 5), confirming that both S1 R antagonism and EET accumulation (due to the inhibition of sEH) participate in the antiallodynic effect of the compounds of the invention.

[0030] Altogether, the compounds of formula (I) mean a great advance in the efficient management of pain, simplifying the management of pain with molecules having a broader analgesic effect by acting on two targets.

[0031] Thus, in a first aspect the present invention provides compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment or prevention in an animal, including a human, of pain, wherein:

[0032] Ri is selected from the group consisting of: H, CF3, OCF3, and OCH3;

[0033] R2to R4are the same or different and are independently selected from the group consisting of: H; CN; halogen; OCH3; OCF3; CF3; and SF5.

[0034] Rs is an aromatic ring system, which is selected from the group consisting of: a) an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRX, and N; Rxbeing selected from the group consisting of: H; OH; CN; halogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (Ci-C10)alkyl substituted with one or more Sui; (C2-C10)alkenyl substituted with one or more SU2; (C2-C10)alkynyl substituted with one or more SU3; -O-(Ci-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2Re; NR?Rs; CONRgR’g; and COOR10; b) an aromatic 5-membered ring system, wherein the members are selected from the group consisting of: CRy, S, N, NH, and O; Rybeing selected from the group consisting of: H; OH; CN; halogen; (C1-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(Ci-C10)haloalkyl; SF5; S(0)2Rn; NR12R13; CONRi4R’i4; and COOR10; c) an aromatic fused ring system consisting of two rings, each one of the aromatic rings having 6 members selected from the group consisting of: CRZand N; Rzbeing selected from the group consisting of: H; OH; CN; halogen; (Ci-C10)haloalkyl; -0-(C1-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2RIS; NRieRi?; CONRi8R’i8; and COOR10; and d) an aromatic fused ring system consisting of two rings, one of the aromatic rings having 6 members selected from CH or N, and the other aromatic ring having 5 members selected from the group consisting of: CRZ, S, N, NH, and O; Rzbeing selected from the group consisting of: H; OH; CN; halogen; (Ci-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(Ci-C10)haloalkyl; SF5; S(O)2Rig; NR20R21; CONR22R 22; and COOR10

[0035] Re, R11, Ris and R19 are selected from the group consisting of: (Ci-C10)alkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl; R7 and R8 are the same or different and are selected from the group consisting of: -H, (Ci- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R23;

[0036] Rg and R’g are the same or different and are selected from the group consisting of: -H, (Ci- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;

[0037] Rw is selected from the group consisting of: -H, (Ci-C10)alkyl; (Ci-C10)haloalkyl; (C3- Cs)cycloalkyl;

[0038] R12 and R13 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R24;

[0039] R14 and R’14 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;

[0040] R16 and R17 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (C3-C8)cycloalkyl; (Ci-C10)haloalkyl; and -S(O)2R2s;

[0041] Ris and R’18 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;

[0042] R20 and R21 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (C3-C8)cycloalkyl; (Ci-C10)haloalkyl; and -S(O)2R2s;

[0043] R22 and R’22 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;

[0044] R23 to R25 are selected from the group consisting of (Ci-C10)alkyl; (C3-C8)cycloalkyl; (C1- C10)haloalkyl; aryl; and heteroaryl;

[0045] Sui to Su3are independently selected from the group consisting of: halogen, cyano, nitro, (C1- Ce)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1- Ce)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, / \ / -(Ci- C4)alkylcarbamoyl, / V, / V-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, / V-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, / V-(C1-C4)alkylsulfamoyl, and / V, / V-di-(C1-C4)alkylsulfamoyl. n is an integer value selected from 1 or 2;

[0046] A is selected from the group consisting of:

[0047]

[0048]

[0049] with the proviso that at least two of R1 to R4 are other than hydrogen.

[0050] “aryl” means an aromatic ring system comprising 6 CRcmembers, being Rcselected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, or -O-(C1-C5)haloalkyl;

[0051] “heteroaryl” means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, cyano, nitro, (C1-C5)alkyl, (C1-C5)haloalkyl, -O-(C1-C5)alkyl, or -O-(C1-C5)haloalkyl;

[0052] This aspect can alternatively be defined as the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, solvate or prodrug, in the manufacture of a medicament for the treatment or prevention of pain. This aspect can alternatively be defined as a method for the treatment or prevention of pain, the method comprising the step of administering a therapeutically effective amount of the compound of formula (I) as defined above, a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof.

[0053] In a second aspect the present invention provides a compound as defined above for use as a medicament, with the proviso that: when Ri and R4 are hydrogen, n is 1 , A is piperazine or 3,7-diazabicyclo[3.3.0]octane, and R2 is chlorine, R3 is other than chlorine; and with the proviso that: formula I does not include any of the compounds selected from the list consisting of:

[0054] In a third aspect the present invention provides a compound as defined in the first or second aspect of the invention, with the proviso that: a) when R1 is OCH3, R2 to R4 are other than OCHsand at least one of R2 to R4 is other than hydrogen; b) when R2 is OCH3, R1, and R3 to R4 are other than OCH3 and at least one of R1, or R3 to R4 is other than hydrogen; c) when R3 is OCH3, R1 to R2 and R4 are other than OCH3 and at least one of R1, or R3 to R4 is other than hydrogen; d) when R1 and R4 are hydrogen, A is piperazine, 1 ,4-diazepine, 3,7- diazabicyclo[3.3.0]octane or 3-azabicyclo[3.1.0]hexane, and R2 is fluorine, R3 is other than halogen; e) when R1 and R4 are hydrogen, n is 1 , A is piperazine, 1 ,4-diazepine, or 3,7- diazabicyclo[3.3.0]octane, and R2 is chlorine, R3 is other than halogen; f) when R1 and R4 are hydrogen, n is 1 , A is piperazine or 1 ,4-diazepine, and R2 is chlorine, R3 is other than methoxy; g) when R1 and R3 are hydrogen, A is piperazine, and R2 = fluorine, R4 is other than halogen; and with the proviso that the following compounds are not included in formula I:

[0055]

[0056] In a fourth aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), or a pharmaceutically salt thereof, as defined in the third aspect of the invention, together with one or more pharmaceutically acceptable salts.

[0057] In final aspects, the present invention provides processes for preparing compounds of formula (I) as indicated at the end of the description of embodiments.

[0058] BRIEF DESCRIPTION OF DRAWINGS

[0059] FIG. 1 represents the S1 R ligand-mediated modulation of S1 R-BiP heterodimerization. The stable S1 RLgBIT / BiPSmBIT HEK-293 cell line was incubated with vehicle or the indicated S1 R ligand (10 pM) during 16 h before the S1 R-BiP heterodimerization was determined after incubation with 1 pM coelenterazine 400a for 15 min, and the end point luminescence recordings were assessed on a CLARIOstar microplate reader. The results are represented as percentage against vehicle basal luminescence (% Basal) and expressed as the mean ± SEM of three independent experiments performed in quintuplicate. The number of replicas was n = 9. Outliers were assessed by the Grubbs test. No outliers were found. Comparisons between experimental groups were made using analysis of variance (ANOVA), followed by Dunnett’s multiple comparison test using GraphPad Prism 9, as indicated. *P < 0.1 : **P < 0.01 : ****P < 0.0001 , when compared to vehicle-treated cells (dashed line). Haloperidol (Halo), PRE- 084 (PRE).

[0060] FIG. 2 represents a dose-response curve of the effects induced by the dual S1 R antagonist / sEHI COMPOUND OF EXAMPLE 1 (compound of the invention, Ex. 1) on capsaicin-induced mechanical allodynia. A: Paw withdrawal latency (s). Effects of the s.c. administration of Ex. 1 (2.5-10 mg / kg) or its solvent (“S”, white square, dose 0) on the latency to paw withdrawal in response to the application of a mechanical stimulus after the intraplantar (i.pl.) administration of capsaicin 1 pg in mice, n = 6-7. Statistically significant differences: *p < 0.05 between nonsensitized mice (dashed lines) and the other experimental groups; #p < 0.05 between capsaicin-treated mice injected with Ex. 1 or its solvent (one-way ANOVA followed by Bonferroni test).

[0061] FIG. 3 represents a dose-response curve of the effects induced by the dual S1 R antagonist / sEHI COMPOUND OF EXAMPLE 28 (compound of the invention, Ex. 28) on capsaicin-induced mechanical allodynia. A: Paw withdrawal latency (s). Effects of the s.c. administration of Ex. 28 (1 .25-5 mg / kg) or its solvent (“S”, white square, dose 0) on the latency to paw withdrawal in response to the application of a mechanical stimulus after the intraplantar (i.pl.) administration of capsaicin 1 pg in mice, n = 6-7. Statistically significant differences: *p < 0.05 between nonsensitized mice (dashed lines) and the other experimental groups; #p < 0.05 between capsaicin-treated mice injected with Ex. 28 or its solvent (one-way ANOVA followed by Bonferroni test).

[0062] FIG. 4 represents a dose-response curve of the effects induced by the dual S1 R antagonist / sEHI COMPOUND OF EXAMPLE 32 (compound of the invention, Ex. 32) on capsaicin-induced mechanical allodynia. A: Paw withdrawal latency (s). Effects of the s.c. administration of Ex. 32 (1 .25-5 mg / kg) or its solvent (“S”, white square, dose 0) on the latency to paw withdrawal in response to the application of a mechanical stimulus after the intraplantar (i.pl.) administration of capsaicin 1 pg in mice, n = 6-7. Statistically significant differences: *p < 0.05 between nonsensitized mice (dashed lines) and the other experimental groups; #p < 0.05 between capsaicin-treated mice injected with Ex. 32 or its solvent (one-way ANOVA followed by Bonferroni test). FIG. 5 represents the antiallodynic effect of COMPOUNDS OF EXAMPLES 1 , 28 and 32 (compounds of the invention, Ex. 1 , Ex. 28, and Ex. 32) in capsaicin-treated mice, which is produced through simultaneous both S1 R antagonism and sEH inhibition. B: % Antiallodynic effect. The data shown represent the effect of the subcutaneous (s.c.) administration of Ex. 1 (10 mg / kg), or Ex. 28 (5 mg / kg) or Ex. 32 (5 mg / kg) alone or associated with the S1 R agonist PRE-084 (32 mg / kg, s.c.) or the CYP450 epoxygenase inhibitor MS-PPOH (20 mg / kg, s.c.), on paw withdrawal latency in mice treated intraplantarly with capsaicin (1 pg), n = 6-7. Statistically significant differences: *p < 0.05 between capsaicin-treated mice injected with Ex. 1 , Ex. 28, Ex. 32 or their solvent (first bar); #p < 0.05 mice treated with Ex.1 , Ex. 28 or Ex. 32 associated or not with PRE-084 or MS-PPOH (one-way ANOVA followed by Bonferroni test).

[0063] DETAILED DESCRIPTION OF THE INVENTION

[0064] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

[0065] Throughout the present specification and the accompanying clauses, the words "comprise" and variations such as "comprises", "comprising" are to be interpreted inclusively. That is, these words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows. The word “comprise” also includes the term “consists of”.

[0066] For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range.

[0067] In a first aspect the present invention provides the use of compounds of formula (I) in the treatment or prevention of pain.

[0068] In the context of the invention, the term "alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. Typical alkyl groups have from 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e. g., methyl, ethyl, n-propyl, / -propyl, n-butyl, f-butyl, n-pentyl, etc. If substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropyl methyl. If substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl or phenethyl. If substituted by heterocyclyl, it corresponds to a "heterocyclylalkyl" radical.

[0069] In the context of the invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one C=C double bond, and which is attached to the rest of the molecule by a single bond. Typical alkenyl radicals have from 2 to about 10, 2 to about 8 or 2 to about 6 carbon atoms. In a particular embodiment, the alkenyl group is vinyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, or butenyl.

[0070] In the context of the invention, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical containing one or more C=C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.

[0071] In the context of the invention, the term “hydroxyalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogens are replaced by -OH. Illustrative non-limitative examples of hydroxyalkyl are methanol, ethanol, isopropanol, isobutanol or f-butanol, among others. In the context of the invention, the term “alkoxy” refers to a -O-alkyl, wherein “alkyl” is as defined above. Illustrative non-limitative examples of alkoxy are methoxy, ethoxy, or f-butoxy, among others.

[0072] In the context of the invention, the term “alkylsulfinyl” refers alkyl-SO-, being “alkyl” as defined above.

[0073] In the context of the invention, the term “alkylsulfonyl” refers to alkyl-SCh-, being “alkyl” as defined above.

[0074] In the context of the invention, the term “alkylcarbonyl” means a straight or branched hydrocarbon chain radical containing no unsaturation, where the alkyl chain is interrupted with a carbonyl (C=O) group (i.e., an alkyl-C(O)-alkylene-group). Representative alkylcarbonyl groups include methylcarbonylmethyl, ethylcarbonylmethyl, methylcarbonylethyl, (2- methylpropyl)carbonylmethyl, and the like.

[0075] In the context of the invention, the term “alkoxycarbonyl” refers to an “alkoxy”, as defined above, where the alkyl chain is interrupted with a carbonyl (C=O) group.

[0076] In the context of the invention, the term “carbamoyl” refers to -C(O)NH2.

[0077] In the context of the invention, the term “alkylcarbonyloxy” refers to -C(O)-O-alkyl, being alkyl as defined above.

[0078] In the context of the invention, the term “sulfamoyl” refers to -S(O)2NH2.

[0079] In the context of the invention, the term "halogen" refers to bromo, chloro, iodo or fluoro.

[0080] In the context of the invention, the term “haloalkyl” refers to a straight or branched hydrocarbon chain radical containing no unsaturation, wherein one or more of the hydrogen atoms are replaced by halogen. Illustrative non-limitative examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, and the like.

[0081] In the context of the present invention, the term "salt" must be understood as any form of a compound used in accordance with this invention in which said compound is in ionic form or is charged and coupled to a counter-ion (a cation or anion) or is in solution. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly, complexes formed via ionic interactions. The definition includes in particular physiologically acceptable salts; this term must be understood as equivalent to "pharmacologically acceptable salts" or "pharmaceutically acceptable salts". In the context of the present invention, the term "pharmaceutically acceptable salts" means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly, as a result of the counter-ion) when used in an appropriate manner for a treatment, applied or used, particularly, in humans and / or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention -normally an acid (deprotonated)- such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used in humans and / or mammals. Salts with alkali and alkaline earth metals are preferred particularly, as well as those formed with ammonium cations (NH4+). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and / or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e., salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and / or mammals. Examples of this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

[0082] In the context of the present invention, the term "solvate" should be understood as meaning any form a compound in accordance with the invention in which said compound is bonded by a non-covalent bond to another molecule (normally a polar solvent), including especially hydrates and alcoholates, like for example, methanolate. A preferred solvate is the hydrate.

[0083] The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (I) that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Preferably, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods.

[0084] Any compound of formula (I) referred to herein is intended to represent such specific compound as well as certain variations or forms. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus, any given compound of formula (I) referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (E)-isomer or (Z)-isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same as, or different from, the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.

[0085] Furthermore, any compound of formula (I) referred to herein may exist as tautomer. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another. In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent A of formula (I) is selected from any of the group consisting of:

[0086]

[0087]

[0088]

[0089] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent A of formula (I) is selected from any of the group consisting of:

[0090]

[0091] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent A of formula (I) is selected from any of the group consisting of: In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent A of formula (I) is selected from:

[0092] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent Ri of formula (I) is selected from the group consisting of: H, CF3 and OCF3, and R2 to R4 are the same or different and are independently selected from the group consisting of: H; CN; F, Cl, Br; OCH3; OCF3; and CF3.

[0093] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent R1 of formula (I) is selected from the group consisting of: CF3 and OCF3.

[0094] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent R1 of formula (I) is selected from the group consisting of: CF3 and OCF3; and R2 and R4 are H, and R3 is other than H.

[0095] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent R1 of formula (I) is selected from the group consisting of: CF3 and OCF3; and R2 and R4 are H, and R3 is CN, F, Cl, Br or CF3.

[0096] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, substituent R1 of formula (I) is selected from the group consisting of: CF3 and OCF3; and R2 and R4 are H, and R3 is CN, F, Cl or CF3.

[0097] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, n = 1.

[0098] In another embodiment of the first aspect of the invention, the compound of formula (I) is selected from any one of the lists consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 4-benzyl- / V-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide f) 4-benzyl- / V-(4-methoxy-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide g) 4-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide h) 4-benzyl- / V-(2-methoxy-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide i) 4-benzyl- / V-(4-methoxy-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride j) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)piperazine-1 -carboxamide k) 4-benzyl- / V-(4-cyano-2-methoxybenzyl)piperazine-1 -carboxamide l) 4-benzyl- / V-(4-iodo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide hydrochloride m) 4-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide n) 4-benzyl- / V-(4-fluoro-2-methoxybenzyl)piperazine-1 -carboxamide o) 4-benzyl- / V-(4-cyano-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide p) 4-benzyl- / V-(4-chloro-2-methoxybenzyl)piperazine-1 -carboxamide q) 4-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide r) 4-benzyl- / V-(2-methoxy-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide s) 4-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)piperazine-1 -carboxamide t) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-fluorobenzyl)piperazine-1 -carboxamide u) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide v) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(2,4-dichlorobenzyl)piperazine-1 -carboxamide w) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-3-ylmethyl)piperazine-1- carboxamide x) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(naphthalen-2-ylmethyl)piperazine-1- carboxamide y) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-iodobenzyl)piperazine-1 -carboxamide z) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-phenethylpiperazine-1 -carboxamide aa) (3a / ?,6aS)-5-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 / - / )-carboxamide bb) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide cc) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride dd) (4aS,7aS)-6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)octahydro-1 / 7-pyrrolo[3,4- £>] py ri d i ne- 1 -carboxamide hydrochloride ee) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxamide ff) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride gg) (3aR,5r,6aS)-2-benzyl- / V-(2,4- bis(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide hh) 7-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxamide hydrochloride ii) / V-(2,4-bis(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide jj) 4-benzyl- / V-(5-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide kk) 4-benzyl- / V-(3-fluoro-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride

[0099] II) (1R,5S,6r)-3-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-6- carboxamide mm) 4-benzyl- / V-(4-cyano-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide nn) 4-benzyl- / V-(3-cyano-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide oo) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-2-ylmethyl)piperazine-1- carboxamide pp) 5-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 / 7)- carboxamide hydrochloride qq) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride rr) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ss) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide tt) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-2- carboxamide uu) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2- carboxamide vv) (1 / ?,5S,6r)-3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azabicyclo[3.1 ,0]hexane- 6-carboxamide ww) 9-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3,9-diazaspiro[5.5]undecane-3- carboxamide xx) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2-carboxamide yy) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1 -carboxamide zz) 2-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8-carboxamide hydrochloride aaa) 3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9- carboxamide bbb) 6-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ccc) / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide ddd) 6-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide eee) 6-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide fff) 6-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ggg) 6-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide hhh) 7-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide iii) 7-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide jjj) 7-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide kkk) 7-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide

[0100] III) / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-(thiophen-3-ylmethyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide mmm) / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.4]octane-6-carboxamide or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0101] In another embodiment of the first aspect of the invention, the compound of formula (I) is selected from any one of the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide f) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0102] Throughout the present description, the term "treatment" includes, but is not limited to, alleviating, diminishing or eliminating one or more symptoms of the disorder (i.e., pain); reducing the degree of the pain, stabilizing (i.e., not worsening) the condition, delaying or slowing the progression of the pain, alleviating or improving its condition, and remitting (whether total or partial). As used in the present invention, the term "prevention" refers to preventing the onset of the pain from occurring in a patient who is predisposed, but who does not yet have symptoms of the disease, or when the intervention is done before pain-inducing procedure.

[0103] As used herein, the term “pain” shall refer to all types of pain. Illustrative non-limitative examples are acute and chronic pains, such as surgical pain, articular pain, neuropathic pain and post-operative pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, migraine, angina pain, and genitourinary tract-related pain including cystitis, the term shall also refer to nociceptive pain or nociception.

[0104] These embodiments can also be used within the context of the treatment of dysmenorrhea, tendinitis, and bursitis. They can also be used in the treatment of pain symptoms of myalgia, dental pain, and migraine, in the treatment of pain of cancerous origin, and also as additional treatments for infectious and febrile states.

[0105] Finally, these embodiments can find use in the treatment of neuropathic pain, and in particular of nervous pain, herpes zoster, desafferentation (phantom member) pain, diabetic neuropathies, and chemotherapy-induced neuropathic pain.

[0106] In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the pain is post-operative pain; a pain induced by tissue damage; pain associated to inflammation; cancer pain; articular pain; chronic pain or any other pain condition involving allodynia and / or hyperalgesia.

[0107] As used herein, the term “animal” shall refer to a vertebrate animal. Such animals include both domestic animals; for example, livestock, laboratory animals and household pets, and non- domestic animals such as wildlife. In one embodiment, the animal is a vertebrate. In a particular embodiment the animal is a domestic mammal or a human. For such purposes, a compound of this invention may be administered as a feed additive.

[0108] In a further embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compounds of formula (I) are administered in combination with a further analgesic compound. In a further embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compounds of formula (I) are administered sequentially, separately or simultaneously with a further analgesic compound.

[0109] In a second aspect the present invention provides a compound as defined above for use as a medicament, with the proviso that: when Ri and R4 are hydrogen, n is 1 , A is piperazine or 3,7-diazabicyclo[3.3.0]octane, and R2 is chlorine, R3 is other than chlorine; and with the proviso that: formula I does not include any of the compounds selected from the list consisting of

[0110] In a third aspect the present invention provides a compound as defined in the first or second aspect of the invention, with the further proviso that: a) when R1 is OCH3, R2 to R4 are other than OCHsand at least one of R2 to R4 is other than hydrogen; b) when R2 is OCH3, R1, and R3 to R4 are other than OCH3 and at least one of R1, or R3 to R4 is other than hydrogen; c) when R3 is OCH3, R1 to R2 and R4 is other than OCH3 and at least one of R1, or R3 to R4 is other than hydrogen; d) when R1 and R4 are hydrogen, A is piperazine, 1 ,4-diazepine, 3,7- diazabicyclo[3.3.0]octane or 3-azabicyclo[3.1.0]hexane, and R2 is fluorine, R3 is other than halogen; e) when R1 and R4 are hydrogen, n is 1 , A is piperazine, 1 ,4-diazepine, or 3,7- diazabicyclo[3.3.0]octane, and R2 is chlorine, R3 is other than halogen; f) when R1 and R4 are hydrogen, n is 1 , A is piperazine or 1 ,4-diazepine, and R2 is chlorine, R3 is other than methoxy; g) when R1 and R3 are hydrogen, A is piperazine, and R2 = fluorine, R4 is other than halogen; and with the further proviso that the following compounds are not included in formula I:

[0111]

[0112] In one embodiment of the third aspect of the invention, the compound is selected from the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 4-benzyl- / V-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide f) 4-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide g) 4-benzyl- / V-(2-methoxy-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide h) 4-benzyl- / V-(4-methoxy-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride i) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)piperazine-1 -carboxamide j) 4-benzyl- / V-(4-cyano-2-methoxybenzyl)piperazine-1 -carboxamide k) 4-benzyl- / V-(4-iodo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide hydrochloride l) 4-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide m) 4-benzyl- / V-(4-fluoro-2-methoxybenzyl)piperazine-1 -carboxamide n) 4-benzyl- / V-(4-cyano-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide o) 4-benzyl- / V-(4-chloro-2-methoxybenzyl)piperazine-1 -carboxamide p) 4-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide q) 4-benzyl- / V-(2-methoxy-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide r) 4-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)piperazine-1 -carboxamide sj / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-fluorobenzyl)piperazine-1 -carboxamide t) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide u) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(2,4-dichlorobenzyl)piperazine-1 -carboxamide v) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-3-ylmethyl)piperazine-1- carboxamide w) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(naphthalen-2-ylmethyl)piperazine-1- carboxamide x) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-iodobenzyl)piperazine-1 -carboxamide y) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-phenethylpiperazine-1 -carboxamide z) (3a / ?,6aS)-5-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 / - / )-carboxamide aa) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide bb) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride cc) (4aS,7aS)-6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)octahydro-1 / 7-pyrrolo[3,4- £>] py ri d i ne- 1 -carboxamide hydrochloride dd) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxamide ee) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride; and ff) (3aR,5r,6aS)-2-benzyl- / V-(2,4- bis(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide gg) 7-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxamide hydrochloride hh) / V-(2,4-bis(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide ii) 4-benzyl- / V-(5-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide jj) 4-benzyl- / V-(3-fluoro-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride kk) (1R,5S,6r)-3-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-6- carboxamide

[0113] II) 4-benzyl- / V-(4-cyano-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide mm) 4-benzyl- / V-(3-cyano-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide nn) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-2-ylmethyl)piperazine-1- carboxamide oo) 5-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 / 7)- carboxamide hydrochloride pp) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride qq) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide rr) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide ss) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-2- carboxamide tt) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2- carboxamide uu) (1 R ,5S,6r)-3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azabicyclo[3.1 ,0]hexane- 6-carboxamide vv) 9-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3,9-diazaspiro[5.5]undecane-3- carboxamide ww) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2- carboxamide xx) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1 -carboxamide yy) 2-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8-carboxamide hydrochloride zz) 3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9- carboxamide aaa) 6-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide bbb) / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide ccc) 6-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ddd) 6-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide eee) 6-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide fff) 6-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ggg) 7-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide hhh) 7-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide iii) 7-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide jjj) 7-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide kkk) / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-(thiophen-3-ylmethyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide

[0114] III) / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.4]octane-6-carboxamide or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0115] In yet another embodiment of the third aspect of the invention, the compound is selected from the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide f) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0116] In a fourth aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the invention, in particular those indicated in the third aspect of the invention, or a pharmaceutical salt thereof, as defined above. It is noted that, in some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the compounds of the invention, in particular those indicated in the third aspect of the invention, or a pharmaceutical salt thereof, as defined above, is for use as defined in the first aspect of the invention or in any of its preferred embodiments. By “therapeutically effective amount”, it is understood the amount of the compound(s) that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.

[0117] The precise therapeutic dose of the component(s), as well as the amount of the compound(s) of the invention, may depend on several variables. Some of these would be: route of administration, time of drug release (e.g., instant or extended), administration schedule, pain severity, condition of the patient, and the like.

[0118] The pharmaceutical compositions can be prepared as a liquid, semi-solid or solid dosage form, for example in the form of solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pills or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, or administered as such.

[0119] These compositions can be prepared with the aid of conventional means, devices, methods or processes known in the art.

[0120] Pharmaceutically acceptable adjuvants, vehicles or excipients which may be used in such compositions are adjuvants, vehicles or excipients known to those skilled in the art or commonly used in the preparation of therapeutic compositions, which may be selected, for example, from the group consisting of excipients, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, flavoring agents or binders.

[0121] The term "pharmaceutically acceptable" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit / risk ratio in animals and, particularly, in humans.

[0122] The selection of physiologically compatible adjuvants or the number of adjuvants to be used depends on the form of administration of the pharmaceutical composition, i.e., oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, otic or intratympanic. Preparations in the form of tablets, dragees, capsules, granules, pills, drops, in particular otic drops, juices or syrups are preferably suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations or also sprays are preferably suitable for parenteral, topical or inhalation administration. The compounds in accordance with the invention used in the pharmaceutical composition in accordance with the invention in a depot, in a dissolved form or in a dressing, or if appropriate having added other agents favoring penetration into the skin, are preparations suitable for percutaneous administration. The preparation forms administrable orally or percutaneously can also release the respective compound according to the invention in a delayed form.

[0123] For instance, for oral administration in the form of a tablet or capsule, the active drug components can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0124] Gelatine capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0125] Liquid dosage forms for oral administration can contain colouring and flavouring to increase patient acceptance.

[0126] The dosage administered of the pharmaceutical composition will, of course, vary depending on the use and known factors such as the age, health, and weight of the recipient, nature and extent of symptoms, concurrent treatments, if any, frequency of treatment, and the effect desired. The recipient may be any type of mammal, but is preferably a human.

[0127] According to another aspect of the present invention, ureas of formula (I) may be prepared by reacting the amine of formula (II), either as free base or in the form of a salt such as the hydrochloride, with triphosgene in the presence of a base to generate the isocyanate of formula (III) followed by the reaction of such isocyanate with a diamine of formula (IV), in an organic solvent such as dichloromethane.

[0128] Scheme 1 :

[0129] According to another aspect of the present invention, amides of formula (I) may be prepared by reacting the amine of formula (II), either as free base or in the form of a salt such as the hydrochloride, with the carboxylic acid of formula (V) in the presence of a coupling agent, such as HATU, in the presence of a base, such as DI PEA, in an organic solvent such as DMF.

[0130] Scheme 2:

[0131] According to another aspect of the present invention, compounds of formula (I), may also be prepared by reacting the amine of formula (II), either as free base or in the form of a salt such as the hydrochloride, with triphosgene in the presence of a base to generate the isocyanate of formula (III) followed by the reaction of such isocyanate with a diamine of formula (VI), wherein PG is a protecting group (e.g., a Boc group), in an organic solvent such as dichloromethane.

[0132] The protected compound of formula (VII) may be deprotected using a standard procedure (e.g., HCI / dioxane or TFA in an organic solvent) to synthesize a urea of formula (VIII), followed by conventional alkylation reactions, such as a reductive alkylation with benzaldehydes and a suitable reducing agent, such as NaBHsCN, to yield compounds of formula (I).

[0133] Scheme 3:

[0134]

[0135] According to another aspect of the present invention, compounds of formula (I) may be prepared by reacting the amine of formula (II), either as free base or in the form of a salt such as the hydrochloride, with a carboxylic acid of formula (IX), wherein PG is a protecting group (e.g., a Boc group), in the presence of a coupling agent such as HATLI, in the presence of a base, such as DIPEA, in an organic solvent such as DMF, or using an acyl chloride in the presence of a base, such as triethylamine, in an organic solvent such as ethyl acetate. The protected compound of formula (X) may be deprotected using a standard procedure (e.g., HCI / dioxane in an organic solvent) to synthesize an amide of formula (XI), followed by conventional alkylation reactions, such as a reductive alkylation with benzaldehydes and a suitable reducing agent, such as NaBHsCN.

[0136] The appropriately substituted starting materials, such as compounds benzylamines of formula (II), amines of formula (IV), protected amines of formula (VI), carboxylic acids of formula (V) and carboxylic acids of formula (IX), not commercially available may be synthesized by methods known in the literature to those skilled in the art and are illustrated in the synthetic examples below.

[0137] To those skilled in the art, other objects, advantages, or features of the invention will be apparent in part from the description or in part from the practice of the invention. The following examples are provided by way of illustration or are not intended to be limiting of the present invention.

[0138] EXAMPLES

[0139] ABBREVIATIONS

[0140] The following abbreviations have been used along the present application:

[0141] AIBN: Azobisisobutyronitrile anh.: anhydrous

[0142] ATR: attenuated total reflectance

[0143] Calcd: calculated

[0144] DCM: dichloromethane

[0145] DI PEA: / V, / V-Diisopropylethylamine

[0146] DMF: / V, / V-dimethylformamide

[0147] EETs: epoxyeicosatrienoic acids

[0148] ESI: electrospray ionization

[0149] Et20: diethylether

[0150] EtsN: triethylamine

[0151] EtOAc: ethyl acetate

[0152] HATU : 1-[Bis(dimethylamino)methylene]-1 / 7-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate h: hours

[0153] HRMS: high resolution mass spectrometry

[0154] IR: infrared MeOH: methanol min: minutes mp: melting point

[0155] NBS: / V-bromosuccinimide

[0156] PG: protecting group

[0157] RT: room temperature

[0158] S1 R: sigma-1 receptor sEH: soluble epoxide hydrolase sEHI: soluble epoxide hydrolase inhibitor sEHIs: soluble epoxide hydrolase inhibitors

[0159] TFA: Trifluoroacetic acid

[0160] THF: tetrahydrofuran

[0161] ANALYTICAL METHODS

[0162] Melting points were determined in open capillary tubes with a MFB 595010 M Gallenkamp melting point apparatus. Infrared (IR) spectra were run on a Perkin-Elmer Spectrum RX I spectrophotometer (using the attenuated total reflectance (ATR) technique). Absorption values are expressed as wavenumbers (cm-1); only significant absorption bands are given. Preparative normal phase chromatography was performed on a CombiFlash Rf 150 (Teledyne Isco) with pre-packed RediSep Rf silica gel cartridges. Thin-layer chromatography was performed with aluminum-backed sheets with silica gel 60 F254 (Merck, ref 1 .05554 or Sigma- Aldrich, ref 60805), and spots were visualized with UV light, 1 % aqueous solution of KMnO4 and / or ninhydrin. High-resolution mass spectrometry (HRMS) analyses were performed either with an LC / MSD TOF Agilent Technologies or a LTQ Orbitrap Velos (Thermo) SN 030136B spectrometers. Analytical grade solvents were used for crystallization, while pure for synthesis solvents were used in the reactions, extractions and column chromatography.

[0163] Synthetic procedure 1 : synthesis of ureas i) Triphosgene (0.37 Eq) is slowly added to a stirring biphasic solution of a primary amine (1 Eq) in DCM (5 mL / mmol) and saturated aqueous NaHCOs solution (4 mL / mmol). The reaction mixture is stirred at RT for 30 min and then, the two phases are separated. The organic layer is washed with brine (10 mL), dried over anh. Na2SO4, filtered, and half-concentrated under vacuum to obtain 3-4 mL of a solution of isocyanate in DCM that is used in the next step without further purification. ii) A solution of the secondary amine (1 .1 Eq) in DCM (5 mL / mmol) is added to the previously obtained isocyanate, and the reaction mixture is stirred at RT overnight (4 Eq of Et3N are added if the secondary amines are used as hydrochloride salts). The solvent is removed under vacuum, and the resulting residue is purified by flash chromatography on a silica gel (SiCh) column.

[0164] Synthetic procedure 2: Reductive alkylation

[0165] A solution of the secondary amine (1 Eq) in MeOH (5.5 mL / mmol) is prepared in a round bottom flask equipped with a CaCh tube. To that, NaBHsCN (95%, 2 Eq), acetic acid (0.4 mL / mmol), and the desired aldehyde (1 .5 Eq) are added. The mixture is stirred at RT for 2 h. Then, more NaBH3CN (95%, 1 Eq) and aldehyde (1 Eq) are added, and the reaction mixture is stirred at RT for another 16 h. The mixture is concentrated under reduced pressure and to the obtained crude is added NaHCCh saturated solution (15 mL) until basic pH is reached and is extracted with DCM (3 x 20 mL). The combined organic extracts are dried over anh. Na2SO4, filtered, and concentrated under vacuum. The resulting residue is purified by flash chromatography on a silica gel (SiCh) column.

[0166] Synthetic procedure 3: A / -Boc deprotection

[0167] Option A: HCI solution 4M in dioxane (10 Eq) is added to a solution of / V-Boc protected amine (1 Eq) in DCM (4 mL / mmol), and the reaction mixture is stirred at RT overnight. Solvent removal under vacuum yields the corresponding deprotected amine as a hydrochloride salt. The amine is used in the next step without further purification.

[0168] Option B. TFA (110 Eq) is added to a solution of / V-Boc protected amine (1 Eq) in DCM (34 mL / mmol), and the reaction mixture is stirred at RT for 2h. Solvent removal under vacuum yields the corresponding deprotected amine as a trifluoroacetate salt. The amine is used in the next step without further purification.

[0169] Synthetic procedure 4: synthesis of amides (coupling reaction)

[0170] DIPEA (2 Eq) is added to a solution of the carboxylic acid (1 Eq) and the amine (1 Eq) in DMF (6 mL / mmol), leading to a mixture that is stirred for 10 minutes at RT. Then, HATU (2 Eq) is added, and the reaction mixture is stirred at RT overnight. The solvent is removed under vacuum yielding a brown residue that is dissolved in DCM (30 mL). The organic solution is washed with 2 N NaOH solution (2 x 25 mL), dried over anh. Na2SO4, filtered, and evaporated to dryness. The resulting residue is purified by flash chromatography on a silica gel (SiCh) column. EXAMPLES

[0171] Example 1 : 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0172] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (200 mg, 1.00 mmol) and 1 -benzylpiperazine (194 mg, 1.10 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a pale white solid (124 mg, 31 % yield), mp: 129-130 °C. IR (ATR) v: 602, 638, 697, 727, 828, 850, 881 , 933, 958, 1005, 1061 , 1111 ,

[0173] 1130, 1173, 1261 , 1298, 1317, 1422, 1493, 1538, 1622, 2234, 2765, 2806, 2902, 2944, 3058, 3081 , 3306 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH2iF3N4O+H]+: 403.1740; Found: 403.1746.

[0174] Example 2: 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide

[0175] Synthesized by procedure 1 from (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (200 mg, 0.89 mmol) and 1 -benzylpiperazine (194 mg, 1.10 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a pale white solid (174 mg, 46% yield), mp: 94-96 °C. IR (ATR) v: 563, 575, 587, 609, 639, 697, 740, 811 , 826, 851 , 945, 1004, 1082,

[0176] 1131 , 1162, 1218, 1245, 1349, 1416, 1432, 1488, 1537, 1621 , 2770, 2813, 2857, 2888, 2918, 3319 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH2iCIF3N302+H]+: 428.1347; Found: 428.1350.

[0177] Example 3: 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0178] Synthesized by procedure 1 from (4-chloro-2-(trifluoromethyl)phenyl)methanamine (250 mg, 1.19 mmol) and 1 -benzylpiperazine (231 mg, 1.30 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a pale white solid (200 mg, 41 % yield), mp: 134-135 °C. IR (ATR) v: 660, 682, 702, 743, 803, 835, 891 , 1006, 1047, 1118, 1147, 1172, 1259, 1303, 1395, 1420, 1540, 1627, 2761 , 2799, 2908, 2936, 3335 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH2iCIF3N30+H]+: 412.1398; Found: 412.1402.

[0179] Example 4: 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0180] Synthesis of (4-bromo-2-(trifluoromethyl)phenyl)methanamine:

[0181] 4-Bromo-2-(trifluoromethyl)benzaldehyde (250 mg, 0.99 mmol) was dissolved in 7 M ammonia in MeOH (7 mL) under an argon atmosphere and was stirred at RT for 16 h. Afterwards, the reaction was carefully treated with NaBH3CN (187 mg, 4.9 mmol) and stirred at RT for another 3 h. Then, EtOAc (15 mL) was added followed by saturated Na2CO3solution (15 mL). The aqueous layer was extracted with further EtOAc (2 x 15 mL). All the organic layers were joined, dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, Hexane / EtOAc mixtures) to afford (4-bromo-2- (trifluoromethyl)phenyl)methanamine (85.4 mg, 34% overall yield) as a white solid.

[0182] Synthesis of 4-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0183] Synthesized by procedure 1 from (4-bromo-2-(trifluoromethyl)phenyl)methanamine (85.4 mg, 0.34 mmol) and 1 -benzylpiperazine (119 mg, 0.67 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a pale white solid (70 mg, 45% yield), mp: 143-144 °C. IR (ATR) v: 572, 594, 669, 701 , 743, 802, 822, 892, 1006, 1046, 1118, 1148, 1171 , 1260, 1300, 1422, 1538, 1622, 2762, 2800, 2907, 2934, 3343 cm’1. HRMS-ESI+m / z [M+H]+calcd for [C2oH2iBrF3N30+H]+: 456.0893; Found: 456.0897.

[0184] Example 5: 4-benzyl- / V-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide

[0185] Synthesis of 4-bromo-2-(trifluoromethoxy)benzylamine hydrochloride

[0186] 4-Bromo-2-(trifluoromethoxy)benzaldehyde (500 mg, 1.86 mmol) was dissolved in 7 M ammonia in MeOH (3 mL) under an argon atmosphere and was stirred at RT for 16 h. Afterwards, the reaction was carefully treated with NaBFU (352 mg, 9.3 mmol) and was stirred at RT for another 3 h. EtOAc (20 mL) was added followed by saturated Na2CO3solution (20 mL). The aqueous layer was extracted with further EtOAc (2 x 20 mL). All the organic layers were joined, dried over anh. Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by column chromatography (SiO2, DCM / MeOH mixtures) to afford 4-bromo- 2-(trifluoromethoxy)benzylamine. The hydrochloride salt of 4-bromo-2- (trifluoromethoxy)benzylamine (185 mg, 33% yield) was obtained by adding 2 mL of HCI in Et2O and filtering the resulting white solid.

[0187] Synthesis of 4-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine- 1 -carboxamide

[0188] Synthesized by procedure 1 from 4-bromo-2-(trifluoromethoxy)benzylamine hydrochloride (176 mg, 0.65 mmol) and 1 -benzylpiperazine (127 mg, 0.72 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a beige solid (198 mg, 64% yield), mp: 95-96 °C. IR (ATR): 557, 563, 587, 638, 696, 741 , 809, 831 , 841 , 937, 1002, 1075, 1146, 1165, 1208, 1221 , 1244, 1349, 1392, 1420, 1484, 1531 , 1623, 2766, 2804, 2919, 2938, 3028, 3064, 3286, 3354 cm’1. HRMS-ESI+m / z [M+H]+calcd for [C2oH2iBrF3N302+H]+: 472.0842; Found: 472.0839.

[0189] Example 6: 4-benzyl- / V-(4-methoxy-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0190] Synthesized by procedure 1 from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine (308 mg, 1.5 mmol) and 1 -benzylpiperazine (291 mg, 1.65 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (322 mg, 53% yield), mp: 205-208 °C. IR (ATR) v: 575, 613, 632, 670, 699, 733, 810, 855, 890, 960, 1002, 1038, 1113, 1149, 1237, 1260, 1294, 1314, 1370, 1402, 1423, 1455, 1499, 1556, 1622, 2389, 2448, 2761 , 2803, 2948, 3292, 3336 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH24F3N3O2+H]+; 408.1893; found: 408.1898.

[0191] Example 7: 4-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0192] Synthesized by procedure 1 from (4-fluoro-2-(trifluoromethyl)phenyl)methanamine (295 mg, 1.53 mmol) and 1 -benzylpiperazine (296 mg, 1.68 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (274 mg, 45% yield), mp: 257-258 °C. IR (ATR) v: 569, 598, 670, 698, 750, 782, 821 , 888, 905, 943, 958, 1008, 1052, 1075, 1113, 1137, 1170, 1213, 1279, 1299, 1319, 1375, 1402, 1429, 1488, 1501 , 1549, 1634, 2389, 2438, 2525, 2943, 3078, 3299 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C20H2IF4N3O+H]+: 396.1694; found: 396.1689.

[0193] Example 8: 4-benzyl- / V-(2-methoxy-4-(trifluoromethoxy)benzyl)piperazine-1 - carboxamide

[0194] Synthesized by procedure 1 from (2-methoxy-4-(trifluoromethoxy)phenyl)methanamine (295 mg, 1.33 mmol) and 1 -benzylpiperazine (259 mg, 1.46 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (265 mg, 47% yield). The analytical sample was obtained by precipitation in pentane / DCM, mp: 229-230 °C. IR (ATR) v: 562, 596, 619, 698, 751 , 803, 849, 878, 954, 975, 1035, 1075, 1100, 1120, 1155, 1217, 1260, 1301 , 1409, 1452, 1502, 1543, 1626, 2451 , 2522, 2922, 3311 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH24F3N3O3+H]+: 424.1843; found: 424.1849.

[0195] Example 9: 4-benzyl- / V-(4-methoxy-2-(trifluoromethoxy)benzyl)piperazine-1 - carboxamide hydrochloride

[0196] Synthesis of (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine

[0197] A solution of 4-methoxy-2-(trifluoromethoxy)benzonitrile (411 mg, 1.89 mmol) in anh. THF (3 mL) was prepared in a 50 mL two-mouth round-bottomed flask under an argon atmosphere and was cooled to 0 °C with an ice bath. Then, UAIH4 (1 M in THF, 5.7 mL, 5.67 mmol) was added dropwise via syringe and the resulting yellow suspension was stirred at RT for 4 hours. The reaction mixture was cooled to 0 °C and quenched adding water dropwise until no more bubbling was observed. The crude was filtered through a pad with Celite® using a mixture of EtOAc / MeOH 1 / 1 (3 x 15 mL) as eluting agent. The solvents were removed under vacuum to yield a yellow oil to which DCM (15 mL) and water (8 mL) were added. The aqueous phase was acidified with 1 N HCI solution until pH = 1-2 and was washed with DCM. Then, the pH of the aqueous phase was adjusted to 12 with 2 N NaOH solution and was extracted with further DCM (5 x 15 mL). The combined organic layers were dried over anh. Na2SC>4, filtered and concentrated in vacuo, yielding the desired amine as an orange oil (240 mg, 57% yield) that was used in the next step without further purification or characterization.

[0198] Synthesis of 4-benzyl-N-(4-methoxy-2 (trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride

[0199] Synthesized by procedure 1 from (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine (240 mg, 1.1 mmol) and 1 -benzylpiperazine (210 mg, 1.2 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a transparent oil (150 mg, 32% yield). Its hydrochloride salt was obtained by adding it an excess of HCI in Et20 and filtering the resulting white solid, mp: 240-242 °C. IR (ATR) v: 595, 665, 701 , 749, 815, 842, 877, 957, 1034, 1052, 1095, 1148, 1218, 1247, 1363, 1407, 1449, 1485, 1508, 1543, 1625, 2462, 2533, 2935, 3065, 3327 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH24F3N3O3+H]+: 424.1843; found: 424.1844.

[0200] Example 10: 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0201] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (305 mg, 1.25 mmol) and 1 -benzylpiperazine (243 mg, 1.38 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (339 mg, 61% yield), mp: 157-158 °C. IR (ATR) v: 571 , 608, 670, 702, 724, 746, 773, 812, 843, 856, 911 , 1000, 1052, 1084, 1125, 1160, 1181 , 1275, 1305, 1346, 1369, 1426, 1477, 1544, 1587, 1626, 2763, 2807, 2879, 2940, 3337 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH2IF6N3O+H]+: 446.1664; found: 446.1662.

[0202] Example 11 : 4-benzyl- / V-(4-cyano-2-methoxybenzyl)piperazine-1 -carboxamide

[0203] Synthesis of 4-(bromomethyl)-3-methoxybenzonitrile

[0204] A mixture of 4-isocyano-2-methoxy-1 -methylbenzene (600 mg, 4.07 mmol) and AIBN (100 mg, 0.61 mmol) in acetic acid (5 mL) was stirred at 40 °C under an argon atmosphere. Then, NBS (725 mg, 4.07 mmol) was slowly added, and the resulted mixture was stirred at 75 °C for 3 h. After the completion of the reaction, the solvent was removed under vacuum and the resulting solid was dissolved in EtOAc (20 mL) and washed with 2 N HCI solution (3 x 20 mL). The organic phase was dried over anh. Na2SO4, filtered and evaporated to give a white solid (855 mg, 93%) that was used in the next step without further purification or characterization.

[0205] Synthesis of 4-(aminomethyl)-3-methoxybenzonitrile

[0206] 4-(bromomethyl)-3-methoxybenzonitrile (855 mg, 3.78 mmol) was dissolved in 7 M ammonia in MeOH solution (23 mL) and stirred at RT for 24 h. The solvent was removed under vacuum to provide an orange solid that was dissolved in 1 N HCI (20 mL) and washed with Et2O (3 x 20 mL). The aqueous phase was then adjusted to a pH of 10-12 with 1 N NaOH solution and extracted with DCM (4 x 40 mL). The combined organic extracts were dried over anh. Na2SO4, filtered and evaporated under vacuum to afford 4-(aminomethyl)-3-methoxybenzonitrile (416 mg, 68% yield) as an orange solid that was used in next step without further purification or characterization.

[0207] Synthesis of 4-benzyl-N-(4-cyano-2-methoxybenzyl)piperazine- 1 -carboxamide

[0208] Synthesized by procedure 1 from 4-(aminomethyl)-3-methoxybenzonitrile (416 mg, 2.56 mmol) and 1 -benzylpiperazine (497 mg, 2.82 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (312 mg, 33% yield). The analytical sample was obtained by precipitation in pentane / DCM, mp: 176-177 °C. IR (ATR) v: 555, 606, 623, 670, 696, 733, 771 , 796, 811 , 829, 861 , 879, 910, 924, 941 , 960, 1002, 1026, 1112, 1150, 1204, 1243, 1256, 1297, 1348, 1366, 1395, 1412, 1455, 1495, 1531 , 1624, 2229, 2770, 2810, 2856, 3074, 3309 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH24N4O2+H]+: 365.1972; found: 365.1972.

[0209] Example 12: 4-benzyl- / V-(4-iodo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide hydrochloride

[0210] Synthesis of 4-iodo-2-(trifluoromethyl)benzamide

[0211] 4-iodo-2-(trifluoromethyl)benzoic acid (500 mg, 1.58 mmol) was suspended in acetonitrile (5 mL) and di-tert-butyl dicarbonate (483 mg, 2.22 mmol) was added in one portion. The mixture was stirred for 15 minutes, and ammonium bicarbonate (113 mg, 1.42 mmol) was added, followed by pyridine (0.18 mL, 2.22 mmol). The orange suspension was stirred at RT for 17 h. Then, the solvents were evaporated under vacuum and the resulting residue was triturated with 2 N NaOH solution until the solutions were clear. The solid was collected by vacuum filtration and washed with water and 5% Et20 in hexane, obtaining 4-iodo-2- (trifluoromethyl)benzamide (332 mg, 67%) as a beige solid that was used in the next step without any further purification or characterization.

[0212] Synthesis of (4-iodo-2-(trifluoromethyl)phenyl)methanamine hydrochloride

[0213] A solution of 4-iodo-2-(trifluoromethyl)benzamide (332 mg, 1.05 mmol) in anh. THF (2 mL) was prepared in a 50 mL two-neck round-bottomed flask under an argon atmosphere. Then, BH3 (1 M in THF, 3.6 mL, 3.58 mmol) was added dropwise via syringe and the resulting suspension was heated to reflux and reacted for 16 h. The reaction was cooled with an ice bath and excess borane was quenched by the slow addition of 5 N HCI solution until gas evolution had ceased and a white precipitate appeared. The precipitate was collected by vacuum filtration and the solid was washed with 5 N HCI solution and THF / Et2O (1 :1) to afford (4-iodo-2- (trifluoromethyl)phenyl)methanamine hydrochloride (123 mg, 39% yield) as a white solid that was used in next step without any further purification or characterization.

[0214] Synthesis of 4-benzyl-N-(4-iodo-2-(trifluoromethyl)benzyl)piperazine- 1 -carboxamide hydrochloride

[0215] Synthesized by procedure 1 from (4-iodo-2-(trifluoromethyl)phenyl)methanamine hydrochloride (117 mg, 0.39 mmol) and 1 -benzylpiperazine (75 mg, 0.43 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a transparent oil (80 mg, 41% yield). Its hydrochloride salt was obtained by adding it an excess of HCI in Et20 and filtering the resulting white solid, mp: 252-253 °C. IR (ATR) v:, 569, 597, 666, 697, 750, 776, 814, 891 , 944, 958, 1007, 1052, 1075, 1111 , 1135, 1162, 1195, 1215, 1279, 1305, 1368, 1399, 1429, 1450, 1487, 1548, 1633, 2394, 2444, 2519, 2922, 3073, 3290 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH2iF3lN30+H]+: 504.0754; found: 504.0747.

[0216] Example 13: 4-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0217] Synthesized by procedure 1 from (4-chloro-3-(trifluoromethyl)phenyl)methanamine (300 mg, 1.43 mmol) and 1 -benzylpiperazine (277 mg, 1.57 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (314 mg, 53% yield), mp: 105-106 °C. IR (ATR) v: 568, 602, 652, 698, 732, 770, 790, 814, 825, 901 , 943, 964, 1000, 1033, 1054, 1112, 1128, 1169, 1194, 1245, 1267, 1303, 1338, 1351 , 1369, 1403, 1423, 1453, 1482, 1549, 1615, 2451 , 2530, 2809, 2916, 3081 , 3289 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C20H2ICIF3N3O+H]+: 412.1398; found: 412.1401.

[0218] Example 14: 4-benzyl- / V-(4-fluoro-2-methoxybenzyl)piperazine-1 -carboxamide

[0219] Synthesized by procedure 1 from (4-fluoro-2-methoxyphenyl)methanamine (300 mg, 1.93 mmol) and 1 -benzylpiperazine (375 mg, 2.13 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (504 mg, 73% yield), mp: 115-116 °C. IR (ATR) v: 611 , 627, 669, 694, 737, 783, 835, 945, 1003, 1034, 1076, 1110, 1144, 1196, 1248, 1294, 1334, 1352, 1367, 1398, 1453, 1496, 1533, 1612, 1625, 2763, 2811 , 2934, 3069, 3351 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH24FN302+H]+: 358.1925; found: 358.1927.

[0220] Example 15: 4-benzyl- / V-(4-cyano-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide

[0221] Synthesis of tert-butyl (4-bromo-2-(trifluoromethoxy)benzyl)carbamate

[0222] A mixture of (4-bromo-2-(trifluoromethoxy)benzylamine hydrochloride (776 mg, 2.53 mmol, see Example 5), di-tert-butyl dicarbonate (829 mg, 3.79 mmol) and NaHCO3(2.13 g, 25.3 mmol) in dioxane (12 mL) was stirred at RT overnight. Then, the solvent was removed under vacuum to give a white oily residue. Column chromatography purification (SiO2, Hexane / EtOAc mixtures) provided tert-butyl 4-bromo-2-(trifluoromethoxy)benzylcarbamate (450 mg, 48% yield) as a colourless oil. The analytical and spectroscopic data matched with those previously described.

[0223] Synthesis of tert-butyl (4-cyano-2-(trifluoromethoxy)benzyl)carbamate

[0224] A solution of tert-butyl 4-bromo-2-(trifluoromethoxy)benzylcarbamate (445 mg, 1.20 mmol), Zn(CN)2 (141 mg, 1 .20 mmol) in anh. DMF (6 mL) was prepared in a 50 mL two-neck round- bottomed flask under an argon atmosphere and was desgassed for 20 minutes at RT. Subsequently, tetrakis(triphenylphosphine) palladium (0) (277 mg, 0.24 mmol) was added and the resulting suspension was degassed again for another 5 minutes and, then, was heated to 100 °C overnight. The solvent was removed under vacuum, yielding a semisolid that was dissolved in EtOAc (15 mL) and H2O (15 mL). The biphasic mixture was filtered through a pad with Celite® using more EtOAc and H2O as eluting agents. Then, the phases were separated, and the aqueous one was extracted with more EtOAc (3 x 30 mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated under reduced pressure to give a yellowish oil. Column chromatography purification (SiO2, Hexane / EtOAc mixtures) gave tert-butyl (4-cyano-2-(trifluoromethoxy)benzyl)carbamate (288 mg, 76% yield) as a colourless oil. The analytical and spectroscopic data matched with those previously described.

[0225] Synthesis of 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile hydrochloride

[0226] Synthesized by procedure 3A from tert-butyl (4-cyano-2-(trifluoromethoxy)benzyl)carbamate (285 mg, 0.9 mmol). The title amine was obtained as a white solid (217 mg, 96% yield).

[0227] Synthesis of 4-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperazine- 1 -carboxamide

[0228] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile hydrochloride (217 mg, 0.86 mmol) and 1 -benzylpiperazine (166 mg, 0.95 mmol). Column chromatography purification (SiO3, DCM / MeOH mixtures) yielded the title urea as a beige solid (251 mg, 70% yield), mp: 135-136 °C. IR (ATR) v: 573, 605, 648, 698, 715, 741 , 765, 797, 817, 843, 871 , 901 , 950, 974, 1004, 1022, 1072, 1109, 1166, 1215, 1249, 1350, 1410, 1431 , 1454, 1496, 1537, 1621 , 2233, 2452, 2813, 2940, 3081 , 3316 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH2iF3N4O2+H]+: 419.1689; found: 419.1686.

[0229] Example 16: 4-benzyl- / V-(4-chloro-2-methoxybenzyl)piperazine-1 -carboxamide

[0230] Synthesis of (4-chloro-2-methoxyphenyl)methanamine hydrochloride

[0231] 4-chloro-2-methoxybenzaldehyde (500 mg, 2.93 mmol) was dissolved in 7 M ammonia in MeOH (10 mL) and stirred at RT for 16 h. Afterwards, the reaction was carefully treated with NaBFL (554 mg, 14.6 mmol) and stirred at RT for another 3 h. The solvent was removed under vacuum and to the resulting solid was added EtOAc (20 mL) and saturated NaHCO3solution (20 mL). The phases were separated, and the aqueous layer was extracted with further EtOAc (4 x 20 mL). All the organic layers were joined, dried over anh. Na2SO4, filtered and concentrated under vacuum yielding (4-chloro-2-methoxyphenyl)methanamine as a yellowish oil. The corresponding hydrochloride salt was obtained by adding an excess of HCI in Et20 and filtering the resulting white solid (173 mg, 28%).

[0232] Synthesis of 4-benzyl-N-(4-chloro-2-methoxybenzyl)piperazine- 1 -carboxamide

[0233] Synthesized by procedure 1 from (4-chloro-2-methoxyphenyl)methanamine hydrochloride (173 mg, 0.83 mmol) and 1 -benzylpiperazine (161 mg, 0.91 mmol). Column chromatography purification (SiO3, DCM / MeOH mixtures) yielded the title urea as a white solid (235 mg, 76% yield), mp: 236-237 °C. IR (ATR) v: 595, 619, 648, 701 , 752, 805, 847, 876, 920, 937, 953, 1035, 1075, 1097, 1122, 1154, 1178, 1218, 1244, 1264, 1279, 1362, 1399, 1414, 1478, 1491 , 1539, 1598, 1620, 2395, 2464, 2512, 2903, 2971 , 3069, 3309 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH24CIN302+H]+: 374.1630; found: 374.1641.

[0234] Example 17: 4-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide

[0235] Synthesized by procedure 1 from (4-fluoro-2-(trifluoromethoxy)phenyl)methanamine (250 mg, 1.19 mmol) and 1 -benzylpiperazine (231 mg, 1.31 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (349 mg, 71 % yield), mp: 94-95 °C. IR (ATR) v: 599, 644, 698, 716, 741 , 766, 802, 826, 865, 884, 914, 943, 962, 983, 999, 1015, 1054, 1088, 1100, 1140, 1162, 1215, 1245, 1343, 1367, 1408, 1434, 1456, 1499, 1539, 1622, 2754, 2797, 2953, 3032, 3333 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH2iF4N302+H]+: 412.1643; found: 412.1642.

[0236] Example 18: 4-benzyl- / V-(2-methoxy-4-(trifluoromethyl)benzyl)piperazine-1 - carboxamide

[0237] Synthesized by procedure 1 from (2-methoxy-4-(trifluoromethyl)phenyl)methanamine (250 mg, 1.22 mmol) and 1 -benzylpiperazine (236 mg, 1.34 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (238 mg, 48% yield), mp: 123-124 °C. IR (ATR) v: 567, 611 , 658, 701 , 737, 761 , 808, 830, 854, 890, 909, 944, 966, 1001 , 1029, 1076, 1113, 1162, 1238, 1271 , 1302, 1328, 1370, 1413, 1454, 1540, 1626, 2769, 2807, 2928, 3063, 3305 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH24F3N3O2+H]+: 408.1893; found: 408.1894.

[0238] Example 19: 4-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0239] Synthesized by procedure 1 from (3-chloro-5-(trifluoromethyl)phenyl)methanamine (250 mg, 1.19 mmol) and 1 -benzylpiperazine (231 mg, 1.31 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (304 mg, 62% yield). The analytical sample was obtained by precipitation in pentane / DCM, mp: 123-124 °C. IR (ATR) v: 569, 601 , 669, 697, 735, 767, 807, 824, 873, 890, 912, 959, 1002, 1020, 1051 , 1075, 1121 , 1171 , 1204, 1244, 1263, 1311 , 1331 , 1361 , 1410, 1455, 1480, 1532, 1621 , 2767, 2809, 2902, 2933, 3028, 3066, 3317 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oH2iCIF3N30+H]+: 412.1398; found: 412.1398.

[0240] Example 20: A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-fluorobenzyl)piperazine-1 - carboxamide

[0241] Synthesis of 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile

[0242] A mixture of 4-methyl-3-(trifluoromethyl)benzonitrile (6 g, 32.4 mmol) and AIBN (798 mg, 4.86 mmol) in acetic acid (50 mL) was stirred at 40 °C under an argon atmosphere. Then NBS (5.76 mg, 32.4 mmol) was slowly added, and the resulted mixture was stirred at 75 °C for 3 h. After the completion of the reaction, the solvent was removed under vacuum and the resulting solid was dissolved in EtOAc (20 mL) and washed with 2 N HCI solution (3 x 20 mL). The organic phase was dried over anh. Na2SO4, filtered and evaporated to give a yellowish oil (5.35 g, 63% yield) that was used in the next step without further purification or characterization.

[0243] Synthesis of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile

[0244] 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile (5.35 g, 20.3 mmol) was dissolved in 7 M ammonia in MeOH solution (155 mL) and stirred at RT for 24 h. The solvent was removed under vacuum and to the resulting white solid was added EtOAc (20 mL) and saturated NaHCO3solution (20 mL). The phases were separated, and the aqueous layer was extracted with further EtOAc (4 x 40 mL). The combined organic extracts were dried over anh. Na2SO4, filtered and evaporated under vacuum to afford 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (4.15 g, 96% yield) as a yellowish solid that was used in next step without any further purification or characterization.

[0245] Synthesis of tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperazine-1- carboxylate

[0246] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (4.10 g, 20.5 mmol) and tert-butyl piperazine-1 -carboxylate (4.20 mg, 22.5 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (3.841 g, 45% yield), mp: 160-161 °C. IR (ATR) v: 569, 598, 638, 677, 706, 727, 772, 811 , 845, 864, 880, 908, 939, 957, 995, 1052, 1086, 1127, 1157, 1207, 1248, 1277, 1321 , 1364, 1412, 1458, 1488, 1541 , 1634, 1686, 2230, 2856, 2928, 2979, 3085, 3332 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [Ci9H23F3N4O3+H]+: 435.1614; found: 435.1607.

[0247] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)piperazine- 1 -carboxamide hydrochloride Synthesized by procedure 3A from tert-butyl 4-((4-cyano-2- (trifluoromethyl)benzyl)carbamoyl)piperazine-1 -carboxylate (3.66 g, 8.88 mmol). The title amine was obtained as a white solid (3.09 g, quantitative yield), mp: > 260 °C (dec). IR (ATR) v: 559, 590, 613, 638, 677, 707, 727, 760, 773, 835, 880, 932, 951 , 1009, 1037, 1044, 1058, 1069, 1111 , 1137, 1167, 1260, 1278, 1319, 1372, 1413, 1430, 1456, 1481 , 1500, 1544, 1633, 2235, 2475, 2495, 2617, 2749, 2827, 2936, 3085, 3322 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [CI4HI5F3N4O+H]+: 313.1271 ; found: 313.1271.

[0248] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-fluorobenzyl)piperazine- 1- carboxamide

[0249] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and 4-fluorobenzaldehyde (267 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (193 mg, 53% yield), mp: 134-135 °C. IR (ATR) v: 561 , 600, 638, 672, 699, 766, 808, 829, 851 , 881 , 909, 933, 958, 1002, 1053, 1113, 1156, 1172, 1220, 1261 , 1297, 1315, 1369, 1418, 1461 , 1508, 1538, 1625, 2234, 2812, 2928, 3087, 3317 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH2oF4N40+H]+: 421.1646; found: 421.1639.

[0250] Example 21 : A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1- carboxamide

[0251] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and 4-methoxybenzaldehyde (293 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (256 mg, 69% yield), mp: 149-150 °C. IR (ATR) v: 598, 638, 682, 708, 726, 752, 772, 795, 833, 880, 933, 954, 1002, 1035, 1057, 1111 , 1130, 1168, 1243, 1262, 1294, 1318, 1345, 1372, 1418, 1460, 1474, 1510, 1542, 1627, 2234, 2796, 2947, 3075, 3314 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H23F3N4O2+H]+: 433.1846; found: 433.1835.

[0252] Example 22: A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(2,4-dichlorobenzyl)piperazine-1 - carboxamide

[0253] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and 2,4-dichlorobenzaldehyde (376 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (55 mg, 14% yield), mp: 161-162 °C. IR (ATR) v: 559, 577, 599, 638, 660, 681 , 702, 728, 746, 773, 793, 832, 851 , 881 , 933, 954, 1002, 1019, 1057, 1111 , 1129, 1153, 1172, 1262, 1292, 1319, 1345, 1374, 1418, 1473, 1499, 1539, 1589, 1626, 2235, 2757, 2810, 2910, 2939, 3084, 3309 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IHI9CI2F3N4O+H]+: 471.0961 ; found: 471.0960. Example 23: A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-3-ylmethyl)piperazine-1 - carboxamide

[0254] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and thiophene-3-carbaldehyde (241 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (115 mg, 33% yield), mp: 117-118°C. IR (ATR) v: 560, 575, 600, 638, 660, 682, 728, 746, 772, 832, 851 , 881 , 933, 955, 1002, 1019, 1057, 1111 , 1129, 1172, 1262, 1291 , 1318, 1346, 1374, 1418, 1473, 1498, 1536, 1625, 2234, 2810, 2934, 3082, 3300 cm’1. HRMS- ESI+m / z [M+H]+: calcd for [Ci9Hi9F3N4OS+H]+: 409.1304; found: 409.1288.

[0255] Example 24: A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(naphthalen-2- ylmethyl)piperazine-1 -carboxamide

[0256] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and 2-naphthaldehyde (336 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (120 mg, 31 % yield). The analytical sample was obtained by precipitation in pentane / DCM, mp: 135-136 °C. IR (ATR) v: 558, 575, 602, 638, 661 , 680, 706, 732, 744, 773, 794, 823, 852, 880, 932, 953, 1002, 1057, 1112, 1130, 1154, 1172, 1262, 1286, 1318, 1373, 1418, 1472, 1538, 1626, 2234, 2811 , 2944, 3051 , 3080, 3299 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C25H23F3N4O+H]+: 453.1897; found: 453.1882.

[0257] Example 25: A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-iodobenzyl)piperazine-1 - carboxamide

[0258] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and 4-iodobenzaldehyde (498 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (115 mg, 25% yield), mp: 169-170 °C. IR (ATR) v: 576, 597, 638, 675, 725, 742, 770, 786, 825, 852, 881 , 933, 954, 1003, 1056, 1112, 1130, 1173, 1262, 1297, 1318, 1346, 1370, 1419, 1475, 1540, 1628, 2235, 2818, 2950, 3085, 3324 cm’1. HRMS-ESI+m / z [M+H]+: C2IH20F3IN4O +H]+: 529.0707; found: 529.0698

[0259] Example 26: A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-phenethylpiperazine-1 - carboxamide

[0260] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (300 mg, 0.86 mmol) and 2-phenylacetaldehyde (258 mg, 2.15 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (240 mg, 67% yield), mp: 93-94 °C. IR (ATR) v: 574, 607, 637, 679, 697, 729, 746, 773, 829, 850, 880, 906, 932, 955, 1001 , 1055, 1112, 1129, 1171 , 1260, 1292, 1317, 1373, 1417, 1454, 1475, 1496, 1537, 1626, 2234, 2809, 2942, 3082, 3305 cm’1. HRMS-ESI m / z [M+H]+: calcd for [C22H23F3N4O +H]+: 417.1897; found: 417.1892

[0261] Example 27: (3a / ?,6aS)-5-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0262] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (218 mg, 0.89 mmol) and (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (200 mg, 0.99 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (295 mg, 70% yield), mp: 155-156 °C. IR (ATR) v: 570, 620, 670, 699, 746, 831 , 855, 909, 1002, 1054, 1083, 1113, 1171 , 1274, 1301 , 1343, 1420, 1475, 1532, 1588, 1629, 2796, 2959, 3051 , 3303 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C23H23F6N3O +H]+: 472.1818; found: 472.1807.

[0263] Example 28: 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide

[0264] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (211 mg, 0.87 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (250 mg, 0.96 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (306 mg, 77% yield). The analytical sample was obtained by precipitation in pentane / DCM, mp: 136-137 °C. IR (ATR) v: 568, 581 , 623, 671 , 697, 726, 746, 760, 813, 837, 856, 910, 973, 997, 1029, 1056, 1083, 1124, 1157, 1171 , 1211 , 1267, 1301 , 1328, 1344, 1360, 1421 , 1470, 1495, 1538, 1587, 1639, 2817, 2869, 2941 , 3032, 3069, 3299 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H21F6N3O +H]+: 458.1662; found: 458.1653.

[0265] Example 29: 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1,4-diazepane-1 -carboxamide hydrochloride

[0266] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (232 mg, 0.95 mmol) and 1-benzyl-1 ,4-diazepane (200 mg, 1.05 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a transparent oil (344 mg, 78% yield). Its hydrochloride salt was obtained by adding an excess of HCI in Et20 and filtering the resulting white solid, mp: 203-204 °C. IR (ATR) v: 568, 599, 670, 699, 746, 760, 811 , 841 , 856, 911 , 967, 1022, 1052, 1083, 1120, 1167, 1218, 1275, 1302, 1346, 1398, 1459, 1537, 1588, 1634, 2483, 2879, 2959, 3340 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H23F6N3O +H]+: 460.1818; found: 460.1812.

[0267] Example 30: (4aS,7aS)-6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)octahydro-1 H- pyrrolo[3,4-b]pyridine-1 -carboxamide hydrochloride Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (153 mg, 0.63 mmol) and (4aS,7aS)-6-benzyloctahydro-1 / 7-pyrrolo[3,4-b]pyridine (150 mg, 0.69 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a transparent oil (285 mg, 93% yield). Its hydrochloride salt was obtained by adding an excess of HCI in Et20 and filtering the resulting white solid, mp: 90-100 °C. IR (ATR) v: 564, 620, 635, 651 , 670, 696, 742, 834, 855, 869, 911 , 970, 994, 1052, 1084, 1110, 1124, 1172, 1196, 1275, 1301 , 1344, 1422, 1455, 1472, 1537, 1585, 1631 , 1639, 2787, 2956, 3069, 3251 cm’1. HRMS- ESI+m / z [M+H]+: calcd for [C24H25F6N3O +H]+: 486.1975; found: 486.1957.

[0268] Example 31 : 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxamide

[0269] Synthesis of tert-butyl 4-benzyl- 1-oxa-4, 9-diazaspiro[5.5]undecane-9-carboxylate

[0270] Synthesized by procedure 2 from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (800 mg, 3.12 mmol) and benzaldehyde (828 mg, 7.8 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title compound as a white solid (990 mg, 92% yield).

[0271] Synthesis of 4-benzyl- 1-oxa-4, 9-diazaspiro[5.5]undecane di hydrochloride

[0272] Synthesized by procedure 3A from tert-butyl 4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate (506 mg, 1.46 mmol). The title dihydrochloride was obtained as a white solid (444 mg, 95%).

[0273] Synthesis of 4-benzyl-N-(2, 4-bis(trifluoromethyl)benzyl)- 1-oxa-4, 9-diazaspiro[5.5]undecane- 9-carboxamide

[0274] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (138 mg, 0.57 mmol) and 4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane dihydrochloride (200 mg, 0.63 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (223 mg, 76% yield), mp: 138-139 °C. IR (ATR) v: 576, 670, 698, 740, 842, 856, 870, 908, 938, 981 , 1003, 1053, 1082, 1122, 1169, 1205, 1273, 1301 , 1344, 1362, 1419, 1455, 1493, 1532, 1588, 1627, 2763, 2808, 2873, 2937, 3339 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C25H27F6N3O2 +H]+: 516.2080; found: 516.2068.

[0275] Example 32: 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7- carboxamide hydrochloride

[0276] Synthesis of tert-butyl 2-benzyl-2, 7-diazaspiro[3.5]nonane-7-carboxylate

[0277] Synthesized by procedure 2 from tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (800 mg, 3.53 mmol) and benzaldehyde (938 mg, 8.83 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title compound as a white solid (610 mg, 55% yield).

[0278] Synthesis of 2-benzyl-2, 7-diazaspiro[3.5]nonane dihydrochloride

[0279] Synthesized by procedure 3A from tert-butyl 2-benzyl-2,7-diazaspiro[3.5]nonane-7- carboxylate (610 mg, 1.93 mmol). The title dihydrochloride was obtained as a white solid (459 mg, 82% yield).

[0280] Synthesis of 2-benzyl-N-(2,4-bis(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-7- carboxamide hydrochloride

[0281] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (191 mg, 0.78 mmol) and 2-benzyl-2,7-diazaspiro[3.5]nonane dihydrochloride (250 mg, 0.86 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a colourless oil (189 mg, 50% yield). Its hydrochloride salt was obtained by adding an excess of HCI in Et20 and filtering the resulting white solid, mp: 145-146 °C. IR (ATR) v: 567, 625, 649, 670, 698, 724, 747, 767, 857, 911 , 957, 971 , 1052, 1083, 1118, 1170, 1274, 1303, 1346, 1363, 1430, 1460, 1538, 1632, 1650, 2450, 2536, 2781 , 2934, 3173 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C24H25F6N3O +H]+: 486.1975; found: 486.1961.

[0282] Example 33: (3a / ?,5r,6aS)-2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl) octahydrocyclopenta[c]pyrrole-5-carboxamide

[0283] Synthesis of tert-butyl (3aR,5r,6aS)-5-((2,4-bls(trlfluoromethyl)benzyl)carbamoyl) hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0284] Synthesized by procedure 4 from (2,4-bis(trifluoromethyl)phenyl)methanamine (238 mg, 0.98 mmol) and (3aR,5r,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-5-carboxylic acid (250 mg, 0.98 mmol). A brown solid was obtained (515 mg, quantitative yield), which was used in the next step without any further purification or characterization.

[0285] Synthesis of (3aR, 5r, 6aS)-N-(2, 4-bis(trifluoromethyl)benzyl) octahydrocyclopenta[c]pyrrole-5- carboxamide hydrochloride

[0286] Synthesized by procedure 3A from tert-butyl (3aR,5r,6aS)-5-((2,4- bis(trifluoromethyl)benzyl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1 H)-carboxylate (515 mg, 1.07 mmol). The title amine was obtained as a beige solid (432 mg, 97% yield).

[0287] Synthesis of (3aR, 5r, 6aS)-2-benzyl-N-(2, 4-bis(trifluoromethyl) benzyl) octahydrocyclopenta[c]pyrrole-5-carboxamide

[0288] Synthesized by procedure 2 from (3aR,5r,6aS)- / V-(2,4- bis(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide hydrochloride (300 mg, 0.72 mmol) and benzaldehyde (191 mg, 1.8 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title amide as a white solid (114 mg, 34% yield), mp: 108-109 °C. IR (ATR) v: 568, 619, 634, 653, 670, 694, 717, 741 , 773, 799, 833, 855, 869, 910, 969, 1051 , 1085, 1108, 1124, 1172, 1197, 1267, 1276, 1301 , 1344, 1363, 1423, 1455, 1495, 1564, 1639, 2738, 2792, 2869, 2957, 3076, 3249 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C24H24F6N2O +H]+: 471.1866; found: 471.1857.

[0289] Example 34: 7-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2- carboxamide hydrochloride

[0290] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (204 mg, 0.84 mmol) and 2-benzyl-2,7-diazaspiro[4.4]nonane (200 mg, 0.92 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a colourless oil (242 mg, 59% yield). Its hydrochloride salt was obtained by adding an excess of HCI in Et20 and filtering the resulting white solid, mp: 84-85 °C. IR (ATR) v: 618, 670, 701 , 747, 856, 911 , 1055, 1083, 1118, 1167, 1275, 1302, 1344, 1402, 1455, 1485, 1531 , 1632, 2507, 2602, 2879, 2950, 3301 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C24H25F6N3O+H]+; 486.1975; found, 486.1973.

[0291] Example 35: A / -(2,4-bis(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 - carboxamide

[0292] Synthesis of tert-butyl 4-((2,4-bis(trifluoromethyl)benzyl)carbamoyl)piperazine-1 -carboxylate

[0293] Synthesized by procedure 1 from (2,4-bis(trifluoromethyl)phenyl)methanamine (4 g, 16.46 mmol) and tert-butyl piperazine-1 -carboxylate (3.37 g, 18.1 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (2.892 g, 77% yield).

[0294] Synthesis of N-(2, 4-bis(trifluoromethyl)benzyl)piperazine- 1 -carboxamide hydrochloride

[0295] Synthesized by procedure 3A from tert-butyl 4-((2,4- bis(trifluoromethyl)benzyl)carbamoyl)piperazine-1 -carboxylate (2.787 g, 6.12 mmol). The title amine was obtained as a white solid (1.928, 80%).

[0296] Synthesis of N-(2,4-bis(trifluoromethyl)benzyl)-4-(4-methoxybenzyl) piperazine-1 -carboxamide

[0297] Synthesized by procedure 2 from / V-(2,4-bis(trifluoromethyl)benzyl)piperazine-1 -carboxamide hydrochloride (175 mg, 0.45 mmol) and 4-methoxybenzaldehyde (152 mg, 1.12 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a beige solid (201 mg, 95% yield), mp: 106-107 °C. IR (ATR) v: 609, 671 , 726, 748, 793, 824, 844, 912, 954, 1005, 1036, 1053, 1084, 1123, 1165, 1252, 1276, 1304, 1348, 1426, 1466, 1512, 1543, 1587, 1625, 2799, 2937, 3337 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H23F6N3O2+H]+; 476.1767; found, 476.1768.

[0298] Example 36: 4-benzyl- / V-(5-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0299] Synthesized by procedure 1 from (5-chloro-2-(trifluoromethyl)phenyl)methanamine hydrochloride (250 mg, 1.01 mmol) and 1 -benzylpiperazine (197 mg, 1.12 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a colourless oil. The product precipitated as a white solid after treatment with pentane / DCM (155 mg, 37% yield), mp: 120-121 °C. IR (ATR) v: 697, 735, 776, 830, 876, 964, 1001 , 1037, 1113, 1165, 1243, 1269, 1303, 1366, 1397, 1421 , 1454, 1534, 1603, 1627, 2805, 2935, 3077, 3334 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C20H21CIF3N3O +H]+; 412.1398; found, 412.1402.

[0300] Example 37: 4-benzyl- / V-(3-fluoro-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride

[0301] Synthesized by procedure 1 from (3-fluoro-4-(trifluoromethoxy)phenyl)methanamine (200 mg, 0.81 mmol) and 1 -benzylpiperazine (158 mg, 0.89 mmol). Column chromatography purification (SiO2, DCM / EtOAc mixtures) yielded the title urea as a yellowish oil. Its hydrochloride salt was obtained as a white solid by adding 2 mL of HCI in Et20 and evaporating the excess of acid (262 mg, 72% yield), mp: 242-243 °C. IR (ATR) v: 699, 736, 749, 763, 790, 829, 875, 955, 1001 , 1037, 1075, 1113, 1167, 1198, 1243, 1268, 1303, 1352, 1417, 1454, 1479, 1538, 1603, 1626, 2462, 2526, 2805, 2922, 3071 , 3318 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C20H2IF4N3O2+H]+; 412.1643; found, 412.1642.

[0302] Example 38: (1 / ?,5S,6r)-3-benzyl-A / -(2,4-bis(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-6-carboxamide

[0303] Synthesized by procedure 4 from (2,4-bis(trifluoromethyl)phenyl)methanamine (168 mg, 0.69 mmol) and (1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (150 mg, 0.69 mmol). Column chromatography purification (SiO2, hexane / EtOAc mixtures) yielded the title amide as a white solid (291 mg, 95% yield), mp: 184-185 °C. IR (ATR) v: 640, 670, 701 , 732, 760, 813, 834, 861 , 905, 966, 1043, 1089, 1119, 1141 , 1164, 1197, 1230, 1268, 1306, 1347, 1421 , 1453, 1493, 1548, 1603, 1635, 2808, 2890, 3065, 3301 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H20F6N2O+H]+; 443.1553; found, 443.1563.

[0304] Example 39: 4-benzyl- / V-(4-cyano-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0305] Synthesis of 4-(bromomethyl)-2-(trifluoromethyl)benzonitrile

[0306] A mixture of 4-methyl-2-(trifluoromethyl)benzonitrile (500 mg, 2.7 mmol) and Al BN (67 mg, 0.4 mmol) in acetic acid (4 mL) was stirred at 40 °C under an argon atmosphere. Then, NBS (481 mg, 2.7 mol) was slowly added, and the resulted mixture was stirred at 75 °C for 3 h. After the completion of the reaction, the solvent was removed under vacuum and the resulting solid was dissolved in EtOAc (20 mL) and washed with 2 N HCI solution (3 x 20 mL). The organic phase was dried over anh. Na2SC>4, filtered and evaporated to give a yellowish oil (635 mg). Column chromatography purification (SiO2, hexane / EtOAc mixtures) yielded the title compound as a colourless oil (255 mg, 36% yield)

[0307] Synthesis of 4-(aminomethyl)-2-(trifluoromethyl)benzonitrile

[0308] 4-(bromomethyl)-2-(trifluoromethyl)benzonitrile (255 mg, 0.96 mmol) was dissolved in 7 M ammonia in MeOH solution (6.9 mL) and stirred at RT for 24 h. The solvent was removed under vacuum to provide a yellowish solid to which 2 N NaOH aqueous solution (30 mL) and EtOAc (30 mL) were added. The aqueous layer was extracted with further EtOAc (2 x 30 mL). The combined organic extracts were dried over anh. Na2SO4, filtered and evaporated under vacuum to afford the tittle amine (188 mg, 97% yield) as a yellowish oil that was used in the next step without further purification or characterization.

[0309] Synthesis of 4-benzyl-N-(4-cyano-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0310] Synthesized by procedure 1 from 4-(aminomethyl)-2-(trifluoromethyl)benzonitrile (188 mg, 0.94 mmol) and 1 -benzylpiperazine (182 mg, 1.03 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a beige solid (115 mg, 30% yield), mp: 111-112 °C. IR (ATR) v: 665, 700, 745, 765, 809, 840, 905, 958, 1000, 1057, 1137, 1171 , 1244, 1273, 1296, 1319, 1365, 1420, 1453, 1476, 1494, 1538, 1620, 2234, 2810, 2910, 3067, 3346 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH2iF3N4O+H]+; 403.1740; found, 403.1749.

[0311] Example 40: 4-benzyl- / V-(3-cyano-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0312] Synthesis of 5-(bromomethyl)-2-(trifluoromethyl)benzonitrile

[0313] A mixture of 5-methyl-2-(trifluoromethyl)benzonitrile (500 mg, 2.7 mmol) and Al BN (67 mg, 0.4 mmol) in acetic acid (4 mL) was stirred at 40 °C under an argon atmosphere. Then, NBS (481 mg, 2.7 mmol) was slowly added, and the resulted mixture was stirred at 75 °C for 3 h. After the completion of the reaction, the solvent was removed under vacuum and the resulting solid was dissolved in EtOAc (20 mL) and washed with 2 N HCI solution (3 x 20 mL). The organic phase was dried over anh. Na2SO4, filtered and evaporated to give an orange oil (539 mg). Column chromatography purification (SiO2, hexane / EtOAc mixtures) yielded the title compound as a colourless oil (361 mg, 51 % yield).

[0314] Synthesis of 5-(aminomethyl)-2-(trifluoromethyl) benzonitrile

[0315] 4-(bromomethyl)-2-(trifluoromethyl)benzonitrile (361 mg, 1.37 mmol) was dissolved in 7 M ammonia in MeOH solution (9.8 mL) and stirred at RT for 24 h. The solvent was removed under vacuum to provide a white solid to which 2 N NaOH aqueous solution (30 mL) and EtOAc (30 mL) were added. The aqueous layer was extracted with further EtOAc (2 x 30 mL). The combined organic extracts were dried over anh. Na2SO4, filtered and evaporated under vacuum to afford the tittle amine (273 mg, 99% yield) as a yellowish oil that was used in the next step without further purification or characterization.

[0316] Synthesis of 4-benzyl-N-(3-cyano-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide

[0317] Synthesized by procedure 1 from 5-(aminomethyl)-2-(trifluoromethyl)benzonitrile (273 mg, 1.36 mmol) and 1 -benzylpiperazine (264 mg, 1.50 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a yellowish oil that was precipitated with Et2O (131 mg, 24% yield), mp: 111-112 °C. IR (ATR) v: 636, 700, 741 , 779, 813, 845, 908, 952, 997, 1018, 1042, 1122, 1138, 1174, 1210, 1292, 1320, 1392, 1452, 1482, 1529, 1622, 2234, 2768, 2805, 2943, 3053, 3257, 3313 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH2IF3N4O+H]+; 403.1740; found, 403.1749.

[0318] Example 41 : A / -(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-2-ylmethyl)piperazine-1- carboxamide

[0319] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1- carboxamide hydrochloride (175 mg, 0.50 mmol) and thiophene-2-carbaldehyde (140 mg, 1 .25 mmol). Column chromatography purification (SiO2, DCM / EtOAc mixtures) yielded the title urea as a white solid (102 mg, 50% yield), mp: 129-130 °C. IR (ATR) v: 638, 689, 774, 828, 850, 880, 932, 956, 1002, 1019, 1058, 1111 , 1172, 1218, 1261 , 1297, 1318, 1372, 1418, 1478, 1537, 1625, 2234, 2808, 2904, 3082, 3292 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [Ci9Hi9F3N4OS+H]+; 409.1304; found, 409.1327.

[0320] Example 42: 5-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4- c]pyrrole-2(1 H)-carboxamide hydrochloride

[0321] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (200 mg, 1 mmol) and (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (222 mg, 1.1 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a colourless oil (224 mg, 52% yield). Its hydrochloride salt was obtained as a white solid by adding 2 mL of HCI in Et20 and evaporating the excess of acid, mp: 205-206 °C. IR (ATR) v: 620, 669, 706, 767, 830, 882, 915, 1002, 1031 , 1056, 1120, 1160, 1189, 1260, 1319, 1354, 1398, 1422, 1488, 1540, 1632, 1650, 2240, 2462, 2861 , 2948, 3399 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C23H23F3N4O+H]+; 429.1897; found, 429.1919.

[0322] Example 43: 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-1,4-diazepane-1- carboxamide hydrochloride Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (191 mg, 0.95 mmol) and 1-benzyl-1 ,4-diazepane (200 mg, 1.05 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a colourless oil (179 mg, 45% yield). Its hydrochloride salt was obtained as a white solid by adding 2 mL of HCI in Et20 and evaporating the excess of acid, mp: 231-232 °C. IR (ATR) v: 668, 698, 739, 758, 842, 918, 1053, 1080, 1113, 1131 , 1174, 1276, 1317, 1365, 1406, 1491 , 1543, 1632, 2235, 2484, 2941 , 3040, 3325 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H23F3N4O+H]+; 417.1897; found, 417.1883.

[0323] Example 44: 6-benzyl-A / -(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane- 2-carboxamide

[0324] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (191 mg, 0.96 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (250 mg, 0.96 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a colourless oil. The product precipitated as a white solid after treatment with pentane / DCM (84 mg, 21 % yield), mp: 177-178 °C. IR (ATR) v: 622, 638, 696, 711 , 721 , 764, 842, 884, 935, 970, 989, 1053, 1112, 1133, 1186, 1273, 1318, 1359, 1408, 1454, 1501 , 1537, 1638, 2234, 2817, 2867, 2940, 3083, 3229 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H2IF3N4O+H]+; 415.1740; found, 415.1720.

[0325] Example 45: 7-benzyl-A / -(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane- 2-carboxamide

[0326] Synthesis of tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-2, 7- diazaspiro[3.5]nonane-7-carboxylate

[0327] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (442 mg, 2.21 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (500 mg, 2.21 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (531 mg, 53 % yield) that was used in the next step without any further characterization.

[0328] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2-carboxamide

[0329] Synthesized by procedure 3B from tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate (508 mg, 1.1 mmol). The product as a trifluoroacetate salt was dissolved in DCM (30 mL) and NaHCCh solution (30 mL). A few drops of 2 N NaOH solution were added to finish raising the pH to 10. The aqueous layer was extracted with further DCM (2 x 20 mL) and EtOAc (2 x 20 mL). The combined organic extracts were dried over anh. Na2SO4, filtered, and concentrated under vacuum, yielding the desired deprotected amine as a white oil (394 mg, quantitative yield) that was used in the next step without any further purification or characterization.

[0330] Synthesis of 7-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2- carboxamide

[0331] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide (387 mg, 1.1 mmol) and benzaldehyde (291 mg, 2.7 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (300 mg, 62% yield), mp: 152-153 °C. IR (ATR) v: 638, 697, 712, 766, 842, 882, 908, 935, 973, 1054, 1113, 1177, 1271 , 1317, 1360, 1408, 1454, 1496, 1538, 1638, 2235, 2805, 2861 , 2933, 3084, 3235 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C24H25F3N4O+H]+; 443.2053; found, 443.2042.

[0332] Example 46: 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane- 2-carboxamide

[0333] Synthesis of tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-2,6- diazaspiro[ 3.4 ]octane-6-carboxylate

[0334] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (471 mg, 2.35 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (500 mg, 2.35 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a white solid (410 mg, 40% yield) that was used in the next step without any further characterization.

[0335] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-2, 6-diazaspiro[3.4]octane-2-carboxamide

[0336] Synthesized by procedure 3B from tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)- 2,6-diazaspiro[3.4]octane-6-carboxylate (382 mg, 0.87 mmol). The product as a trifluoroacetate salt was dissolved in DCM (30 mL) and NaHCCh solution (30 mL). A few drops of 2 N NaOH solution were added to finish raising the pH to 10. The aqueous layer was extracted with further DCM (2 x 20 mL) and EtOAc (2 x 20 mL). The combined organic extracts were dried over anh. Na2SO4, filtered, and concentrated under vacuum, yielding the desired deprotected amine as a yellow oil (223 mg, 76% yield) that was used in the next step without any further purification or characterization.

[0337] Synthesis of 6-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)-2, 6-diazaspiro[3.4]octane-2- carboxamide

[0338] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6- diazaspiro[3.4]octane-2-carboxamide (223 mg, 0.66 mmol) and benzaldehyde (175 mg, 1.65 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (171 mg, 61 % yield), mp: 176-177 °C. IR (ATR) v: 639 , 698, 746, 772, 847, 879, 923, 996, 1055, 1128, 1176, 1262, 1312, 1347, 1363, 1403, 1455, 1476, 1493, 1543, 1639, 2233, 2799, 2869, 2947, 3077, 3264 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C23H23F3N4O+H]+; 429.1897; found, 429.1889.

[0339] Example 47: 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane- 2-carboxamide

[0340] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (139 mg, 0.69 mmol) and 2-benzyl-2,7-diazaspiro[4.4]nonane (150 mg, 0.69 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (150 mg, 49 % yield), mp: 67-68 °C. IR (ATR) v: 637, 673, 700, 747, 847, 881 , 905, 1054, 1121 , 1168, 1261 , 1316, 1362, 1398, 1453, 1493, 1530, 1634, 2233, 2786, 2867, 2947, 3065, 3287 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C24H25F3N4O+H]+; 443.2053; found, 443.2045.

[0341] Example 48: (1 R,5S,6r)-3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3- azabicyclo[3.1.0]hexane-6-carboxamide

[0342] Synthesized by procedure 4 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (99 mg, 0.49 mmol) and (1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (107 mg, 0.49 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title urea as a beige solid (104 mg, 53 % yield), mp: 169-170 °C. IR (ATR) v: 671 , 698, 837, 860, 882, 929, 1042, 1056, 1109, 1141 , 1171 , 1201 , 1264, 1316, 1358, 1424, 1495, 1542, 1638, 2236, 2797, 2904, 3059, 3293 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H20F3N3O+H]+; 400.1631 ; found, 400.1621.

[0343] Example 49: 9-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3,9- diazaspiro[5.5]undecane-3-carboxamide

[0344] Synthesized by procedure 1 from -(aminomethyl)-3-(trifluoromethyl)benzonitrile (123 mg, 0.61 mmol) and 3-benzyl-3,9-diazaspiro[5.5]undecane (150 mg, 0.61 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a white solid (157 mg, 54%). mp: 103-104 °C. IR (ATR) v: 638, 675, 699, 741 , 796, 841 , 881 , 905, 1001 , 1052, 1123, 1166, 1261 , 1317, 1364, 1417, 1442, 1493, 1531 , 1626, 2233, 2761 , 2811 , 2842, 2922, 3053, 3313 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C26H29F3N4O+H]+; 471 .2366; found, 471.2369.

[0345] Example 50: 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2- carboxamide

[0346] Synthesis of tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-7- azaspiro[3.5]nonane-7-carboxylate Synthesized by procedure 4 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (186 mg, 0.93 mmol) and 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (250 mg, 0.93 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title amide as a yellow solid (248 mg, 59 % yield) that was used in the next step without any further characterization.

[0347] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2-carboxamide trifluoroacetate

[0348] Synthesized by procedure 3B from tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)- 7-azaspiro[3.5]nonane-7-carboxylate (216 mg, 0.48 mmol). The title amine was obtained as a yellow oil (quantitative yield).

[0349] Synthesis of 7-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2- carboxamide

[0350] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-7- azaspiro[3.5]nonane-2-carboxamide trifluoroacetate (227 mg, 0.49 mmol) and benzaldehyde (130 mg, 1.22 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title amide as a colourless oil. The product precipitated as a white solid after treatment with pentane / DCM (127 mg, 59 % yield), mp: 100-101 °C. IR (ATR) v: 639, 670, 696, 733, 799, 844, 882, 929, 983, 1057, 1117, 1139, 1170, 1219, 1258, 1293, 1318, 1348, 1365, 1421 , 1452, 1494, 1544, 1645, 2235, 2755, 2798, 2917, 3071 , 3260 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C25H26F3N3O+H]+; 442.2101 ; found, 442.2109.

[0351] Example 51 : 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1- carboxamide

[0352] Synthesis of tert-butyl 1-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-6- azaspiro[2.5]octane-6-carboxylate

[0353] Synthesized by procedure 4 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (235 mg, 1.17 mmol) and 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1 -carboxylic acid (300 mg, 1.17 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title amide as a white solid (303 mg, 59 % yield) that was used in the next step without any further characterization.

[0354] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1 -carboxamide trifluoroacetate

[0355] Synthesized by procedure 3B from tert-butyl 1-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)- 6-azaspiro[2.5]octane-6-carboxylate (286 mg, 0.65 mmol). The title amine was obtained as a yellow oil (quantitative yield). Synthesis of 6-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1- carboxamide

[0356] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-

[0357] 1 -carboxamide trifluoroacetate (351 mg, 0.78 mmol) and benzaldehyde (206 mg, 1.95 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title amide as a yellowish oil. The product precipitated as a white solid after treatment with pentane / DCM (135 mg, 41 % yield), mp: 133-134 °C. IR (ATR) v: 638, 671 , 696, 742, 799, 834, 850, 880, 927, 941 , 989, 1058, 1101 , 1142, 1180, 1208, 1238, 1278, 1297, 1320, 1363, 1421 , 1453, 1494, 1545, 1646, 2238, 2801 , 2930, 3084, 3285 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C24H24F3N3O+H]+; 428.1944; found, 428.1950.

[0358] Example 52: 2-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8- carboxamide hydrochloride

[0359] Synthesis of tert-butyl 8-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-2- azaspiro[4.5]decane-2-carboxylate

[0360] Synthesized by procedure 4 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (177 mg, 0.88 mmol) and 2-(tert-butoxycarbonyl)-2-azaspiro[4.5]decane-8-carboxylic acid (250 mg, 0.88 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title amide as a white solid (208 mg, 51 % yield) that was used in the next step without any further characterization.

[0361] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8-carboxamide hydrochloride

[0362] Synthesized by procedure 3A from tert-butyl 8-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-

[0363] 2-azaspiro[4.5]decane-2-carboxylate (188 mg, 0.4 mmol). The title amine was obtained as a white solid (167 mg, quantitative yield).

[0364] Synthesis of 2-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8- carboxamide hydrochloride

[0365] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-2- azaspiro[4.5]decane-8-carboxamide hydrochloride (142 mg, 0.35 mmol) and benzaldehyde (93 mg, 0.88 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title amide as a colourless oil (48 mg, 30 % yield). Its hydrochloride salt was obtained as a white solid by adding 1 mL of HCI in Et2O and evaporating the excess of acid, mp: 80-81 °C. IR (ATR) v: 638, 673, 701 , 757, 844, 882, 905, 1053, 1122, 1167, 1263, 1317, 1418, 1498, 1455, 1537, 1651 , 2234, 2507, 2602, 2854, 2927, 3040, 3251 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C26H28F3N3O+H]+; 456.2257; found, 456.2264. Example 53: 3-benzyl-A / -(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9- carboxamide

[0366] Synthesis of tert-butyl 9-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-3- azaspiro[5.5]undecane-3-carboxylate

[0367] Synthesized by procedure 4 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (183 mg, 0.91 mmol) and 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (272 mg, 0.91 mmol). Column chromatography purification (SiO2, Hexane / EtOAc mixtures) yielded the title amide as a yellowish solid (255 mg, 58 % yield) that was used in the next step without any further characterization.

[0368] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride

[0369] Synthesized by procedure 3A from tert-butyl 9-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)- 3-azaspiro[5.5]undecane-3-carboxylate (232 mg, 0.48 mmol). The title amine was obtained as a white solid (200 mg, quantitative yield).

[0370] Synthesis of 3-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9- carboxamide

[0371] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-2- azaspiro[4.5]decane-8-carboxamide hydrochloride (190 mg, 0.46 mmol) and benzaldehyde (121 mg, 1.14 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title amide as a white solid (139 mg, 59 % yield), mp: 79-80 °C. IR (ATR) v: 638, 673, 699, 740, 795, 822, 881 , 906, 996, 1053, 1123, , 1168, 1263, 1317, 1368, 1418, 1450, 1494, 1534, 1650, 2234, 2768, 2805, 2925, 3053, 3287 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C27H30F3N3O+H]+; 470.2414; found, 470.1427.

[0372] Example 54: 6-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide

[0373] Synthesized by procedure 1 from (3-chloro-5-(trifluoromethyl)phenyl)methanamine (200 mg, 0.95 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (249 mg, 0.95 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title urea as a colourless oil. The product precipitated as a white solid after treatment with pentane / DCM (189 mg, 47% yield), mp: 134-135 °C. IR (ATR) v: 622, 698, 727, 761 , 776, 823 869, 895, 911 , 999, 1043, 1060, 1102, 1124, 1167, 1207, 1250, 1332, 1354, 1390, 1419, 1444, 1454, 1496, 1534, 1589, 1638, 2820, 2880, 2942, 3066, 3287 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH2ICIF3N3O+H]+; 424.1398; found, 424.1397. Example 55: A / -(4-cyano-2-(trifluoromethyl)benzyl)-6-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide

[0374] Synthesis of tert-butyl 6-(thiophen-3-ylmethyl)-2, 6-diazaspiro[3.3]heptane-2-carboxylate

[0375] Synthesized by procedure 2 from tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 2.02 mmol) and thiophene-3-carbaldehyde (565 mg, 565 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title compound as a yellow oil (485 mg, 82 % yield) that was used in the next step without any further characterization.

[0376] Synthesis of 2-(thiophen-3-ylmethyl)-2, 6-diazaspiro[3.3]heptane

[0377] Synthesized by procedure 3B from tert-butyl 6-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (443 mg, 1.50 mmol). The product as a trifluoroacetate salt was dissolved in DCM (30 mL) and NaHCO3solution (30 mL). A few drops of 2 N NaOH solution were added to finish raising the pH to 10. The aqueous layer was extracted with further DCM (2 x 20 mL) and EtOAc (2 x 20 mL). The combined organic extracts were dried over anh. Na2SC>4, filtered, and concentrated under vacuum, yielding the desired deprotected amine as a brown oil (245 mg, 84% yield) that was used in the next step without any further purification or characterization.

[0378] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-6-(thiophen-3-ylmethyl)-2, 6- diazaspiro[3.3]heptane-2-carboxamide

[0379] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (234 mg, 1.17 mmol) and 2-(thiophen-3-ylmethyl)-2,6-diazaspiro[3.3]heptane (227 mg, 1.17 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by Cis, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (45 mg, 9% yield), mp: 178-179 °C. IR (ATR) v: 638, 689, 712, 739, 763, 842, 883, 935, 970, 989, 1054, 1112, 1173, 1273, 1319, 1359, 1409, 1458, 1535, 1639, 2234, 2811 , 2866, 2940, 3082, 3235 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2oHi9F3N4OS+H]+; 421.1304; found, 421.1300.

[0380] Example 56: 6-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide

[0381] Synthesized by procedure 1 from (4-chloro-3-(trifluoromethyl)phenyl)methanamine (200 mg, 0.95 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (249 mg, 0.95 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by C18, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (120 mg, 30 % yield), mp: 144-145 °C. IR (ATR) v: 682, 696, 726, 761 , 793, 839, 890, 997, 1050, 1121 , 1159, 1176, 1272, 1303, 1329, 1360, 1401 , 1453,1484, 1540, 1638, 2808, 2869, 2941 , 3083, 3263 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH2ICIF3N3O+H]+; 424.1398; found, 424.1397. Example 57: 6-benzyl-A / -(4-chloro-2-(trifluoromethoxy)benzyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide

[0382] Synthesized by procedure 1 from (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (200 mg, 0.89 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (231 mg, 0.89 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by Cis, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (156 mg, 40 % yield), mp: 129-130 °C. IR (ATR) v: 640, 659, 696, 727, 758, 791 , 822, 850, 873, 905, 946, 1000, 1028, 1083, 1159, 1212, 1251 , 1329, 1358, 1400, 1418, 1454, 1486, 1553, 1630, 2819, 2868, 2937, 3065, 3249 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH2iCIF3N3O2+H]+; 440.1347; found, 440.1347.

[0383] Example 58: 6-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane- 2-carboxamide

[0384] Synthesized by procedure 1 from (4-fluoro-2-(trifluoromethyl)phenyl)methanamine (200 mg, 1.03 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (270 mg, 1.03 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by C18, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (85 mg, 20 % yield), mp: 119-120 °C. IR (ATR) v: 616, 665, 696, 717, 761 , 826, 857, 874, 889, 906, 987, 1046, 1116, 1164, 1212, 1282, 1312, 1358, 1407, 1433, 1461 , 1498, 1544, 1606, 1637, 2817, 2869, 2943, 3065, 3231 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH2IF4N3O+H]+; 408.1694; found, 408.1693.

[0385] Example 59: 6-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide

[0386] Synthesized by procedure 1 from (4-fluoro-2-(trifluoromethoxy)phenyl)methanamine (200 mg, 0.96 mmol) and 2-benzyl-2,6-diazaspiro[3.3]heptane dihydrochloride (250 mg, 0.96 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by C18, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (215 mg, 53 % yield), mp: 81-82 °C. IR (ATR) v: 642, 697, 730, 760, 773, 819, 861 , 887, 948, 980, 1008, 1038, 1091 , 1144, 1160, 1183, 1209, 1231 , 1242, 1257, 1322, 1353, 1377, 1440, 1504, 1553, 1603, 1628, 2783, 2882, 2941 , 3083, 3298, 3481 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2IH2IF4N3O2+H]+; 424.1643; found, 424.1643.

[0387] Example 60: 7-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane- 2-carboxamide

[0388] Synthesis of tert-butyl 2-((4-chloro-3-(trifluoromethyl)benzyl)carbamoyl)-2, 7- diazaspiro[3.5]nonane-7-carboxylate Synthesized by procedure 1 from (4-chloro-3-(trifluoromethyl)phenyl)methanamine (400 mg, 1.91 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (432 mg, 1.91 mmol). Column chromatography purification (SiO2, Hexane / Ethyl Acetate mixtures) yielded the title urea as a white solid (285 mg, 32 % yield) that was used in the next step without any further characterization.

[0389] Synthesis of N-(4-chloro-3-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate

[0390] Synthesized by procedure 3B from tert-butyl 2-((4-chloro-3-(trifluoromethyl)benzyl)carbamoyl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate (253 mg, 0.55 mmol). The title amine was obtained as a yellow oil (quantitative yield).

[0391] Synthesis of 7-benzyl-N-(4-chloro-3-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2- carboxamide

[0392] Synthesized by procedure 2 from / V-(4-chloro-3-(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate (312 mg, 0.66 mmol) and benzaldehyde (173 mg, 1.64 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by Cis, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (58 mg, 20 % yield), mp: 65-66 °C. IR (ATR) v: 661 , 698, 739, 828, 910, 976, 1034, 1127, 1169, 1207, 1262, 1316, 1343, 1393, 1423, 1478, 1534, 1637, 2761 , 2799, 2861 , 2928, 3059, 3279 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C23H25CIF3N3O+H]+; 452.1711 ; found, 452.1707.

[0393] Example 61 : 7-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane- 2-carboxamide

[0394] Synthesis of tert-butyl 2-((3-chloro-5-(trifluoromethyl)benzyl)carbamoyl)-2, 7- diazaspiro[3.5]nonane-7-carboxylate

[0395] Synthesized by procedure 1 from (3-chloro-5-(trifluoromethyl)phenyl)methanamine (400 mg, 1.91 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (432 mg, 1.91 mmol). Column chromatography purification (SiO2, Hexane / Ethyl Acetate mixtures) yielded the title urea as a yellowish solid (559 mg, 63 % yield) that was used in the next step without any further characterization.

[0396] Synthesis of N-(3-chloro-5-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate

[0397] Synthesized by procedure 3B from tert-butyl 2-((3-chloro-5-(trifluoromethyl)benzyl)carbamoyl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate (536 mg, 1.16 mmol). The title amine was obtained as a yellow oil (quantitative yield). Synthesis of 7-benzyl-N-(3-chloro-5-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2- carboxamide

[0398] Synthesized by procedure 2 from / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate (544 mg, 1.14 mmol) and benzaldehyde (303 mg, 2.85 mmol). Purification by a first column chromatography (SiO2, DCM / MeOH mixtures) followed by a reversed-phase chromatography (Cis, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (28 mg, 5 % yield), mp: 153-154 °C. IR (ATR) v: 697, 737, 764, 799, 824, 874, 907, 976, 996, 1029, 1101 , 1124, 1167, 1204, 1321 , 1344, 1396, 1445, 1478, 1532, 1590, 1635, 2755, 2801 , 2867, 2927, 3064, 3283 cm’1. HRMS-ESF m / z [M+H]+: calcd for [C23H25CIF3N3O+H]+; 452.1711 ; found, 452.1708.

[0399] Example 62: 7-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane- 2-carboxamide

[0400] Synthesis of tert-butyl 2-((4-chloro-2-(trifluoromethyl)benzyl)carbamoyl)-2, 7- diazaspiro[3.5]nonane-7-carboxylate

[0401] Synthesized by procedure 1 from (4-chloro-2-(trifluoromethyl)phenyl)methanamine (400 mg, 1.91 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (432 mg, 1.91 mmol). Column chromatography purification (SiO2, Hexane / Ethyl Acetate mixtures) yielded the title urea as a white solid (294 mg, 33 % yield) that was used in the next step without any further characterization.

[0402] Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate

[0403] Synthesized by procedure 3B from tert-butyl 2-((4-chloro-2-(trifluoromethyl)benzyl)carbamoyl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate (254 mg, 0.55 mmol). The title amine was obtained as a yellow oil (quantitative yield).

[0404] Synthesis of 7-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)-2, 7-diazaspiro[3.5]nonane-2- carboxamide

[0405] Synthesized by procedure 2 from / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate (321 mg, 0.67 mmol) and benzaldehyde (179 mg, 1.68 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title compound as a white solid (120 mg, 39 % yield), mp: 113-114 °C. IR (ATR) v: 617, 681 , 701 , 746, 773, 797, 837, 899, 975, 998, 1047, 1078, 1124, 1161 , 1183, 1211 , 1261 , 1304, 1352, 1394, 1422, 1482, 1548, 1636, 2757, 2803, 2869, 2926, 3078, 3240 cm’1. HRMS- ESF m / z [M+H]+: calcd for [C23H25CIF3N3O+H]+; 452.1711 ; found, 452.1708. Example 63: 7-benzyl-A / -(4-chloro-2-(trifluoromethoxy)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide

[0406] Synthesis of tert-butyl 2-((4-chloro-2-(trifluoromethoxy)benzyl)carbamoyl)-2, 7- diazaspiro[3.5]nonane-7-carboxylate

[0407] Synthesized by procedure 1 from (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (400 mg, 1.77 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (401 mg, 1.77 mmol). Column chromatography purification (SiO2, Hexane / Ethyl Acetate mixtures) yielded the title urea as a white solid (355 mg, 42 % yield) that was used in the next step without any further characterization.

[0408] Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-2, 7-diazaspiro[3.5]nonane-2- carboxamide tri fluoroacetate

[0409] Synthesized by procedure 3B from tert-butyl 2-((4-chloro-2- (trifluoromethoxy)benzyl)carbamoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (326 mg, 0.68 mmol). The title amine was obtained as a yellow oil (quantitative yield).

[0410] Synthesis of 7-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)-2, 7-diazaspiro[3.5]nonane-2- carboxamide

[0411] Synthesized by procedure 2 from / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate (347 mg, 0.71 mmol) and benzaldehyde (187 mg, 1.77 mmol). Double purification by column chromatography (SiO2, DCM / MeOH mixtures; followed by Cis, H2O / ACN with 0.05 % formic acid), yielded the title urea as a white solid (85 mg, 26 % yield), mp: 136-137 °C. IR (ATR) v: 639, 697, 736, 799, 821 , 852, 947, 976, 1029, 1090, 1164, 1210, 1248, 1346, 1392, 1480, 1538, 1639, 2762, 2801 , 2867, 2927, 3063, 3283 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C23H25CIF3N3O2+H]+; 468.1660; found, 468.1658.

[0412] Example 64: A / -(4-cyano-2-(trifluoromethyl)benzyl)-7-(thiophen-3-ylmethyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide

[0413] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide trifluoroacetate (344 mg, 0.74 mmol) and thiophene-3- carbaldehyde (207 mg, 1.85 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title compound as a white solid (120 mg, 36 % yield), mp: 155-156 °C. IR (ATR) v: 638, 673, 769, 803, 835, 857, 881 , 915, 977, 998, 1054, 1128, 1162, 1178, 1214, 1264, 1316, 1362, 1418, 1477, 1494, 1539, 1639, 2235, 2779, 2869, 2937, 3077, 3286 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C22H23F3N4OS+H]+; 449.1617; found, 449.1613. Example 65: A / -(4-cyano-2-(trifluoromethyl)benzyl)-2-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.4]octane-6-carboxamide

[0414] Synthesis of tert-butyl 6-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)-2,6- diazaspiro[ 3.4 ]octane-2-carboxylate

[0415] Synthesized by procedure 1 from 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (400 mg, 2.00 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (424 mg, 2.00 mmol). Column chromatography purification (SiO2, Hexane / Ethyl Acetate mixtures) yielded the title urea as a white solid (243 mg, 28 % yield) that was used in the next step without any further characterization.

[0416] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-6-carboxamide trifluoroacetate

[0417] Synthesized by procedure 3B from tert-butyl 6-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)- 2,6-diazaspiro[3.4]octane-2-carboxylate (208 mg, 0.47 mmol). The title amine was obtained as a yellow oil (quantitative yield).

[0418] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-2-(thiophen-3-ylmethyl)-2, 6- diazaspiro[ 3.4 ]octane-6-carboxamide

[0419] Synthesized by procedure 2 from / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6- diazaspiro[3.4]octane-6-carboxamide trifluoroacetate (254 mg, 0.56 mmol) and thiophene-3- carbaldehyde (157 mg, 1.4 mmol). Column chromatography purification (SiO2, DCM / MeOH mixtures) yielded the title compound as a white solid (85 mg, 35 % yield), mp: 167-168 °C. IR (ATR) v: 625, 671 , 707, 748, 773, 800, 817, 832, 858, 879, 896, 931 , 970, 996, 1055, 1117, 1155, 1174, 1230, 1265, 1313, 1340, 1366, 1399, 1417, 1470, 1493, 1538, 1636, 2234, 2830, 2866, 2933, 3079, 3321 cm’1. HRMS-ESI+m / z [M+H]+: calcd for [C2iH2iF3N4OS+H]+; 435.1461 ; found, 435.1461.

[0420] IN VITRO TESTS OF THE COMPOUNDS OF THE INVENTION

[0421] Determination of Ki value of S1 R antagonists

[0422] The binding properties of the test compounds to human S1 R were studied in transfected HEK- 293 membranes using [3H]-(+)-pentazocine (PerkinElmer, NET-1056) as the radioligand. The assay was carried out with 7 pg of membrane suspension, [3H]-(+)-pentazocine (5 nM) in either absence or presence of either buffer or 10 pM haloperidol for total and nonspecific binding, respectively. Binding buffer contained Tris-HCI (50 mM, at pH 8). Plates were incubated at 37 °C for 120 min. After the incubation period, the reaction mix was transferred to MultiScreen HTS, FC plates (Millipore) which had been presoaked in 0.1 % polyethylenimine and filtered. Then, plates were washed (3 times) with ice-cold Tris-HCI (10 mM, pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (PerkinElmer) using EcoScint liquid scintillation cocktail.

[0423] Determination of IC50 value of sEHIs

[0424] The sEH inhibition activity (IC50) can be determined by the following fluorescent assay with a purified recombinant human sEH protein using cyano(6-methoxynaphthalen-2-yl)methyl 2-(3- phenyloxiran-2-yl)methylcarbonate as the substrate (cf. Morisseau, C.; Hammock, B. D. Measurement of soluble epoxide hydrolase (sEH) activity. Curr Protoc Toxicol. 2007, Chapter 4, Unit 4.23.).

[0425] The enzyme is incubated at 30 °C with the inhibitor ([l]final = 0.4 - 100,000 nM) for 5 min in 100 mM sodium phosphate buffer (200 pL, pH 7.4) containing 0.1 mg / mL BSA and 1% DMSO. The substrate (CMNPC) is then added ([S]final = 5 pM). Activity is assessed by measuring the appearance of the fluorescent 6-methoxynaphthaldehyde product (Aex= 330 nm, Aem= 465 nm) every 30 seconds for 10 min at 30 °C on a SpectraMax M2 (Molecular Devices).

[0426] Results are obtained by regression analysis from a linear region of the curve.

[0427] Table 1 below summarizes the obtained results for the tested compounds:

[0428] TABLE 1

[0429] Results regarding sEH:

[0430] The following scale has been adopted for representing the inhibition of human sEH expressed as IC50: A IC50 (sEH) < 10 nM;

[0431] B 10 < IC50 (sEH) < 50 nM;

[0432] C 50 < IC50 (sEH) < 100 nM;

[0433] D 100 < IC50 (sEH) < 1000 nM;

[0434] E IC50 (sEH) > 1000 nM;

[0435] Results regarding S1R:

[0436] The following scale has been adopted for representing the binding to S1R expressed as K\.

[0437] A Ki (S1R) < 50 nM;

[0438] B 50 < K (S1R) < 150 nM; C 150 < K (S1R) < 400 nM;

[0439] D 400 < K (S1R) < 1000 nM;

[0440] E K (S1R) > 1000 nM. In the case of sEH, it is considered that the compound has negligible inhibitory effect when the IC50 value is higher than 1000 nM. IC50 values between 100-1000 nM indicate that the compound has a low / very low potency for the inhibitory effect. A significant inhibitory effect is considered when the IC50 is below 100 nM; it is considered especially good when the IC50 value is below 50 nM and excellent when IC50 is below 10 nM.

[0441] As it can be derived from Table 1 , all the compounds of the invention have IC50 values below 100 nM, providing, at least, a significant inhibitory effect of sEH.

[0442] It is well-established that a compound has a negligible affinity for S1 R when the Ki value is higher than 1000 nM. When the K value is between 400 and 1000 nM means that the compound has a low affinity. A K value between 150-400 nM means that the compound has a significant affinity for S1 R. K values between 50-150 nM mean that the compounds have high affinity for the receptor and a K below 50 nM means that the compound has a very high affinity.

[0443] As it can be derived from Table 1 , all the evaluated compounds of the invention have K values below 400 nM, providing, at least, a significant binding effect of the S1 R.

[0444] The comparative compounds provided at the end of the table are sEHIs with no significant binding to S1 R (EC5026, AR9281) and S1 R ligands (S1 RA, BMY-14802, dextromethorphan, NE-100, BD-1063, PRE-084) inactive in sEH. In fact, compound 9 from table 1 of W02007133481 A2 shows a Ki > 10 pM.

[0445] Assessment of the antagonist character of the compounds in the S1 R

[0446] In order to confirm that the effect of the compounds on S1 R was an antagonistic effect, the following assay was performed.

[0447] The assay is a nanoluciferase binary technology test based on the ability of S1 R to heteromerize with the binding immunoglobulin protein (BiP) in living cells (cf. Morato et al., ACS Chem Neurosci., 2023, 14(11):2201-2207). The S1 R-BiP heterodimerization biosensor allows for rapid and accurate identification of S1 R ligands by monitoring the dynamics of association-dissociation of S1 R and BiP. Acute treatment of cells with the S1 R agonist PRE- 084 produced rapid and transient dissociation of the S1 R-BiP heterodimer, which was blocked by haloperidol, a S1 R antagonist. The effect of PRE-084 was enhanced by calcium depletion, leading to a higher reduction in heterodimerization even in the presence of haloperidol. Prolonged incubation of cells with S1 R antagonists (e.g., haloperidol, NE-100, BD-1047) increased the formation of S1 R-BiP heteromers, while agonists (e.g., PRE-084) did not alter heterodimerization under the same experimental conditions (see Morato et al., ACS Chem Neurosci., 2023, 14(11):2201-2207 for details). Drugs S1 R antagonist haloperidol (Halo) and S1 R agonist PRE-084 (PRE) were purchased from Sigma-Aldrich (St. Louis, MO, USA). A 10 mM stock solution of each ligand was prepared in DMSO and stored at -20 °C.

[0448] S1 R-BiP Association . The association between S1 R and BiP has been used in the past to identify the functional profile of S1 R ligands through a commercial coimmunoprecipitation- coupled enzyme-linked immunosorbent assay (ELISA) (Malik et al. Br J Pharmacol., 2015, 172(10):2519-2531). In summary, CHO cells that grow in MEM / Alpha culture medium supplemented with 2 mM Glutamax and 10% (v / v) FBS were treated with the indicated S1 R ligands for 30 min at 37 °C. Subsequently, cells were treated with cross-linker dithiobis(succinimidyl propionate) (50 μg / mL) before solubilization and coimmunoprecipitation using rabbit anti-S1 R (Abeam, Cambridge, U.K.). The coimmunoprecipitates were analyzed by ELISA as described by the manufacturer.

[0449] NanoBiT Assay. HEK-293s1R KO-S1 RLgBiT-BIPSmBiTcells were transferred to a white 96-well plate (Corning 96-well, cell culture-treated, flat-bottom microplate) at a density of 90.000 cells / cm2. The cells were incubated with the S1 R ligands (10 pM) during 16 h before the S1 R- BiP heterodimerization was determined after incubation with 10 μL of a 10 μM coelenterazine 400a solution (NanoLight Technologies, Pinetop, AZ, USA) was added to each well. After 15 min of incubation luminescence was recorded using a CLARIOstar Optima plate reader (BMG Labtech GmbH, Ortenberg, Germany) and the output luminescence was reported as integrated relative luminescence units (RLU).

[0450] The results are provided in FIG. 1. and show that the compounds of the invention present antagonism towards S1 R.

[0451] IN VIVO TESTS OF THE COMPOUNDS OF THE INVENTION

[0452] In the following section, the different experimental set-ups for carrying out the assays will be described, including the drugs used as well as the experimental models used to assess the analgesic effects in mice.

[0453] Test 1 : evaluation of tactile allodynia in an experimental pain model in mice

[0454] Animals

[0455] Female CD1 mice (Envigo) were used in the experiments. Mice weighing 24-30 g were tested randomly throughout the estrous cycle. They were housed in colony cages with free access to food and water prior to the experiments, and were maintained in temperature- and light- controlled rooms (22 ± 2 °C, lights on at 08:00 h and off at 20:00 h). The experiments were performed during the light phase (from 9:00 h to 16:00 h). Animal care was provided in accordance with institutional (Research Ethics Committee of the University of Granada, Granada, Spain), regional (Junta de Andalucia, Spain) and international standards (European Communities Council directive 2010 / 63).

[0456] Drugs and drug administration

[0457] The compounds of Example 1 , 28, and 32 above were used as a prototypic dual S1 R antagonist / sEHI.

[0458] To reverse the effect of S1 R antagonism, the S1 R agonist PRE-084 (2-[4-morpholinethyl]-1- phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China) was used. This compound is considered to be a selective S1 R agonist (cf. Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66; Ruiz-Cantero et al., Pharmacol Res. 2021 , 163:105339).

[0459] MS-PPOH ( / V-(methylsulfonyl)-2-(2-propynyloxy)benzenehexanamide) (Cayman Chemicals, Ann Arbor, Michigan, USA), a selective inhibitor of CYP450 epoxygenase which leads to the production of epoxyeicosatrienoic acids (EETs) (cf. Wang et al., J Pharmacol Exp Then, 1998, 284:966-973) was used to reverse the effect of sEH inhibition.

[0460] PRE-084 was dissolved in sterile physiological saline, and Compounds of Example 1 , 28, and 32 were dissolved in 1% Tween-80 in physiological saline. MS-PPOH was dissolved in a solution containing 5% DMSO in 40% (2-hydroxypropyl)-p-cyclodextrin in ultrapure water. All drugs were prepared just before administration, and injected subcutaneously (s.c.) in the interscapular area in an injection volume of 5 mL / kg. Compounds of example 1 , 28, and 32 were administered 45 min before the behavioral evaluation. PRE-084 or MS-PPOH were administered 5 min before the administration of compounds of examples 1 , 28, and 32 (50 min before the behavioral evaluation). Experimental model of tactile allodynia in mice and results

[0461] The effects of COMPOUNDS OF EXAMPLES 1 , 28, AND 32 were tested on capsaicin-induced secondary tactile hypersensitivity, which is developed in the area surrounding capsaicin injection and it is known to result from central sensitization, a feature of pathological pain (cf. Baron R, Lancet, 2000, 356:785-7).

[0462] The procedure for assessing tactile allodynia was performed as previously described (cf. Entrena et al., Pain, 2009, 143(3):252-261). Briefly, animals were placed into individual test compartments for 2 h to habituate them to the test conditions. The test compartments had black walls and were situated on an elevated mesh-bottomed platform with a 0.5 cm2grid to provide access to the ventral surface of the hind paws. Then, animals were carefully removed from the compartment to be s.c. injected with the drugs to be tested (see section above), and returned to the compartment. 30 min after drug injection, mice were removed from the compartment again to be injected intraplantarly (i.pl.) with 20 pL of a solution containing 1 pg capsaicin (Sigma-Aldrich Quimica S.A., Madrid, Spain) or its solvent (1% DMSO in physiological saline). Injection was performed into the right hind paw, proximate to the heel, using a 1710 TLL Hamilton microsyringe (Teknokroma, Barcelona, Spain) with a 301 / 2-gauge needle. Immediately after the i.pl. administration, mice were returned to the compartment. Punctate mechanical stimulation was applied with a Dynamic Plantar Aesthesiometer (Ugo Basile, Varese, Italy) at 15 min after the administration of capsaicin or its solvent. A nonflexible filament (0.5 mm diameter) was electronically driven into the ventral side of the right hind paw, at least 5 mm away from the site of the injection towards the fingers. The intensity of the stimulation was fixed at 0.5 g force. When a paw withdrawal response occurred, the stimulus was automatically terminated, and the response latency was automatically recorded. The filament was applied three times, separated by intervals of 0.5 min, and the mean value of the three trials was considered the withdrawal latency time of the animal. A cut-off time of 50 s was used.

[0463] As shown in Fig. 2, 3, and 4, capsaicin administration induced a marked decrease in the paw withdrawal latency in comparison to control nonsensitized mice (dashed lines), denoting the presence of tactile allodynia (compare the point at the 0 mg / kg dose with the dashed lines from nonsensitized control mice value). The administration of COMPOUNDS OF EXAMPLE 1 (2.5- 10 mg / kg, s.c.), 28 (1.25-5 mg / kg, s.c.), and 32 (1.25-5 mg / kg, s.c.) dose-dependently increased the paw withdrawal latency, indicating that these compounds are able to induce marked antiallodynic effects. The s.c. treatment with a dose of 10 mg / kg of COMPOUND OF EXAMPLE 1 was enough to induce a prominent increase in paw withdrawal latency in capsaicin-treated mice (59.05% antiallodynic effect) (Fig. 2). Also, the s.c. treatment with a dose of 5 mg / kg of COMPOUND OF EXAMPLE 28 or 32 was enough to induce a prominent increase in paw withdrawal latency in capsaicin-treated mice (84.38% and 84.15% antiallodynic effect, respectively) (Fig. 3 and 4). The administration of either PRE-084 (32 mg / kg, s.c.) or MS-PPOH (20 mg / kg, s.c.) was able to fully reverse this antiallodynic effect induced by COMPOUNDS OF EXAMPLES 1 , 28, and 32 (Fig. 5). These data indicate that both S1R antagonism and EET accumulation (due to the inhibition of sEH) participate in the antiallodynic effect observed, and therefore COMPOUNDS OF EXAMPLES 1, 28, and 32 induce their in vivo effects on capsaicin-induced tactile allodynia through the interaction of both intended pharmacological targets.

Claims

CLAIMS1. A compound of formula (I):(I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention in an animal, including a human, of pain, wherein:Ri is selected from the group consisting of: H, CF3, OCF3, and OCH3;R2to R4are the same or different and are independently selected from the group consisting of: H; CN; halogen; -OCH3; OCF3; CF3; and SF5.Rs is an aromatic ring system, which is selected from the group consisting of: a) an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRX, and N; Rxbeing selected from the group consisting of: H; OH; CN; halogen; (Ci-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; (Ci-C10)alkyl substituted with one or more Sui; (C2-C10)alkenyl substituted with one or more SU2; (C2-C10)alkynyl substituted with one or more SU3; -O-(Ci-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2Rs; NR?Rs; CONRgR’g; and COOR10; b) an aromatic 5-membered ring system, wherein the members are selected from the group consisting of: CRy, S, N, NH, and O; Rybeing selected from the group consisting of: H; OH; CN; halogen; (Ci-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(Ci-C10)haloalkyl; SF5; S(0)2Rn; NR12R13; CONRi4R’i4; and COOR10; c) an aromatic fused ring system consisting of two rings, each one of the aromatic rings having 6 members selected from the group consisting of: CRZand N; Rzbeing selected from the group consisting of: H; OH; CN; halogen; (Ci-C10)haloalkyl; -0-(C1-C10)alkyl; -0-(C1-C10)haloalkyl; SF5; S(O)2RIS; NRieRi?; CONRi8R’i8; and COOR10; and d) an aromatic fused ring system consisting of two rings, one of the aromatic rings having 6 members selected from CH or N, and the other aromatic ring having 5 members selected from the group consisting of: CRZ, S, N, NH, and O; Rzbeing selected from the group consisting of: H; OH; CN; halogen; (Ci-C10)haloalkyl; -0-(C1-C10)alkyl; -O-(Ci-C10)haloalkyl; SF5; S(O)2Rig; NR20R21; CONR22R 22; and COOR10Re, R11, Ris and R19 are selected from the group consisting of: (Ci-C10)alkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;R7 and Rs are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R23;R9 and R’9 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;R10 is selected from the group consisting of: -H, (Ci-C10)alkyl; (Ci-C10)haloalkyl; (C3- Cs)cycloalkyl;R12 and R13 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; and -S(O)2R24;R14 and R’14 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;R16 and R17 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (C3-C8)cycloalkyl; (Ci-C10)haloalkyl; and -S(O)2R2s;Ris and R’18 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;R20 and R21 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (C3-C8)cycloalkyl; (Ci-C10)haloalkyl; and -S(O)2R2s;R22 and R’22 are the same or different and are selected from the group consisting of: -H, (C1- C10)alkyl; (Ci-C10)haloalkyl; (C3-C8)cycloalkyl; aryl; and heteroaryl;R23 to R25 are selected from the group consisting of (Ci-C10)alkyl; (C3-C8)cycloalkyl; (C1- C10)haloalkyl; aryl; and heteroaryl;Sui to Su3are independently selected from the group consisting of: halogen, cyano, nitro, (C1- Ce)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1- Ce)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, / \ / -(Ci- C4)alkylcarbamoyl, / V, / V-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, / V-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, / V-(C1-C4)alkylsulfamoyl, and / V, / V-di-(C1-C4)alkylsulfamoyl. n is an integer value selected from 1 or 2;A is selected from the group consisting of:5 with the proviso that at least two of Ri to R4 are other than hydrogen.

2. The compound for use according to claim 1 , wherein A is selected from the group consisting of:

3. The compound for use according to claim 1, wherein A is selected from the group consisting of:

4. The compound for use according to claim 1, wherein A is selected from the group consisting of:

5. The compound for use according to claim 1, wherein A is selected from the group consisting of:

6. The compound for use according to any one of claims 1 to 5, wherein Ri is selected from the group consisting of: H, CF3 and OCF3, and R2 to R4 are the same or different and are independently selected from the group consisting of: H; CN; F, Cl, Br; -OCH3; -OCF3; and -CF3.

7. The compound for use according to any one of claims 1 to 6, wherein R1 is selected from the group consisting of CF3 and OCF3.

8. The compound for use according to claim 7, wherein R2, and R4 are H, and R3 is other than H.

9. The compound for use according to any one of claims 1 to 8, wherein n = 1 .

10. The compound for use according to any one of claims 1 to 9, wherein the compound is selected from any one of the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 4-benzyl- / V-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide f) 4-benzyl- / V-(4-methoxy-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide g) 4-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide h) 4-benzyl- / V-(2-methoxy-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide i) 4-benzyl- / V-(4-methoxy-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride j) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)piperazine-1 -carboxamide k) 4-benzyl- / V-(4-cyano-2-methoxybenzyl)piperazine-1 -carboxamide l) 4-benzyl- / V-(4-iodo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide hydrochloride m) 4-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide n) 4-benzyl- / V-(4-fluoro-2-methoxybenzyl)piperazine-1 -carboxamide o) 4-benzyl- / V-(4-cyano-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide p) 4-benzyl- / V-(4-chloro-2-methoxybenzyl)piperazine-1 -carboxamide q) 4-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamider) 4-benzyl- / V-(2-methoxy-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide s) 4-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)piperazine-1 -carboxamide t) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-fluorobenzyl)piperazine-1 -carboxamide u) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide v) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(2,4-dichlorobenzyl)piperazine-1 -carboxamide w) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-3-ylmethyl)piperazine-1- carboxamide x) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(naphthalen-2-ylmethyl)piperazine-1- carboxamide y) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-iodobenzyl)piperazine-1 -carboxamide z) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-phenethylpiperazine-1 -carboxamide aa) (3a / ?,6aS)-5-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl) hexahydropyrrolo[3,4-c]pyrrole- 2(1 / - / )-carboxamide bb) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide cc) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride dd) (4aS,7aS)-6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)octahydro-1 / 7-pyrrolo[3,4-£>] py ri d i ne- 1 -carboxamide hydrochloride ee) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxamide ff) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride gg) (3aR,5r,6aS)-2-benzyl- / V-(2,4- bis(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide hh) 7-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxamide hydrochloride ii) / V-(2,4-bis(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide jj) 4-benzyl- / V-(5-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide kk) 4-benzyl- / V-(3-fluoro-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochlorideII) (1R,5S,6r)-3-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-6- carboxamide mm) 4-benzyl- / V-(4-cyano-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide nn) 4-benzyl- / V-(3-cyano-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide oo) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-2-ylmethyl)piperazine-1- carboxamide pp) 5-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 / 7)- carboxamide hydrochlorideqq) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride rr) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ss) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide tt) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-2- carboxamide uu) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2- carboxamide vv) (1 / ?,5S,6r)-3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane- 6-carboxamide ww) 9-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3,9-diazaspiro[5.5]undecane-3- carboxamide xx) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2-carboxamide yy) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1 -carboxamide zz) 2-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8-carboxamide hydrochloride aaa) 3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9- carboxamide bbb) 6-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ccc) / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide ddd) 6-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide eee) 6-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide fff) 6-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ggg) 6-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide hhh) 7-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide iii) 7-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide jjj) 7-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamidekkk) 7-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamideIII) / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-(thiophen-3-ylmethyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide, and mmm) / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.4]octane-6-carboxamide or a pharmaceutically acceptable salt thereof.

11. The compound for use according to claim 10, wherein the compound is selected from any one of the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide, and f) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride or a pharmaceutically acceptable salt thereof.

12. A compound as defined in any one of claims 1 to 11 for use as a medicament, with the proviso that: when Ri and R4 are hydrogen, n is 1 , A is piperazine or 3,7-diazabicyclo[3.3.0]octane, and R2 is chlorine, R3 is other than chlorine; and with the proviso that: formula I does not include any of the compounds selected from the list consisting of13. A compound as defined in claim 12, with the proviso that:a) when Ri is OCH3, R2 to R4 are other than OCHsand at least one of R2 to R4 is other than hydrogen; b) when R2 is OCH3, R1, and R3 to R4 are other than OCH3 and at least one of R1, or R3 to R4 is other than hydrogen; c) when R3 is OCH3, R1 to R2 and R4 is other than OCH3 and at least one of R1, or R3 toR4 is other than hydrogen; d) when R1 and R4 are hydrogen, A is piperazine, 1 ,4-diazepine, 3,7- diazabicyclo[3.3.0]octane or 3-azabicyclo[3.1.0]hexane, and R2 is fluorine, R3 is other than halogen; e) when R1 and R4 are hydrogen, n is 1 , A is piperazine, 1 ,4-diazepine, or 3,7- diazabicyclo[3.3.0]octane, and R2 is chlorine, R3 is other than halogen; f) when R1 and R4 are hydrogen, n is 1 , A is piperazine or 1 ,4-diazepine, and R2 is chlorine, R3 is other than methoxy; g) when R1 and R3 are hydrogen, A is piperazine, and R2 = fluorine, R4 is other than halogen; and with the further proviso that the following compounds are not included in formula I:

14. The compound according to claim 13, wherein the compound is selected from the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 4-benzyl- / V-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide f) 4-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide g) 4-benzyl- / V-(2-methoxy-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide h) 4-benzyl- / V-(4-methoxy-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride i) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)piperazine-1 -carboxamide j) 4-benzyl- / V-(4-cyano-2-methoxybenzyl)piperazine-1 -carboxamide k) 4-benzyl- / V-(4-iodo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide hydrochloride l) 4-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide m) 4-benzyl- / V-(4-fluoro-2-methoxybenzyl)piperazine-1 -carboxamide n) 4-benzyl- / V-(4-cyano-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide o) 4-benzyl- / V-(4-chloro-2-methoxybenzyl)piperazine-1 -carboxamide p) 4-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide q) 4-benzyl- / V-(2-methoxy-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide r) 4-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)piperazine-1 -carboxamide sj / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-fluorobenzyl)piperazine-1 -carboxamide t) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide u) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(2,4-dichlorobenzyl)piperazine-1 -carboxamide v) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-3-ylmethyl)piperazine-1- carboxamide w) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(naphthalen-2-ylmethyl)piperazine-1- carboxamidex) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(4-iodobenzyl)piperazine-1 -carboxamide y) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-phenethylpiperazine-1 -carboxamide z) (3a / ?,6aS)-5-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl) hexahydropyrrolo[3,4-c]pyrrole- 2(1 / - / )-carboxamide aa) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide bb) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride cc) (4aS,7aS)-6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)octahydro-1 / 7-pyrrolo[3,4-£>] py ri d i ne- 1 -carboxamide hydrochloride dd) 4-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxamide ee) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride ff) (3aR,5r,6aS)-2-benzyl- / V-(2,4- bis(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide gg) 7-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxamide hydrochloride hh) / V-(2,4-bis(trifluoromethyl)benzyl)-4-(4-methoxybenzyl)piperazine-1 -carboxamide ii) 4-benzyl- / V-(5-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide jj) 4-benzyl- / V-(3-fluoro-4-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide hydrochloride kk) (1R,5S,6r)-3-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-6- carboxamideII) 4-benzyl- / V-(4-cyano-3-(trifluoromethyl)benzyl)piperazine-1 -carboxamide mm) 4-benzyl- / V-(3-cyano-4-(trifluoromethyl)benzyl)piperazine-1 -carboxamide nn) / V-(4-cyano-2-(trifluoromethyl)benzyl)-4-(thiophen-2-ylmethyl)piperazine-1- carboxamide oo) 5-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 / 7)- carboxamide hydrochloride pp) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-1 ,4-diazepane-1 -carboxamide hydrochloride qq) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide rr) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide ss) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane-2- carboxamidett) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane-2- carboxamide uu) (1 R,5S,6r)-3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane- 6-carboxamide vv) 9-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3,9-diazaspiro[5.5]undecane-3- carboxamide ww) 7-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-azaspiro[3.5]nonane-2- carboxamide xx) 6-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-1 -carboxamide yy) 2-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-azaspiro[4.5]decane-8-carboxamide hydrochloride zz) 3-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)-3-azaspiro[5.5]undecane-9- carboxamide aaa) 6-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide bbb) / V-(4-cyano-2-(trifluoromethyl)benzyl)-6-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.3]heptane-2-carboxamide ccc) 6-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ddd) 6-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide eee) 6-benzyl- / V-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide fff) 6-benzyl- / V-(4-fluoro-2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide ggg) 7-benzyl- / V-(4-chloro-3-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide hhh) 7-benzyl- / V-(3-chloro-5-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide iii) 7-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide jjj) 7-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)-2,7-diazaspiro[3.5]nonane-2- carboxamide kkk) / V-(4-cyano-2-(trifluoromethyl)benzyl)-7-(thiophen-3-ylmethyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide, andIII) / V-(4-cyano-2-(trifluoromethyl)benzyl)-2-(thiophen-3-ylmethyl)-2,6- diazaspiro[3.4]octane-6-carboxamideor a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14, wherein the compound is selected from any one of the list consisting of: a) 4-benzyl- / V-(4-cyano-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide b) 4-benzyl- / V-(4-chloro-2-(trifluoromethoxy)benzyl)piperazine-1 -carboxamide c) 4-benzyl- / V-(4-chloro-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide d) 4-benzyl- / V-(4-bromo-2-(trifluoromethyl)benzyl)piperazine-1 -carboxamide e) 6-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide, and f) 2-benzyl- / V-(2,4-bis(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxamide hydrochloride or a pharmaceutically acceptable salt thereof.

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