Dual inhibitors of sigma-1 receptors and soluble epoxide hydrolase and their use in the treatment of pain

Abstract

The present invention provides compounds of formula (I) for use in the treatment or prevention of pain. The present invention further provides compounds of formula (I') or formula (Ibis), and pharmaceutical compositions comprising them. Advantageously, compounds of formula (I), formula (I') and formula (Ibis) exhibit the dual effect of inhibiting soluble epoxide hydrolase and binding to S1 receptors, two well-documented targets involved in pain. TIFF2025539118000045.tif36170

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and in particular to the field of analgesia. Specifically, the present invention provides compounds and pharmaceutical compositions and their use in the treatment or prevention of pain. [Background technology]

[0002] The treatment of pain conditions is of great importance in medicine. Currently, there is a worldwide need for additional pain therapies. The urgent need for specific treatments for pain conditions is reported in numerous scientific studies that have recently appeared in the field of analgesic drug applications.

[0003] Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with or resembling actual or potential tissue damage" (IASP Pain Terminology, https: / / www.iasp-pain.org / resources / terminology / ).

[0004] The IASP recommends using certain characteristics to describe a patient's pain: (a) the body part involved (e.g., abdomen, legs), (b) the system whose dysfunction may be causing the pain (e.g., nervous system, digestive system), (c) duration and pattern of occurrence, (d) intensity, and (e) cause.

[0005] Pain can be broadly divided into three types: nociceptive pain, inflammatory pain, and neuropathic pain. Nociceptive pain corresponds to sensations associated with the detection of noxious stimuli that can induce tissue damage, whereas inflammatory pain is related to the environment of factors released during tissue inflammation, and neuropathic pain is induced in response to damage to the nervous system due to either trauma or chemical insult (e.g., treatment with anti-cancer drugs) (see Non-Patent Document 1).

[0006] In diseases such as rheumatoid arthritis, there is clearly a predominant inflammatory component contributing to the pain state, however in other situations, such as the immediate post-operative period, there may be an inflammatory component but also a strong nociceptive pain component.

[0007] Neuropathic pain is a complex phenomenon, with a significant contribution from central mechanisms. Intradermal injection of capsaicin reduces the mechanical pain threshold around the injection site, even in areas not stimulated by capsaicin (so-called secondary hypersensitivity sites). This reduction in mechanical threshold may be due to central sensitization, an important feature of neuropathic pain. Indeed, since anti-neuropathic drugs show antiallodynic activity in this test in both humans and rodents, this model is considered a surrogate model of neuropathic pain (see Non-Patent Document 2).

[0008] Inadequate treatment of pain is widespread in surgical wards, intensive care units and emergency departments, general practice, the management of all forms of chronic pain, including cancer pain, and end-of-life care. The problem affects all age groups, from newborns to medically frail elderly people.

[0009] Current analgesics (including opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and gabapentinoids) have limited efficacy in many pain conditions or numerous side effects, limiting their use. For example, NSAIDs have limited analgesic effects, are inadequate for treating severe pain conditions, and may induce gastrointestinal or renal dysfunction, among other adverse effects (see Non-Patent Document 3). Opioids provide much greater analgesic efficacy, but also cause constipation, respiratory depression, tolerance, vomiting, and physical dependence, among other adverse events (see Non-Patent Document 4). Gabapentinoids are used in patients with neuropathic pain, but can cause dizziness, somnolence, peripheral edema, ataxia or gait difficulty, and diarrhea (see Non-Patent Document 5).

[0010] Researchers have turned to other targets in an attempt to overcome the limitations of known painkillers.

[0011] Sigma-1 receptors (S1Rs) are unique ligand-activated chaperones present in both the peripheral and central nervous systems in areas important for pain management (see Non-Patent Document 6). S1R antagonists modify the chaperone activity of S1Rs by increasing opioid signaling and reducing N-methyl-D-aspartate receptor (NMDAR) responses, thereby enhancing opioid antinociception and reducing the hypersensitivity that characterizes pathological pain states. Furthermore, S1R 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 drug paclitaxel), and more recently, in inflammatory pain. While most studies have attributed the analgesic properties of S1R antagonists to their central actions, it is now known that peripheral S1Rs also contribute to their actions (see Non-Patent Document 6, cited above).

[0012] On the other hand, epoxyeicosatrienoic acids (EETs) are potent endogenous anti-inflammatory and antinociceptive mediators, but they are rapidly degraded by soluble epoxide hydrolase (sEH) to less active or inactive dihydroxyeicosatrienoic acids. In vitro and in vivo studies have demonstrated that EET regulation of chronic inflammation and neuropathic pain is inversely dependent on the extent of their hydrolysis by sEH. Therefore, the use of sEH inhibitors (sEHIs) to maintain high in vivo levels of EETs is a promising pharmacological approach for treating pain and inflammation. Consequently, sEHIs are being developed for the treatment of neuropathic pain in human patients. sEHIs may also be suitable analgesics for veterinary use in addition to human use (see Non-Patent Document 7). [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Woolf, J Clin Invest., 2010, 120(11): 3742-3744 [Non-patent document 2] Sanchez-Fernandez et al., Adv Exp Med Biol., 2017, 964:109-132 [Non-patent document 3] Yaksh et al., F1000Prime Rep., 2015, 7, 56 [Non-patent document 4] Al-Hasani and Bruchas, Anesthesiology, 2011, 115:1363-1381 [Non-Patent Document 5] Meng et al., Minerva Anestesiol., 2014, 80(5):556-67 [Non-patent document 6] Ruiz-Cantero et al., Pharmacol Res., 2021, 163:105339 [Non-Patent Document 7] Hammock et al., J Med Chem., 2021, 64(4):1856-1872 Summary of the Invention [Problem to be solved by the invention]

[0014] Despite past efforts, there remains a need for additional therapeutic approaches to the adequate management of pain. [Means for solving the problem]

[0015] The inventors of the present invention have for the first time designed a molecule of formula (I) that acts efficiently on S1R and sEH.

[0016] As shown in Table 1 below, compounds of formula (I) significantly inhibited sEH (requiring concentrations of less than 100 nM) and bound to S1R (requiring concentrations of less than 400 nM).

[0017] As discussed above, S1R and sEH have been widely reported to be involved in pain and are recognized as targets in pain suppression. Therefore, the data presented in Table 1 below support the suitability of the compound of formula (I) as a candidate for the treatment and prevention of pain.

[0018] To assess the agonist or antagonist properties of the compounds of the present invention for S1R, a well-documented phenytoin-based functional assay was performed (see Cobos et al., Synapse, 2005, 55:192-195). Previous studies have shown that phenytoin, a low-potency allosteric modulator of S1R, differentially modulates the affinity of S1R ligands depending on their agonist versus antagonist functionality. Phenytoin enhances the receptor binding affinity of S1R agonists (K without phenytoin / with phenytoin > 1). i ratio), does not affect or slightly reduces the receptor binding affinity of S1R antagonists (K without phenytoin / with phenytoin less than 1). i ratio).

[0019] Both the compounds of the present invention and the representative S1R antagonist BD-1063 showed a very small shift in receptor binding affinity, with K without / with phenytoin, respectively. i The ratios were found to be 0.8 and 0.7. However, a representative S1R agonist, SKF-10047, showed a ratio of 6.0 in the presence of 1 mM phenytoin. These observations indicated that the compounds of the present invention act as antagonists to S1R.

[0020] The above points were further confirmed in two in vivo pain models, one for tactile allodynia and the other for postoperative pain.

[0021] As shown below, administration of compounds of the present invention was able to induce significant antiallodynic effects in capsaicin-induced mechanical hypersensitivity (Figures 1 and 2) and postoperative pain (Figures 3 and 4). In addition, this effect was found to be reversed when either PRE-084 (an S1R agonist) or MS-PPOH (a CYP450 epoxygenase inhibitor) was administered (Figures 2 and 4), confirming that both S1R antagonism and EET accumulation (via inhibition of sEH) are involved in the antiallodynic effects of compounds of the present invention.

[0022] Overall, the compounds of formula (I) represent a major advance in efficient pain management and, by acting on two targets, simplify pain management with molecules that have a broader analgesic effect.

[0023] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, R1 is CN, halogen, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl and -O-(C1-C 10 ) haloalkyl; R2 to R4 may be the same or different and independently represent H, CN, halogen, (C1 to C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C1-C 10 ) alkyl, (C2-C 10 ) alkenyl, (C2-C substituted with one or more substituents Su3 10 ) alkynyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl, -O-(C1-C5) substituted with one or more substituents Su5 10) haloalkyl, -SF5, -S(O)2R9, -NR 10 R 11 aryl and heteroaryl; R5 is CR x R' x and R x and R' x are the same or different and are independently selected from —H, (C1-C5) alkyl, or (C1-C5) haloalkyl, or alternatively, R x and R' x form, together with the C atoms to which they are attached, a ring having 3 to 6 elements, R6 is an aromatic known ring system, which is The element is CR y and N, R y H, OH, CN, halogens, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, (C1-C substituted with one or more substituents Su6 10 ) alkyl, substituted with one or more substituents Su7 (C2-C 10 ) alkenyl, (C2-C substituted with one or more substituents Su8 10 ) alkynyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 13 , N.R. 14 R 15 , CONR8R'8 and COOR 24 an aromatic six-membered ring system selected from the group consisting of The element is CR z , S, N, NH, and O; R z H, OH, CN, halogens, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 17 , N.R. 18 R 19 ,CONR 12 R'12 and COOR 24 an aromatic five-membered ring system selected from the group consisting of an aromatic fused ring system consisting of two rings, each of the aromatic rings having six elements selected from CH or N; and Formula (XI): [ka] (In the formula, R t1 ~R t9 is N, NR p or CR' p Selected from R p is H, (C1~C 10 ) haloalkyl, S(O)R t10 ,CONR t11 R' t11 and COOR' t12 and R' is selected from the group consisting of p H, OH, CN, halogens, (C1-C 10 ) haloalkyl, O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R' 17 , NR' 18 R' 19 ,CONR 16 R' 16 and COOR 25 an aromatic fused ring system selected from the group consisting of is selected from the group consisting of R7 is CR v R' v and R v and R' v are the same or different and are independently selected from H, (C1-C5) alkyl or (C1-C5) haloalkyl, or alternatively, R v and R' v form a ring with three to six elements together with the C atoms to which they are attached, R and R' may be the same or different, -H, (C 10 ) alkyl, (C1-C 10) haloalkyl, (C-C) cycloalkyl, aryl, and heteroaryl; R9, R 13 , R 17 and R t10 (C1~C 10 ) alkyl, (C-C) cycloalkyl, aryl, and heteroaryl; R 10 and R 11 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C3-C8) cycloalkyl; R 12 and R' 12 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl and (C3-C8) cycloalkyl; R 14 and R 15 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C3-C8) cycloalkyl and -S(O)R 21 is selected from the group consisting of R 16 and R' 16 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl and (C3-C8) cycloalkyl; R 18 and R 19 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C3-C8) cycloalkyl and -S(O)R 22 is selected from the group consisting of R' 18 and R' 19 are the same or different, -H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl, (C1-C 10) haloalkyl and -S(O)R 23 is selected from the group consisting of R t10 and R' t10 are the same or different, -H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl, (C1-C 10 ) haloalkyl and -S(O)R t13 is selected from the group consisting of R 21 ~R 23 and R t13 (C1~C 10 ) alkyl, (C3-C8) cycloalkyl or (C1-C 10 ) haloalkyl; R 24 , R 25 and R' t12 is -H, (C1~C 10 ) alkyl, (C3-C8) cycloalkyl and (C1-C 10 ) haloalkyl; m is an integer value selected from 0, 1, or 2; n is an integer value selected from 1 or 2, "Aryl" is a compound with six CR c means an aromatic ring system containing the element R c is selected from H, halogen, cyano, nitro, (C1-C5) alkyl, (C1-C5) haloalkyl, —O—(C1-C5) alkyl, or —O—(C1-C5) haloalkyl; "Heteroaryl" is a CR d R means an aromatic ring system containing five or six elements selected from the group consisting of O, N, NH and S; d is selected from H, halogen, cyano, nitro, (C1-C5) alkyl, (C1-C5) haloalkyl, —O—(C1-C5) alkyl, —O—(C1-C5) haloalkyl; Su1 to Su8 are independently selected from the group consisting of halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N—(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N—(C1-C4)alkylsulfamoyl and N,N-di-(C1-C4)alkylsulfamoyl; provided that at least one of R2 to R4 is other than H), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0024] This aspect may alternatively be defined as the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of pain. This aspect may alternatively be defined as a method of treating or preventing pain, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof.

[0025] In a second aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Formula (I'): [ka] The compound Formula (Ibis): [ka] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R1, R2, R3, R4, R6 and R7, m and n are as defined in the first aspect of the invention; R5' is CR f R' f where R f and R' f are the same or different and are selected from the group consisting of H and (C1-C5)haloalkyl, or alternatively, R f and R' f form a ring with three to six elements together with the C atom to which they are attached, however, At least one of R2 to R4 is other than hydrogen; R6 is of formula (i): [ka] other than the ring of R1 and R4 are the same, -O-(C1-C 10 ) alkyl or halogen, and when R2 and R3 are H, m=n=1, R5 is -CH2-, and R7=-CH2- or CH(CH3)-, R6 is All six elements are CR as defined above. y (i.e., phenyl or phenyl-substituted) aromatic six-membered ring systems, and Frills, Other than that, R1 to R3 are the same, and -O-(C1 to C 10 ) alkyl, and when R4 is H, m=1, n=1 or 2, and R5=R7=—CH2—, then R6 is other than phenyl; R1 to R3 are the same, and -O-(C1 to C 10 ) alkyl, and when R4 is H, m=1, n=1, and R5=R7=—CH2—, R6 represents a group of formula (ii): [ka] wherein Ri=Me or Et, R1 to R3 are the same, and -O-(C1 to C 10 ) alkyl, and when R4 is H, m=1, n=1, and R5=R7=—CH2—, R6 is (C1-C 10 ) other than phenyl substituted by alkyl or one or more halogens; When R1 and R3 are Cl, m=n=1, R2=R4=H, and R5=R7=—CH2—, R6 is phenyl ring, (C1~C 10 ) alkyl, meta-O-(C1-C 10 ) a phenyl ring substituted with alkyl or one or more halogens, or naphthalenyl ring, Other than that, R1 and R3 are the same or different and represent halogen, R2 = R4 = H, m = n = 1, R5 = R7 = -CH2-, and R6 is a group represented by formula (VI) or formula (VII): [ka] If R is one of z1 ~R z5 is H, When R1 and R3 are the same or different and represent halogen, R2 = R4 = H, m = n = 1, R5 = R7 = -CH2- and R6 is one of the formulas (XI) defined above, R p is H, When R1 and R3 are F, R2=R4=H, m=1, n=2, and R5=R7=—CH2—, then R6 is other than a 1H-pyrrolo[2,3-b]pyridin-3-yl ring; When R1 is ethoxy, R2 = R3 = H, R4 is methyl, m = 0, n = 1, and R5 = R7 = -CH2-, then R6 is other than a phenyl ring.

[0026] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I'), formula (Ibis) or a pharmaceutical salt thereof as defined in the second aspect of the invention together with one or more pharmaceutically acceptable salts.

[0027] In a fourth aspect, the present invention provides a compound of formula (I'), formula (Ibis) or a pharmaceutical salt thereof for use in therapy.

[0028] In a final aspect, the present invention provides methods for preparing compounds of formula (I), formula (I') and formula (Ibis).

[0029] In particular, the present invention provides a process for preparing a compound of formula (I), formula (I') or formula (Ibis) as defined in any of the above aspects, the process comprising reacting in the presence of an amide coupling reagent and a base: Formula (VIII) in either the free base or pharmaceutically acceptable salt form: [ka] and a compound of Formula (IX): [ka] wherein R1-R7, n, and m are as defined in any of the preceding paragraphs.

[0030] The present invention relates to a compound of formula (X): [ka] to reductive alkylation with a benzaldehyde of formula (XI) in the presence of a reductor agent, or alternatively to nucleophilic substitution with a compound of formula (XII) in the presence of a base, [ka] Here, "Hal" represents halogen, R1 to R7, m and n are as defined above, and w is 0 or 1. [Brief explanation of the drawings]

[0031] [Figure 1] Figure 1 shows the dose-response curve of the effect induced by the compound of Example 2 (compound of the present invention, Ex. 2), a dual S1R antagonist / sEH inhibitor (sEHI), on capsaicin-induced mechanical allodynia. A: Paw withdrawal latency (seconds). Effect of sc administration of Ex. 2 (0.625 mg / kg-10 mg / kg) or its vehicle ("S", open squares, dose 0) on paw withdrawal latency in response to application of a mechanical stimulus after intraplantar (i.p.l.) administration of 1 μg of capsaicin in mice. N=8-11. Statistically significant difference: * p<0.05 between non-sensitized mice (dashed line) and other experimental groups; # p<0.05 between capsaicin-treated mice injected with Ex. 2 or its vehicle (one-way ANOVA followed by Bonferroni's test). [Figure 2] Figure 1 shows the antiallodynic effect of the compound of Example 2 (compound of the present invention, Ex. 2) in capsaicin-treated mice via both S1R antagonism and sEH inhibition. B: % antiallodynic effect. Data shown represent the effect of subcutaneous (sc) administration of Ex. 2 (2.5 mg / kg) alone or in combination with the S1R agonist PRE-084 (32 mg / kg, sc) or the CYP450 epoxygenase inhibitor MS-PPOH (20 mg / kg, sc) on paw withdrawal latency in mice treated intraplantar with capsaicin (1 μg). N = 8-11. Statistically significant difference: * p < 0.05 between capsaicin-treated mice injected with Ex. 2 or its vehicle (first bar); # p < 0.05 between Ex. 2-treated mice combined with or without PRE-084 or MS-PPOH (one-way ANOVA followed by Bonferroni's test). [Figure 3]Figure 1 shows the time course of the effect of the compound of Example 2 (Ex.2), a dual S1R antagonist / sEHI, on associated postoperative pain. F: von Frey threshold (g). T: time after treatment (min). L: 2.5 hours after laparotomy. The data show that subcutaneous (sc) administration of Ex.2 (10 mg / kg-40 mg / kg) induces a significant alleviation of hypersensitivity in laparotomy-treated mice, especially at 120 minutes after drug administration. Statistically significant difference: * p<0.05 between baseline (BL) recordings and values ​​after laparotomy; # p<0.05 between values ​​obtained in mice treated with Ex.2 or its vehicle ("S", open squares) (two-way ANOVA repeated measures followed by Bonferroni test). [Figure 4] This figure shows the antiallodynic effect induced by the compound of Example 2 (Ex.2) in mice with postoperative pain through both S1R antagonism and sEH inhibition. F: von Frey threshold (g). T: time after treatment (min). L: 2.5 hours after laparotomy. The data shown represent the effect of subcutaneous (sc) administration of Ex.2 (20 mg / kg) alone or in combination with the S1R agonist PRE-084 (32 mg / kg, sc) or the CYP450 epoxygenase inhibitor MS-PPOH (20 mg / kg, sc) to mice after laparotomy. N=8-11. Statistically significant differences: * p<0.05 between baseline (BL) recordings and post-laparotomy values; # p<0.05 between values ​​obtained in mice treated with Ex.2 or its vehicle ("S", open squares); † p<0.05 for mice treated with Ex.2 in combination with or without PRE-084 or MS-PPOH (one-way ANOVA followed by Bonferroni test). [Figure 5] Figure 1 shows the displacement of [H]-(+)-pentazocine binding with increasing concentrations of BD-1063, SKF-10047, and the compound of Example 2 (Ex. 2) in the presence of 1 mM phenytoin (DPH, solid line) or its solvent (dotted line). The y-axis is % specific binding (A), and the x-axis is the logarithm of the ligand concentration (B). DETAILED DESCRIPTION OF THE INVENTION

[0032] Terms not specifically defined herein should be given the meaning that would be given them by one of ordinary skill in the art in light of the present disclosure and the context. However, as used herein, unless otherwise specified, the following terms have the meanings indicated and the following conventions are observed:

[0033] Throughout this specification and the accompanying sections below, the word "comprise" and variations such as "comprises," "comprising," etc. are to be interpreted inclusively. That is, these words are intended to convey the possibility that other elements or integers not specifically recited may be included, where the context allows. The word "comprise" also includes the term "consists of."

[0034] For purposes of the present invention, any range given includes both the lower and upper endpoints of the range.

[0035] In a first aspect, the present invention provides the use of a compound of formula (I) in the treatment or prevention of pain.

[0036] In the context of this invention, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing no unsaturation and attached to the remainder of the molecule by a single bond. Typical alkyl groups have 1 to about 10, 1 to about 8, or 1 to about 6 carbon atoms, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and the like. When substituted by cycloalkyl, it corresponds to a "cycloalkylalkyl" group such as cyclopropylmethyl. When substituted by aryl, it corresponds to an "arylalkyl" group such as benzyl, benzhydryl, or phenethyl. When substituted by heterocyclyl, it corresponds to a "heterocyclylalkyl" group.

[0037] In the context of this invention, the term "alkenyl" refers to a straight- or branched-chain hydrocarbon group containing at least two carbon atoms and at least one C=C double bond, and attached to the remainder of the molecule by a single bond. Typical alkenyl groups have 2 to about 10, 2 to about 8, or 2 to about 6 carbon atoms. In certain embodiments, the alkenyl group is vinyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, or butenyl.

[0038] In the context of this invention, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more C≡C triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl.

[0039] In the context of the present invention, the term "hydroxyalkyl" refers to a straight or branched chain hydrocarbon group containing no unsaturation, in which one or more of the hydrogens have been replaced by -OH. Illustrative, non-limiting examples of hydroxyalkyl are, inter alia, methanol, ethanol, isopropanol, isobutanol or t-butanol.

[0040] In the context of the present invention, the term "alkoxy" refers to -O-alkyl, wherein "alkyl" is as defined above. Illustrative, non-limiting examples of hydroxyalkyl are especially methoxy, ethoxy or t-butoxy.

[0041] In the context of this invention, the term "alkylsulfinyl" refers to alkyl-SO-, wherein "alkyl" is as defined above.

[0042] In the context of the present invention, the term "alkylsulfonyl" refers to alkyl-SO2-, wherein "alkyl" is as defined above.

[0043] In the context of the present invention, the term "alkylcarbonyl" means a straight or branched chain hydrocarbon group containing no unsaturation, in which the alkyl chain is interrupted by 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.

[0044] In the context of this invention, the term "alkoxycarbonyl" refers to an "alkoxy" as defined above, wherein an alkyl chain is interrupted by a carbonyl (C=O) group.

[0045] In the context of the present invention, the term "carbamoyl" refers to -C(O)NH2.

[0046] In the context of the present invention, the term "alkylcarbonyloxy" designates -C(O)-O-alkyl, wherein alkyl is as defined above.

[0047] In the context of the present invention, the term "sulfamoyl" refers to -S(O)2NH2.

[0048] In the context of the present invention, the term "halogen" refers to bromo, chloro, iodo or fluoro.

[0049] In the context of the present invention, the term "haloalkyl" refers to a straight or branched chain hydrocarbon group containing no unsaturation, in which one or more of the hydrogen atoms has been replaced by a halogen. Illustrative, non-limiting examples of haloalkyl are chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, etc.

[0050] In the context of the present invention, the group R x -R' x , R v -R' v and R f -R' fWhen referring to "form a ring having 3 to 6 elements together with the C atom to which they are attached," the expression refers to any known saturated or partially saturated ring having 3 to 6 elements selected from H, (C1-C5) alkyl, or (C1-C5) haloalkyl. In one embodiment, optionally in combination with any of the embodiments provided above or below, the ring is saturated. In another embodiment, optionally in combination with any of the embodiments provided above or below, the ring is cyclopropyl.

[0051] In the context of the present invention, R6 represents an aromatic ring system as defined in the first aspect of the present invention. In one embodiment, optionally in combination with any of the embodiments provided above or below, R6 comprises one or more heteroatoms. Illustrative, non-limiting examples of R6 aromatic ring systems comprising one or more heteroatoms include: [ka]

[0052] In the context of the present invention, the term "salt" should be understood as any form of a compound used according to the present invention in which the compound is in ionic form or charged, coupled with a counterion (cation or anion), or in solution. This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, especially complexes formed by ionic interactions. This definition especially includes physiologically acceptable salts. This term should be understood as synonymous with "pharmacologically acceptable salt" or "pharmaceutically acceptable salt."

[0053] In the context of the present invention, the term "pharmaceutically acceptable salt" means any salt that is physiologically acceptable (meaning that it is not toxic, usually, especially as a result of the counterion), when used in a manner appropriate for the treatment applied or used, especially in humans and / or mammals. These physiologically acceptable salts may be formed with cations or bases, and in the context of the present invention, especially when used in humans and / or mammals, are understood to be salts formed by at least one compound used according to the present invention, preferably inorganic, usually an acid (deprotonated), such as an anion, and at least one physiologically acceptable cation. Salts with alkali metals and alkaline earth metals, as well as ammonium cations (NH4 + ) are particularly preferred. Preferred salts are those formed with (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium, or calcium. These physiologically acceptable salts may be formed with anions or acids, and in the context of the present invention, especially when used with humans and / or mammals, are usually understood to be salts formed with at least one compound used according to the present invention, for example a cation, protonated, for example, at nitrogen, and at least one physiologically acceptable anion. This definition in the context of the present invention, especially when used with humans and / or mammals, particularly includes salts formed with physiologically acceptable acids, i.e., salts of a particular active compound with a physiologically acceptable organic or inorganic acid. Examples of such salts are salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, or citric acid.

[0054] In the context of the present invention, the term "solvate" should be understood to mean any form of a compound according to the invention in which said compound is non-covalently bound to another molecule (usually a polar solvent), and includes in particular hydrates and alcoholates, such as methanolates. Preferred solvates are hydrates.

[0055] The term "prodrug" is used in the broadest sense and includes derivatives that are converted into the compounds of the present invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds of formula (I) that contain a biohydrolyzable moiety, such as biohydrolyzable amide, biohydrolyzable ester, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ureide, and biohydrolyzable phosphate analogs. Preferably, prodrugs of compounds with a carboxyl functional group are lower alkyl esters of the carboxylic acid. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using known methods.

[0056] Any compound of formula (I) referred to herein is intended to represent not only that specific compound, but also a specific modification or form. In particular, the compounds referred to herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. Therefore, 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. Similarly, stereoisomerism or geometric isomerism about double bonds is also possible, and thus, in some cases, molecules may exist as (E)-isomers or (Z)-isomers (trans isomers and cis isomers). When a molecule contains several double bonds, each double bond has its own stereoisomerism, which may be the same as or different from the stereoisomerism of other double bonds in the molecule. Furthermore, the compounds referred to herein may exist as atropisomers. All stereoisomers, including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, as well as mixtures thereof, are considered to be within the scope of the present invention.

[0057] Additionally, any compound of formula (I) referred to herein may exist as a 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.

[0058] In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R y H, OH, CN, halogens, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 )alkynyl, one or more halogens, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-( (C1-C4) alkylcarbamoyl, (C1-C6) alkylcarbonyloxy, (C3-C6) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4) alkylsulfamoyl, N,N-di-(C1-C4) alkylsulfamoyl (C1-C 10) alkyl, substituted with one or more halogens, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl 10 ) alkenyl, one or more halogens, cyano, nitro, (C1-C6) haloalkyl, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, carbamoyl, N-(C1-C4) alkylcarbamoyl, N,N-di-( (C2-C substituted with C1-C4) alkylcarbamoyl, (C1-C6) alkylcarbonyloxy, (C3-C6) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4) alkylsulfamoyl, N,N-di-(C1-C4) alkylsulfamoyl 10 ) alkynyl, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 13 , N.R. 14 R 15 and COOR 24 is selected from the group consisting of R' p H, OH, CN, halogens, (C1-C 10) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R' 17 , NR' 18 R' 19 and COOR 25 is selected from the group consisting of R z H, OH, CN, halogens, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 17 , N.R. 18 R 19 and COOR 24 is selected from the group consisting of R9, R 13 and R 17 is (C1~C 10 ) alkyl and (C3-C8) cycloalkyl; R 18 and R 19 are the same or different, H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl and (C1-C 10 ) haloalkyl; R' 18 and R' 19 are the same or different, H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl and (C1-C 10 ) haloalkyl; R 23 and R 24 is H and (C1 to C 10 ) alkyl and (C3-C8) cycloalkyl.

[0059] In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compound has the formula (Ibis): [ka] (wherein R1 to R3, R6 and n are as defined in the first aspect of the present invention).

[0060] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is halogen, —O—(C1-C 10 ) haloalkyl and (C1-C 10 ) haloalkyl.

[0061] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R2 is H, CN, halogen, —O—(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl and (C1-C 10 ) haloalkyl.

[0062] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R2 is selected from the group consisting of H, halogen and (C1-C 10 ) haloalkyl.

[0063] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R3 is H, CN, halogen, —O—(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl, SF5, S(O)2R9, where R9 is as defined above, and in particular R9 is selected from the group consisting of (C1-C 10 ) alkyl or aryl, in particular R9 is selected from (C1-C 10 ) alkyl.

[0064] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R3 is CN, halogen, —O—(C1-C 10 ) alkyl, -O-(C1-C 10) selected from the group consisting of haloalkyl and SF5.

[0065] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R6 is an aromatic 5- or 6-membered ring system as defined in the first aspect of the invention.

[0066] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R6 is selected from the group consisting of formula (II) and formula (III): [ka] (In the formula, R 7a ~R 7e are the same or different and are H, OH, CN, halogen, nitro, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted with one or more Su8 (C1-C 10 ) alkyl, substituted with one or more Su9 (C2-C 10 ) alkenyl, one or more Su 10 (C2~C 10 ) alkynyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl, -SF5 and -S(O)2R 26 In particular, R 7a ~R 7e are the same or different and are H, halogen, (C1 to C 10 ) alkyl, -O-(C1-C 10 ) alkyl and COOR 24 is selected from the group consisting of R 26 (C1~C 10 ) alkyl, (C3-C8) cycloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) selected from the group consisting of alkynyl, aryl, and heteroaryl; Su8~Su 10are independently halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, and an aromatic six-membered ring system selected from the group consisting of (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, and N,N-di-(C1-C4)alkylsulfamoyl.

[0067] Alternatively, in another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R6 is a group represented by formula (IV): [ka] It is an aromatic five-membered ring system.

[0068] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R2 represents -H.

[0069] In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below provided embodiments, R3 represents -H.

[0070] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is halogen, CN, -O-(C1~C 10 ) alkyl, (C1-C 10 ) haloalkyl and -O-(C1-C 10 ) haloalkyl; R2 represents H; R3 is -CN, halogen, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) selected from the group consisting of haloalkyl, —SF5, and —S(O)2R9; R6 is (a) The element is CR y and each R y are independently H, halogen, nitro, CN, (C1-C5)alkyl, (C1-C5)alkyl substituted with one or more halogens, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl, -SF5, -S(O)2R9, -NR 10 R 11 and -COOR 23 In particular, each R y are independently selected from the group consisting of H, halogen, (C1-C5) alkyl, -O-(C1-C5) alkyl, and -COOH; (b) One of the elements is N and the remaining elements are CR y and R y as defined in the previous paragraph, in particular aromatic 6-membered ring systems corresponding to the systems of formula (III) defined above, and (c) The element is CR z , N and S, with the proviso that at least one of the elements is S, in particular aromatic 5-membered ring systems corresponding to the systems of formula (IV) defined above, is selected from the group consisting of:

[0071] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is halogen, -O-(C1-C 10 ) alkyl, (C1-C 10 ) alkyl and -O-(C1-C 10 ) haloalkyl; R3 is CN, -O-(C1~C 10 ) alkyl, -O-(C1-C 10 ) selected from the group consisting of haloalkyl and halogen.

[0072] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is a halogen atom, substituted with one or more halogen atoms (C1-C 10 ) alkyl and -O-(C1-C 10 ) haloalkyl; R2 is H, R3 is CN, -O-(C1~C 10 ) alkyl, -O-(C1-C 10 ) selected from the group consisting of haloalkyl and halogen.

[0073] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is a halogen atom, substituted by one or more halogen atoms (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R2 represents H; R3 is -CN, halogen, -O-(C1-C 10 ) haloalkyl and -O-(C1-C 10 ) alkyl; R6 is (a) The element is CR y and each R y are independently H, halogen, nitro, CN, (C1-C5)alkyl, (C1-C5)alkyl substituted with one or more halogens, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl, -SF5, -S(O)2R9, -NR 10 R 11 and -COOR 23 In particular, each R y are independently selected from the group consisting of H, halogen, (C1-C5) alkyl, -O-(C1-C5) alkyl, and -COOH; (b) One of the elements is N and the remaining elements are CR y and R yas defined in the previous paragraph, in particular aromatic 6-membered ring systems corresponding to the systems of formula (III) defined above, and (c) The element is CR z , N and S, with the proviso that at least one of the elements is S, in particular aromatic 5-membered ring systems corresponding to the systems of formula (IV) defined above, is selected from the group consisting of:

[0074] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is a halogen atom, substituted by one or more halogen atoms (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R2 represents H; R3 is -CN, halogen, -O-(C1-C 10 ) haloalkyl and -O-(C1-C 10 ) alkyl; R6 is a six-membered aromatic ring system and is a ring of formula (II) as defined above, where R y is H, halogen, (C1-C5) alkyl, (C1-C5) alkyl substituted with one or more halogens, -O-(C1-C5) alkyl, -O-(C1-C5) haloalkyl, and -COOR 23 In particular, each R y are independently selected from the group consisting of H, halogen, (C1-C5) alkyl, —O—(C1-C5) alkyl, and —COOH.

[0075] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is a halogen atom, substituted by one or more halogen atoms (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R2 represents H; R3 is -CN, halogen, -O-(C1-C 10) haloalkyl and -O-(C1-C 10 ) alkyl; R6 is a ring of formula (IV) as defined above.

[0076] In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is halogen, (C1-C 10 ) haloalkyl and -O-(C1-C 10 ) haloalkyl; R2 is a halogen and (C1-C 10 ) haloalkyl; R3 represents -H, R6 is a six-membered aromatic ring system, a ring of formula (II) as defined above, in particular R6 represents phenyl.

[0077] As used throughout this specification, the term "treatment" includes, but is not limited to, alleviating, reducing, or eliminating one or more symptoms of a disorder (i.e., pain), reducing the intensity of pain, stabilizing the condition (i.e., not worsening), delaying or slowing the progression of pain, alleviating or ameliorating the condition, and remission (whether complete or partial).

[0078] As used herein, the term "prophylaxis" refers to preventing the occurrence of pain in patients who are predisposed but do not yet have symptoms of the disease, or when intervention occurs before a pain-causing procedure.

[0079] As used herein, the term "pain" refers to all types of pain. Illustrative, non-limiting examples are acute and chronic pain, such as surgical pain, arthritic pain, neuropathic and post-operative pain, chronic low back pain, cluster headache, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, bone injury pain, labor and delivery pain, pain caused by burns, including sunburn, postpartum pain, migraine, angina pain, and urogenital-related pain, including cystitis; this term also refers to nociceptive pain or nociception.

[0080] These embodiments may also be used in the context of treating dysmenorrhea, tendonitis and bursitis, they may also be used to treat the painful symptoms of muscle pain, toothache and migraine, in the treatment of pain resulting from cancer, and as an adjunct treatment for infectious and febrile conditions.

[0081] Finally, these embodiments can be used to treat neuropathic pain, particularly nerve pain, shingles, deafferentation pain (phantom limb pain), diabetic neuropathy, and chemotherapy-induced neuropathic pain.

[0082] 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, pain induced by tissue injury, pain associated with inflammation, cancer pain, arthritic pain, chronic pain, or any other pain condition involving allodynia and / or hyperalgesia.

[0083] As used herein, the term "animal" refers to a vertebrate. Such animals include both domestic animals, such as livestock, laboratory animals, and household pets, as well as non-domestic animals, such as wild animals. In one embodiment, the animal is a vertebrate. In a particular embodiment, the animal is a domestic mammal or a human. For this purpose, the compounds of the present invention can be administered as a feed additive.

[0084] In a further embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the compound of formula (I) is 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 compound of formula (I) is administered sequentially, separately or simultaneously with the further analgesic compound.

[0085] In a second aspect, the present invention provides a compound of formula (I').

[0086] All embodiments provided under the first aspect of the invention are also embodiments of compound (I') of the second aspect of the invention, subject to the provisos indicated under the second aspect of the invention with respect to R1 to R7, m and n.

[0087] Alternatively, the second aspect of the invention also provides compounds of formula (Ibis) as defined above. All embodiments provided for compounds of formula (Ibis) in the context of the first aspect are also embodiments of the compounds in the context of the second aspect of the invention, subject to the corresponding provisos pointed out above.

[0088] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound (Ibis) or (I') of the present invention or a pharmaceutical salt thereof, as defined above.

[0089] A "therapeutically effective amount" is understood to be that amount of compound(s) that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the disease being addressed.

[0090] The precise therapeutic amount of the component(s) and amount of the compound(s) of the present invention may depend on several variables, some of which are the route of administration, the time of drug release (e.g., immediate or extended), the administration schedule, the severity of the pain, the condition of the patient, etc.

[0091] Pharmaceutical compositions can be prepared as liquid, semi-solid or solid dosage forms, for example in the form of injections, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols, or in multiparticulate forms, for example pills or granules, which can be compressed into tablets, decanted into capsules, suspended in liquid, or administered as such, if appropriate.

[0092] These compositions may be prepared using conventional means, devices, methods or processes known in the art.

[0093] Pharmaceutically acceptable adjuvants, vehicles or excipients that may be used in such compositions are those known to those skilled in the art or commonly used in the preparation of therapeutic compositions, and may, for example, be selected from the group consisting of excipients, fillers, solvents, diluents, surfactants, colorants, preservatives, disintegrants, sliding agents, lubricants, flavoring agents or binders.

[0094] The term "pharmaceutically acceptable" refers to a pharmaceutically acceptable material, composition, or vehicle. Each component must be pharmaceutically acceptable in the sense of being compatible with the other components of a pharmaceutical composition. It must also be suitable for use in animals, particularly humans, in contact with human tissues or organs without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0095] The choice of physiologically compatible adjuvants or the number of adjuvants used depends on the administration form of the pharmaceutical composition: oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal, intraauricular, or otic. Formulations in the form of tablets, dragees, capsules, granules, pills, drops, especially ear drops, juices, or syrups are preferably suitable for oral administration, while solutions, suspensions, easily reconstituted dry preparations, or even sprays are preferably suitable for parenteral, topical, or inhalation administration. The compounds according to the invention used in the pharmaceutical compositions according to the invention in depot, dissolved form, or dressing, or, if appropriate, with the addition of other active substances favoring penetration through the skin, are formulations suitable for transdermal administration. Orally or transdermally administrable formulations can also release the respective compounds according to the invention in a delayed manner.

[0096] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. For oral administration in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, gum tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, etc. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

[0097] Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can also be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained-release formulations that provide sustained release of medication over several 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.

[0098] Liquid dosage forms for oral administration may contain coloring and flavoring to increase patient acceptance.

[0099] The dosage of the pharmaceutical composition will, of course, vary depending on the application and known factors such as the age, health and weight of the recipient, the nature and extent of the condition, concurrent treatments, if any, frequency of treatment, and the desired effect, etc. The recipient may be a mammal of any species, but is preferably a human.

[0100] According to another aspect of the present invention, compounds of formula (I) can be prepared by reacting an amine of formula (VIII), either in the form of a free base or a salt such as the hydrochloride, with a carboxylic acid of formula (IX) (such as 1-benzylpiperidine-4-carboxylic acid and N-boc-piperidine-4-carboxylic acid) using an acyl chloride in the presence of a coupling agent such as EDCI or HOBt, or in the presence of a base such as triethylamine, in an organic solvent such as ethyl acetate. [ka]

[0101] According to another aspect of the present invention, compounds of formula (I) may also be prepared according to the three-step reaction scheme shown below: [ka]

[0102] Compounds of formula (I) can be prepared by reacting an amine of formula (VIII), preferably in the form of a salt such as the hydrochloride, with a carboxylic acid of formula (XIII), in which PG is a protecting group (e.g., a Boc group), using an acyl chloride in the presence of a coupling agent such as EDCI or HOBt, or in the presence of a base such as triethylamine, in an organic solvent such as ethyl acetate. The protected compound of formula (XIV) can be deprotected using standard procedures (e.g., HCl / dioxane in an organic solvent) to produce an amide of formula (X), followed by a conventional alkylation reaction, such as reductive alkylation using a benzaldehyde of general structure (XI) and a suitable reducing agent such as NaBHCN, or a nucleophilic substitution reaction using an appropriate halide compound of formula (XII) in the presence of a base such as NaCO, in an organic solvent such as acetonitrile at 80°C.

[0103] Amines of formula (VIII) are commercially available or can be obtained using various reactions already disclosed in the literature (see, for example, WO 2009 / 049157, WO 2007 / 098352, WO 2010 / 096722, Bioorg Med Chem. 2006, 14, 3307 and J Med Chem. 2017, 60, 7703).

[0104] Other objects, advantages, and features of the present invention will become apparent to those skilled in the art from this specification or from the practice of the present invention. The following examples are offered by way of illustration and are not intended to limit the invention. [Example]

[0105] Abbreviation The following abbreviations are used throughout this application: anh.: anhydrous ATR: Attenuated Total Reflection Calcd: Calculated value DCM: dichloromethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI: electrospray ionization Et2O: Diethyl ether Et3N: Triethylamine EtOAc: ethyl acetate HOBt: Hydroxybenzotriazole h: time HRMS: High resolution mass spectrometry IR: Infrared MeOH: Methanol min:minutes mp: melting point NBS: N-bromosuccinimide RT: room temperature THF: tetrahydrofuran

[0106] Analysis method Melting points were determined in open capillary tubes using an MFB 595010 M Gallenkamp melting point apparatus. Infrared (IR) spectra were performed on a Perkin-Elmer Spectrum RX I spectrophotometer using the attenuated total reflectance (ATR) technique. Absorption values ​​are expressed in wavenumbers (cm -1 ) and only significant absorption bands are shown. Elemental analyses were performed at the Microanalysis Service of IIQAB (CSIC, Barcelona, ​​Spain) using a Carlo Erba model 1106 analyzer. Preparative normal-phase chromatography was performed using prepacked RediSep Rf silica gel cartridges on a CombiFlash Rf 150 (Teledyne Isco). Thin-layer chromatography was performed on aluminum-backed sheets using silica gel 60 F254 (Merck, ref. 1.05554 or Sigma-Aldrich, ref. 60805), and spots were visualized with UV light, 1% aqueous KMnO4, and / or ninhydrin. High resolution mass spectrometry (HRMS) analysis was performed on an Agilent Technologies LC / MSD TOF spectrometer. Analytical grade solvents were used for crystallization, and synthetically pure solvents were used for reactions, extractions and column chromatography.

[0107] Example 1: 1-benzyl-N-(2-fluoro-4-(pentafluoro-λ) 6 Synthesis of (-sulfanyl)benzyl)piperidine-4-carboxamide To a solution of 2-fluoro-4-pentafluorosulfanylbenzylamine (249 mg, 0.99 mmol) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (198 mg, 0.90 mmol), HOBt (182 mg, 1.35 mmol), EDCI·HCl (259 mg, 1.35 mmol), and EtN (0.25 mL, 1.80 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 15 mL) and brine (3 × 10 mL), dried over anh. Na SO , filtered, and evaporated to give 1-benzyl-N-(2-fluoro-4-(pentafluoro-λ)). 6 (365 mg, 90% yield)-sulfanyl)benzyl)piperidine-4-carboxamide was obtained as a white solid. An analytical sample was obtained by crystallization from hot ethyl acetate. mp 123-124°C. IR(ATR): 733 cm -1 , 804cm -1 , 844cm -1 , 922cm -1 , 994cm -1 , 1022cm -1 , 1128cm -1 , 1228cm -1 , 1369cm -1 , 1419cm -1 , 1495cm -1 , 1541cm -1 , 1641cm -1 , 2759cm -1 , 2945cm -1 , 3064cm -1 , 3229cm -1 HRMS-ESI + m / z [M+H] + [C 20H 22 F6N2OS+H] + Calculated value: 453.1430, measured value: 453.1427. C 20 H 22 Analytical Calculated Values ​​for F6N2OS: C 53.09, H 4.90, N 6.19, S 7.09. Found Values: C 52.94, H 5.06, N 6.20, S 6.96.

[0108] Example 2: Synthesis of 1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (264 mg, 1.32 mmol, synthesized as in WO 2009049157) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI·HCl (345 mg, 1.80 mmol), and EtN (0.34 mL, 2.40 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (10 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 15 mL) and brine (3 × 10 mL), dried over anh.NaSO, filtered, and evaporated to give a yellowish solid (490 mg). Crystallization from hot ethyl acetate gave 1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (420 mg, 87% yield) as a white solid. mp 113-114°C. IR(ATR): 725cm -1 , 791cm -1 , 841cm -1 , 881cm -1 , 929cm -1 , 994cm -1 , 1056cm -1 , 1106cm -1 , 1142cm -1 , 1172cm -1 , 1206cm -1 , 1231cm -1 , 1267cm -1 , 1319cm -1 , 1369cm-1 , 1425cm -1 , 1540cm -1 , 1650cm -1 , 2237cm -1 , 2762cm -1 , 2803cm -1 , 2937cm -1 , 3065cm -1 , 3086cm -1 , 3291cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 22 F3N3O+H] + Calculated value: 402.1788, measured value: 402.1794. C 22 H 22 Analytical calculated for F3N3O: C 65.82, H 5.52, N 10.47. Found: C 65.57, H 5.63, N 10.30.

[0109] Example 3: Synthesis of 1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide To a solution of 4-methoxy-2-(trifluoromethyl)benzylamine (271 mg, 1.32 mmol) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI·HCl (345 mg, 1.80 mmol), and EtN (0.34 mL, 2.40 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 15 mL) and brine (3 × 10 mL), dried over anh. Na SO , filtered, and evaporated to give 1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (420 mg, 86% yield) as a white solid. An analytical sample was obtained by crystallization from hot ethyl acetate. mp 101-102°C. IR(ATR): 699cm -1 , 731cm -1 , 748cm -1, 865cm -1 , 989cm -1 , 1036cm -1 , 1107cm -1 , 1159cm -1 , 1245cm -1 , 1289cm -1 , 1316cm -1 , 1336cm -1 , 1432cm -1 , 1449cm -1 , 1538cm -1 , 1640cm -1 , 2760cm -1 , 2770cm -1 , 2799cm -1 , 2819cm -1 , 2935cm -1 , 3278cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F3N2O2+H] + Calculated value: 407.1941, measured value: 407.1941. C 22 H 25 Analytical calculated for F3N2O2: C 65.01, H 6.20, N 6.89. Found: C 65.24, H 6.35, N 6.78.

[0110] Example 4: Synthesis of 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide To a solution of 2,4-dichlorobenzylamine (232 mg, 1.32 mmol) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI·HCl (345 mg, 1.80 mmol), and EtN (0.34 mL, 2.40 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 15 mL) and brine (3 × 10 mL), dried over anh.NaSO, filtered, and evaporated to give a white solid (452 ​​mg). Crystallization from EtOAc gave 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide (320 mg, 71% yield) as a white solid. An analytical sample was obtained by washing with EtO and pentane. mp 122-123 °C. IR (ATR): 685 cm -1 , 697cm -1 , 735cm -1 , 810cm -1 , 832cm -1 , 865cm -1 , 994cm -1 , 1045cm -1 , 1121cm -1 , 1231cm -1 , 1257cm -1 , 1295cm -1 , 1423cm -1 , 1445cm -1 , 1471cm -1 , 2755cm -1 , 2806cm -1 , 2915cm -1 , 2942cm -1 , 3289cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 22 Cl2N2O+H] + Calculated value: 377.1182, measured value: 377.184. C 20 H 22Analytical calculated for Cl2N2O: C 63.67, H 5.88, N 7.42. Found: C 63.51, H 5.81, N 7.28.

[0111] Example 5: Synthesis of 1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide To a solution of 4-bromo-2-trifluoromethoxybenzylamine (146 mg, 0.54 mmol, synthesized as in WO 2007098352) in EtOAc (10 mL) was added 1-benzylpiperidine-4-carboxylic acid (129 mg, 0.59 mmol), HOBt (109 mg, 0.81 mmol), EDCI HCl (155 mg, 0.81 mmol), and EtN (0.15 mL, 1.08 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (10 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 (3 x 5 mL) and brine (2 x 5 mL), dried over anh. Na2SO4, filtered, and evaporated to give 1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (238 mg, 93% yield) as a beige solid. An analytical sample was obtained by crystallization from hot ethyl acetate. mp 112-113 °C. IR (ATR): 732 cm -1 , 792cm -1 , 821cm -1 , 845cm -1 , 879cm -1 , 939cm -1 , 994cm -1 , 1023cm -1 , 1069cm -1 , 1130cm -1 , 1167cm -1 , 1206cm -1 , 1251cm -1 , 1340cm -1 , 1368cm -1 , 1398cm -1 , 1432cm -1 , 1484cm -1 , 1551cm -1 , 1601cm -1 , 1643cm-1 , 2756cm -1 , 2802cm -1 , 2935cm -1 , 2947cm -1 , 3085cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 BrF3N2O2+H] + Calculated value: 471.089, measured value: 471.0893. C 21 H 22 Analytical calculated for BrF3N2O2: C 53.52, H 4.71, N 5.94. Found: C 53.61, H 4.75, N 5.84.

[0112] Example 6: Synthesis of 1-benzyl-N-(2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide To a solution of 2-chloro-4-(methylsulfonyl)benzylamine hydrochloride (338 mg, 1.32 mmol, synthesized as in WO 2009098352) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI HCl (345 mg, 1.80 mmol), and EtN (0.84 mL, 6.0 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 (3 x 15 mL) and brine (3 x 10 mL), dried over anh. Na2SO4, filtered, and evaporated to give 1-benzyl-N-(2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide (450 mg, 89% yield) as a white solid. An analytical sample was obtained by crystallization from hot ethyl acetate. mp 165-166 °C. IR (ATR): 737 cm -1 , 764cm -1 , 789cm -1 , 833cm -1 , 891cm -1 , 976cm -1, 986cm -1 , 1055cm -1 , 1100cm -1 , 1125cm -1 , 1147cm -1 , 1158cm -1 , 1215cm -1 , 1267cm -1 , 1298cm -1 , 1316cm -1 , 1370cm -1 , 1392cm -1 , 1452cm -1 , 1550cm -1 , 1640cm -1 , 2769cm -1 , 2812cm -1 , 2941cm -1 , 3065cm -1 , 3283cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 25 ClN2O3S+H] + Calculated value: 421.1347; Measured value: 421.1347. C 21 H 25 Analytical calculated for ClN2O3S: C 59.92, H 5.99, N 6.65, S 7.62. Found: C 60.12, H 6.01, N 6.45, S 7.55.

[0113] Example 7: Synthesis of 1-benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide To a solution of 2-methoxy-4-(trifluoromethoxy)benzylamine (292 mg, 1.32 mmol) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI·HCl (345 mg, 1.8 mmol), and EtN (0.34 mL, 2.40 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 15 mL) and brine (3 × 10 mL), dried over anh.NaSO, filtered, and evaporated to give a yellowish solid (509 mg). Crystallization from hot ethyl acetate gave 1-benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (364 mg, 72% yield) as a white solid. mp 101-102°C. IR(ATR): 775 cm -1 , 791cm -1 , 845cm -1 , 877cm -1 , 914cm -1 , 975cm -1 , 995cm -1 , 1033cm -1 , 1071cm -1 , 1124cm -1 , 1159cm -1 , 1222cm -1 , 1253cm -1 , 1273cm -1 , 1367cm -1 , 1430cm -1 , 1448cm -1 , 1503cm -1 , 1549cm -1 , 1609cm -1 , 1641cm -1 , 2766cm -1 , 2801cm -1 , 2919cm -1 , 2945cm -1 , 3310cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25F3N2O3+H] + Calculated value: 423.1890, measured value: 423.1893. C 22 H 25 Analytical calculated for F3N2O3: C 62.55, H 5.97, N 6.63. Found: C 62.41, H 5.89, N 6.45.

[0114] Example 8: Synthesis of 1-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide To a solution of 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile hydrochloride (104 mg, 0.41 mmol, synthesized as in WO 2010096722) in EtOAc (7 mL) was added 1-benzylpiperidine-4-carboxylic acid (81 mg, 0.37 mmol), HOBt (76 mg, 0.56 mmol), EDCI·HCl (107 mg, 0.56 mmol), and EtN (0.26 mL, 1.85 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (7 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 5 mL) and brine (3 × 3 mL), dried over anh.NaSO, filtered, and evaporated to give an orange oil that crystallized to a solid (167 mg). Column chromatography (SiO2, DCM / MeOH mixture) afforded 1-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (121 mg, 79% yield) as a beige solid. mp 117-118 °C. IR (ATR): 649 cm -1 , 697cm -1 , 731cm -1 , 792cm -1 , 832cm -1 , 875cm -1 , 921cm -1 , 972cm -1 , 993cm -1 , 1025cm -1 , 1068cm -1 , 1100cm -1 , 1126cm -1 , 1144cm -1 , 1167cm-1 , 1219cm -1 , 1248cm -1 , 1365cm -1 , 1426cm -1 , 1542cm -1 , 1646cm -1 , 2237cm -1 , 2760cm -1 , 2797cm -1 , 2807cm -1 , 2918cm -1 , 2948cm -1 , 3072cm -1 , 3283cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 22 F3N3O2+H] + Calculated value: 418.1737, measured value: 418.1738. C 22 H 22 Analytical calculated for F3N3O2: C 63.30, H 5.31, N 10.07. Found: C 63.35, H 5.35, N 9.80.

[0115] Example 9: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide Synthesis of tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (264 mg, 1.32 mmol) in EtOAc (15 mL) was added N-boc-piperidine-4-carboxylic acid (263 mg, 1.20 mmol), HOBt (243 mg, 1.80 mmol), EDCI·HCl (345 mg, 1.80 mmol), and EtN (0.34 mL, 2.40 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 15 mL) and brine (3 × 10 mL), dried over anh.NaSO, filtered, and evaporated to give a beige solid (550 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (430 mg, 87% yield) as an off-white foamy solid. mp 163 °C. IR(ATR): 639 cm -1 , 675cm -1 , 771cm -1 , 818cm -1 , 839cm -1 , 880cm -1 , 931cm -1 , 1017cm -1 , 1055cm -1 , 1104cm -1 , 1143cm -1 , 1168cm -1 , 1225cm -1 , 1277cm -1 , 1319cm -1 , 1365cm -1 , 1416cm -1 , 1557cm -1 , 1651cm -1 , 1694cm -1 , 2845cm -1 , 2974cm -1 , 3077cm -1 , 3273cm -1 HRMS-ESI - m / z [MH] - [C 20 H 24 F3N3O3-H]- Calculated value: 410.1697, measured value: 410.1708. C 20 H 24 Analytical calculated for F3N3O3: C 58.39, H 5.88, N 10.21. Found: C 58.47, H 5.88, N 10.00.

[0116] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride To a solution of tert-butyl 4-((4-cyano-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (430 mg, 1.05 mmol) in DCM (2.5 mL) was added 4N HCl in dioxane (2.5 mL). The reaction mixture was stirred at RT for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride salt (384 mg, quantitative yield) as a white solid. HRMS-ESI + m / z [M+H] + [C 15 H 16 F3N3O+H] + Calculated value: 312.1318; Measured value: 312.1320.

[0117] Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.58 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 77 mg, 1.16 mmol), acetic acid (0.3 mL), and 3-fluorobenzaldehyde (108 mg, 0.87 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 40 mg, 0.61 mmol) and 3-fluorobenzaldehyde (60 mg, 0.48 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and to the resulting crude material was added water (20 mL). Then, 1N NaOH solution was added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellowish oil (309 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide (82 mg, 34% yield) as a white solid. mp 115-116 °C. IR (ATR): 638 cm -1 , 685cm -1 , 745cm -1 , 774cm -1 , 793cm -1 , 839cm -1 , 879cm -1 , 924cm -1 , 995cm -1 , 1025cm -1 , 1056cm -1 , 1108cm -1 , 1142cm -1 , 1171cm -1 , 1263cm -1 , 1317cm -1 , 1426cm -1 , 1447cm -1 , 1485cm -1 , 1543cm -1 , 1587cm -1 , 1615cm -1 , 1649cm -1, 2236cm -1 , 2762cm -1 , 2805cm -1 , 2942cm -1 , 3081cm -1 , 3282cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 21 F4N3O+H] + Calculated value: 420.1694, measured value: 420.1698. C 22 H 21 Analytical calculated for F4N3O: C 63.00, H 5.05, N 10.02. Found: C 62.78, H 5.07, N 10.00.

[0118] Example 10: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL), and 3-methylbenzaldehyde (130 mg, 1.08 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 50 mg, 0.76 mmol) and 3-methylbenzaldehyde (72 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. Then, 2N NaOH solution was added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an orange oil (392 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide (134 mg, 45% yield) as a beige solid. mp 110-111 °C. IR (ATR): 639 cm -1 , 671cm -1 , 692cm -1 , 765cm -1 , 793cm -1 , 840cm -1 , 881cm -1 , 927cm -1 , 1056cm -1 , 1105cm -1 , 1142cm -1 , 1171cm -1 , 1266cm -1 , 1296cm -1 , 1318cm -1 , 1368cm -1 , 1425cm -1 , 1496cm -1 , 1539cm -1 , 1649cm -1 , 2237cm -1 , 2756cm -1 , 2798cm -1, 2933cm -1 , 3064cm -1 , 3287cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 24 F3N3O+H] + Calculated value: 416.1944, measured value: 416.1943. C 23 H 24 Analytical calculated for F3N3O: C 66.49, H 5.82, N 10.11. Found: C 62.27, H 5.85, N 10.10.

[0119] Example 11: Synthesis of 1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4-carboxamide To a solution of 2,4-dichloro-5-fluorobenzylamine (321 mg, 1.65 mmol) in EtOAc (20 mL) was added 1-benzylpiperidine-4-carboxylic acid (329 mg, 1.50 mmol), HOBt (306 mg, 2.26 mmol), EDCI·HCl (433 mg, 2.26 mmol), and EtN (0.4 mL, 2.71 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (15 mL), dried over anh. NaSO, filtered, and evaporated to give 1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4-carboxamide (403 mg, 68% yield) as a white solid. An analytical sample was obtained by crystallization from hot ethyl acetate. mp 114℃~115℃. IR(ATR):732cm -1 , 876cm -1 , 992cm -1 , 1027cm -1 , 1088cm -1 , 1139cm -1 , 1230cm -1 , 1270cm -1 , 1384cm -1 , 1421cm -1 , 1474cm -1 , 1549cm -1, 1641cm -1 , 1744cm -1 , 2799cm -1 , 2946cm -1 , 3253cm -1 , 3668cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 Cl2FN2O+H] + Calculated value: 395.10, Measured value: 395.4083. C 20 H 21 Analysis calculated for Cl2FN2O·0.25H2O: C 60.08, H 5.42, N 7.01. Found: C 60.02, H 5.56, N 6.72.

[0120] Example 12: Synthesis of 1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide To a solution of (2,3,5-trichlorophenyl)methanamine (589 mg, 2.80 mmol) in EtOAc (15 mL) was added 1-benzylpiperidine-4-carboxylic acid (557 mg, 2.54 mmol), HOBt (515 mg, 3.81 mmol), EDCI·HCl (730 mg, 3.81 mmol), and EtN (0.5 mL, 4.57 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (15 mL), dried over anh.NaSO, filtered, and evaporated to give a yellow oil. Column chromatography (4 g, SiO2, DCM / MeOH mixture) afforded 1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide (364 mg, 35% yield) as a white solid. mp 127-128 °C. IR (ATR): 737 cm -1 , 813cm -1 , 994cm -1 , 1048cm -1 , 1108cm -1 , 1230cm -1 , 1384cm -1 , 1414cm -1, 1534cm -1 , 1640cm -1 , 1656cm -1 , 2823cm -1 , 2893cm -1 , 3068cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 Cl3N2O+H] + Calculated value: 411.07, measured value: 411.0711. C 20 H 21 Cl3N2O Analysis: C 58.34, H 5.14, N 6.80. Found: C 57.97, H 5.09, N 6.61.

[0121] Example 13: Synthesis of N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide Synthesis of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride To a solution of tert-butyl 4-((2,4-dichlorobenzyl)carbamoyl)piperidine-1-carboxylate (750 mg, 1.94 mmol, synthesized as in WO2009097476) in DCM (5 mL) was added 4N HCl in dioxane (5 mL). The reaction mixture was stirred at RT for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride salt (640 mg, quantitative yield) as an off-white solid. The product was used in the next reaction without further purification. HRMS-ESI + m / z [M+H] + [C 13 H 16 Cl2N2O+H] + Calculated value: 287.0712, measured value: 287.0715.

[0122] Synthesis of N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (350 mg, 1.08 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 143 mg, 2.16 mmol), acetic acid (0.4 mL), and 3-fluorobenzaldehyde (201 mg, 1.62 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 75 mg, 1.14 mmol) and 3-fluorobenzaldehyde (112 mg, 0.90 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. 2N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an orange oil (636 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide (175 mg, 41% yield) as a colorless gummish solid. An analytical sample (119 mg) was obtained by a second column chromatography purification (SiO2, DCM / MeOH mixtures). mp 116-117 °C. IR (ATR): 669 cm -1 , 685cm -1 , 722cm -1 , 780cm -1 , 795cm -1 , 867cm -1 , 925cm -1 , 996cm -1 , 1045cm -1 , 1104cm -1 , 1120cm -1 , 1146cm -1 , 1231cm -1 , 1255cm -1 , 1300cm -1 , 1322cm -1 , 1338cm -1 , 1421cm -1 , 1444cm -1 , 1472cm -1, 1487cm -1 , 1555cm -1 , 1567cm -1 , 1594cm -1 , 1650cm -1 , 2756cm -1 , 2799cm -1 , 2919cm -1 , 2925cm -1 , 2944cm -1 , 3092cm -1 , 3289cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 Cl2FN2O+H] + Calculated value: 395.1088, measured value: 395.1086. C 20 H 21 Analytical calculated for Cl2FN2O: C 60.77, H 5.35, N 7.09. Found: C 60.75, H 5.34, N 7.04.

[0123] Example 14: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL), and 3-chlorobenzaldehyde (152 mg, 1.08 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 50 mg, 0.76 mmol) and 3-chlorobenzaldehyde (84 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. 2N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellow oil (461 mg). Column chromatography (SiO2, DCM / MeOH mixture) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide (128 mg, 41% yield) as an off-white solid. An analytical sample (81 mg) was obtained by a second column chromatography purification (SiO2, DCM / MeOH mixture). mp 143-145 °C. IR (ATR): 637 cm -1 , 674cm -1 , 682cm -1 , 694cm -1 , 780cm -1 , 794cm -1 , 829cm -1 , 850cm -1 , 932cm -1 , 998cm -1 , 1055cm -1 , 1091cm -1 , 1114cm -1 , 1141cm -1 , 1170cm -1 , 1264cm -1 , 1304cm -1 , 1323cm -1 , 1367cm -1 , 1424cm -1, 1475cm -1 , 1547cm -1 , 1646cm -1 , 2234cm -1 , 2762cm -1 , 2805cm -1 , 2935cm -1 , 3075cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 21 ClF3N3O+H] + Calculated value: 436.1398, measured value: 436.1393. C 22 H 21 Analytical calculated for ClF3N3O: C 60.62, H 4.86, N 9.64. Found: C 60.47, H 4.69, N 9.40.

[0124] Example 15: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL), and 4-fluorobenzaldehyde (134 mg, 1.08 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 50 mg, 0.76 mmol) and 4-fluorobenzaldehyde (75 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and to the resulting crude material was added water (20 mL). Then, 2N NaOH solution was added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an orange oil (475 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (108 mg, 36% yield) as an off-white crystalline solid. mp 169-170°C. IR (ATR): 589 cm -1 , 638cm -1 , 667cm -1 , 681cm -1 , 768cm -1 , 824cm -1 , 836cm -1 , 859cm -1 , 925cm -1 , 989cm -1 , 1056cm -1 , 1091cm -1 , 1121cm -1 , 1146cm -1 , 1164cm -1 , 1220cm -1 , 1225cm -1 , 1294cm -1 , 1320cm -1 , 1423cm -1 , 1507cm -1 , 1554cm -1 , 1645cm-1 , 2239cm -1 , 2916cm -1 , 2945cm -1 , 3079cm -1 , 3311cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 21 F4N3O+H] + Calculated value: 420.1694; Measured value: 420.1686. C 22 H 21 Analysis calculated for F4N3O·0.35CH3OH: C 62.34, H 5.24, N 9.76. Found: C 62.13, H 4.99, N 9.67.

[0125] Example 16: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.86 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 114 mg, 1.72 mmol), acetic acid (0.4 mL), and 4-iodobenzaldehyde (299 mg, 1.29 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 60 mg, 0.91 mmol) and 4-iodobenzaldehyde (167 mg, 0.72 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and to the resulting crude material was added water (20 mL). 1N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an orange oil (746 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (180 mg, 40% yield) as an off-white crystalline solid. mp 144-146 °C. IR (ATR): 638 cm -1 , 670cm -1 , 786cm -1 , 800cm -1 , 928cm -1 , 990cm -1 , 1006cm -1 , 1057cm -1 , 1117cm -1 , 1138cm -1 , 1174cm -1 , 1267cm -1 , 1298cm -1 , 1319cm -1 , 1386cm -1 , 1421cm -1 , 1446cm -1 , 1481cm -1 , 1541cm -1 , 1649cm -1 , 2236cm -1 , 2755cm -1 , 2787cm-1 , 2938cm -1 , 3282cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 21 F3IN3O+H] + Calculated value: 528.0754, measured value: 528.0750. C 22 H 21 Analytical calculated for F3IN3O: C 50.11, H 4.01, N 7.97. Found: C 50.16, H 3.74, N 7.74.

[0126] Example 17: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (350 mg, 1.01 mmol) in MeOH (6 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 134 mg, 2.02 mmol), acetic acid (0.4 mL), and thiophene-2-carbaldehyde (169 mg, 1.51 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 70 mg, 1.06 mmol) and thiophene-2-carbaldehyde (94 mg, 0.84 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. 1N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an orange oil (506 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide (167 mg, 41% yield) as an off-white crystalline solid. mp 136-137°C. IR (ATR): 639 cm -1 , 696cm -1 , 840cm-1 , 881cm -1 , 927cm -1 , 992cm -1 , 1023cm -1 , 1054cm -1 , 1105cm -1 , 1140cm -1 , 1171cm -1 , 1263cm -1 , 1317cm -1 , 1369cm -1 , 1423cm -1 , 1538cm -1 , 1649cm -1 , 2236cm -1 , 2762cm -1 , 2803cm -1 , 2937cm -1 , 3065cm -1 , 3081cm -1 , 3291cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 20 F3N3OS+H] + Calculated value: 408.1352, measured value: 408.1352. C 20 H 20 Analytical Calculated for F3N3OS: C 58.96, H 4.95, N 10.31, S 7.87. Found: C 58.89, H 4.99, N 10.27, S 7.59.

[0127] Example 18: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.86 mmol) in MeOH (6 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 114 mg, 1.72 mmol), acetic acid (0.4 mL), and thiophene-3-carbaldehyde (145 mg, 1.29 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 60 mg, 0.91 mmol) and thiophene-3-carbaldehyde (81 mg, 0.72 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. 1N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an orange oil (433 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (147 mg, 42% yield) as an off-white solid. mp 122-124 °C. IR (ATR): 638 cm -1 , 673cm -1 , 766cm -1 , 794cm -1 , 839cm -1 , 882cm -1 , 929cm -1 , 994cm -1 , 1056cm -1 , 1106cm -1 , 1141cm -1 , 1172cm -1 , 1267cm -1 , 1296cm -1 , 1319cm -1 , 1372cm -1 , 1424cm -1 , 1449cm -1 , 1540cm -1 , 1650cm -1 , 2237cm -1 , 2751cm -1 , 2786cm-1 , 2935cm -1 , 3080cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 20 F3N3OS+H] + Calculated value: 408.1352, measured value: 408.1351.

[0128] Example 19: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.72 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 95 mg, 1.44 mmol), acetic acid (0.3 mL), and 4-methoxybenzaldehyde (147 mg, 1.08 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 50 mg, 0.76 mmol) and 4-methoxybenzaldehyde (82 mg, 0.60 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. 1N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a colorless oil (443 mg). Column chromatography (SiO2, DCM / MeOH mixture) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (111 mg, 36% yield) as a white solid. An analytical sample (79 mg) was obtained by a second column chromatography purification (SiO2, DCM / MeOH mixture). mp 119-120 °C. IR (ATR): 591 cm -1 , 638cm -1 , 671cm -1 , 706cm -1, 785cm -1 , 806cm -1 , 840cm -1 , 928cm -1 , 993cm -1 , 1024cm -1 , 1036cm -1 , 1056cm -1 , 1105cm -1 , 1142cm -1 , 1170cm -1 , 1259cm -1 , 1318cm -1 , 1366cm -1 , 1425cm -1 , 1515cm -1 , 1538cm -1 , 1617cm -1 , 1649cm -1 , 2237cm -1 , 2756cm -1 , 2799cm -1 , 2934cm -1 , 3063cm -1 , 3290cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 24 F3N3O2+H] + Calculated value: 432.1893, measured value: 432.1893.

[0129] Example 20: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.86 mmol) in MeOH (5 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 114 mg, 1.72 mmol), acetic acid (0.4 mL), and 2-phenylacetaldehyde (155 mg, 1.29 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 60 mg, 0.91 mmol) and 2-phenylacetaldehyde (87 mg, 0.72 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. 1N NaOH solution was then added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 10 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give an off-white solid (640 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide (134 mg, 38% yield) as a white solid. mp 189-191 °C. IR (ATR): 638 cm -1 , 671cm -1 , 698cm -1 , 742cm -1 , 841cm -1 , 881cm -1 , 927cm -1 , 994cm -1 , 1024cm -1 , 1057cm -1 , 1105cm -1 , 1141cm -1 , 1171cm -1 , 1230cm -1 , 1267cm -1 , 1291cm -1 , 1318cm -1 , 1371cm -1 , 1425cm -1 , 1449cm -1 , 1496cm -1 , 1540cm -1 , 1649cm -1, 2237cm -1 , 2768cm -1 , 2810cm -1 , 2940cm -1 , 3067cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 24 F3N3O+H] + Calculated value: 416.1944, measured value: 416.1944.

[0130] Example 21: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (234 mg, 0.72 mmol) in MeOH (4 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 91 mg, 1.44 mmol), acetic acid (0.3 mL), and 4-methoxybenzaldehyde (148 mg, 1.09 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 50.3 mg, 0.76 mmol) and 4-methoxybenzaldehyde (83.1 mg, 0.61 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the resulting crude material. Then, 2N NaOH solution was added until a basic pH was reached, and the aqueous phase was extracted with EtOAc (3 x 20 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo to give an orange oil (546 mg). Column chromatography (SiO2, DCM / MeOH mixtures) afforded N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (138 mg, 47% yield) as an off-white solid. mp 133 °C. IR (ATR): 570 cm -1 , 640cm -1 , 691cm -1 , 742cm -1 , 793cm -1 , 809cm -1, 817cm -1 , 831cm -1 , 866cm -1 , 982cm -1 , 995cm -1 , 1030cm -1 , 1099cm -1 , 1121cm -1 , 1144cm -1 , 1167cm -1 , 1223cm -1 , 1244cm -1 , 1297cm -1 , 1330cm -1 , 1384cm -1 , 1422cm -1 , 1469cm -1 , 1509cm -1 , 1546cm -1 , 1643cm -1 , 2754cm -1 , 2793cm -1 , 2938cm -1 , 2955cm -1 , 3072cm -1 , 3281cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 24 Cl2N2O2+H] + Calculated value: 407.1288, measured value: 407.1293. C 21 H 24 Analytical calculated for Cl2N2O2: C 61.92, H 5.94, N 6.88. Found: C 61.71, H 5.90, N 6.69.

[0131] Example 22: Synthesis of 1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (239 mg, 1.09 mmol) and EtN (0.41 mL, 2.97 mmol) in EtOAc (6 mL) was added 4-(aminomethyl)-3-chlorobenzonitrile (165 mg, 0.99-0.88 mmol, synthesized as in WO 2009049157), HOBt (200 mg, 1.48 mmol), and EDCI·HCl (284 mg, 1.48 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with saturated NaSO (2 × 20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO2, hexane / EtOAc mixtures) to give 1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide (70 mg, 19% yield) as a beige solid. mp 158-159 °C. IR(ATR): 589 cm -1 , 696cm -1 , 732cm -1 , 791cm -1 , 871cm -1 , 992cm -1 , 1051cm -1 , 1128cm -1 , 1196cm -1 , 1228cm -1 , 1295cm -1 , 1321cm -1 , 1340cm -1 , 1411cm -1 , 1446cm -1 , 1540cm -1 , 1647cm -1 , 2234cm -1 , 2756cm -1 , 2798cm -1 , 2927cm -1 , 2948cm -1 , 3069cm -1 , 3266cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClNO+H] +Calculated value: 368.1524; Measured value: 368.1520. C 21 H 22 Analytical calculated for ClN3O: C 68.56, H 6.03, N 11.42. Found: C 68.51, H 5.89, N 11.23.

[0132] Example 23: Synthesis of 1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (30 mg, 0.14 mmol) and EtN (60 μL, 0.41 mmol) in EtOAc (1 mL) was added 4-bromo-2-chlorobenzylamine (31 mg, 0.14 mmol), HOBt (27 mg, 0.20 mmol), and EDCI·HCl (39 mg, 0.20 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (30 mL) was added, and the mixture was washed with water (3 × 30 mL). The organic layer was dried over anh. Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO2, DCM / MeOH mixtures) to give 1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4-carboxamide (30 mg, 51% yield) as a white solid. mp 117-118 °C. IR(ATR):605cm -1 , 697cm -1 , 735cm -1 , 813cm -1 , 863cm -1 , 988cm -1 , 1046cm -1 , 1268cm -1 , 1295cm -1 , 1380cm -1 , 1469cm -1 , 1538cm -1 , 1584cm -1 , 1645cm -1 , 2757cm -1 , 2801cm -1 , 2921cm -1 , 3063cm -1 , 3278cm -1 HRMS-ESI +m / z [M+H] + [C 21 H 22 BrClNO+H] + Calculated value: 421.0677; Measured value: 421.0682. C 21 H 22 Analytical calculated for BrClN2O: C 56.96, H 5.26, N 6.64. Found: C 56.87, H 5.24, N 6.37.

[0133] Example 24: Synthesis of 1-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (136 mg, 0.62 mmol) and EtN (0.23 mL, 1.68 mmol) in EtOAc (4 mL) was added 4-bromo-2-(trifluoromethyl)benzylamine (142 mg, 0.56 mmol), HOBt (114 mg, 0.84 mmol), and EDCI·HCl (161 mg, 0.84 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with water (3 × 20 mL). The organic layer was dried over anh.Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, DCM / MeOH mixtures) to give 1-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (34 mg, 13% yield) as a white solid. mp 88℃~89℃. IR(ATR):669cm -1 , 698cm -1 , 732cm -1 , 827cm -1 , 889cm -1 , 1048cm -1 , 1125cm -1 , 1165cm -1 , 1304cm -1 , 1411cm -1 , 1556cm -1 , 1646cm -1 , 2802cm -1 , 2942cm -1 , 3073cm -1, 3273cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 BrF3N2O+H] + Calculated value: 455.0940; Measured value: 455.0941.

[0134] Example 25: Synthesis of 1-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (105 mg, 0.48 mmol) and EtN (0.18 mL, 1.32 mmol) in EtOAc (3 mL) was added (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (99 mg, 0.44 mmol), HOBt (84 mg, 0.62 mmol), and EDCI·HCl (119 mg, 0.62 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with water (3 × 20 mL). The organic layer was dried over anh.NaSO, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO, hexane / EtOAc mixtures) to give 1-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (70 mg, 37% yield) as a white solid. mp 97℃~98℃. IR(ATR):585cm -1 , 638cm -1 , 697cm -1 , 735cm -1 , 792cm -1 , 854cm -1 , 947cm -1 , 989cm -1 , 1067cm -1 , 1164cm -1 , 1207cm -1 , 1252cm -1 , 1450cm -1 , 1488cm -1 , 1552cm -1 , 1642cm -1 , 2765cm -1, 2945cm -1 , 3085cm -1 , 3287cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClF3N2O2+H] + Calculated value: 427.1395; Measured value: 427.1397. C 21 H 22 Analytical calculated for ClF3N2O2: C 59.09, H 5.19, N 6.56. Found: C 58.83, H 5.25, N 6.25.

[0135] Example 26: Synthesis of 1-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (167 mg, 0.76 mmol) and EtN (0.29 mL, 2.07 mmol) in EtOAc (5 mL) was added (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine (153 mg, 0.69 mmol), HOBt (141 mg, 1.04 mmol), and EDCI·HCl (199 mg, 1.04 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with water (3 × 20 mL). The organic layer was dried over anh.NaSO, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO, hexane / EtOAc mixtures) to give 1-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (104 mg, 36% yield) as a white solid. mp 90℃~91℃. IR(ATR):643cm -1 , 698cm -1 , 727cm -1 , 844cm -1 , 878cm -1 , 971cm -1 , 994cm -1 , 1032cm -1 , 1145cm -1 , 1206cm -1, 1288cm -1 , 1435cm -1 , 1508cm -1 , 1548cm -1 , 1642cm -1 , 2801cm -1 , 2942cm -1 , 3294cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F3N2O3+H] + Calculated value: 423.1890; Measured value: 423.1894.

[0136] Example 27: Synthesis of 1-benzyl-N-(2-chloro-3-(trifluoromethyl)benzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (92 mg, 0.42 mmol) and EtN (0.16 mL, 1.14 mmol) in EtOAc (1.5 mL) was added (2-chloro-3-(trifluoromethyl)benzylamine (80 mg, 0.38 mmol), HOBt (77 mg, 0.57 mmol), and EDCI·HCl (109 mg, 0.57 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with water (2 × 20 mL). The organic layer was dried over anh. Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO2, DCM / MeOH mixtures) to give 1-benzyl-N-(2-chloro-3-(trifluoromethyl)benzyl)piperidine-4-carboxamide (50 mg, 32% yield) as a white solid. 120℃~121℃. IR(ATR):598cm -1 , 696cm -1 , 735cm -1 , 769cm -1 , 788cm -1 , 990cm -1 , 1091cm -1 , 1119cm -1 , 1163cm -1 , 1228cm -1 , 1295cm-1 , 1327cm -1 , 1433cm -1 , 1554cm -1 , 1645cm -1 , 2767cm -1 , 2809cm -1 , 2945cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClF3N2O+H] + Calculated value: 411.1446; Measured value: 411.1445. C 21 H 22 Analytical calculated for ClF3N2O: C 61.39, H 5.40, N 6.82. Found: C 61.53, H 5.57, N 6.55.

[0137] Example 28: Synthesis of 1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (138 mg, 0.63 mmol) and EtN (0.24 mL, 1.71 mmol) in EtOAc (3 mL) was added 2,3-dichlorobenzylamine (100 mg, 0.57 mmol), HOBt (115 mg, 0.85 mmol), and EDCI·HCl (163 mg, 0.85 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with water (2 × 20 mL). The organic layer was dried over anh.Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO2, DCM / MeOH mixtures) to give 1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4-carboxamide (101 mg, 47% yield) as a white solid. mp 124℃~125℃. IR(ATR):694cm -1 , 731cm -1 , 786cm -1 , 992cm -1 , 1120cm -1 , 1221cm -1 , 1297cm-1 , 1329cm -1 , 1414cm -1 , 1448cm -1 , 1543cm -1 , 1636cm -1 , 2753cm -1 , 2941cm -1 , 3068cm -1 , 3278cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 22 Cl2N2O+H] + Calculated value: 377.1182, measured value: 377.1180. C 20 H 22 Analytical calculated for Cl2N2O: C 63.67, H 5.88, N 7.42. Found: C 63.72, H 5.96, N 7.40.

[0138] Example 29: Synthesis of 1-benzyl-N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (125 mg, 0.57 mmol) and EtN (0.22 mL, 1.56 mmol) in EtOAc (3 mL) was added 4-fluoro-2-(trifluoromethyl)benzylamine (100 mg, 0.52 mmol), HOBt (105 mg, 0.78 mmol), and EDCI·HCl (150 mg, 0.78 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with water (2 × 20 mL). The organic layer was dried over anh.Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO2, DCM / MeOH mixtures) to give 1-benzyl-N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (108 mg, 53% yield) as a white solid. mp 112℃~113℃. IR(ATR):668cm -1 , 698cm -1 , 714cm -1 , 735cm -1, 884cm -1 , 903cm -1 , 991cm -1 , 1046cm -1 , 1122cm -1 , 1163cm -1 , 1212cm -1 , 1316cm -1 , 1427cm -1 , 1494cm -1 , 1567cm -1 , 1641cm -1 , 2803cm -1 , 2947cm -1 , 3086cm -1 , 3251cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 F4N2O+H] + Calculated value: 395.1741, measured value: 395.1739. C 21 H 22 Analytical calculated for F4N2O: C 63.95, H 5.62, N 7.10. Found: C 63.98, H 5.63, N 6.87.

[0139] Example 30: Synthesis of 1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide To a solution of 1-benzylpiperidine-4-carboxylic acid (116 mg, 0.53 mmol) and EtN (0.20 mL, 1.44 mmol) in EtOAc (3 mL) was added 4-chloro-2-(trifluoromethyl)benzylamine (100 mg, 0.48 mmol), HOBt (97 mg, 0.72 mmol), and EDCI·HCl (138 mg, 0.72 mmol). The reaction mixture was stirred at RT for 16 h. Then, EtOAc (15 mL) was added, and the mixture was washed with saturated NaCO (2 × 20 mL) and brine (20 mL). The organic layer was dried over anh. NaSO, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO2, DCM / MeOH mixtures) to give 1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (155 mg, 79% yield) as a white solid. mp 97-98 °C. IR(ATR): 678 cm -1 , 697cm -1 , 737cm -1 , 839cm -1 , 891cm -1 , 991cm -1 , 1047cm -1 , 1137cm -1 , 1157cm -1 , 1261cm -1 , 1300cm -1 , 1416cm -1 , 1556cm -1 , 1650cm -1 , 2807cm -1 , 2947cm -1 , 3086cm -1 , 3273cm -1 .C 21 H 22 Analytical calculated for ClF3N2O: C 61.39, H 5.40, N 6.82. Found: C 61.64, H 5.45, N 6.61.

[0140] Example 31: Synthesis of 1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide A mixture of 1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (215 mg, 0.46 mmol, see Example 5), sodium methanesulfinate (70.4 mg, 0.69 mmol), N,N'-dimethylethylenediamine (0.06 mL, 0.55 mmol), water (0.3 mL, 16.6 mmol), and CuI (104.7 mg, 0.55 mmol) in DMF (3 mL) was heated in a microwave reactor at 120 °C for 2 h. After cooling to ambient temperature, the mixture was filtered through a pad of Celite™ using EtOAc as the eluent. EtOAc (20 mL) was then added to the filtrate, which was washed with water acidified to pH = 3 with 2 N HCl solution (3 × 40 mL). The organic layer was dried over anh. Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by column chromatography (SiO, DCM / MeOH mixtures) to give 1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (23 mg, 11% yield) as a white solid. An analytical sample was obtained by washing with EtO (2 x 5 mL). mp 170-171 °C. IR (ATR): 592 cm -1 , 637cm -1 , 699cm -1 , 738cm -1 , 765cm -1 , 793cm -1 , 820cm -1 , 857cm -1 , 947cm -1 , 973cm -1 , 1031cm -1 , 1087cm -1 , 1128cm -1 , 1150cm -1 , 1171cm -1 , 1208cm -1 , 1258cm -1 , 1314cm -1 , 1357cm -1 , 1404cm -1 , 1416cm -1 , 1462cm -1 , 1494cm -1, 1635cm -1 , 2421cm -1 , 2766cm -1 , 2812cm -1 , 2946cm -1 , 3028cm -1 , 3083cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F3N2O4S+H] + Calculated value: 471.1560; Measured value: 471.1562.

[0141] Example 32: Synthesis of 1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide To a solution of (2-chloro-3-fluorophenyl)methanamine (276 mg, 1.73 mmol) in EtOAc (20 mL) was added 1-benzylpiperidine-4-carboxylic acid (344 mg, 1.57 mmol), HOBt (319 mg, 2.36 mmol), EDCI·HCl (452 ​​mg, 2.36 mmol), and EtN (0.4 mL, 2.83 mmol). The reaction mixture was stirred at RT for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (15 mL), dried over anh. NaSO, filtered, and evaporated to give a clear oil. Column chromatography (4 g, SiO, DCM / MeOH mixtures) afforded 1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide (394 mg, 69% yield) as a white solid. mp 140℃~141℃. IR(ATR):732cm -1 , 991cm -1 , 1067cm -1 , 1171cm -1 , 1266cm -1 , 1362cm -1 , 1422cm -1 , 1446cm -1 , 1488cm -1 , 1542cm -1 , 1639cm -1, 1744cm -1 , 2798cm -1 , 2935cm -1 , 3048cm -1 , 3265cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 22 ClFNO+H] + Calculated value: 361.14, Measured value: 361.1467. C 20 H 22 Analytical calculated for ClFN2O: C 66.57, H 6.15, N 7.76. Found: C 66.55, H 6.23, N 7.66.

[0142] Example 33: Synthesis of 1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4-carboxamide (336 mg, 86% yield) was obtained from (3-bromo-2-chlorophenyl)methanamine (225 mg, 1.02 mmol) as an orange solid. mp 122°C-123°C. IR (ATR): 697 cm -1 , 724cm -1 , 770cm -1 , 831cm -1 , 905cm -1 , 991cm -1 , 1025cm -1 , 1096cm -1 , 1118cm -1 , 1145cm -1 , 1230cm -1 , 1265cm -1 , 1335cm -1 , 1365cm -1 , 1417cm -1 , 1447cm -1 , 1493cm -1 , 1560cm -1 , 1638cm -1 , 2762cm -1 , 2804cm -1 , 2939cm -1 , 3245cm-1 HRMS-ESI + m / z [M+H] + [C 20 H 22 BrClNO+H] + Calculated value: 423.06, measured value: 423.0644. C 20 H 22 Analytical calculated for BrClNO: C 56.96, H 5.26, N 6.51. Found: C 56.70, H 5.14, N 6.51.

[0143] Example 34: Synthesis of 1-benzyl-N-(3-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(3-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (395 mg, 79% yield) was obtained from (3-fluoro-2-(trifluoromethyl)phenyl)methanamine (270 mg, 1.40 mmol) as an orange solid. mp 109°C-110°C. IR (ATR): 697 cm -1 , 735cm -1 , 785cm -1 , 988cm -1 , 1035cm -1 , 1056cm -1 , 1119cm -1 , 1188cm -1 , 1266cm -1 , 1288cm -1 , 1337cm -1 , 1365cm -1 , 1423cm -1 , 1439cm -1 , 1475cm -1 , 1556cm -1 , 1585cm -1 , 1644cm -1 , 2760cm -1 , 2797cm -1 , 2936cm -1 , 3087cm -1 , 3296cm -1 HRMS-ESI + m / z [M+H] +[C 21 H 22 F4N2O+H] + Calculated value: 395.17, Measured value: 395.1729. C 21 H 22 Analytical calculated for F4N2O: C 63.95, H 5.62, N 7.10. Found: C 64.04, H 5.81, N 7.05.

[0144] Example 35: Synthesis of 1-benzyl-N-(3-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(3-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (346 mg, 59% yield) was obtained from (3-chloro-2-(trifluoromethyl)phenyl)methanamine (300 mg, 1.43 mmol) as a beige solid. mp 95°C-96°C. IR (ATR): 696 cm -1 , 732cm -1 , 780cm -1 , 844cm -1 , 991cm -1 , 1035cm -1 , 1121cm -1 , 1169cm -1 , 1228cm -1 , 1282cm -1 , 1338cm -1 , 1366cm -1 , 1448cm -1 , 1494cm -1 , 1543cm -1 , 1642cm -1 , 2758cm -1 , 2803cm -1 , 2936cm -1 , 3266cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClF3N2O+H] + Calculated value: 411.14, Measured value: 411.1440. C 21 H 22Analytical calculated for ClF3N2O·0.25H2O: C 60.72, H 5.46, N 6.74. Found: C 60.93, H 5.73, N 6.42.

[0145] Example 36: Synthesis of 1-benzyl-N-(3-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(3-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (248 mg, 70% yield) was obtained from (3-methoxy-2-(trifluoromethyl)phenyl)methanamine (197 mg, 0.96 mmol) as a white solid. mp 120°C-121°C. IR (ATR): 697 cm -1 , 735cm -1 , 785cm -1 , 988cm -1 , 1035cm -1 , 1056cm -1 , 1119cm -1 , 1188cm -1 , 1266cm -1 , 1288cm -1 , 1337cm -1 , 1365cm -1 , 1423cm -1 , 1439cm -1 , 1475cm -1 , 1556cm -1 , 1585cm -1 , 1644cm -1 , 2760cm -1 , 2797cm -1 , 2936cm -1 , 3087cm -1 , 3296cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F3N2O2+H] + Calculated value: 407.19, measured value: 407.1945. C 22 H 25Analytical calculated for F3N2O2: C 65.01, H 6.20, N 6.89. Found: C 64.99, H 6.34, N 6.87.

[0146] Example 37: Synthesis of 1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4-carboxamide (355 mg, 70% yield) was obtained from (4-bromo-2-fluorophenyl)methanamine (280 mg, 1.37 mmol) as a salmon-colored solid. mp 102°C-103°C. IR (ATR): 696 cm -1 , 729cm -1 , 746cm -1 , 818cm -1 , 865cm -1 , 985cm -1 , 1176cm -1 , 1211cm -1 , 1265cm -1 , 1361cm -1 , 1448cm -1 , 1481cm -1 , 1547cm -1 , 1638cm -1 , 2748cm -1 , 2794cm -1 , 2933cm -1 , 3070cm -1 , 3286cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 22 BrFNO+H] + Calculated value: 405.09, Measured value: 405.0973. C 20 H 22 Analytical calculated for BrFN2O: C 59.27, H 5.47, N 6.91. Found: C 59.24, H 5.59, N 6.84.

[0147] Example 38: Synthesis of 1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4-carboxamide (456 mg, 73% yield) was obtained from (2-chloro-4-methoxyphenyl)methanamine (315 mg, 1.84 mmol) as a beige solid. mp 92°C-93°C. IR (ATR): 693 cm -1 , 735cm -1 , 816cm -1 , 853cm -1 , 885cm -1 , 984cm -1 , 1052cm -1 , 1117cm -1 , 1213cm -1 , 1239cm -1 , 1283cm -1 , 1451cm -1 , 1494cm -1 , 1547cm -1 , 1638cm -1 , 2768cm -1 , 2818cm -1 , 2939cm -1 , 3283cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 25 ClN2O2+H] + Calculated value: 373.16, Measured value: 373.1679. C 21 H 25 Analytical calculated for ClN2O2: C 67.64, H 6.76, N 7.51. Found: C 67.64, H 6.71, N 7.49.

[0148] Example 39: Synthesis of 1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4-carboxamide According to the procedure of Example 32, 1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4-carboxamide (157 mg, 84% yield) was obtained from (2-bromo-4-chlorophenyl)methanamine hydrochloride (108 mg, 0.49 mmol) as a beige solid. mp 116°C-117°C. IR (ATR): 696 cm-1 , 734cm -1 , 807cm -1 , 860cm -1 , 993cm -1 , 1031cm -1 , 1122cm -1 , 1228cm -1 , 1256cm -1 , 1293cm -1 , 1421cm -1 , 1445cm -1 , 1484cm -1 , 1554cm -1 , 1647cm -1 , 2755cm -1 , 2923cm -1 , 2943cm -1 , 3086cm -1 , 3288cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 22 BrClNO+H] + Calculated value: 423.06, measured value: 423.0657. C 20 H 22 Analytical calculated for BrClNO: C 56.96, H 5.26, N 6.64. Found: C 56.84, H 5.35, N 6.73.

[0149] Example 40: Synthesis of N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) in MeOH (10 mL) was prepared in a round-bottom flask equipped with a CaCl tube. NaBHCN (95%, 176 mg, 2.80 mmol), acetic acid (0.4 mL), and 2-phenylacetaldehyde (253 mg, 2.10 mmol) were added. The mixture was stirred at RT for 2 h. Additional NaBHCN (95%, 92 mg, 1.47 mmol) and 2-phenylacetaldehyde (140 mg, 1.16 mmol) were then added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (5 mL) and saturated aqueous NaHCO were added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a white solid. Column chromatography (10 g, Al2O3, DCM / MeOH mixture) followed by a second column chromatography (10 g, SiO2, Hex / AcOEt / MeOH mixture) afforded N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide (208 mg, 38% yield) as a white solid. mp 158-159 °C. IR (ATR): 670 cm -1 , 767cm -1 , 833cm -1 , 856cm -1 , 913cm -1 , 993cm -1 , 1054cm -1 , 1084cm -1 , 1117cm -1 , 1164cm -1 , 1197cm -1 , 1228cm -1 , 1277cm -1 , 1345cm -1 , 1424cm -1 , 1446cm -1 , 1543cm -1 , 1647cm -1 , 2784cm -1 , 2940cm -1 , 3290cm -1 HRMS-ESI + m / z [M+H]+ [C 21 H 24 Cl2N2O+H] + Calculated value: 391.13, measured value: 391.1336. C 21 H 24 Analytical calculated for Cl2N2O: C 64.45, H 6.18, N 7.16. Found: C 64.39, H 6.13, N 6.85.

[0150] Example 41: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (430 mg, 1.33 mmol) in MeOH (15 mL) was prepared in a round-bottom flask equipped with a CaCl tube. NaBHCN (95%, 174 mg, 2.76 mmol), acetic acid (0.4 mL), and 2-naphthaldehyde (323 mg, 2.07 mmol) were added. The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 91 mg, 1.45 mmol) and 2-naphthaldehyde (143 mg, 1.15 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (5 mL) and saturated aqueous NaHCO were added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture) followed by column chromatography (10 g, SiO2, Hex / AcOEt / MeOH mixture) to give N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4-carboxamide (257 mg, 38% yield) as a white solid. mp 166-167 °C. IR (ATR): 672 cm -1 , 751cm -1 , 830cm -1 , 865cm -1 , 888cm -1 , 948cm -1, 995cm -1 , 1072cm -1 , 1106cm -1 , 1151cm -1 , 1223cm -1 , 1281cm -1 , 1323cm -1 , 1439cm -1 , 1546cm -1 , 1591cm -1 , 1630cm -1 , 2868cm -1 , 2943cm -1 , 3073cm -1 , 3289cm -1 HRMS-ESI + m / z [M+H] + [C 26 H 24 F3N3O+H] + Calculated value: 452.19, Measured value: 452.1939. C 26 H 24 Analytical calculated for F3N3O·0.5H2O: C 67.81, H 5.47, N 9.12. Found: C 67.87, H 5.42, N 8.94.

[0151] Example 42: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (480 mg, 1.38 mmol) in MeOH (15 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 174 mg, 2.76 mmol), acetic acid (0.4 mL), and 2-fluorobenzaldehyde (323 mg, 2.6 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 68 mg, 1.08 mmol) and 2-fluorobenzaldehyde (143 mg, 1.15 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (5 mL) and saturated aqueous NaHCO were added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). Further purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide (216 mg, 37% yield) as a white solid. mp 120-121 °C. IR (ATR): 670 cm -1 , 750cm -1 , 839cm -1 , 881cm -1 , 926cm -1 , 995cm -1 , 1025cm -1 , 1055cm -1 , 1105cm -1 , 1141cm -1 , 1170cm -1 , 1225cm -1 , 1267cm -1 , 1317cm -1 , 1369cm -1 , 1425cm -1 , 1453cm -1 , 1487cm -1 , 1541cm -1 , 1648cm -1 , 2236cm -1 , 2818cm-1 , 2924cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 21 F4N3O+H] + Calculated value: 420.16, measured value: 420.1690. C 22 H 21 Analytical calculated for F4N3O·0.25H2O: C 62.33, H 5.11, N 9.91. Found: C 62.54, H 5.27, N 9.71.

[0152] Example 43: Synthesis of N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 42, N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide (397 mg, 72% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) as a white solid. mp 97°C-98°C. IR (ATR): 679 cm -1 , 755cm -1 , 802cm -1 , 830cm -1 , 993cm -1 , 1099cm -1 , 1137cm -1 , 1220cm -1 , 1292cm -1 , 1324cm -1 , 1380cm -1 , 1422cm -1 , 1469cm -1 , 1551cm -1 , 1588cm -1 , 1640cm -1 , 2789cm -1 , 2937cm -1 , 3076cm -1 , 3256cm -1 HRMS-ESI + m / z [M+H] + [C 20 H21 Cl2FN2O+H] + Calculated value: 395.10, measured value: 395.1090. C 20 H 21 Analytical calculated for Cl2FN2O: C 60.77, H 5.35, N 7.09. Found: C 60.39, H 5.33, N 7.17.

[0153] Example 44: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (350 mg, 1.08 mmol) in MeOH (10 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 136 mg, 2.16 mmol), acetic acid (0.4 mL), and 4-fluorobenzaldehyde (201 mg, 1.62 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 66 mg, 1.13 mmol) and 4-fluorobenzaldehyde (134 mg, 1.08 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, and water (5 mL) and saturated aqueous NaHCO were added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a white solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second column chromatography (10 g, SiO2, Hex / AcOEt / MeOH) gave N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (354 mg, 83% yield) as a white solid. mp 121-122 °C. IR (ATR): 650 cm -1 , 823cm -1 , 992cm -1 , 1100cm -1 , 1134cm -1 , 1226cm -1 , 1270cm -1 , 1293cm -1 , 1361cm-1 , 1420cm -1 , 1444cm -1 , 1467cm -1 , 1507cm -1 , 1546cm -1 , 1639cm -1 , 2791cm -1 , 2936cm -1 , 3078cm -1 , 3269cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 Cl2FN2O+H] + Calculated value: 395.10, Measured value: 395.1088. C 20 H 21 Analytical calculated for Cl2FN2O: C 60.77, H 5.35, N 7.09. Found: C 60.76, H 5.31, N 6.98.

[0154] Example 45: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (348 mg, 1.00 mmol) in MeOH (15 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 142 mg, 2.25 mmol), acetic acid (0.4 mL), and 3,4-difluorobenzaldehyde (240 mg, 1.68 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 74 mg, 1.18 mmol) and 3,4-difluorobenzaldehyde (132 mg, 0.93 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO was added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide (166 mg, 38% yield) as a white solid. mp 147-148 °C. IR (ATR): 676 cm -1 , 779cm -1 , 836cm -1 , 876cm -1 , 927cm -1 , 993cm -1 , 1023cm -1 , 1055cm -1 , 1121cm -1 , 1142cm -1 , 1162cm -1 , 1205cm -1 , 1226cm -1 , 1287cm -1 , 1319cm -1 , 1422cm -1 , 1433cm -1 , 1517cm -1 , 1552cm -1 , 1612cm -1 , 1645cm-1 , 2239cm -1 , 2761cm -1 , 2800cm -1 , 2945cm -1 , 3084cm -1 , 3314cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 20 F5N3O+H] + Calculated value: 438.15, measured value: 438.1606. C 22 H 20 Analytical calculated for F5N3O·0.5H2O: C 59.19, H 4.74, N 9.41. Found: C 58.91, H 5.08, N 9.39.

[0155] Example 46: Synthesis of N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 45, N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide (329 mg, 57% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) as a white solid. mp 109°C-110°C. IR (ATR): 777 cm -1 , 806cm -1 , 882cm -1 , 938cm -1 , 955cm -1 , 1109cm -1 , 1150cm -1 , 1200cm -1 , 1222cm -1 , 1270cm -1 , 1368cm -1 , 1388cm -1 , 1426cm -1 , 1511cm -1 , 1644cm -1 , 2753cm -1 , 2798cm -1 , 2933cm -1 , 3283cm -1HRMS-ESI + m / z [M+H] + [C 20 H 20 Cl2F2N2O+H] + Calculated value: 413.09, Measured value: 413.0995. C 20 H 20 Analysis calculated for Cl2F2N2O·0.25H2O: C 57.25, H 4.97, N 6.68. Found: C 57.00, H 4.73, N 6.48.

[0156] Example 47: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide A solution of N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) in MeOH (10 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 176 mg, 2.80 mmol), acetic acid (0.4 mL), and 4-iodobenzaldehyde (488 mg, 2.10 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 92 mg, 1.47 mmol) and 4-iodobenzaldehyde (270 mg, 1.16 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO was added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a white solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (444 mg, 63% yield) as a white solid. mp 161-162 °C. IR (ATR): 686 cm -1 , 802cm -1 , 830cm -1 , 864cm -1 , 978cm -1 , 1025cm-1 , 1039cm -1 , 1099cm -1 , 1136cm -1 , 1230cm -1 , 1324cm -1 , 1380cm -1 , 1422cm -1 , 1470cm -1 , 1551cm -1 , 1590cm -1 , 1639cm -1 , 2750cm -1 , 2789cm -1 , 2937cm -1 , 3076cm -1 , 3258cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 Cl2IN2O+H] + Calculated value: 503.01, measured value: 503.0147. C 20 H 21 Analytical calculated for Cl2IN2O: C 47.74, H 4.21, N 5.57. Found: C 47.74, H 4.23, N 5.42.

[0157] Example 48: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (350 mg, 1.00 mmol) in MeOH (10 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 142 mg, 2.26 mmol), acetic acid (0.4 mL), and 4-methylbenzaldehyde (236 mg, 2.10 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 75 mg, 1.18 mmol) and 4-methylbenzaldehyde (112 mg, 0.93 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO was added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide (292 mg, 70% yield) as a white solid. mp 158-159 °C. IR (ATR): 638 cm -1 , 709cm -1 , 781cm -1 , 846cm -1 , 880cm -1 , 990cm -1 , 1022cm -1 , 1055cm -1 , 1121cm -1 , 1168cm -1 , 1207cm -1 , 1223cm -1 , 1264cm -1 , 1314cm -1 , 1367cm -1 , 1418cm -1 , 1450cm -1 , 1545cm -1 , 1611cm -1 , 1655cm -1 , 2238cm -1, 2873cm -1 , 2966cm -1 , 3299cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 24 F3N3O+H] + Calculated value: 416.19, Measured value: 416.1950. C 23 H 24 Analytical calculated for F3N3O·0.5H2O: C 65.08, H 5.94, N 9.9. Found: C 65.31, H 5.99, N 9.52.

[0158] Example 49: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide According to the procedure of Example 48, N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide (459 mg, 84% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) as a white solid. mp 160°C-161°C. IR (ATR): 651 cm -1 , 804cm -1 , 865cm -1 , 993cm -1 , 1024cm -1 , 1100cm -1 , 1136cm -1 , 1202cm -1 , 1231cm -1 , 1272cm -1 , 1325cm -1 , 1363cm -1 , 1469cm -1 , 1514cm -1 , 1552cm -1 , 1590cm -1 , 1639cm -1 , 2754cm -1 , 2792cm -1 , 2936cm -1 , 3070cm -1 , 3251cm -1 HRMS-ESI +m / z [M+H] + [C 21 H 24 Cl2N2O+H] + Calculated value: 391.13, measured value: 391.1342. C 21 H 24 Analysis calculated for Cl2N2O·0.25H2O: C 63.72, H 6.24, N 7.08. Found: C 63.75, H 6.07, N 7.01.

[0159] Example 50: Synthesis of 1-(4-chlorobenzyl)-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (348 mg, 1.00 mmol) in MeOH (10 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 142 mg, 2.26 mmol), acetic acid (0.4 mL), and 4-chlorobenzaldehyde (240 mg, 1.70 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 75 mg, 1.19 mmol) and 4-chlorobenzaldehyde (132 mg, 0.94 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO was added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave 1-(4-chlorobenzyl)-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (287 mg, 66% yield) as a yellow solid. mp 147-148 °C. IR (ATR): 745 cm -1 , 784cm -1 , 824cm -1 , 844cm -1 , 883cm -1, 929cm -1 , 973cm -1 , 988cm -1 , 1014cm -1 , 1057cm -1 , 1084cm -1 , 1117cm -1 , 1175cm -1 , 1207cm -1 , 1255cm -1 , 1290cm -1 , 1317cm -1 , 1366cm -1 , 1389cm -1 , 1449cm -1 , 1490cm -1 , 1531cm -1 , 1574cm -1 , 1614cm -1 , 1651cm -1 , 2233cm -1 , 2866cm -1 , 2978cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 21 ClF3N3O+H] + Calculated value: 436.13, measured value: 436.1405. C 22 H 21 Analytical calculated for ClF3N3O·1H2O: C 58.22, H 5.11, N 9.26. Found: C 58.54, H 5.09, N 9.09.

[0160] Example 51: Synthesis of 1-(4-chlorobenzyl)-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide According to the procedure of Example 50, N-(2,4-dichlorobenzyl)-1-(4-chlorobenzyl)piperidine-4-carboxamide (315 mg, 55% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) as a white solid. mp 148°C-149°C. IR (ATR): 690 cm -1 , 809cm -1, 831cm -1 , 864cm -1 , 995cm -1 , 1014cm -1 , 1087cm -1 , 1135cm -1 , 1230cm -1 , 1282cm -1 , 1326cm -1 , 1382cm -1 , 1422cm -1 , 1487cm -1 , 1549cm -1 , 1647cm -1 , 2749cm -1 , 2783cm -1 , 2939cm -1 , 3078cm -1 , 3277cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 Cl3N2O+H] + Calculated value: 411.07, measured value: 411.0793. C 20 H 21 Analytical calculated for Cl3N2O: C 58.34, H 5.14, N 6.80. Found: C 58.07, H 5.10, N 6.70.

[0161] Example 52: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (430 mg, 1.24 mmol) in MeOH (15 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 174 mg, 2.76 mmol), acetic acid (0.4 mL), and 2,4-dichlorobenzaldehyde (363 mg, 2.07 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 91 mg, 1.15 mmol) and 2,4-dichlorobenzaldehyde (201 mg, 1.15 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure to give the crude material. Water (5 mL) and saturated aqueous NaHCO were then added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4-carboxamide (168 mg, 29% yield) as a white solid. mp 190-191 °C. IR (ATR): 671 cm -1 , 790cm -1 , 818cm -1 , 864cm -1 , 926cm -1 , 995cm -1 , 1056cm -1 , 1103cm -1 , 1140cm -1 , 1170cm -1 , 1232cm -1 , 1268cm -1 , 1317cm -1 , 1369cm -1 , 1425cm -1 , 1448cm -1 , 1544cm -1 , 1649cm -1 , 2236cm -1 , 2808cm -1 , 2924cm-1 , 3073cm -1 , 3274cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 20 Cl2F3N3O+H] + Calculated value: 470.09, measured value: 470.1001. C 23 H 20 Analytical calculated for Cl2F3N3O: C 56.18, H 4.29, N 8.93. Found: C 55.96, H 4.41, N 8.72.

[0162] Example 53: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (348 mg, 1.00 mmol) in MeOH (10 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 142 mg, 2.26 mmol), acetic acid (0.4 mL), and 3,4-dichlorobenzaldehyde (296 mg, 1.70 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 75 mg, 1.18 mmol) and 3,4-dichlorobenzaldehyde (164 mg, 0.94 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO was added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide (360 mg, 76% yield) as a white solid. mp 122-123 °C. IR (ATR): 673 cm -1, 811cm -1 , 928cm -1 , 993cm -1 , 1055cm -1 , 1120cm -1 , 1105cm -1 , 1171cm -1 , 1263cm -1 , 1316cm -1 , 1420cm -1 , 1543cm -1 , 1650cm -1 , 2748cm -1 , 2933cm -1 , 3073cm -1 , 3288cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 20 Cl2F3N3O+H] + Calculated value: 470.09, measured value: 470.1012. C 22 H 20 Analytical calculated for Cl2F3N3O: C 56.18, H 4.29, N 8.93. Found: C 55.85, H 4.25, N 8.91.

[0163] Example 54: Synthesis of N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide According to the procedure of Example 53, N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide (379 mg, 61% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.39 mmol) as a white solid. mp 148°C-149°C. IR (ATR): 687 cm -1 , 802cm -1 , 829cm -1 , 864cm -1 , 911cm -1 , 928cm -1 , 994cm -1 , 1026cm -1 , 1098cm -1 , 1137cm -1, 1230cm -1 , 1281cm -1 , 1325cm -1 , 1379cm -1 , 1422cm -1 , 1444cm -1 , 1469cm -1 , 1550cm -1 , 1590cm -1 , 1640cm -1 , 2789cm -1 , 2938cm -1 , 3077cm -1 , 3267cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 20 Cl4N2O+H] + Calculated value: 447.03, measured value: 447.0385. C 20 H 20 Analytical calculated for Cl4N2O: C 53.84, H 4.52, N 6.28. Found: C 53.59, H 4.64, N 6.46.

[0164] Example 55: Synthesis of N-(2,4-dichlorobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(2,4-dichlorobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (223 mg, 42% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (450 mg, 1.40 mmol) as a white solid. mp 119°C-120°C. IR (ATR): 670 cm -1 , 767cm -1 , 833cm -1 , 856cm -1 , 913cm -1 , 992cm -1 , 1053cm -1 , 1118cm -1 , 1164cm -1 , 1277cm -1 , 1345cm -1 , 1423cm -1, 1543cm -1 , 1644cm -1 , 2793cm -1 , 2941cm -1 , 3284cm -1 HRMS-ESI + m / z [M+H] + [C 18 H 20 Cl2N2OS+H] + Calculated value: 383.07, measured value: 383.0742. C 18 H 20 Analytical calculated for Cl2N2OS·0.25H2O: C 55.74, H 5.33, N 7.22. Found: C 55.89, H 5.23, N 6.91.

[0165] Example 56: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4-carboxamide To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (200 mg, 1.00 mmol) in EtOAc (15 mL) was added 1-(furan-2-ylmethyl)piperidine-4-carboxylic acid (209 mg, 1.00 mmol), HOBt (203 mg, 1.50 mmol), EDCI·HCl (288 mg, 1.50 mmol), and EtN (0.25 mL, 1.80 mmol). The reaction mixture was stirred at RT for 24 h. After 24 h, water was added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (15 mL), dried over anh.NaSO, filtered, and evaporated to give an oil. Column chromatography (4 g, SiO2, DCM / MeOH mixture) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4-carboxamide (336 mg, 86% yield) as a white solid. mp 127-128 °C. IR(ATR): 684 cm -1 , 744cm -1 , 813cm -1 , 881cm -1 , 995cm -1 , 1053cm -1 , 1116cm-1 , 1171cm -1 , 1261cm -1 , 1316cm -1 , 1424cm -1 , 1490cm -1 , 1540cm -1 , 1645cm -1 , 2237cm -1 , 2749cm -1 , 2787cm -1 , 2937cm -1 , 3072cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 20 F3N3O2+H] + Calculated value: 392.15, measured value: 392.1576. C 20 H 20 Analytical calculated for F3N3O: C 61.38, H 5.15, N 10.74. Found: C 61.24, H 5.20, N 10.45.

[0166] Example 57: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide To a solution of 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (200 mg, 1.0 mmol) in EtOAc (15 mL) was added 1-(pyridin-4-ylmethyl)piperidine-4-carboxylic acid (221 mg, 1.0 mmol), HOBt (203 mg, 1.50 mmol), EDCI·HCl (288 mg, 1.50 mmol), and EtN (0.25 mL, 1.80 mmol). The reaction mixture was stirred at RT for 24 h. After 24 h, water was added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (15 mL), dried over anh.NaSO, filtered, and evaporated to give an oil. Column chromatography (4 g, SiO2, DCM / MeOH mixture) afforded N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide (229 mg, 57% yield) as a beige solid. mp 139-140 °C. IR (ATR): 670 cm -1 , 803cm -1 , 834cm -1 , 928cm -1 , 993cm -1 , 1054cm -1 , 1106cm -1 , 1170cm -1 , 1229cm -1 , 1267cm -1 , 1315cm -1 , 1418cm -1 , 1543cm -1 , 1648cm -1 , 2803cm -1 , 2941cm -1 , 3284cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 21 F3N4O+H] + Calculated value: 403.17, measured value: 403.1733. C 21 H 21 Analytical calculated for F3N4O·0.25H2O: C 61.98, H 5.33, N 13.77. Found: C 62.05, H 5.42, N 13.54.

[0167] Example 58: Synthesis of N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide A solution of N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (490 mg, 1.41 mmol) in MeOH (15 mL) was prepared in a round-bottom flask equipped with a CaCl tube. To this was added NaBHCN (95%, 197 mg, 3.14 mmol), acetic acid (0.4 mL), and 4-(trifluoromethyl)benzaldehyde (411 mg, 2.36 mmol). The mixture was stirred at RT for 2 h. Then, additional NaBHCN (95%, 104 mg, 1.08 mmol) and 4-(trifluoromethyl)benzaldehyde (226 mg, 1.30 mmol) were added, and the reaction mixture was stirred at RT for an additional 16 h. The mixture was concentrated under reduced pressure, water (5 mL) was added, and saturated aqueous NaHCO was added until a basic pH was achieved. The aqueous phase was extracted with DCM (3 x 20 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo to give a beige solid. The crude material was purified several times using column chromatography (10 g, Al2O3, DCM / MeOH mixture). A second purification (10 g, SiO2, Hex / AcOEt / MeOH mixture) gave N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide (201 mg, 30% yield) as a white solid. mp 136-137 °C. IR (ATR): 670 cm -1 , 789cm -1 , 823cm -1 , 881cm -1 , 912cm -1 , 927cm -1 , 994cm -1 , 1018cm -1 , 1067cm -1 , 1104cm -1 , 1161cm -1 , 1232cm -1 , 1267cm -1 , 1317cm -1 , 1336cm-1 , 1370cm -1 , 1424cm -1 , 1449cm -1 , 1541cm -1 , 1619cm -1 , 1650cm -1 , 2237cm -1 , 2798cm -1 , 2925cm -1 , 3289cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 21 F6N3O+H] + Calculated value: 470.16, measured value: 469.1659. C 23 H 21 Analytical calculated for F6N3O: C 58.85, H 4.51, N 8.95. Found: C 58.88, H 4.60, N 8.81.

[0168] Example 59: Synthesis of N-(2,4-dichlorobenzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide According to the procedure of Example 58, N-(2,4-dichlorobenzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide (234 mg, 57% yield) was obtained from N-(2,4-dichlorobenzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.93 mmol) as a white solid. mp 142°C-133°C. IR (ATR): 812 cm -1 , 826cm -1 , 909cm -1 , 995cm -1 , 1054cm -1 , 1066cm -1 , 1115cm -1 , 1160cm -1 , 1232cm -1 , 1280cm -1 , 1306cm -1 , 1324cm -1 , 1365cm -1 , 1422cm -1 , 1469cm -1, 1515cm -1 , 1545cm -1 , 1647cm -1 , 2754cm -1 , 2791cm -1 , 2941cm -1 , 3075cm -1 , 3279cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 21 Cl2F3N2O+H] + Calculated value: 445.10, measured value: 445.1065. C 21 H 21 Analytical calculated for Cl2F3N2O: C 56.64, H 4.75, N 6.89. Found: C 57.54, H 4.82, N 6.17.

[0169] Example 60: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 44, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (130 mg, 27% yield) was obtained from N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (400 mg, 1.00 mmol) as a white solid. mp 99°C-100°C. IR (ATR): 670 cm -1 , 812cm -1 , 824cm -1 , 889cm -1 , 991cm -1 , 1054cm -1 , 1114cm -1 , 1164cm -1 , 1278cm -1 , 1302cm -1 , 1408cm -1 , 1432cm -1 , 1513cm -1 , 1547cm -1 , 1645cm -1 , 2754cm -1 , 2794cm-1 , 2937cm -1 , 3074cm -1 , 3291cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 21 BrF4N2O+H] + Calculated value: 473.08, Measured value: 473.0848. C 21 H 21 Analytical calculated for BrF4N2O: C 53.29, H 4.47, N 5.92. Found: C 53.34, H 4.64, N 5.62.

[0170] Example 61: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide According to the procedure of Example 47, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (353 mg, 58% yield) was obtained from N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (420 mg, 1.05 mmol) as a white solid. mp 163°C-164°C. IR (ATR): 670 cm -1 , 825cm -1 , 909cm -1 , 988cm -1 , 1054cm -1 , 1113cm -1 , 1163cm -1 , 1198cm -1 , 1230cm -1 , 1278cm -1 , 1305cm -1 , 1344cm -1 , 1515cm -1 , 1545cm -1 , 1644cm -1 , 2752cm -1 , 2792cm -1 , 2940cm -1 , 3075cm -1 , 3290cm -1 HRMS-ESI +m / z [M+H] + [C 21 H 21 BrF3IN2O+H] + Calculated value: 580.98, Measured value: 580.9896. C 21 H 21 Analytical calculated for BrF3IN2O: C 43.40, H 3.64, N 4.82. Found: C 43.46, H 3.92, N 4.61.

[0171] Example 62: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide According to the procedure of Example 19, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (184 mg, 40% yield) was obtained from N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (380 mg, 0.95 mmol) as a white solid. mp 111°C-112°C. IR (ATR): 670 cm -1 , 812cm -1 , 824cm -1 , 991cm -1 , 1053cm -1 , 1114cm -1 , 1164cm -1 , 1279cm -1 , 1302cm -1 , 1432cm -1 , 1446cm -1 , 1513cm -1 , 1547cm -1 , 1646cm -1 , 2754cm -1 , 2794cm -1 , 2936cm -1 , 3073cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 24 BrF3N2O2+H] + Calculated value: 485.10, measured value: 485.1046. C22 H 24 Analytical calculated for BrF3N2O2·0.5H2O: C 53.45, H 5.10, N 5.67. Found: C 53.79, H 5.22, N 5.52.

[0172] Example 63: Synthesis of N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (300 mg, 0.75 mmol) was used to obtain N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (273 mg, 79% yield) as a yellow oil. IR (ATR): 670 cm -1 , 825cm -1 , 909cm -1 , 990cm -1 , 1054cm -1 , 1113cm -1 , 1163cm -1 , 1279cm -1 , 1305cm -1 , 1344cm -1 , 1446cm -1 , 1515cm -1 , 1544cm -1 , 1646cm -1 , 2792cm -1 , 2939cm -1 , 3075cm -1 , 3289cm -1 HRMS-ESI + m / z [M+H] + [C 19 H 20 BrF3N2OS+H] + Calculated value: 461.04, measured value: 461.0486. C 19 H 20 Analytical calculated for BrF3N2OS: C 59.56, H 5.35, N 6.04. Found: C 49.02, H 3.42, N 5.46.

[0173] Example 64: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide According to the procedure of Example 40, N-(4-chloro-2-(trifluoromethyl)benzyl)-4-carboxamide hydrochloride (250 mg, 0.70 mmol) gave N-(4-chloro-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide (44 mg, 13% yield) as a white crystalline solid. mp 161°C-162°C. IR(ATR): 720 cm -1 , 823cm -1 , 840cm -1 , 888cm -1 , 1033cm -1 , 1051cm -1 , 1121cm -1 , 1142cm -1 , 1157cm -1 , 1257cm -1 , 1305cm -1 , 1416cm -1 , 1454cm -1 , 1487cm -1 , 1555cm -1 , 1635cm -1 , 2462cm -1 , 2914cm -1 , 2949cm -1 , 3309cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 ClF3N2O] + Calculated value: 425.1602, measured value: 425.1602. C 22 H 24 Analytical calculated for ClF3N2O: C 62.19, H 5.69, N 6.59. Found: C 61.96, H 5.68, N 6.38.

[0174] Example 65: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4-carboxamide N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4-carboxamide was obtained from N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.79 mmol) according to the procedure of Example 40 as a white crystalline solid (152 mg, 50% yield). mp: 191°C-192°C. IR(ATR): 694 cm -1 , 740cm -1 , 823cm -1 , 871cm -1 , 904cm -1 , 995cm -1 , 1023cm -1 , 1117cm -1 , 1129cm -1 , 1230cm -1 , 1310cm -1 , 1340cm -1 , 1392cm -1 , 1481cm -1 , 1536cm -1 , 1646cm -1 , 2232cm -1 , 2765cm -1 , 2805cm -1 , 2948cm -1 , 3066cm -1 , 3275cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 ClNO] + Calculated value: 382.1681, measured value: 382.1671.

[0175] Example 66: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide According to the procedure of Example 40, N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) gave N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide (26 mg, 9% yield) as a beige crystalline solid. mp 143°C-144°C. IR(ATR): 697 cm -1 , 745cm -1 , 820cm -1 , 854cm -1 , 945cm -1 , 1161cm -1 , 1209cm -1 , 1257cm -1 , 1430cm -1 , 1488cm -1 , 1546cm -1 , 1642cm -1 , 1738cm -1 , 2760cm -1 , 2806cm -1 , 2942cm -1 , 3280cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 ClF3N2O2] + Calculated value: 441.1551, measured value: 441.1550. C 22 H 24 Analytical calculated for ClF3N2O2: C 59.93, H 5.49, N 6.35. Found: C 59.91, H 5.84, N 5.95.

[0176] Example 67: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) was used according to the procedure of Example 40 to give N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide as a beige crystalline solid (58 mg, 20% yield). mp 157°C-158°C. IR(ATR): 637 cm -1 , 695cm -1 , 742cm -1 , 817cm -1 , 846cm -1 , 881cm -1 , 936cm -1 , 995cm -1 , 1022cm -1 , 1079cm -1 , 1122cm -1 , 1148cm -1 , 1206cm -1 , 1252cm -1 , 1362cm -1 , 1432cm -1 , 1485cm -1 , 1548cm -1 , 1602cm -1 , 1645cm -1 , 2765cm -1 , 2939cm -1 , 3027cm -1 , 3275cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 BrF3N2O2] + Calculated value: 485.1046, measured value: 485.1036. C 19 H 20 Analytical calculated for BrF3N2O2S: C 54.44, H 4.98, N 5.77. Found: C 54.49, H 4.88, N 5.43.

[0177] Example 68: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) was used according to the procedure of Example 40 to give N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide as a beige crystalline solid (115 mg, 48% yield). mp 161°C-162°C. IR(ATR): 698 cm -1 , 750cm -1 , 850cm -1 , 977cm -1 , 1030cm -1 , 1119cm -1 , 1161cm -1 , 1210cm -1 , 1262cm -1 , 1413cm -1 , 1446cm -1 , 1508cm -1 , 1544cm -1 , 1637cm -1 , 2234cm -1 , 2445cm -1 , 2757cm -1 , 2800cm -1 , 2923cm -1 , 3064cm -1 , 3282cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 25 F3N3O2] + Calculated value: 432.1893, measured value: 432.1889.

[0178] Example 69: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) was prepared according to the procedure of Example 13 to give N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide as a beige crystalline solid (93 mg, 13% yield). mp 127°C-128°C. IR(ATR): 684 cm -1 , 780cm -1 , 860cm -1 , 924cm -1 , 976cm -1 , 1027cm -1 , 1122cm -1 , 1164cm -1 , 1206cm -1 , 1263cm -1 , 1445cm -1 , 1508cm -1 , 1546cm -1 , 1638cm -1 , 2235cm -1 , 2765cm -1 , 2800cm -1 , 2921cm -1 , 3281cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 BrF4N2O2] + Calculated value: 489.0795, measured value: 489.0800. C 21 H 21 Analytical calculated for BrF4N2O2: C 51.55, H 4.33, N 5.73. Found: C 51.74, H 4.53, N 5.52.

[0179] Example 70: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 44, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (50 mg, 17% yield) was obtained from N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) as an off-white crystalline solid. mp 127°C-128°C. IR(ATR): 667 cm -1 , 760cm -1 , 821cm -1 , 829cm -1 , 882cm -1 , 901cm -1 , 979cm -1 , 1015cm -1 , 1046cm -1 , 1125cm -1 , 1161cm -1 , 1209cm -1 , 1281cm -1 , 1315cm -1 , 1363cm -1 , 1464cm -1 , 1505cm -1 , 1635cm -1 , 2389cm -1 , 2757cm -1 , 2793cm -1 , 2947cm -1 , 3089cm -1 , 3258cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 F5N2O] + Calculated value: 413.1647, measured value: 413.1651. C 21 H 21 Analytical calculated for F5N2O: C 61.16, H 5.13, N 6.79. Found: C 60.96, H 5.39, N 6.49.

[0180] Example 71: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 44, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (101 mg, 39% yield) was obtained from N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (215 mg, 0.60 mmol) as an off-white crystalline solid. mp 121°C-122°C. IR(ATR): 683 cm -1 , 767cm -1 , 782cm -1 , 824cm -1 , 841cm -1 , 856cm -1 , 883cm -1 , 913cm -1 , 991cm -1 , 1053cm -1 , 1123cm -1 , 1220cm -1 , 1276cm -1 , 1302cm -1 , 1341cm -1 , 1417cm -1 , 1454cm -1 , 1508cm -1 , 1551cm -1 , 1636cm -1 , 2464cm -1 , 2758cm -1 , 2798cm -1 , 2917cm -1 , 2948cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClF4N2O] + Calculated value: 429.1351, measured value: 429.1346. C 21 H 21 Analytical calculated for ClF4N2O·0.25H2O: C 58.81, H 4.94, N 6.53. Found: C 58.44, H 5.24, N 6.48.

[0181] Example 72: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 44, N-(2-chloro-4-cyanobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (63 mg, 21% yield) was obtained from N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.79 mmol) as a beige crystalline solid. mp 153°C-154°C. IR(ATR): 688 cm -1 , 767cm -1 , 785cm -1 , 827cm -1 , 871cm -1 , 989cm -1 , 1051cm -1 , 1119cm -1 , 1220cm -1 , 1265cm -1 , 1333cm -1 , 1391cm -1 , 1411cm -1 , 1482cm -1 , 1508cm -1 , 1556cm -1 , 1641cm -1 , 2236cm -1 , 2751cm -1 , 2939cm -1 , 3067cm -1 , 3251cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClFNO] + Calculated value: 386.1430, measured value: 386.1426. C 21 H 21 Analytical calculated for ClFN3O·0.25H2O: C 64.61, H 5.55, N 10.76. Found: C 64.71, H 5.41, N 10.54.

[0182] Example 73: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide According to the procedure of Example 44, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide (59 mg, 20% yield) was obtained from N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) as a beige crystalline solid. mp 103°C-104°C. IR(ATR): 786 cm -1 , 822cm -1 , 946cm -1 , 993cm -1 , 1069cm -1 , 1083cm -1 , 1125cm -1 , 1162cm -1 , 1210cm -1 , 1250cm -1 , 1366cm -1 , 1453cm -1 , 1487cm -1 , 1508cm -1 , 1543cm -1 , 1644cm -1 , 2466cm -1 , 2755cm -1 , 2793cm -1 , 2939cm -1 , 3293cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 ClF4N2O2] + Calculated value: 445.1300, measured value: 445.1301. C 21 H 21 Analytical calculated for ClF4N2O2: C 56.70, H 4.76, N 6.30. Found: C 56.76, H 5.02, N 6.13.

[0183] Example 74: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) was prepared according to the procedure of Example 44 to give N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide as a beige crystalline solid (139 mg, 47% yield). mp 112°C-113°C. IR(ATR): 712 cm -1 , 761cm -1 , 788cm -1 , 815cm -1 , 827cm -1 , 845cm -1 , 937cm -1 , 974cm -1 , 1162cm -1 , 1202cm -1 , 1265cm -1 , 1464cm -1 , 1484cm -1 , 1505cm -1 , 1545cm -1 , 1601cm -1 , 1629cm -1 , 2401cm -1 , 2758cm -1 , 2793cm -1 , 2929cm -1 , 3258cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 BrF4N2O2] + Calculated value: 489.0795, measured value: 489.0799. C 21 H 21 Analytical calculated for BrF4N2O2: C 51.55, H 4.33, N 5.73. Found: C 51.51, H 4.28, N 5.56.

[0184] Example 75: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) was prepared according to the procedure of Example 44 to give N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide as a beige crystalline solid (57 mg, 24% yield). mp 121°C-122°C. IR(ATR): 648 cm -1 , 712cm -1 , 807cm -1 , 827cm -1 , 874cm -1 , 972cm -1 , 1125cm -1 , 1167cm -1 , 1212cm -1 , 1250cm -1 , 1363cm -1 , 1424cm -1 , 1456cm -1 , 1508cm -1 , 1637cm -1 , 1737cm -1 , 2235cm -1 , 2447cm -1 , 2795cm -1 , 2951cm -1 , 3287cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 22 F4N3O2] + Calculated value: 436.1643, measured value: 436.1642. C 22 H 21 Analysis calculated for F4N3O2·0.25H2O: C 60.69, H 4.86, N 9.65. Found: C 60.38, H 4.71, N 9.23.

[0185] Example 76: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) was prepared according to the procedure of Example 19 to give N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (150 mg, 48%) as an off-white crystalline solid. mp 112°C-113°C. IR(ATR): 666 cm -1 , 696cm -1 , 821cm -1 , 878cm -1 , 902cm -1 , 983cm -1 , 1046cm -1 , 1125cm -1 , 1162cm -1 , 1210cm -1 , 1316cm -1 , 1363cm -1 , 1430cm -1 , 1505cm -1 , 1556cm -1 , 1637cm -1 , 2390cm -1 , 2793cm -1 , 2941cm -1 , 3267cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F4N2O2] + Calculated value: 425.1847, measured value: 425.1846. C 22 H 24 Analytical calculation for F4N2O2·0.5H2O: C 60.96, H 5.81, N 6.46. Found: C 61.08, H 6.18, N 6.20.

[0186] Example 77: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide According to the procedure of Example 19, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.70 mmol) was used to give N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (289 mg, 94% yield) as an off-white crystalline solid. mp 129°C-130°C. IR(ATR): 783 cm -1 , 819cm -1 , 881cm -1 , 1032cm -1 , 1054cm -1 , 1117cm -1 , 1138cm -1 , 1165cm -1 , 1247cm -1 , 1305cm -1 , 1423cm -1 , 1452cm -1 , 1512cm -1 , 1551cm -1 , 1636cm -1 , 2468cm -1 , 2763cm -1 , 2804cm -1 , 2818cm -1 , 2944cm -1 , 3327cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 ClF3N2O2] + Calculated value: 441.1551, measured value: 441.1553. C 22 H 24 Analytical calculated for ClF3N2O2·0.25H2O: C 59.33, H 5.54, N 6.29. Found: C 59.16, H 5.44, N 6.17.

[0187] Example 78: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide N-(2-chloro-4-cyanobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide was obtained from N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.79 mmol) according to the procedure of Example 19 as a beige crystalline solid (34 mg, 11% yield). mp 129°C-130°C. IR(ATR): 682 cm -1 , 813cm -1 , 830cm -1 , 912cm -1 , 991cm -1 , 1024cm -1 , 1185cm -1 , 1243cm -1 , 1257cm -1 , 1302cm -1 , 1418cm -1 , 1513cm -1 , 1541cm -1 , 1613cm -1 , 1645cm -1 , 2238cm -1 , 2520cm -1 , 2755cm -1 , 2932cm -1 , 3064cm -1 , 3328cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 ClN3O2] + Calculated value: 398.1630, measured value: 398.1619. C 22 H 24 Analysis calculated for ClN3O2·0.35H2O: C 65.37, H 6.16, N 10.40. Found: C 65.71, H 6.02, N 10.00.

[0188] Example 79: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide According to the procedure of Example 19, N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) was used to give N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (65 mg, 21% yield) as a beige crystalline solid. mp 116°C-117°C. IR(ATR): 735 cm -1 , 812cm -1 , 822cm -1 , 948cm -1 , 993cm -1 , 1032cm -1 , 1160cm -1 , 1212cm -1 , 1243cm -1 , 1490cm -1 , 1512cm -1 , 1550cm -1 , 1612cm -1 , 1644cm -1 , 2759cm -1 , 2841cm -1 , 2935cm -1 , 3319cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 ClF3N2O3] + Calculated value: 457.1500, measured value: 457.1494. C 22 H 24 Analytical calculated for ClF3N2O3·0.25H2O: C 57.27, H 5.35, N 6.07. Found: C 57.14, H 5.50, N 6.08.

[0189] Example 80: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide According to the procedure of Example 19, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide was obtained from N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) as a beige crystalline solid (104 mg, 35% yield). mp 115°C-116°C. IR(ATR): 636 cm -1 , 715cm -1 , 753cm -1 , 811cm -1 , 940cm -1 , 993cm -1 , 1033cm -1 , 1126cm -1 , 1164cm -1 , 1213cm -1 , 1247cm -1 , 1431cm -1 , 1452cm -1 , 1512cm -1 , 1551cm -1 , 1613cm -1 , 1640cm -1 , 2471cm -1 , 2759cm -1 , 2795cm -1 , 2936cm -1 , 3322cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 BrF3N2O3] + Calculated value: 501.0995, measured value: 501.0998. C 22 H 24 Analytical calculated for BrF3N2O3: C 52.71, H 4.83, N 5.59. Found: C 52.74, H 4.77, N 4.46.

[0190] Example 81: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) was used to give N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (87 mg, 30% yield) as an off-white crystalline solid. mp 115°C-116°C. IR(ATR): 666 cm -1 , 696cm -1 , 764cm -1 , 823cm -1 , 878cm -1 , 904cm -1 , 984cm -1 , 1016cm -1 , 1046cm -1 , 1126cm -1 , 1164cm -1 , 1210cm -1 , 1316cm -1 , 1364cm -1 , 1430cm -1 , 1504cm -1 , 1554cm -1 , 1640cm -1 , 2763cm -1 , 2803cm -1 , 2941cm -1 , 3271cm -1 HRMS-ESI + m / z [M+H] + [C 19 H 21 F4N2OS] + Calculated value: 401.1305, measured value: 401.1316. C 19 H 20 Analytical Calculated for F4N2OS: C 56.99%, H 5.03%, N 7.00. Found: C 56.96%, H 5.23%, N 6.65.

[0191] Example 82: Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.70 mmol) gave N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (290 mg, 99% yield) as a beige crystalline solid. mp 131°C-132°C. IR(ATR): 682 cm -1 , 765cm -1 , 820cm -1 , 841cm -1 , 1035cm -1 , 1052cm -1 , 1111cm -1 , 1138cm -1 , 1165cm -1 , 1247cm -1 , 1305cm -1 , 1413cm -1 , 1452cm -1 , 1635cm -1 , 2464cm -1 , 2755cm -1 , 2815cm -1 , 2919cm -1 , 2959cm -1 , 3298cm -1 HRMS-ESI + m / z [M+H] + [C 19 H 21 ClF3N2OS] + Calculated value: 417.1010, measured value: 417.1014. C 19 H 20 Analytical calculated for ClF3N2OS·0.25H2O: C 54.74, H 4.84, N 6.72. Found: C 54.27, H 5.07, N 6.56.

[0192] Example 83: Synthesis of N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide was obtained from N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.80 mmol) according to the procedure of Example 18 as a beige crystalline solid (106 mg, 35% yield). mp 152°C-153°C. IR(ATR): 685 cm -1 , 766cm -1 , 790cm -1 , 829cm -1 , 871cm -1 , 993cm -1 , 1022cm -1 , 1051cm -1 , 1119cm -1 , 1228cm -1 , 1297cm -1 , 1322cm -1 , 1444cm -1 , 1542cm -1 , 1643cm -1 , 2233cm -1 , 2743cm -1 , 2779cm -1 , 2944cm -1 , 3069cm -1 , 3258cm -1 HRMS-ESI + m / z [M+H] + [C 19 H 21 ClN3OS] + Calculated value: 374.1088, measured value: 374.1084. C 19 H 20 Analytical calculated for ClN3OS·0.2H2O: C 61.03, H 5.39, N 11.24. Found: C 60.64, H 5.36, N 10.91.

[0193] Example 84: Synthesis of N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.67 mmol) was used to give N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (106 mg, 37% yield) as a beige crystalline solid. mp 126°C-127°C. IR(ATR): 769 cm -1 , 788cm -1 , 849cm -1 , 945cm -1 , 1073cm -1 , 1122cm -1 , 1158cm -1 , 1208cm -1 , 1250cm -1 , 1431cm -1 , 1483cm -1 , 1547cm -1 , 1640cm -1 , 2462cm -1 , 2750cm -1 , 2780cm -1 , 2933cm -1 , 3296cm -1 HRMS-ESI + m / z [M+H] + [C 19 H 21 ClF3N2O2S] + Calculated value: 433.0959, measured value: 433.0953. C 19 H 20 Analytical calculated for ClF3N2O2S·0.25H2O: C 52.72, H 4.66, N 6.47. Found: C 52.25, H 4.83, N 6.15.

[0194] Example 85: Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.60 mmol) gave N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (177 mg, 62% yield) as a beige crystalline solid. mp 113°C-114°C. IR(ATR): 711 cm -1 , 765cm -1 , 841cm -1 , 937cm -1 , 991cm -1 , 1023cm -1 , 1072cm -1 , 1156cm -1 , 1208cm -1 , 1250cm -1 , 1362cm -1 , 1481cm -1 , 1556cm -1 , 1643cm -1 , 2754cm -1 , 2780cm -1 , 2941cm -1 , 3080cm -1 , 3258cm -1 HRMS-ESI + m / z [M+H] + [C 19 H 21 BrF3N2O2S] + Calculated value: 477.0454, measured value: 477.0452. C 19 H 20 Analytical calculated for BrF3N2O2S: C 47.81, H 4.22, N 5.87. Found: C 47.75, H 4.12, N 5.76.

[0195] Example 86: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) gave N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (137 mg, 59% yield) as a beige crystalline solid. mp 127°C-128°C. IR(ATR): 674 cm -1 , 775cm -1 , 789cm -1 , 859cm -1 , 974cm -1 , 1026cm -1 , 1122cm -1 , 1158cm -1 , 1209cm -1 , 1261cm -1 , 1330cm -1 , 1445cm -1 , 1508cm -1 , 1543cm -1 , 1643cm -1 , 2234cm -1 , 2755cm -1 , 2789cm -1 , 2921cm -1 , 3064cm -1 , 3283cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 21 F3N3O2S] + Calculated value: 424.1301, measured value: 424.1303. C 20 H 20 Analytical calculated for F3N3O2S: C 56.73, H 4.76, N 9.92. Found: C 56.48, H 4.99, N 9.57.

[0196] Example 87: Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (200 mg, 0.55 mmol) was prepared according to the procedure of Example 19 to give N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide as a beige crystalline solid (68 mg, 29% yield). mp 138°C-139°C. IR(ATR): 749 cm -1 , 810cm -1 , 819cm -1 , 859cm -1 , 987cm -1 , 1028cm -1 , 1120cm -1 , 1165cm -1 , 1209cm -1 , 1242cm -1 , 1264cm -1 , 1415cm -1 , 1508cm -1 , 1544cm -1 , 1612cm -1 , 1640cm -1 , 2235cm -1 , 2755cm -1 , 2790cm -1 , 2922cm -1 , 2955cm -1 , 3062cm -1 , 3280cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 25 F3N3O3] + Calculated value: 448.1843, measured value: 448.1845. C 23 H 24 Analysis calculated for F3N3O3·0.25H2O: C 61.12, H 5.46, N 9.30. Found: C 60.94, H 5.24, N 9.00.

[0197] Example 88: Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide According to the procedure of Example 47, N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.73 mmol) gave N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide (163 mg, 43% yield) as an off-white crystalline solid. mp 161°C-162°C. IR(ATR): 693 cm -1 , 744cm -1 , 798cm -1 , 828cm -1 , 883cm -1 , 906cm -1 , 988cm -1 , 1006cm -1 , 1160cm -1 , 1112cm -1 , 1050cm -1 , 1216cm -1 , 1281cm -1 , 1295cm -1 , 1318cm -1 , 1363cm -1 , 1432cm -1 , 1480cm -1 , 1499cm -1 , 1551cm -1 , 1639cm -1 , 2755cm -1 , 2781cm -1 , 2949cm -1 , 3285cm -1 HRMS-ESI + m / z [M+H] + [C 21 H 22 F4IN2O] + Calculated value: 521.0707, measured value: 521.0713. C 21 H 21 Analytical calculated for F4IN2O: C 48.48, H 4.07, N 5.38. Found: C 48.67, H 4.21, N 5.16.

[0198] Example 89: Synthesis of 1-(4-iodobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide According to the procedure of Example 47, 1-(4-iodobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (141 mg, 38% yield) was obtained from N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) as an off-white crystalline solid. mp 142°C-143°C. IR(ATR): 673 cm -1 , 793cm -1 , 858cm -1 , 960cm -1 , 992cm -1 , 1034cm -1 , 1106cm -1 , 1158cm -1 , 1212cm -1 , 1245cm -1 , 1430cm -1 , 1508cm -1 , 1547cm -1 , 1643cm -1 , 2754cm -1 , 2811cm -1 , 2909cm -1 , 2932cm -1 , 3295cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F3IN2O3] + Calculated value: 549.0856, measured value: 549.0872. C 22 H 24 Analytical calculated for F3IN2O3: C 48.19, H 4.41, N 5.11. Found: C 48.19, H 4.67, N 4.89.

[0199] Example 90: Synthesis of 1-(4-fluorobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide According to the procedure of Example 44, 1-(4-fluorobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide (91 mg, 30% yield) was obtained from N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) as an off-white crystalline solid. mp 109°C-110°C. IR(ATR): 663 cm -1 , 789cm -1 , 826cm -1 , 862cm -1 , 959cm -1 , 993cm -1 , 1031cm -1 , 1106cm -1 , 1157cm -1 , 1214cm -1 , 1243cm -1 , 1429cm -1 , 1453cm -1 , 1509cm -1 , 1541cm -1 , 1623cm -1 , 1641cm -1 , 2758cm -1 , 2795cm -1 , 2940cm -1 , 3298cm -1 HRMS-ESI + m / z [M+H] + [C 22 H 25 F4N2O3] + Calculated value: 441.1796, measured value: 441.1798. C 22 H 24 Analytical calculated for F4N2O3: C 60.00, H 5.49, N 6.36. Found: C 60.01, H 5.59, N 6.14.

[0200] Example 91: Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide According to the procedure of Example 19, N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide (97 mg, 32% yield) was obtained from N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) as an off-white crystalline solid. mp 113°C-114°C. IR(ATR): 639 cm -1 , 675cm -1 , 747cm -1 , 812cm -1 , 863cm -1 , 961cm -1 , 991cm -1 , 1033cm -1 , 1162cm -1 , 1213cm -1 , 1240cm -1 , 1433cm -1 , 1453cm -1 , 1513cm -1 , 1547cm -1 , 1640cm -1 , 2761cm -1 , 2799cm -1 , 2838cm -1 , 2934cm -1 , 3290cm -1 HRMS-ESI + m / z [M+H] + [C 23 H 28 F3N2O4] + Calculated value: 453.1996, measured value: 453.1996.

[0201] Example 92: Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide According to the procedure of Example 18, N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (250 mg, 0.68 mmol) gave N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide (157 mg, 54% yield) as a beige crystalline solid. mp 98°C-99°C. IR(ATR): 681 cm -1 , 765cm -1 , 786cm -1 , 815cm -1 , 962cm -1 , 988cm -1 , 1035cm -1 , 1113cm -1 , 1155cm -1 , 1210cm -1 , 1252cm -1 , 1439cm -1 , 1511cm -1 , 1548cm -1 , 1618cm -1 , 1644cm -1 , 2781cm -1 , 2936cm -1 , 3076cm -1 , 3292cm -1 HRMS-ESI + m / z [M+H] + [C 20 H 24 F3N2O3S] + Calculated value: 429.1454, measured value: 429.1467. C 20 H 23 Analytical calculated for F3N2O3S: C 56.06, H 5.41, N 6.54. Found: C 55.72, H 5.74, N 6.23.

[0202] Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of tert-butyl 4-((4-chloro-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate. To a solution of (4-chloro-2-(trifluoromethyl)phenyl)methanamine (2 g, 9.54 mmol) in EtOAc (115 mL) was added N-boc-piperidine-4-carboxylic acid (1.98 g, 8.67 mmol), HOBt (1.75 g, 13.01 mmol), EDCI·HCl (2.49 g, 13.01 mmol), and triethylamine (2.63 g, 13.01 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was then added (80 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 20 mL) and brine (3 × 20 mL), dried over anh.NaSO, filtered, and evaporated to give a white solid (4.12 g). Column chromatography (SiO, DCM / MeOH mixtures) afforded the desired product as a yellowish solid (3.66 g, quantitative yield).

[0203] b) Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-chloro-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (3.66 g, 8.69 mmol) in DCM (21 mL) was added 4N HCl in dioxane (21 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (1.36 g, 44% yield) as a white solid. IR(ATR): 665 cm -1 , 811cm -1 , 826cm -1 , 842cm -1 , 894cm -1 , 913cm -1 , 1014cm -1 , 1048cm -1 , 1107cm -1 , 1164cm -1 , 1188cm -1 , 1227cm-1 , 1261cm -1 , 1302cm -1 , 1366cm -1 , 1418cm -1 , 1429cm -1 , 1486cm -1 , 1551cm -1 , 1652cm -1 .

[0204] Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of tert-butyl 4-((4-chloro-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate. To a solution of (4-chloro-2-(trifluoromethoxy)phenyl)methanamine (1.40 g, 6.20 mmol) in EtOAc (80 mL) was added N-boc-piperidine-4-carboxylic acid (1.29 g, 5.63 mmol), HOBt (1.14 g, 8.46 mmol), EDCI·HCl (1.62 g, 8.46 mmol), and triethylamine (1.71 g, 16.92 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 10 mL) and brine (3 × 10 mL), dried over anh.NaSO, filtered, and evaporated to give a white solid (3.0 g). Column chromatography (SiO, DCM / MeOH mixtures) afforded the desired product as a yellowish solid (2.42 g, 98% yield).

[0205] b) Synthesis of N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-chloro-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (2.42 g, 5.54 mmol) in DCM (14 mL) was added 4N HCl in dioxane (14 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (1.85 g, 93% yield) as a white solid. IR(ATR): 638 cm -1 , 666cm -1 , 708cm -1 , 821cm -1 , 854cm -1 , 949cm -1 , 1003cm -1 , 1071cm -1 , 1162cm -1 , 1211cm -1 , 1256cm -1 , 1429cm -1 , 1489cm -1 , 1567cm -1 , 1654cm -1 , 2503cm -1 , 2739cm -1 , 2808cm -1 , 2850cm -1 , 2956cm -1 , 3299cm -1 , 3535cm -1 .

[0206] Synthesis of N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of 4-(bromomethyl)-3-chlorobenzonitrile. A mixture of 4-methyl-3-chlorobenzonitrile (2.5 g, 16.49 mmol) and 2,2'-azobis(2-methylpropionitrile) (406 mg, 2.47 mmol) in acetic acid (20 mL) was stirred at 40 °C under an argon atmosphere. N-Bromosuccinimide (2.93 g, 16.49 mol) was then added to the reaction mixture in five portions. The resulting mixture was stirred at 75 °C for 3 h. After completion of the reaction, the mixture was evaporated and extracted with EtOAc (3 × 20 mL). The organic layer was then washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give 4-(bromomethyl)-3-chlorobenzonitrile (3.57 g, 94% yield) as a yellow solid.

[0207] b) Synthesis of 4-(aminomethyl)-3-chlorobenzonitrile. 4-(Bromomethyl)-3-chlorobenzonitrile (3.57 g, 15.48 mmol) was dissolved in a 7 M solution of ammonia in MeOH (62 mL) and stirred at room temperature for 24 h. The solvent was removed in vacuo, and EtOAc (15 mL) was added to the resulting crude material, followed by water. The mixture was basified with NaHCO solution (15 mL, pH = 10), and the layers were separated. The aqueous layer was further extracted with EtOAc (15 mL). The organic layers were combined, dried over anh.NaSO, filtered, and evaporated in vacuo to give 4-(aminomethyl)-3-chlorobenzonitrile (2.48 g, 96% yield), which was used directly without further purification or characterization.

[0208] c) Synthesis of tert-butyl 4-((2-chloro-4-cyanobenzyl)carbamoyl)piperidine-1-carboxylate. To a solution of 4-(aminomethyl)-3-chlorobenzonitrile (2.48 g, 14.91 mmol) in EtOAc (141 mL) was added N-boc-piperidine-4-carboxylic acid (3.10 g, 13.55 mmol), HOBt (2.74 g, 20.33 mmol), EDCI·HCl (3.89 g, 20.33 mmol), and triethylamine (4.11 g, 40.67 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was then added (20 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 (3 × 10 mL) and brine (3 × 10 mL), dried over anh.Na2SO4, filtered, and evaporated to give a yellow oil (4.69 g). Column chromatography (SiO2, hexane / EtOAc mixtures) afforded the desired product as a yellowish solid (2.69 g, 53% yield).

[0209] d) Synthesis of N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((2-chloro-4-cyanobenzyl)carbamoyl)piperidine-1-carboxylate (2.69 g, 7.12 mmol) in DCM (15 mL) was added 4 N HCl in dioxane (15 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated, and the resulting crude material was triturated in DCM and dried to give N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide hydrochloride (2.0 g, 89% yield) as a yellowish solid. IR(ATR): 684, 711, 829, 888, 960, 1008, 1045, 1235, 1305, 1389, 1453, 1561, 1639, 1737, 2234, 2503, 2725.

[0210] Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of (4-bromo-2-(trifluoromethoxy)benzylamine. 4-Bromo-2-(trifluoromethoxy)benzaldehyde (10.0 g, 37.17 mmol) was dissolved in 7 M ammonia in MeOH (183 mL) under argon and stirred at room temperature overnight. The reaction was then carefully treated with NaBH (3.09 mg, 81.77 mmol) and stirred at room temperature for 3 h. The solvent was evaporated, and the residue was slowly taken up in 5% HCl solution and washed three times with EtO. The phases were separated, and the aqueous phase was basified with 2 N NaOH solution and extracted with DCM (3 × 20 mL). The combined organic phases were dried over anh. NaSO, filtered, and concentrated under reduced pressure to give (4-bromo-2-(trifluoromethoxy)benzylamine (3.84 g, 38% yield) as a colorless oil. The product was used in the next step without further purification or characterization.

[0211] b) Synthesis of tert-butyl 4-((4-bromo-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate. To a solution of (4-bromo-2-(trifluoromethoxy)phenyl)methanamine (3.84 g, 14.21 mmol) in EtOAc (216 mL) was added N-boc-piperidine-4-carboxylic acid (2.96 g, 12.92 mmol), HOBt (2.61 g, 19.38 mmol), EDCI·HCl (3.72 g, 19.4 mmol), and triethylamine (3.92 mg, 38.8 mmol). The reaction mixture was stirred at room temperature for 24 h. Then, water was added (80 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 20 mL) and brine (3 × 20 mL), dried over anh.NaSO, filtered, and evaporated to give a beige solid (7.15 g). Column chromatography (SiO, hexane / AcOEt mixtures) afforded the desired product as a white crystalline solid (5.21 g, 84% yield).

[0212] c) Synthesis of N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-bromo-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (2.00 g, 4.15 mmol) in DCM (11 mL) was added 4N HCl in dioxane (11 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (1.73 g, quantitative yield) as a white solid. IR(ATR): 635 cm -1 , 694cm -1 , 761cm -1 , 806cm -1 , 846cm -1 , 941cm -1 , 960cm -1 , 1008cm -1 , 1072cm -1 , 1155cm -1 , 1199cm -1 , 1248cm -1 , 1282cm -1 , 1452cm -1 , 1487cm -1 , 1565cm -1 , 1597cm -1 , 1652cm -1 , 2510cm -1 , 2735cm -1 , 2802cm -1 , 2946cm -1 , 3092cm -1 , 3290cm -1 , 3396cm -1 , 3511cm -1 .

[0213] Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of tert-butyl 4-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate. A mixture of tert-butyl 4-((4-bromo-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (3.20 g, 6.65 mmol), Zn(CN) (780 mg, 6.65 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.15 g, 0.99 mmol) in DMF (43 mL) was degassed for 10 minutes and then heated to 90 °C overnight. The reaction mixture was filtered, and the resulting filtrate was washed three times with water and extracted with EtOAc. The resulting organic layers were combined, dried over anh. NaSO, filtered, and concentrated under reduced pressure to give a yellow gummy oil (4.11 g). Column chromatography (SiO2, hexane / EtOAc mixtures) afforded tert-butyl 4-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (1.51 mg, 53% yield) as a white solid.

[0214] b) Synthesis of N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (1.51 g, 3.53 mmol) in DCM (8.25 mL) was added 4N HCl in dioxane (8.25 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (1.01 g, 79% yield) as a white solid. IR(ATR): 644 cm -1 , 686cm -1 , 708cm -1 , 829cm -1 , 868cm -1 , 976cm -1 , 1008cm -1 , 1071cm -1 , 1160cm -1 , 1202cm-1 , 1252cm -1 , 1269cm -1 , 1295cm -1 , 1418cm -1 , 1450cm -1 , 1565cm -1 , 1655cm -1 , 2236cm -1 , 2511cm -1 , 1730cm -1 , 2802cm -1 , 2957cm -1 , 3266cm -1 , 3471cm -1 .

[0215] Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of tert-butyl 4-((4-fluoro-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate. To a solution of (4-fluoro-2-(trifluoromethyl)phenyl)methanamine (2.5 g, 12.94 mmol) in EtOAc (140 mL) was added N-boc-piperidine-4-carboxylic acid (2.69 g, 11.73 mmol), HOBt (2.38 g, 17.65 mmol), EDCI·HCl (3.38 g, 17.65 mmol), and triethylamine (3.57 g, 35.30 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was then added (40 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (3 × 20 mL) and brine (3 × 20 mL), dried over anh.NaSO, filtered, and evaporated to give a beige solid (5.0 g). Column chromatography (SiO, hexane / AcOEt mixtures) afforded the desired product as a white crystalline solid (4.74 g, quantitative yield).

[0216] b) Synthesis of N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-fluoro-2-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (4.74 g, 11.73 mmol) in DCM (33 mL) was added 4N HCl in dioxane (33 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide hydrochloride (3.42 g, 85% yield) as a white solid. IR(ATR): 668 cm -1 , 696cm -1 , 825cm -1 , 867cm -1 , 907cm -1 , 960cm -1 , 1008cm -1 , 1043cm -1 , 1072cm -1 , 1120cm -1 , 1162cm -1 , 1216cm -1 , 1259cm -1 , 1319cm -1 , 1394cm -1 , 1432cm -1 , 1451cm -1 , 1493cm -1 , 1576cm -1 , 1650cm -1 , 2510cm -1 , 2733cm -1 , 2802cm -1 , 2838cm -1 , 2947cm -1 , 3097cm -1 , 3261cm -1 , 3487cm -1 .

[0217] Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride a) Synthesis of (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine. To a solution of 4-methoxy-2-(trifluoromethoxy)benzonitrile (2 g, 9.21 mmol) in anh.THF (13 mL) at 0 °C was added a solution of LiAlH in THF (1.04 g, 1 M, 27.63 mmol) dropwise. The suspension was then stirred at RT for 4 h. The reaction suspension was quenched by the dropwise addition of water in an ice bath until no more bubbling was observed. Anh.Na2SO4 was then added, and the mixture was filtered through a pad of Celite™ using a 1 / 1 EtOAc / MeOH mixture (3 × 15 mL) as the eluent. The solvent was concentrated in vacuo, and the resulting crude material (1.54 g, 75% yield) was used directly without further purification.

[0218] b) Synthesis of tert-butyl 4-((4-methoxy-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate. To a solution of (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine (1.54 g, 6.96 mmol) in EtOAc (86 mL) was added N-boc-piperidine-4-carboxylic acid (1.45 g, 6.33 mmol), HOBt (1.28 g, 9.49 mmol), EDCI·HCl (1.82 g, 9.49 mmol), and triethylamine (1.92 g, 18.98 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was then added (40 mL), and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 (3 × 20 mL) and brine (3 × 20 mL), dried over anh.Na2SO4, filtered, and evaporated to give a beige solid. Column chromatography (SiO2, hexane / AcOEt mixtures) afforded the desired product as a brown crystalline solid (2.06 g, 75% yield).

[0219] c) Synthesis of N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride. To a solution of tert-butyl 4-((4-methoxy-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carboxylate (2.06 g, 4.76 mmol) in DCM (11 mL) was added 4N HCl in dioxane (11 mL). The reaction mixture was stirred at room temperature for 24 h. The organics were evaporated and the resulting crude material was triturated in DCM and dried to give N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide hydrochloride (1.40 g, 80% yield) as a white solid. IR(ATR): 648 cm -1 , 709cm -1 , 744cm -1 , 849cm -1 , 877cm -1 , 926cm -1 , 970cm -1 , 991cm -1 , 1030cm -1 , 1075cm -1 , 1102cm -1 , 1132cm -1 , 1152cm -1 , 1165cm -1 , 1207cm -1 , 1245cm -1 , 1269cm -1 , 1405cm -1 , 1443cm -1 , 1463cm -1 , 1505cm -1 , 1522cm -1 , 1644cm -1 , 2499cm -1 , 2705cm -1 , 2811cm -1 , 2926cm -1 , 3381cm -1 .

[0220] In vitro testing of compounds of the invention S1R antagonist K i Determining Values The binding properties of the test compound to human S1R were evaluated using a radioactive ligand [3 H]-(+)-pentazocine (PerkinElmer, NET-1056) was used to study transfected HEK-293 membranes. Assays were performed using 7 μg of membrane suspension, [H]-(+)-pentazocine (PerkinElmer, NET-1056) in the absence or presence of either buffer or 10 μM haloperidol for total and nonspecific binding, respectively. 3 The assay was performed using [H]-(+)-pentazocine (5 nM). The binding buffer contained Tris-HCl (50 mM, pH 8). The plate was incubated at 37°C for 120 min. After the incubation period, the reaction mixture was transferred to a MultiScreen HTS, FC plate (Millipore) presoaked in 0.1% polyethyleneimine and filtered. The plate was then washed (3 times) with ice-cold Tris-HCl (10 mM, pH 7.4). The filter was dried and counted in a MicroBeta scintillation counter (PerkinElmer) using EcoScint liquid scintillation cocktail at approximately 40% efficiency.

[0221] sEHI IC 50 Determining Values sEH inhibitory activity (IC 50 ) can be determined by the following fluorometric assay with purified recombinant human sEH protein using cyano(6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxiran-2-yl)methyl carbonate as the substrate (see Morrisseau, C.; Hammock, BD Measurement of soluble epoxide hydrolase (sEH) activity. Curr Protoc Toxicol. 2007, Chapter 4, Unit 4.23.).

[0222] The enzyme was incubated with the inhibitor ([I] final = 0.4 nM to 100,000 nM) in 100 mM sodium phosphate buffer (200 μL, pH 7.4) containing 0.1 mg / mL BSA and 1% DMSO for 5 min at 30°C. The substrate (CMNPC) was then added ([S] final = 5 μM). Activity was monitored at 30°C for 10 min, every 30 seconds, by measuring the fluorescent 6-methoxynaphthaldehyde product (λ) using a SpectraMax M2 (Molecular Devices). ex = 330 nm, λ em The fluorescence is assessed by measuring the appearance of IR (radiation wavelength = 465 nm).

[0223] The results are obtained by regression analysis from the linear region of the curve.

[0224] Table 1 below summarizes the results obtained for the test compounds.

[0225] [Table 1] TIFF2025539118000020.tif250170TIFF2025539118000021.tif113170

[0226] Results for sEH: I C 50 The following scale was adopted to indicate the inhibition of human sEH, expressed as: AIC 50 (sEH)<10nM, B 10≦IC 50 (sEH)<50nM, C 50≦IC 50 (sEH)<100nM, D 100≦IC 50 (sEH)≦1000nM, E.I.C. 50 (sEH)>1000nM.

[0227] Results for S1R: K i The following scale was adopted to indicate binding to S1R, expressed as: AK i (S1R)<50nM, B 50≦K i (S1R)<150nM, C 150≦K i (S1R)<400nM, D 400≦K i (S1R)≦1000nM, EK i (S1R)>1000nM.

[0228] For sEH, IC 50 If the IC value is higher than 1000 nM, the inhibitory effect of the compound is considered negligible. 50 The IC value indicates that the compound has low / very low potency for inhibitory effects. 50 An IC of less than 100 nM is considered to have a significant inhibitory effect. 50 Values ​​below 50 nM are considered particularly good, with IC 50 A value of less than 10 nM is considered excellent.

[0229] As can be derived from Table 1, all of the compounds of the present invention had IC values ​​less than 100 nM. 50 value and results in at least a significant inhibitory effect of sEH.

[0230] K i It is well established that when the K value is higher than 1000 nM, the affinity of the compound for S1R is negligible. i A K value between 400 nM and 1000 nM indicates a low affinity for the compound. i A K value of 50 nM to 150 nM indicates that the compound has significant affinity for S1R. i A K value of less than 50 nM means that the compound has high affinity for the receptor. i means that the compound has very high affinity.

[0231] As can be derived from Table 1, all of the compounds of the present invention have a K of less than 400 nM. i value and result in at least a significant binding effect of S1R.

[0232] The comparative compounds shown at the end of the table are sEHs that do not have significant binding to S1R (EC5026, AR9281, Compound 8-42, Compound 6-26, Compound 6-29, and compounds disclosed in WO2007098352) and S1R ligands that are inactive for sEH (S1RA, BMY-14802, dextromethorphan, NE-100, BD-1063, PRE-084).

[0233] Assessment of the antagonist properties of compounds at S1R To confirm that the effect of the compounds on S1R is antagonistic, the following assay was performed.

[0234] Rat livers (male Sprague-Dawley rats, Envigo RMS Srl) were homogenized in ice-cold phosphate buffer (10 mM, pH 7.4) containing 0.32 M sucrose using a Potter-Elvehjem glass homogenizer. The suspension was centrifuged at 3,000 × g for 10 min at 4 °C. The supernatant was separated and centrifuged at 21,100 × g for 60 min at 4 °C. The pellet was resuspended in ice-cold buffer and incubated at RT for 20 min. The suspension was then centrifuged at 21,100 × g for 30 min at 4 °C. Protein concentration was determined by the Bradford method.

[0235] Binding experiments were performed by injecting 200 μL of membrane preparation into 50 μL of 20 nM [ 3The assay was performed by incubating the cells with [H](+)-pentazocine (26.9 Ci / mmol, PerkinElmer), 50 μL of cold ligand or its solvent, and 20 μL of 25 mM DPH (Merck Life Science Srl) or its solvent (0.3 M NaOH) at 37°C for 120 min. The final volume was 0.5 mL. Test compound solutions were prepared by dissolving approximately 10 μmol of test compound in DMSO to obtain a 10 mM stock solution. The test concentration required for the assay (10 -5 M~10 -10 Radioligand concentrations (M) were prepared by diluting the DMSO stock solution with the respective assay buffer. Unlabeled (+)-pentazocine (10 μM) was used to measure nonspecific binding. Bound and free radioligand were separated by rapid filtration under reduced pressure through Whatman GF / 6 glass fiber filters presoaked in 0.5% aqueous poly(ethyleneimine) solution for 120 min using a Millipore filter device. Each filter paper was rinsed three times with 3 mL of ice-cold Tris buffer (50 mM, pH 8), dried at room temperature, and incubated overnight with 3 mL of scintillation cocktail in a pony vial. Bound radioactivity was determined using a liquid scintillation counter (Beckman LS 6500).

[0236] K i Values ​​were calculated with the GraphPad Prism™ 7.0 program (GraphPad Software, San Diego, CA, USA). i Values ​​are presented as the mean ± SD from at least two independent experiments performed in duplicate.

[0237] The results are presented in Figure 5 and show that compounds of the present invention exhibit antagonism towards S1R.

[0238] In vivo testing of compounds of the invention The following sections describe the different experimental set-ups for performing the assays, including the drugs used and the experimental models used to assess analgesic effects in mice.

[0239] Study 1: Assessment of tactile allodynia in a mouse experimental pain model animal Female CD1 mice (Charles River) were used in the experiments. Mice weighing 24–30 g were randomly assigned throughout the estrous cycle. Prior to the experiment, mice were housed in colony cages with free access to food and water in a temperature- and light-controlled room (22 ± 2°C, lights on at 08:00 h and off at 20:00 h). Experiments were performed during the light phase (9:00 h–16:00 h). Animal care was in accordance with institutional (University of Granada Research Ethics Committee, Granada, Spain), local (Junta de Andalucia, Spain), and international (European Community Council Directive 2010 / 63) standards.

[0240] Drugs and drug administration The compound of Example 2 above was used as a prototypical dual S1R antagonist / sEHI.

[0241] To reverse the effects of S1R antagonism, we used the S1R agonist PRE-084 (2-[4-morpholinethyl]-1-phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China), which is considered to be a selective S1R agonist (Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66).

[0242] MS-PPOH (N-(methylsulfonyl)-2-(2-propynyloxy)benzenehexanamide) (Cayman Chemicals, Ann Arbor, MI, USA), a selective inhibitor of CYP450 epoxygenase, which leads to the production of epoxyeicosatrienoic acids (EETs) (see Wang et al., J Pharmacol Exp Ther., 1998, 284:966-973), was used to reverse the effects of sEH inhibition.

[0243] PRE-084 was dissolved in sterile saline, and the compound of Example 2 was dissolved in 1% Tween-80 in saline. MS-PPOH was dissolved in 5% DMSO in 40% (2-hydroxypropyl)-β-cyclodextrin in ultrapure water. All drugs were prepared immediately before administration and injected subcutaneously (sc) into the interscapular region at an injection volume of 5 mL / kg. The compound of Example 2 was administered 45 min before behavioral assessment. PRE-084 or MS-PPOH was administered 5 min before administration of the compound of Example 2 (50 min before behavioral assessment).

[0244] Experimental models and outcomes of tactile allodynia in mice. The effect of the compound of Example 2 on capsaicin-induced secondary tactile hypersensitivity, which appears around the injection of capsaicin and is known to result from central sensitization, a hallmark of pathological pain (Baron R, Lancet, 2000, 356:785-7), was tested.

[0245] The procedure for assessing tactile allodynia was performed as previously described (Entrena et al., Pain, 2009, 143(3):252-261). Briefly, animals were placed in individual test compartments for 2 h to allow them to become accustomed to the test conditions. The test compartments had black walls and were separated by a 0.5 cm gap to allow access to the ventral surface of the hind paw. 2The animals were then carefully removed from the compartment, injected sc with the drug to be tested (see section above), and returned to the compartment. 30 min after drug injection, the mice were again removed from the compartment and injected intraplantarly (i.pl.) with 20 μL of a solution containing 1 μg of capsaicin (Sigma-Aldrich Quimica SA, Madrid, Spain) or its vehicle (1% DMSO in saline). Injections were administered 30 min after the injection. 1 / 2 The injection was performed using a 1710 TLL Hamilton microsyringe (Teknokroma, Barcelona, ​​Spain) with a 1.5-gauge needle, adjacent to the heel of the right hind paw. Immediately after i.p. administration, the mice were returned to the compartment. 15 min after administration of capsaicin or its vehicle, a punctate mechanical stimulus was administered using a Dynamic Plantar Aesthesiometer (Ugo Basile, Varese, Italy). A non-flexible filament (0.5 mm diameter) was electronically injected into the ventral side of the right hind paw, at least 5 mm away from the injection site toward the digit. The intensity of the stimulus was fixed at 0.5 g force. Upon paw withdrawal, the stimulus was automatically terminated, and the response latency was automatically recorded. The filament was applied three times with a 0.5 min interval, and the average of the three trials was considered the animal's withdrawal latency. A cutoff time of 50 s was used.

[0246] As shown in Figure 1, capsaicin administration induced a significant decrease in paw withdrawal latency compared to control, unsensitized mice (dashed line), indicating the presence of tactile allodynia (compare the 0 mg / kg dose point with the dashed line for unsensitized control mice). Administration of the compound of Example 2 (0.625 mg / kg to 10 mg / kg, sc) dose-dependently increased the paw withdrawal latency of mice to the value of control, unsensitized mice, indicating that this compound can induce a significant antiallodynic effect. Sc treatment with a 2.5 mg / kg dose of the compound of Example 2 was sufficient to induce a significant increase in paw withdrawal latency in capsaicin-treated mice (75.49% antiallodynic effect) (Figure 2). Administration of either PRE-084 (32 mg / kg, sc) or MS-PPOH (20 mg / kg, sc) was able to completely reverse this antiallodynic effect induced by the compound of Example 2 (Figure 2). These data indicate that both S1R antagonism and EET accumulation (via inhibition of sEH) are responsible for the observed antiallodynic effects, and therefore that the compound of Example 2 mediates its in vivo effects on capsaicin-induced tactile allodynia via the interaction of both intended pharmacological targets.

[0247] Study 2: Assessment of postoperative pain in mice animal Female CD1 mice (Charles River) were used in the experiments. Mice weighing 24–30 g were randomly assigned throughout the estrous cycle. Prior to the experiment, mice were housed in colony cages with free access to food and water in a temperature- and light-controlled room (22 ± 2°C, lights on at 08:00 h and off at 20:00 h). Experiments were performed during the light phase (9:00 h–16:00 h). Animal care was in accordance with institutional (University of Granada Research Ethics Committee, Granada, Spain), local (Junta de Andalucia, Spain), and international (European Community Council Directive 2010 / 63) standards.

[0248] Drugs and drug administration The compound of Example 2 was used as a prototypical dual S1R antagonist / sEHI.

[0249] To reverse the effects of sigma-1 antagonism, we used the S1R agonist PRE-084 (2-[4-morpholinethyl]-1-phenylcyclohexanecarboxylate hydrochloride) (DC Chemicals, Shanghai, China), which is considered to be a selective S1R agonist (Cobos et al., Curr Neuropharmacol., 2008, 6(4):344-66).

[0250] MS-PPOH (N-(methylsulfonyl)-2-(2-propynyloxy)benzenehexanamide) (Cayman Chemicals, Ann Arbor, MI, USA), a selective inhibitor of CYP450 epoxygenase, which leads to the production of epoxyeicosatrienoic acids (EETs) (see Wang et al., J Pharmacol Exp Ther., 1998, 284:966-973), was used to reverse the effects of sEH inhibition.

[0251] PRE-084 was dissolved in sterile saline, and the compound of Example 2 was dissolved in 1% Tween-80 in saline. MS-PPOH was dissolved in 5% DMSO in 40% (2-hydroxypropyl)-β-cyclodextrin in ultrapure water. All drugs were prepared immediately before administration and injected subcutaneously (sc) in the interscapular region at an injection volume of 5 mL / kg. PRE-084 or MS-PPOH was administered 5 min before administration of the compound of Example 2. Mice were evaluated before and at several time points (60 min, 120 min, and 180 min) after drug administration.

[0252] Postoperative pain model and outcomes in mice Baseline mechanical thresholds were recorded in the abdomen of mice using a previously described procedure (Gonzalez-Cano et al., Anesthesiology, 2013, 118(3):691-700). Briefly, forces ranging from 0.02 g to 2 g were applied to the abdomen with a series of calibrated von Frey filaments (Touch-Test Sensory Evaluator; North Coast Medical Inc., Gilroy, CA) using an up-and-down paradigm. A 5-second application interval was used. Tests began with a 0.4 g von Frey filament. In each successive test, if there was no response to the filament, a stronger stimulus was selected. If there was a positive response, a weaker stimulus was used. A response to the filament was considered positive if immediate licking / scratching at the application site, abrupt abdominal withdrawal, or jumping was observed. The typical mechanical threshold in the abdomen of naive mice is approximately 1.7 g (see baseline BL in Figure 3).

[0253] After determining baseline mechanical thresholds, laparotomy was performed in mice according to a previously described protocol (Roughan et al., Eur J Pain, 2016, 20(2):231-40). Mice were anesthetized with 3% isoflurane. Ophthalmic ointment was applied during the procedure to prevent ocular irritation. The abdomen was shaved and aseptically prepared for surgery. A 1.5 cm midline incision was made in the skin along the linea alba, followed by incision of the peritoneum. The peritoneum was closed with simple interrupted sutures, and the muscle layer and skin edges were closed with horizontal mattress sutures.

[0254] A new threshold determination was performed 2.5 h after surgery. The mice showed a significant decrease in von Frey threshold (Figure 3, time point 0). The compound of Example 2 (10 mg / kg to 40 mg / kg) or its vehicle (1% Tween-80 in saline) was then administered sc, and the mechanical threshold was assessed 60, 120, and 180 min after drug injection. The compound of Example 2 dose-dependently increased the sensory threshold, particularly at 120 min after drug administration, indicating that this compound could induce a significant antiallodynic effect in mice after laparotomy (Figure 3).

[0255] A 20 mg / kg dose of the compound of Example 2 was selected and tested in vivo for S1R and sEH components. BL determinations were performed as shown in Figure 4. Mice were tested again 2.5 h after laparotomy (time point 0). The compound of Example 2 was then administered alone or in combination with PRE-084 (32 mg / kg, sc) or MS-PPOH (20 mg / kg, sc). Administration of either PRE-084 or MS-PPOH was able to completely reverse the antiallodynic effect induced by the compound of Example 2. These data indicate that both S1R antagonism and EET accumulation (via inhibition of sEH) are involved in the observed antiallodynic effect, and therefore, the compound of Example 2 induces its in vivo effect on postoperative pain through the interaction of both intended pharmacological targets.

[0256] item: For completeness, various aspects of the invention are described in the following numbered paragraphs. Item 1. A compound of formula (I): [ka] (In the formula, R1 is CN, halogen, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl and -O-(C1-C 10 ) haloalkyl; R2 to R4 may be the same or different and independently represent H, CN, halogen, (C1 to C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted with one or more Su1 (C1-C 10 ) alkyl, substituted with one or more Su2 (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl, -O-(C1-C 10 ) haloalkyl, -SF5, -S(O)2R9, -NR 10 R 11 aryl and heteroaryl; R5 is CR x R' x and R x and R' x are the same or different and are independently selected from —H, (C1-C5) alkyl, or (C1-C5) haloalkyl, or alternatively, R x and R' x form, together with the C atoms to which they are attached, a ring having 3 to 6 elements, R6 is an aromatic known ring system, which is The element is CR y and N, R y H, OH, CN, halogens, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted with one or more Su6 (C1-C 10 ) alkyl, substituted with one or more Su7 (C2-C 10 ) alkenyl, substituted with one or more Su8 (C2-C 10 ) alkynyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10)Haloalkyl, SF5, S(O)2R 13 , N.R. 14 R 15 , CONR8R'8 and COOR 24 an aromatic six-membered ring system selected from the group consisting of The element is CR z , S, N, NH, and O; R z H, OH, CN, halogens, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 17 , N.R. 18 R 19 ,CONR 12 R' 12 and COOR 24 an aromatic five-membered ring system selected from the group consisting of an aromatic fused ring system consisting of two rings, each of the aromatic rings having six elements selected from CH or N; and Formula (XI): [ka] (In the formula, R t1 ~R t9 is N, NR p or CR' p Selected from R p is H, (C1~C 10 ) haloalkyl, S(O)R t10 ,CONR t11 R' t11 and COOR' t12 and R' is selected from the group consisting of p H, OH, CN, halogens, (C1-C 10 ) haloalkyl, O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R' 17 , NR' 18 R' 19 ,CONR 16 R' 16 and COOR 25 an aromatic fused ring system selected from the group consisting of is selected from the group consisting of R7 is CR v R' v and R v and R' v are the same or different and are independently selected from H, (C1-C5) alkyl or (C1-C5) haloalkyl, or alternatively, R v and R' v form a ring with three to six elements together with the C atoms to which they are attached, R and R' may be the same or different, -H, (C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C-C) cycloalkyl, aryl, and heteroaryl; R9, R 13 , R 17 and R t10 (C1~C 10 ) alkyl, (C-C) cycloalkyl, aryl, and heteroaryl; R 10 and R 11 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C3-C8) cycloalkyl; R 12 and R' 12 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl and (C3-C8) cycloalkyl; R 14 and R 15 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C3-C8) cycloalkyl and -S(O)R 21 is selected from the group consisting of R 16 and R' 16 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10) haloalkyl and (C3-C8) cycloalkyl; R 18 and R 19 are the same or different, -H, (C1 to C 10 ) alkyl, (C1-C 10 ) haloalkyl, (C3-C8) cycloalkyl and -S(O)R 22 is selected from the group consisting of R' 18 and R' 19 are the same or different, -H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl, (C1-C 10 ) haloalkyl and -S(O)R 23 is selected from the group consisting of R t10 and R' t10 are the same or different, -H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl, (C1-C 10 ) haloalkyl and -S(O)R t13 is selected from the group consisting of R 21 ~R 23 and R t13 (C1~C 10 ) alkyl, (C3-C8) cycloalkyl or (C1-C 10 ) haloalkyl; R 24 , R 25 and R' t12 is -H, (C1~C 10 ) alkyl, (C3-C8) cycloalkyl and (C1-C 10 ) haloalkyl; m is an integer value selected from 0, 1, or 2; n is an integer value selected from 1 or 2, "Aryl" is a compound with six CR c means an aromatic ring system containing the element R c is selected from H, halogen, cyano, nitro, (C1-C5) alkyl, (C1-C5) haloalkyl, —O—(C1-C5) alkyl, or —O—(C1-C5) haloalkyl; "Heteroaryl" is a CR d R means an aromatic ring system containing five or six elements selected from the group consisting of O, N, NH and S; d is selected from H, halogen, cyano, nitro, (C1-C5) alkyl, (C1-C5) haloalkyl, —O—(C1-C5) alkyl, —O—(C1-C5) haloalkyl; Su1 to Su8 are independently selected from the group consisting of halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N—(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N—(C1-C4)alkylsulfamoyl and N,N-di-(C1-C4)alkylsulfamoyl; provided that at least one of R2 to R4 is other than H), or a pharmaceutically acceptable salt, solvate or prodrug thereof. Item 2.R y H, OH, CN, halogens, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10)alkynyl, (C1-C1) substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)alkylcarbonyloxy, (C3-C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4)alkylsulfamoyl, N,N-di-(C1-C4)alkylsulfamoyl 10 ) alkyl, substituted with one or more halogens, cyano, nitro, trifluoromethyl, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, carbamoyl, N-(C1-C4) alkylcarbamoyl, N,N-di-(C1-C4) alkylcarbamoyl, (C1-C6) alkylcarbonyloxy, (C3-C6) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4) alkylsulfamoyl, N,N-di-(C1-C4) alkylsulfamoyl 10) alkenyl, (C2-C substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, carbamoyl, N-(C1-C4) alkylcarbamoyl, N,N-di-(C1-C4) alkylcarbamoyl, (C1-C6) alkylcarbonyloxy, (C3-C6) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C1-C4) alkylsulfamoyl, N,N-di-(C1-C4) alkylsulfamoyl 10 ) alkynyl, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 13 , N.R. 14 R 15 and COOR 24 selected from the group consisting of: R' p H, OH, CN, halogens, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R' 17 , NR' 18 R' 19 and COOR 25 selected from the group consisting of: R z H, OH, CN, halogens, (C1-C 10 ) haloalkyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 )Haloalkyl, SF5, S(O)2R 17 , N.R. 18 R 19 and COOR 24 selected from the group consisting of: R9, R 13and R 17 (C1~C 10 ) alkyl and (C3-C8) cycloalkyl; R 18 and R 19 are the same or different, H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl and (C1-C 10 ) haloalkyl; R' 18 and R' 19 are the same or different, H, (C1 to C 10 ) alkyl, (C3-C8) cycloalkyl and (C1-C 10 ) haloalkyl; and R 23 and R 24 However, H and (C1~C 10 2. The compound of item 1, wherein the alkyl is selected from the group consisting of (C3-C8)alkyl and (C3-C8)cycloalkyl. Item 3. Formula (Ibis): [ka] (wherein R1 to R3 and R6 and n are as defined in item 1). Item 4. R2 is H, CN, halogen, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl and (C1-C 10 ) haloalkyl. Item 5. R3 is H, CN, halogen, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl, SF5, S(O)2R9, where R9 is as defined above, and in particular R9 is selected from the group consisting of (C1-C 10 ) alkyl or aryl, in particular R9 is selected from (C1-C 10 ) alkyl. Item 6. The compound of any one of the preceding items, wherein R6 is an aromatic 5- or 6-membered ring system as defined in item 1. Item 7. R6 is represented by formula (II) and formula (III): [ka] (In the formula, R 7a ~R 7e are the same or different and are H, OH, CN, halogen, nitro, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted with one or more Su8 (C1-C 10 ) alkyl, substituted with one or more Su9 (C2-C 10 ) alkenyl, one or more Su 10 (C2~C 10 ) alkynyl, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) haloalkyl, -SF5 and -S(O)2R 26 In particular, R 7a ~R 7e are the same or different and are H, halogen, (C1 to C 10 ) alkyl, -O-(C1-C 10 ) alkyl and COOR 24 is selected from the group consisting of R 26 (C1~C 10 ) alkyl, (C3-C8) cycloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) selected from the group consisting of alkynyl, aryl, and heteroaryl; Su8~Su 10are independently selected from halogen, cyano, nitro, (C1-C6)haloalkyl, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, N,N-di-(C1-C4)alkylcarbamoyl, (C1-C6)a aryl, (C-C)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C-C)alkylsulfamoyl, and N,N-di-(C-C)alkylsulfamoyl. Item 8. R6 is formula (IV): [ka] The compound of any one of the preceding items 1 to 6, wherein the aromatic five-membered ring system is Item 9. R1 is halogen, -O-(C1-C 10 ) haloalkyl and (C1-C 10 ) haloalkyl. Item 10. R2 is H, halogen and (C1-C 10 ) haloalkyl. Item 11. The compound of the previous item, wherein R2 represents H. Item 12. R3 is H, CN, halogen, -O-(C1-C 10 ) alkyl, -O-(C1-C 10 ) The compound of any one of the preceding items, wherein the compound is selected from the group consisting of haloalkyl and SF5. Item 13. The compound of the previous item, wherein R3 represents H. Item 14. R1 is halogen, CN, -O-(C1-C 10 ) alkyl, (C1-C 10) haloalkyl and -O-(C1-C 10 ) haloalkyl; R2 represents H, R3 is -CN, halogen, -O-(C1~C 10 ) alkyl, -O-(C1-C 10 ) selected from the group consisting of haloalkyl, —SF5, and —S(O)2R9; R6, (a) The element is CR y and each R y are independently H, halogen, nitro, CN, (C1-C5)alkyl, (C1-C5)alkyl substituted with one or more halogens, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl, -SF5, -S(O)2R9, -NR 10 R 11 and -COOR 23 In particular, each R y are independently selected from the group consisting of H, halogen, (C1-C5) alkyl, -O-(C1-C5) alkyl, and -COOH; (b) One of the elements is N and the remaining elements are CR y and R y as defined in the previous paragraph, in particular aromatic 6-membered ring systems corresponding to the systems of formula (III) defined in paragraph 7, and (c) The element is CR z , N and S, with the proviso that at least one of the elements is S, in particular aromatic 5-membered ring systems corresponding to the systems of formula (IV) defined in item 8, 13. The compound of any one of the preceding items 1 to 12, selected from the group consisting of: Item 15. R1 is halogen, -O-(C1-C 10 ) alkyl, (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R3 is CN, -O-(C1~C 10 ) alkyl, -O-(C1-C 10) a compound of any of the preceding items, wherein the aryl group is selected from the group consisting of haloalkyl and halogen. Item 16. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, R1 is halogen, substituted with one or more halogen atoms (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R2 is H, R3 is CN, -O-(C1~C 10 ) alkyl, -O-(C1-C 10 ) a compound of any of the preceding items, wherein the aryl group is selected from the group consisting of haloalkyl and halogen. Item 17. R1 is halogen, (C1-C 10 ) haloalkyl and -O-(C1-C 10 ) haloalkyl; R2 represents H, R3 is -CN, halogen, -O-(C1~C 10 ) haloalkyl and -O-(C1-C 10 ) alkyl; R6, (a) The element is CR y and each R y are independently H, halogen, nitro, CN, (C1-C5)alkyl, (C1-C5)alkyl substituted with one or more halogens, -O-(C1-C5)alkyl, -O-(C1-C5)haloalkyl, -SF5, -S(O)2R9, -NR 10 R 11 and -COOR 23 In particular, each R y are independently selected from the group consisting of H, halogen, (C1-C5) alkyl, -O-(C1-C5) alkyl, and -COOH; (b) One of the elements is N and the remaining elements are CR y and R y as defined in the previous paragraph, in particular aromatic 6-membered ring systems corresponding to the systems of formula (III) defined above, and (c) The element is CR z , N and S, with the proviso that at least one of the elements is S, in particular aromatic 5-membered ring systems corresponding to the systems of formula (IV) defined above, The compound of any of the preceding items selected from the group consisting of: Item 18. R1 is halogen, (C1-C 10 ) haloalkyl and -O-(C1-C 10 ) haloalkyl; R2 is halogen and (C1-C 10 ) haloalkyl; R3 represents -H, A compound according to any of the preceding paragraphs wherein R6 is a six-membered aromatic ring system, a ring of formula (II) as defined in paragraph 7, in particular wherein R6 represents phenyl. Item 19. R1 is halogen, substituted by one or more halogen atoms (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R2 represents H, R3 is -CN, halogen, -O-(C1~C 10 ) haloalkyl and -O-(C1-C 10 ) alkyl; R6 is a 6-membered aromatic ring system and is a ring of formula (II) as defined above, where R y is H, halogen, (C1-C5) alkyl, (C1-C5) alkyl substituted with one or more halogens, -O-(C1-C5) alkyl, -O-(C1-C5) haloalkyl, and -COOR 23 In particular, each R y is independently selected from the group consisting of H, halogen, (C1-C5) alkyl, —O—(C1-C5) alkyl, and —COOH. Item 20. R1 is halogen, substituted by one or more halogen atoms (C1-C 10 ) alkyl, and -O-(C1-C 10 ) haloalkyl; R2 represents H, R3 is -CN, halogen, -O-(C1~C 10 ) haloalkyl and -O-(C1-C 10 ) alkyl; A compound of any of the preceding items wherein R6 is a ring of formula (IV) as defined above. Item 21. The compound of any one of the preceding items, wherein the pain is postoperative pain, pain induced by tissue injury, pain associated with inflammation, cancer pain, arthralgia, chronic pain, or any other pain condition involving allodynia and / or hyperalgesia. Item 22. Formula (I'): [ka] (In the formula, R1, R2, R3, R4, R6, R7, m and n are as defined in any of the preceding items; R5' is CR f R' f where R f and R' f are the same or different and are selected from the group consisting of H and (C1-C5)haloalkyl, or alternatively, R f and R' f form a ring with three to six elements together with the C atom to which they are attached, however, At least one of R2 to R4 is other than hydrogen; R6 is of formula (i): [ka] other than the ring of R1 and R4 are the same, -O-(C1-C 10 ) alkyl or halogen, and when R2 and R3 are H, m=n=1, R5 is -CH2-, and R7=-CH2- or CH(CH3)-, R6 is All six elements are defined in claim 9. y an aromatic six-membered ring system in which Frills, Other than that, R1 to R3 are the same, and -O-(C1 to C 10 ) alkyl, and when R4 is H, m=1, n=1 or 2, and R5=R7=—CH2—, then R6 is other than phenyl; R1 to R3 are the same, and -O-(C1 to C 10 ) alkyl, and when R4 is H, m=1, n=1, and R5=R7=—CH2—, R6 represents a group of formula (ii): [ka] wherein Ri=Me or Et, R1 to R3 are the same, and -O-(C1 to C 10 ) alkyl, and when R4 is H, m=1, n=1, and R5=R7=—CH2—, R6 is (C1-C 10 ) other than phenyl substituted by alkyl or one or more halogens; When R1 and R3 are Cl, m=n=1, R2=R4=H, and R5=R7=—CH2—, R6 is phenyl ring, (C1~C 10 ) alkyl, meta-O-(C1-C 10 ) a phenyl ring substituted with alkyl or one or more halogens, or naphthalenyl ring, Other than that, R1 and R3 are the same or different and represent halogen, R2 = R4 = H, m = n = 1, R5 = R7 = -CH2-, and R6 is a group represented by formula (VI) or formula (VII): [ka] If R is one of z1 ~R z5 is H, When R1 and R3 are the same or different and represent halogen, R2 = R4 = H, m = n = 1, R5 = R7 = -CH2- and R6 is one of the formulas (XI) defined in item 1, R p is H, When R1 and R3 are F, R2=R4=H, m=1, n=2, and R5=R7=—CH2—, then R6 is other than a 1H-pyrrolo[2,3-b]pyridin-3-yl ring; when R1 is ethoxy, R2 = R3 = H, R4 is methyl, m = 0, n = 1, and R5 = R7 = -CH2-, then R6 is other than a phenyl ring, The formula (Ibis) defined in item 3: [ka] The compound or a pharmaceutical salt, solvate or prodrug thereof. Item 23. The compound of item 22, which is a compound of formula (Ibis), wherein R2 represents H and R3 is as defined in any of the preceding items, except that it is other than hydrogen. Item 24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I') or formula (Ibis) defined in item 22 or 23 or a pharmaceutical salt thereof, together with one or more pharmaceutically acceptable salts. Item 25. A compound as defined in items 23 or 24 for therapeutic use. Item 26. Compounds are 1-benzyl-N-(2-fluoro-4-(pentafluoro-λ) 6 -sulfanyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-3-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, and 1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide, 1-(4-chlorobenzyl)-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-(4-chlorobenzyl)-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, 1-(4-iodobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-(4-fluorobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, The compound of any one of the preceding items 1 to 21 or 25, the compound of item 22 or 23, or the pharmaceutical composition of item 24, selected from the group consisting of: Item 27. The compound 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide for use in the treatment or prevention of pain. Item 28. A method for preparing a compound of formula (I) as defined in any of the preceding items, comprising reacting in the presence of an amide coupling reagent and a base: Formula (VIII) in either the free base or pharmaceutically acceptable salt form: [ka] and a compound of Formula (IX): [ka] wherein R1 to R7, n and m are as defined in any of the preceding items. Item 29. A method for preparing a compound of formula (I) as defined in any of the preceding items, comprising the step of: [ka] to reductive alkylation with a benzaldehyde of formula (XI) in the presence of a reducing agent, or alternatively to nucleophilic substitution with an alkylaryl halide of formula (XII) in the presence of a base, [ka] The method wherein "Hal" represents halogen, R1 to R7, m and n are as defined in the preceding paragraphs, and w is 0 or 1.

Claims

1. 1. A compound of formula (I): 【Chemistry 1】 (In the formula, R １ is CN, halogen, (C １ ~C １０ ) haloalkyl, —O—(C １ ~C １０ ) alkyl and —O—(C １ ~C １０ ) haloalkyl; R ２ ~R ４ are the same or different and independently represent H, CN, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) alkynyl, one or more Su １ (C １ ~C １０ ) alkyl, one or more Su ２ (C ２ ~C １０ ) alkenyl, one or more Su ３ (C ２ ~C １０ ) alkynyl, —O—(C １ ~C １０ ) alkyl, one or more Su ４ -O-(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) haloalkyl, one or more Su ５ -O-(C １ ~C １０ ) haloalkyl, -SF ５ , -S(O) ２ R ９ , -NR １０ R １１ aryl and heteroaryl; R ５ is CR ｘ R' ｘ and R ｘ and R' ｘ are the same or different and independently represent —H, (C １ ~C ５ ) alkyl or (C １ ~C ５ ) haloalkyl, or alternatively, R ｘ and R' ｘ form together with the C atoms to which they are attached a ring having 3 to 6 elements, R ６ is a known aromatic ring system, which is a) The element is CR ｙ and N, R ｙ H, OH, CN, halogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) alkynyl, one or more Su ６ (C １ ~C １０ ) alkyl, one or more Su ７ (C ２ ~C １０ ) alkenyl, one or more Su ８ (C ２ ~C １０ ) alkynyl, —O—(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) Haloalkyl, SF ５ , S(O) ２ R １３ , N.R. １４ R １５ , C.O.R. ８ R' ８ and COOR ２４ an aromatic six-membered ring system selected from the group consisting of b) The element is CR ｚ , S, N, NH, and O; R ｚ H, OH, CN, halogen, (C １ ~C １０ ) haloalkyl, —O—(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) Haloalkyl, SF ５ , S(O) ２ R １７ , N.R. １８ R １９ , C.O.R. １２ R' １２ and COOR ２４ an aromatic five-membered ring system selected from the group consisting of c) an aromatic fused ring system consisting of two rings, each of the aromatic rings having six elements selected from CH or N; and d) Formula (XI): 【Chemistry 2】 (In the formula, R ｔ１ ~R ｔ９ is N, NR ｐ or CR' ｐ and R ｐ is H, (C １ ~C １０ ) haloalkyl, S(O) ２ R ｔ１０ , C.O.R. ｔ１１ R' ｔ１１ and COOR' ｔ１２ and R' is selected from the group consisting of ｐ H, OH, CN, halogen, (C １ ~C １０ ) haloalkyl, O—(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) Haloalkyl, SF ５ , S(O) ２ R' １７ , NR' １８ R' １９ , C.O.R. １６ R' １６ and COOR ２５ an aromatic fused ring system selected from the group consisting of is selected from the group consisting of R ７ is CR ｖ R' ｖ and R ｖ and R' ｖ are the same or different and independently represent H, (C １ ~C ５ ) alkyl or (C １ ~C ５ ) haloalkyl, or alternatively, R ｖ and R' ｖ form together with the C atoms to which they are attached a ring having 3 to 6 elements, R ８ and R' ８ are the same or different, -H, (C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl, (C ３ ~C ８ ) selected from the group consisting of cycloalkyl, aryl, and heteroaryl; R ９ , R １３ , R １７ and R ｔ１０ (C １ ~C １０ ) alkyl, (C ３ ~C ８ ) selected from the group consisting of cycloalkyl, aryl, and heteroaryl; R １０ and R １１ are the same or different, -H, (C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl, (C ３ ~C ８ ) cycloalkyl; R １２ and R' １２ are the same or different, -H, (C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl and (C ３ ~C ８ ) cycloalkyl; R １４ and R １５ are the same or different, -H, (C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl, (C ３ ~C ８ ) cycloalkyl and —S(O) ２ R ２１ is selected from the group consisting of R １６ and R' １６ are the same or different, -H, (C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl and (C ３ ~C ８ ) cycloalkyl; R １８ and R １９ are the same or different, -H, (C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl, (C ３ ~C ８ ) cycloalkyl and —S(O) ２ R ２２ is selected from the group consisting of R' １８ and R' １９ are the same or different, -H, (C １ ~C １０ ) alkyl, (C ３ ~C ８ ) cycloalkyl, (C １ ~C １０ ) haloalkyl and —S(O) ２ R ２３ is selected from the group consisting of R ｔ１０ and R' ｔ１０ are the same or different, -H, (C １ ~C １０ ) alkyl, (C ３ ~C ８ ) cycloalkyl, (C １ ~C １０ ) haloalkyl and —S(O) ２ R ｔ１３ is selected from the group consisting of R ２１ ~R ２３ and R ｔ１３ (C １ ~C １０ ) alkyl, (C ３ ~C ８ ) cycloalkyl or (C １ ~C １０ ) haloalkyl; R ２４ , R ２５ and R' ｔ１２ -H, (C １ ~C １０ ) alkyl, (C ３ ~C ８ ) cycloalkyl and (C １ ~C １０ ) haloalkyl; m is an integer value selected from 0, 1, or 2; n is an integer value selected from 1 or 2; "Aryl" is a compound with six CRs. ｃ means an aromatic ring system containing an element, R ｃ is H, halogen, cyano, nitro, (C １ ~C ５ ) alkyl, (C １ ~C ５ ) haloalkyl, —O—(C １ ~C ５ ) alkyl or —O—(C １ ~C ５ ) haloalkyl; "Heteroaryl" refers to a CR ｄ , O, N, NH and S; R ｄ is H, halogen, cyano, nitro, (C １ ~C ５ ) alkyl, (C １ ~C ５ ) haloalkyl, —O—(C １ ~C ５ ) alkyl, —O—(C １ ~C ５ ) haloalkyl; Su １ ~Su ８ are independently halogen, cyano, nitro, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkylsulfinyl, (C １ ~C ６ ) alkylsulfonyl, (C １ ~C ６ ) alkylcarbonyl, (C １ ~C ６ ) alkoxycarbonyl, carbamoyl, N—(C １ ~C ４ ) alkylcarbamoyl, N,N-di-(C １ ~C ４ ) alkylcarbamoyl, (C １ ~C ６ ) alkylcarbonyloxy, (C ３ ~C ６ ) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C １ ~C ４ ) alkylsulfamoyl and N,N-di-(C １ ~C ４ ) alkylsulfamoyl, However, R ２ ~R ４ wherein at least one of is other than H, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

2. Formula (Ibis): 【Transformation 3】 (In the formula, R １ ~R ３ , R ６ and n is as defined in claim 1.

3. R ２ is H, CN, halogen, —O—(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) haloalkyl and (C １ ~C １０ 3. The compound of claim 1, wherein the aryl group is selected from the group consisting of aryl, ...

4. R ３ is H, CN, halogen, —O—(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) Haloalkyl, SF ５ , S(O) ２ R ９ wherein R ９ is as defined above, in particular R ９ (C １ ~C １０ ) alkyl or aryl, in particular R ９ (C １ ~C １０ 4. The compound according to claim 1, wherein the aryl group is selected from the group consisting of aryl, ...

5. R ６ A compound according to any one of claims 1 to 4, wherein is an aromatic 5- or 6-membered ring system as defined in claim 1.

6. R ６ Formula (II) and Formula (III): 【Chemistry 4】 (In the formula, R ７ａ ~R ７ｅ are the same or different and are H, OH, CN, halogen, nitro, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) alkynyl, one or more Su ８ (C １ ~C １０ ) alkyl, one or more Su ９ (C ２ ~C １０ ) alkenyl, one or more Su １０ (C ２ ~C １０ ) alkynyl, —O—(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) haloalkyl, -SF ５ and -S(O) ２ R ２６ In particular, R ７ａ ~R ７ｅ are the same or different, and are H, halogen, (C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) alkyl and COOR ２４ is selected from the group consisting of R ２６ (C １ ~C １０ ) alkyl, (C ３ ~C ８ ) cycloalkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) selected from the group consisting of alkynyl, aryl, and heteroaryl; Su ８ ~Su １０ are independently halogen, cyano, nitro, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkylsulfinyl, (C １ ~C ６ ) alkylsulfonyl, (C １ ~C ６ ) alkylcarbonyl, (C １ ~C ６ ) alkoxycarbonyl, carbamoyl, N—(C １ ~C ４ ) alkylcarbamoyl, N,N-di-(C １ ~C ４ ) alkylcarbamoyl, (C １ ~C ６ ) alkylcarbonyloxy, (C ３ ~C ６ ) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C １ ~C ４ ) alkylsulfamoyl and N,N-di-(C １ ~C ４ 6. The compound of claim 1, wherein the aromatic 6-membered ring system is selected from the group consisting of:

7. R ２ A compound according to any one of claims 1 to 6, wherein represents -H.

8. R ３ A compound according to any one of claims 1 to 6, wherein represents -H.

9. R １ is halogen, CN, —O—(C １ ~C １０ ) alkyl, (C １ ~C １０ ) haloalkyl and —O—(C １ ~C １０ ) haloalkyl; R ２ represents H, R ３ -CN, halogen, -O-(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) haloalkyl, -SF ５ and -S(O) ２ R ９ is selected from the group consisting of R ６ but, (a) The element is CR ｙ and each R ｙ are independently H, halogen, nitro, CN, (C １ ~C ５ ) alkyl, substituted with one or more halogens (C １ ~C ５ ) alkyl, —O—(C １ ~C ５ ) alkyl, —O—(C １ ~C ５ ) haloalkyl, -SF ５ , -S(O) ２ R ９ , -NR １０ R １１ and -COOR ２３ In particular, each R ｙ are independently H, halogen, (C １ ~C ５ ) alkyl, —O—(C １ ~C ５ ) an aromatic 6-membered ring system selected from the group consisting of alkyl and —COOH; (b) One of the elements is N and the remaining elements are CR ｙ and R ｙ as defined in claims 1 to 8, in particular aromatic 6-membered ring systems corresponding to the systems of formula (III) as defined in claim 7, and (c) The element is CR ｚ , N and S, with the proviso that at least one of the elements is S, and in particular is selected from the group consisting of the formula (IV): 【Transformation 5】 an aromatic five-membered ring system corresponding to the system or alternatively selected from the group consisting of: R １ is halogen, —O—(C １ ~C １０ ) alkyl, substituted with one or more halogen atoms (C １ ~C １０ ) alkyl, and —O—(C １ ~C １０ ) haloalkyl; R ３ is CN, -O-(C １ ~C １０ ) alkyl, —O—(C １ ~C １０ ) selected from the group consisting of haloalkyl and halogen; Or alternatively, R １ is halogen, (C １ ~C １０ ) haloalkyl and —O—(C １ ~C １０ ) haloalkyl; R ２ is halogen and (C １ ~C １０ ) haloalkyl; R ３ represents -H, R ６ is a six-membered aromatic ring system and is a ring of formula (II) as defined in claim 7, in particular R ６ A compound according to any one of claims 1 to 8, wherein represents phenyl.

10. 10. The compound according to any one of claims 1 to 9, wherein the pain is post-operative pain, pain induced by tissue injury, pain associated with inflammation, cancer pain, arthritic pain, chronic pain, or any other pain condition involving allodynia and / or hyperalgesia.

11. Formula (I'): 【Transformation 6】 (In the formula, R １ , R ２ , R ３ , R ４ , R ６ , R ７ , m and n are as defined in any one of claims 1 to 9, R ５ ' is CR ｆ R' ｆ where R ｆ and R' ｆ are the same or different, H and (C １ ~C ５ ) haloalkyl, or alternatively, R ｆ and R' ｆ form, together with the C atoms to which they are attached, a ring having 3 to 6 elements, however, R ２ ~R ４ is other than hydrogen, R ６ is of formula (i): 【Transformation 7】 other than the ring of R １ and R ４ are the same, and —O—(C １ ~C １０ ) represents alkyl or halogen, R ２ and R ３ is H, m=n=1, and R ５ Ga-CH ２ - and R ７ =-CH ２ - or CH(CH ３ )-, then R ６ teeth, All six elements are CR as defined in claim 9. ｙ an aromatic six-membered ring system in which Frills, Other than that, R １ ~R ３ are the same, and —O—(C １ ~C １０ ) alkyl, R ４ is H, m=1, n=1 or 2, and R ５ =R ７ =-CH ２ -, then R ６ is other than phenyl, R １ ~R ３ are the same, and —O—(C １ ~C １０ ) alkyl, R ４ is H, m=1, n=1, and R ５ =R ７ =-CH ２ -, then R ６ is represented by formula (ii): 【Transformation 8】 wherein Ri=Me or Et, R １ ~R ３ are the same, and —O—(C １ ~C １０ ) alkyl, R ４ is H, m=1, n=1, and R ５ =R ７ =-CH ２ -, then R ６ is (C １ ~C １０ ) other than phenyl substituted by alkyl or one or more halogens; R １ and R ３ is Cl, m=n=1, and R ２ =R ４ = H, and R ５ =R ７ =-CH ２ -, then R ６ teeth, phenyl ring, (C １ ~C １０ ) alkyl, meta-O—(C １ ~C １０ ) a phenyl ring substituted with alkyl or one or more halogens; and naphthalenyl ring, Other than that, R １ and R ３ are the same or different and represent halogen; R ２ =R ４ = H, m = n = 1, and R ５ =R ７ =-CH ２ - and R ６ is represented by formula (VI) or formula (VII): 【Chemistry 9】 If R is one of ｚ１ ~R ｚ５ is H, R １ and R ３ are the same or different and represent halogen; R ２ =R ４ = H, m = n = 1, and R ５ =R ７ =-CH ２ - and R ６ is one of the formulae (XI) defined in claim 1, R ｐ is H, R １ and R ３ is F and R ２ =R ４ = H, m = 1, n = 2, and R ５ =R ７ =-CH ２ -, then R ６ is other than a 1H-pyrrolo[2,3-b]pyridin-3-yl ring, R １ is ethoxy, and R ２ =R ３ = H, and R ４ is methyl, m=0, n=1, and R ５ =R ７ =-CH ２ -, then R ６ is other than a phenyl ring, A compound of formula (Ibis) as defined in claim 2, or a pharmaceutical salt, solvate or prodrug thereof.

12. A compound of formula (Ibis), wherein R ２ represents H, and R ３ 12. The compound of claim 11, wherein is as defined in any one of claims 1 to 11, except that is other than hydrogen.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I'), formula (Ibis) or a pharmaceutical salt thereof according to claim 11 or 12, together with one or more pharmaceutically acceptable salts thereof.

14. 13. A compound according to claim 11 or 12 for use in therapy.

15. the compound is for treating or preventing pain; 1-benzyl-N-(2-fluoro-4-(pentafluoro-λ ６ -sulfanyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-4-(methylsulfonyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-methoxy-4-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-methylbenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3-chlorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-2-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-4-cyanobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-chlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-chloro-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-3-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2,3-dichlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, and 1-benzyl-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(2,4-dichloro-5-fluorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2,3,5-trichlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-3-fluorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-bromo-2-chlorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-fluoro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-chloro-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(3-methoxy-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-benzyl-N-(4-bromo-2-fluorobenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-chloro-4-methoxybenzyl)piperidine-4-carboxamide, 1-benzyl-N-(2-bromo-4-chlorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(naphthalen-2-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(2-fluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(3,4-difluorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-methylbenzyl)piperidine-4-carboxamide, 1-(4-chlorobenzyl)-N-(4-cyano-2-(trifluoromethyl)benzyl)piperidine-4-carboxamide, 1-(4-chlorobenzyl)-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(2,4-dichlorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(furan-2-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide, N-(2,4-dichlorobenzyl)-1-(4-(trifluoromethyl)benzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-phenethylpiperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(3-fluorobenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-fluorobenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethyl)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(2-chloro-4-cyanobenzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-chloro-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-bromo-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-fluoro-2-(trifluoromethyl)benzyl)-1-(4-iodobenzyl)piperidine-4-carboxamide, 1-(4-iodobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, 1-(4-fluorobenzyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)piperidine-4-carboxamide, N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)piperidine-4-carboxamide, N-(4-methoxy-2-(trifluoromethoxy)benzyl)-1-(thiophen-3-ylmethyl)piperidine-4-carboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or alternatively, the compound 1-benzyl-N-(2,4-dichlorobenzyl)piperidine-4-carboxamide, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; The compound of any one of claims 1 to 9 or 14, the compound of claim 11 or 12, or the pharmaceutical composition of claim 13, selected from the group consisting of:

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