BR112017009042B1 - COMPOUND OF FORMULA (I) OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

COMPOUND OF FORMULA (I) OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PHARMACEUTICAL COMPOSITION. The disclosure relates to new dopamine D3 receptor antagonists, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing the same and their use in therapy, including the treatment of drug addiction and psychosis.

Description

Related Requests

[1] This application claims priority to United Kingdom Applications Nos. GB1419430.2 and GB1419433.6, both filed on October 31, 2014, the disclosures of which are incorporated by reference herein in their entirety.

Field of Invention

[2] The present invention relates to new compounds, processes for their preparation, intermediates used in the processes, pharmaceutical compositions that contain them and their use in therapy, such as dopamine D3 receptor modulators.

Fundamentals of Invention

[3] Dopamine is a neurotransmitter that plays an essential role in normal brain functions. As a chemical messenger, dopamine is similar to adrenaline. In the brain, dopamine is synthesized in presynaptic neurons and released into the space between presynaptic and postsynaptic neurons. Dopamine affects brain processes that control movement, emotional response, and the ability to feel pleasure and pain. Therefore, dopamine regulation plays an important role in physical and mental health. Dopamine-containing neurons are clustered in the area of the midbrain called the substantia nigra. Abnormal dopamine signaling in the brain has been attributed to a substantial number of pathological conditions, including drug abuse, depression, anxiety, schizophrenia, Tourette's syndrome, eating disorders, alcoholism, chronic pain, obsessive compulsive disorder, restless legs syndrome, and Parkinson's disease.

[4] Dopamine molecules bind and activate dopamine receptors on postsynaptic neurons. Dopamine molecules are then transported via the dopamine transporter protein (DAT) back to presynaptic neurons, where they are metabolized by monoamine oxidase (MAO). In conditions such as drug abuse, the drug binds to the dopamine transporter and blocks the normal flow of dopamine molecules. Excessive concentrations of dopamine cause overactivation of dopamine receptors. In other conditions, such as Parkinson's disease, the lack of sufficient dopamine receptors in the brain causes insufficient activation of dopamine receptors.

[5] Dopaminergic neurotransmission is mediated by five dopamine receptors, which can be grouped into the D1 (i.e., D1 and D5) and D2 (i.e., D2, D3, and D4) receptor subtypes. The dopamine D3 receptor has been considered an important target for agents currently used clinically for the treatment of schizophrenia, Parkinson's disease, depression and other neurological diseases. The studies also provided evidence that potent and selective D3 receptor antagonists may have therapeutic potential as pharmacotherapies for the treatment of drug abuse. Therefore, considerable effort has been devoted to the discovery and development of potent and selective D3 receptor antagonists.

Summary of the invention

[6] A new class of compounds has been found that have affinity for dopamine receptors, especially the dopamine D3 receptor. These compounds are useful in treating conditions in which modulation, especially antagonism/inhibition, of the D3 receptor is beneficial, for example, to treat drug addiction or antipsychotic agents.

[7] The disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof: The disclosure discloses methods for antagonizing the D3 receptor to treat diseases, including psychosis and substance abuse.

Detailed Description

[8] The present invention features a compound of formula (I) or its pharmaceutically acceptable salt: wherein A is a 3- to 6-membered carbocyclic ring and that ring may be substituted by one or more C1-4 alkyl groups; B is a 4- to 6-membered saturated heterocyclic ring, in which one or two carbon atoms may be replaced by a heteroatom selected from at least one Nitrogen or Oxygen and the bonding atom is always a Nitrogen atom; this ring can also be replaced by carbon atoms or, possibly, by a different Nitrogen atom, by one or more C1-4 alkyl groups; G is aryl or a 5- to 6-membered heteroaromatic group or 8 to 11-membered heteroaromatic group, which may be benzofused or optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, SF5, C (=O)NH2 and C(=O)(O)zR3; W is S1 SO2, O, CHR2 or NR3; n is 0 or i; m is i or 2; p is i or 2; z is, independently, 0 or i; R is hydrogen or Ci-4alkyl; Ci-4alkoxy; Ri is, independently, hydrogen or F, Ci-4alkyl; OH, Ci-4alkoxy; R2 is, independently, hydrogen F, Ci-4alkyl; OH, Ci-4alkoxy; R3 is, independently, hydrogen or Ci-4alkyl; R4 is, independently, hydrogen or Ci-4alkyl; or -C(=O)Ci-4alkyl; - C(=O)Ci-4alkoxyCi-4alkyl; -C(=O)C3-6cycloalkyl; Rs is, independently, hydrogen or Ci-4alkyl; R6 is, independently, hydrogen or Ci-4alkyl; R7 is, independently, halogen, Ci-4alkyl; OH, Ci-4alkoxy; Gi is a phenyl group or a 5 to 6 membered heteroaromatic group or an 8 to ii membered heteroaromatic group; any of the groups may be optionally substituted by i, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, haloCi- 4alkoxy, Ci-4alkoxy, SF5, C (=O)NH2 and C(=O)(O)zR3; Y is phenyl or a moiety selected from the group consisting of: a 5- to 6-membered heteroaromatic group, an 8 to 11-membered heteroaromatic group, a 3 to 7 mono- and saturated carbocyclic group, and an 8-membered bicyclic carbocyclic group. to 11 members and for any of these groups one or more ring carbons can be replaced by N(R4)z,O, S; any of these groups may be optionally substituted by 1, 2 or 3 substituents selected from: halogen, cyano, hydroxyl, C1-4alkylamino, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, oxo, -NHC (=O)C1-4alkyl, -NR5R6, SF5, -(CH2)ZC(=O)NR5R6, -C(=O)(O)zR3,-Ci-4alkylCN, -SO2NR5R6, Y' or OY';Y' is phenyl or a 5 to 6 membered heteroaromatic group optionally substituted by 1 or 2 R7 groups; provided that Y, Y' and G1 are not simultaneously phenyl.

[9] The term "aryl" refers to an aromatic carbocyclic moiety such as phenyl, biphenyl, or naphthyl.

[10] The term "5- to 6-membered heteroaromatic group" refers to a 5- or 6-membered monocyclic aromatic heterocyclic group containing 1, 2, 3, or 4 heteroatoms, e.g., 1 to 3 heteroatoms, selected from O , N and S. When the group contains 2 to 4 heteroatoms, one can be selected from O, N and S and the rest of the heteroatoms can be N. Examples of 5 to 6 membered heteroatom groups include pyrrolyl, imidazolyl, pyrazolyl, oxazolyl , isoxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, furyl, thienyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

[11] The term "8- to 11-membered heteroaromatic group" refers to a bicyclic aromatic ring system containing a total of 8, 9, 10, or 11 ring atoms, wherein 1, 2, 3, 4, or 5 ring atoms are a heteroatom independently selected from O, S, and N. The term includes bicyclic systems in which both rings are aromatic, as well as bicyclic ring systems in which one of the rings is partially or fully saturated and the other ring is aromatic . Examples of 8- to 11-membered bicyclic heteroaromatic groups with 1, 2, 3, 4 or 5 heteroatoms, where both rings are aromatic, include: 6H-thieno[2,3-b]pyrrolyl, imidazo[2,1- b][1,3]thiazolyl, imidazo[5,1-b][1,3]thiazolyl, [1,3]thiazol [3,2-b][1,2,4]triazolyl, indolyl, isoindolyl, indazlyl, benzimidazole, e.g. benzimidazol-2-yl, benzoxazolyl, e.g. benzoxazol-2-yl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl, naftridinyl, quinolyl, quinoxalinyl, quinazolinyl, cinolinyl, isoquinolyl, 1H-imidazo[ 4,5-b]pyridin-5-yl and [1,2,4]triazol[4,3-a]pyridinyl. Examples of 8- to 11-membered bicyclic heteroaromatic groups with 1, 2, 3, 4 or 5 heteroatoms, wherein one of the rings is partially or fully saturated include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxazinyl and benzoazepinyl.

[12] The term "C1-4 akyl" refers to an alkyl group having one to four carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert- butyl. The term "n-C1-4alkyl" refers to the unbranched alkyls defined above.

[13] The term "C1-4alkoxy" refers to a single-chain or branched-chain alkoxy group (or "alkyloxy") with one to four carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[14] The term -C1-4alkylCN refers to a C1-4alkyl group substituted by a cyano group, for example -CH2CN.

[15] The term "-C(=O)C1-4alkoxyC1-4alkyl" refers to the C1-4alkoxy carbon that is attached to the C(=O) group, to obtain, for example, a group of formula -C (O)-(CH2)1-4-O-C1-4alkyl.

[16] The term "halogen" and its abbreviation "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). When the term "halo" is used before another group, it indicates that the group is replaced by one, two, or three halogen atoms. For example, "haloC1-4alkyl" refers to groups such as trifluoromethyl, bromoethyl, trifluoropropyl and other groups derived from C1-4alkyl groups defined above; and the term "halo C1-4alkoxy" refers to groups such as trifluoromethoxy, bromoethoxy, trifluoropropoxy and other groups derived from C1-4alkoxy groups defined above.

[17] The term "3- to 7-membered mono- and saturated carbocyclic group" and the term "8- to 11-membered bicyclic carbocyclic group" refer to 3-, 4-, 5-, 6-, or 7-membered saturated monocyclic or bicyclic groups saturated 8-, 9-, 10-, 11-membered atoms in which 1, 2, 3, 4 or 5 of the carbon atoms are optionally replaced by a heteroatom selected independently from O, S and N(R4)Z (e.g. NR3) and which are partially or fully saturated. Examples of 3- to 7-membered carbocyclic groups containing heteroatoms that are fully saturated include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolyl, thiazolyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, dioxanyl, tetrahydro-2Hpyranyl and dithianyl.

[18] Examples of carbocyclic groups or saturated 3- to 7-membered rings (e.g., 3 to 6 members) containing only ring carbon atoms that are fully saturated include C3-7cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclo -hexyl and cycloheptyl. Examples of carbocyclic groups containing only ring carbon atoms that are partially saturated include C4-7cycloalkenyl, for example, cyclopentenyl and cyclohexenyl.

[19] Examples of "3- to 7-membered carbocyclic groups containing heteroatoms" that are partially saturated 5- or 6-membered monocyclic rings include oxazolinyl, isoaxazolinyl, imidazolinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridyl, and 3,6- dihydro-2H-pyranyl.

[20] Examples of "8- to 11-membered bicyclic carbocyclic group" include decahydroquinolinyl, octahydro-2H-1,4-benzoxazinyl, 8-oxabicyclo[3.2.1]octan-3-yl, 8-oxa-3- azabicyclo[3.2.1]-octane and octahydro-1H-cyclopenta[b]pyridinyl.

[21] Examples of "8- to 11-membered bicyclic groups" include 2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and 2,3,4,5-tetrahydro-1H-3-benzazepinyl.

[22] As will be recognized, B is a saturated 4- to 6-membered heterocyclic ring that contains at least 1 ring nitrogen and in which B is bonded to -(CHR)n(CR1R2)p- by the ring nitrogen group in B. In addition to this ring, nitrogen B optionally contains one or two additional ring heteroatoms selected from O and N. B is unsubstituted or may be substituted on a ring carbon or ring nitrogen atom available by one or more C1-4alkyl groups.

[23] As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an organic or inorganic acid or base, quaternary ammonium salts and internally formed salts . Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility compared to parent compounds. These salts must clearly have a physiologically acceptable anion or cation. Suitable physiologically acceptable salts of the compounds of the present invention include acid addition salts formed by inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids and by organic acids such as tartaric, acetic, trifluoroacetic, citric, malic acids. , lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isotinic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic) ), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinyl, alginic, galacturonic and arylsulfonic, for example, benzenesulfonic and p-toluenesulfonic acids; basic addition salts formed by alkali metals and alkaline earth metals and organic bases such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and salts formed internally. Salts with a non-physiologically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of such physiologically acceptable salts and/or for use in non-therapeutic situations, for example, in vitro.

[24] In a preferred embodiment, compounds of formula (IA) are presented in which A and B of compounds of formula (I) can be selected from the following: and wherein G, G1, W, Y, n, m, p, z, R1, R2 and R3 are defined as above for compounds of formula (I).

[25] In another embodiment of the present invention, compounds of formula (II) are presented in which A and B of the compound of formula (I) correspond to a 5-azaspiro[2,4]heptane derivative wherein G, G1, W, Y, n, m, p, z, R1, R2 and R3 are defined as above for compounds of formula (I).

[26] In another embodiment of the present invention, compounds of formula (III) are presented in which A and B of the compound of formula (I) correspond to a 6-azaspiro[3.4]octane derivative wherein G, G1, W, Y, n, m, p, z, R1, R2 and R3 are defined as above for compounds of formula (I).

[27] In another embodiment of the present invention, compounds of formula (IV) are presented in which A and B of the compound of formula (I) correspond to a 6-azaspiro[2.5]octane derivative. wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined as above for compounds of formula (I).

[28] In another embodiment of the present invention, compounds of formula (V) are presented in which A and B of the compound of formula (I) correspond to a 5-azaspiro[2.5]octane derivative. wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined as above for compounds of formula (I).

[29] The position of the G substituent in relation to the B ring may or may not be in a "cis" or "trans" arrangement.

[30] Relative "cis" stereochemistry is represented using the bold line of bonds, while relative "trans" stereochemistry is represented using the bold, dotted line of bonds.

[31] In a preferred embodiment, compounds of formula (IB) are presented in which A and B of compounds of formula (I) can be selected from the following: and wherein G, G1, W, Y, n, m, p, z, R1, R2 and R3 are defined above for compounds of formula (I).

[32] In another embodiment of the present invention, compounds of formula (IIA) are presented that correspond to compounds of formula (II) with the "cis" arrangement, represented by the bold line of the bonds. wherein G, G1, W, Y, n, m, p, z, R1, R2 and R3 are defined as above for compounds of formula (I).

[33] In another embodiment of the present invention, compounds of formula (IIB) are presented that correspond to compounds of formula (II) with a "trans" arrangement, represented by the dotted and bold line of the bonds and wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined above for compounds of formula (I).

[34] In another embodiment of the present invention, compounds of formula (IIIA) are presented that correspond to compounds of formula (III) with the "cis" arrangement, represented by the bold line of the bonds wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined as above for compounds of formula (I).

[35] In another embodiment of the present invention, compounds of formula (III) are presented that correspond to compounds of formula (III) with a "trans" arrangement, represented by the dotted and bold line of the bonds wherein G, G1, W, Y, n, m, p, z, R1, R2 and R3 are defined as above for compounds of formula (I).

[36] In another embodiment of the present invention, compounds of formula (VA) are presented that correspond to compounds of formula (V) with the "cis" arrangement, represented by the bold line of the bonds wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined as above for compounds of formula (I).

[37] In another embodiment of the present invention, compounds of formula (VB) are presented that correspond to compounds of formula (V) with a "trans" arrangement, represented by the dotted and bold line of the bonds and wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined above for compounds of formula (I).

[38] It will be appreciated that compounds of formula (IIA) have at least two chiral centers, namely at positions 1 and 3 in the 5-azaspiro[2,4]heptane part of the molecule. Due to the fixed cis arrangement, compounds can exist in two stereoisomers that are enantiomers relative to the chiral centers in cyclopropane. It will also be appreciated, in common with most biologically active molecules, that the level of biological activity can vary between the individual stereoisomers of a given molecule.

[39] In compounds of formula (IIA) there are at least two chiral centers, which are located in the cyclopropane moiety, as represented below (the bold line of bonds refers to the "cis" configuration):

[40] Depending on the substituents in group G, the configuration may become (1S, 3S) due to different priorities of the Cahn-Ingold-Prelog nomenclature.

[41] In another embodiment of the present invention, compounds of formula (IIC) are presented that correspond to stereochemical isomers of compounds of formula (IIA), enriched in the configuration (1R,3S) or (1S,3S) wherein G, G1, W, Y, n, m, p, z, R, R1, R2 and R3 are defined as above for compounds of formula (I).

[42] It is intended, in the context of the present invention, that the stereochemical isomers enriched in the (1R,3S) or (1S,3S) configuration of the formula (IIC) correspond in one embodiment to at least 90% enantiomeric excess (e.e. ). In another embodiment, the isomers correspond to at least 95% e.e. In another embodiment, the isomers correspond to at least 99% e.e.

[43] The strategy for determining the absolute configuration of the compounds of the present invention comprises, as a first step, the preparation of the chiral intermediate (1R,3S)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, by the preparation of (1R,3S/1S,3R)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (preparation 14) and the resolution of the racemic mixture by using the chiral HPLC procedure (preparation 15) .

[44] The designation of the absolute configuration of the title compound was determined by a single crystal x-ray structure obtained from a crystal of 5-(4-methylbenzenesulfonyl)-(1R, 3S)-[4-( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane derived from the desired enantiomer and crystallized in EtOH as solvent (see preparation 290) to obtain a single crystal.

[45] The present molecule has two stereocenters. According to absolute structure determination, the configuration on the carbon atom corresponding to C1 is R, while the configuration on the carbon atom corresponding to C3 is S.

[46] To further confirm the absolute stereochemistry, the opposite enantiomer (1S,3R)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane was also analogously derivatized (see preparation 291) and subjected to the same analyzes as confirmed that the configuration on the carbon atom corresponding to C1 is S, while the configuration on the carbon atom corresponding to C3 is R.

[47] For these compounds synthesized from (1R,3S)-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane or (1S,3R)-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (with known absolute stereochemistry based on x-ray structure) a common trend was recognized between the absolute configuration of the 5-azaspiro[2.4]heptane moiety and binding activity was measured at the dopamine D3 receptor for each pair of enantiomers. For the remainder of the compounds of the present invention, where the stereoisomers were evaluated separately, the absolute configuration was assigned based on a reasonable assumption by one of skill in the art, i.e., the absolute configuration was then assigned based on the binding activity measured in the dopamine D3 receptor for both enantiomers and comparison with data from these compounds that were subjected to detailed analysis.

[48] A compound of formula (PI) or its pharmaceutically acceptable salt is also presented: wherein: A is a 3- to 6-membered carbocyclic ring and this ring can be substituted by one or more C1-4alkyl groups; B is a 4- to 6-membered saturated carbocyclic ring, in which one or two carbon atoms may be replaced by a heteroatom selected from at least one Nitrogen or Oxygen and the bonding atom is always a Nitrogen atom; this ring can also be replaced by carbon atoms or, possibly, by a different Nitrogen atom, by one or more C1-4alkyl groups; G is aryl, a 5- to 6-membered heteroaromatic group or an 8 to 11-membered heteroaromatic group, which may be benzofused or optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano , hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2, C(=O)OR3; W is S, SO2, O, CHR2, NR3; n is 0 or i; m is i or 2; p is i or 2; R is hydrogen or Ci-4alkyl; Ci-4alkoxy; Ri is hydrogen or F, Ci-4alkyl; OH, Ci-4alkoxy; R2 is hydrogen or F, Ci-4alkyl; OH, Ci-4alkoxy; R3 is hydrogen or Ci-4alkyl; Gi is phenyl, a 5 to 6 membered heteroaromatic group or an 8 to ii membered heteroaromatic group, any of these groups may be optionally substituted by i, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2, C(=O)OR3; Y is H or a moiety selected from the group consisting of: 5- to 6-membered heteroaromatic group, 3- to 7-membered carbocyclic group, mono- and saturated, or 8 to ii-membered bicyclic carbocyclic group in which one or more atoms of carbon can be replaced by NR3, O, S; any of the groups may be optionally replaced by one or two substituents selected from: halogen, cyano, hydroxyl, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2 , C(=O)OR3; or, when Gi is a phenyl group, Gi and Y may be fused to form a benzofused aromatic or heteroaromatic system which may optionally be replaced by one or two substituents selected from: halogen, cyano, hydroxy, amide, ester, amino Ci -4alkyl, haloCi-4alkyl, Ci-4alkoxy, Ci-4alkanoyl, SF5.

[49] In another embodiment of the present invention, compounds of formula (PII) are presented in which A and B of the compound of formula (PI) correspond to a 5-azaspiro[2,4]heptane derivative.

[50] In another embodiment of the present invention, compounds of formula (PIII) are presented in which A and B of the compound of formula (PI) correspond to a 6-azaspiro[3.4]octane derivative.

[51] In another embodiment, compounds of the formula (PIV) are presented in which A and B of the compound of the formula (PI) correspond to a 6-azaspiro[2.5]octane derivative.

[52] The position of the G substituent in relation to the B ring may or may not be in a "cis" or "trans" arrangement.

[53] Relative "cis" stereochemistry is represented using the bold line of bonds, while relative "trans" stereochemistry is represented using the bold, dotted line of bonds.

[54] In another embodiment, compounds of formula (PIIA) are presented that correspond to compounds of formula (PII) with the "cis" arrangement, represented by the bold line of the bonds and wherein G, G1, W, Y, n, m, p, R1, R2 and R3 are defined above for compounds of formula (PI).

[55] In another embodiment, compounds of formula (PIIB) are presented that correspond to compounds of formula (PII) with a "trans" arrangement, represented by the bold line of the bonds wherein G, p, R1, R2, R3, R4, and R5 are defined above for compounds of formula (PI).

[56] In another embodiment of the present invention, compounds of formula (PIIIA) are presented that correspond to compounds of formula (PIII) with the "cis" arrangement, represented by the bold line of the bonds wherein G, G1, W, Y, n, m, p, R1, R2 and R3 are defined as above for compounds of formula (PI).

[57] In another embodiment, compounds of formula (PIIIB) are presented that correspond to compounds of formula (PIII) with a "trans" arrangement, represented by the bold line of the bonds wherein G, p, R1, R2, R3, R4, and R5 are defined as above for compounds of formula (PI).

[58] Compounds of the formula (PNI) or its pharmaceutically acceptable salt are also presented: where A and B are selected from: G is phenyl, a 5- to 6-membered heteroaromatic group or an 8 to 11-membered heteroaromatic group, which may be benzofused or optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano , hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2, C(=O)OR3; W is S, SO2, O, CHR2, NR3; n is 0 or i; m is i or 2; p is i or 2; R is hydrogen or Ci-4alkyl; Ci-4alkoxy; Ri is hydrogen or F, Ci-4alkyl; OH, Ci-4alkoxy; R2 is hydrogen or F, Ci-4alkyl; OH, Ci-4alkoxy; R3 is hydrogen or Ci-4alkyl; Gi is phenyl, a 5 to 6 membered heteroaromatic group or an 8 to ii membered heteroaromatic group, any of these groups may be optionally substituted by i, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2, C(=O)OR3; Y is H or a moiety selected from the group consisting of: 5- to 6-membered heteroaromatic group, 3- to 7-membered carbocyclic group, mono- and saturated, or 8 to 11-membered bicyclic carbocyclic group in which one or more atoms of carbon can be replaced by NR, O, S; any of the groups may be optionally substituted by one or two substituents selected from: halogen, cyano, hydroxyl, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5,C(=O)NH2 , C(=O)OR3; or, when Gi is a phenyl group, Gi and Y may be fused to form a benzofused aromatic or heteroaromatic system which may optionally be replaced by one or two substituents selected from: halogen, cyano, hydroxy, amide, ester, amino Ci -4alkyl, haloCi-4alkyl, Ci-4alkoxy, Ci-4alkanoyl, SF5.

[59] Suitably, in the compounds of formulas (PI) to (PIV), (PIIA), (PIIB), (PIIIA), (PIIIB) and (PNi) Y is not H.

[60] Suitably, in the compounds of formulas (PI) to (PIV), (PIIA), (PIIB), (PIIIA), (PIIIB) and (PNi) the -(CRiR2)P-W-Gr group is present in the compound.

[61] Particular compounds of the invention include, for example, compounds of formulas (I), (IA), (IB), (II), (IIA), (MB), (IIC), (III), (IIIA) , (IV), (V), (VA) or (VB) or their pharmaceutically acceptable salts and prodrugs wherein, unless otherwise indicated, each of A, B, G, G1, Y, Y', R1 , R2, R3, R4, R5, R6, R7, N, m, pez has any of the meanings defined above or in any paragraphs (1) to (42) hereinafter: (1) A, in formula (I) , is a saturated 3- to 6-membered carbocyclic ring and this ring can be replaced by one or more C1-4alkyl groups, wherein the carbocyclic ring contains only carbon atoms in the ring. (2) A, in the formula, is selected from s(3) G is aryl, a 5- to 6-membered heteroaromatic group or an 8 to 11-membered heteroaromatic group, which may be benzofused or optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of : halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2, C(=O)OR3. (4) G is a phenylpyridyl optionally substituted by 1, 2, 3, 4 or 5 (e.g. 1 or 2) substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1- 4alkylamino, C1-4alkyl, haloC1-4alkyl, haloC1-4alkoxy, CMalkoxy, -C(=O)NH2 and -C(=O)(O)zR3. (5) G is a phenyl or pyridyl optionally substituted by 1, 2, 3, 4 or 5 (e.g. 1 or 2) substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, C1-4alkyl , haloC1-4alkyl, haloC1-4alkoxy and C1-4alkoxy. (6) G is phenyl or pyridyl substituted, optionally, by 1, 2 or 3 groups independently selected from halo, C1-4alkyl and haloC1-4alkyl. (7) G is phenyl or pyridyl substituted, optionally, by 1 or 2 groups independently selected from fluorine, chlorine and trifluoromethyl. (8) G is phenyl optionally substituted by 1,2, 3, 4 or 5 (e.g. 1 or 2) substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, C1-4alkyl, haloC1- 4alkyl, haloC1-4alkoxy and C1-4alkoxy. (9) G is phenyl substituted, optionally, by 1, 2 or 3 groups selected, independently, from halo, C1-4alkyl and haloC1-4alkyl. (10) G is phenyl substituted, optionally, by 1 or 2 groups independently selected from fluorine, chlorine and trifluoromethyl. (11) G is phenyl. (12) G is phenyl substituted by 1, 2 or 3 (e.g., 1 or 2) groups independently selected from halo, C1-4alkyl and haloC1-4alkyl. (13) G is pyridyl optionally substituted by haloC1-4alkyl, for example trifluoromethyl. For example, G is 6-(trifluoromethyl)pyridin-3-yl. For example, G is pyridyl. (14) G is 4-(haloC1-4alkyl)phenyl, for example 4-trifluoromethylphenyl. (15) G is phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 2,4-difluorophenyl, 4-fluorophenyl, 2-trifluoromethyl-phenyl, 2-trifluoromethyl-4-fluorophenyl or 3,5 - dichlorophenyl. (16) The group -(CHR)n(CRi R2)m(CRi R2)p is selected from (17) The group (CHR) n (CR1R2) m (CR1R2) p is (18) W is selected from S, O and CHR2. (19) W is CHR2. (20) W is S or O. (21) W is S. (22) The group-(CHR)n(CR1R2)m(CR1R2)pW-is (23) W is S and R, R1 and R2 are hydrogen. (24) Gi is phenyl, a 5- to 6-membered heteroaromatic group or an 8 to 11-membered heteroaromatic group, any of these groups may be optionally substituted by 1, 2, 3 or 4 substituents selected from the group that consists of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, CI-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O)NH2, C(=O)OR3. (25) G1 is a phenyl group or a 5-6 membered heteroaromatic group, any of the groups may be optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, haloC1-4alkoxy, C1-4alkoxy, SF5, -C(=O)NH2 and -C(=O)(O) z R3. (26) G1 is phenyl or a 5- to 6-membered heteroaromatic group, any of the groups may be optionally substituted by 1 or 2 substituents selected from the group consisting of: halogen, hydroxyl, C1-4alkyl, haloC1- 4alkyl, haloC1-2alkoxy and C1-4alkoxy. (27) G1 is phenyl or a 5- to 6-membered heteroaromatic group, any of which groups may be optionally substituted by 1, 2, 3 or 4 substituents selected independently from the group consisting of: halogen, cyano , hydroxyl, amino, C1-4alkylamino, C1-4alkyl, halC1-4alkyl, haloC1-4alkoxy, C1-4alkoxy, -C(=O)NH2 and -C(=O)(O)zR3. (28) G1 is a 5- to 6-membered heteroaromatic group containing at least one ring nitrogen and, optionally, one or two additional ring heteroatoms selected from O and S, wherein the heteroaromatic group is optionally substituted by 1, 2, 3 or 4 (e.g. 1, 2 or 3) substituents selected, independently, from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, haloC1-4alkoxy , C1-4alkoxy, -C(=O)NH2 and -C(=O)(O) z R3. (29) G1 is a 5- to 6-membered heteroaromatic group containing at least one ring nitrogen (e.g. 1,2 or 3 ring nitrogens) in which the heteroaromatic group is optionally substituted by 1,2, 3 or 4 (e.g. 1, 2 or 3, preferably 1 or 2) substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, haloC1-4alkoxy , C1-4alkoxy, -C (= O) NH2 andC(=O)(O) z R3. (30) G1 is a 5 to 6 member heteroaromatic group, any of the groups can be optionally replaced by 1 or 2 substituents selected from the group consisting of: C1-4alkyl and haloC1-4alkyl. (31) G1 is a 5-membered heteroaromatic group containing at least one ring nitrogen atom (e.g. 1, 2 or 3 ring nitrogens) in which the heteroaromatic group is optionally substituted by 1 or 2 substituents independently selected from from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, haloC1-4alkoxy and C1-4alkoxy; wherein, optionally, the heteroaromatic group is optionally substituted by 1 or 2 substituents selected from the group consisting of: C1-4alkyl and haloC1-4alkyl. (32) G1 is any of the groups mentioned in paragraphs (24) to (31), wherein G1 is linked to W and Y by carbon atoms in the G1 ring. (33) G1 is a triazole, for example, 1,2,4-triazole optionally substituted by C1-4alkyl. (34) Gi is where Ra is H or Ci-4alkyl. Suitably, Ra is C1-4alkyl. (35) Gi is (36) Y is a moiety selected from the group consisting of: 5- to 6-membered heteroaromatic group, 3- to 7-membered carbocyclic group, mono- and saturated, or 8 to ii-membered bicyclic carbocyclic group in which one or more atoms carbon can be replaced by NR3, O, S; Any of the groups may be optionally substituted by one or two substituents selected from: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5, C(=O )NH2, C(=O)OR3. (37) Y is selected from phenyl, a 5- to 6-membered heteroaromatic group, C3-7cycloalkyl, any of the groups may be optionally substituted by i, 2 or 3 substituents selected from: halogen, cyano, hydroxyl, C1-4alkylamino, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, oxo, NHC(=O )Ci-4alkyl, -NR5R6, SF5, -(CH2)ZC(=O)NR5R6, —C(=O)(O)zR3, CH2CN, SO2NH2, Y' or OY'; and wherein an NH ring in Y is optionally substituted by R4; and Y' is phenyl or a 5 to 6 membered heteroaromatic group optionally substituted by 1 or 2 R7 groups; provided that Y, Y' and G1 are not simultaneously phenyl. (38) Y is selected from phenyl, oxazolyl, isoxazolyl, furanyl, thiazolyl, isothiazolyl, pyrrolyl, imadazolyl, thiophenyl, thiodiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, i,2-dihydropyridinyl, oxanyl, 8-oxabicyclo[3.2 .i]octanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, cyclopropyl, cyclobutyl, cyclohexyl, Any of the groups may be optionally substituted on a carbon atom of the ring by i, 2 or 3 substituents selected from: halogen, cyano, hydroxyl, C1-4alkylamino, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy , oxo, -NHC(=O)Ci-4alkyl, -NR5R6, -(CH2)ZC(=O)NR5R6, -C(=O)R3, CH2CN, SO2NH2, Y' or OY'; and wherein an NH ring in Y is optionally substituted by R4; and Y' is phenyl, oxadiazolyl, tetrazolyl, pyrazolyl, triazolyl, oxazolyl or pyridyl, optionally substituted by one or two R7 groups; provided that Y, Y' and Gi are not simultaneously phenyl. (39) Y is phenyl substituted by 1 or 2 substituents (e.g., 1 substituent) selected from cyano, CH2CN, -C(=O)R3,-(CH2)ZC(=O)NR5R6,- SO2NH2 and Y', wherein Y' is selected from oxadiazolyl, tetrazolyl, triazolyl and oxazolyl, wherein Y' is optionally substituted by C1-4alkyl. For example, Y is phenyl substituted by 1 substituent selected from cyano, CH2CN, acetyl, -CH2C(=O)NH2, -C(=O)NH2, -SO2NH2 and Y', where Y' is selected from oxadiazolyl, tetrazolyl, triazolyl and oxazolyl, where Y' is optionally substituted by methyl. (40) Y is selected from pyridyl, pyrimidinyl, pyrazinyl any of the groups can be optionally substituted by 1 or 2 substituents selected from: fluoro, cyano, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl and -C(=O) NR5R6. For example, Y is pyridyl optionally substituted by 1 or 2 substituents selected from: C1-4alkyl and -C(=O)NH2. (41) Y is selected from the group consisting of: • phenyl optionally substituted by one or two substituents selected from: cyano, C(=O)NH2, sulfonamide, acetyl, CH2CN, CH2C(=O) NH2 or Y\ preferably Y' is a 5-membered heteroaromatic group (for example, Y is selected from 4-(1H-1,2,3,4-tetrazol-5-yl)phenyl, 4-(1,3,4-oxadiazol- 2-yl)phenyl, 4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl, 4-(4-H-1,2,4-triazol-4-yl)phenyl, 4- (1,3-oxazol-2-yl)phenyl and 3-(1,3-oxazol-2-yl)phenyl); • a 3- to 7-membered, mono, saturated carbocyclic group in which 0 or 1 or 2 carbon atoms are replaced by a heteroatom independently selected from O or NR3 (e.g., cyclohexyl, morpholinyl, piperidinyl, tetrahydropyranyl, azetidinyl or piperidin-2-one) optionally substituted by one or more substituents selected from -NHC(=O) C1-4alkyl, -NR5R6, C1-4alkyl; in a preferred embodiment R3 is C(=O) C1-4alkyl; • an 8- to 11-membered bicyclic carbocyclic group (e.g. 3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}), optionally substituted by one or more (e.g. example 1 or 2) C1-4alkyl; • a 5 to 6 membered heteroaromatic group (e.g. oxazolyl, thiazolyl, 1-methyl-1H-pyrazol-4-yl, furanyl, thiophenyl, 1-methyl-1H- pyrrolyl, thiadiazolyl, pyridinyl, 1,2-dihydropyridin-2-methyl, pyrimidinyl, pyrazyl, pyridazinyl) optionally substituted by one or two substituents selected from: halogen, cyano, hydroxyl, C1-4alkyl, haloC1-4alkyl, C1- 4alkoxy, (CH2)ZC(=O)N(R4R5), Y' and OY'. In a preferred embodiment, C1-4alkyl is methyl, haloC1-4alkyl is trifluoromethyl, C1-4alkoxy is methoxy and Y' is phenyl or pyridine ; • an 8 to 11 membered heteroaromatic group in which 1, 2 or 3 carbon atoms may be substituted by N, optionally substituted by one or more (e.g. 1 or 2) C1-4alkyl (e.g. -{3 -[(4-methyl-5-{[1,2,4]triazol[4,3- a]pyridin-8-yl}. (42) G1 is a phenyl group, G1 and Y can be fused to form a benzofused aromatic or heteroaromatic system that can be optionally replaced by one or two substituents selected from: halogen, cyano, hydroxy, amide, ester, amino C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, C1-4alkanoyl, SF5.

[62] It should be understood that two or more features mentioned in paragraphs (1) to (42) may be applied to any of the compounds of formulas (I), (IA), (IB), (II), (IIA) , (IIB), (IIC), (III), (IIIA), (IIIB), (IV), (V), (VA) or (VB) or its pharmaceutically acceptable salt. For example, the features of paragraph (41) for Y may be combined with any of paragraphs (3) through (15) defining group G. As another representative example, paragraph (41) defining Y may be combined with any one of paragraphs (16) to (23). By way of further example, paragraphs (15), (22) and (41) may be combined. Other combinations of two, three or four paragraphs (1) to (42) are also contemplated.

[63] Some compounds of the invention can form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[64] Certain groups/substituents included in the present invention may be present as isomers. The present invention includes within its scope all such isomers, including racemates, enantiomers, tautomers and mixtures thereof. Some substituted heteroaromatic groups included in the compounds of formula (I) may exist in one or more tautomeric forms.

[65] Pharmaceutically acceptable salts can also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.

[66] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate." Solvates of the compound of the invention are within the scope of the invention. The compounds of formula (I) can be easily isolated in association with solvent molecules by crystallization or evaporation from an appropriate solvent to obtain the corresponding solvates.

[67] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" means a compound that is converted within the body, for example by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987) and in D.

[68] Fleisher, S. Ramon and H. Barbra “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated to this instrument by reference.

[69] Prodrugs are any covalently linked carriers that release a compound of structure (I) in vivo when that prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in such a way that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention in which hydroxy, amine or sulfhydryl groups are attached to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (among others) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of compounds of structure (I). Furthermore, in the case of a carboxylic acid (-COOH), esters such as methyl esters, ethyl esters and the like may be employed. Esters can be active by themselves and/or be hydrolyzable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those that readily break down in the human body to leave the parent acid or salt thereof.

[70] Furthermore, some crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.

[71] It will be appreciated by those skilled in the art that in preparing the compound of the invention or its solvate, it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to avoid undesirable side reactions. Protecting groups suitable for use in accordance with the present invention are well known to those skilled in the art and can be used in a conventional manner. See, for example, “Protective groups in organic synthesis” by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or “Protecting Groups” by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl-type protecting groups (e.g., formyl, trifluoroacetyl, acetyl), aromatic urethane-type protecting groups (e.g., benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g., e.g., 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl-type protecting groups (e.g., benzyl, trityl, chlorothrityl). Examples of suitable oxygen protecting groups may include, for example, alkyl silyl groups such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.

[72] When a specific enantiomer of a compound of general formula (I) is required, it can be obtained, for example, by resolving a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Thus, the required enantiomer can be obtained from the racemic compound of formula (I) by using a chiral HPLC procedure. Alternatively, a specific enantiomer of a compound of general formula (I) can be obtained by reacting the single specific enantiomer of the intermediate.

[73] The invention in question also includes isotopically labeled compounds, which are identical to those reported in formula (I) et seq., except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that atomic mass or the mass number generally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O,31P, 32P, 35S, 18F, 36CI, 123l and 125l. The compounds of the present invention and the pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. The 11C and 18F isotopes are particularly useful in PET (positron emission tomography) and the I125 isotopes are particularly useful in SPECT (single photon emission computed tomography), all of which are useful for brain imaging. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and can therefore be used in some specific circumstances. The isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or Examples below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[74] Certain groups/substituents included in the present invention may be present as isomers. The present invention includes within its scope all such isomers, including racemates, enantiomers, tautomers and mixtures thereof. Some substituted heteroaromatic groups included in the compounds of formula (I) may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.

[75] Generally, among others, these compounds may have greater oral bioavailability and, sometimes, greater solubility and/or brain penetration. The molecular weight here refers to that of the unsolvated free base compound, excluding any molecular weight contributed by addition salts, solvent molecules (e.g., water), prodrug molecular parts cleaved in vivo, etc.

[76] In general, the compounds or salts of the invention should be interpreted as excluding those compounds (if any) chemically unstable, either by themselves or in water, which are clearly unsuitable for pharmaceutical use through all routes of administration, oral, parenteral or otherwise. These compounds are known to those skilled in the art. However, prodrugs or compounds that are stable ex vivo and that can be converted in the mammalian (e.g., human) body into inventive compounds are included.

[77] Exemplary compounds of the present invention include a compound selected from: Ex. 1 (1S, 3S/1R,3R)-5-(2-{[4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 2 (1 R,3R or 1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]sulfanyl}-ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 3 (1S,3S or 1R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]-sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 4 (1R.3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 5 (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 6 (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 7 (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 8 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 9 (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 10 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 11 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 12 (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 13 (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 14 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (TRANS); Ex. 15 (1 R,3R or 1S, 3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 16 (1S,3S or 1R, 3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 17 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS); Ex. 18 (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 19 (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 20 (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 21 (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS); Ex. 22 (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 23 (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 24 (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 25 (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 26 (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); Ex. 27 (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 28 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 29 (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 30 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 31 (1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5(4-methyl-1,3-oxazol-5-yl) - 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS) Ex. 32 (1R,3S or 1S,3R)-1-(2,4- difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 33 (1S,3R or 1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 34 (1R,3S or 1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 35 (1S,3R or 1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 36 (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); Ex. 37 (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 38 (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 39 (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 40 (1S,3S/1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS); Ex.41 (1S,3S or 1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 42 (1S,3S or 1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 43 (1 R,3R or 1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) - 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 44 (1S,3S or 1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 45 (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); Ex. 46 (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 47 (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 48 (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 49 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 50 (1S.3S or 1R.3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}-propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 51 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 52 (1R,3R or 1S.3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 53 (1S.3S or 1 R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]sulfanyl}-propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 54 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 55 (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 56 (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 57 (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 58 (1R,3R or 1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 59 (1S,3S/1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS); Ex. 60 (1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); Ex. 61 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane (CIS); Ex. 62 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl }propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS); Ex. 63 (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 64 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 65 (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 66 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 67 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl }propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 68 (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 69 (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 70 (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-,sulfanyl}-, propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 71 (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (TRANS); Ex. 72 (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoro-methyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl) -4H-1,24-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 73 (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 74 (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,24-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 75 (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,24-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 76 (1S,3S /1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS); Ex. 77 (1R,3R)-1--,[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1 ,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 78 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1.2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 79 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1.2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 80 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl }propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS); Ex. 81 (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - phenyl-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 82 (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - phenyl-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 83 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1.2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 84 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane (CIS); Ex. 85 (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4- triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 86 (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 87 (1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 88 (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- il)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 89 (1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- 1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 90 (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 91 (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 92 (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 93 (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 94 (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 95 (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 96 (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 97 (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- ( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiometer 1); Ex. 98 (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2.4]heptane (Enantiometer 2); Ex. 99 1-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one (CIS); Ex. 100 1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}etan-1-one (CIS, Enantiometer 1); Ex. 101 1-{4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one (CIS); Ex. 102 1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one (CIS); Ex. 103 3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one (CIS, Enantiometer 1); Ex. 104 3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one (CIS, Enantiometer 1); Ex. 105 (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 106 (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 107 1-{3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidin-1-yl}ethan-1-one (CIS); Ex. 108 3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] -propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine (CIS); Ex. 109 N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS); Ex. 110 N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, Enantiometer 1); Ex. 111 N-{4-[4-methyl-5-({3-[(1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, Enantiometer 2); Ex. 112 N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, Enantiometer 1); Ex. 113 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 114 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 115 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 116 (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 117 (1S, 3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiometer 2); Ex. 118 (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 119 4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1); Ex. 120 1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1); Ex. 121 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1); Ex. 122 6-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 123 6-[5-({3-[(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS); Ex. 124 3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] -propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 125 3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]-propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); Ex. 126 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS); Ex. 127 5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 128 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]-propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); Ex. 129 5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl )-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 130 5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl )-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 131 5-[5-({3-[(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 132 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS); Ex. 133 1-methyl-4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); Ex. 134 4-[4-methyl-5-({3-[(1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); Ex. 135 4-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS); Ex. 136 1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1); Ex. 137 1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1); Ex. 138 4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one (CIS, Enantiometer 1);[5-({3- [(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl)-4-methyl-4H-1,2, 4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one (CIS, Enantiometer 1); Ex. 140 (1S,3S/1R,3S)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS); Ex. 141 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 142 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS); Ex. 143 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 144 (1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4- (trifluoromethyl)phenyl]-5azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 145 (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2); Ex. 146 (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 2); Ex. 147 (1S,3S/1R,R3)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS); Ex. 148 (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H- 1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiometer 1); Ex. 149 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H- 1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2); Ex. 150 (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H- 1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 151 -1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiometer 2); Ex. 152 (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2, 4-triazol-3-yl]-sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS); Ex. 153 (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 154 (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2); Ex. 155 (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 156 (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2); Ex. 157 (1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2, 4-triazol-3-yl]sulfanyl]propyl)-5-azaspiro[2,4]heptane (CIS); Ex. 159 (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2); Ex. 160 (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2); Ex. 161 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-phenyl-5-azaspiro[2,4]heptane (CIS); Ex. 162 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS); Ex. 163 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 164 (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)- 4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (TRANS); Ex. 165 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 166 (1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 167 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS); Ex. 169 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 170 (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 171 (1R,3S)-5-(3-{[5-(2,6-dimethylpIridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 172 (1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 173 (1R,3S/1S,3R)-5-(3-{[5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 174 (1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}- sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 175 (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 176 (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 177 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (CIS, Enantiometer 1); Ex. 178 4-[4-methyl-5-({3-[(1s,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4h-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); Ex. 179 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS); Ex. 180 [4-methyl-5-({3-[(1S,3S or 1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, Enantiometer 1); Ex. 181 azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, Enantiometer 2); Ex. 182 5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] -propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS); Ex. 183 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 184 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 185 5-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 186 5-[5-({3-[(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 2); Ex. 187 6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 188 6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 acid formate -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxylic acid (CIS, Enantiometer 1); Ex. 189 6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiometer 1); Ex. 190 6-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4-methyl-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiometer 1); Ex. 191 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 192 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiometer 1); Ex. 193 6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 194 N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 195 N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 196 N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 197 N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 198 5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 199 5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiometer 1); Ex. 200 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 201 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 202 (1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 203 (1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 204 (1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 205 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS); Ex. 206 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-pyridazin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 207 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 208 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 209 (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 210 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 211 (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 212 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 213 (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS); Ex. 214 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 215 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 216 (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 217 (1R,3S/1S,R3)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 218 (1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 219 (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 220 (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 221 (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS); Ex. 222 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 223 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(5-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 224 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 225 (1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 226 (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 227 (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 228 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4H-1,2,4-triazol-3-yl]pyrazine-2-carboxamide (CIS); Ex. 229 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 230 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 231 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 232 (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 233 (1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 234 (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 235 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 236 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 237 (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 238 (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 239 (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 240 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS); Ex. 241 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 242 (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 243 (1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 244 (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 245 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 246 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 247 (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 248 (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 249 (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 250 C(1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 251 (1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 252 (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 253 (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 2); Ex. 254 (1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 255 (1R,3S/1S,3R)-5-(3-{[5-(furan-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 256 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 257 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrroyl-2-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 258 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrroyl-2-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 259 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol- 3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS); Ex. 260 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS); Ex. 261 (1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 262 (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 263 (1R,3S)-5-[3-({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]-4H-1,2, 4-triazol-3-yl}-sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiometer 1); Ex. 264 (1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 265 (1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 266 (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazol[4,3-a]pyridin-8-yl}-4H-1,2 ,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 267 (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazol[4,3-a]pyridin-6-yl}-4H-1,2 ,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 268 (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazol[4,3-a]pyridin-6-yl}-4H-1,2 ,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 269 (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazol[4,3-a]pyridin-7-yl}-4H-1,2 ,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 270 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3 - a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 271 (1R,3S)-5-{3-[(4-methyl-5-{3-methyl-[1,2,4]triazol[4,3-a]pyridin-6-yl}-4H -1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); Ex. 272 (1R, 3S)-5-{3-[(5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-Triazol- 3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 273 (1R,3S)-5-[3-({4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl) phenyl]-4H-1,2 ,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 274 (1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazole -3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 1); Ex. 275 (1R,3S)-5-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2 ,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 1); Ex. 276 (1R,3S)-5-[3-({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4 -triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 1); Ex. 277 (1R, 3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl) phenyl] -4H- 1,2,4-triazol-3 - yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 278 (1R, 3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl) phenyl]-4H-1,2,4-triazol-3 - yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 279 (1R, 3S)-5-[3-({4-methyl-5-[3-(1,3-oxazol-2-yl) phenyl]-4H- 1,2,4-triazol-3 - yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1); Ex. 280 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1); Ex. 281 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1); Ex. 282 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1); Ex. 283 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1); Ex. 284 1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}ethan-1-one (CIS, Enantiometer 1); Ex. 285 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzene-1-sulfonamide (CIS, Enantiomer 1); Ex. 286 2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl ]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetonitrile (CIS, Enantiomer 1); Ex. 287 2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl ]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetamide (CIS, Enantiomer 1); Ex. 288 3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1); Ex. 289 3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1); Ex. 290 2-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1); Ex. 291 1-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]-heptan-5-yl}propan-2-ol (CIS) diastereoisomeric mixture; Ex. 292 (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)- 4H- 1, 2,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane (CIS); Ex. 293 (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2, 4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane (Enantiometer 1); Ex. 294 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2, 4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane (Enantiometer 2); Ex. 295 (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2, 4-triazol-3-yl]butyl}-5-azaspiro[2.4]-,heptane (Enantiometer 2); Ex. 296 (1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 297 (1S,3S or 1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer); Ex. 298 (1R,3R or 1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 299 (1S,3S or 1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 300 (1R,3R or 1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex. 301 (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); Ex. 302 (1R,3S)-5-(4-{[4-methyl -5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4]heptane (CIS, Enantiometer1); Ex. 303 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2, 4-triazol-3-yl]oxy}-,propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); Ex. 304 (1S,3S or 1R,3R )-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}-,propyl)-1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 1); Ex. 305 (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4- il)-4H-1,2,4-triazol-3-yl]oxy}-,propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiometer 2); Ex .306 (1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane; Ex. 307 (1R or 1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazole -5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane (Enantiometer 1); Ex. 308 (1R or 1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane (Enantiometer 2); Ex. 309 (1R or 1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)--,4H-1,2,4-triazol- 3-yl]sulfanyl}_,propyl)-1-phenyl-6-azaspiro[2.5]octane (Enantiometer 1); Ex. 310 (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS); Ex. 311 (1R,3S or 1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, Enantiometer 1); Ex. 312 (1S,3R or 1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, Enantiometer 2); Ex. 313 (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS); Ex. 314 (1S,3S or 1 R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS, Enantiometer 1); Ex. 315 (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS, Enantiometer 2); Ex. 316 6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-,sulfanyl} propyl)-1-phenyl-6-azaspiro[3.4]octane; Ex. 317 (1R,4S or 1S.4R or 1S.4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane: (Diastereomer 1 Enantiometer 1); Ex. 318 (1R,4S or 1S.4R or 1S.4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane: (Diastereomer 1 Enantiometer 2); Ex. 320 (1R,4S or 1S.4R or 1S.4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane: (Diastereomer 2 Enantiometer 1); Ex.321 (1R,4S or 1S.4R or 1S.4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane: (Diastereomer 2 Enantiometer 2); or its pharmaceutically acceptable salt.

[78] A compound selected from: (1S.3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, TRANS; (1R,3R or 1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}-ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1 (1S.3S or 1 R,3R)-5-(2-{[4 -methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl ]-5-azaspiro[2.4]heptane, Enantiometer 2 (1R.3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R.3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]-sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]-sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, TRANS; (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R.3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3R or 1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3 -yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane, TRANS; (1R,3R or 1S, 3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S or 1R, 3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane, CIS; (1S,3R or 1R, 3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3 -yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3S or 1S, 3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3 -yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S or 1S, 3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3 -yl]sulfanyl}-propyl)-1-phenyl-5-azaspiro[2.4]heptane hydrochloride, Enantiometer 2; (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, TRANS; (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1) (1R,3S or 1S,3R)-1-[2-fluoro -4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] heptane, CIS; (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane, TRANS; (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R,3S or 1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3R 1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S or 1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane, TRANS; (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 24-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 24-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1S,3S /1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane, CIS; (1S,3S or 1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 24-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl) -1-phenyl-5-azaspiro[2.4]heptane, CIS; (1R,3S or 1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-phenyl-5-azaspiro[2.4]heptane, Enantiometer 1; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3 -yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R,3S or 1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3 -yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3R 1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S or 1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3 -yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- 1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, TRANS; (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, CIS; (1R,3S or 1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3R or 1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; (1R,3S or 1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 1; (1S,3R or 1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, Enantiometer 2; 1-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1-[4 - (trifluoromethyl)phenyl]-5-azaspiro[2.4]-heptan-5-yl}propan-2-ol, CIS, diastereoisomeric mixture; (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)- 4H- 1.2 ,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane (CIS, E69); (1S,3S or 1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2 ,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane, Enantiometer 1; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2 ,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane, Enantiometer 2; (1R,3R or 1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2 ,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane, Enantiometer 2; (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane; (1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-phenyl-6-azaspiro[2.5]octane; (1S or 1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-phenyl-6-azaspiro[2.5]octane, Enantiometer 1; (1R or 1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-phenyl-6-azaspiro[2.5]octane, Enantiometer 2; (1S or 1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-phenyl-6-azaspiro[2.5]octane, Enantiometer 1; 1R,4S or 1S,4R or 1S,4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane, diastereoisomeric mixture; (1R,4S or 1S,4R or 1S,4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane, Diastereomer 1 Enantiometer 1; (1R,4S or 1S,4R or 1S,4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane, Diastereomer 1 Enantiometer 2; (1R,4S or 1S,4R or 1S,4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane, Diastereomer 2, Enantiometer 1; (1R,4S or 1S,4R or 1S,4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane, Diastereomer 2 Enantiometer 2; (1R, 4S or 1S,4R or 1S,4S or 1R,4R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[3.4]octane, Diastereomer 1, Enantiometer 2; or pharmaceutically acceptable salts thereof.

[79] The present invention also presents a process for preparing a compound of formula (I) or its pharmaceutically acceptable salt defined above.

[80] The process of the present invention for the preparation of compounds of formula (I) comprises the steps of: (a) reacting a compound of formula (VI): where G is as defined in formula (I), with a compound of formula (V): wherein R, R1, R2, n, m, p, W, G1 and Y are as defined for formula (I) and X is a leaving group or an aldehyde, and subsequently for the process ( a): (i) removal of any protective groups; and/or (ii) formation of a salt; and/or (iii) converting a compound of formula (I) or its salt into another compound of formula (I) or its salt.

[81] Process (a) can be carried out using conventional methods for the formation of a tertiary amine. When X is a leaving group, it can be halogen, such as chlorine. Alternatively, or arylsulfonyloxy wherein aryl is optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaromatic group, or an optionally substituted bicyclic group, e.g., optionally substituted phenyl, wherein in each case the optional substituents are one or more C1 groups -2alkyl; for example, para-toluenesulfonyloxy. When °C.

[82] When as room temperature.

[83] In one aspect of the present invention, synthetic processes for preparing compounds of formula (VI) are presented.

[84] Compounds of formula (VI) where A and B form a 5-azaspiro [2.4]heptane system of formula (Via) can be synthesized with a process comprising the following Scheme 1:Scheme 1 on what:

[85] Step a means the cycloropanation of (IX) to provide bicyclic spiroimide (X);

[86] Step b means the reduction of imide (X) to obtain tertiary benzylamine (XI).

[87] Step c means deprotection of benzylamine (XI) to obtain compounds of formula (VIa).

[88] Step a can be carried out by generating in situ the intermediate diazo compound to be reacted in a 1,3-dipolar cycloaddition with the appropriate double bond. In many cases, this step is suitably carried out by applying a procedure in which the hydrazone (VIII) is treated with an oxidizing agent, such as manganese dioxide, in a suitable solvent, such as dioxane, and at room temperature to form the intermediate diazocompound which it was then added to a solution of imide (IX) in a suitable solvent such as dioxane. This is followed by allowing it to react appropriately and proper purification.

[89] Step b can be carried out using an appropriate reducing agent in a compatible solvent, such as lithium aluminum hydride solution in THF, at an appropriate temperature, such as 68°C. This is followed by appropriate purification.

[90] Step c consists of deprotection of benzylamine using well-known procedures, for example, through reflux hydrogenation of a solution of benzylamine in a suitable solvent such as methanol in the presence of a hydrogen source such as ammonium formate and a catalyst of hydrogenation such as palladium or carbon. This is followed by allowing it to react appropriately and proper purification.

[91] Compounds of formula (VIII) can be obtained using well-known procedures by reacting the corresponding aldehyde (XII) with hydrazine in a suitable solvent such as ethanol. This is followed by allowing it to react appropriately and proper purification.

[92] The compound of formula (IX) can be obtained through the Wittig reaction between ylide, generated in situ by treating benzylmaleimide with triphenylphosphine in acetic acid as a solvent, with formaldehyde. This is followed by allowing it to react appropriately and proper purification.

[93] Compounds of formula (VI) where A and B form a 6-azaspiro [3.4]octane system of formula (VIb) can be synthesized with a process comprising Scheme 2: Scheme 2 on what:

[94] Step a means double alkylation of malonate to form cyclobutane (XVI);

[95] Step b means mono-decarboxylation of (XVI) to obtain the corresponding monoester (XVII);

[96] Step c means alkylation of (XVII) to obtain the corresponding allyl derivative (XVIII);

[97] Step d means ozonolysis of the allyl derivative (XVIII) to obtain the corresponding aldehyde (XIX);

[98] Step e means closing the ring of (XIX) with benzylamine to obtain corresponding spiro lactam (XX);

[99] Step f means reduction of lactam (XX) to obtain the corresponding spiroamine (XXI);

[100] Step g means deprotection of benzylamine (XXI) to obtain compounds of formula (VIb).

[101] Step a can be carried out by reacting dimethyl malonate with a dihalo compound in the presence of a base such as sodium hydride in a solvent such as dioxane and at a temperature of 90°C. Time is then provided to react as appropriate and an appropriate closure is provided.

[102] Step b can be carried out by thermal decarboxylation by heating the diester (XVI) in a mixture of DMSO and water until reflux in the presence of salts such as LiCl. This is followed by allowing it to react appropriately and proper purification.

[103] Step c can be carried out by treating the cyclobutane monoester (XVII) with a strong base such as lithium bis(trimethylsilyl)amide and adding an allyl halide such as allyl bromide in a suitable solvent such as THF at a temperature ranging between -78°C and ambient temperature. This is followed by allowing it to react appropriately and proper purification.

[104] Step d can be carried out through ozonolysis which passes a flow of ozone in oxygen through a solution of allyl derivative (XVIII) in a suitable solvent such as dichloromethane at low temperature such as -78°C. This is followed by allowing him to react as appropriate and a proper finish.

[105] Step e can be carried out by first reacting the aldehyde (XIX) with benzylamine in the presence of a reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as THF at a temperature such as room temperature. In a second step, after adequate completion, the reductive amination intermediate can be refluxed in a suitable solvent such as THF to close the ring that forms the spiro lactam (XX). This is followed by allowing it to react appropriately and proper purification.

[106] Step b can be carried out using an appropriate reducing agent in a compatible solvent, such as lithium aluminum hydride solution in THF, at an appropriate temperature, such as 68°C. This is followed by appropriate purification.

[107] Step g consists of deprotection of benzylamine using well-known procedures, for example through reflux hydrogenation of a solution of benzylamine derivative (XXI) in a suitable solvent such as methanol in the presence of a hydrogen source such as hydrogen formate. ammonium and a hydrogenation catalyst such as palladium or carbon. This is followed by allowing it to react appropriately and proper purification.

[108] Compounds of formula (XV) can be obtained using well-known procedures by first reacting the corresponding ketone with a reducing agent such as sodium borohydride in a suitable solvent such as a mixture of ethanol and THF at a temperature ranging from -10°C at -5°C. This is followed by allowing it to react in an appropriate manner and by suitable purification. In a second step the hydroxyl group can be converted to bromide using known procedures such as its treatment with hydrobromic acid at a temperature such as room temperature. This is followed by allowing it to react appropriately and proper purification.

[109] Compounds of formula (VI) where A and B form a 6-azaspiro [2.5]octane system of formula (VIc) can be synthesized analogously to that described in WO03091220 (A1) with a process comprising the following steps of Scheme 3: Scheme 3 on what:

[110] Step a means Wittig reaction between Boc-piperidinone and suitable triphenylphosphonium bromide (XXV);

[111] Step b means cyclpropanation of the double bond of the derivative (XXVI);

[112] Step c means deprotection of the amine (XXVII);

[113] Step d means protection as amine trifluoroacetamide (XXVIII);

[114] Step e means reduction of dichlorocyclopropane (XXIX);

[115] Step f means deprotection of trifluoroacetamide (XXX) to obtain compounds of formula (VIc).

[116] Step a can be carried out by treating suitable triphenylphosphonium bromide with a base such as sodium hydride in a suitable solvent such as THF at a temperature ranging from 0°C and room temperature so as to form the corresponding ylide which is to react with N-Boc-piperidinone in a suitable solvent such as THF and at a temperature such as room temperature. This is followed by allowing it to react appropriately and proper purification.

[117] Step b can be carried out by reacting the double bond derivative (XXVI) with chloroform in the presence of a base such as sodium hydroxide and a phase transfer catalyst such as tetrabutylammonium bromide. This is followed by allowing it to react appropriately and proper purification.

[118] Step c can be carried out following well-known procedures for removing the Boc protecting group such as treating the protected compound with an acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane at a temperature such as room temperature.

[119] Step d can be carried out following well-known procedures for protecting amines such as trifluoroacetic amides such as treating the amine derivative with trifluoroacetic anhydride in a suitable solvent such as dichloromethane. This is followed by allowing it to react appropriately and proper purification.

[120] Step e can be carried out by treating the dichlorocyclopropane derivative with a reducing agent such as zinc powder in a suitable solvent such as a mixture of ethanol and water at a temperature ranging from 80°C to 95°C. This is followed by allowing it to react appropriately and proper purification.

[121] Step f consists of deprotection of trifluoroacetamide using well-known procedures, for example, under basic conditions such as treating the compound with a suitable base such as potassium carbonate, in a suitable solvent such as a mixture of methanol and water and in a temperature as room temperature. This is followed by allowing it to react appropriately and proper purification.

[122] Compounds of formula (XXV) can be obtained using well-known procedures by reacting benzyl bromides (XXXI) with triphenylphosphine in a suitable solvent such as toluene at reflux temperature. This is followed by allowing it to react appropriately and proper purification.

[123] Compounds of formula (VI) where A and B form a 5-azaspiro [2.5]octane system of formula (VId) can be synthesized analogously to that described in Scheme 1 with a process comprising the following steps of Scheme 4:Scheme 4 wherein: Step a means the cycloropanation of (XXXII) to provide the bicyclic spiroimide (XXXIII); Step b means the reduction of imide (XXXIII) to obtain tertiary benzylamine (XXXIV). Step c means deprotection of benzylamine (XXXIV) to obtain compounds of formula (Vld).

[124] Step a can be carried out by generating in situ the intermediate diazo compound to be reacted in a 1,3-dipolar cycloaddition with the appropriate double bond. In many cases, this step is suitably carried out by applying a procedure in which the hydrazone (VIII) is treated with an oxidizing agent, such as manganese dioxide, in a suitable solvent, such as dioxane, and at room temperature to form the intermediate diazocompound which it was then added to a solution of imide (XXXII) in a suitable solvent such as dioxane. This is followed by allowing it to react appropriately and proper purification.

[125] Step b can be carried out using an appropriate reducing agent in a compatible solvent, such as lithium aluminum hydride solution in THF, at an appropriate temperature, such as 68 ° C. This is followed by appropriate purification.

[126] Step c consists of deprotection of benzylamine using well-known procedures, for example through reflux hydrogenation of a solution of benzylamine in a suitable solvent such as methanol in the presence of a hydrogen source such as ammonium formate and an ammonium catalyst. hydrogenation such as palladium or carbon. This is followed by allowing it to react appropriately and proper purification.

[127] Compounds of formula (XXXII) can be obtained by reacting N-benzylchloroacetamide (XXXV) with triphenylphosphine in a suitable solvent such as toluene at reflux temperature, then treating the corresponding phosphonium chloride with methyl acrylate in the presence of a base such as sodium methoxide, in a suitable solvent such as MeOH and at 0°C. The phosphanylidene intermediate thus obtained can be reacted with formaldehyde in a suitable solvent, such as Toluene, and at a suitable temperature, such as room temperature. This is followed by allowing it to react appropriately and proper purification.

[128] If a compound of formula (VII) can be prepared by reacting a compound of formula (XXXVII): wherein G1 and Y are as defined hereinabove with a compound of formula (XXXVIII) wherein X is defined as for formula (VII) and L is a leaving group, for example a bromide atom. For 5 typical reaction conditions, see Preparation 148 below.

[129] A compound of formula (VII) in which W is SO or SO2 can be prepared by a) reacting a compound of formula (XXXIX): wherein G1 and Y are as defined hereinbefore and S is a sulfur atom with a compound of formula (XL): wherein X is defined as for formula (VI) and L is a leaving group, for example a bromide atom. For typical reaction conditions, see Preparation 148 below. b) oxidize the sulfur with a suitable oxidizing agent such as oxone or m-chloroperbenzoic acid in a suitable solvent such as dichloromethane.

[130] Compounds of formula (I) in which oxygen Wis and G, R, R1, R2, n, m, p, G1 and Y are as defined above, can be prepared by reacting a compound of formula (XL): wherein G, R, R1, R2, n, m and p are as defined for formula (I), with a compound of formula (XLI): where G1 and Y are defined as above and X is a leaving group such as methyl sulfone. For typical reaction conditions, see Example 303.

[131] Interconversion reactions between compounds of formula (I) and salts thereof can be carried out using methods known in the art.

[132] Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of diseases that require modulation of such receptors, such as psychotic conditions.

[133] Such affinity is typically calculated at IC50 as the concentration of a compound required to displace 50% of the radiolabeled ligand from the receptor and is reported as a "Ki" value calculated by the following equation: where L = radioligands and Kd = affinity of radioligands for receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).

[134] In the context of the present invention pKi (corresponding to the antilogarithm of Ki) is used instead of Ki and compounds of the present invention typically show pKi greater than 7.

[135] In one aspect, the present invention provides compounds of formula (I) having a pKi comprised between 7 and 8. In another aspect, the present invention provides compounds of formula (I) having a pKi comprised between 8 and 9. In In another aspect, the present invention provides compounds of formula (I) having a pKi greater than 9.

[136] Many of the compounds of formula (I) have also been found to have greater affinity for dopamine D3 receptors than for D2. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted through blockade of D2 receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. It has been suggested that blockades of the recently characterized dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant EPS. (see, for example, Sokoloff et al, Nature, 1990; 347: 146151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No.4, 295-314, 1993). In one embodiment compounds of the present invention are provided that have greater (e.g., >10x or >100x greater) affinity for dopamine D3 than dopamine D2 receptors (such affinity can be measured using standard methodology, e.g., using receptors cloned dopamine receptors - see here). Suitably mentioned compounds can be used as selective modulators of D3 receptors.

[137] From the location of D3 receptors, it could also be predicted that the compounds could also have utility for the treatment of substance abuse where it has been suggested that D3 receptors are involved (e.g., see Levant, 1997, Pharmacol. Rev ., 49, 231-252). Examples of such substance abuse include alcohol, cocaine, heroin and nicotine. Other conditions that can be treated by the compounds include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, cognitive impairment, including memory disorders such as Alzheimer's disease, eating disorders, sexual dysfunction, premature ejaculation, sleep disorders, vomiting, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders, e.g. IBS.

[138] The compounds of formula (I) can be used for the treatment of all aspects of drug addiction including withdrawal symptoms from drugs of abuse such as alcohol, cocaine, opiates, nicotine, benzodiazepines and inhibition of opioid-induced tolerance. Furthermore, compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof can be used to reduce craving and will therefore be useful in treating drug craving. Drug craving can be defined as the encouraging motivation to self-administer a psychoactive substance that has previously been consumed. Three main factors are involved in the development and maintenance of drug craving: (1) Dysphoric states during drug withdrawal can function as a negative reinforcer, leading to craving (2) Environmental stimuli associated with drug effects can become progressively (3) A cognition (memory) of the ability of drugs to promote pleasurable effects and to alleviate a dysphoric state during withdrawal. Craving may represent the difficulty individuals have in giving up drugs of abuse and, therefore, contributes significantly to the development and maintenance of drug addiction.

[139] The compounds of formula (I) are of potential use as antipsychotic agents, for example in the treatment of schizophrenia, schizoaffective disorders, psychotic depression, mania, paranoid and delusional disorders. Furthermore, they would have utility as adjunctive therapy in Parkinson's disease, particularly with compounds such as l-dopa and possibly dopaminergic agonists, to reduce the side effects experienced with these treatments in long-term use (e.g., see Schwartz et al. al., Schwartz et al., Brain Res. Reviews, 1998, 26, 236-242).

[140] In the context of the present invention, terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, published by the American Psychiatric Association (DSM-V). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention.

[141] In the context of the present invention, the term "schizophrenia spectrum and psychotic disorder" includes: Schizotypal (personality disorder; Delusional disorder; Brief psychotic disorder; Schizopreniform disorder; Schizophrenia; Schizoaffective disorder; Substance/Medication-Induced Psychotic disorder; Psychotic Disorder due to another Medical Condition.

[142] In the context of the present invention, the term "catatonia" includes: Catatonia Associated with another Mental Disorder (Catatonia Specifier); Catatonic Disorder Due to Another Medical Condition; Unspecified Catatonia; Other Specified Schizophrenia Spectrums and Psychotic Disorder; Unspecified Schizophrenia Spectrum and other Psychotic Disorder.

[143] In the context of the present invention, the term "obsessive-compulsive disorder" includes: Obsessive-Compulsive disorder; Body Dysmorphic disorder; Hoarding Disorder; Trichotillomania (Hair Pulling Disorder); Excoriation (Skin Picking) disorder; Obsessive-Compulsive Disorder Induced by and Related to Substance/Medication; Obsessive-Compulsive Disorder Due to and Related to Another Medical Condition; Other Specified and Related Obsessive-Compulsive Disorders; Unspecified and Related Obsessive-Compulsive Disorders.

[144] In the context of the present invention, the term "eating disorders" includes: Pica; Ruminant disorder; Avoidant/Restrictive Food Intake Disorder; Anorexia Nervosa; Nervous bulimia; Binge Eating Disorder; Other Specified Eating Disorders; Unspecified eating disorders.

[145] In the context of the present invention, the term "sexual dysfunctions" includes: Delayed Ejaculation; Erectile Dysfunction; female orgasmic disorder; female sexual interest/arousal disorder; Genito-Pelvic Pain Disorder; Hypoactive Male Sexual Desire Disorder; Premature Ejaculation; Substance/Medication Induced Sexual Dysfunction; Unspecified Sexual Dysfunction.

[146] In the context of the present invention, the term "substance-related disorders and addictive disorders" includes: Substance-Related disorders such as Substance Use Disorder;

[147] Substance-Induced Disorders; Substance Intoxication and Withdrawal; Substance/Medication Induced Mental Disorders; Alcohol-Related Disorders, such as Alcohol Use Disorder;: Alcohol Poisoning; Alcohol Abstinence; Other Alcohol-Induced Disorders; Unspecified Alcohol-Related Disorders; Caffeine-Related Disorders, such as Caffeine Poisoning; Caffeine withdrawal; Other Caffeine-Induced Disorders; Unspecified Caffeine-Related Disorders; Cannabis-Related Disorders such as Cannabis Use Disorder;: Cannabis Intoxication; Cannabis withdrawal; Other Cannabis-Induced Disorders; Unspecified Cannabis-Related Disorders; hallucinogen-related disorders such as phencyclidine use disorder; Other Hallucinogen Use Disorder; Phencyclidine poisoning; Other Hallucinogen Poisoning; Persistent Hallucinogenic Perception Disorder; Other Phencyclidine-Induced Disorders; Other Unspecified Hallucinogen-Induced Disorders Related to Phencyclidine; Unspecified Hallucinogen-Related Disorders; Inhalant-Related Disorders such as Inhalant Use Disorder;: Inhalant Poisoning; Other Inhalant-Induced Disorders; Unspecified Inhalant-Related Disorders; Opioid-Related Disorders such as Opioid Use Disorder; Opioid Poisoning; Opioid Withdrawal; Other Opioid-Induced Disorders; Unspecified Opioid-Related Disorders; Sedative, Hypnotic or Anxiolytic Poisoning; Withdrawal from sedatives, hypnotics, anxiolytics; Other disorders induced by sedative, hypnotic or anxiolytic; Stimulant-Related Disorders such as Stimulant Use Disorder;: Stimulant Intoxication; Abstinence from Stimulants; Other Stimulant-Induced Disorders; disorders Related to Unspecified Stimulants; tobacco-related disorders such as tobacco use disorder; Tobacco Poisoning; Tobacco abstinence; Other Tobacco-Induced Disorders; Unspecified Tobacco-Related Disorders; Other (or Unknown) Substance-Related disorders such as Other (or Unknown) Substance Use disorders; Poisoning by Other (or Unknown) Substances; Abstinence from Other (or Unknown) Substances; Other (or Unknown) Substance-Induced Disorders; Other (or Unknown) Disorders Related to Unspecified Substances.

[148] In the context of the present invention, the term "non-substance related disorders and addictive disorders" includes: Gambling disorders.

[149] In another aspect, therefore, the present invention provides a method of treating a condition for which modulation (especially antagonism/inhibition) of dopamine receptors (especially dopamine D3 receptors) is beneficial, which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g. physiologically). These conditions, in particular, include psychoses/psychotic conditions, such as schizophrenia, and substance abuse.

[150] The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition in a mammal for which modulation (especially antagonism/inhibition) of receptors of dopamine (especially dopamine D3 receptors) is beneficial.

[151] The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a condition in a mammal for which modulation (especially antagonism/inhibition) of dopamine receptors (especially dopamine receptors D3) is beneficial.

[152] In one embodiment, D3 antagonists according to the present invention are used in the treatment of psychoses such as schizophrenia or in the treatment of substance abuse.

[153] Thus, an even further aspect of the invention provides a method of treating a psychotic condition (e.g., schizophrenia) or substance abuse that comprises administering to a mammal (e.g., human) in need thereof an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[154] Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a psychotic condition (e.g., schizophrenia) or substance abuse in a mammal.

[155] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a psychotic condition (e.g., schizophrenia) or substance abuse in a mammal.

[156] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal, for example for use in treating any of the conditions described herein.

[157] "Treatment" includes prophylaxis, where appropriate for the relevant condition(s).

[158] For use in medicine, the compounds of the present invention are normally administered as a standard pharmaceutical composition. The present invention thus provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable (i.e. physiologically) salt thereof and a pharmaceutically acceptable (i.e. physiologically) carrier. The pharmaceutical composition may be for use in treating any of the conditions described herein.

[159] The compounds of formula (I) can be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and pharmaceutical compositions adapted accordingly.

[160] The compounds of formula (I) and the pharmaceutically acceptable salts thereof that are active when administered orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

[161] A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt thereof in a suitable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerin, or a non- aqueous, such as polyethylene glycol or anoyl. The formulation may also contain a suspending agent, preservative, flavoring or coloring agent.

[162] A composition in the form of a tablet can be prepared using any appropriate pharmaceutical carrier(s) routinely used to prepare solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

[163] A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, granules containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension may be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension is then introduced into a soft gelatin capsule.

[164] Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous vehicle or parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent immediately prior to administration.

[165] Compositions for nasal administration can conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or nonaqueous solvent and are usually presented in single or multiple quantities in sterile form in a sealed container which may take the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container may be a unitary dispensing device such as a single-dose nasal inhaler or an aerosol dispenser equipped with a dosing valve that is intended to be disposed of once the contents of the container have been exhausted. When the dosage form comprises an aerosol dispenser, it will contain a propellant which may be a compressed gas such as compressed air or an organic propellant such as a fluorine hydrocarbon. Aerosol dosage forms may also take the form of a spray.

[166] Compositions suitable for buccal or sublingual administration include tablets, lozenges and lozenges, in which the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth or gelatin and glycerin.

[167] In one embodiment, the composition is in unit dose form such as a tablet, capsule or ampoule.

[168] Each dosage unit for oral administration contains, for example, from 1 to 250 mg (and for parenteral administration contains, for example, from 0.1 to 25 mg) of a compound of formula (I) or a pharmaceutically acceptable salt. acceptable from the same calculated as the free base.

[169] The pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, for example between 10 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous or intramuscular dose between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, eg between 1 and 25 mg of the compound of formula (I) or a salt thereof pharmaceutically acceptable calculated as the free base, the compound being administered 1 to 4 times per day. Suitably, the compounds will be administered over a period of continuous therapy, for example for a week or more.

Examples

[170] This invention is further illustrated by the following non-limiting examples.

[171] In the procedures that follow, after each primary material, reference to a Preparation or Example is typically provided by number. This is provided solely for the assistance of chemists skilled in the art. The primary material may not necessarily have been prepared from the batch referred to in the example of reaction temperature, amount of reagent/solvent, reaction time, treatment conditions or chromatographic purification conditions.

[172] In the procedures that follow, "up" or "down" absolute stereochemical configurations in structures should be considered correct if accompanied by a unique absolute stereochemical assignment in the name (e.g. (1R, 3S)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane). On the contrary, absolute "up" or "down" stereochemical configurations in structures should be considered arbitrarily assigned for the sole purpose of distinguishing one enantiomer from another if not accompanied by a single absolute stereochemical assignment in the name (e.g. (1R, 3S or 1S, 3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane).

[173] All temperatures refer to °C.

[174] Proton Magnetic Resonance (NMR) spectra can typically be recorded on a Varian instrument at 400 or 500 MHz, or on a Bruker instrument at 400 MHz.

[175] Chemical variations are expressed in parts per million (ppm, δ units). Chemical shifts are reported in ppm downfield (δ) of Me4Si, used as an internal standard, and are typically designated as singulars, broad singulars (br.s.), doublets (d), doublets of doublets (dd), doublets of doublets of doublets (ddd), doublets of triplets (Tt), triplets (t), triplets of doublets (td), quartets (q) or multiplets (m).

[176] LCMS can be registered under the following conditions:

[177] DAD chromatographic traces, mass chromatograms and mass spectra can be taken on the AcquityTM UPLC/PDA/MS system together with Micromass ZQ™ or Águas SQD single quadrupole mass spectrometer operated in positive or negative ES ionization mode. There were two QC methods used, one operated under low pH conditions and another operated under high pH conditions. Details of the method operated under low pH conditions were: column, Acquity BEH C18, 1.7 pm, 2.1 x 50 mm or Acquity CSH C18, 1.7 pm, 2.1 x 50 mm, temperature column it was 40°C; Mobile phase solvent A was milliQ water + 0.1% HCOOH, mobile phase solvent B MeCN + 0.1% HCOOH. The flow was 1 ml/min. The gradient table was t = 0 min 97% A-3% B, t = 1.5 min 0.1% A-99.9% B, t = 1.9 min 0.1% A-99.9 % B and t = 2 min 97% A-3% B. The UV detection range was 210-350 nm and the ES+/ES'- range was 100-1000 amu.

[178] The details of the method operated under high pH conditions were the same as those listed above for the low pH method, with the exception of: Acquity BEH C18 column, 1.7 pm, 2.1 x 50 mm; mobile phase solvent A was 10 mM aqueous solution of NH 4 HCO 3 adjusted to pH = 10 with ammonia, mobile phase solvent B MeCN.

[179] Mass-directed semipreparative autopurifications (MDAP) were performed using Waters Fractionlynx™ systems operated under low or high pH chromatographic conditions. The stationary phases used were, XTerra C18, XBridge C18, Sunfire C18, XSelect C18, Gemini AXIA C18. The length of the columns was 5, 10 or 15 cm, while the internal diameter was 19, 21 or 30 mm. The particle size of the stationary phases was 5 or 10 pm. Purifications were performed using low pH or high pH chromatographic conditions. The solvent composition of the mobile phase was the same as that used for QC analysis. The combinations of stationary/mobile phases used were: XTerra, XBridge, Sunfire, XSelect-low pH mobile phases and XTerra, XBridge, Gemini AXIA-high pH mobile phases. All purifications were carried out with the column maintained at room temperature. The flow rate used was 17 or 20 ml/min for columns with an internal diameter of 19 or 21 mm and 40 or 43 ml/min for columns with an internal diameter of 30 mm. The trigger for collecting the target species was the presence of the target m/z ratio value in the TIC MS signal. The time gradient was customized to the Rt behavior of the target species.

[180] Purification can also be performed using Biotage® Isolera or Biotage® SP1 flash chromatography systems, these instruments work with Biotage® KP-SIL cartridges, Biotage® KP-NH Cartridges or Biotage® KP-C18 cartridges.

[181] Unless otherwise indicated, all reactions are typically carried out under an inert atmosphere (e.g. under Nitrogen).

[182] Tic refers to thin layer chromatography on silica plates and dry refers to a dry solution over anhydrous sodium sulfate,

[183] The following abbreviations are used in the text: EtOAc, AcOEt, EA = ethyl acetate; Et2O = diethyl ether; MeOH = methanol; THF = tetrahydrofuran; Rt (RT) refers to room temperature, DMSO = dimethyl sulfoxide; DMF = N,N'-dimethylformamide; DCM = dichloromethane; EtOH = ethanol; DCE = dichloroethane; DME = 1,2-Dimethoxyethane; Cy, cHex = cyclohexane; ACN = Acetonitrile; tBuOH = tert-Butanol; TEA = triethylamine; DIPEA = N,N-disopropylethylamine; BoC2O = Di-tert-butyl dicarbonate; TFA = trifluoroacetic acid; Pd2(dba)3 = Tris (dibenzylideneacetone) dipalladium (0); TPP = triphenylphosphine; AcOH = acetic acid; LAH = lithium aluminum hydride; T3P = propylphosphonic anhydride; SCX Cartridge = Strong cation exchange cartridge; ipa = isopropylamine; FA = formic acid; Py = pyridine; TBAF = tetrabutylammonium fluoride; TBDMSCI = tert-butyldimethylsilyl chloride; HOBt * H2O = 1-hydroxybenzotriazole hydrate; EDC * HCL = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; DMAP = 4-(dimethylamino) pyridine; TMSCN = trimethylsilyl cyanide; mCPBA = 3-chloroperbenzoic acid; MCBA = 3-chlorobenzoic acid; CbzCl = Benzyl chloroformate; ACE-CI = 1-chloroethyl chloroformate.Preparation 1: {[4-(trifluoromethyl)phenyl] methylidene} hydrazine

[184] To a solution of hydrazine hydrate (6.4 mL, 86.1 mmol) in EtOH (25 mL) was added 4-(trifluoromethyl) benzaldehyde (3.92 mL, 28.7 mmol) dropwise under hydrogen over 10 min. The resulting solution was stirred at RT for 1 h. The solution was cooled to RT, then diluted with water and DCM. The phases were separated; The organic was dried and concentrated under reduced pressure giving {[4-(trifluoromethyl)phenyl] methylidene} hydrazine (P1, 5.2 g, y = 96%) as a pale yellow oil which was used as such in the next step .MS (m/z): 189.2 [MH]+ Preparation 2: (phenylmethylidene) hydrazine

[185] To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL) was added benzaldehyde (1.04 mL, 10 mmol) dropwise under nitrogen over 10 min. The resulting solution was stirred at RT for 1.5 h. After this time, water was added and the ethanol was evaporated under vacuum. The aqueous phase was extracted with DCM (x 4). The combined organic phases were dried and concentrated to obtain (phenylmethylidene) hydrazine (P2, 1.2 g, y = quant.) as a yellow oil MS (m/z): 121.1 [MH]+ Preparation 3: [ 2-fluoro-4-(trifluoromethyl)phenyl] methylidene} hydrazine

[186] To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL) was added 2-fluoro-4-(trifluoromethyl) benzaldehyde (1.36 mL, 10 mmol) dropwise under nitrogen over 10 min. The resulting solution was stirred at reflux for 1 h, then cooled to room temperature for 1 h. After this time, water was added and the aqueous phase was extracted with DCM (x 4). The combined organic phases were dried and concentrated to obtain [2-fluoro-4-(trifluoromethyl)phenyl] methylidene} hydrazine (P3, 2.15 g, y = quant.) as a yellow liquid. MS (m/z ): 207.3 [MH]+ Preparation 4: [(2,4-difluorophenyl) methylidene] hydrazine

[187] To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL) was added dropwise 2,4-difluorobenzaldehyde (1.09 mL, 10 mmol). The resulting solution was stirred at RT for 1 h, then water was added and the aqueous phase was extracted with DCM (x 4). The combined organic phases were dried and concentrated to obtain [(2,4-difluorophenyl) methylidene] hydrazine (P4, 1.8 g, y = quant.) as a white solid.NMR: 1H NMR (DMSO-d6) δ: 7.81 (s, 1H), 7.70-7.78 (m, 1H), 7.21 (d, 1H), 7.08 (s, 2H), 7.05 (d, 1H) Preparation 5: [(4-fluorophenyl) methylidene] hydrazine

[188] To a solution of hydrazine hydrate (2.5 mL, 30 mmol) in EtOH (10 mL) was added dropwise 4-fluorobenzaldehyde (1.07 mL, 10 mmol). The resulting solution was stirred at reflux for 1 h, then cooled to room temperature. After this time, water was added and the aqueous phase was extracted with DCM (x 4). The combined organic phases were dried and concentrated to obtain [(4-fluorophenyl) methylidene] hydrazine (P5, 1.5 g, y = quant.) as yellow wax. NMR: 1H NMR (DMSO-d6) δ: 7, 71 (s, 1H), 7.47-7.55 (m, 2H), 7.15 (m, 2H), 6.75 (s, 2H) Preparation 6: [(3,5-dichlorophenyl) methylidene] hydrazine

[189] To a solution of hydrazine hydrate (0.72 mL, 8.55 mmol) in EtOH (6 mL) was gradually added 3,5-dichlorobenzaldehyde (1 g, 5.7 mmol) in a nitrogen atmosphere to the over 5 min. The resulting solution was stirred at RT for 3 h. The solution was evaporated and the residue was partitioned between DCM and water and extracted several times with DCM. The combined organic phases were washed with brine (15 ml), dried, filtered and evaporated to give a yellow solid which was purified by FC on silica gel (eluting from cHex to 30% EtOAc) to obtain [(3 ,5-dichlorophenyl)methylidene]hydrazine (p6, 510 mg, y = 47%) as a yellow solid.NMR: 1H NMR (DMSO-d6) δ:7.62 (s, 1H), 7.48 (d, 2H), 7.38-7.43 (m, 1H), 7.25 (s, 2H) Preparation 7: {[2-(trifluoromethyl)phenyl] methylidene}

[190] To a solution of 60% hydrazine hydrate in water (2.1 mL, 25.8 mmol) in EtOH (7.5 mL) was added dropwise 2-(trifluoromethyl) benzaldehyde (1.13 mL , 8.6 mmol) under nitrogen for 10 min. The resulting solution was stirred at RT for 1.5 h. After this time, water was added and the aqueous phase was extracted with DCM (x 3). The combined organic phases were dried and concentrated to obtain {[2-(trifluoromethyl)phenyl] methylidene} hydrazine (P7, 1.31 g, y = 71%) as a yellow oil.NMR: 1H NMR (DMSO-d6) δ: 8.01 (d, 1H), 7.89-7.96 (m, 1H), 7.65 (d, 1H), 7.59 (m, 1H), 7.34-7.43 ( m, 3H) Preparation 8: {[4-fluoro-2-(trifluoromethyl)phenyl] methylidene} hydrazine

[191] To a solution of hydrazine hydrate (1.9 mL, 23.4 mmol) in EtOH (7.5 mL) was added dropwise 4-fluoro-2-(trifluoromethyl) benzaldehyde (1.07 mL , 7.8 mmol) under nitrogen over 10 min. The resulting solution was stirred at RT for 1 h. After this time, water was added and the aqueous phase was extracted with DCM (x 3). The combined organic phases were dried and concentrated to obtain {[4-fluoro-2-(trifluoromethyl)phenyl] methylidene} hydrazine (p8, 1.81 g, y = 98%) as a pale yellow solid. NMR: 1H NMR (DMSO-d6) δ: 8.03 (m, 1H), 7.89 (m, 1H), 7.54 (m, 1H), 7.48 (d, 1H), 7.39 (s, 2H) Preparation 9: 5-methanehydrazonoyl-2-(trifluoromethyl) pyridine

[192] To a solution of hydrazine hydrate (0.48 ml, 5.7 mmol) in EtOH (5 ml) was added 6-(trifluoromethyl)-3-pyridinecarboxaldehyde (1 g, 5.7 mmol) in portions under nitrogen over 5 min. The resulting solution was stirred at RT for 3 h. The solution was evaporated and the residue was partitioned between DCM and water and extracted several times with DCM. The combined organic phases were washed with brine (15 ml), dried, filtered and evaporated to give 5-methanehydrazonoyl-2-(trifluoromethyl)pyridine (P9, 0.87 g, y = quant.) as a white solid which was used as such in the next step. MS (m/z): 190.4 [MH]+ Preparation 10: 1-benzyl-3-methylidene-pyrrolidine-2,5-dione

[193] 1-Benzyl-2,5-dihydro-1H-pyrrole-2,5-dione (25 g, 134 mmol) was dissolved in AcOH (80 ml) and PPh3 (35 g, 134 mmol). The resulting solution was stirred for 1 h at RT and then 37% formaldehyde in water (15 mL, 252 mmol) was added. The resulting solution was stirred at RT for 2.5 h. Volatiles were removed under reduced pressure. The residue was partitioned between water (300 ml) and DCM (350 ml). The layers were separated and the organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluent: cyclohexane-EtOAc, 80:20 to 60:40) providing 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (P10, 24. 44 g, y = 90%) as a colorless oil. MS (m/z): 202.2 [MH]+. Preparation 11 and 12: (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (TRANS, p11) and (1S, 3R/1R, 3S)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (CIS, p12)

[194] To a solution of {[4-(trifluoromethyl)phenyl] methylidene} hydrazine (p1, 11.29 g, 60 mmol) in dioxane (65 mL) at 10 °C, MnO2 (52.16 g) was added , 600 mmol) in portions. The resulting mixture was stirred at RT for 1 h, then filtered over a pad of Celite washing with dioxane (70 ml). This pale yellow solution was then added to a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10, 12.07 g, 60 mmol) in dioxane (30 mL). The resulting orange/red solution was left stirring at RT for 40 h. The solvent was removed and the residue was purified by FC on silica gel (eluent: from cHex to 30% EtOAc) to obtain: (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, TRANS, P11): 7.2 g, y = 33%, 96% purity (1S, 3R/1R, 3S )-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p12): 7.5 g, y = 35% , 60% purity which were used as such in the next step. MS (m/z): 360.3 [MH]+. Preparation 13: (1S, 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS) Step a:

[195] (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane-4,6-dione (Diastereoisomer 1, TRANS, p11 , 0.91 g, 2.53 mmol) in THF (15 mL) and LiAH41M in THF (5.06 mL, 5.06 mmol) was added dropwise. The resulting orange solution was heated at reflux for 1 h. It was then cooled with an ice bath and quenched with Na2SO4 * 10 H2O until gas evolution ceased. The mixture was filtered over a pad of Celite washing with EtOAc and the solution was concentrated to give (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (TRANS, 810 mg) as oil which was used as such in the next step.Step b:

[196] (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, 810 mg from step a) was dissolved in MeOH (20 ml) under N2 and ammonium formate (1.55 g, 24.4 mmol) was added. After 2 cycles of vacuum/N2 Pd/C (0.25 g) was added. The resulting mixture was stirred at reflux for 1 h. After cooling to room temperature, it was filtered over a pad of Celite, the solvent was evaporated and the residue was loaded onto the SCX cartridge (eluting with 1N NH3 in MeOH) to give, after evaporation, (1S, 3S/ 1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, P13, 495 mg, y = 81%) as a pale yellow oil.MS (m /z): 242.3 [MH]+.Preparation 14: (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS) Step a:

[197] (1S,3R/1R,3S)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p12 , 7.5 g, 20.87 mmol) was dissolved in THF (120 mL) and 1 M LiAH4 in THF (15.65 mL, 15.65 mmol) was added dropwise at 0 °C. The resulting orange solution was heated at reflux for 1 h. It was then cooled with an ice bath and quenched with Na2SO4 * 10 H2O until gas evolution ceased. The mixture was filtered over a Celite pad washing with EtOAc, and the solution was concentrated to obtain (1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2 .4]heptane (CIS, 6.9 g) as the oil that was used as such in the next step.Step b:

[198] (1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, 6.9 g, from step a) was dissolved in MeOH (200 mL) under N2 and ammonium formate (6.58 g, 104.35 mmol) was added. Then Pd/C (800 mg) was added. The resulting mixture was stirred at reflux for 5 hours. After cooling, it was filtered over a Celite pad, the solvent was evaporated and 12 mL of 1.25M HCI in MeOH were added. Solvent was removed under reduced pressure and the residue was loaded onto an SCX cartridge with washing MeOH and eluting with 1M NH3 in MeOH. The solvent was removed under reduced pressure, yielding (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, P14, 3.89 g , y = 77%).MS (m/z): 242.0 [MH]+.Preparation 15: (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 1)

[199] (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 3.89 g) was subjected to chiral preparative HPLC ( SFC) to separate the enantiomers: (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p15, 1.5 g) Enantiomer 1: Ret. Time 6.4 min, 100% ee.MS (m/z):242.0 [MH]+. Preparation 16 and 17: (1S, 3S/1R, 3R)-5-benzyl-1-phenyl-5-azaspiro[2,4]heptane-4,6-dione (TRANS, p16) and (1R, 3S/1S , 3R)-benzyl-phenyl-5-azaspiro[2,4]heptane-4,6-dione (CIS, p17)

[200] To a solution of (phenylmethylidene) hydrazine (p2, 0.6 g, 5 mmol) in dioxane (10 mL) at 10 ° C, MnO2 (4.4 g, 50 mmol). The resulting mixture was stirred at RT for 30 min, then filtered over a pad of Celite washed with dioxane and this solution was added to a solution of 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (p10, 1 g , 5 mmol) in dioxane (3.5 mL). The resulting orange/red solution was left stirring at room temperature overnight. The solvent was removed and the residue was purified by FC on silica gel (eluent: from cHex to 30% EtOAc) to obtain: (1S, 3S/1R, 3R)-5-benzyl-1-phenyl-5-azaspiro [2,4]heptane-4,6-dione (Diastereoisomer 1, TRANS, p16): 524 mg, y = 36%, 70% purity and 171 mg, y = 12%, 90% purity. (1R, 3S/1S, 3R)-5-benzyl-1-phenyl-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p17): 550 mg, y = 38%, 76% that were used as such in the next stage. MS (m/z): 292.2 [MH]+. Preparation 18: (1S, 3S/1R, 3R)-1-phenyl-5-azaspiro[2,4]heptane (TRANS)

[201] The compound was synthesized in analogy with the method described for Preparation 13 starting from (1S, 3S/1R, 3R)-5-benzyl-1-phenyl-5-azaspiro[2,4]heptane-4,6 -dione (TRANS, p16, 524 mg, 1.8 mmol) and providing (1S, 3S/1R, 3R)-1-phenyl-5-azaspiro[2,4]heptane (p18, TRANS, 166 mg, 60% of purity). MS (m/z): 242.3 [MH]+. Preparation 19: (1R, 3S/1S, 3R)-1-phenyl-5-azaspiro[2,4]heptane (CIS)

[202] The compound was synthesized by analogy with the method described for Preparation 13 starting from (1R, 3S/1S, 3R)-5-benzyl-1-phenyl-5-azaspiro[2,4]heptane-4,6 -dione (p17, CIS, 1.13 g, 3.88 mmol) and providing (1R, 3S/1S, 3R)-1-phenyl-5-azaspiro[2.4]heptane (p19, CIS, 42 mg, y = 6%). MS (m/z):174.1 [MH]+. Preparation 20 and 21: (1R, 3S/1S, 3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione ( TRANS, p20) and (1S, 3S/1R, 3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione ( CIS, p21)

[203] To a solution of {[2-fluoro-4-(trifluoromethyl)phenyl] methylidene} hydrazine (p3, 1.05 g, 5 mmol) in dioxane (10 ml) at 10 °C, MnO2 ( 4.4 g, 50 mmol) in portions. The resulting mixture was stirred at RT for 30 min, then filtered over a pad of Celite washing with dioxane (10 ml) directly into a solution of 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (p10, 1 g , 5 mmol) in dioxane (10 mL). The resulting orange/red solution was left stirring at room temperature overnight. The solvent was removed and the residue was purified by FC on a Si cartridge (eluent: from cHex to 30% EtOAc) to obtain: (1R, 3S/1S, 3R)-5-benzyl-1-[2-fluoro- 4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, TRANS, p20): 1.12 g, 55% purity (1S, 3S/1R, 3R) -5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p21): 518 mg, 86% purity which were used as such in the next step. MS (m/z): 378.3 [MH]+. Preparation 22: (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro-[2,4]heptane (TRANS)

[204] The compound was synthesized in analogy with the method described for the preparation of 13 from (1R,3S/1S,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptane-4,6-dione (p20, TRANS, 1.2 g, 3.18 mmol) and obtaining (1R,3S/1S,3R)-1-[2-fluoro -4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p22, TRANS, 308 mg, y = 37%). MS (m/z): 260.2 [MH]+ Preparation 23: (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro-[2.4 ] heptane (CIS)

[205] The compound was synthesized in analogy with the method described for Preparation 14 from (1S, 3S/R,3R)-5-benzyl-1-[2-fluoro-4-(trifluoromethyl)phenyl]- 5- azaspiro[2,4]heptane-4,6-dione (p21, CIS, 0.654 g, 1.73 mmol) and obtaining (1S,3S/1R,3R)-1-[2-fluoro-4-( trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p23, CIS, 234 mg, y =52%).MS (m/z): 260.2 [MH]+ Preparation 24 and 25: (1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (p24, CIS, Enantiomer 1) and (1R, 3R) [2-fluoro-4- (trifluoromethyl )phenyl] -5-azaspiro[2,4]heptane (p25, CIS, Enantiomer 2) (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (prepared as in p23, CIS, 1 g) was subjected to preparative HPLC chiral (SFC) to separate the enantiomers: (1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p24, CIS, 351 mg) Enantiomer 1: Ret. Time 4.7 min, 100% ee. MS (m/z): 260.2 [MH]+ (1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p25, CIS, 378 mg) Enantiomer 2: Ret. Time 6.2 min, 98.8% ee. MS (m/z): 260.2 [MH]+ Preparation 26 and 27: (1R, 3S/1S, 3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2.4 ]heptane-4,6-dione (TRANS, p26) and (1S,3S/1R, 3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro [2,4]heptane-4, 6-dione (CIS, p27)

[206] To a solution of [(2,4-difluorophenyl) methylidene] hydrazine (p4, 0.78 g, 5 mmol) in dioxane (10 mL) at 10 °C, MnC2 (4.4 g, 50 mmol) was added portion by portion. The resulting mixture was stirred at RT for 30 min, then filtered over a Celite pad washed with dioxane (10 ml) directly into a solution of 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (p10, 1 g , 5 mmol) in dioxane (10 mL). The resulting orange/red solution was left stirring at room temperature overnight. The solvent was removed and the residue was purified by FC on silica gel (eluent: from cHex to 30% EtOAc) to obtain: (1R,3S/1S,3R)-5-benzyl-1-(2,4- difluorophenyl)-5-azaspiro[2.4]heptane-4,6-dione (Diastereoisomer 1, TRANS, p26): 791 mg, 69% purity (1S,3S/1R,3R)-5-benzyl-1-(2 ,4-difluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p27): 653 mg, 87% purity which were used as in the next step. MS (m/z): 328.3 [MH]+. Preparation 34: (1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane (TRANS)

[207] (1R, 3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (p32, TRANS, 791 mg, 2.42 mmol) was dissolved in THF (15 mL) and LiAIH41 M in THF (4.83 mL, 4.83 mmol) was added dropwise at 0 °C. The reaction was refluxed for 1h, then refrigerated to -20 °C and quenched with Na2SO4 * 10 H2O. The mixture was filtered over a celite pad washing with EtOAc, and the solution was concentrated to obtain (1R,3S/1S,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2, 4]heptane (p34, TRANS, 734 mg) as the oil that was used as crude in the next step. MS (m/z): 300.4 [MH]+. Preparation 28: (1R, 3S/1S, 3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane (TRANS) Step a:

[208] (1R, 3S/1S, 3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (p26, TRANS, 791 mg, 2.42 mmol) was dissolved in THF (15 mL) and LiAIH41M in THF (4.83 mL, 4.83 mmol) was added dropwise at 0 °C. The reaction was refluxed for 1 h, then cooled to -20 °C and quenched with Na2SO4 * 10 H2O. The mixture was filtered over an EtOAc-washed celite pad and the solution was concentrated to give (1R, 3S/1S, 3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2,4 ]heptane (TRANS, 734 mg) as oil which was used as crude product in the next step.Step b:

[209] (1R, 3S/1S, 3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane (TRANS, 734 mg, from step a) in DCM (15 ml) and the mixture was cooled to 0°C. ACE-Cl (520 uL, 4.82 mmol) was added and the mixture was allowed to reach RT and left stirring at that temperature overnight. The day after the solvent was removed under reduced pressure and the residue dissolved in MeOH (12 mL). The mixture was then refluxed for 30 min, then cooled to room temperature and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluent: DCM to DCM/MeOH 9:1), obtaining (1R, 3S/1S, 3R)-1-(2,4-difluorophenyl)-5- azaspiro[2,4]heptane (p28, TRANS, 158 mg, y = 31%). MS (m/z): 210.2 [MH]+.Preparation 29: (1S, 3S/1R, 3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (CIS)

[210] The compound was synthesized in analogy to the method described for Preparation 14 starting from (1S,3S/1R,3R)-5-benzyl-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane -4,6- dione (p27, CIS, 0.653 g, 1.99 mmol) and obtaining (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4 ]heptane (p29, CIS, 326 mg, y= 78%).MS (m/z): 210.2 [MH]+. Preparation 30 and 31: (1S, 3S/1R, 3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (TRANS, p30) and (1R , 3S/1S, 3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (CIS, p31)

[211] To a solution of [(4-fluorophenyl)methylidene]hydrazine (p5, 0.82 g, 6 mmol) in dioxane (10 mL) at 10 °C, MnO2 (4.4 g, 50 mmol) was added portion by portion. The resulting mixture was stirred at RT for 30 min and then filtered over a pad of Celite washed with dioxane (10 ml) directly into a solution of 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (p10.1. 2 g, 6 mmol) in dioxane (10 mL). The resulting orange/red solution was left stirring at room temperature overnight.

[212] The solvent was removed and the residue was purified by FC on silica gel (eluent: cHex to 30% EtOAc) to obtain: (1S, 3S/1R, 3R)-5-benzyl-1-(4- fluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, TRANS, p30): 951 mg, 82% purity (1R, 3S/1S, 3R)-5-benzyl-1- (4-fluorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p31): 765 mg, 70% purity which were used as such in the next step. MS (m/z): 310.3 [MH]+. Preparation 32: (1S, 3S/1R, 3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane (TRANS)

[213] The compound was synthesized by analogy with the method described for Preparation 28 starting from (1S,3S/1R,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane -4,6-dione (p30, 951 mg, 3.07 mmol) and providing (1S,3S/1R,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane (p32, TRANS , 257 mg, y = 44%). MS (m/z): 192.2 [MH]+.Preparation 33: (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane (CIS)

[214] The compound was synthesized by analogy with the method described for Preparation 14 starting from (1R,3S/1S,3R)-5-benzyl-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane -4,6-dione 5 dione (p31, CIS, 765 mg, 2.47 mmol) and providing (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane (p33, CIS, 366 mg, y = 77%).MS (m/z): 192.2 [MH]+.Preparation 34 and 35: (1S,3S/1R,3R)-5-benzyl-1- (3,5-dichlorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (TRANS, p34) and (1R,3S/1S,3R)-5-benzyl-1-(3,5- dichlorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (CIS, p35)

[215] To a solution of [(3,5-dichlorophenyl)methylidene]hydrazine (p6, 0.85 g, 4.49 mmol) in dioxane (10 mL) at 10 °C, MnO2 (3.9 g, 45 mmol) portion by portion. The resulting mixture was stirred at RT for 50 min, and then filtered over a Celite pad washing with dioxane (10 mL) directly into a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10.0. 885 g, 4.4 mmol) in dioxane (5 mL). The resulting orange/red solution was left stirring at room temperature overnight. The solvent was removed and the residue was purified by FC on silica gel (eluent: from cHex to 30% EtOAc) to obtain: (1S,3S/1R,3R)-5-benzyl-1-(3,5- dichlorophenyl)-5-azaspiro[2,4]heptane-4,6- dione (Diastereoisomer 1, TRANS, p34): 440 mg, 89% purity (1R,3S/1S,3R)-5-benzyl-1- (3,5-dichlorophenyl)-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, p35): 440 mg, 40% purity which were used as in the next MS step (m /z): 359.9 [M]+.Preparation 36: (1S,3S/1R/3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2,4]heptane (TRANS)

[216] The compound was synthesized in analogy to the method described for Preparation 28 starting from (1S,3S/1R,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2,4]heptane -4,6-dione (p34, TRANS, 440 mg, 1.22 mmol) and obtaining (1S.3S/1R,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2,4 ]heptane (p36, TRANS, 164 mg, y = 55%).MS (m/z): 241.9 [M]+. Preparation 37: (1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2,4]heptane (CIS)

[217] The compound was synthesized in analogy to the method described for preparation 28 starting from (1R,3S/1S,3R)-5-benzyl-1-(3,5-dichlorophenyl)-5-azaspiro[2,4]heptane -4,6- dione (p35, CIS, 440 mg, 1.22 mmol) and obtaining (1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2,4 ]heptane (p37, CIS, 110 mg, y= 27%).MS (m/z): 241.9 [M]+. Preparation 38 and 39: (1R,3S/1S,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (CIS, p38) and (1S,3S/1R,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (TRANS, p39)

[218] To a solution of {[2-(trifluoromethyl)phenyl]methylidene}hydrazine (p7, 0.935 g, 4.97 mmol) in dioxane (6 mL) at 10 °C, MnO2 (4.32 g, 49. 7 mmol) was added portion by portion. The resulting mixture was stirred at RT for 30 min, then filtered over a Celite pad washed with dioxane (15 mL) directly into a solution of 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (p10, 1 g , 4.97 mmol) in dioxane (3 mL). The resulting orange/red solution was left stirring at room temperature overnight. The solvent was removed and the residue was purified by FC on silica gel (eluent: cHex to 30% EtOAc, then to 100% EtOAc) obtaining a mixture of both diastereomers that were separated by chiral preparative HPLC (1R,3S)/1S,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-4,6-dione (Diastereoisomer 1, CIS, p38): 531 mg , 100% purity, ta 1.17 min (1S,3S/1R,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6- dione (Diastereoisomer 2, TRANS, p39): 425 mg, 100% purity, rt, 1.20 min MS (m/z): 360.0 [MH]+. Preparation 40: (1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS)

[219] The compound was synthesized in analogy to the method described for Preparation 13 starting from (1S,3S/1R,3R)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane-4,6-dione (p39, TRANS, 128 mg, 0.36 mmol) and obtaining (1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2 ,4]heptane (p40, TRANS, 52 mg, y= 60%).MS (m/z): 241.9 [M]+. Preparation 41: (1R,3S/1S,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS)

[220] The compound was synthesized in analogy with the method described by Preparation 14 starting from (1S,3R/1R,3S)-5-benzyl-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane-4,6-dione (p38, CIS, 529 mg, 1.48 mmol) and obtaining (1R, 3S/1S, 3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[ 2.4]heptane (p41, CIS, 181 mg, y = 51%).MS (m/z): 241.9 [M]+. Preparation, 42, 43, 44 and 45: (1R,3S or 1S,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4 ,6-dione (CIS, enantiomer 1, p42), (1S,3R or 1R,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane-4,6-dione (CIS, enantiomer 2, p43), (1S,3S or 1R,3R)- 5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2 ,4]heptane-4,6-dione (TRANS, Enantiomer 1, p44) and (1R,3R or 1S,3S)-5-benzyl-1-[4-fluoro-2- (trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane-4,6-dione (TRANS, Enantiomer 2, p45)

[221] To a solution of {[4-fluoro-2-(trifluoromethyl)phenyl]methylidene}hydrazine (P8, 1.81 g, 8.78 mmol) in dioxane (12 ml) at 10 °C, MnO2 (7 .26 g, 83.5 mmol). The resulting mixture was stirred at RT for 30 min and then it was filtered over a Celite pad washing with dioxane (30 mL) directly into a solution of 1-benzyl-3-methylidenepyrrolidine-2,5-dione (p10 , 1.68 g, 8.35 mmol) in dioxane (6 mL). The resulting orange/red solution was left stirring at room temperature overnight. The solvent was removed to obtain an orange gum which was purified by FC on silica gel (eluent from Cy to 40% EtOAc) to obtain a mixture of both racemic diastereomers (2.2 g) which was separated into 4 single enantiomers through chiral preparative HPLC. (1R,3S or 1S,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, CIS, Enantiomer 1, p42): 500 mg, 98.4% purity, rt 5.8 min (1S,3R or 1R,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, CIS, Enantiomer 2, p43): 441 mg, 98% purity, rt 6.6 min (1S,3S or 1R,3R)- 5-Benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, TRANS, 1 Enantiomer, p44): 361 mg, 99 % purity, rt 7.3 min (1R,3R or 1S,3S)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4, 6-dione (Diastereoisomer 2, TRANS, Enantiomer 2, p45): 403 mg, 100% purity, rt 9.3 min MS (m/z): 378.2 [MH]+.Preparation 46: (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, Enantiomer 1) Step a:

[222] (1S,3S or 1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2 , TRANS, Enantiomer 1, p44, 361 mg, 0.96 mmol) was dissolved in THF (5 mL) and 1M LiAlH4 in THF (1.92 mL, 1.92 mmol) was added dropwise at 0 °C. The resulting orange solution was heated at reflux for 1 h. It was then cooled to 0 °C and quenched with Na2SO 4 * 10 H2O until gas evolution ceased. Filtered over a pad of Celite washing with EtOAc, the solution was concentrated to obtain (1S,3S or 1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]- 5- azaspiro[2,4]heptane (TRANS, Enantiomer 1, 291 mg) as a colorless oil.Step b:

[223] (1S,3S or 1R,3R)-5-benzyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (TRANS, Enantiomer 1.291 mg, from step a) MeOH (10 ml) under N2 and ammonium formate (523 mg, 8.3 mmol) was added. Then Pd/C (33 mg) was added. The resulting mixture was stirred for 1h. After cooling it was filtered over a Celite pad, the solvent was evaporated and MeOH and 1.5 ml of -1.25M HCl in MeOH were added. Solvent was removed under reduced pressure and the residue was loaded onto a 5g SCX cartridge washing with MeOH and eluting with NH31M in MeOH. The solvent was eliminated under reduced pressure to obtain a yellow oil which was purified by C18 cartridge (eluent of Water + 0.1% HCOOH to 25% ACN + 0.1% HCOOH) then loaded onto an SCX cartridge (washing with MeOH and eluting with NH31M in MeOH) to obtain (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p46, 42 mg , y= 17%) as a yellow oil. MS (m/z): 260.2 [MH]+.Preparation 47: (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2.4 ]heptane (CIS, Enantiomer 2)

[224] The compound was synthesized in analogy with the method described for the preparation of 46 from (1R,3R or 1S,3S)-5-benzyl-1-[4-fluoro-2- (trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2,TRANS, Enantiomer 2, p45, 403 mg, 1.07 mmol) and obtaining (1R,3R or 1S,3S)-1- [4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p47, TRANS, Enantiomer 2, 93 mg, y = 33%) MS (m/z): 260.2 [M ]+. Preparation 48: (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1)

[225] The compound was synthesized by analogy with the method described for Preparation 46 starting from (1R,3S or 1S,3R)-5-benzyl-1-[4-fluoro-2- (trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, CIS, Enantiomer 1, P42, 500 mg, 1.33 mmol) and obtaining (1R,3S or 1S,3R)-1-[4 - fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (P48, CIS, Enantiomer 1, 126 mg, y = 36%). MS (m/z): 260.2 [M]+ Preparation 49: (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 2)

[226] The compound was synthesized by analogy with the method described for Preparation 46 starting from (1S,3R or 1R,3S)-5-benzyl-1-[4-fluoro-2- (trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, CIS, Enantiomer 2, P43, 441 mg, 1.17 mmol) and obtaining (1S,3R or 1R,3S)-1-[4 - fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (P49, CIS, Enantiomer 2, 76 mg, y = 25%). MS (m/z): 260.2 [M]+. Preparation 50 and 51: (1S,3S/1R,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5 -azaspiro[2,4]heptane-4,6-dione (TRANS, p50) and (1R,3S/1S,3R)-5-benzyl-1-[6-(trifluoromethyl)pyridin-3-yl]-5 -azaspiro[2,4]heptane-4,6-dione (CIS, p51)

[227] To a solution of 5-methanehydrazonoyl-2-(trifluoromethyl)pyridine (P9, 0.8 g, 4.22 mmol) in dioxane (15 mL) at 10 °C, MnC2 (3.6 g, 42.2 mmol) was added portion by portion. The resulting mixture was stirred at RT for 45 min, then filtered over a pad of Celite washed with dioxane and this solution was added to a solution of 1-benzyl-3-methylidene-pyrrolidine-2,5-dione (p10, 0.766 g, 3.8 mmol) in dioxane (5 mL). The resulting orange solution was left stirring at room temperature overnight. The solvent was removed and the residue was purified by FC on silica gel (eluent: from cHex to 45% EtOAc) to obtain: (1S,3S/1R,3R)-5-benzyl-1-[6-(trifluoromethyl )pyridin-3-yl]-5- azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 1, TRANS, p50): 450 mg (1R,3S/1S,3R)-5-benzyl-1- [6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2,4]heptane-4,6-dione (Diastereoisomer 2, CIS, P51): 360 mg which were used as such in the next step.MS ( m/z): 361.0 [MH]+.Preparation 52: (1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2,4]heptane (CIS)

[228] The compound was synthesized by analogy with the method described for Preparation 14 starting from (1R,3S/1S,3R)-5-benzyl-1-[6-(trifluoromethyl) pyridin-3-yl]-5- azaspiro[2,4]heptane-4,6-dione (p51, CIS, 0.36 g, 1 mmol) and obtaining (1R, 3S/1S, 3R)-1-[6-(trifluoromethyl) pyridin- 3-yl]-5-azaspiro[2,4]heptane (P52, CIS, 100 mg, y = 41%) MS (m/z): 243.3 [MH]+. Preparation 53: 4-methyl-1,3-oxazole-5-carboxylic acid

[229] A stirred mixture of ethyl 2-chloro-3-oxobutanoate (16.8 mL, 121.51 mmol) and formamide (13.5 mL, 340.23 mmol) was heated to 120 °C. After 6 hours the mixture was allowed to cool to room temperature and stirred under nitrogen overnight. The mixture was treated with 3M NaOH (120 mL, moderately exothermic reaction) and stirred at RT for 4 hours. EtOAc (120 ml) was added and the phases were separated. The organic layer was discarded while the aqueous phase was acidified with 37% aqueous HCl to pH 2 (~40 mL). A precipitate began to form. The suspension was treated with EtOAc (160 ml) and stirred vigorously until the precipitate dissolved. The phases were separated and the aqueous layer was additionally extracted with EtOAc twice (120 mL). The combined organic layers were concentrated to low volume. Fresh EtOAc (160 mL) was added and the mixture was evaporated to dryness under vacuum. The collected solid was placed in the oven at 45 °C overnight under reduced pressure to obtain 4-methyl-1,3-oxazol-5-carboxylic acid (p53, 8.52 g, y = 44%) as solid rusty brown.MS (m/z):128.0 [MH]+. Preparation 54: 1-methanesulfonyl-1H-1,2,3-bezotriazole

[230] To a solution of benzotriazole (5 g, 42 mmol) and pyridine (5.4 mL, 67.2 mmol) in dry toluene (50 mL) MsCI (3.9 mL, 50.36 mmol) in dry toluene (10 mL) was added dropwise at 0°C under N2 atmosphere and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), washed with water (2 x 30 mL), brine (30 mL), dried over MgSO4, filtered and evaporated under vacuum yielding 1-methanesulfonyl-1H-1,2, 3,- benzotriazole (p54, 8.44 g, y = quantity). NMR: 1H NMR (Acetone-d6) δ: 8.21 (dt, 1H), 8.04 (dt, 1H), 7.86-7.75 (m, 1H), 7.67-7.57 ( m, 1H), 3.76 (s, 3H) Preparation 55: Methyl 6-(1H-1,2,3-benzotriazol-1-carbonyl) pyridine-2-carboxylate

[231] A mixture of 6-(methoxycarbonyl)pyridine-2-carboxylic acid (4 g, 22.08 mmol), 1-methanesulfonyl-1H-1,2,3-benzotriazole (p54, 4.35 g, 22. 08 mmol) and triethylamine (6.15 mL, 44.16 mmol) was heated to reflux in THF (150 mL) for 4 h. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with water, dried and evaporated to give methyl 6-(1H-1,2,3-benzotriazol-1-carbonyl)pyridine-2-carboxylate (p55, 5.8 g, y = 93%) .MS (m/z): 283.2 [MH]+. Preparation 56: Methyl 6-carbamoylpyridine-2-carboxylate

[232] Methyl 6-(1H-1,2,3-benzotriazol-1-carbonyl)pyridine-2-carboxylate (p55, 1.9 g, 6.73 mmol) was stirred with ammonium hydroxide (aqueous solution 30%, 40 drops, 43 mmol) in MeOH (8 mL) and THF (15 mL) at RT for 2 h. After evaporation of the solvents under vacuum, 2M NaOH (20 mL) was added to the residue and the mixture was then extracted with EtOAc. The combined organic layers were dried and evaporated. Evaporation of the solvent obtained methyl 6-carbamoylpyridine-2-carboxylate (p56, 310 mg, y = crude). MS (m/z): 181.1 [MH]+. Preparation 57: 6-carbamoylpyridine-2-carboxylic acid

[233] A solution of methyl 6-carbamoylpyridine-2-carboxylate (p56, 0.31 g, 1.72 mmol) in THF (5 mL) and water (2 mL) at RT was treated with lithium hydroxide (0.072 g, 1.72 mmol), stirred for 2 h and concentrated. The concentrate was dissolved in water (5 mL) and adjusted to pH 7 with 1N HCl. The aqueous solution was evaporated giving 6-carbamoylpyridine-2-carboxylic acid (p57, 550 mg, y = crude). MS (m/z): 166.0 [M]+.Preparation 58: Methyl 6-(methylcarbamoyl)pyridine-2-carboxylate

[234] Methyl 6-(1H-1,2,3-benzotriazol-1-carbonyl)pyridine-2-carboxylate (p55, 0.75 g, 2.66 mmol) was stirred with 2m methylamine in THF (1 .33 mL, 2.66 mmol) in THF (25 mL) at RT for 4 h. After evaporation of the solvents in vacuo, 2M NaOH (20 ml) was added to the residue and extracted with EtOAc. The combined organic layers were dried and evaporated. Evaporation of the solvent obtained methyl 6-(methylcarbamoyl)pyridine-2-carboxylate (p58, 350 mg, y =68%).MS (m/z): 195.1 [MH]+. Preparation 59: 6-(methylcarbamoyl)pyridine-2-carboxylic acid

[235] A solution of methyl 6-(methylcarbamoyl) pyridine-2-carboxylate (p58, 0.592 g, 3.05 mmol) in THF (7 mL) and water (3 mL) at RT was treated with LIOH-H2O ( 0.128 g, 3.05 mmol), stirred for 1 h, and concentrated. The concentrate was dissolved in water (5 mL) and adjusted to pH 7 with 1N HCl. The aqueous solution was evaporated and the residue was purified by C18 cartridge (eluent: water to 10% CH3CN) to give after evaporation 6-(methylcarbamoyl)pyridine-2-carboxylic acid (p59, 540 mg, y = 98%) . MS (m/z): 181.1 [MH]+. Preparation 60: Methyl 6-(dimethylcarbamoyl)pyridine-2-carboxylate

[236] Methyl 6-(1H-1,2,3-benzotriazol-1-carbonyl)pyridine-2-carboxylate (p55, 1.5 g, 5.32 mmol) was stirred with 2M dimethylamine in THF (2. 66 mL, 5.32 mmol) in THF (35 mL) at RT for 4 h. After evaporation of solvents in vacuo, 2 M NaOH (20 mL) was added to the residue and extracted with EtOAc. The combined organic layers were dried and evaporated. Evaporation of the solvent obtained methyl 6-(dimethylcarbamoyl)pyridine-2-carboxylate (p60, 250 mg, y = 22%).MS (m/z): 209.1 [MH]+.Preparation 61: acid 6- (dimethylcarbamoyl)pyridine-2-carboxylic acid

[237] A solution of methyl 6-(dimethylcarbamoyl)pyridine-2-carboxylate (p60, 0.36 g, 1.73 mmol) in THF (6 mL) and water (2 mL) at RT was treated with LIOH- H2O (g 0.072, 1.73 mmol), stirred for 1h and then concentrated. The concentrate was dissolved in water (5 mL) and adjusted to pH 7 with 1N HCl. The aqueous solution was evaporated and the residue was purified by FC on a C18 cartridge (eluent: water up to 10% CH3CN). After evaporation, 6-(dimethylcarbamoyl)pyridine-2-carboxylic acid was obtained (p61, 500 mg, y = crude). MS (m/z): 195.2 [MH]+. Preparation 62: Ethyl 2-(pyridin-3-yl)-1,3-oxazol-4-carboxylate

[238] Ethyl 2-bromo-1,3-oxazol-4-carboxylate (200 mg, mmol 0.9), 3-pyridineboronic acid (144 mg, mmol 1.17), were combined in a cap bottle. screw, to this was added 1,4-dioxane (5 mL) and 2 M Na2CO3 (1.13 mL, 2.27 mmol); N2 was bubbled through the mixture to 1' and then Pd(PPh3)4 (100 mg, 0.09 mmol) was added. The flask was capped, then heated to 100°C. After 2 hours the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc and concentrated. The crude material was purified by FC on a silica cartridge (eluent: from cHex to EtOAc) to obtain ethyl 2-(pyridin-3-yl)-1,3-oxazol-4-carboxylate (p62, 71 mg, y = 35%). MS (m/z): 219.1 [MH]+.Preparation 63: ethyl 2-(pyridin-3-yl)-1,3-oxazol-4-carboxylate

[239] Ethyl 2-(pyridin-3-yl)-1,3-oxazol-4-carboxylate (p62, 380 mg, 1.74 mmol) was dissolved in water/THF (5 mL/2 mL) and LiOH H2O (72 mg, 1.74 mmol) was added. The mixture was stirred at RT for 2h. Solvent was removed in vacuo, the residue was dissolved with water and acidified with 6N HCl to pH 4. No precipitation was observed, the solution was evaporated yielding 2-(pyridin-3-yl)-1,3-oxazole Ethyl -4-carboxylate (p63, 330 mg, y = crude). MS (m/z): 191.1 [MH]+.Preparation 64: 4-(1,3-oxazol-2-yl)benzoic acid

[240] A solution of 4-carbamoylbenzoic acid (4.8 g, 29 mmol) and 2-bromo-1,1-diethoxyethane (8.7 mL, 58 mmol) in Dioxane (60 mL) was stirred at reflux (101° C) for 3.5 hours. The solids were filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography on a C18 cartridge (eluent: water + 0.1% HCOOH to 30% ACN + 0.1% HCOOH) to obtain 4-(1,3-oxazol-2-yl) acid benzoic (p64, mg 232, y = 4%). MS (m/z): 190.1 [MH]+. Preparation 65: 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3-thiol

[241] For a solution of 4-methyl-1,3-oxazol-5-carboxylic acid (p53, 2G, 15.7 mmol) in DMF (9 mL), 4-methyl-3-thiosemicarbazide (1.82 g , 17.27 mmol) was added. DIPEA (4.8 mL, 28.26 mmol) was added dropwise at RT, then the mixture was cooled with an ice bath before adding T3P (50% w/w in EtOAc) (14 mL, 23 .55 mmol). The reaction was stirred at room temperature overnight. 4M NaOH solution (15 ml) was added (resulting in pH = 8). The reaction was diluted with EtOAc and the two resulting phases were separated (upper organic layer eliminated). Additional 4M NaOH was added until pH 11 and the mixture was heated at 70°C for 40 min. The clear rustic red solution was then cooled to room temperature in 3 hours, then 37% HCl was added slowly to pH 5. The clear solution was extracted 3 times with DCM, the combined organic phases were dried and concentrated to obtain a brown solid.

[242] The crude material was purified by C18 cartridge (eluting from 0.1% H2O+HCOOH to 20% MeCN+0.1% HCOOH). Fractions containing product were collected and concentrated to reduce volume, then extracted twice with DCM to obtain 4-methyl-5-(4-methyl-1,3-oxazol-4-yl)-4H-1,2 ,4-triazol-3-thiol (p65, 605 mg, y = 17%) as a yellow solid. MS (m/z): 197.1 [MH]+. Preparation 66: 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-thiol

[243] To a solution of oxane-4-carboxylic acid (5g, 38.42 mmol) in DMF (23 mL), 4-Methyl-3-thiosemicarbazide (4.45 g, 42.26 mmol) was added. DIPEA (11.8 mL, 69.15 mmol) was added dropwise at RT, then the mixture was cooled with an ice bath before adding T3P (50% w/w in EtOAc) (35 mL, 57 .63 mmol). The reaction was stirred at room temperature overnight. 4M NaOH solution was added (resulting pH = 8). The reaction was diluted with EtOAc and the two resulting phases were separated (upper organic layer eliminated). Additional 4M NaOH was added until pH 11 and the mixture was heated at 70°C for 40 min. The solution was then cooled to RT, then cooled to 0°C and 6N HCl was slowly added until pH~5. The white precipitate was filtered and washed with cHex, then dried at 50°C overnight to obtain 3.47 g of 4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-thiol as a white solid.

[244] The mother liquor was extracted with DCM (2x), the organic layer was dried and evaporated to obtain an oil which was triturated with Et2O to obtain an off-white precipitate which was filtered and dried overnight at 50 °C to give another 1.8 g of the title compound 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-thiol (p66, total y = 69%) as a yellow solid pale.MS (m/z): 200.2 [MH]+.

[245] The following intermediates were prepared in analogy to Preparation 66 from the corresponding carboxylic acids either previously described or commercially available. Preparation 128: 5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

[246] For a stirred solution of 6-cyanopyridine-3-carboxylic acid (230 mg, 1.55 mmol) in DMF (0.9 mL), 4-methyl-3-thiosemicarbazide (180 mg, 1.71 mmol) and DIPEA (0.49 mL, 2.79 mmol) were added later. The mixture was cooled to 0°C and then T3P (50% wt/EA) (1.38 mL, 2.33 mmol) was added portionwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight. An aqueous 0.5 M NaOH solution (resulting pH ~ 8) was added and the resulting two phases were separated (the upper organic layer was eliminated), then the mixture was heated to 75 °C and stirred for 1.5 h . The solution was cooled to room temperature and 37% HCl was added slowly until pH ~ 6. The mixture was extracted with DCM, the organic phase was dried using a phase separator cartridge and concentrated. The residue was treated with water, the mixture was filtered, the white solid was washed with water and dried under vacuum at 45°C overnight to obtain 5-(4-methyl-5-sulfanyl-4H-1,2, 4-triazol-3-yl)pyridine-2-carbonitrile (p128, 224 mg, y = 66%).MS (m/z): 218.1 [MH]+. Preparation 129: 4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

[247] To a stirred solution of 2-cyanopyridine-4-carboxylic acid (1.0 g, 6.75 mmol) in DMF (3.9 ml), 4-methyl-3-thiosemicarbazide (0.78 g, 7.43 mmol) and DIPEA (2.1 mL, 12.15 mmol) were added subsequently. The mixture was cooled to 0°C, then T3P (50% wt/EA) (6.0 mL, 10.13 mmol) was added portion by portion. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight. An aqueous 0.5 M NaOH solution (resulting pH ~ 8) was added and the resulting two phases were separated (the upper organic layer was eliminated), then the mixture was heated to 75 °C and stirred for 1.5 h . The solution was cooled to room temperature and 37% HCl was slowly added until pH ~ 5. The mixture was stirred for 5 min, then filtered. The solid was washed with water and dried under vacuum at 45 °C overnight, obtaining a ~1:1 mixture of 4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl ) pyridine-2-carbonitrile and 4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) pyridine-2-carboxamide derivatives (p129, 0.74 g) which was used as crude product in the next step. MS (m/z): 218.1 [MH]+. Preparation 130: 5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) pyridine-2-carboxamide

[248] To a solution of 6-cyanopyridine-3-carboxylic acid (0.5 g, 3.35 mmol) in DMF (5 ml), 4-methyl-3-thiosemicarbazide (390 mg, 3.71 mmol); DIPEA (1.1 mL, 6.75 mmol) was added dropwise at RT, then the mixture was cooled in an ice bath before adding T3P (50% w/w in EtOAc) (3 mL, 5.05 mmol ). The reaction was stirred at room temperature overnight. 4M NaOH solution was added until the precipitate, formed during the addition, dissolved (resulting in pH = 8). The reaction was diluted with EtOAc and the two resulting phases were separated (upper organic layer eliminated). Additional 4M NaOH was added until pH 11 and the mixture was heated to 70°C for 2.5 hours. Then, the pH was increased to 11 by adding NaOH (beads) and the reaction was stirred at 70 °C for 1 h. The solution was cooled to 0°C, then 6N HCl was added slowly until pH 5. A precipitate formed and was filtered under vacuum to obtain 5-(4-methyl-5-sulfanyl-4H-1,2,4 -triazol-3-yl) pyridine-2-carboxamide (p130, 585 mg, y = 74%).MS (m/z): 236.1 [MH]+.Preparation 131: 6-(4-methyl-5 -sulfanyl-4H-1,2,4-triazol-3-yl) pyridine-3-carbonitrile

[249] For a stirred solution of 5-cyanopyridine-2-carboxylic acid (1.0 g, 6.75 mmol) in DMF (3.9 mL), 4-methyl-3-thiosemicarbazide (0.78 g, 7 .43 mmol) and DIPEA (2.1 mL, 12.15 mmol) were added later. The mixture was cooled to 0°C, then T3P (50% wt/EA) (6.0 mL, 10.13 mmol) was added portion by portion. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight. 0.5 M NaOH aqueous solution was added (resulting pH ~8) and the resulting two phases were separated (upper organic layer was eliminated) then the mixture was heated to 70 °C and stirred for 1.5 h. The solution was cooled to RT and 37% HCl was slowly added until pH ~ 6. The mixture was stirred for 5 min, then filtered. The solid was washed with water and dried under vacuum at 45°C overnight to give 6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carbonitrile (p131 , 1.47 gy = 96%).MS (m/z): 218.1 [MH]+.Preparation 132: 6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3 -yl)pyridine-3- carboxamide

[250] A mixture of 6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carbonitrile (p131, 1.47 g, 6.75 mmol) and Crushed KOH (1.14 g, 20.25 mmol) in f-BuOH (90 mL) was heated to 90 °C and stirred for 1.5 h. Allowing the mixture to reach RT it was filtered and the yellow solid washed with t-BuOH after drying under vacuum. The solid was taken up with water, the pH was brought to 4-5 by addition of 37% HCl, then the mixture was filtered, the solid was washed with water and dried under vacuum at 45°C overnight, giving 6- (4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) pyridine-3-carboxamide (p132, 1.39 g, y = 88%). MS (m/z): 236.1 [MH]+.Preparation of 133:4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl } pyridine -2-carboxamide Step a:

[251] Pyridine-2,4-dicarboxylic acid (2.5 g, 14.95 mmol) was dissolved in MeOH (9 mL) and 1.25 M hydrogen chloride solution in methanol (6 mL) was added . The suspension was left stirring at 50°C for 8 hours. The mixture was concentrated under reduced pressure to obtain 2.35 g (crude) of 2-(methoxycarbonyl)pyridine-4-carboxylic acid in the form of a mainly mono- and partially diester mixture which was used as such in the next step.Step b:

[252] 2-(Methoxycarbonyl)pyridine-4-carboxylic acid (2.35 g from step a) was dissolved in water (5 mL), treated with 28% aqueous NH4OH solution (15 mL) and the solution was left in Stir at room temperature overnight. The solvent was removed under reduced pressure giving 2-carbamoylpyridine-4-carboxylic acid and 4-carbamoylpyridine-2-carboxylic acid (1.27 g) which was used as such in the next step.Step c:

[253] For a stirred solution of 4-carbamoylpyridine-2-carboxylic acid (1.27 g from step b) in DMF (5 mL), 4-methyl-3-thiosemicarbazide (884 mg, 8.4 mmol) and DIPEA (2.4 mL, 13.7 mmol) were added later. The mixture was cooled to 0°C and then T3P (50% wt/EA) (6.82 mL, 11.39 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight.

[254] 3M NaOH aqueous solution was added (resulting pH ~ 8) followed by AcOEt and the two resulting phases were separated (upper organic layer was eliminated). Additional 3M NaOH was added until pH 11, then the mixture was heated to 70 °C and stirred for 40 min. The solution was cooled to RT and 6N HCl was slowly added until pH 5. The precipitate formed was collected by filtration and washed with water and Cy, then dried under high vacuum, obtaining 4-{5-[(3-chloropropyl) sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-pyridine-2-carboxamide (p133, mg 745, y = 21%).MS (m/z): 236.1 [ MH]+.Preparation 134: 2-(methoxycarbonyl)-3-methylpyridin-N oxide

[255] To a solution of ethyl 2-methyl-3-pyridinecarboxylate (1.86 mL, 12.1 mmol) in DCM (50 mL) mCPBA (4.18 g, 24.2 mmol) was added at RT . The solution was stirred at RT for 24 h. The solution was filtered and concentrated. The residue was purified by FC on silica (eluent: DCM to 15% MeOH) from a solid still containing mCBA which was dissolved with DCM and washed with NaHCO3, the organic phase was dried and evaporated to obtain 2-(methoxycarbonyl)-3 oxide - methylpyridin-N (p134, 1.9 g, y = 85%).MS (m/z): 168.1 [M]+.Preparation 135: methyl 6-cyano-3-methylpyridine-2-carboxylate

[256] To a solution of 2-(methoxycarbonyl)-3-methylpyridin-N oxide (p134, 1.9 G, 11.29 mmol) in DCM (80 ml) was added TMSCN (2.1 ml, 16. 93 mmol) followed, after 5 min, by dimethylcarbamyl chloride (1.56 mL, 16.93 mmol). The solution was stirred at RT for 48 h. Then 10% K2CO3 was slowly added to make the basic reaction mixture. Organic layer was separated, dried and evaporated to give the crude oil, which was purified by FC on the silica cartridge (eluent: Cy to 20% EtOAc) to obtain methyl 6-cyano-3-methylpyridine-2-carboxylate (p135 , mg 370, y = 19%).MS (m/z): 177.1 [MH]+. Preparation 136: 6-cyano-2-methylpyridine-3-carboxylic acid

[257] A solution of methyl 6-cyano-3-methylpyridine-2-carboxylate (p135, 0.37 g, 2.1 mmol) in THF (6 mL) and water (2 mL) at RT was treated with LIOH -H2O (0.097 g, 2.3 mmol), stirred for 1h and concentrated. The concentrate was dissolved in water (5 mL) and adjusted to pH 2 with 1N HCl to provide a precipitate. The precipitate was filtered and washed with cold water, then dried to obtain 6-cyano-2-methylpyridine-3-carboxylic acid (p136, 320 mg, y = 94%).MS (m/z): 163.0 [MH]+.Preparation of 137: 5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

[258] For a solution of 6-cyano-2-methylpyridine-3-carboxylic acid (p136, 320 mg, 1.97 mmol) in DMF (2 mL), 4-methyl-3-thiosemicarbazide (228 mg, 2.117 mmol ) was added; DIPEA (0.605 mL, 3.54 mmol) was added dropwise at RT and then the mixture was cooled in an ice bath before adding T3P (50% w/w in EtOAc) (1.76 mL, 2.96 mmol). The reaction was stirred at room temperature overnight. 4M NaOH solution was added until pH = 8. The reaction was diluted with EtOAc and the two resulting phases were separated (upper organic layer eliminated). Additional 4M NaOH solution was added until pH 9 and the mixture was heated at 70°C for 5 h. The solution was then cooled to 0°C and 6N HCl was added slowly until pH 5. A precipitate formed and was filtered. The mother liquor was extracted several times with DCM, the organic phase was dried and evaporated to obtain an oil. After addition of water (~ 2 mL) a precipitate was obtained. It was filtered and combined with the previous precipitate to obtain 5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile (P137 , 160 mg, y~35%).MS (m/z): 232.1 [MH]+. Preparation 138: 1-methyl-4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)-1,2-dihydropyridin-2-one

[259] A mixture of 5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) pyridine-2-carbonitrile (p137, 0.16 g, 0. 69 mmol) and crushed KOH (0.116 mg, 2.06 mmol) in t-BuOH (5 ml) was heated to 85 °C and stirred for 1 h. After allowing the mixture to reach RT, the solvent was decanted. The yellow solid was taken up with water, the pH was brought to 4-5 by addition of 6N HCl and a precipitate was obtained. After filtering, the solid was dried to obtain 5-methyl-6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-2-carboxamide (p138, 120 mg, Y = 70%). MS (m/z): 250.2 [MH]+.Preparation 139: 2,5-dimethyl pyrazine-2,5-dicarboxylate

[260] Pyrazine-2,5-dicarboxylic acid (900 mg, 5.35 mmol) was dissolved in MeOH (9 ml) and ~ 1.25 M hydrogen chloride solution in methanol (9 ml) was added. Then, the mixture was heated to 50 °C and stirred at that temperature for 8 h. It was then left under stirring at RT overnight. The day after another 2 mL of ~ 1.25 M HCl in MeOH was added and the mixture was heated to 50 °C and stirred at that temperature for another 1 h. The mixture was cooled to room RT and concentrated under reduced pressure to obtain 2,5-dimethyl pyrazine-2,5-dicarboxylate (p139, 949 mg, y = 90%).MS (m/z): 197.1 [MH]+. Preparation 140: 5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyrazine-2-carboxamide Step a:

[261] 2,5-dimethyl pyrazine-2,5-dicarboxylate (p139, 949 mg, 4.84 mmol) was dissolved in methanol (10 mL) and 1M NaOH (4.84 mL, 4.84 mmol). The resulting suspension was stirred for 1 h at RT, then the organic solvent was evaporated and the aqueous residue was acidified to pH 2 and concentrated to obtain 1.23 g of 5-(methoxycarbonyl)pyrazine-2- acid. carboxylic acid as used in the next step.Step b:

[262] 5-(Methoxycarbonyl)pyrazine-2-carboxylic acid (1.23 g from step a) was dissolved in water (5 ml) and then an aqueous solution of 28% NH4OH (10 ml) was added and left the solution under stirring at room temperature overnight. The solvent was removed under reduced pressure to obtain 845 mg of 5-carbamoylpyrazine-2-carboxylic acid which was used as such in the next step.Step c:

[263] To a stirred solution of 5-carbamoylpyrazine-2-carboxylic acid (845 mg from step b) in DMF (3 ml), 4-methyl-3-thiosemicarbazide (585 mg, 5.56 mmol) was added and DIPEA (1.59 mL, 9.1 mmol) was added subsequently. The mixture was cooled to 0°C and then T3P (50% wt/EA) (4.52 mL, 7.55 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight.

[264] 3M aqueous NaOH solution (resulting pH ~ 8) was added followed by AcOEt and the two resulting phases were separated (the upper organic layer was eliminated). Additional 3M NaOH was added until pH 11, then the mixture was heated to 70 °C and stirred for 40 min. The solution was cooled to RT and 6N HCl was slowly added until pH 5. The product was collected by filtration washing with water and Cy. The solid was dried under high vacuum to obtain 5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyrazine-2-carboxamide (p140, 218 mg, y = 19 %NMR: 1H NMR (DMSO-d6) δ: 9.18-9.26 (m, 2H), 8.35-8.44 (m, 1H), 7.928.05 (m, 1H), 3 .83 (s, 3H) Preparation 141: 1,5-di-tert-butyl 1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate

[265] To a stirred solution of 3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.0 g, 6.13 mmol) TEA (2.4 mL, 15.33 mmol) and DMAP (0.15 g, 1.23 mmol) in DMF (10 mL), Boc2O (2.94 g, 13.49 mmol) was added in portions and the resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with saturated ammonium chloride solution, water, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by FC on a silica cartridge (eluting with Cy/EA from 100/0 to 90/10) to give 1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate of 1,5 -di-tert-butyl (p141, 1.37 g, y = 85%) as a white foam.MS (m/z): 320.2 [MH]+.Preparation 142: 1-benzyl 5- tert-butyl 1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate Step a:

[266] A stirred solution of 1-[(tert-butoxy)carbonyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid (p141, 1.37 g, 5.20 mmol) in MeOH ( 15 mL) at 0°C was treated with CS2CO3 (0.17 g, 0.52 mmol) and stirred at this temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM and saturated NH4Cl solution. The organic phase was dried over sodium sulfate and the solvent was removed under vacuum, obtaining 0.89 g of tert-butyl 1H-imidazo[4,5-b]pyridine-5-carboxylate which was used as such.Step b:

[267] To a stirred solution of tert-butyl 1H-imidazo[4,5-b]pyridine-5-carboxylate (0.89 g from step a) and TEA (0.74 ml, 5.28 mmol) in DCM (10 mL) at 0 °C and under a nitrogen atmosphere, CbzCl (0.61 mL, 4.26 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with saturated ammonium chloride solution, water, dried over sodium sulfate and the solvent removed under vacuum. The crude material was purified by FC on a silica cartridge (eluting with Cy/EA from 100/0 to 35/65) obtaining 1-benzyl 5-tert-butyl 1H-imidazo[4,5- b]pyridine-1 .5 dicarboxylate (p142.0.42 g, y = 23%) as a white foam. MS (m/z): 354.3 [MH]+. Preparation 143: 5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazol-3-thiol Step a:

[268] To a stirred solution of 1-benzyl 5-tert-butyl 1H-imidazo[4,5-b]pyridine-1,5-dicarboxylate (p142, 0.42 g, 1.19 mmol) in DCM (5 mL), at RT, TFA (1.8 mL) was added and the resulting reaction mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure and the residue was taken up with DCM. The solution was passed through a phase separator cartridge and the solution was concentrated under vacuum to obtain 1-[(benzyloxy)carbonyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid (225 mg) as raw product that was used as such in the next step.Step b:

[269] To a stirred solution of 1-[(benzyloxy)carbonyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid (225 mg, from step a) in DMF (0.8 mL), 4-methyl-3-thiosemicarbazide (88 mg, 0.83 mmol) and DIPEA (0.24 mL, 1.37 mmol) were subsequently added. The mixture was cooled to 0°C and then T3P (50% wt/EA) (0.68 mL, 1.14 mmol) was added portionwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight. An aqueous 4 M NaOH solution was added (resulting pH ~ 8) and the two resulting phases were separated (the upper organic layer was eliminated). More 4 M NaOH was added until pH ~ 11, then the mixture was heated to 70 °C and stirred for 1.5 h. The solution was cooled to RT and 37% HCl was added slowly until pH ~ 5. The mixture was stirred for 5 min, then filtered. The solid was washed with water and dried under vacuum at 45°C overnight to give 5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2, 4-triazol-3-thiol (p143, 125 mg, y = 45%) as a pale yellow solid. MS (m/z): 233.2 [MH]+. Preparation 144: 2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl] acetonitrile

[270] To a stirred solution of 4(cyanomethyl) benzoic acid (1 g, 6.2 mmol) in DMF (4 ml) was added, 4-methyl-3-thiosemicarbazide (0.72 g, 6.2 mmol) was added. 82 mmol) and DIPEA (1.95 mL, 11.16 mmol) were subsequently added. The mixture was cooled to 0°C and then T3P (50% wt/EA) (5.36 mL, 9.3 mmol) was added portionwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight. An aqueous 4 M NaOH solution was added (resulting pH ~ 8). The reaction was diluted with EtOAc and the two resulting phases were separated (the upper organic layer was eliminated). Additional 4M NaOH was added until pH ~9, then the mixture was heated to 70 °C and stirred for 6 h. An additional 4 M NaOH was added to adjust the pH ~ 9. The solution was heated at 70 °C for 4 h, then cooled to RT and 6N HCl was slowly added until pH 4 and a precipitate was obtained. The precipitate was filtered and dried to obtain 2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetonitrile (p144, 900 mg, y = 63% ).MS (m/z): 231.2 [MH]+. Preparation 145: 2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetamide

[271] A mixture of 2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetonitrile (p144, 0.75 g, 3.25 mmol) and crushed KOH (0.55 mg, 9.75 mmol) in f-BuOH (10 mL) was heated to 90 °C and stirred for 3 h. After allowing the mixture to reach RT the solvent was decanted. The yellow solid was taken up with water, the pH was brought to 4-5 by adding 6 N HCI and a precipitate was obtained. Filter and dry to obtain 2-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)phenyl]acetamide (p145, 420 mg, y = 80 %MS (m/z): 249.1 [MH]+.Preparation 146: 3-[(2-chloroethyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5 -il)-4H-1,2,4-triazole

[272] To a suspension of 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-thiol (p65, 300 mg, 1. 53 mmol) in a mixture of MeOH/acetone (0.75 ml/1.6 ml) at RT, 1-Bromo-2-chloroethane (165 μL, 1.99 mmol) was added followed by K2CO3 (296 mg, 2 .14 mmol) and the mixture was stirred at RT for 4 h. The mixture was then partitioned between water and EtOAc and the phases were separated. Organic was washed with brine and then dried and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluting from cHex to EtOAc) yielding 3-[(2-chloroethyl)sulfanyl]-4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H -1,2,4-triazole (p146, 237 mg, y = 60%). MS (m/z): 259.1 [MH]+.Preparation 147: (4-chlorobutyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole

[273] To a suspension of 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-thiol (p65, 300mg, 1.53 mmol) in a MeOH/acetone mixture (0.75 mL/1.6 mL) at RT, 1-Bromo-4-chlorobutane (230 μL, 1.99 mmol) was added followed by K2CO3 (296 mg, 2. 14 mmol) and the mixture was stirred at RT for 4 h. Then, it was partitioned between water and EtOAc and the phases were separated. Organic was washed with brine and then dried and concentrated under reduced pressure. Crude material was purified by FC on silica gel (elution of cHex to EtOAc) obtaining (4-chlorobutyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H -1,2,4-triazole (p147, 270 mg, y = 61%). MS (m/z): 287.1 [MH]+. Preparation of 148: 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4 triazole

[274] To a suspension of 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-thiol (p65, 400 mg, 2. 03 mmol) in a MeOH/acetone mixture (1.3 mL/3.2 mL) at RT, 1-Bromo-3-chloropropane (260 μL, 2.64 mmol) was added, followed by K2CO3 (392 mg, 2.84 mmol) and the mixture was stirred at RT for 4.5 h. This was partitioned between water and EtOAc and phases were separated. Organic was washed with brine and then dried and concentrated under reduced pressure. Crude material was purified by FC on silica gel (elution of cHex to EtOAc) obtaining 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazole (p148, 400 mg, y = 65%), as a pale yellow solid. MS (m/z): 273.1 [MH]+.

[275] The following intermediates were prepared in analogy with Preparation 148 by reacting the corresponding previously described or commercially available thiotriazoles with 1-Bromo-3-chloropropane. Preparation 221: 1-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]ethan-1-one

[276] For a stirred solution of 1-acetylpiperidine-4-carboxylic acid (1 g, 5.84 mmol) in DMF (3 mL), 5 4-methyl-3-thiosemicarbazide (676 mg, 6.4 mmol) and DIPEA (1.83 mL, 10.5 mmol) was subsequently added. The mixture was cooled to 0°C and then T3P (50% wt/EA) (5.21 mL, 8.7 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was stirred at RT for 2 h.

[277] 3 M NaOH aqueous solution (resulting pH ~ 8) was added followed by EtOAc and the two resulting phases were separated (the upper organic layer was eliminated). Additional 3M NaOH was added until pH 11, then the mixture was heated to 70 °C and stirred for 40 min. The solution was cooled to RT and 6N HCl was added slowly until pH 5. The mixture was extracted with DCM several times. The aqueous phase was concentrated under reduced pressure and the residue was purified by FC on a C18 cartridge (water eluent + 0.1% HCOOH - > 50% ACN + 0.1% HCOOH), obtaining 1-[4- (4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl] ethan-1-one (p221, 793 mg, y = 56%). MS (m/z): 241.2 [MH]+. Preparation 222: 1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-1-yl)ethan-1-one

[278] To a suspension of 1-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) piperidin-1-yl] ethan-1-one (p221, 793 mg, 3.3 mmol) in a MeOH/Acetone mixture (4 mL/9 mL) at RT was added 1-bromo-3-chloropropane (424 uL, 4.3 mmol) followed by K2CO3 (1.14 g, 8.25 mmol) and the mixture was stirred at room temperature overnight. 1-Bromo-3-chloropropane (230 uL, 2.31 mmol) was added followed by K2CO3 (594 mg, 4.3 mmol) and the mixture was stirred at RT for 2 h.

[279] The mixture was divided between water and DCM and phases were separated. Organic was washed with brine and then dried and concentrated under reduced pressure. The crude material was purified by FC on a silica cartridge (eluent: DCM to DCM/MeOH 9:1) providing 1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H- 1, 2,4-triazol-3-yl}piperidin-1-yl)ethan-1-one (p222, 224 mg, y = 21%).MS (m/z): 317.3 [MH]+. Preparation 223: tert-butyl 4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate

[280] To a stirred solution of 1-Boc-piperidine-4-carboxylic acid (1.0 g, 4.36 mmol) in DMF (3 mL), 4-methyl-3-thiosemicarbazide (0.504 g, 4.8 mmol) and DIPEA (1.37 ml, 7.85 mmol) were subsequently added. The mixture was cooled to 0°C and then T3P (50% wt/EA) (3.9 ml, 6.54 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was stirred at RT for 3 h.

[281] 3 M NaOH aqueous solution (resulting pH ~ 8) was added followed by EtOAc and the two resulting phases were separated (the upper organic layer was eliminated). Additional 4M NaOH was added until pH 11, then the mixture was heated to 70°C and stirred for 40 min. The solution was cooled to RT and 6N HCl was added slowly until pH 5. The product was extracted several times with DCM. The organic phase was washed with brine, filtered and evaporated to obtain tert-butyl 4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (p223 , 1.08 g, y = 83%) as a white solid.MS (m/z): 299.2 [MH]+.Preparation 224: 4-{5-[(3-chloropropyl)sulfanyl] tert-butyl -4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate

[282] To a suspension of tert-butyl 4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) piperidine-1-carboxylate (p223, 1.08 g, 3 .62 mmol) in a MeOH/Acetone mixture (4 mL/9 mL) at RT. Bromo-3-chloropropane (465 uL, 4.7 mmol) was added followed by K2CO3 (700 mg, 5.07 mmol) and the mixture was stirred at room temperature overnight. Then, it was partitioned between water and DCM and the phases were separated. Organic was washed with brine and then dried and concentrated under reduced pressure. The crude material was purified by FC on an NH column (eluent: Cy to Cy/AcOEt 1:1) obtaining 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2, tert-butyl 4-triazol-3-yl}piperidine-1-carboxylate (p224, 1.08 g, y = 79%). MS (m/z): 375.3 [MH]+.3-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)azetidine-1-tert-butyl carboxylate

[283] To a solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (1 g, 4.97 mmol) in DMF (3.5 mL), 4-methyl-3-thiosemicarbazide (0.575 g, 5.47 mmol) was added. DIPEA (1.5 mL, 8.95 mmol) was added at RT, then the mixture was cooled in an ice bath before adding T3P (50% w/w in EtOAc) (4.1 mL, 6.958 mmol) . The reaction was stirred at room temperature overnight. 4M NaOH solution (3 mL) was added (resulting pH =8). The reaction was diluted with EtOAc and water. NaOH 4M sol. (1 mL) and the mixture was stirred until dissolved. The phases were then separated (the upper organic layer was eliminated). Additional 4M NaOH was added until pH 11 (8 mL) and the clear orange solution was heated at 70°C for 1.5 h. The light yellow solution was then cooled to room temperature, then 37% HCl was slowly added until pH 4.5. The milky suspension was extracted with DCM (x4) and the combined organic phases were dried and concentrated. To the residue (containing DMF) a few drops of water were added and a precipitate was formed which was filtered and dried under vacuum to obtain 3-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3 tert-butyl-yl)azetidine-1-carboxylate (p225, 1.09 g, y = 81%) as a white solid.MS (m/z): 271.2 [MH]+.Preparation 226: 3-{ tert-butyl 5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}azetidine-1-carboxylate

[284] To a suspension of tert-butyl 3-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl) azetidine-1-carboxylate (p225, 1.09 g, 4 .02 mmol) in a mixture of MeOH/Acetone (2.2 mL/5.7 mL) at RT, 1-bromo-3-chloropropane (437 uL, 4.42 mmol) K2CO3 (778 mg, 5. 63 mmol) and the mixture was stirred at RT for 5 h. The mixture was filtered by washing with DCM and the filtrate was concentrated in vacuo. The crude product was purified by FC on a silica cartridge (eluent from Cy to EtOAc, then AcOEt to 20% MeOH) to obtain 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H- tert-butyl 2,4-triazol-3-yl}azetidine-1-carboxylate (p226, 1.05 g, y = 72%) as a yellow oil. MS (m/z): 347.0 [MH]+.Preparation 227: Methyl 4-oxocyclohexane-1-carboxylate

[285] To a solution of 4-oxocyclohexane-1-carboxylic acid (840 mg, 5.91 mmol) in methanol (8 mL) was slowly added thionyl chloride (0.51 mL, 7.09 mmol) to TA. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The residue was taken up in DCM and saturated aqueous sodium bicarbonate, the organic phase was washed with water, dried over sodium sulfate and the solvent was removed in vacuo to obtain sodium 4-oxocyclohexane-1-carboxylate. methyl (p227, 840 mg) which was used as crude product in the next step. MS (m/z): 157.1 [MH]+.Preparation 228: Methyl 4-(benzylamino)cyclohexane-1-carboxylate

[286] To a solution of methyl 4-oxocyclohexane-1-carboxylate (p227, 0.84 g, 5.38 mmol) in 1,2-DCE (20 ml) was added benzylamine (0.62 ml , 5.65 mmol) followed by sodium triacetoxyborohydride (1.71 g, 8.07 mmol) in portions and the resulting reaction mixture was stirred at RT. The mixture was diluted with saturated aqueous sodium bicarbonate solution and DCM. The organic phase was washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. The crude material thus obtained was subjected to SCX cartridge purification (eluting with MeOH and 1N NH3/MeOH) obtaining methyl 4-(benzylamino) cyclohexane-1-carboxylate (p228, 1.05 g) which was used as crude. in the next step.MS (m/z): 248.3 [MH]+. Preparation 229: Methyl 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylate Step a:

[287] A mixture of methyl 4-(benzylamino)cyclohexane-1-carboxylate (p228, 1.05 g, 4.25 mmol) and palladium hydroxide on carbon (20% by weight, 0.15 g) in MeOH (25 ml) was hydrogenated at atmospheric pressure for 24 h at RT. Additional palladium hydroxide on carbon (20% by weight, 0.15 g) and the reaction mixture was placed under a hydrogen atmosphere again. After 24 hours, the reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to give methyl 4-aminocyclohexane-1-carboxylate (0.61 g). Step b:

[288] To a stirred solution of methyl 4-aminocyclohexane-1-carboxylate (0.61 g, from step a) in DCM (5 ml), at RT, a solution of BoC2O (0.14 g, 0.64 mmol) in DCM (0.5 ml) was added portionwise and the resulting reaction mixture was stirred at RT. The reaction mixture was concentrated under vacuum and the crude product was purified by FC on a silica cartridge (elution with Cy/EA from 100/0 to 90/10) to give 4-{[(tert-butoxy)carbonyl]amino }cyclohexane-1-carboxylate (p229, 0.24 g, y = 22%). MS (m/z): 258.3 [MH]+.Preparation 230: N-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3 ter-butyl-yl}cyclohexyl)carbamate

[289] To a stirred solution of methyl 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylate (p229, 236 mg, 0.92 mmol) in THF/MeOH/water (2 mL/0 .5 mL/0.3 mL), at RT, LiOH (58 mg, 1.38 mmol) was added and the reaction mixture was heated to 50 ° C and stirred in a PLS apparatus for 3 h. The mixture was concentrated in vacuo, the residue was run with DCM and 0.1N aqueous HCl, the organic phase was dried and the solvent was removed under reduced pressure to obtain 4-{[(tert-butoxy)carbonyl]amino}cyclo -hexane-1-carboxylic acid (225 mg) which was used as crude product in the next step.Step b:

[290] To a stirred solution of 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid (225 mg from step a) in DMF (0.6 mL), 4- methyl-3-thiosemicarbazide (107 mg, 1.02 mmol) and DIPEA (0.29 mL, 1.66 mmol). The mixture was cooled to 0 °C and then T3P (50% wt/EA) (0.83 mL, 1.38 mmol) was added portionwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight. 4M NaOH aqueous solution was added (resulting pH ~ 8) and the two resulting phases were separated (the upper organic layer was eliminated). Additional 4M NaOH was added until pH ~11 and then the mixture was heated to 70 °C and stirred for 40 min. The solution was cooled to RT and 37% HCI was added slowly until pH ~5. The reaction mixture was extracted twice with EA, the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo to yield N tert-butyl-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate (275 mg) which was used as such in the next step.Step c:

[291] A mixture of tert-butyl N-[4-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate (275 mg from step b) and carbonate of potassium (158 mg, 1.14 mmol) in MeOH/Acetone (0.6 mL/1.6 mL), 1-bromo-3-chloropropane (0.096 mL, 0.97 mmol) was added and the mixture resulting from The reaction was stirred at RT in a PLS apparatus overnight. The mixture was diluted with EA and filtered, the solid was washed with EA and the filtrate was concentrated under reduced pressure. The crude material was purified by FC on the NH column (elution with Cy/EA from 100/0 to 55/45) and provided N-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H tert-butyl-1,2,4-triazol-3-yl}cyclohexyl)carbamate (p230, 139 mg, y = 39%). MS (m/z): 389.3 [MH]+. Preparation 231: 3-(ethoxycarbonyl)-2-methylpyridine-N-oxide

[292] To a solution of ethyl 2-methyl-3-pyridinecarboxylate (mL 1.86, 12.1 mmol) in DCM (50 mL) was added mCPBA (4.18 g, 24.2 mmol) at RT. The solution was stirred at RT for 24h. The solution was filtered and concentrated. The residue was purified by FC on a silica cartridge (eluent: DCM to 10% MeOH) to give 3-(ethoxycarbonyl)-2-methylpyridine-N-oxide (p231, 2.23 g, y = quant). MS (m/z): 183.0 [MH]+ Preparation 232: ethyl 6-cyano-2-methylpyridine-3-carboxylate

[293] To a solution of 3-(ethoxycarbonyl)-2-methylpyridine-N-oxide (p231, 2G, 10.92 mmol) in DCM (80 mL), TMSCN (mL 2.05, 16.37 mmol) was added ) followed, after 5 min, by dimethylcarbamyl chloride (mL 1.5, 16.37 mmol). The solution was stirred at RT for 48h. Then 10% K2CO3 was slowly added to make the reaction mixture basic. The organic layer was separated, dried and evaporated to give the crude material, which was purified by FC on a silica cartridge (eluent: Cy to 20% EtOAc) to give ethyl 6-cyano-2-methylpyridine-3-carboxylate (p232 , 1.23 g, y = 59%). MS (m/z): 191.1 [MH]+ Preparation 233: 6-cyano-2-methylpyridine-3-carboxylic acid

[294] A solution of ethyl 6-cyano-2-methylpyridine-3-carboxylate (p232, 1.37 g, 7.2 mmol) in THF (25 mL) and water (10 mL) at room temperature was treated with LiOH H2O (0.453 g, 10.8 mmol), mixed for two hours and concentrated. The concentrate was dissolved in water (10 mL) and adjusted to pH 2 with 1N HCl to provide a precipitate. The precipitate was filtered and washed with cold water. The original liquid was extracted several times with EtOAC, the organic solution was dried and evaporated and added to the previous solid to obtain 6-cyano-2-methylpyridine-3-carboxylic acid (p233, 1.08 g, y= 92%) . MS (m/z): 163.0 [MH]+. Preparations 234 and 235: 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxamide (p234) and 5 -{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxylic acid (p235)

[295] To a solution of 6-cyano-2-methylpyridine-3-carboxylic acid (p234, 1.08 g, 6.66 mmol) in DMF (5 mL), 4-methyl-3-thiosemicarbzide (770 mg, 7 .32 mmol) was added, DIPEA (2.05 mL, 11.99 mmol) was added dropwise at room temperature, and then the mixture was cooled on ice before adding T3P (50% w/w in ETOAc) ( 5.953 mL, 9.99 mmol). The reaction was mixed at room temperature overnight. A NaOH solution was added until pH=8. The reaction was diluted with EtOAc and the two resulting phases were separated (the upper organic layer was eliminated). Additional 4M NaOH was added until pH 11 and the mixture was heated to 70°C for 2.5 hours. Then, the pH was increased to 11 by adding NaOH (pellet) and the reaction was mixed at 70°C for 1 hour. The solution was then cooled to 0°C, so 6N HCl was slowly added until pH 5. A precipitate formed which was filtered under vacuum to obtain a solid containing two products (87% of the derivative carboxylic acid, 12% of the primary amide derivative). It was suspended in a mixture of MeOH/Acetone (5 mL/10 mL) at room temperature, 1-bromo-3-chloropropane (435 μL, 4.4 mmol) was added, followed by K2CO3 (1.32 g, 9.6 mmol) and the mixture was mixed at room temperature overnight. The amide derivative was extracted into the organic phase, which was dried and concentrated under reduced pressure, and the crude material was purified by FC on a silica cartridge (eluent: from Cy to AcOEt), obtaining 5-(5-[ (3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxamide (p234, 37 mg, y=3%).MS (m/ z): 326.1 [MH]+.

[296] The aqueous phase containing the derivative carboxylic acid was dried and provided 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6 -methylpyridine- 2-carboxylic acid (p235, 1 g, y = crude) MS (m/z): 327.2 [MH]+ Preparation 236: 5-{5-[(3-chloropropyl)sulfanyl]-4- methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide Step a

[297] 3,5-dimethyl pyridine-3,5-dicarboxylate (500 mg, 2.56 mmol) was dissolved in methanol (2 mL) and 1M NaOH (2.56 mL, 2.56 mmol) was added slowly. The resulting yellow solution was stirred for 15 minutes at RT, and then organic solvent was evaporated and the aqueous residue was acidified to pH 2 and extracted with DCM (4x). Material detected in the aqueous phase, therefore aqueous and organic phases were combined and concentrated to provide 5-(methoxycarbonyl)pyridine-3-carboxylic acid (561 mg) as a yellow solid. Presence of -10% raw materials and 10% dicarboxylic acid detected. Used as such in the next step.Step b:

[298] 5-(methoxycarbonyl)pyridine-3-carboxylic acid (561 mg from step a) was dissolved in 7M NH3 in MeOH (10 mL, 70 mmol). The resulting pale yellow solution became a suspension and was stirred at room temperature overnight. No traces of the desired compound were detected, therefore the solvent was evaporated under reduced pressure and the residue was treated with 28% aqueous NH4OH solution (10 mL) and the solution was stirred at RT for 3h. The mixture was then concentrated under reduced pressure, providing 5-carbamoylpyridine-3-carboxylic acid (235 mg) which was used as such in the next step.Step c:

[299] To a stirred solution of 5-carbamoylpyridine-3-carboxylic acid (235 mg in step b) in DMF (1.5 mL), 4-methyl-3-thiosemicarbazide (164 mg, 1.56 mmol) and DIPEA (0.444 mL, 2.55 mmol) were added later. The mixture was cooled to 0°C, then T3P (50% wt/EA) (1.26 mL, 2.1 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight.

[300] 3M NaOH aqueous solution was added (resulting pH ~ 8) followed by AcOEt and the two resulting phases were separated (the upper organic layer was eliminated). Additional 3M NaOH was added until pH 11 and then the mixture was heated to 70°C and stirred for 40 min. The solution was cooled to RT and 6N HCl was added slowly until pH 5. No precipitate was observed. The aqueous solution was then concentrated under reduced pressure, affording 5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carboxamide (705 mg) used as crude in the next step.Step d:

[301] To a suspension of 5-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)pyridine-3-carboxamide (705 mg) in a MeOH/acetone mixture (4 mL/9 mL) at RT was added 1-bromo-3-chloropropane (182 uL, 1.84 mmol) followed by K2CO3 (488 mg, 3.53 mmol) and the mixture was stirred at room temperature overnight. This was then divided between water and DCM and the phases were separated. The organic phase was washed with brine and then dried and concentrated under reduced pressure. The crude material was purified by FC on a silica cartridge (eluent: DCM in DCM/MeOH 9:1) to obtain 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2, 4-triazol-3-yl}pyridine-3-carboxamide (P236, 73 mg, y = 9%).MS (m/z): 312.2 [MH]+.Preparation 237: 3-[(2.2 -dimethoxyethyl)carbamoyl]methylbenzoate

[302] A mixture of 3-(methoxycarbonyl)benzoic acid (500 mg, 2.77 mmol), 1-hydroxybenzotriazole hydrate (397 mg, 2.94 mmol), N-(3-dimethylaminopropyl)-N' hydrochloride -ethylcarbodiimide (564 mg, 2.94 mmol) and TEA (1.16 ml, 8.31 mmol) in DCM (15 ml) was stirred at 0°C for 10 min, and then 2,2-dimethoxyethane was added -1-amine (0.301 ml, 2.77 mmol) and the mixture was stirred at room temperature overnight. It was washed with NaHCO3 (x1), NH4CI (X3) and brine, the organic phase was separated, dried and concentrated under reduced pressure to obtain methyl 3-[(2,2-dimethoxyethyl)carbamoyl]benzoate (P237, 548 mg , y = 74%) which was used as such in the next step. MS (m/z): 268.2 [MH]+. Preparation 238: Methyl 3-(1,3-oxazol-2-yl)benzoate Step a:

[303] To a solution of methyl 3-[(2,2-dimethoxyethyl)carbamoyl]benzoate (P237, 548 mg, 2.05 mmol) in THF (4 ml), HCl was added 6N (1 ml) and the mixture was stirred at RT for 1.5 h. Then, the mixture was partitioned between brine and EtOAc and the organic layer was dried, filtered and concentrated, resulting in methyl 3-[(2-oxoethyl)carbamoyl]benzoate (426 mg). Used as such in the next step.Step b:

[304] To a solution of PPh3 (1 g, 3.85 mmol) in DCM (35 mL) at RT, iodine (977 mg, 3.85 mmol) was added followed by a solution of 3-[(2- methyl oxoethyl)carbamoyl]benzoate (426 mg from step a) in DCM (4 ml) and the mixture was stirred at RT for 48h. The mixture was washed with sodium thiosulfate solution and water. The organic layer was then dried and concentrated under reduced pressure. The crude product was purified by FC on silica gel (eluent: Cy to AcOEt) to obtain methyl 3-(1,3-oxazol-2-yl)benzoate (P238, 137.6 mg, y = 33%) .MS (m/z): 204.1 [MH]+. Preparation 239: 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole Step a:

[305] Methyl 3-(1,3-oxazol-2-yl)benzoate (P238, 137.6 mg, 0.68 mmol) was dissolved in MeOH (2 ml) and 1 M NaOH (0 .68 ml, 1.08 mmol). The resulting yellow solution was stirred for 30 minutes at RT, and then organic solvent was evaporated and the aqueous residue was acidified to pH 2 and extracted with DCM. The organic phase was dried and concentrated to give 148 mg of 3-(1,3-oxazol-2-yl)benzoic acid which was used as such in the next step.Step b:

[306] To a stirred solution of 3-(1,3-oxazol-2-yl) benzoic acid (148 mg from step a) in DMF (0.5 ml), 4-methyl-3-thiosemicarbazide was subsequently added (79 mg, 0.75 mmol) and DIPEA (0.213 mL, 1.22 mmol). The mixture was cooled to 0 °C and then T3P (50 wt%/EA) (0.61 mL, 1.02 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was stirred at room temperature overnight.

[307] 3M NaOH aqueous solution was added (resulting pH ~ 8) followed by AcOEt and the two resulting phases were separated (the upper organic layer was eliminated). Additional 3M NaOH was added until pH 11 and then the mixture was heated to 70°C and stirred for 40 min. The solution was cooled to RT and 6N HCl was added slowly until pH 5. The precipitate was filtered and washed with water and Cy, then collected and dried under high vacuum, resulting in 4-methyl-5-[3-(1, 3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-thiol (67.6 mg).Step c:

[308] To a suspension of 4-methyl-5-[3-(1,3-oxazol-2-yl) phenyl]-4H-1,2,4-triazol-3-thiol (67.6 mg of step b) in a MeOH/acetone mixture (1 mL/2.25 mL) at RT was added 1-bromo-3-chloropropane (34 uL, 0.34 mmol) followed by K2CO3 (90 mg, 0.65 mmol) and the mixture was stirred at room temperature overnight. It was then divided between water and DCM and the phases were separated. The organic phase was washed with brine and then dried and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluent: Cy to Cy/AcOEt 100%) to obtain 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[3-(1,3 -oxazol-yl)phenyl]-4H-1,2,4-triazole (P239, 44.3 mg, y = 19%).MS (m/z): 259.2 [MH]+. Preparation 240: 1-chloro-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propane -2-ol

[309] To a suspension of 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-thiol (P65, 100 mg, 0. 51 mmol) in a mixture of MeOH/acetone (0.33 mL/0.82 mL) at RT, 1-bromo-3-chloropropan-2-ol (64 uL, 0.663 mmol) was added, followed by K2CO3 (99 mg, 0.714 mmol) and the mixture was stirred at room temperature overnight. The mixture was divided between water and DCM and the phases were separated. The organic phase was dried and concentrated under reduced pressure to obtain 1-chloro-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4 - triazol-3-yl]sulfanyl}propan-2-ol (P240, 117 mg, y = 69%) in the form of a yellow solid which was used as such in the next step. MS (m/z): 289.1 [MH]+ Preparation 241: oxane-4-carbohydrazide

[310] To a stirred solution of methyl tetrahydro-2H-pyran-4-carboxylate (4 g, 27.75 mmol) in MeOH (50 mL) at RT was added hydrazine monohydrate (10.8 mL, 222 mmol) in portions and the resulting reaction mixture was stirred at reflux overnight. The mixture was allowed to reach RT and concentrated in vacuo to give the title compound oxane-4-carbohydrazide (P241, 3.9 g, y = 98%) as a white solid. MS (m/z): 145.1 [MH]+.Preparation 242: ({[(tert-butoxycarbonyl]amino}amino)(4-methyl-1,3-oxazol-5-yl)methanone

[311] To a stirred suspension of 1.0 g (7.87 mmol) of 4-methyl-1,3-oxazol-5-carboxylic acid in 10 ml of DCM at RT was added oxalyl chloride (1.5 ml , 11.81 mmol) in portions, followed 3 min later by a catalytic amount of DMF (4 drops). The resulting reaction mixture was stirred at RT for 2h; then, the clear mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 ml) and this solution was added dropwise to a stirred solution of tert-butyl carbazate (3.64 g, 27.55 mmol) and TEA (4.1 ml, 11.02 mmol) in DCM (10 ml) at 0 °C and in a nitrogen atmosphere. The resulting reaction mixture was stirred at 0° C. for 3 hours, then allowed to reach room temperature and then stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in EA and water. The organic phase was washed with water, saturated ammonium chloride solution, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by FC on a silica cartridge (elution with Cy/EA from 100/0 to 40/60) to give ({[(tert-butoxy)carbonyl]amino}amino)(4-methyl-1 ,3-oxazol-5-yl)methanone (P242, 2.45 g, y = quant.) in the form of a white waxy solid. MS (m/z): 242.2 [MH]+ Preparation 243: 4- methyl-1,3-oxazole-5-carbohydrazide

[312] To a stirred solution of ({[(tert-butoxy)carbonyl]amino}amino)(4-methyl-1,3-oxazol-5-yl)methanone (P242, 1.23 g, 5.1 mmol ) in dioxane (5 ml) at RT, 4N/dioxane HCL (26 ml, 104 mmol) was added in portions and the resulting mixture was stirred at RT for 3h. The mixture was filtered and the solid was dried under vacuum overnight and subsequently loaded onto an SCX cartridge (elution with MeOH and 2N NH3/MeOH) to obtain 4-methyl-1,3-oxazol-5-carbohydrazide (P243, 366 mg, y = 51%) as a light yellow solid.NMR: 1H NMR (DMSO-d6) δ: 9.68 (br. s., 1H), 8.38 (s., 1H), 4.47 (br. s., 2H), 2.37 (s, 3H) Preparation 244: methyl hex-5-enecarboximidate hydrochloride

[313] In a stirred solution of 5-hexenenitrile (2 g, 21.02 mmol) and MeOH (0.96 ml) in Et2O (20 mL), at 0 ° C, gaseous HCl was bubbled for 10 min. The reaction mixture was concentrated under vacuum and the brown oil was taken up with Et2O. The solid was filtered, washed with ether and dried under vacuum to obtain methyl hex-5-enecarboximidate hydrochloride (P244, 1.20 g, y = 42%) as a white solid which was used as such in next step.NMR: 1H NMR (DMSO-d6) δ: 11.34-11.86 (m, 1H), 5.68-5.89 (m, 1H), 4.93-5.11 (m, 2H), 3.98-4.14 (m, 3H), 2.56-2.69 (m, 2H), 2.00-2.13 (m, 2H), 1.62-1.78 ( m, 2H) Preparation 245: N,N'-dimethylhexa-5-enimidamide hydrochloride

[314] To a stirred solution of methyl hex-5-enecarboximidate hydrochloride (P244, 1.29 g, 7.88 mmol) in MeOH (6 Ml) at RT was added a 33 wt% solution of MeNH2 in ethanol (5.9 mL, 47.28 mmol) and the resulting reaction mixture was stirred at reflux for 6 h and at room temperature overnight. The mixture was then concentrated in vacuo to provide crude N,N'-dimethylhexa-5-enimidamide hydrochloride (P245, 1.47 g) as a pale brown oil which was used as such in the next step. MS (m/z): 141.1 [MH]+. Preparation 246: 4-methyl-3-(oxan-4-yl)-5-(pent-4-en-1-yl)-4H-1, 2,4-triazole

[315] A suspension of N,N'-dimethylhexa-5-enimidamide hydrochloride (P245, 1.47 g, 8.32 mmol), oxane-4-carbohydrazide (P241, 1.20 g, 8.32 ) and K2CO3 (1.15 g, 8.32 mmol) in MeOH (50 ml) was heated to reflux and stirred for 24h. The mixture was then filtered and the organic solution was concentrated in vacuo. The crude material was purified by FC on a silica cartridge (10% MeOH DCM elution) to produce two batches of the title compound 4-methyl-3-(oxan-4-yl)-5-(pent-4 -en-1-yl)-4H-1,2,4-triazole (P246, lot 1: 0.20 g, purity >80% by NMR and lot 2: 0.75 g, purity <70% by NMR) .NMR: 1H NMR (CDCI3) δ: 5.74-5.91 (m, 1H), 4.94-5.12 (m, 2H), 3.99-4.17 (m, 2H), 3.53-3.61 (m, 2H), 3.52 (s, 3H), 2.87-2.96 (m, 1H), 2.70-2.77 (m, 2H), 2.05-2.25 (m, 4H), 1.83-2.02 (m, 3H) Preparation 247: 4-[4-methyl-5- (oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal

[316] A slow flow of O3 in O2 was passed through a solution of 4-methyl-3-(oxan-4-yl)-5-(pent-4-en-1-yl)-4H-1,2 ,4-triazole (p246, 203 mg, 0.86 mmol) in DCM (10 mL) cooled to -78 °C until a pale blue color persists (40 min). Excess O3 was purged by bubbling N2 and then a solution of PPh3 (248 mg, 0.946 mmol) in DCM (2 ml) was added. The solution was allowed to reach 25°C and stirred for 2h. The solvent was removed under vacuum and the crude material was purified by FC on a silica cartridge (elution of DCM in MeOH), to obtain 4-[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]butanal (P247, 100 mg, 60% pure) in the form of a colorless oil which was used as such in the next step.NMR: 1H NMR (Acetone-dβ) δ: 9.76 (m, 1H), 3.89-4.03 (m, 2H), 3.58-3.65 (m, 3H), 3.44-3.56 (m, 2H), 3.01-3 .12 (m, 2H), 2.75 (s, 2H), 2.60-2.66 (m, 1H), 2.29-2.39 (m, 1H), 1.76-1.98 (m, 5H) Preparation 248: 4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2, 4-triazole

[317] A mixture of N,N'-dimethylhexa-5-enimidamide hydrochloride (P245, 458 mg, 2.59 mmol), 4-methyl-1,3-oxazol-5-carbohydrazide (P243, 366 mg , 2.59 mmol) and K2CO3 (537 mg, 3.89 mmol) in MeOH (20 ml) was refluxed for 32 hours. The mixture was then allowed to reach RT, concentrated under reduced pressure and the residue was taken up in DCM and concentrated aqueous sodium bicarbonate solution. The organic phase was washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The crude material was purified by FC on a silica cartridge (elution with DCM/MeOH from 100/0 to 96/4) and then purified by FC on an NH column (elution with Cy/EA from 100/0 to 65/35) to provide 4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4-triazole (P248, 107 mg, y = 18%) as a pale yellow waxy solid. MS (m/z): 233.2 [MH]+. Example 1: (1 S.3S/1 R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2, 4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, (TRANS, E1)

[318] (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4]heptane (TRANS, p13, 23 mg, 0.096 mmol), 3-[(3-chloropropyl )sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p146, 25 mg, 0.096 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) were dissolved in DMF (0.2 mL) and heated at 60 °C overnight. The mixture was diluted with water and EtOAc and extracted several times with EtOAc. The organic phase was washed with brine, dried and evaporated. The residue was purified by FC on silica gel (elution of DCM 5% MeOH) to provide (1S,3S/1R,3R)-5-(2-{[4-methyl-5-(4-methyl- 1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (E1.23 mg, y = 51%) in the form of a yellow foam.NMR: 1H NMR (Acetone-dβ) δ: 8.27 (s, 1H), 7.62 (d, 2H) 7.34 (d, 2H), 3.81 (s, 2H), 3.39 (m, 2H), 2.87 (m, 2H), 2.75-2.83 (m, 3H), 2.61-2.73 (m, 3H), 2.43 (s, 2H), 2.21-2.29 (m , 1H), 1.61-1.70 (m, 1H), 1.44 (s, 1H), 1.26 (m, 1H), 1.17-1.23 (m, 1H) MS (m/z): 464.3 [MH]+. Example 2 and Example 3: (1R,3R or 1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (E2, Enantiomer 1) and (1S,3S or 1R,3R) -5-(2-{[4-methyl- 5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}ethyl)- 1-[4-5(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (E3, Enantiomer 2)

[319] (1S.3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E1, 23mg) was separated into the individual enantiomers by chiral preparative HPCL. Each Enantiomer was treated with 1N HCI in Et2O (1.1 eq) and evaporated, resulting in (1 R,3R or 1S,3S)-5-(2-{[4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfaniyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride ( E2, 5.2 15 mg) Enantiomer 1: retention time 11.7 min, 100% ee MS (m/z): 464.3 [MH]+. (1S,3S or 1 R,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E3, 6 mg) Enantiomer 2: retention time 13.1 min, 97.2% ee MS (m/z): 464.3 [MH]+ Example 4: (1 R.3S/1 S,3R)-5-(2-{[4-methyl-5-(4-methyl-1, 3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, (CIS, E4)

[320] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 50 mg , 0.195 mmol), 3-[(3-chloroethyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole(p146, 57 mg, 0.22 mmol), Na2CO3 (23 mg, 0.22 mmol) and Nal (33 mg, 0.22 mmol) in DMF (0.2 mL) resulting in (1R,3S/1S,3R)-5- (2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E4, 20.5 mg, y= 22%) in the form of a pale yellow foam. NMR: 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.54 (d, 2H), 7.14-7.23 (m, 2H), 3.68 (s, 3H), 3.28-3.44 (m, 2H), 2.85 ( s, 3H), 2.68-2.76 (m, 1H), 2.51-2.57 (m, 3H), 2.43-2.50 (m, 1H), 2.19-2.25 (m, 1H), 2.11-2.18 (m, 1H), 1.94-2.05 (m, 2H), 1.151.24 (m, 2H) MS (m/z): 464.3 [MH]+ Example 5 (1 R.3S/1 S,3R)-5-(2- {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl )phenyl]-5- azaspiro[2.4]heptane hydrochloride (CIS, E5)

[321] (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E4, 20.5 mg) was dissolved in Et2O and treated with 1.1 eq of 1N HCI in Et2O resulting , after evaporation, in (1R,3S/1S,3R)-5-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2, 4-triazol-3-yl]sulfanyl}ethyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E5, 22.5 mg) as an off-white solid. MS (m/z): 464.3 [MH]+. Example 6: (1 R.3S/1 S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2, 4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane, (CIS, E6)

[322] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 50 mg , 0.2 mmol), 4-[(chlorobutyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p147, 63 mg, 0.22 mmol), Na2CO3 (23 mg, 0.22 mmol) and Nal (33 mg, 0.22 mmol) in DMF (0.2 mL) resulting in (1R,3S/1S,3R)-5- (4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E6, 14.5 mg, y= 15%) in the form of a pale yellow foam. NMR: 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.55 (d, 2H), 7.22 (d, 2H), 3.65-3.74 (m, 3H), 3.20-3.33 (m, 2H), 2.94 ( br. s, 1H), 2.70 (br. s, 1H), 2.54 (s, 6H), 2.142.27 (m, 2H), 2.05 (d, 2H), 1.82 (m, 3H), 1.19-1.32 ( m, 3H) MS (m/z): 492.3 [MH]+ Example 7 (1 R.3S/1 S,3R)-5-(4-{[4-methyl-5-(4-methyl- 1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (CIS, E7)

[323] (1 R,3S/1 S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2, 4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E6, 14.5 mg) was dissolved in Et2O and treated with 1.1 eq of 1N HCl in Et2O resulting, after evaporation, in (1R,3S/1S,3R)-5-(4-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}butyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E7, 13.5 mg) as a solid white.MS (m/z): 492.3 [MH]+. Example 8: (1 S,3S/1 R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2, 4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E8)

[324] The compound was prepared as in Example 1, by reaction of (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13, 47 mg , 0.195 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole (p148, 58 mg, 0.21 mmol), Na2CO3 (22 mg, 0.21 mmol) and Nal (31 mg, 0.21 mmol) in DMF (0.2 mL) resulting in (1 S,3S/1R,3R)-5-( 3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E8, 35 mg, y= 37%) in the form of a pale yellow foam. NMR: 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.54 (d, 2H), 7.23 (br. S., 2H), 3.73 (m, 2H), 2.59-2.94 (m, 5H), 2.55 (s, 3H), 1.97-2.31 (m, 3H), 1.63 (br. S., 4H), 1.25-1.36 (m, 1H), 1.11-1.19 (m, 1H)MS (m/z ): 478.3 [MH]+ Example 9 and Example 10: (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E9, Enantiomer 1) and (1S,3S or 1 R,3R)- 5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1 - [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E10,Enantiomer 2)

[325] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS) (E8, 31 mg) was separated into individual enantiomers by preparative chiral HPLC.

[326] Each Enantiomer was treated with 1N HCI in Et2O (1.2 eq) and or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol- 5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E9, 8.3 mg) Enantiomer 1: retention time 8.5 min, 100% ee MS (m/z): 478.3 [MH]+.

[327] (1S,3S or 1 R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E10, 12.9 mg) Enantiomer 2: retention time 10.9 min , 100% ee MS (m/z): 478.3 [MH]+ Example 11: (1 R.3S/1 S,3R)-5-(3-{[4-methyl-5-(4-methyl -1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane ( CIS, E11)

[328] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 47 mg , 0.195 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 58 mg, 0.21 mmol), Na2CO3 (22 mg, 0.21 mmol) and Nal (31 mg, 0.21 mmol) in DMF (0.2 mL), obtaining (1R,3S/1S,3R )-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E11, 29 mg, y=31%) as a yellow oil.NMR: 1H NMR (Acetone-dβ) δ : 8.28 (s, 1H), 7.63 (d, 2H0, 7.40 (d, 2H), 3.77 (s, 3H), 3.16-3-36 (m, 2H), 2.46-2.69 (m, 5H), 2.44 ( s, 3H), 2.22-2.30 (m, 1H), 1.79-2.03 (m, 5H), 1.26-1.35 (m, 1H), 1.19-1.26 (m, 1H) MS (m/z): 478.3 [MH]+ Example 12 and Example 13: (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane hydrochloride (E12, Enantiomer 1) and (1S,3R)-5- (3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4 - (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E13, Enantiomer 2)

[329] (1R.3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E11, 26 mg) was separated into individual Enantiomers by preparative chiral HPLC.

[330] Each Enantiomer was treated with 1N HCI in Et2O (1.1 eq) and evaporated, resulting in (1 R,3S)-5-(3-{[4-methyl-5-(4-methyl-1, 3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E12 , 3.1 mg) Enantiomer 1: retention time 7.3 min, 100% ee MS (m/z): 478.3 [MH]+.

[331] (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E13, 4.5 mg) Enantiomer 2: retention time 9.7 min, 100% ee MS (m/z): 478.3 [MH]+ Example 14: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol- 5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (TRANS, E14)

[332] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-phenyl-5-azaspiro[2.4]heptane (TRANS, p18, 77 mg, 0.44 mmol), 3- [(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 120 mg, 0.44 mmol ), Na2CO3 (56 mg, 0.53 mmol) and Nal (79 mg, 0.53 mmol) in DMF (0.360 mL) to give (1 S,3S/1 R,3R)-5-(3-{[ 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4 ]heptane (TRANS, E14, 20.5 mg, y= 11%). NMR: 1H NMR (Acetone-d6) δ: 8.26 (s, 1H), 7.09-7.33 (m, 5H), 3.78 (s, 3H), 3.27-3.36 (m, 2H), 2.47-2.76 (m, 6H ), 2.41 (s, 3H), 2.09-2.15 (m, 1H), 1.87-2.00 (m, 2H), 1.37-1.65 (m, 2H), 1.04-1.17 (m, 2H) MS (m/z) : 410.3 [MH]+.Example 15 and Example 16: (1R,3R or 1S, 3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E15, Enantiomer 1) and (1S,3S or 1R, 3R) -5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -phenyl-5-azaspiro[2.4]heptane (E15, Enantiomer 1) and (1S,3S or 1R, 3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazole -5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E16, Enantiomer 2) (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2,4]heptane (TRANS) (E14, 15 mg) was separated into individual enantiomers by preparative chiral HPLC.

[333] (1R,3R or 1S, 3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E15, 5 mg) Enantiomer 1: retention time 10.5 min MS (m/z): 410.4 [ MH]+

[334] (1S,3S or 1R, 3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E16, 5 mg) Enantiomer 2: ret. time. 12.1 min MS (m/z): 410.4 [MH]+ Example 17: (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(4-methyl -1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS, E17)

[335] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (CIS, p19, 42 mg, 0.24 mmol), 3- [(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 65 mg, 0.24 mmol ), Na2CO3 (31 mg, 0.29 mmol) and Nal (43 mg, 0.29 mmol) in DMF (0.2 mL) to provide (1R,3S/1S,3R)-5-(3-{[ 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4 ]heptane (CIS, E17, 22.5 mg, y= 23%). NMR: 1H NMR (Acetone-dβ) δ: 8.26 (s, 1H), 7.09-7.33 (m, 5H), 3.78(s,3H) 3.27- 3.36 (m, 2H), 247-2.76 (m, 6H) , 2.41 (s, 3H), 2.09-2.15 (m, 1H), 1.87-2.00 (m, 2H), 1.37-1.65 (m, 2H), 1.04-1.17 (m, 2H) MS (m/z): 410.3 [MH]+.Example 18 and Example 19: (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E18, Enantiomer 1) and (1R,3S)-5-(3-{[4 -methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4] heptane (E19, Enantiomer 2)

[336] (1 R.3S/1 S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2, 4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS) (E17, 17 mg) was separated into individual enantiomers by preparative chiral HPLC.

[337] (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E18, 6.6 mg) Enantiomer 1: retention time 7.9 min, 100% ee MS (m/z): 410.3 [MH]+.

[338] (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E19, 6.6 mg) Enantiomer 2: retention time 9.3 min, 95.8% ee MS (m/z): 410 .3 [MH]+ Example 20: (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane hydrochloride (E20, Enantiomer 2)

[339] (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (Enantiomer 2, E19, 27 mg) was treated with 1.1 eq of HCI in Et2O, resulting in (1R,3S)-5- salt (3-{[4-methyl- 5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl- 5- azaspiro[2.4]heptane hydrochloride (Enantiomer 2, E20, 29 mg).MS (m/z): 410.4 [MH]+ Example 21: (1 R,3S/1 S,3R)-1 - [2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E21)

[340] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p22, 50 mg, 0.193 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole ( p148, 58 mg, 0.212 mmol), Na2CO3 (25 mg, 0.23 mmol) and Nal (35 mg, 0.23 mmol) in DMF (0.2 mL), to give (1R,3S/1S,3R)-1- [2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E21, 59 mg, y= 62%).NMR: 1H NMR (Acetone-dβ) δ: 8.27 (s, 1H), 7.49 (m, 2H), 7.29-7.37 (m, 1H), 3.80 (s, 3H), 3.32-3.38 (m, 2H), 2.47-3.12 (m, 6H), 2.47-3.12 (m, 6H), 2.42 (s, 3H), 2.35 (m, 1H), 1.69 (br. Ss., 1H), 1.42 (br. S., 1 H), 1.28-1.39 (m, 3H) MS (m/z): 496.3 [MH]+.Example 22 and Example 23: (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl- 5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E22, TRANS, Enantiomer 1) and (1 R,3S or 1 S,3R)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl- 1, 3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E23, TRANS, Enantiomer 2)

[341] (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS) (E21, 57 mg) was separated into individual enantiomers by HPLC preparative chiral.

[342] (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E22, 19.4 mg) Enantiomer 1: ret. time. 7.7 min, 100% ee MS (m/z): 496.3 [MH]+.

[343] (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E23, 19.7 mg) Enantiomer 2: retention time 9.3 min, 98.6% ee MS (m/z): 496.3 [MH]+.Example 24: (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]- 5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane hydrochloride (E24, TRANS, Enantiomer 1)

[344] (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 1, E22, 19.4 mg) was treated with 1.1 eq of HCI in Et2O, resulting in (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl) salt -1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (Enantiomer 1, E24, 18 mg). MS (m/z): 496.3 [MH]+ Example 25: (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4 -methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride ( E25, TRANS, Enantiomer 2)

[345] (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 2, E23, 19.4 mg) was treated with 1.1 eq of HCl in Et2O, resulting in (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3 - oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (Enantiomer 2, E25, 18 mg).MS (m /z): 496.3 [MH]+ Example 26: (1S,3S/1 R,3R)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl -5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E26)

[346] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p23, 50 mg, 0.193 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazole ( p148, 58 mg, 0.212 mmol), Na2CO3 (25 mg, 0.23 mmol) and Nal (35 mg, 0.23 mmol) in DMF (0.2 mL), resulting in (1S,3S/1R,3R) -1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E26, 39 15 mg, y=41%).

[347] NMR: 1H NMR (Acetone-d6) δ: 8.27 (s, 1H), 7.49 (d, 2H), 7.38 (s, 1H), 3.76 (m, 3H), 3.20-3.35 (m, 2H) , 2.87-3.19 (m, 3H), 2.42 (s, 3H), 2.33-2.39 (m, 1H), 2.10-2.19 (m, 1H), 1.92-2.02 (m, 2H), 1.42-1.50 (m, 1H), 1.27-1.36 (m, 2H) MS (m/z): 496.3 [MH]+ Example 27 and Example 28: (1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl ]-5- (3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5- azaspiro[2.4]heptane (E27, CIS, Enantiomer 1) and (1S, 3S)-1-[2-fluoro-4- (trifluoromethyl)phenyl]-5-(3-{[4-methyl-5- (4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E28, CIS, Enantiomer 2)

[348] (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E26, 37 mg) was separated into individual enantiomers by chiral HPLC preparative.

[349] (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E27, 14 mg) Enantiomer 1: retention time 7.6 min, 100 % ee MS (m/z): 496.3 [MH]+

[350] (1S,3S)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E28, 13.8 mg) Enantiomer 2: retention time8.8 min, 94, 6% ee MS (m/z): 496.3 [MH]+ Example 29: (1R,3R)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4- methyl-5-(4-methyl-1,2,4-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E29, CIS, Enantiomer 1)

[351] (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E27, 14 mg) was treated with 1.2 eq of HCl in Et2O, resulting in ( 1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H -1,2,4-triazol-3- yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (Enantiomer 1, CIS, E29, 11 mg).MS (m/z): 496.3 [MH]+ Example 30: (1S,3S)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,2 ,4-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E30, CIS, Enantiomer 2)

[352] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E28, 13.8 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (Enantiomer 2, CIS, E30, 11 mg). MS (m/z): 496.3 [MH]+. Example 31: (1R,3S/1 S,3R)-1 -(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E31)

[353] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (TRANS, p28, 0.24 mmol) , 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 71 mg, 0 .26 mmol), Na2CO3 (31 mg, 0.29 mmol) and Nal (43 mg, 0.29 mmol) in DMF (0.2 mL), resulting in (1R,3S/1S,3R)-1-(2,4- difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -5-azaspiro[2.4]heptane (TRANS, E31.45 mg, y= 42%).

[354] NMR: 1H NMR (Acetone-d6) δ: 8.26-8.29 (m, 1H), 7.06-7.17 (m, 1H), 6.93-7.05 (m, 2H), 3.81 (s, 3H), 3.33 ( s, 2H), 2.52-2.74 (m, 6H), 2.44 (s, 3H), 2.12-2.19 (m, 1H), 1.93-2.02 (m, 2H), 1.54 (d, 1H), 1.29-1.40 ( m, 1H), 1.17-1.24 (m, 1H), 1.1-1.16 (m, 1H) MS (m/z): 446.4 [MH]+ Example 32 and Example 33: (1R,3S or 1S,3R )-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (E32, TRANS, Enantiomer 1) and (1S,3R or 1R,3S)-1- (2,4-difluorophenyl)-5-(3 -{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4] heptane (E33, TRANS, Enantiomer 2)

[355] (1R,3S/1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E31.45 mg) was separated into individual enantiomers by preparative chiral HPLC.

[356] (1R,3S or 1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E32, 10.8 mg) Enantiomer 1: retention time 11.5 min, 100 % ee MS (m/z): 446.4 [MH]+.

[357] (1S,3R or 1R,3S)-1-(2,4-dfluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E33, 14.6 mg) Enantiomer 2: retention time 15.5 min, 100% ee MS (m/z): 446.4 [MH]+ Example 34: (1R,3S or 1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5 -(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (E34, TRANS, Enantiomer 1 )

[358] (1R,3S or 1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS,E32, 10.8 mg) was treated with 1.1 eq of HCl in Et2O, resulting in (1R ,3S or 1S,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (TRANS, Enantiomer 1, E34, 11 mg). MS (m/z): 446.5 [MH]+. Example 35: (1S,3R or 1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E35, TRANS, Enantiomer 2)

[359] (1S,3R or 1R, 3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (TRANS,E33, 14.6 mg) was treated with 1.1 eq of HCl in Et2O, obtaining (1S,3R or 1R,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane hydrochloride salt (TRANS, Enantiomer 2, E35, 14.6 mg).MS ( m/z): 446.5 [MH]+ Example 36: (1S,3S/1 R,3R)-1 -(2,4-difluorophenyl)-5-(3-{[4-methyl-5-( 4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E36)

[360] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2.4]heptane (CIS, p29, 50 mg, 0.24 mmol ), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 71 mg, 0.26 mmol), Na2CO3 (31 mg, 0.29 mmol) and Nal (43 mg, 0.29 mmol) in DMF (0.2 mL), resulting in (1S,3S/1R,3R)-1-(2,4-difluorophenyl)- 5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (CIS, E36, 52 mg, y= 49%). NMR: 1H NMR (Acetone-d6) δ: 8.28 (s, 1H), 7.09-7.19 (m, 1H), 6.88-7.04 (m, 2H), 3.77 (s, 5H), 3.19-3.31 (m, 2H ), 2.73-2.78 (m, 1H), 2.57-2.65 (m, 1H), 2.46-2.55 (m, 2H), 2.43 (s, 3H), 2.34-2.39 (m, 1H), 2.09-2.14 (m , 1H), 1.93-2.01 (m, 3H), 1.84 (m, 2H), 1.18-1.25 (m, 1H), 1.11-1.16 (m, 1H) MS (m/z): 446.4 [MH] +. Example 37 and Example 38: (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (E37, CIS, Enantiomer 1) and (1S,3S)-1-(2,4- difluorophenyl )-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2.4]heptane (E38, CIS, Enantiomer 2)

[361] (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS) (E36, 50 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC) .

[362] (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E37, 14.4 mg) Enantiomer 1: retention time 14.1 min, 100% ee MS (m/ z): 446.4 [MH]+.

[363] (1S,3S)-1 -(2,4-dfluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H -1,2,4-triazol-3yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E38, 17.1 mg) Enantiomer 2: retention time 18.5 min, 98.8% ee MS (m /z): 446.4 [MH]+ Example 39: (1 S,3S)-1 -(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E39, CIS, Enantiomer 2)

[364] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E38, 17.1 mg) was treated with 1.1 eq of HCl in Et2O, resulting in (1S,3S)-1-(2,4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[ 2.4]heptane hydrochloric salt (CIS, Enantiomer 2, E39, 18 mg). MS (m/z): 446.4 [MH]+. Example 40: (1S,3S/1 R,3R)-1 -(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E40)

[365] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (TRANS, p32, 50 mg, 0.26 mmol ), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 79 mg, 0.29 mmol), Na2CO3 (31 mg, 0.29 mmol) and Nal (43 mg, 0.29 mmol) in DMF (0.2 mL), to give (1S,3S/1R,3R)-1-(4- fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -5-azaspiro[2.4]heptane (TRANS, E40, 42 mg, y= 38%). NMR: 1H NMR (Acetone-d6) δ: 8.25-8.31 (m, 1H), 7.11-7.21 (m, 2H), 7.007.11 (m, 2H), 3.80 (s, 3H), 3.29-3.37 (m , 2H), 2.66-2.75 (m, 1H), 2.50-2.66 (m, 5H), 2.44 (s,3H), 2.10-2.17 (m, 1H), 1.90-2.02 (m, 2H), 1.48-1.63 (m, 1H), 1.351.47 (m, 1H), 1.11-1.19 (m, 1H), 1.04-1.08 (m, 1H) MS (m/z): 428.4 [MH]+ Example 41 and Example 42: (1R,3R or 1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (E41, TRANS, Enantiomer 1) and (1S,3S or 1R,3R)-1-(4- fluorophenyl )-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2.4]heptane (E42, TRANS, Enantiomer 2)

[366] (1S,3S/1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E40, 40 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC).

[367] (1R,3R or 1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS,E41, 14.5 mg) Enantiomer 1: retention time 11.7 min, 100% ee MS (m/z): 428.4 [MH]+.

[368] (1S,3S or 1R,3R)-1-(2,4-dfluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E42, 14 mg) Enantiomer 2: retention time 16.3 min, 100% ee MS (m/z): 428.4 [MH]+ Example 43: (1S,3R or 1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-( 4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E43, TRANS, Enantiomer 1 )

[369] (1R,3R or 1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E41, 14.5 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1R,3R or 1S,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (TRANS, Enantiomer 1, E43, 14.7 mg). MS (m/z): 428.5 [MH]+ Example 44: (1S,3S or 1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4 -methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (TRANS, E44, Enantiomer 2) [

[370] (1S,3S or 1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E42, 14 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1S ,3S or 1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (TRANS, Enantiomer 2, E44, 14.3 mg). MS (m/z): 428.5 [MH]+. Example 45: (1R,3S/1 S,3R)-1 -(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E45)

[371] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane (CIS, p33, 50 mg, 0.26 mmol ), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 79 mg, 0.29 mmol), Na2CO3 (31 mg, 0.29 mmol) and Nal (43 mg, 0.29 mmol) in DMF (0.2 mL), resulting in (1R,3S/1S,3R)-1-(4-fluorophenyl)- 5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (CIS, E45, 52 mg, y= 46%). NMR: 1H NMR (Acetone-dβ) δ: 8.26-8.30 (m, 1H), 7.16-7.21 (m, 2H), 7.007.08 (m, 2H), 3.77 (s, 3H), 3.15-3.31 (m , 2H), 2.62-2.75 (m, 2H), 2.50 (m, 2H), 2.43 (s, 3H), 2.37 (d, 1H), 2.09- 2.13 (m, 2H), 1.89-1.99 (m, 2H ), 1.79-1.88 (m, 2H), 1.06-1.14 (m, 2H) MS (m/z): 428.4 [MH]+. Example 46 and Example 47: (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (E46, CIS, Enantiomer 1) and (1R,3S)-1-(4-fluorophenyl)-5- (3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[ 2.4]heptane (E47, CIS, Enantiomer 2)

[372] (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E45, 50 mg) was separated into individual enantiomers by preparative chiral HPLC (SFC). Preparative Chromatography:

[373] (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E46, 17.9 mg) Enantiomer 1: retention time 12.1 min, 100% ee MS (m/z) : 428.4 [MH]+.

[374] (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E47, 18.6 mg). Enantiomer 2: retention time 15.0 min, 100% ee MS (m/z ): 428.4 [MH]+.Example 48: (1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3) hydrochloride -oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E48, CIS, Enantiomer 2)

[375] (1R,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E47, 18.6 mg) was treated with 1.1 eq of HCl in Et2O generating hydrochloride salt of (1R, 3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3- yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 2, E48, 20 mg).MS (m/z): 428.5 [MH]+.Example 49: (1S) hydrochloride ,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E49)

[376] The compound was prepared as in Example 1 by reacting (1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p40, 30 mg, 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole (p148 , 36 mg, 0.13 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.13 mL), resulting in (1S,3S/1R,3R)-5-(3 -{[4-methyl- 5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2- ( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane which was dissolved with Et2O and DCM and salted with 1.2 eq of 1M HCl in Et2O to obtain (1S,3S/1R,3R)-5-(3-{[ 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl ]-5-azaspiro[2.4]heptane hydrochloride (TRANS, E49, 9 mg, y= 13%).NMR: 1H NMR (DMSO-d6) δ: 10.13-10.56 (m, 1H), 8.58 (s, 1H ), 7.74-7.80 (m, 1H), 7.60-7.68 (m, 1H), 7.43-7.52 (m, 1H), 7.36 (d, 1H), 3.71 (s, 3H), 3.49-3.68 (m, 2H ), 3.28 (m, 4H), 3.12- 3.22 (m, 1H), 2.93-3.07 (m, 1H), 2.48 (br. s., 2H), 2.39 (s, 3H), 2.10 (br. s., 2H), 1.52-1.72 (m, 2H), 1.32-1.50 (m, 2H)MS (m/z): 478.4 [MH]+. Example 50 and Example 51: (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E50, TRANS, Enantiomer 1) and (1S,3S or 1R,3R) -5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[2- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E51, TRANS, Enantiomer 2)

[377] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, 55 mg) prepared according to Example 1, reacting with (1S,3S/1R, 3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p40, 50 mg, 0.21 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5- (4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 63 mg, 0.23 mmol), Na2CO3 (27 mg, 0.25 mmol) and Nal (38 mg, 0.25 mmol) in DMF (0.2 mL) was separated into individual enantiomers by preparative chiral HPLC.

[378] (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E50, 17.7 mg) Enantiomer 1: retention time 7.2 min, 100% ee MS (m/z): 478.4 [MH]+.

[379] (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E51, 19.4 mg) Enantiomer 2: retention time 8.4 min, 95 .5% ee MS (m/z): 478.5 [MH]+ Example 52: (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride ( E52, TRAMS, Enantiomer 1)

[380] (1R,3R or 1S.3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E50, 17.7 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)- 1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloric salt (TRANS, Enantiomer 1, E52, 17.5 mg).MS (m/z): 478 .4 [MH]+. Example 53: (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (TRANS, E53, Enantiomer 2)

[381] (1S,3S or 1R,3R)-5-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E51, 19.4 mg) was treated with 1.2 eq of HCl in Et2O, obtaining (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (TRANS, Enantiomer 2, E53, 13 mg).MS (m/ z): 478.4 [MH]+ Example 54: (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E54)

[382] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p41, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole ( p148, 36 mg, 0.13 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.13 mL), obtaining (1R,3S/1S,3R )-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)1 -[2-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (CIS, E54, 26 mg, y= 45%).NMR: 1H NMR (Acetone-d6) δ: 8.29 (s, 1H) , 7.71-7.78 (m, 1H), 7.54-7.62 (m, 1H), 7.38-7.47 (m, 1H), 7.27-7.33 (m, 1H), 1.37 (s, 3H), 3.17-3.37 (m, 3H), 2.83-3.06 (m, 2H), 2.60 (br., s., 4H), 2.44 (s, 3H), 2.41 (br., s., 1H), 1.80-2.02 (m, 4H), 1.51-1.60 (m, 1H), 1.14-1.25 (m, 1H) MS (m/z): 478.4 [MH]+. Example 55: (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (CIS, E55, Enantiomer 1)

[383] The compound was prepared as in Example 1, reacting (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS ,Enantiomer 1, p48, 25 mg, 0.096 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1, 2,4-triazole (p148, 29 mg, 0.1 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.11 mL), obtaining (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxozol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, 30 mg, 0.06 mmol) which was dissolved in Et2O and DCM and salted with 1 .2 eq of 1M HCl in Et2O to obtain (1R,3S or 1S,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5- (4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 1, E55, 30 mg, y= 58%) as a yellow solid.NMR: 1H NMR (DMSO-d6) δ: 10.12 (br. s., 1H), 8.57 (s, 1H), 7.66 (d, 1H ) 7.49 (m, 1H), 7.33-7.42 (m, 1H), 3.72-3.84 (m, 1H), 3.61-3.69 (m, 3H), 3.39-3.25 (m, 6H), 2.84-3.00 (m, 1H), 2.52-2.62 (m, 2H), 2.37 (s, 3H), 1.91-2.27 (m, 4H), 1.61-1.75 (m, 1H), 1.22-1.42 (m, 1H) MS (m/z ): 496.4 [MH]+ Example 56: (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3- {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (CIS, E56, Enantiomer two)

[384] The compound was prepared as in Example 1, reacting (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, p49, 25 mg, 0.096 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazole (p148, 29 mg, 0.1 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.11 mL), obtaining (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, 29 mg, 0.06 mmol) which was dissolved in Et2O and DCM and salted with 1. 2 eq of 2M HCl in Et2O to obtain (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-( 4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 2 , E56, 30 mg, y= 58%).NMR: 1H NMR (DMSO-d6) δ: 9.84-10.29 (m, 1H), 8.57 (s, 1H), 7.66 (d, 1H) 7.44-7.54 (m , 1H), 7.32-7.42 (m, 1H), 3.71-3.82 (m, 1H), 3.61-3.70 (m, 3H), 3.043.24 (m, 6H), 2.85-2.99 (m, 1H), 2.52 -2.62 (m, 2H), 2.37 (s, 3H), 2.11-2.01 (m, 4H), 1.61-1.74 (m, 1H), 1.26 (m, 1H) MS (m/z): 496.4 [ MH]+.Example 57: (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl- 1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (TRANS, E57, Enantiomer 1)

[385] The compound was prepared as in Example 1, reacting (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, Enantiomer 1, p46, 25 mg, 0.096 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazole (p148, 29 mg, 0.1 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.11 mL), obtaining -se (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazole -5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (TRANS, E1, 24 mg, 0.048 mol) which was dissolved in Et2O and DCM and salted with 1.2 eq of 1M HCl in Et2O to give (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[ 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]hydrochloride of heptane (TRANS, Enantiomer 1, E57, 24 mg, y= 47%) as a yellow solid.NMR: 1H NMR (DMSO-d6) δ: 9.93-10.30 (m, 1H), 8.57 (s, 1H), 7.61-7.70 (d, 1H) 7.46-7.55 (m, 1H), 7.36-7.44 (m, 1H), 3.69 (s, 4H), 3.48-3.62 (m, 2H), 3.343.39 (m, 1H) , 3.27 (d, 3H), 3.10-3.22 (m, 1H), 2.94-3.08 (m, 1H), 2.41-2.47 (m, 1H), 2.38 (s, 3H), 2.09 (br. s., 2H), 1.51-1.70 (m, 2H), 1.39-1.49 (m, 1H), 1.30-1.39 (m, 1H) MS (m/z): 496.4 [MH]+. Example 58: (1R,3R or 1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3- oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (TRANS, E58, Enantiomer 2)

[386] The compound was prepared as in Example 1, reacting (1R,3R or 1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, Enantiomer 2, p47, 25 mg, 0.096 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H-1,2,4-triazole (p148, 29 mg, 0.1 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.11 mL), obtaining -se (1R,3R or 1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazole -5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] heptane (TRANS, E2, 29 mg, 0.006 mmol) which was dissolved in Et2O and DCM and salted with 1.2 eq of 1M HCl in Et2O to give (1R,3R or 1S,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[ 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] hydrochloride of heptane (TRANS, Enantiomer 2, E58, 29 mg, y=57%) as a yellow solid. NMR: 1H NMR (DMSO-d6) δ: 10.15 (br. s., 1H), 8.57 (s, 1H) , 7.66 (d, 1H), 7.51 (br. s., 1H), 7.38-7.46 (m, 1H), 3.69 (s, 4H), 3.47-3.63 (m, 2H), 3.35-3.46 (m, 1H ), 3.11-3.27 (m, 4H), 2.94-3.08 (m, 1H), 2.41-2.47 (m, 1H), 2.38 (s, 3H), 2.022.15 (m, 2H), 1.52-1.68 (m , 2H), 1.40-1.50 (m, 1H), 1.28-1.38 (m, 1H) MS (m/z): 496.4 [MH]+. Example 59: (1 S,3S/1 R,3R)-1 -(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E59)

[387] The compound prepared as in Example 1, reacting (1S,3S/1R,3R)- 1-(3,5-dichlorophenyl)-5-azaspiro[2,4]heptane (TRANS, p36, 55 mg, 0.227 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 68 mg , 0.25 mmol), Na2CO3 (29 mg, 0.27 mmol) and Nal (40 mg, 0.27 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)- 1-(3,5-dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (TRANS, E59, 23 mg, y= 21%). NMR: 1H NMR (Acetone-d6) δ: 8.30 (s, 1H), 7.32 (s, 3H), 3.82 (s, 3H), 3.37-3.53 (m, 3H), 2.79-2.84 (m, 2H), 2.44 (s, 3H), 2.33-2.41 (m, 1H), 2.13-2.22 (m, 2H), 179, 1.90 (m, 2H), 1.51-1.72 (m, 3H), 1.28-1.44 (m, 3H ) MS (m/z): 478.3 [M]+ Example 60: (1 R,3S/1 S,3R)-1 -(3,5-dichlorophenyl)-5-(3-{[4-methyl -5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E60)

[388] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-azaspiro[2.4]heptane (CIS, p37, 55 mg, 0.227 mmol ), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 68 mg, 0.249 mmol), Na2CO3 (29 mg, 0.272 mmol) and Nal (40 mg, 0.272 mmol) in DMF (0.13 mL), obtaining (1R,3S/1S,3R)-1-(3.5- dichlorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -5- azaspiro[2.4]heptane (CIS, E60, 37 mg, y=34%). NMR: 1H NMR (Acetone-d6) δ: 8.28 (s, 1H), 7.27-7.31 (m, 1H), 7.22 (s, 2H), 3.78 (s, 3H), 3.25-3.36 (m, 2H), 2.78-2.85 (m, 3H), 2.43 (s, 3H), 2.24-2.39 (m, 2H), 2.08 (br. s., 2H), 1.97 (d, 4H), 1.22-1.52 (m, 3H) MS (m/z): 477.9 [M]+.Example 61: (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(4-methyl-1, 3-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane (CIS, E61)

[389] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2,4]heptane (CIS, p52, 40 mg, 0.165 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4- triazole (p148, 50 mg, 0.18 mmol), Na2CO3 (21 mg, 0.2 mmol) and Nal (30 mg, 0.2 mmol) in DMF (0.2 mL), obtaining (1R,3S /1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane (CIS, E61.34 mg, y= 43%).NMR: 1H NMR (Acetone-d6) δ : 8.62 (s, 1H), 8.28 (s, 1H), 7.69-7.85 (m, 2H), 3.77 (s, 3H), 3.16-3.37 (m, 2H), 2.73 (br. s., 1H), 2.47-2.71 (m, 4H), 2.44 (s, 3H), 2.26-2.34 (m, 1H), 2.09-2.15 (m, 2H), 1.94-2.04 (m, 2H), 1.80-1.93 (m, 2H) ), 1,351.43 (m, 1H), 1.27-1.34 (m, 1H) MS (m/z): 479.4 [MH]+. Example 62: (1 S,3S/1 R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl] -sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E62)

[390] The compound was prepared as in Example 1, by reaction of (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p149, 63 mg, 0.228 mmol), Na2CO3 (26 mg, 0.25 mmol) and Nal (38 mg, 0.25 mmol) in DMF (0.2 mL), resulting in (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan -4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E62, 49 mg , y= 49%).NMR: 1H NMR (CDCl3) δ: 7.56 (d, 2H), 7.09-7.26 (d, 2H), 4.06-4.18 (m, 2H), 3.46-3.63 (m, 6H), 3.27 (s, 2H), 2.66-3.05 (m, 6H), 2.00-2.34 (m, 6H), 1.811.97 (m, 3H), 1.26-1.38 (m, 1H), 1.12-1.23 (m, 1H ) MS (m/z): 481.5 [MH]+. Example 63 and Example 64: (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (E63, Enantiomer 1) and (1S,3S or 1R,3R)-5-(3-{[4- methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane ( E64, Enantiomer 2)

[391] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E62, 49 mg) was separated into individual enantiomers by preparative chiral HPLC.

[392] (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E63, 18 mg) Enantiomer 1: retention time 7.6 min, 100% ee MS (m/z): 481, 5 [MH]+.

[393] (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E64, 19 mg) Enantiomer 2: retention time 9.1 min, 100% ee MS (m/z): 481 .5 [MH]+ Example 65: (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol- 3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E65, Enantiomer 1)

[394] (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E63, 18 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1R,3R or 1S,3S) -5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl ]-5- azaspiro[2.4]heptane hydrochloric salt (Enantiomer 1, E65, 19 mg). MS (m/z): 481.5 [MH]+ Example 66: (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E66, Enantiomer 2)

[395] (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E64, 19 mg) was treated with 1.2 eq of HCl in Et2O resulting in (1S,3S or 1R,3R)- 5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl ]-5- azaspiro[2.4]heptane hydrochloric salt (Enantiomer 2, E66, 20 mg). MS (m/z): 481.5 [MH]+ Example 67: (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,E67)

[396] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 35 mg , 0.145 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p149, 44 mg, 0.16 mmol), Na2CO3 (19 mg, 0.174 mmol) and Nal (26 mg, 0.174 mmol) in DMF (0.14 mL), resulting in (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan -4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E67, 30 mg , y= 43%). NMR: 1H NMR (Acetone-d6) δ: 7.63 (d, 2H), 7.41 (s, 2H), 3.93-4.07 (m, 2H), 3.58 (s, 3H), 3.47-3.56 (m, 2H), 3.31-3.35 (m, 1H), 3.05-3.23 (m, 3H), 2.42-2.71 (m, 5H), 2.20-2.30 (m, 1H), 1.76-2.02 (m, 8H), 1.28-1.35 (m , 1H), 1.19-1.26 (m, 1H) MS (m/z): 481.4 [MH]+. Example 68 and Example 69: (1R,3S)-5-(3-{[4-methyl- 5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E68, Enantiomer 1) and (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E69, Enantiomer 2)

[397] (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E67, 28 mg) was separated into individual enantiomers by preparative chiral HPLC.

[398] (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E68, 10.8 mg) Enantiomer 1: retention time 8.4 min, 100% ee MS (m/z): 481, 3 [MH]+.

[399] (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E69, 10.7 mg) Enantiomer 2: retention time 11.9 min, 100% ee MS (m/z): 481, 3 [MH]+ Example 70: (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E70, CIS, Enantiomer 1)

[400] (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E68, 10.8 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1R,3S)-5-(3- {[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4]heptane hydrochloric salt (Enantiomer 1, CIS, E70, 11 mg). MS (m/z): 481.3 [MH]+ Example 71: (1 R,3S/1 S,3R)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{ [4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E71)

[401] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p22, 50 mg, 0.193 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p149, 58 mg, 0.212 mmol), Na2CO3 (25 mg, 0.23 mmol) and Nal (35 mg, 0.23 mmol) in DMF (0.2 mL), resulting in (1R,3S/1S,3R)-1-[2-fluoro-4- (trifluoromethyl )phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2.4] heptane (TRANS, E71.40 mg, y= 41%).NMR: 1H NMR (Acetone-dβ) δ: 7.50 (m, 2H), 7.32 (br. s., 1H), 3.99 (d, 2H), 3.62 (s. 3H), 3.48-3.57 (m, 2H), 3.19-3.28 (m, 2H), 3.07-3.17 (m, 1H), 2.53-2.74 (m, 6H), 2.29-2.36 (m, 1H ), 1.89 (br. s., 6H), 1.57-1.71 (m, 2H), 1.26-1.43 (m, 4H) MS (m/z): 499.4 [MH]+. Example 72 and Example 73: (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl )-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (E72, TRANS, Enantiomer 1) and (1R,3S or 1S,3R)-1 -[ 2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-5-azaspiro[2.4]heptane (E73, TRANS, Enantiomer 2)

[402] (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E71, 38 mg) was separated into individual enantiomers by preparative chiral HPLC.

[403] (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E72, 13 mg) Enantiomer 1: retention time 8.1 min, 100% ee MS (m /z): 499.4 [MH]+

[404] (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, E73, 13 mg) Enantiomer 2: retention time 9.4 min, 98.8% ee MS (m/z): 499.4 [MH]+ Example 74: (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3- {[4- methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E74, TRANS, Enantiomer 1)

[405] (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS,E72, 13 mg) was treated with 1.2 eq of HCl in Et2O, resulting in (1S, 3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (Enantiomer 1, TRANS, E74, 12 mg). MS (m/z): 499.4 [MH]+ Example 75: (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4 -methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E75, TRANS, Enantiomer 2)

[406] (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS,E73, 13.8 mg) was treated with 1.2 eq of HCl in Et2O resulting in (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloric salt (Enantiomer 2, TRANS, E75, 12 mg). MS (m/z): 499.4 [MH]+. Example 76: (1S,3S/1 R,3R)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E76)

[407] The compound was prepared as in Example 1, by reaction of (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p23, 50 mg, 0.193 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p149, 58 mg, 0.212 mmol), Na2CO3 (25 mg, 0.23 mmol) and Na1 (35 mg, 0.23 mmol) in DMF (0.2 mL) resulting in the title compound (1S,3S/1R,3R)-1-[2-fluoro-4- (trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[ 2.4]heptane (CIS, E76, 45 mg, y= 47%). NMR: 1H NMR (Acetone-d6) δ: 7.45-7.52 (m, 2H), 7.35 (m, 1H), 3.98 (m, 2H), 3.46-3.59 (m, 5H), 3.03-3.21 (m, 4H ), 2.40-2.70 (m, 5H), 2.24-2.33 (m, 1H), 2.02 (d, 2H), 1.74-1.94 (m, 6H), 1.39 (m, 1H), 1.25 (m, 1H) MS (m/z): 499.4 [MH]+. Example 77 and Example 78: (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5- (3-{[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (E77, CIS, Enantiomer 1) and (1S,3S)-1-[2-fluoro-4- (trifluoromethyl )phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4] heptane (E78, CIS, Enantiomer 2)

[408] (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E76, 42 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC).

[409] (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E77, 15 mg) Enantiomer 1: retention time 8.2 min, 100% ee MS (m/z): 499.4 [MH]+.

[410] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E78, 15 mg) Enantiomer 2: retention time 9.5 min, 97% ee MS (m/z): 499.4 [MH]+ Example 79: (1S,3S)- 1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride (E79, CIS, Enantiomer 2)

[411] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4] heptane (CIS, E78, 15 mg) was treated with 1.2 eq of HCl in Et2O, obtaining (1S,3S)- 1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-5-azaspiro[2.4]heptane hydrochloride salt (Enantiomer 2, CIS, E79, 16.6 mg). MS (m/z): 499.4 [MH]+. Example 80: (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl] - sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS, E80)

[412] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-phenyl-5-azaspiro[2.4]heptane (CIS, p19, 50 mg, 0.29 mmol), 3- [(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p149, 80 mg, 0.29 mmol), Na2CO3 (37 mg, 0.384 mmol) and Nal (52 mg, 0.348 mmol) in DMF (0.2 mL), obtaining the title compound (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4- yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS, E80, 23 mg, y= 19%) NMR: 1H NMR (Acetone-d6) δ: 7.24-7.35 (m, 2H), 7.11-7.19 (m, 3H), 3.99 (m, 2H), 3.59 (s, 3H), 3.48-3.57 (m, 2H), 3.06 -3.22 (m, 3H), 2.34-2.71 (m, 5H), 2.14 (br., s., 1H), 2.11 (d, 1H), 1.76-2.01 (m, 8H), 1.08-1.23 (m, 2H) MS (m/z): 413.4 [MH]+ Example 81 and Example 82: (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E81, CIS,Enantiomer 1) and (1R,3S)-5-(3-{ [4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane (E82, CIS, Enantiomer 2)

[413] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-phenyl-5-azaspiro[2.4]heptane (CIS, E80, 22 mg) was separated into individual enantiomers by preparative chiral HPLC.

[414] (1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1 -phenyl-5-azaspiro[2.4]heptane (CIS, E81, 8 mg) Enantiomer 1: retention time 8.4 min, 100% ee MS (m/z): 413.4 [MH]+.

[415] (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1 -phenyl-5-azaspiro[2.4]heptane hydrochloric salt (CIS, E82, 9 mg). Enantiomer 2: ret time. 10.3 min., 100%% ee MS (m/z): 413.4 [MH]+ Example 83: (1 R,3S/1 S,3R)-5-(3-{[4-methyl- 5-(oxan-4-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane hydrochloride (E83, CIS, Enantiomer 2)

[416] (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1 -phenyl-5-azaspiro[2.4]heptane (CIS, E82, 9 mg) was treated with 1.2 eq of HCl in Et2O resulting in (1R,3S)-5-(3-{[4-methyl-5- (oxan-4-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2.4]heptane hydrochloric salt (Enantiomer 2, CIS, E83, 7.8 mg).MS (m/z): 413.4 [MH]+ Example 84: (1R,3S/1 S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane (CIS, E84)

[417] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[2.4]heptane (CIS, p52, 60 mg, 0.247 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p149, 75 mg, 0.272 mmol), Na2CO3 (31 mg, 0.3 mmol) and Nal (44 mg, 0.3 mmol) in DMF (0.2 mL) resulting in the title compound (1R,3S/1S,3R)-5-(3-{[4- methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-5-azaspiro[ 2.4]heptane (CIS, E84, 25 mg, y= 21%).NMR: 1H NMR (Acetone-dβ) δ: 8.62 (s, 1H), 7.73-7.84 (m, 2H), 3.95-4.04 (m, 2H), 3.58 (s, 3H), 3.49-3.56 (m, 2H), 3.05-3.25 (m, 4H), 2.46-2.72 (m, 5H), 2.28-2.37 (m, 1H), 2.10-2.19 ( m, 2H), 1.79-1.97 (m, 7H), 1.37-1.48 (m, 1H), 1,281.36 (m, 1H) MS (m/z): 482.5 [MH]+. Example 85: (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4- triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E85)

[418] The compound was prepared as in Example 1 by reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 50 mg, 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazole (p150.69 mg, 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL) resulting in the title compound (1R,3S/1S,3R)-5-{3-[ (4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2.4]heptane (CIS, E85, 54 mg, y= 52%).NMR: 1H NMR (Acetone-d6) δ: 7.62 (d, 2H), 7.40 (s, 2H), 4.33 -4.48 (m, 2H), 3.57 (s, 3H), 3.28-3.46 (m, 2H), 3.03-3.22 (m, 2H), 2.38-2.72 (m, 5H), 2.20-2.29 (m, 1H) , 1.96 (d, 7H), 1.69-1.86 (m, 5H), 1.27-1.35 (m, 1H), 1.17-1.25 (m, 1H) MS (m/z): 507.1 [MH]+.Example 86 and Example 87: (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol- 3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E86, CIS, Enantiomer 1) and (1S,3R)-5-{3-[(4 -methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1 -[4-(trifluoromethyl)phenyl] -5-azaspiro[2.4]heptane (E87, CIS, Enantiomer 2)

[419] (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4- triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E85, 54 mg) was separated into the individual enantiomers by preparative chiral HPLC.

[420] (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E86, 24 mg) Enantiomer 1: ret. time. 6.5 min, 100% ee MS (m/z): 507.4 [MH]+

[421] (1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E87, 23 mg) Enantiomer 2: ret. time. 9.6 min, 100% ee MS (m/z): 507.4 [MH]+ Example 88: (1 R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[ 3.2.1]octan-3-yl}-4H- 1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E88, CIS, Enantiomer 1)

[422] (1R, 3S)-5- {3-[(4-methyl-5- {8-oxabicyclo [3.2.1]octan-3-yl}-4H-1,2,4-triazol-3- il) sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E86, 24 mg) with 1.2 eq. From HCl in Et2O providing (1R, 3S)-5-{3-[(4-methyl- 5-{8-oxabicyclo [3.2.1] octan-3-yl}-4H-1,2,4-triazol- 3-yl)sulfanylpropyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (Enantiomer 1, CIS, E88, 24.3 mg). MS (m/z): 507.4 [MH]+. Example 89: (1 S,3S/1 R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E89)

[423] The compound was prepared as in Example 1 by reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13, 50 mg, 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-5-cyclohexyl-4-methyl-4H-1,2,4-triazole (p151.63 mg, 0.228 mmol), Na2CO3 (26 mg, 0.25 mmol) and Nal (38 mg, 0.25 mmol) in DMF (0.2 mL) resulting in the title compound (1 S,3S/1 R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1 ,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E89, 37 mg, y= 37%).NMR: 1H NMR (CDCI3) δ: 7.51-7.66 (m, 2H), 7.31-7.42 (m, 2H), 3.53 (s, 3H), 3.24 (m, 2H), 2.74-3.15 (m, 5H), 2.58- 2.71 (m, 1H), 2.09-2.41 (m, 3H), 1.95 (m, 4H), 1.68-1.84 (m, 5H), 1.16-1.48 (m, 6H) MS (m/z): 479, 5 [MH]+ Example 90 and Example 91: (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl) sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (E90, TRANS, Enantiomer 1) and (1S,3S or 1R,3R)-5-{3- [(5 -cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E91, TRANS, Enantiomer two)

[424] (1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(Trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E89, 34 mg) was separated into individual enantiomers by preparative chiral HPLC.

[425] (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E90, 14 mg) Enantiomer 1: retention time 8.8 min, 100% ee MS (m/z): 479.5 [MH] +.

[426] (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E91, 10.5 mg) Enantiomer 2: retention time 10.5 min, 100% ee MS (m/z): 479.5 [ MH]+.Example 92: (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl }-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E92, TRANS, Enantiomer 1)

[427] (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E90, 14 mg) was treated with 1.2 eq of HCl in Et2O resulting in (1R,3R or 1S,3S)-5-{3 - [(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]hydrochloric salt heptane (Enantiomer 1, TRANS, E92, 15 mg). MS (m/z): 479.5 [MH]+.Example 93: (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4 - triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E93, TRANS, Enantiomer 2)

[428] (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E91, 10.5 mg) was treated with 1.2 eq of HCl in Et2O resulting in (1S,3S or 1R,3R)- 5-{3 -[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]hydrochloric salt heptane (Enantiomer 2, TRANS, E93, 11 mg). MS (m/z): 479.5 [MH]+ Example 94: (1 R,3S/1 S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2, 4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E94)

[429] The compound was prepared as in example 1, by reaction of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 50 mg , 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-5-cyclohexyl-4-methyl-4H-1,2,4-triazole (p151.63 mg, 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol ) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL) resulting in the title compound (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H- 1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E94, 32 mg, y= 32%). NMR: 1H NMR (Acetone-d6) δ: 7.63(d, 2H), 7.39 (d, 2H), 3.54 (s, 3H), 3.42 (m, 1H), 3.02-3.23 (m, 2H), 2.37- 2.66 (m, 4H), 2.35-2.67 (m, 1H), 2.18-2.31 (m, 2H), 1.96 (br. s., 4H), 1.83 (br.s., 5H), 1.54-1.67 (m , 2H), 1.27-1.51 (m, 4H), 1,171.25 (m, 1H) MS (m/z): 479.5 [MH]+. Example 95 and Example 96: (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E95, CIS, Enantiomer 1) and (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2, 4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E96, CIS, Enantiomer 2)

[430] (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[ 4-(Trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E94, 30 mg) was separated into individual enantiomers by preparative chiral HPLC.

[431] (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- 1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4]heptane (CIS, E95, 12 mg) Enantiomer 1: retention time 6.6 min, 100% ee MS (m/z): 479.5 [MH]+.

[432] (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- 1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4]heptane (CIS, E96, 11.5 mg) Enantiomer 2: RET time 8.4 min, 100% ee MS (m/z): 479.5 [MH]+. Example 97: (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E97, CIS, Enantiomer 1)

[433] (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- 1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4]heptane (CIS, E95, 12 mg) was treated with 1.2 eq of HCl in Et2O, obtaining (1R,3S)-5-{3-[(5-cyclohexyl -4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride salt (Enantiomer 1, CIS, E97, 12.5 mg) MS (m/z): 479.5 [MH]+.Example 98: (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1 ,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (E98, CIS, Enantiomer 2)

[434] (1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}- 1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4] heptane (CIS, E96, 11.5 mg) was treated with 1.2 eq of HCl in Et2O, obtaining (1S,3R)-5-{3-[(5 -cyclohexyl-4-methyl-4H- 1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride salt (Enantiomer 2, CIS, E98, 12.1 mg).MS (m/z): 479.1 [MH]+ Preparation 249: tert-butyl 4-[4-methyl-5-({3-[(1R,3S /1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine- 1-carboxylate (CIS, p249)

[435] (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 50 mg, 0.21 mmol), tert-butyl 4-{5 -[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate (p224, 78 mg, 0.21 mmol), Na2CO3 (27 mg, 0.252 mmol ) and Nal (38 mg, 0.252 mmol) were dissolved in DMF (0.2 mL) and heated to 60 ° C and stirred in a PLS apparatus at that temperature overnight. The mixture was diluted with water and extracted twice with DCM. The organic phase was dried and evaporated. The crude material was purified by FC on a silica cartridge (elution of DCM at 100% MeOH) resulting in tert-butyl 4-[4-methyl-5-({3- [(1R,3S/1S,3R)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate (CIS, p249, 63 mg, y= 35%) which was used as such in the next step MS (m/z): 580.4 [MH]+. Preparation 250: (1 R,3S/1 S,3R)-5- (3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5 -azaspiro[2.4]heptane (CIS, p250)

[436] To a solution of 4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan- tert-butyl 5-yl]propyl}sulfanyl)-4H-1,24-triazol-3-yl]piperidine-1-carboxylate (p249, CIS, 63 mg, 0.11 mmol) in DCm (2.5 mL ), TFA (0.5 mL) was added and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto an SCX cartridge and eluted with 1M MeOH/NH3 in MeOH to obtain (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(piperidin-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p250, CIS, 42 mg, y= 80%) as a pale yellow gum.MS (m/z): 480.4 [MH]+ Example 99: 1 -{4-[4-methyl-5-({3-[(1 R,3S/1 S,R3 )-1 -[4-(trifluoromethyl)phenyl]- 5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin- 1yl}ethane- 1- one (CIS, E99)

[437] To a solution of (1R,3S/ 1S,3R)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H- 1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p250, CIS, 42 mg, 0.088 mmol) in DCM (2 mL), Ac2O (11 uL) was added , 0.11 mmol) and Py (16 uL, 0.2 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was diluted in water and extracted with DCM. The organic phase was dried and concentrated under reduced pressure to obtain 1-{4-[4-methyl-5-({3-[(1R,3S/1S, R3)-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1yl}etan-1-one (E99, CIS, 38 mg , y= 77%) in the form of a colorless oil. NMR: 1H NMR (Acetone-de) 7.62 (d, 2H), 7.32-7.47 (m, 2H), 4.74-4.74 (m, 1H), 4.43-4.58 (m, 1H), 3.93-4.08 (m, 1 H), 3.59 (s, 3H), 3.28 (br. s., 5H), 2.822.95 (m, 2H), 2.52 (br. s., 4H), 2.27 (br. s., 1 H) , 2.08-2.18 (m, 2H), 1.92-2.03 (m, 4H), 1.85 (d, 2H), 1.60-1.73 (m, 1H), 1.17-1.39 (m, 3H) MS (m/z) : 522.5 [MH]+. Preparation 251: 4-[4-methyl-5-({3-[(1R,3S)-1 -[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptan-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]piperidine-1- tert-butyl carboxylate (CIS, Enantiomer 1, p251)

[438] (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, p15, 300 mg, 1.24 mmol) was added 4-{5- tert-butyl [(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate (p224, 510 mg, 1.36 mmol) Na2CO3 (159 mg, 1.5 mmol) and Nal (225 mg, 1.5 mmol) were dissolved in DMF (1.4 mL) and heated at 60°C overnight.Additionally, 4-{5-[(3-chloropropyl tert-butyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate (100 mg, 0.27 mmol) was added to the reaction and the reaction was mixed at 60°C for 4 hours. The mixture was diluted with water and extracted three times with DCM. The organic phase was dried and evaporated to give an oil which was purified by FC on silica gel (eluting from DCM to 10% MeOH) to give a yellow foam which was dissolved in DCM (3 mL). and treated with isocyanate-MP resin, stirred for 1 hour. The resin was filtered and washed with DCM and MeOH. The solvent was evaporated, obtaining 4-[4-methyl-5-({3- [(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl tert-butyl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate (CIS, Enantiomer 1, p251, 550 mg) which was used as a crude material in the next step .MS (m/z): 580.5 [MH]+. Preparation 252: (1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, p252)

[439] 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) tert-butyl -4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate (p251, CIS, Enantiomer 1, 550 mg, 0.95 mmol), was dissolved in DCM (mL 5) and TFA (1 mL) was added. The resulting solution was stirred at RT for 1 h, the solvent was then evaporated and the residue material was purified by SCX cartridge (eluent MeOH/NH31M in MeOH) to obtain (1R,3S)-5-(3 -{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4]heptane (p252, CIS, Enantiomer 1, 232 mg, y= 48%) in the form of a yellow sticky oil. MS (m/z): 480.4 [MH]+.Example 100: 1 -{4-[4-methyl-5-({3-[(1 R,3S)-1 -[4-(trifluoromethyl) phenyl]-5- azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1yl}etan- 1-one (CIS, Enantiomer 1, E100 )

[440] To a solution of (1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p252, CIS, Enantiomer 1.232 mg, 0.48 mmol) in DCM (5 mL), Ac2O (55 uL, 0.576 mmol) and Py (89 uL, 1.1 mmol) were added and the mixture was stirred at RT for 1 h. The reaction mixture was diluted in water and extracted several times with DCM. The organic phase was dried and concentrated under reduced pressure. The crude material was purified by FC on an NH cartridge (elution of cHex to 100% EtOAc, then 100% MeOH) to obtain 1-{4-[4-methyl-5-({3-[(1R ,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1yl} etan-1-one (E100, CIS, Enantiomer 1, 198 mg, y= 79%) in the form of a colorless sticky oil.MS (m/z): 522.4 [MH]+. Preparation 253: 4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl] tert-butylpropyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate (CIS, p253)

[441] The compound was prepared as in Example 1, by reaction of (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p23, 50 mg, 0.193 mmol), tert-butyl 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine-1-carboxylate (p224, 76 mg, 0.2 mmol), Na2CO3 (25 mg, 0.23 mmol) and Na1 (35 mg, 0.23 mmol) in DMF (0.2 mL) resulting in the title compound 4-[5-({3 -[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H- tert-butyl 1,2,4-triazol-3-yl]piperidine-1-carboxylate (CIS, p253, 38 mg, y= 33%) which was used as such in the next step MS (m/z): 598 .6 [MH]+. Preparation 254: (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, p254)

[442] To a stirred solution of 4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan tert-butyl-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate (CIS, p253, 37 mg, 0.062 mmol) in DCM (3 mL) TFA (0.3 mL) was added and the resulting reaction solution was left stirring at RT for 1 h. The solvent was removed in vacuo and the residue was loaded into SCX eluting with 1M NH3 in MeOH to give, after evaporation, (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl) phenyl]-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (p254, 28 mg, y= 91%). This was used as such in the next step. MS (m/z): 498.5 [MH]+. Example 101: 1-{4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}etan-1-one (CIS, E101)

[443] To a solution of (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5- (3-{[4-methyl-5-(piperidin-4- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (p254, CIS, 28 mg, 0.056 mmol) in DCM (1.25 mL), were Ac2O (6 uL, 0.067 mmol) and Py (10 uL, 0.129 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted in water and extracted with DCM. The organic phase was dried and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluent: DCM 100% MeOH) to obtain 1-{4-[5-({3-[(1S,3S/1R,3R)-1-[ 2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1 -yl}etan-1- one (E101, CIS, 17 mg, y= 56%).NMR: 1H NMR (Acetone-dβ) δ: 7.43-7.54 (m, 2H), 7.35 (s, 1H), 4.44 -4.56 (m, 1H), 3.98-4.05 (m, 1H), 3.57-3.65 (m, 3H), 3.05-3.35 (m, 4H), 2.72-2.87 (m, 4H), 2.40-2.68 (m, 4H), 2.24-2.33 (m, 1H), 1.57-2.06 (m, 10H), 1.21 -1.40 (m, 2H) MS (m/z): 540.4 [MH]+. Example 102: 1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl hydrochloride ]propyl}sulfanyl)-4-methyl-4H- 1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one (CIS, E102)

[444] The compound was prepared as in Example 1, reacting (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, p24, 25 mg, 0.096 mmol), 1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-1-yl)ethan- 1-one (p222, 32 mg, 0.1 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 mL) resulting in the title compound 1 -{4-[5-({3-[(1S,3S or 1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]- 5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}etan-1-one (CIS, Enantiomer 1, 24 mg) which was dissolved in DCM and Et2O and was salted by 1.2 eq of 2M HCI in Et2O to obtain 1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl) hydrochloric salt phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethan-1-one ( E102, Enantiomer 1, 22.7 mg, y= 42%) as a yellow solid. NMR: 1H NMR (DMSO-d6) δ: 10.16-10.73 (m, 1H), 7.67 (d, 1H), 7.52 (s, 1H), 7.33-7.42 (m, 1H), 4.33-4.44 (m, 1H ), 3.82-3.96 (m, 1H), 3.69-3.76 (m, 1H), 3.45-3.51 (m, 3H), 3.03-3.37 (m, 9H), 2.58-2.83 (m, 2H), 2.20-2.31 (m, 1H), 2.052.16 (m, 1H), 2.02 (s., 3H), 1.94-2.01 (m, 2H), 1.88 (br. s., 2H), 1.58-1.74 (m, 1H), 1.41-1.57 (m, 2H), 1.20-1.38 (m, 2H) MS (m/z): 540.4 [MH]+ Example 103: 3-methoxy-1-{4-[4-methyl-5- ({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 -yl]piperidin-1-yl}propan-1-one (CIS, Enantiomer 1, E103)

[445] To a solution of (1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p252,CIS, Enantiomer 1, 37 mg, 0.077 mmol) Hydroxybenzotriazole 1-hydrate (11 mg, 0.081 mmol), N- Ethylcarbodiimide (3-Dimethylaminopropyl)-N'-hydrochloride (15 mg, 0.078 mmol), 3-Methoxypropionic acid (8 uL, 0.077 mmol) and TEA (32 uL, 0.23 mmol) in DCM (2 mL) was added and the mixture was stirred at room temperature overnight. It was then washed with NaHCO3 (x1), NH4Cl (x3) and brine, dried and concentrated under reduced pressure. The crude mass was purified by FC on an NH column (eluent: Cy at 100% AcOEt) to obtain 3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan -1-a(E103, CIS, Enantiomer 1, 24 mg, y= 55%).NMR: 1H NMR (Acetone-dβ) δ: 7.58-7.68 (m, 2H), 7.33-7.43 (m, 2H), 4,494.57 (m, 1H), 4.03- 4.14 (m, 1H), 3.65 (s, 2H), 3.60 (s, 3H), 3.23-3.34 (m, 4H), 3.05-3.23 (m, 3H), 2.84-2.90 (m, 1H), 2.69-2.76 (m, 1H), 2.57-2.68 (m, 3H), 2.51 (s, 3H), 2.20-2.26 (m, 1H), 1.98 (s, 5H), 1.63- 1.90 (m, 4H), 1.26-1.32 (m, 1H), 1.18-1.24 (m, 1H)MS (m/z): 566.5 [MH]+.Example 104: 3-methoxy hydrochloride 1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4H-1,2,4- triazol-3-yl]piperidin-1-yl}propan-1-one (CIS, Enantiometer 1, E104)

[446] 3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one (E103, CIS, Enantiomer 1.24 mg) was dissolved in MeOH/Et2O and treated with 2M HCl in Et2O (1.1 eq) to form the corresponding hydrochloride salt. The solvent was removed under reduced pressure; the solid was triturated with Et2O and dried under high vacuum yielding 3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl hydrochloride ]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol- 3-yl]piperidin-1-yl}propan-1-one (E104, CIS, Enantiomer 1, 23.4 mg).MS (m/z): 566.5 [MH]+.Example 105: (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl )-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (CIS, Enantiomer 1, E105 )

[447] To a solution of (1R,3S)-5-(3-{[4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p252,CIS, Enantiomer 1, 37 mg, 0.077 mmol) 1-Hydroxybenzotriazole hydrate(11 mg, 0.081 mmol), N- Ethylcarbodiimide (3-Dimethylaminopropyl)-N'-hydrochloride (15 mg, 0.078 mmol), cyclopropanecarboxylic acid (7 uL, 0.077 mmol) and TEA (32 uL, 0.23 mmol) in DCM (2 mL) were added and the mixture was stirred at room temperature overnight. It was then washed with NaHCO3 (x1), NH4CI (x3) and brine, dried and concentrated under reduced pressure. The crude product was purified by FC on a NH column (eluent: Cy at 100% EtOAc) obtaining (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4 -methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E105, CIS, Enantiomer 1, 35 mg , y= 83%). NMR: 1H NMR (Acetone-dβ) δ: 7.58-7.68 (m, 2H), 7.36-7.44 (m, 2H), 4.374.57 (m, 2H), 3.60 (s, 3H), 3.32-3.45 (m , 1H), 3.05-3.24 (m, 3H), 2.85-2.97 (m, 1H), 2.69-2.76 (m, 1H), 2.57-2.65 (m, 1H), 2.40-2.53 (m, 3H), 2.19 -2.27 (m, 1H),447.1- 05 (m, 6H), 1.64-1.84 (m, 4H), 1.26-1.31 (m, 1H), 1.18-1.24 (m, 1H), 0.83 (d, 2H) , 0.73 (d, 2H) MS (m/z): 548.5 [MH]+. Example 106: (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} hydrochloride propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,Enantiomer 1, E106)

[448] (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E105, CIS, Enantiomer 1, 35 mg) was dissolved in MeOH/Et2O and treated with 2M HCl in Et2O (1.1 eq) to form the corresponding hydrochloride salt. The solvent was removed under reduced pressure; the solid was triturated with Et2O and dried under vacuum to give (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H-1,2 hydrochloride, 4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (E106, CIS, Enantiomer 1, 30.8 mg).MS (m/z ): 548.4 [MH]+ Preparation 255: 3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro tert-butyl [2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]zetidine-1-carboxylate (CIS, p255)

[449] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 30 mg , 0.12 mmol), tert-butyl 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}azetidine-1-carboxylate (p226, 46 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL) resulting in the title compound tert-butyl 3-[4-methyl-5-({3 -[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazole- 3-yl]azetidine-1-carboxylate (CIS, p255, 37 mg, y= 37%) which was used as such in the next step. MS (m/z): 552.5 [MH]+. Preparation 256: (1R,3S/1S,3R)-5-(3-{[5-(azetidin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p256)

[450] To a solution of 3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan- tert-butyl 5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidine-1-carboxylate (p255, 37 mg, 0.11 mmol) in DCM (2 mL), TFA (0.5 mL) was added and the reaction was stirred at RT for 1.5 h. The reaction mixture was concentrated under vacuum. The residue was loaded onto an SCX cartridge and eluted with MeOH/NH31M in MeOH to obtain (1R,3S/1S,3R)-5-(3-{[5-(azetidin-3-yl)-4-methyl -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p256, CIS, 25 mg, y= 82% ) in the form of a pale yellow gum. MS (m/z): 452.4 [MH]+ Example 107: 1-{3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4- ( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidin-1-yl}ethan-1-one (CIS, E107)

[451] To a solution of (1R,3S/1S,3R)-5-(3-{[5-(azetidin-3-yl)-4-methyl-4H- 1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p256, CIS, 25 mg, 0.055 mmol) in DCM (1.25 mL), Ac2O (6 uL, 0.066 mmol) and Py (10 uL, 0.127 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted in water and extracted with DCM. The organic phase was dried and concentrated under reduced pressure. The crude product was purified by FC on a silica cartridge (eluent from DCM to MeOH) to obtain 1-{3-[4-methyl-5-({3-[(1R,3S/1S,3R)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]azetidin-1-yl}etan-1 -one (E107, CIS, 7.2 mg, y= 27%) in the form of a colorless gum. NMR: 1H NMR (Acetone-dβ) δ: 7.63 (d, 2H), 7.39 (d, 2H), 4.51-4.65 (m, 2H), 4.26-4.35 (m, 1H), 4.15-4.23 (m, 1H ), 4.00-4.12 (m, 1H), 3.51 (s, 3H), 3.06-3.26 (m, 3H), 2.68-2.76 (m, 1H), 2.57-2.67 (m, 1H), 2.42-2.56 (m , 3H), 2.20-2.30 (m, 2H), 1.89-2.04 (m, 2H), 1.82 (s, 4H), 1.27-1.37 (m, 2H), 1.17-1.25 (m, 1H): MS (m /z): 494.4 [MH]+. Preparation 257: N-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5 tert-butyl -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate (CIS, p257)

[452] The compound was prepared as in Example 1 by reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 40 mg, 0.17 mmol), tert-butyl N-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)carbamate (p230 , 66 mg, 0.17 mmol), Na2CO3 (22 mg, 0.2 mmol) and Nal (25 mg, 0.17 mmol) in DMF (0.3 mL) resulting in N-{4-[4-methyl -5- ({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1, tert-butyl 2,4-triazol-3-yl]cyclohexyl}carbamate (CIS, p257, 33 mg, y= 33%) which was used as such in the next step.MS (m/z): 594.5 [ MH]+. Example 108: 4-[4-methyl-5-({3-[(1 R,3S/1 S,3R)-1 -[4-(trifluoromethyl)phenyl]- 5-azaspiro[2.4]heptan-5- yl]-propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine (CIS, E108)

[453] To a solution of N-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4 tert-butyl]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate (CIS, p257, 33 mg, 0.56 mmol) in DCM ( 0.2 ml) at room temperature, TFA (0.085 ml) was added and the resulting mixture was allowed to react at room temperature. After 1.5 h the mixture was concentrated in vacuo and the residue was taken up with DCM. The solution was washed with concentrated aqueous sodium bicarbonate solution, water, dried over sodium sulfate and the solvent was removed under reduced pressure to give 4-[4-methyl-5-({3-[(1R,3S/ 1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4-triazol-3-yl]cyclohexan-1 -amine (E108, CIS, 24 mg, y= 87%).NMR: 1H NMR (CDCI3) 5: 7.53 (d, 2H), 7.20 (d, 2H), 3.44 (s, 3H), 3.19 (d, 2H), 2.99-3.07 (m, 1H), 2.73-2.84 (m, 2H), 2.57-2.66 (m, 1H), 2.50 (s, 2H), 2.39 (s, 1H), 2.11 (d, 2H) , 1.93-2.08 (m, 4H), 1.88 (d, 2H), 1.71-1.82 (m, 7H), 1.15-1.23 (m, 2H) MS (m/z): 494.4 [MH]+. Example 109: N-{4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan hydrochloride -5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, E109)

[454] To a solution of 4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan- 5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine (E108, CIS, 24 mg, 0.049 mmol) and DIPEA (0.020 mL, 0.12 mmol) in DCM (0.2 mL), at room temperature, Ac2O (0.005 mL, 0.053 mmol) was added and the resulting reaction mixture was allowed to react for 24h. The mixture was diluted with DCM and washed twice with saturated aqueous sodium carbonate. The organic phase was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure to give N-{4-[4-methyl-5-({3-[(1R,3S/1S,3R) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, 20 mg). The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (0.021 mL) was added and the reaction mixture was concentrated under vacuum. The solid thus obtained was triturated with ether and dried under vacuum at 40 °C overnight, resulting in N-{4-[4-methyl-5-({3-[(1R,3S/1S,3R) hydrochloride -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (E109, CIS , 21 mg, y= 75%). NMR: 1H NMR (DMSO-d6) δ: 10.79-11.23 (m, 1H), 7.83-7.91 (m, 1H), 7.67 (d, 2H), 7.45 (d, 2H), 3.83-3.91 (m, 1H ), 3.59-3.72 (m, 1H), 3.55 (s, 3H), 3.34-3.46 (m, 1H), 3.00-3.33 (m, 7H), 2.56-2.66 (m, 1H), 2.35-2.44 (m , 1H), 2.17-2.32 (m, 1H), 1.87-1.98 (m, 3H), 1.85 (s, 3H), 1.68-1.79 (m, 4H), 1.54-1.67 (m, 2H), 1.351.53 (m, 2H), 1.22-1.33 (m, 2H) MS (m/z): 536.5 [MH]+. Example 110 and 111: N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl ]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]cyclohexyl}acetamide (CIS, Enantiomer 1, E110) and N-{4-[4-methyl-5- ({3-[( 1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, Enantiomer 2, E111)

[455] To a solution of 4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan- 5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexan-1-amine (E108, 69 mg, 0.14 mmol) and DIPEA (0.061 mL, 0.35 mmol) in DCM (0.5 mL) at RT, Ac2O (0.016 mL, 0.16 mmol) was added and the resulting reaction mixture was allowed to react for 24h. The mixture was diluted with DCM and washed with ammonium chloride; the solvent was removed under reduced pressure. The crude material was purified by FC on silica gel (DCM/MeOH from 100/0 to 55/45) to provide 73 mg of racemic product which was subjected to chiral preparative HPLC

[456] N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (E110,CIS, 24 mg) Enantiomer 1: ret. time. 8.7 min, 100% ee MS (m/z): 536.6 [MH]+

[457] N-{4-[4-methyl-5-({3-[(1 S,3R)-1 -[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptan-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (E111, CIS, 24 mg) Enantiomer 2: ret. time. 10.7 min, 98.2% ee MS (m/z): 536.6 [MH]+ Example 112: N-{4-[4-methyl-5-({3-[(1R,3S) hydrochloride )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (E112, CIS, Enantiomer 1)

[458] N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (E110, CIS, 24 mg) was dissolved in DCM (0.2 mL) and then 2N HCl/ether (0.025 mL) was added and the mixture was concentrated in vacuo. The solid thus obtained was triturated with ether and dried under vacuum at 40 °C overnight, resulting in N-{4-[4-methyl-5-({3-[(1R,3S)-1-[ hydrochloride 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (E112, Enantiomer 1.23 mg ).MS (m/z): 536.4 [MH]+ Example 113: (1 S,3S/1 R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl )-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E113)

[459] The compound was prepared as in Example 1, by reaction of (1S,3S or 1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}morpholine (p152, 63 mg, 0.228 mmol), Na2CO3 ( 26 mg, 0.25 mmol) and Nal (37 mg, 0.25 mmol) in DMF (0.2 mL) resulting in the title compound (1S,3S/1R,3R)-5-(3-{[4 - methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E113, 7.7 mg, y= 8%).NMR: 1H NMR (Acetone-d6) δ: 7.64 (d, 2H), 7.36 (d, 2H), 3.74-3.84 (m, 4H), 3.49 (s, 3H), 3.09-3.23 (m, 6H), 2.72 (d, 1H), 2.49-2.63 (m, 5H), 2.21-2.31 (m, 1H), 2.09 (br. s., 1H) , 1.89 (s, 2H), 1.59-1.70 (m, 1H), 1.37-1.49 (m, 1H), 1.24-1.29 (m, 1H), 1.19-1.24 (m, 1H) MS (m/z): 482.5 [MH]+. Example 114: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (TRANS, E114)

[460] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E113, 7.7 mg) was treated with 1.2 eq of HCl in Et2O resulting in hydrochloric salt of (1S, 3S/1R,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E114, 8 mg). MS (m/z): 482.5 [MH]+ Example 115: (1 R,3S/1 S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E115)

[461] The compound was prepared as in Example 1, by reaction of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 50 mg , 0.2 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}morpholine (p152, 59 mg, 0.212 mmol), Na2CO3 (25 mg, 0.231 mmol) and Nal (35 mg, 0.231 mmol) in DMF (0.2 mL) resulting in the title compound (1R,3S/1S,3R)-5-(3-{[4-methyl-5 -(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E115 , 45 mg, y= 47%).NMR: 1H NMR (CDCI3) δ: 7.55 (d, 2H), 7.23 (d, 2H), 3.82-3.91 (m, 4H), 3.39 (s, 3H), 3.09 - 3.25 (m, 6H), 2.39-2.96br. s., 5H), 2.12-2.22 (m, 2H), 1.87-2.08 (m, 4H), 1.18-1.28 (m, 2H) MS (m/z): 482.5 [MH]+. Example 116 and 117: (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E116) and (1S,3R)-5-(3-{[4-methyl-5-(morpholin- 4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 2, E117)

[462] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E115, 40 mg) was separated into individual enantiomers by preparative chiral HPLC.

[463] (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E116, 10.8 mg) Enantiomer 1: ret. time. 6.2 min, 100% ee MS (m/z): 482.5 [MH]+.

[464] (1S,3R)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E117, 9.8 mg) Enantiomer 2: ret, time 10.0 min, 100% ee MS (m/z): 482.5 [MH]+. Example 118: (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride (CIS, Enantiomer 1, E118)

[465] (1R, 3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E116, 10.8 mg) with 1.2 eq. From HCl to Et2O providing (1R, 3S)-5-(3- {[4-methyl-5-(morpholin-4-yl)- 4H-1,2,4-triazol- 3-yl] sulfanyl} propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E118, 11 mg). MS (m/z): 482.5 [MH]+.Example 119: 4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5 - azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1, diastereomeric mixture, E119)

[466] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, p15, 25 mg, 0. 1 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-2-one (p153, 32 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 ml), obtaining the compound 4-[4-methyl-5-({3-[ (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl] piperidin-2-one (CIS, Enantiomer 1, 23.7 mg).

[467] The latter was dissolved with DCM/Et2O and treated with 1.2 eq of HCl in Et2O, obtaining N4-[4-methyl-5-({3-[(1R, 3S)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one (E119, CIS, Enantiomer 1.19 mg, y = 36%) as diastereomeric mixture. NMR: 1H NMR (DMSO-d6) δ: 9.96-10.25 (m, 1H), 7.68 (d, 2H), 7.60 (br. s., 1H), 7.44 (br. s., 2H), 3.59-3.76 (m, 2H), 3.50 (s, 3H), 3.40 (br. s., 2H), 3.11 (br. s., 5H), 2.40-2.48 (m, 3H), 2.19-2.31 (m, 2H) , 1.87-2.16 (m, 4H), 1.71-1.85 (m, 2H), 1.26-1.55 (m, 3H) MS (m/z): 494.5 [MH]+.Example 120: 1-methyl-4 -[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1, diastereomeric mixture, E120)

[468] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.1 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methylpiperidin-2-one (p154.35 mg, 0.113 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 mL), giving the title compound 1-methyl-4-[4 -methyl-5-({3-[(1R,3S)-1-[4-trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2 ,4-triazol-3-yl]piperidine-2-one (CIS, Enantiomer 1,E120, 28.8 mg, y=55%).NMR: 1H NMR (Acetone-d6) δ: 7.63 (s, 2H) , 7.33-7.46 (m, 2H), 3.62 (s, 3H), 3.35-3.52 (m, 3H), 3.04-3.25 (m, 2H), 2.91 (s, 3H), 2.33-2.74(m, 7H) , 2.19-2.31 (m, 2H), 1.69-2.06 (m, 6H), 1.20-1.36 (m, 2H) MS (m/z): 508.4 [MH]+.Example 121: 5-[4- methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptan-5-yl]propyl}sulfanyl)-4H-1,2 ,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1, diastereomeric mixture, E121)

[469] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantomer 1, p15, 25 mg, 0.103 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidin-2-one (P155, 33 mg, 0.113 mmol) , Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 mL), obtaining 5-[4-methyl-5-({3-[(1R , 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin- 2-one (CIS, Enantiomer 1, 12 mg).

[470] The latter was dissolved with DCM/Et2O and treated with 1.2 eq of HCl in Et2O, obtaining 5-[4-methyl-5-({3-[(1R,3S)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-2-one hydrochloride (E121, CIS, Enantiomer 1.10 mg, y= 18%) as a diastereomeric mixture.NMR: 1H NMR (DMSO-d6) δ: 10.40-10.71 (m, 1H), 7.57-7.74 (m, 3H), 7.44 (d , 2H), 3.61-3.74 (m, 1H), 3.54 (s, 3H), 2.88-3.45 (m, 10H), 2.18-2.67 (m, 4H), 1.84-2.16 (m, 5H), 1.25-1.55 (m, 2H) MS (m/z): 494.3 [MH]+. Preparation 258: (1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p258)

[471] To a solution of (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (P14, 56 mg, 0.23 mmol) in THF (0.4 ml), in a vial, DIPEA (0.12 ml, 0.69 mmol) and 1-bromo-3-chloropropane (0.21 ml, 2.07 mmol) were added, the vial was sealed and the resulting mixture was stirred at 65°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with EA and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by FC on silica gel (elution with DCM/MeOH from 100/0 to 4/96), obtaining (1R,3S/1S,3R)-5- (3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p258, 51 mg, y = 68%) as pale yellow oil.MS (m/z) : 318.3 [MH]+.Example 122: 6-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E122)

[472] A sealed vial containing a mixture of (1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (p258 , CIS, 25 mg, 0.079 mmol), 6-(4-methyl-5-sulfanyl-4H-1,2,4-triazol-3-yl)-1,2-dihydroporidin-2-one (p72, 18 mg , 0.087 mmol), Na2CO3 (10 mg, 0.095 mmol) and Nal (12 mg, 0.079 mmol) and DMF (0.2 mL) were stirred overnight at 60°C in a PLS apparatus. The mixture was diluted with DCM, the organic phase was washed twice with water, dried over sodium sulfate and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (elution with DCM/MeOH 100/0 to 50/50) to give 6-[4-methyl-5-({3-[(1R,3S/1S,3R )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-di -hydropyridin-2-one (CIS, E122, 26 mg, y = 66%).NMR: 1H NMR (DMSO-d6) δ: 11.06-11.17 (m, 1H), 7.73-7.81 (m, 1H), 7.56 -7.67 (m, 2H), 7.29-7.46 (m, 3H), 6.68-6.76 (m, 1H), 3.86 (s, 3H), 3.14 (d, 2H), 2.64-2.78 (m, 1H), 2.36 -2.50 (m, 4H), 2.18-2.26 (m, 1H), 1.83-2.01 (m, 3H), 1.75 (m, 2H), 1.23-1.31 (m, 1H), 1.14-1.23 (m, 1H) MS (m/z): 490.4 [MH]+.Example 123: 6-[5-({3-[(1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl) phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2 -one (TRANS, E123)

[473] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (P13, TRANS, 30 mg, 0.12 mmol), 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-di- hydropyridin-2-one (P156, 38 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.13 mL), obtaining 6-[5-( {3-[(1R, 3S/1S, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4- methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS, E123, 30 mg, y = 44%).NMR: 1H NMR (Acetone-d6 ) δ: 7.75-7.82 (m, 1H), 7.51-7.57 (m, 1H), 7.457.51 (m, 2H), 7.26- 7.32 (m, 1H), 6.72-6.77 (m, 1H), 3.97 ( s, 3H), 3.33 (m, 2H), 2.75 (d, 1H), 2.63-2.70 (m, 2H), 2.53-2.63 (m, 3H), 2.26-2.33 (m, 1H), 1.93-2.00 ( m, 2H), 1.57-1.67 (m, 1H), 1.23-1.39 (m, 3H) MS (m/z): 508.0 [MH]+.Example 124: 3-[4-methyl-5-( {3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2.4]heptan-5-yl]propyl}sulfani)-4H-1,2,4- triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E124)

[474] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (p14, CIS, 30 mg, 0.116 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one (p157, 36 mg, 0.13 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (21 mg, 0.144 mmol) in DMF (0.2 mL), obtaining 3-[4-methyl-5-({3 -[(1R 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazole -3-yl]-1,2-dihydropyridin-2-one (CIS, E124, 23 mg, y = 40%). NMR: 1H NMR (CDC/3) 5: 7.64-7.72 (m, 1H), 7.50-7.59 (m, 3H), 7.17-7.25 (m, 2H), 6.32-6.39 (m, 1H), 3.46 (s , 3H), 3.17-3.25 (m, 2H), 2.76-2.85 (m, 1H), 2.57-2.65 (m, 1H), 2.46-2.54 (m, 2H), 2.42 (d, 1H), 2.10-2.16 (m, 2H), 1.81-2.02 (m, 4H), 1.16-1.23 (m, 2H) MS (m/z): 490.4 [MH]+. Example 125: azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one 3- hydrochloride [4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-(CIS, Enantiomer 1, E125)

[475] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p15, CIS, Enantiomer 1, 25mg, 0 .1 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one ( p157, 32 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (15 mg, 0.1 mmol) in DMF (0.2 mL), obtaining 3-[4-methyl -5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]-1,2-dihydropyridin-2-one (25 mg).

[476] The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (eq 1.1) was added and the reaction mixture was concentrated under vacuum. The solid then obtained was triturated with ether and dried under vacuum at 45 °C overnight, obtaining 3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl--1,2-dihydropyridin-2-hydrochloride one (CIS, Enantiomer 1, E125, 26 mg, y = 49%) as a white solid.NMR: 1H NMR (DMSO-d6) δ: 12.22 (br. s., 1H), 10.23-10.66 (m, 1H ), 7.74 (m, 1H), 7.61-7.69 (m, 3H), 7.36-7.49 (m, 2H), 6.38 (m, 1H), 2.59-3.79 (m, 11H), 2.25 (m, 5H), 1.23-1.56 (m, 2H) MS (m/z): 490.4 [MH]+. Example 126: 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS, E126)

[477] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p13, TRANS, 50 mg , 0.207 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one ( p158, 65 mg, 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining 5-[4-methyl-5-({3 -[(1S 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 -yl]- 1,2-dihydropyridin-2-one (TRANS, E126, 48 mg, y = 47%). NMR: 1H NMR (Acetone-d6) δ: 7.87 (d, 1H), 7.75-7.83 (m, 1H), 7.64 (d, 2H), 7.35 (d, 2H), 6.52 (d, 1H), 3.71 ( s, 3H), 3.29 (m, 2H), 2.75 (d, 2H), 2.53-2.67 (m, 5H), 2.23-2.32 (m, 1H), 1.90-2.00 (m, 2H), 1.61-1.73 ( m, 1H), 1.37-1.49 (m, 1H), 1.27 (d, 1H), 1.22 (d, 1H) MS (m/z): 490.4 [MH]+ Example 127: 5-[4-methyl -5-({3-[(1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4] heptan-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E127)

[478] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (p14, CIS, 35 mg, 0 .15 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one ( p158, 43 mg, 0.15 mmol), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.15 mmol) in DMF (0.2 mL), obtaining 5-[4-methyl -5-({3-[(1R 3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1 ,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E127, 33 mg, y = 45%).NMR: 1H NMR (DMSO-d6) δ: 11.96- 12.10 (m, 1H), 7.68-7.80 (m, 2H), 7.55-7.64 (m, 2H), 7.27-7.36 (m, 2H), 6.44-6.53 (m, 1H), 3.52 (s, 3H), 3.01-3.15 (m, 2H), 2.68 (br. s., 1H), 2.33- 2.48 (m, 4H), 2.16-2.26 (m, 1H), 1.81-2.02 (m, 3H), 1.73 (m, 2H), 1.27 (m, 1H), 1.18 (m, 1H) MS (m/z): 490.5 [MH]+. Example 128: 5-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E128)

[479] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p15, CIS, Enantiomer 1, 35 mg, 0.15 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridine-2-one (P158, 43 mg, 0.15 mmol), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.15 mmol) in DMF (0.2 ml), obtaining 5-[4-methyl- 5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4 -triazol-3-yl]- 1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E128, 23 mg, y = 31%).NMR: 1H NMR (Acetone-d6) δ: 7.87-7.91 (m, 1H), 7.73-7.79 (m, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 6.46-6.52 (m, 1H), 3.66 (s, 3H), 3.10-3.27 (m , 3H), 2.68-2.78 (m, 2H), 2.56-2.65 (m, 1H), 2.47 (s, 3H), 2.18-2.27 (m, 1H), 1.92-2.02 (m, 2H), 1.75-1.87 (m, 2H), 1.25-1.30 (m, 1H), 1.17-1.22 (m, 1H) MS (m/z): 490.5 [MH]+. Example 129: 5-[5-({3-[(1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E129)

[480] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p23, CIS, 50 mg, 0.193 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin- 2-one (p158, 60 mg, 0.23 mmol) Na2CO3 (25 mg, 0.23 mmol) and Nal (35 mg, 0.23 mmol) in DMF (0.2 ml), yielding 5-[5-({ 3-[(1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl -4H- 1,2,4-triazol-3-yl] -1,2-dihydropyridin-2-one(CIS, E129, 17.8 mg, y = 18%).NMR: 1H NMR (Acetone- d6) δ: 10.73-10.95 (m, 1H), 7.84 (m, 1H), 7.77 (m, 1H), 7.43-7.52 (m, 2H), 7.27-7.39 (m, 1H), 6.51 (m, 1H ), 3.66 (s, 3H), 3.10-3.34 (m, 2H), 2.75 (br. s., 1H), 2.38-2.67 (m, 4H), 2.19-2.33 (m, 1H), 1.92-2.03 ( m, 3H), 1.73-1.87 (m, 2H), 1.31-1.38 (m, 1H), 1.19-1.28 (m, 1H) MS (m/z): 508.4 [MH]+. Example 130: 5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl )-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E130)

[481] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane (p29, CIS, 50 mg, 0.24 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one (p158, 74 mg, 0.26 mmol), Na2CO3 (31 mg, 0.28 mmol) and Nal (43 mg, 0.288 mmol) in DMF (0.2 mL), obtaining 5-[5-({3- [(1S, 3S/1R,3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2, 4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E130, 38 mg, y = 34%). NMR: 1H NMR (Acetone-d6) δ: 7.83-7.88 (m, 1H), 7.74-7.79 (m, 1H), 7.087.18 (m, 1H), 6.88- 7.03 (m, 2H), 6.47-6.54 (m, 1H), 3.66 (s, 3H), 3.13-3.27 (m, 2H), 2.60 (d, 1H), 2.48 (m, 2H), 2.35 (d, 1H), 2.08-2.13 (m, 2H ), 1.92-2.00 (m, 3H), 1.77-1.86 (m, 2H), 1.17-1.24 (m, 1H), 1.10-1.16 (m, 1H) MS (m/z): 458.3 [MH] +. Example 131: 5-[5-({3-[(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E131)

[482] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane (p33, CIS, 50 mg, 0. 26 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one (p158 , 83 mg, 0.29 mmol), Na2CO3 (33 mg, 0.31 mmol) and Nal (47 mg, 0.31 mmol) in DMF (0.2 mL), obtaining 5-[5-({ 3-[(1R, 3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2, 4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E131, 30 mg, y = 26%). NMR: 1H NMR (Acetone-d6) δ: 7.82-7.87 (m, 1H), 7.75-7.81 (m, 1H), 7.167.21 (m, 2H), 7.03 (s, 2H), 6.47 -6.54 (m, 1H), 3.67 (s, 3H), 3.12-3.26 (m, 2H), 2.59-2.74 (m, 3H), 2.48 (s, 2H), 2.35 (s, 1H), 1.91-2.01 (m, 2H), 1.76-1.87 (m, 2H), 1.11 (s, 2H) MS (m/z): 440.4 [MH]+ Example 132: 5-[4-methyl-5-({3 -[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS, E132)

[483] The compound was prepared as in Example 1 by reacting (1S, 3S/1R, 3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p40, Trans, 30 mg, 0.124 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one (p158, 35 mg, 0.124 mmol), Na2CO3 (16 mg, 0.15 mmol) and Nal (19 mg, 0.124 mmol) in DMF (0.2 ml), yielding 5-[4-methyl-5-({3- [(1S, 3S/1R, 3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazole -3-yl]-1,2-dihydropyridin-2-one (TRANS, E132, 25 mg, y = 41%). NMR: 1H NMR (CDCl3) δ: 7.71-7.80 (m, 2H), 7.66 (d, 1H), 7.46 (m, 1H), 7.26-7.32 (m, 1H), 7.09 (d, 1H), 6.65- 6.80 (m, 1H), 3.59 (s, 3H), 3.35 (m, 2H), 2.48-2.95 (m, 5H), 2.27-2.44 (m, 2H), 1.91-2.09 (m, 2H), 1.45- 1.61 (m, 1H), 1,121.34 (m, 3H) MS (m/z): 490.4 [MH]+.Example 133: 1-methyl-5-[4-methyl-5-({ 3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 -yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E133)

[484] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p15, CIS, Enantiomer 1, 35 mg, 0.15 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methyl-1,2-dihydropyridin -2-one (p159, 50 mg, 0.165 mmol), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.18 mmol) in DMF (0.2 mL), obtaining 1-methyl -5-[4-methyl-5-({3-[(1R 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (45 mg) which was dissolved in Et2O (0.5 mL) and treated with 1.1 eq of 2N HCI in the ether. The solvent was removed under vacuum and the solid obtained was triturated with ether and dried under vacuum, obtaining 1-methyl-5-[4-methyl-5-({3-[(1R,3S)-1- hydrochloride [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin -2-one (CIS, Enantiomer 1, E133, 46.8 mg, y= 58%). NMR: 1H NMR (DMSO-d6) δ: 10.36 (s, 1H), 10.14-10.15 (m, 1H), 8.17 (br. s., 1H), 7.61-7.79 (m, 3H), 7.45 (d, 2H), 6.55 (d, 1H), 3.71 (br. s.,2H), 3.48-3.64 (m, 6H), 3.24-3.47 (m, 2H), 3.18 (d, 4H), 2.99 (br. s ., 1H), 2.26 (d,, 1H), 1.88-2.18 (m, 3H), 1.25-1.54 (m, 2H) MS (m/z): 504.5 [MH]+. Example 134: 4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E134)

[485] The compound was prepared as in Example 1, reacting (1R, 3S/1S, R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p14, CIS, 40 mg , 0.17 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2- one (p160, 48 mg, 0.17 mmol), Na2CO3 (22 mg, 0.2 mmol) and Nal (25 mg, 0.17 mmol) in DMF (0.25 mL), obtaining 4-[4 -methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, E134, 14 mg, y = 17%). NMR: 1H NMR (DMSO-d6) δ: 7.61 (d, 2H), 7.54 (d, 1H), 7.32 (d, 2H), 6.63 (d, 1H), 6.46-6.53 (m, 1H), 3.61 ( s, 3H), 3.07-3.19 (m, 2H), 2.65-2.74 (m, 1H), 2.35-2.49 (m, 5H), 2.17-2.24 (m, 1H), 1.83-1.98 (m, 3H), 1.70-1.79 (m, 2H), 1.241.30 (m, 1H), 1.13-1.21 (m, 1H) MS (m/z): 490.4 [MH]+. Example 135: 4-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS, E135)

[486] The compound was prepared as in Example 1, reacting (1S, 3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (p40, TRANS, 30 mg, 0.124 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2-dihydropyridin-2-one (p160, 35 mg, 0.124 mmol), Na2CO3 (16 mg, 0.15 mmol) and Nal (19 mg, 0.124 mmol) in DMF (0.25 mL), obtaining 4-[4-methyl-5-({3 - [(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4- triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS, E135, 12 mg, y = 20%). NMR: 1H NMR (CDCI3) δ: 7.66 (d, 1H), 7.38-7.50 (m, 2H), 7.22-7.33 (m, 1H), 7.09 (d, 1H), 6.76-6.84 (m, 2H), 3.70 (s, 3H), 3.40 (m, 2H), 2.53-2.93 (m, 5H), 2.29-2.40 (m, 2H), 2.02 (m, 2H), 1.48-1.69 (m, 1H), 1.16- 1.34 (m, 3H) MS (m/z): 490.4 [MH]+. Example 136: 1-methyl-4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E136)

[487] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p15, CIS, Enantiomer 1, 25 mg, 0.096 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H- 1,2,4-triazol-3-yl}-1-methyl-1, 2-dihydropyridin-2 -one (p161, 30 mg, 0.1 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol in DMF (0.2 Ml), obtaining 1-methyl-4- [4-methyl-5-({3- [(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E136, 40 mg, y = 82%).NMR: 1H NMR (Acetone-d6) δ: 7.72-7.77 (m, 1H), 7.59-7.65 (m, 2H), 7.367.43 (m, 2H), 6.68- 6.73 (m, 1H), 6.56-6.63 (m, 1H), 3.76 (s , 3H), 3.51-3.58 (m, 3H), 3.15-3.35 (m, 2H), 2.58 (br. S., 4H), 2.23-2.29 (m, 1H), 2.17 (br. S., 1H) , 1.812.02 (m, 5H), 1.29-1.35 (m, 1H), 1.20-1.26 (m, 1H) MS (m/z): 504.3 [MH]+.Example 137: 1-methyl-4 -[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H -1,2,4-triazol-3-yl] -1,2-dihydropyridin-2-one(CIS, Enantiomer 1, E137)

[488] 1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E136, 40 mg) was dissolved in MeOH and treated with 2M HCl in Et2O (1.1 eq) to form the corresponding hydrochloride salt. The solvent was removed under reduced pressure; the solid was triturated with Et2O and dried under high vacuum, obtaining 1-methyl-4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]- 5- azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1 , E137, 42 mg).MS (m/z): 504.3 [MH]+.Example 138: 4-[5-({3-[(1S, 3S)-1-[2-fluoro-4- (trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1, 2-dihydropyridin-2-one (CIS, Enantiomer 1, E138)

[489] The compound was prepared as in Example 1, reacting (1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (P24, CIS, 26 mg , 0.1 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methyl-dihydropyridin-2- one (p161, 33 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.113 ml), obtaining 4-[5-( {3-[(1S,3S)-1-[2-fluoro- 4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H- 1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E138, 29 mg, y = 55%). NMR: 1H NMR (Acetone-d6) δ: 7.72-7.81 (m, 1H), 7.45-7.54 (m, 2H), 7.307.45 (m, 1H), 6.68- 6.76 (m, 1H), 6.55-6.63 (m, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 3.19-3.37 (m, 2H), 2.26-2.68 (m, 7H), 1.77-2.01 (m, 4H), 1.19-1.48 (m, 2H) MS (m/z): 522.4 [MH]+. Example 139: 4-[5-({3-[(1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E139)

[490] 4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one (CIS, Enantiomer 1, E138, 29 mg) was dissolved in MeOH and treated with 2M HCl in Et2O (1.1 eq) to form the corresponding hydrochloride salt. The solvent was removed under reduced pressure; the solid was triturated with Et2O and dried under high vacuum, obtaining 4-[5-({3-[(1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[ 2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H- 1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2- hydrochloride one (CIS, Enantiomer 1, E139, 30.7 mg).MS (m/z): 522.3 [MH]+.Example 140: (1S,3S/1R,3R)-5-(3-{[ 4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2, 4] heptane (TRANS, E140)

[491] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p13, TRANS, 50 mg , 0.207 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H- 1,2,4-triazol-3-yl}pyridine (p162, 62 mg, 0.228 mmol), Na2CO3 ( 26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3-{[4-methyl-5- (pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E140, 57 mg, y= 58%). NMR: 1H NMR (Acetone-d6) δ: 8.68-8.73 (m, 1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.62 (d, 2H), 7.45-7.51 (m, 1H), 7.35 (d, 2H), 4.05 (s, 3H), 3.30-3.39 (m, 2H), 2.71-2.77 (m, 2H), 2.54-2.68 (m, 5H), 2.23-2.31 (m, 1H), 1.93-2.02 (m, 2H), 1.61-1.71 (m, 1H), 1.37-1.47 (m, 1H), 1.23- 1.29 (m, 1H), 1.18-1.23 (m, 1H) MS (m/z) : 474.4 [MH]+.Example 141: (1R,3S /1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H- 1,2,4 - triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, E141)

[492] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 35 mg , 0.15 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl} pyridine (p162, 39 mg, 0.15 mmol ), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.15 mmol) in DMF (0.2 mL), obtaining (1R,3S /1S,3R)-5-(3- {[4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[ 2,4]heptane (23 mg).

[493] The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (0.049 mL) was added and the reaction mixture was concentrated under vacuum. The solid then obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining (1R,3S /1S,3R)-5-(3-{[4-methyl-5-(pyridin-2 -yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, E141, 25 mg, y= 30%).NMR: 1H NMR (DMSO-d6) δ: 10.54-10.84 (m, 1H), 8.73 (d, 1H), 8.12 (d, 1H), 8.01 (m, 1H), 7.66 (d, 2H), 7.54 (m, 1H), 7.44 (d, 2H), 3.92 (d, 3H), 3.65-3.75 (m, 1H), 2.92-3.46 (m, 7H), 2.59-2.70 ( m, 1H), 2.18-2.43 (m, 2H), 1.92-2.16 (m, 3H), 1.25-1.53 (m, 2H) MS (m/z): 474.5 [MH]+.Example 142: ( 1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E142)

[494] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p13, TRANS, 50 mg , 0.207 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H- 1,2,4-triazol-3-yl}pyridine (p163, 62 mg, 0.228 mmol), Na2CO3 ( 26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3-{[4-methyl-5- (pyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E142, 58 mg, y= 59%). NMR: 1H NMR (Acetone-d6) δ: 8.96 (d, 1H), 8.73 (m, 1H), 8.15 (d, 1H), 7.63 (d, 2H), 7.54- 7.60 (m, 1H), 7.35 ( d, 2H), 3.76 (s, 3H), 3.33 (m, 2H), 2.73-2.77 (m, 1H), 2.54-2.68 (m, 6H), 2.24-2.31 (m, 1H), 1.97 (s, 2H), 1.62-1.72 (m, 1H), 1.38-1.49 (m, 1H), 1.27 (m, 1H), 1.19- 1.24 (m, 1H) MS (m/z): 474.4 [MH]+ Example 143: (1R,3S /1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, E143)

[495] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 35 mg , 0.15 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl} pyridine (p163, 39 mg, 0.15 mmol ), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.15 mmol) in DMF (0.2 mL), obtaining (1R,3S /1S,3R)-5-(3- {[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[ 2,4]heptane (25 mg).

[496] The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (0.049 mL) was added and the reaction mixture was concentrated under vacuum. The solid then obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, E143, 28 mg, y= 34%).NMR: 1H NMR (DMSO-d6) δ: 11.12-11.38 (m, 1H), 9.02 (d, 1H), 8.84 (m, 1H), 8.36 (d, 1H), 7.78 (m, 1H), 7.65 (m, 2H), 7.45 (m, 2H), 3.60-3.72 (m, 4H), 2.89-3.46 (m, 7H), 2.56-2.66 (m, 1H), 2.18- 2.48 (m, 2H), 1.94-2.16 (m, 3H), 1.48 (s, 2H) MS (m/z): 474.5 [MH]+. Examples 144 and 145: (1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E144) and (1R,3S)-5-(3-{[4-methyl-5-( pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E145)

[497] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane prepared in analogy with E143 (CIS, 56 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC).

[498] (1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl-5-azaspiro[2,4]heptane(CIS, E144, 16.6 mg) Enantiomer 1: retention time 6.3 min, 100% ee MS (m/z): 474 .4 [MH]+

[499] (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane(CIS, E145, 15.8 mg Enantiomer 2: retention time 10.0 min, 100% ee MS (m/z): 474 .4 [MH]+ Example 146: (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3 dihydrochloride -yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E146)

[500] (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E145, 15.8 mg) with 2.2 eq. of HCl in Et2O, obtaining (1R, 3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl dihydrochloride ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E146, 13.8 mg).MS (m/z): 482.5 [MH]+. Example 147: (1S,3S /1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro [2,4]heptane (CIS, E147)

[501] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p23, 50 mg, 0.193 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine (P163, 57 mg, 0.212 mmol ), Na2CO3 (25 mg, 0.23 mmol) and Nal (35 mg, 0.23 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-1-[2- fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2,4]heptane (CIS, E147, 47 mg, y = 49%).NMR: 1H NMR (Acetone-d6) δ: 8.96 (d, 1H), 8.72-8.77 (m, 1H), 8.13-8.18 (m, 1H), 7.56-7.60 (m, 1H), 7.49 (d, 2H), 7.32-7.38 (m, 1H), 3.73 (s, 3H), 3.17-3.36 (m, 2H), 2.44-2.71 (m, 5H), 2.26-2.30 (m, 1H), 1.96-2.05 (m, 3H), 1.83-1.90 (m, 2H), 1.22-1.41 (m, 2H) MS (m/z) : 492.4 [MH]+.Example 148 and 149: (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin -3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, E148) and (1S,3S)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-5-azaspiro[2,4] heptane (CIS, Enantiomer 2, E149)

[502] (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E147.56 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC).

[503] (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E148, 12 mg) Enantiomer 1: retention time 6.7 min, 100% ee MS (m/z ): 492.4 [MH]+.

[504] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E149, 12.4 mg) Enantiomer 2: retention time 9.1 min, 99.8% ee MS (m/z): 492.4 [MH]+. Example 150: (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1 dihydrochloride ,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E150)

[505] (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E148, 12 mg) was treated with 2.2 eq of HCl in Et2O, obtaining the dihydrochloride salt of (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,24-triazole- 3- yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E150, 13 mg). MS (m/z): 492.4 [MH]+. Example 151: (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-) dihydrochloride methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E151)

[506] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E149, 12.4 mg) was treated with 2.2 eq of HCl in Et2O, obtaining salt of (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2 dihydrochloride, 4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] heptane (CIS, Enantiomer 2, E151, 13 mg). MS (m/z): 492.4 [MH]+.Example 152: (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5 -(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E152)

[507] The compound was prepared as in example 1, reacting (1S, 3S/1R, 3R)-1-(2,4-difluorophenyl)-5-azaspiro[2,4]heptane (CIS, p29, 50 mg, 0.24 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine (p163, 71mg, 0.26 mmol), Na2CO3 (31 mg, 0.28 mmol) and Nal (43 mg, 0.288 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-1-(2,4-difluorophenyl) -5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E152, 41 mg, y = 39%). NMR: 1H NMR (Acetone-d6) δ: 8.94-8.99 (m, 1H), 8.72-8.77 (m, 1H), 8.148.19 (m, 1H), 7.55- 7.62 (m, 1H), 7.12-7.20 (m, 1H), 6.90-7.04 (m, 2H), 3.74 (s, 3H), 3.26 (d, 2H), 2.74-2.78 (m, 1H), 2.59-2.66 (m, 1H), 2.47-2.56 (m, 2H), 2.38 (d, 1H), 2.09-2.15 (m, 1H), 1.95-2.02 (m, 3H), 1.82-1.92 (m, 2H), 1.20-1.25 (m, 1H), 1.12 -1.19 (m, 1H) MS (m/z): 442.4[MH]+. Examples 153 and 154: (1R, 3R)-1-(2,4-difluorophenyl)-5-(3-{[ 4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E153) e(1S, 3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS,Enantiomer 2, E154)

[508] (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H- 1,2, 4-Triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E152, 41 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC).

[509] (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl]propyl)-5-azaspiro[2,4]heptane (CIS, E153, 13 mg) Enantiomer 1: retention time 7.8 min, 100% ee MS (m/z): 442.3 [MH]+.

[510] (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, E154, 12.8 mg) Enantiomer 2: retention time 11.6 min, 99.8% ee MS (m/z): 442 .4[MH]+. Example 155: (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4- dihydrochloride triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, E155).

[511] (1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E153, 13 mg) was treated with 2.2 eq of HCl in Et2O, obtaining dihydrochloride salt of (1R,3R) -1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -5- azaspiro[2,4]heptane (CIS, Enantiomer 1, E155, 15 mg).MS (m/z): 442.4[MH]+. Example 156: (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4- dihydrochloride triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4] heptane (CIS, Enantiomer 2, E156).

[512] (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole- 3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E154, 12.8 mg) was treated with 2.2 eq of HCl in Et2O, obtaining dihydrochloride salt of (1S, 3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-5- azaspiro[2,4]heptane (CIS, Enantiomer 2, E156, 14.5 mg).MS (m/z): 442.3 [MH]+. Example 157: (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E157)

[513] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-(4-fluorophenyl)-5-azaspiro[2,4]heptane (CIS, p33, 50 mg, 0. 26 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl} pyridine (p163, 77mg, 0.29 mmol), Na2CO3 ( 33 mg, 0.31 mmol) and Nal (47 mg, 0.31 mmol) in DMF (0.2 mL), giving (1R,3S/1S,3R)-1-(4-fluorophenyl)-5 -(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS , E157, 34 mg, y= 31%).NMR: 1H-NMR (Acetone-d6) δ: 8.97 (d, 1H), 8.74 (m, 1H), 8.16 (m, 1H), 7.58 (m, 1H ), 7.17- 7.24 (m, 2H), 7.01-7.09 (m, 2H), 3.72-3.76 (m, 3H), 3.18-3.32 (m, 2H), 2.62-2.78 (m, 2H), 2.52 (m , 2H), 2.36-2.44 (m, 1H), 2.09-2.15 (m, 2H), 1.82-2.02 (m, 4H), 1.06-1.16 (m, 2H) MS (m/z): 424.4 [ MH]+.Examples 158 and 159: (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2, 4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS,Enantiomer 1, E158) and (1R,3S)-1-(4-fluorophenyl)-5-(3- {[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E159)

[514] (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E157, 34 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC). (1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-5-azaspiro[2,4]heptane (CIS, E158, 10.7 mg) Enantiomer 1: retention time 10.2 min, 100% ee MS (m/z): 424.4 [MH] +.(1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E159, 10.8 mg) Enantiomer 2: retention time 15.9 min, 99.8% ee MS (m/z): 424, 4 [MH]+.Example 160: (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2, 4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane dihydrochloride (CIS, Enantiomer 2, E160)

[515] (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol- 3- yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E159, 13 mg) was treated with 2.2 eq of HCI in Et2O, obtaining (1R,3S)-1- (4-fluoropheinyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[ 2,4]heptane (CIS, Enantiomer 2, E160, 10 mg).MS (m/z): 424.5 [MH]+. Example 161: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-phenyl-5-azaspiro[2,4]heptane (CIS, E161)

[516] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-phenyl-5-azaspiro[2,4]heptane (CIS, p19, 50 mg, 0.289 mmol), 3- {5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine (p163, 85 mg, 0.317 mmol), Na2CO3 (37 mg, 0.35 mmol ) and Nal (53 mg, 0.35 mmol) in DMF (0.2 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin- 3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-5-azaspiro[2,4]heptane (CIS, E161, 55mg, y= 47%) .NMR: 1H-NMR (Acetone-d6) δ: 8.94-9.00 (m, 1H), 8.72-8.79 (m, 1H), 8.138.21 (m, 1H), 7.54- 7.62 (m, 1H), 7.29 (s, 2H), 7.19 (d, 3H), 3.74 (s, 3H), 3.20-3.36 (m, 3H), 2.52-3.00 (m, 5H), 2.26-2.38 (m, 1H), 2.17 (d , 1H), 1.87-2.04 (m, 4H), 1.22 (d, 1H), 1.12-1.19 (m, 1H) MS (m/z): 406.4 [MH]+. Example 162: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E162)

[517] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine (p164, 62 mg, 0.228 mmol), Na2CO3 ( 26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3-{[4-methyl-5- (pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)]-5-azaspiro[2,4]heptane (TRANS, E162 , 61 mg, y= 62%). NMR: 1H NMR (Acetone-d6) δ: 8.74-8.80 (m, 2H), 7.75-7.80 (m, 2H), 7.63 (d, 2H), 7.36 (d, 2H), 3.81 (s, 3H), 3.35 (m, 2H), 2.64 (br. s., 6H), 2.24-2.32 (m, 1H), 2.09-2.13 (m, 1H), 1.99 (m, 2H), 1.62-1.75 (m, 1H) , 1.38-1.50 (m, 1H), 1.27 (d, 1H), 1.22 (s, 1H) MS (m/z): 474.4 [MH]+.Example 163: (1R,3S /1S,3R) -5-(3-{[4-methyl-5-(pyridin-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl ]-5-azaspiro[2,4]heptane dihydrochloride (CIS, E163)

[518] The compound was prepared as in Example 1, reacting (1R,3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 35 mg , 0.15 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl} pyridine (p164, 39 mg, 0.15 mmol ), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.15 mmol) in DMF (0.2 mL), obtaining (1R,3S /1S,3R)-5-(3- {[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[ 2,4]heptane (27 mg).

[519] The latter was dissolved in DCM (0.2 mL) and then 2N HCl / ether (eq 2) was added and the reaction mixture was concentrated under vacuum. The solid then obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining (1R, 3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane dihydrochloride (CIS, E163, 30 mg, y= 30%).NMR: 1H NMR (DMSO-d6) δ: 11.13-11.35 (m, 1H), 8.92 (d, 2H), 8.07 (d, 2H), 7.61-7.72 (m, 2H ), 7.45 (m, 2H), 3.73 (d, 3H), 3.61-3.70 (m, 1H), 3.35-3.45 (m, 1H), 3.23-3.35 (m, 3H), 3.03-3.22 (m, 2H ), 2.56-2.65 (m, 1H), 2.56-2.98 (m, 1H), 2.36-2.49 (m, 1H), 1.94-2.34 (m, 4H), 1.25-1.51 (m, 2H) MS (m/ z): 474.4 [MH]+. Example 164: (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl- 5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (TRANS, E164)

[520] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, p22, 30 mg, 0.12 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine (p164, 35 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R, 3S/1S 3R)-1-[2-fluoro-4- ( trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2 ,4]heptane (TRANS, E164, 35.5 mg, y= 56%). NMR: 1H NMR (Acetone-d6) δ: 8.77 (d, 2H), 7.73-7.79 (m, 2H), 7.45-7.54 (m, 2H), 7.27-7.34 (m, 1H), 3.82 (s, 3H ), 3.36 (m, 2H), 2.59-2.78 (m., 6H), 2.33 (m, 1H), 1.95-2.04 (m, 2H), 1.63- 1.72 (m, 1H), 1.23-1.46 (m, 3H) MS (m/z): 492.4 [MH]+. Example 165: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3- yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E165).

[521] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 40 mg , 0.17 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine (p165, 48 mg, 0 .17 mmol), Na2CO3 (22 mg, 0.2 mmol) and Nal (25 mg, 0.17 mmol) in DMF (0.25 mL), obtaining (1R,3S/1S,3R)-5- (3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl] -5-azaspiro[2,4]heptane (CIS, E165, 24 mg, y= 29%). NMR: 1H NMR (CDCI3) δ: 8.68 (m, 1H), 7.66 (m, 1H), 7.54 (d, 2H), 7.267.33 (m, 1H), 7.22 (d, 2H), 3.27-3.43 ( m, 5H), 2.79-2.88 (m, 1H), 2.63-2.72 (m, 1H), 2.57 (s, 2H), 2.50 (s, 3H), 2.41-2.47 (m, 1H), 2.16 (d, 2H), 1.90-2.07 (m, 4H), 1.74-1.78 (m, 1H), 1.16-1.26 (m, 2H) MS (m/z): 488.5 [MH]+. Example 166: (1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, Enantiomer 1, E166).

[522] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 30 mg, 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine (p165, 35mg, 0.12 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL), obtaining (1R,3S or 1S,3R)-5-(3-{[4-methyl -5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)]-5-azaspiro[2,4] heptane (11 mg).

[523] The latter was dissolved in DCM (0.2 mL) and then 2N HCI / ether (eq 2.1) was added and the reaction mixture was concentrated under vacuum. The solid obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining (1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, Enantiomer 1, E166, 12 mg, y= 18%).NMR: 1H NMR (DMSO-d6) δ: 10.72-10.99 (m, 1H), 8.70-8.77 (m, 1H), 8.04-8.14 (m, 1H), 7.66 (d , 2H), 7.56-7.62 (m, 1H), 7.45 (d, 2H), 3.63-3.73 (m, 2H), 3.36-3.48 (m, 4H), 3.07-3.34 (m, 6H), 2.91-3.01 (m, 1H), 2.59-2.71 (m, 1H), 2.172.44 (m, 2H), 2.09 (br. s., 3H), 1.36-1.53 (m, 2H), 1.21-1.35 (m, 1H ) MS (m/z): 488.4 [MH]+. Example 167: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H- 1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E167)

[524] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p40, 30 mg , 0.124 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine (p165, 35 mg, 0.124 mmol) , Na2CO3 (16 mg, 0.15 mmol) and Nal (19 mg, 0.124 mmol) in DMF (0.25 mL), obtaining (1S, 3S/1R, 3R)-5-(3-{[4 -methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2 ,4]heptane (TRANS, E167, 14.5 mg, y= 24%). NMR: 1H NMR (CDCl3) δ: 8.69 (s, 1H), 7.66-7.72 (m, 2H), 7.45-7.52 (m, 1H), 7.32 (s, 2H), 7.09-7.14 (m, 1H), 3.41 (s, 5H), 2.85-2.93 (m, 1H), 2.62-2.76 (m, 4H), 2.50-2.54 (m, 3H), 2.34-2.43 (m, 2H), 2.03-2.12 (m, 2H ), 1.58 (br. s., 1H), 1.23-1.35 (m, 4H) MS (m/z): 488.4 [MH]+. Example 168: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (TRANS, E168)

[525] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E167, 14.5 mg) was dissolved in Et2O and treated with 2.2 eq of HCl in Et2O , obtaining (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride salt (TRANS, E168, 13.7 mg). MS (m/z): 488.4 [MH]+. Example 169: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E169)

[526] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 40 mg , 0.17 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylpyridine (p166, 48 mg, 0 .17 mmol), Na2CO3 (22 mg, 0.2 mmol) and Nal (25 mg, 0.17 mmol) in DMF (0.25 mL), obtaining (1R,3S/1S,3R)-5- (3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl] -5-azaspiro[2,4]heptane (CIS, E169, 35 mg, y= 42%). NMR: 1H NMR (CDCI3) δ: 8.77 (d, 1H), 7.91 (m, 1H), 7.54 (d, 2H), 7.33 (d, 1H), 7.21 (d, 2H), 3.59 (s, 3H) , 3.23-3.37 (m, 2H), 2.79-2.89 (m, 1H), 2.67 (s, 4H), 2.57 (s, 2H), 2.42-2.48 (m, 1H), 2.11-2.19 (m, 2H) , 1.90-2.07 (m, 5H), 1.21 (s, 2H) MS (m/z): 488.5 [MH]+.Example 170: (1R,3S)-5-(3-{[4-methyl -5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane dihydrochloride (CIS, Enantiomer 1, E170)

[527] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.1 mmol) 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-3-methylpyridine (p167, 31 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.113 mL), obtaining (1R,3S)-5-(3-{[4-methyl -5-(3-methylpyridin-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane (28.8 mg).

[528] The latter was dissolved in DCM/Et2O then 2N HCl/ether (2.2 eq) was added and the reaction mixture was concentrated under vacuum, obtaining (1R,3S)- 5-(3-{[ 4-methyl-5-(3-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [ 2.4] heptane dihydrochloride (CIS, Enantiomer 1, E170, 30.9 mg, y = 55%).NMR: 1H NMR (DMSO-d6) δ: 9.84-10.16 (m, 3H), 8.54-8.60 ( m, 1H), 7.847.91 (m, 1H), 7.66 (d, 2H), 7.45 (d, 3H), 3.67-3.77 (m, 2H), 3.60 (s, 3H), 3.39 (br. s. , 2H), 3.22 (d, 3H), 2.45 (s, 3H), 2.36-2.43 (m, 1H), 2.18-2.30 (m, 2H), 1.95-2.15 (m, 3H), 1.26-1.52 (m , 3H) MS (m/z): 488.4 [MH]+. Example 171: (1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4- methyl-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, E171)

[529] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, P15, 25 mg, 0.1 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2,6-dimethylpyridine (P168, 34 mg, 0.11 mmol), Na2CO3 (13 mg, 0.123 mmol) and Nal (19 mg, 0.123 mmol) in DMF (0.15 mL) generating (1R,3S)-5-(3-{[5-(2, 6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E171, 36 mg, y= 71%). NMR: 1H NMR (Acetone-d6) δ: 7.66-7.70 (m, 1H), 7.59-7.64 (m, 2H), 7.387.44 (m, 2H), 7.21- 7.26 (m, 1H), 3.45 (s , 3H), 3.18-3.36 (m, 3H), 2.82-2.90 (m, 1H), 2.57-2.74 (m, 3H), 2.55 (s, 3H), 2.39 (s, 3H), 2.25-2.34 (m , 1H), 2.09-2.15 (m, 1H), 1.98-2.05 (m, 3H), 1.89-1.97 (m, 2H), 1.21-1.38 (m, 2H) MS (m/z): 502.4 [ MH]+. Example 172: (1R,3S)-5-(3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} Propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, E172)

[530] (1R, 3S)-5-(3 - {[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl} propyl) 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E171, 36 mg) was dissolved in Et2O and treated with 2.2 eq of HCl in Et2O. The solid then obtained was triturated with ether and dried under vacuum, obtaining (1R,3S)-5- (3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H- 1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane dihydrochloride salt (CIS, E172, 40.8 mg) . MS (m/z): 502.4 [MH]+. Example 173: (1R,3S/1S,3R)-5-(3-{[5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E173)

[531] A sealed vial containing a mixture of (1R,3S/1S,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p258 , 25 mg, 0.079 mmol), 5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (p85, 17 mg, 0.083 mmol), Na2CO3 (10 mg, 0.095 mmol) and Nal (12 mg, 0.079 mmol) and DMF (0.2 mL) was stirred overnight at 60 ° C in a PLS apparatus. The mixture was diluted with DCM, the organic phase was washed twice with water, dried over sodium sulfate and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with 100/0 to 90/10 DCM/MeOH) to yield (1R,3S/1S,3R)-5-(3-{[5-(2 -fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E173, 24.5 mg, y = 63%).NMR: 1H NMR (DMSO-d6) δ: 8.47-8.51 (m, 1H), 8.21-8.28 (m, 1H), 7.577.64 (m , 3H), 7.34 (d, 2H), 3.46 (d, 3H), 3.10-3.21 (m, 2H), 2.74 (br. s., 1H), 2.38- 2.56 (m, 3H), 2.24 (br. s., 1H), 1.72-2.05 (m, 6H), 1.25-1.33 (m, 1H), 1.14-1.25 (m, 1H) MS (m/z): 492.4 [MH]+. Example 174: (1R,3S)-5-[3-({4-methyl-5[2-(trifluoromethyl) pyridin-3-yl]-4H- 1,2,4-triazol-3-yl}sulfanyl) propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane dihydrochloride (CIS, Enantiomer 1, E174)

[532] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 30 mg, 0.12 mmol) of 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-(trifluoromethyl)pyridine (p169, 44 mg , 0.13 mmol), Na2CO3 (15mg, 0.14mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 ml), obtaining (1R,3S)-5-[3-( {4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4] Heptane (40 mg).

[533] The latter was dissolved in DCM and then 2N HCl/ether (2.2 eq) was added and the reaction mixture was concentrated under vacuum. The solid obtained was triturated with ether and dried under vacuum at 45° C overnight, obtaining (1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3 heptane dihydrochloride (CIS, Enantiomer 1) , E174, 41 mg, y= 55%).NMR: 1H NMR (DMSO-d6) δ: 10.24-10.57 (m, 1H), 8.98 (d, 1H), 8.25 (d, 1H), 7.95 (m, 1H), 7.66 (d, 2H), 7.44 (m, 2H), 3.65-3.77 (m, 1H), 3.41-3.48 (m, 1H), 3.35 (br. s., 3H), 3.23 (d, 6H ), 2.63-3.04 (m, 1H), 2.20-2.45 (m, 2H), 1.92-2.16 (m, 3H), 1.27-1.53 (m, 2H) MS (m/z): 542.4 [MH] +. Example 175: (1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}sulfanyl )propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 1, E175)

[534] The compound was prepared as in example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, p15, 30 mg, 0.12 mmol) 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methoxypyridine (p170, 39 mg, 0.13 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL), obtaining (1R,3S)-5-(3-{[5 -(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)]-5-azaspiro[2, 4] heptane (CIS, Enantiomer 1, E175, 33 mg, y = 52%).

[535] NMR: 1H NMR (CDCI3) δ: 8.32-8.39 (m, 1H), 7.84-7.92 (m, 1H), 7.55 (d, 2H), 7.21-7.27 (m, 2H), 7.04-7.10 ( m, 1H), 4.00 (s, 3H), 3.43 (s, 3H), 3.29 (m, 2H), 2.98-3.12 (m, 1H), 2.59-2.98 (m, 4H), 2.25-2.38 (m, 1H), 2.18-2.25 (m, 1H), 2.06 (d, 4H), 1.28 (d, 2H) MS (m/z): 504.4 [MH]+. Example 176: (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, Enantiomer 1, E176)

[536] (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E175, 28 mg) was dissolved in DCM and treated with 2.2 eq of HCI in Et2O. The solid then obtained was triturated with ether and dried under vacuum, obtaining (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane dihydrochloride salt (CIS, E176, 30 mg). MS (m/z): 504.4 [MH]+. Example 177: 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitril dihydrochloride (CIS, Enantiomer 1, E177)

[537] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.10 mmol) 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carbonitrile (p171, 30 mg, 0. 10 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (15 mg, 0.10 mmol) in DMF (0.15 mL), obtaining 5-[4-methyl-5-({3- [(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl ]pyridine-2-carbonitril (15 mg).

[538] The latter was dissolved in DCM and then 2N HCl/ether (eq 2.1) was added and the reaction mixture was concentrated under vacuum. The solid obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile dihydrochloride (CIS, Enantiomer 1, E177 , 17 mg, y = 30%).NMR: 1H NMR (DMSO-d6) δ: 10.41-10.70 (m, 1H), 9.11 (s, 1H), 8.42 (s, 1H), 8.27 (d, 1H) , 7.66 (d, 2H), 7.38-7.49 (m, 2H), 3.67 (d, 3H), 3.06-3.47 (m, 7H), 2.61-3.01 (m, 1H), 2.45-2.50 (m, 1H) , 2.20-2.44 (m, 2H), 1.92-2.15 (m, 3H), 1,261.53 (m, 2H) MS (m/z): 499.5 [MH]+.Example 178: 4-[4- methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2 ,4-triazol-3-yl]pyridine-2-carbonitrile (CIS, Enantiomer 1, E178)

[539] The compound was prepared as in [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 80 mg,0.33 mmol) 4-{5-[( 3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carbonitrile (p172, 98 mg, 0.33 mmol), Na2CO3 (42 mg, 0.4 mmol) and Nal (49 mg, 0.33 mmol) in DMF (0.5 mL), obtaining 4-[4-methyl-5-({3-[(1R,3S)-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (CIS, Enantiomer 1, E178, 53 mg, y= 32%). NMR: 1H NMR (CDCI3) δ: 8.88-8.94 (m, 1H), 8.05-8.08 (m, 1H), 7.88-7.92 (m, 1H), 7.52-7.60 (m, 2H), 7.22-7.27 (m , 2H), 3.73 (s, 3H), 3.31-3.40 (m, 2H), 3.03-3.16 (m, 1H), 2.64-3.01 (m, 4H), 2.30-2.42 (m, 1H), 2.21-2.27 (m, 1H), 2.022.20 (m, 4H), 1.30 (d, 2H) MS (m/z): 499.4 [MH]+. Example 179: 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, E179)

[540] The compound was prepared as in Example 1, reacting (1S, 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, p13, 50 mg , 0.21 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (p173, 72 mg, 0.231 mmol), Na2CO3 (38 mg, 0.252 mmol) and Nal (38 mg, 0.252 mmol) in DMF (0.236 mL), obtaining 5-[4-methyl-5-({3- [(1S,3S/ 1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4-triazol-3-yl]pyridine -2-carboxamide (TRANS, E179, 47.6 mg, y= 43%). NMR: 1H-NMR (Acetone-d6) δ: 8.99-9.01 (m, 1H), 8.36 (d, 1H), 8.29 (d, 1H), 7.95-8.04 (m, 1H), 7.62 (d, 2H) , 7.32-7.39 (m, 2H), 6.87-6.95 (m, 1H), 3.81 (s, 3H), 3.30-3.38 (m, 2H), 2.72-2.75 (m, 1H), 2.54-2.66 (m, 5H), 2.23-2.30 (m, 1H), 1.92- 2.02 (m, 2H), 1.61-1.70 (m, 1H), 1.40-1.48 (m, 1H), 1.23-1.29 (m, 1H), 1.17- 1.23 (m, 1H) MS (m/z): 517.4 [MH]+. Examples 180 and 181: 5-[4-methyl-5-({3-[(1S,3S or 1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan- 5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-(TRANS, 1 Enantiomer, E180) and 5-[4-methyl-5-({3-[ (1R,3R or 1S, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)- 4H-1,2,4-triazol- 3-yl]pyridine-2-carboxamide (TRANS, Enantiomer 2, E181)

[541] 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, E179, 47.6 mg) was separated into individual enantiomers by preparative chiral HPLC. 5-[4-methyl-5-({3-[(1S, 3S or 1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, E180, 15.6 mg) Enantiomer 1: retention time 4.8 min, 100% ee MS (m /z): 517.3 [MH]+ 5-[4-methyl-5-({3-[(1R,3R or 1S,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [ 2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, E181, 14.4 mg) Enantiomer 2: retention time 5.6 min, 99.8% ee MS (m/z): 517.3 [MH]+ Example 182: 5-[4-methyl-5-({3-[(1R,3S/1S,3R) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, E182)

[542] The compound was prepared as in Example 1, reacting (1R,3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, P14, 30 mg , 0.116 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (P173, 41 mg, 0. 13 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (21 mg, 0.14 mmol) in DMF (0.2 ml), obtaining 5-[4-methyl-5-({3 -[( 1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 - yl]pyridine-2-carboxamide (CIS, E182, 23 mg, y = 38%). NMR: 1H NMR (CDC/3) δ: 8.90-8.96 (m, 1H), 8.36-8.41 (m, 1H), 8.15-8.20 (m, 1H), 7.81-7.91 (m, 1H), 7.52-7.59 (m, 2H), 7.20-7.26 (m, 2H), 5.64-5.74 (m, 1H), 3.66 (s, 3H), 3.26-3.41 (m, 2H), 2.84-2.95 (m, 1H), 2.74 (d, 1H), 2.63 (m, 2H), 2.50 (d, 1H), 2.14-2.26 (m, 2H), 1.92-2.11 (m, 4H), 1.19-1.33 (m, 2H) MS (m/ z): 517.5 [MH]+. Example 183: 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E183)

[543] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.096 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (p173, 33 mg, 0.106 mmol) , Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.1 mL), obtaining 5-[4-methyl-5-({3-[(1R,3S)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide ( CIS, Enantiomer 1, E183, 13 mg, y= 26%). NMR: 1H NMR (Acetone-d6) δ: 8.97-9.02 (m, 1H), 8.36 (d, 1H), 8.25-8.31 (m, 1H), 7.95-8.07 (m, 1H), 7.62 (d, 2H ), 7.39 (d, 2H), 6.85-6.98 (m, 1H), 3.73-3.81 (m, 3H), 3.18-3.36 (m, 2H), 2.39-2.71 (m, 5H), 2.24 (d, 1H ), 2.10-2.17 (m, 1H), 1.79-2.04 (m, 4H), 1.30 (br. s., 1H), 1.23 (d, 1H) MS (m/z): 517.5 [MH]+ . Example 184: 5-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide dihydrochloride (CIS, Enantiomer 1, E184)

[544] 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]-pyridine-2-carboxamide (CIS, Enantiomer 1, E183, 13 mg) was dissolved in DCM and treated with 2.2 eq of HCl in Et2O. The solid then obtained was triturated with ether and dried under vacuum, obtaining 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide dihydrochloride salt (CIS, Enantiomer 1, E184, 14 mg) . MS (m/z): 517.4 [MH]+. Example 185: 5-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptan-5-yl]propyl} sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E185)

[545] The compound was prepared as in Example 1, reacting (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p24 , 25 mg, 0.096 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (p173, 34 mg , 0.11 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.108 mL), obtaining 5-[5-({3 -[(1S,3S)- 1- [2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H- 1,2,4-triazol-3- yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E185, 26.5 mg, y= 52%). NMR: 1H NMR (Acetone-d6) δ: 8.96-9.02 (m, 1H), 8.33-8.39 (m, 1H), 8.268.31 (m, 1H), 7.97- 8.06 (m, 1H), 7.45-7.51 (m, 2H), 7.32-7.39 (m, 1H), 6.84-6.97 (m, 1H), 3.78 (s, 3H), 3.19- 3.33 (m, 2H), 2.77 (br. s., 6H), 2.24-2.33 (m, 1H), 2.03 (br. s., 2H), 1.82-1.94 (m, 2H), 1.35-1.42 (m, 1H), 1.22-1.29 (m, 1H) MS (m/z ): 535.4 [MH]+. Example 186: 5-[5-({3-[(1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 2, E186)

[546] The compound was prepared as in Example 1, reacting (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, p25 , 25 mg, 0.096 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (p173, 34 mg , 0.11 mmol), Na2CO3 (12mg, 0.115mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.108 ml), obtaining 5-[5-({3-[(1R,3R)-1 -[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl ]pyridine-2-carboxamide (CIS, Enantiomer 2, E186, 19.9 mg, y= 38%). NMR: 1H NMR (Acetone-d6) δ: 8.96-9.02 (m, 1H), 8.33-8.39 (m, 1H), 8.268.31 (m, 1H), 7.97- 8.06 (m, 1H), 7.45-7.51 (m, 2H), 7.32-7.39 (m, 1H), 6.84-6.97 (m, 1H), 3.78 (s, 3H), 3.19- 3.33 (m, 2H), 2.77 (br. s., 6H), 2.24-2.33 (m, 1H), 2.03 (br. s., 2H), 1.82-1.94 (m, 2H), 1.35-1.42 (m, 1H), 1.22-1.29 (m, 1H) MS (m/z ): 535.4 [MH]+. Example 187: 6-methyl-5-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E187)

[547] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg , 0.1 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxamide (P234, 37 mg, 0.11 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.108 ml) to obtain 6-methyl-5-[4-methyl-5-({ 3-[1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3- yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E187, 27 mg, y = 51%).NMR: 1H NMR (DMSO-d6) δ: 8.10-8.16 (m, 1H), 8.01 (d, 2H) , 7.73-7.78 (m, 1H), 7.59 (s, 2H), 7.29-7.36 (m, 2H), 3.37 (s, 3H), 3.10-3.20 (m, 2H), 2.69-2.74 (m, 1H) , 2.36-2.54 (m, 7H), 2.17-2.24 (br. s., 1H), 1.82-1.98(m, 3H), 1.71-1.81 (m, 2H), 1.23-1.31 (m, 1H), 1.16 (d, 1H) MS (m/z): 531.4 [MH]+. Example 188: 6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxylic acid form (CIS, Enantiomer 1, E188)

[548] (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane Enantiomer 1, p15, 30 mg, 0.096 mmol), 5-{5-[(3- chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyridine-2-carboxylic acid (p235, 300 mg, 0.9 mmol assumed), Na2CO3 (120 mg, 1.15 mmol) and Nal (17 mg, 0.115 mmol) were dissolved in DMF (0.4 mL) and heated at 60°C overnight. The mixture was charged to C18 and was purified by FC in a C18 cartridge (water eluent + 0.1% FA 60% water + 0.1% FA 40% MeOH + 0.1%), obtaining 6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl }sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxylic acid form (CIS, Enantiomer 1, E188, 12 mg, y= 18%) as a white solid.NMR: 1H NMR (Acetone-d6) δ: 8.15 (s, 1H), 8.10-8.13 (m, 1H), 7.61 (s, 2H), 7.36-7.43 (m, 2H), 3.54 (s, 3H), 3.18-3.37 (m, 4H), 2.72 (br. s., 1H), 2.51-2.64 (m, 6H), 2.25-2.31 (m, 1H), 2.09 (br. s., 2H), 1.93-2.02 (m, 2H), 1.86-1.90 (m, 1H), 1.28-1.35 (m, 1H), 1.21-1.26 (m, 1H) MS (m/z): 532.4 [MH]+. Example 189: 6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide dihydrochloride (CIS, Enantiomer 1, E189)

[549] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 30 mg, 0.12 mmol) of 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide (p174, 43 mg, 0 .14 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL), obtaining 6-[4-methyl-5-({3 -[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3- yl]pyridine-3-carboxamide (27.5 mg).

[550] The latter was dissolved in DCM and then 2N HCl/ether (2.2 eq) was added and the reaction mixture was concentrated under vacuum. The solid then obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining 6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl )phenyl]-5-azaespiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiomer 1, E189, 31 mg, y = 44%). NMR: 1H NMR (DMSO-d6) δ: 10.66-10.87 (m, 1H), 9.15 (d, 1H), 8.38-8.44 (m, 1H), 8.30 (br. s., 1H), 8.22 (d, 1H), 7.72 (br. s., 1H), 7.67 (d, 2H), 7.45 (d, 2H), 3.95 (d, 3H), 3.66-3.75 (m, 1H), 2.94-3.46 (m, 7H ), 1.96-2.69 (m, 5H), 1.28-1.53 (m, 2H) MS (m/z): 517.4 [MH]+.Example 190: 6-[5-({3-[(1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H-1,2,4-triazole -3-yl]pyridine-3-carboxamide (CIS, Enantiomer 1, E190)

[551] The compound was prepared as in Example 1, reacting (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p24 , 26 mg, 0.1 mmol) of 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide (p174, 34mg, 0.11mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.113 mL), obtaining 6-[5-({3-[(1S ,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4-methyl-4H- 1,2,4- triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiomer 1, E190, 20.5 mg, y= 38%). NMR: 1H NMR (DMSO-d6) δ: 9.08-9.18 (m, 1H), 8.35-8.44 (m, 1H), 8.248.29 (m, 1H), 8.19- 8.24 (m, 1H), 7.68-7.74 (m, 1H), 7.58-7.64 (m, 1H), 7.45-7.50 (m, 1H), 7.25-7.32 (m, 1H), 3.92 (s, 3H), 3.10-3.22 (m, 2H), 2.69 -2.78 (m, 1H), 2.35-2.43 (m, 4H), 2.21 (m, 1H), 1.93 (m, 2H), 1.84 (d, 1H), 1.75 (m, 2H), 1.35 (m, 1H ), 1.20 (m, 1H) MS (m/z): 535.3 [MH]+.Example 191: 4-[4-methyl-5-({3-[(1R,3S)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1 , E191)

[552] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.1 mmol) of 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (p175, (34 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 mL), obtaining 4-[4-methyl-5-({ 3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 - yl]pyridine-2- carboxamide (CIS, Enantiomer 1, E191, 34.7 mg, y= 67%).NMR: 1H NMR (Acetone-d6) δ: 8.80 (m, 1H), 8.49 (m, 1H ), 7.99-8.04 (m, 1H), 7.97 (m, 1H), 7.61 (d, 2H), 7.38 (d, 2H), 6.82-6.96 (m, 1H), 3.82 (s, 3H), 3.183. 34 (m, 2H), 2.70-2.75 (m, 1H), 2.58-2.66 (m, 1H), 2.43-2.57 (m, 3H), 2.20-2.27 (m, 1H), 1.81-2.03 (m, 5H ), 1.26-1.31 (m, 1H), 1.21 (m, 1H) MS (m/z): 517.4 [MH]+. Example 192: 5-[4-methyl-5-({3-[( 1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine -3- carboxamide (CIS, Enantiomer 1, E192)

[553] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.1 mmol) 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-3-carboxamide (p236, 36 mg, 0. 11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 mL), obtaining 5-[4-methyl-5-({3- [(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl ]pyridine-3-carboxamide (CIS, Enantiomer 1, E192, 31 mg, y= 60%). NMR: 1H NMR (Acetone-d6) δ: 9.22 (d, 1H), 9.07 (d, 1H), 8.56 (s, 1H), 7.74-7.88 (m, 1H), 7.60 (s, 2H), 7.39 ( s, 2H), 6.93-7.06 (m, 1H), 3.76 (s, 3H), 3.16-3.34 (m, 2H), 2.70-2.76 (m, 1H), 2.58-2.67 (m, 1H), 2.43- 2.56 (m, 3H), 2.18-2.27 (m, 1H), 2.08-2.11 (m, 1H), 1.92-2.03 (m, 2H), 1.81-1.92 (m, 2H), 1.25-1.32 (m, 1H ), 1.17-1.24 (m, 1H) MS (m/z): 517.3 [MH]+. Example 193: 6-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E193)

[554] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.096 mmol) 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine-2-carboxamide (p176, 32 mg, 0.1 mmol ), Na2CO3 (13 mg, 0.115 mmol) and Nal (18 mg, 0.115 mmol) in DMF (0.1 ml), providing 6-[4-methyl-5-({3-[(1R,3S)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS , Enantiomer 1, E193, 25.5 mg, y= 51%). NMR: 1H NMR (DMSO-d6) δ: 8.23-8.29 (m, 1H), 8.11-8.22 (m, 2H), 7.968.01 (m, 1H), 7.80- 7.88 (m, 1H), 7.58-7.64 (m, 2H), 7.30-7.35 (m, 2H), 3.93 (s, 3H), 3.11-3.23 (m, 2H), 2.66- 2.76 (m, 1H), 2.37-2.49 (m, 4H), 2.21 (m, 1H), 1.832.01 (m, 3H), 1.77 (m, 2H), 1.27 (m, 1H), 1.18 (m, 1H) MS (m/z): 517.4 [MH]+. Example 194: N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E194)

[555] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.096 mmol) of 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-N-methylpyridine-2-carboxamide (P177, 33 mg, 0.1 mmol), Na2CO3 (13 mg, 0.115 mmol) and Nal (18 mg, 0.115 mmol) in DMF (0.2 mL), obtaining N-methyl-6-[4-methyl-5-({ 3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 -yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E194, 33 mg, y= 64%). NMR: 1H NMR (Acetone-d6) δ: 8.30-8.36 (m, 1H), 8.16-8.29 (m, 3H), 7.607.65 (m, 2H), 7.37-7.43 (m, 2H), 4.02 (s , 3H), 3.24-3.38 (m, 2H), 3 (d, 3H), 2.512.71 (m, 4H), 2.13-2.33 (m, 2H), 1.85-2.03 (m, 5H), 1.28-1.36 (m, 1H), 1.20-1.28 (m, 1H) MS (m/z): 531.4 [MH]+.Example 195: N-methyl-6-[4-methyl-5-({3-[ (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl] pyridine-2-carboxamide (CIS, Enantiomer 1, E195)

[556] N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E194, 33 mg) was dissolved in MeOH and treated with 1.1 eq of HCl in Et2O. The solid then obtained was triturated with ether and dried under vacuum, obtaining N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl] -5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide hydrochloride salt (CIS, Enantiomer 1, E195 , 34.6 mg). MS (m/z): 531.4 [MH]+. Example 196: N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan- 5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E196)

[557] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0.096 mmol) 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-N,N-dimethylpyridine-2-carboxamide (p178, 34 mg , 0.1 mmol), Na2CO3 (13 mg, 0.115 mmol) and Nal (18 mg, 0.115 mmol) in DMF (0.2 mL), obtaining N,N-dimethyl-6-[4-methyl-5 -({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E196, 33 mg, y= 63%).NMR: 1H NMR (Acetone-d6) δ: 8.27-8.32 (m, 1H), 8.07- 8.13 (m, 1H), 7.657.70 (m, 1H), 7.60-7.65 (m, 2H), 7.36-7.42 (m, 2H), 4.03 (s, 3H), 3.20-3.36 (m, 2H), 3.12 (d, 6H), 2.72-2.75 (m, 1H), 2.64 (d, 1H), 2.52 (br. s., 3H), 2.21-2.28 (m, 1H), 1.94-2.04 (m, 3H) , 1.82-1.94 (m, 2H), 1.30 (m, 1H), 1.22 (m, 1H) MS (m/z): 545.3 [MH]+. Example 197: N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan- 5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]pyridine-2-carboxamide dihydrochloride (CIS, Enantiomer 1, E197)

[558] N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan- 5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E196, 33 mg) was dissolved in MeOH and treated with 1.1 eq of HCl in Et2O. The solid obtained was triturated with ether and dried under vacuum, obtaining N,N-dimethyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl ]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide dihydrochloride salt (CIS, Enantiomer 1, E197, 35.5 mg).MS (m/z): 545.4 [MH]+. Example 198: 5-methyl-6-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E198)

[559] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, (p15, 25 mg , 0.096 mmol) 6-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-5-methylpyridine-2-carboxamide (p179, 33 mg, 0.1 mmol), Na2CO3 (13 mg, 0.115 mmol) and Nal (18 mg, 0.115 mmol) in DMF (0.2 mL), obtaining 5-methyl-6-[4-methyl-5-({ 3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3 -yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E198, 40 mg, y= 78%).NMR: 1H NMR (DMSO-d6) δ: 8.00-8.11 (m, 3H), 7.58-7.72 (m , 3H), 7.307.40 (m, 2H), 3.65 (s, 3H), 3.15-3.26 (m, 3H), 2.54 (s, 3H), 2.41-2.49 (m, 2H), 1.75-2.29 (m , 8H), 1.15-1.38 (m, 2H) MS (m/z): 531.3 [MH]+. Example 199: 5-methyl-6-[4-methyl-5-({3-[(1R ,3S)-1-[4-(trifluoromethyl)phenyl-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2 - carboxamide hydrochloride (CIS, Enantiomer 1, E199).

[560] 5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptan-5- yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1, E198, 40 mg) was dissolved in MeOH and treated with 1.1 eq of HCl in Et2O. The solid then obtained was triturated with ether and dried under vacuum, obtaining 5-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl- 5- azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide hydrochloride salt (CIS, Enantiomer 1, E199, 38mg). MS (m/z): 531.3 [MH]+. Example 200: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E200)

[561] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.21 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine (p180, 62 mg, 0.228 mmol), Na2CO3 (26 mg, 0.25 mmol) and Nal (37 mg, 0.25 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3-{[ 4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2, 4]heptane (TRANS, E200, 46 mg, y= 47%). NMR: 1H NMR (Acetone-d6) δ: 9.65 (m, 1H), 9.40 (m, 1H), 8.05 (m, 1H), 7.64 (d, 2H), 7.36 (d, 2H), 3.90 (s, 3H), 3.38 (m, 2H), 2.56-2.67 (m, 5H), 2.25-2.31 (m, 1H), 2.09-2.13 (m, 1H), 1.94-2.03 (m, 2H), 1.63-1.72 ( m, 1H), 1.39-1.48 (m, 1H), 1.25-1.30 (m, 1H), 1.20-1.24 (m, 1H) MS (m/z): 475.4 [MH]+.Example 201: ( 1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E201)

[562] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, p14, 30 mg , 0.124 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine (p180, 33 mg, 0.12 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (21 mg, 0.14 mmol) in DMF (0.1 mL), obtaining (1R,3S/1S,3R)-5-(3-{[ 4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane (CIS, E201, 37 mg, y= 63%). NMR: 1H NMR (Acetone-d6) δ: 9.60-9.66 (m, 1H), 9.37-9.42 (m, 1H), 8.028.08 (m, 1H), 7.60-(m, 2H), 7.36-7.43 ( m, 2H), 3.86 (s, 3H), 3.21-3.36 (m, 2H), 2.45-2.73 (m, 4H), 2.21- 2.27 (m, 1H), 2.08-2.15 (m, 1H), 1.83- 2.03 (m, 5H), 1,191.33 (m, 2H) MS (m/z): 475.4 [MH]+. Examples 202 and 203: (1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E202) and (1S,3R)-5-(3-{[4-methyl-5-( pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E203)

[563] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E201, 37 mg) was separated into individual enantiomers by preparative chiral HPLC. Obtaining (1R,3S)-5-(3-{[4-methyl-5-(pyradazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E202, 11 mg) Enantiomer 1: retention time 8.5 min, 100% ee MS (m/z): 475, 3 [MH]+.(1S, 3R)-5-(3 - {[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E203, 11.8 mg) Enantiomer 2: ret, time 10.3 min, 100% ee MS (m/ z): 475.5 [MH]+. Example 204: (1R,3S)-5-(3-{[4-methyl-5-(pyradazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride (CIS, 1-enantiomer, E204)

[564] (1R, 3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspir[2,4]heptane (CIS, E202, 11 mg) was plotted with 1.1 eq. of HCl in Et2O, obtaining (1R,3S)-5-(3-{[4-methyl-5-(morpholin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl } propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (CIS, Enantiomer 1 E204, 11.9 mg). MS (m/z): 475.4 [MH]+. Example 205: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E205)

[565] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.21 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine (p181.62 mg, 0.228 mmol), Na2CO3 (26 mg, 0.25 mmol) and Nal (37 mg, 0.25 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3-{[ 4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2, 4]heptane (TRANS, E205, 38 mg, y= 39%). NMR: 1H NMR (Acetone-d6) δ: 9.27-936 (m, 1H), 8.40 (d, 1H), 7.89 (d, 1H), 7.63 (d, 2H), 7 .36 (d, 2H), 3.86 (s, 3H), 4.13 (s 3H), 3.33-3.49 (m, 2H), 2.74- 2.79 (m, 2H) , 2.56-2.68 (m, 4H), 2.24-2.31 (m, 1H), 2.10-2.13 (m, 1H), 2.09-2.13 (m, 2H), 1.95-2.04 (m, 2H), 1.62-1.71 (m, 1H), 1.39-1.49 (m, 1H), 1.25-1.30 ( m, 1H), 1.18-1.24 (m, 1H) MS (m/z): 475.4 [MH]+ Example 206: (1R,3S/1S,3R)-5-(3-{ [4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2 ,4]heptane (CIS, E206)

[566] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.124 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyridazine (p181, 33 mg, 0.12 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (21 mg, 0.14 mmol) in DMF (0.1 mL), obtaining (1R,3S/1S,3R)-5-(3-{[ 4-methyl-5-(pyridazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)]-5-azaspiro[2,4 ] heptane (CIS, E206, mg 34, y= 62%). NMR: 1H NMR (Acetone-d6) δ: 9.28-9.34 (m, 1H), 8.37-8.44 (m, 1H), 7.84-7.91 (m, 1H), 7.59-7.66 (m, 2H), 7.37-7.45 (m, 2H), 4.09 (s, 3H), 3.25-3.41 (m, 2H), 2.52-2.95 (m., 6H), 2.24- 2.32 (m, 1H), 1.87-2.04 (m, 4H), 1.20-1.38 (m, 2H) MS (m/z): 475.4 [MH]+.Example 207: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-( pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E207 )

[567] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.21 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrimidine (p182, 62.3 mg, 0.231 mmol ), Na2CO3 (27 mg, 0.252 mmol) and Nal (38 mg, 0.252 mmol) in DMF (0.22 mL), obtaining (1S,3S/1R,3R)-5-(3-{[4- methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E207, 21 mg, y=19%). NMR: 1H NMR (Acetone-d6) δ: 9.28 (d, 1H), 8.95 (d, 1H), 8.23 (m, 1H), 7.63 (d, 2H), 7.31-7.45 (m, 2H), 4.09 ( s, 3H), 3.34-3.47 (m, 2H), 2.56-2.75 (m., 4H), 2.26- 2.39 (m, 1H), 1.97-2.05 (m, 3H), 1.63-1.80 (m, 1H) , 1.40-1.55 (m, 1H). 1,191.37 (m, 3H) MS (m/z): 475.5 [MH] +.Examples 208 and 209: (1S,3S or 1R,3R)-5-(3-{[4-methyl-5 -(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS , Enantiomer 1, E208) and (1R,3R or 1S,R3)-5-(3- {[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, Enantiomer 2, E209).

[568] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E207, mg 21) was separated into individual enantiomers by preparative chiral HPLC. Obtaining (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E208, 5.4 mg) Enantiomer 1: retention time 12.3 min, 100% ee MS (m /z): 475.0 [MH]+ (1R, 3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E209, 8.3 mg) Enantiomer 2: retention time 16.3 min, 100% ee MS (m/z): 475.0 [MH]+ Example 210: (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (TRANS, Enantiomer 1, E210)

[569] (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E208, 5.4 mg) was treated with 1.2 eq of HCl in Et2O, obtaining (1S ,3S or 1R,3R)-5- (3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (TRANS Enantiomer 1, E210, 5 mg). MS (m/z): 475.0 [MH]+.Example 211: (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (TRANS, Enantiomer 2, E211)

[570] (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E209, 8.3 mg) was treated with 1.2 eq of HCl in Et2O, obtaining (1R,3R or salt 1S,R3)- 5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (TRANS, Enantiomer 1, E211, 2.5 mg). MS (m/z): 475.0 [MH]+. Example 212: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E212)

[571] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 50 mg , 0.21 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl} pyrimidine (p182, mg 62.3, 0.231 mmol ), Na2CO3 (27 mg, 0.252 mmol) and Nal (38 mg, 0.252 mmol) in DMF (0.22 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4- methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)]-5-azaspiro[2,4] heptane (CIS, E212, 57.2 mg, y= 55%).

[572] NMR: 1H NMR (Acetone-d6) δ: 9.27-9.31 (m, 1H), 8.92-8.99 (m, 1H), 8.22-8.26 (m, 1H), 7.59- 7.65 (m, 2H), 7.36-7.42 (m, 2H), 4.07 (s, 3H), 3.22-3.39 (m, 2H), 2.71-2.76 (m, 2H), 2.59- 2.68 (m, 1H), 2.46-2.56 (m, 3H ), 2.21-2.27 (m, 1H), 1.83-2.03 (m, 4H), 1.26-1.32 (m, 1H), 1.22 (m, 1H) MS (m/z): 475.1 [MH]+. Example 213: (1S,3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2,4]heptane (CIS, E213)

[573] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, p23, 50 mg, 0.19 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrimidine (p182, 56.4 mg, 0.209 mmol), Na2CO3 (24 mg, 0.228 mmol) and Nal (mg 34, 0.228 mmol) in DMF (0.22 mL), obtaining (1S,3S/1R,3R)-1-[2- fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2,4]heptane (CIS, E213, 11.8 mg, y = 12%). NMR: 1H-NMR (Acetone-d6) δ: 9.27-9.32 (m, 1H), 8.93-8.98 (m, 1H), 8.208.26 (m, 1H), 7.45- 7.53 (m, 2H), 7.29- 7.38 (m, 1H), 4.07 (s, 3H), 3.24-3.45 (m, 2H), 2.44-2.67 (m, 5H), 2.25- 2.35 (m, 1H), 1.98-2.05 (m, 3H), 1.83-1.95 (m, 2H), 1.35-1.41 (m, 1H), 1.23-1.29 (m, 1H) MS (m/z): 475.1 [MH]+. Example 214: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E214)

[574] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.21 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine (p183, 62.3 mg, 0.231 mmol ), Na2CO3 (27 mg, 0.252 mmol) and Nal (38 mg, 0.252 mmol) in DMF (0.22 mL), obtaining (1S, 3S/1R, 3R)-5-(3-{[4- methyl-5-(pyrazine-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E214, 25.5 mg, y = 25%. NMR: 1H-NMR (Acetone-d6) δ: 9.38 (d, 1H), 8.72 (m, 2H), 7.63 (d, 2H), 7.33 -7.52 (m, 2H), 4.02 (s, 3H), 3.40-3.50 (m, 2H), 2.89-3.15 (m, 3H), 2.31-2.47 (m, 1H), 2.11-2.19 (m, 1H) , 5 2.02 (br. s., 1H), 1.72-1.86 (m, 2H), 1.43-1.65 (m, 2H), 1.25-1.41 (m, 3H) MS (m/z): 475.1 [MH ]+. Examples 215 and 216: (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H- 1,2,4-triazol-3 -yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, Enantiomer 1, E215) and (1R,3R or 1S,R3)-5-( 3- {[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (TRANS, Enantiomer 2, E216)

[575] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E214, 24.5 mg) was separated into individual enantiomers by preparative chiral HPLC. Obtaining (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E215, 8.5 mg) Enantiomer 1: retention time 11.7 min, 100% ee MS (m /z): 475.1 [MH]+. (1R, 3R or 1S,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E216, 8.5 mg) Enantiomer 2: retention time 16.0 min, 100% ee MS (m/z) : 475.1 [MH]+. Example 217: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E217).

[576] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 50 mg , 0.21 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine (p183, 62.3 mg, 0.231 mmol ), Na2CO3 (27 mg, 0.252 mmol) and Nal (38 mg, 0.252 mmol) in DMF (0.22 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4- methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)]-5-azaspiro[2,4] heptane (CIS, E217, 56.3 mg, y= 54%).NMR: 1H-NMR (Acetone-d6) δ: 9.39 (d, 1H), 8.69-8.76 (m, 2H), 7.62 (d, 2H) , 7.39 (d, 2H), 4.00 (s, 3H), 3.21-3.38 (m, 2H), 2.72-2.77 (m, 2H), 2.60-2.68 (m, 1H), 2.47-2.57 (m, 3H) , 2.21-2.28 (m, 1H), 1.93-2.03 (m, 2H), 1.83-1.93 (m, 2H), 1.251.32 (m, 1H), 1.19-1.24 (m, 1H) MS (m/z ): 475.1 [MH]+.Examples 218 and 219: (1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E218) and (1R,3S)-5-(3 -{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 2, E219)

[577] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E217, 56.3 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC). Obtaining (1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E218, 21.8 mg) Enantiomer 1: retention time 6.3 min, 100% ee MS (m/z): 475.5 [MH]+. (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E219, 11.4 mg) Enantiomer 2: retention time 10.5 min, 89.2% ee MS (m/z): 475 .5 [MH]+. Example 220: (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 2, E220)

[578] (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E219, 11.4 mg) was dissolved in Et2O/DCM and treated with 1.2 eq of 2N HCl in Et2O, obtaining -se (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride salt (CIS Enantiomer 2, E220, 10.8 mg). MS (m/z): 475.1 [MH]+. Example 221: (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro [2,4]heptane (CIS, E221)

[579] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p23, 50 mg, 0.19 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine (p183, 56.4 mg, 0.209 mmol), Na2CO3 (24 mg, 0.228 mmol) and Nal (34 mg, 0.228 mmol) in DMF (0.22 mL), obtaining (1S,3S/1R,3R)-1-[2- fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 5-azaspiro[2,4]heptane (CIS, E221, 52.7 mg, y = 51%). NMR: 1H-NMR (Acetone-d6) δ: 9.39 (d, 1H), 8.70-8.77 (m, 2H), 7.47-7.52 (m, 2H), 7.34 (m, 1H), 4.00 (s, 3H) , 3.22-3.41 (m, 3H), 2.76 (br. s., 1H), 2.58-2.65 (m,1H), 2.44-2.56 (m, 2H), 2.24-2.30 (m, 1H), 1.96-2.05 (m, 3H), 1.83-1.94 (m, 2H), 1.35-1.41 (m, 1H), 1.22-1.29 (m, 1H) MS (m/z): 493.1 [MH]+. Example 222: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E222)

[580] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-6-methylpyrazine (p184, 37 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl -5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane (CIS, E222, 24.8 mg, y = 41%). NMR: 1H-NMR (Acetone-d6) δ: 9.17 (s, 1H), 8.61 (s, 1H), 7.63 (d, 2H), 7.39-7.46 (m, 2H), 4.01 (s, 3H), 3.23 -3.40 (m, 2H), 2.57-2.94 (m, 9H), 2.30 (m, 1H), 1.90-2.04 (m, 4H), 1.29- 1.37 (m, 1H), 1.23-1.29 (m, 1H) MS (m/z): 489.5 [MH]+. Example 223: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(5-methylpyrazin-2-yl)-4H- 1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E223)

[581] The compound was prepared as in Example 1, reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-5-methylpyrazine (p185, 37 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl -5-(5-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane (CIS, E223, 37.7 mg, y = 63%).NMR: 1H NMR (Acetone-d6) δ: 9.24 (d, 1H), 8.64 (s, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 3.97 (s, 3H), 3.22-3.40 (m, 2H), 2.63 (s, 3H), 2.59-2.96 (m, 6H), 2.25-2.34 (m, 1H), 1.89- 2.04 (m, 4H), 1.21-1.39 (m, 2H) MS (m/z): 489.4 [MH]+. Example 224: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E224)

[582] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg ,0.12 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-3-methylpyrazine (p186, 37 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl -5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane (CIS, E224, 37.8 mg, y = 63%). NMR: 1H NMR (Acetone-d6) δ: 8.62 (s, 2H), 7.60-7.68 (m, 2H), 7.39-7.46 (m, 2H), 3.77 (s, 3H), 3.33 (m, 2H), 2.82 (s, 3H), 2.62-2.83 (m, 6H), 2.25-2.34 (m, 1H), 1.92-2.05 (m, 4H), 1.32-1.38 (m, 1H), 1.22-1.31 (m, 1H) ) MS (m/z): 489.5 [MH]+. Examples 225 and 226: (1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS,Enantiomer 1, E225) and (1R,3S)-5-(3-{[4-methyl-5 -(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E226)

[583] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E224, 37.8 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC). Obtaining (1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E225, 10.2 mg) Enantiomer 1: retention time 3.8 min, 100% ee MS (m/z ): 489.5 [MH]+.(1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3 - yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E226, 11.3 mg) Enantiomer 2: retention time 5.1 min, 99 .8% ee MS (m/z): 489.5 [MH] + Example 227: (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 2, E227)

[584] (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E226, 11.3 mg) was dissolved in Et2O/DCM and treated with 1.2 eq of 2N HCl in Et2O, obtaining (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride salt (CIS Enantiomer 2, E227, 11.7 mg). MS (m/z): 489.4 [MH] + Example 228: 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyrazine-2-carboxamide (CIS, E228)

[585] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 15 mg, 0.064 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}pyrazine-2-carboxamide (p187, 20 mg, 0.064 mmol) , Na2CO3 (8 mg, 0.077 mmol) and Nal (12 mg, 0.077 mmol) in DMF (0.1 mL), obtaining 5-[4-methyl-5-({3-[(1R,3S)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]pyrazine-2-carboxamide ( CIS, E228, 14.4 mg, y = 43%). NMR: 1H NMR (Acetone-d6) δ: 9.28-9.42 (m, 2H), 7.93-8.07 (m, 1H), 7.597.68 (m, 2H), 7.38- 7.45 (m, 2H), 7.02-7.15 (m, 1H), 4.04 (s, 3H), 3.35 (d, 2H), 2.57-2.93 (m, 8H), 2.30 (br. s., 1H), 1.98 (br. s., 2H), 1.22 -1.39 (m, 2H) MS (m/z): 518.4 [MH]+.Example 229: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1 ,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane ( CIS, E229)

[586] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1,2-oxazol-5-yl)-4H-1,2,4-triazole (p188, 34 mg , 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4 -methyl-5(1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[ 2,4]heptane (CIS, E229, 13 mg, y= 20%). NMR: 1H NMR (Acetone-d6) δ: 7.62 (d, 3H), 7.36-7.45 (m, 3H), 3.82 (s, 3H), 3.28-3.45 (m, 3H), 2.40-2.71 (m, 6H ), 2.23-2.34 (m, 2H), 1.97 (br. s., 2H), 1.31 (br. s., 2H), 1.22-1.26 (m, 1H) MS (m/z): 464.4 [ MH]+. Example 230: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H- 1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E230)

[587] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazole (p189, 62 mg, 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3 -{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E230, 54 mg, y= 55%). NMR: 1H-NMR (Acetone-d6) δ: 7.64 (d, 2H), 7.35 (d, 2H), 6.90 (s, 1H), 3.89 (s, 3H), 3.36 (m, 3H), 2.75 (d , 1H), 2.55-2.66 (m, 5H), 2.39 (s, 3H), 2.24-2.30 (m, 1H), 1.93-2.02 (m, 2H), 1.61-1.72 (m, 1H), 1.37-1.48 (m, 1H), 1.24-1.29 (m, 1H), 1.21 (s, 1H) MS (m/z): 478.4 [MH]+.Example 231: (1R,3S/1S,3R)-5 -(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E231)

[588] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazole ( p189, 36 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3 -{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3yl]sulfanyl}propyl)-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2,4]heptane (CIS, E231, 38 mg, y=64%). NMR: 1H-NMR (Acetone-d6) δ: 7.58-7.65 (m, 2H), 7.37-7.41 (m, 2H), 6.88-6.91 (m, 1H), 3.84 (s, 3H), 3.28 (m, 2H), 2.81-2.90 (m, 2H), 2.60 (br. s., 3H), 2.38 (s, 3H), 2.23-2.30 (m, 1H), 1.84-2.03 (m, 5H), 1.29-1.34 (m, 1H), 1.23 (m, 1H) MS (m/z): 478.1 [MH]+. Examples 232 and 233: (1R,3S)-5-(3-{[4-methyl-5 -(3-methyl-1,2-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro [2,4]heptane (CIS, Enantiomer 1, E232) and (1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E233)

[589] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS,E231, 38 mg) was separated in preparation. Obtaining (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E232, 13 mg) Enantiomer 1: retention time 10, 1 min, 100% ee MS (m/z): 478.5 [MH]+. (1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl }propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E233, 10.8 mg) Enantiomer 2: retention time 14.7 min, 100% ee MS ( m/z): 478.5 [MH]+.Example 234: (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl) -4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride (CIS, 1 enantiomer, E234)

[590] (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E232, 13 mg) was dissolved in Et2O/DCM and treated with 1.2 eq of HCl 2N in Et2O, obtaining (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (CIS, Enantiomer 1, E234, 10.8 mg). MS (m/z): 478.5 [MH]+. Example 235: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H- 1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E235)

[591] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazole (p190, 62 mg, 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3 -{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E235, 56 mg, y= 55%). NMR: 1H-NMR (Acetone-d6) δ: 9.15 (s, 1H), 7.64 (d, 2H), 7.39 (d, 2H), 3.62 (s, 3H), 3.36 (s, 2H), 2.72 (br .s., 5H), 2.50 (s, 3H), 2.28-2.36 (m, 1H), 1.97-2.06 (m, 3H), 1.67-1.79 (m, 1H), 1.41-1.53 (m, 1H), 1.23-1.35 (m, 3H) MS (m/z): 494.4 [MH]+. Example 236: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E236)

[592] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazole ( p190, 38 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3 -{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E236, 25 mg, y= 40%). NMR: 1H-NMR (Acetone) δ: 9.15 (s, 1H), 7.60-7.67 (m, 2H), 7.37-7.42 (m, 2H), 3.58 (s, 3H), 3.25 (m, 2H), 2.72 -2.77 (m, 2H), 2.60-2.67 (m, 1H), 2.46-2.56 (m, 6H), 2.21-2.26 (m, 1H), 1.95-2.03 (m, 2H), 1.82-1.92 (m, 2H), 1.30 (m, 1H), 1.22 (m, 1H) MS (m/z): 494.5 [MH]+. Examples 237 and 238: (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H- 1,2,4-thiazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 1, E237) and (1S,3R)-5-(3-{ [4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl) phenyl]-5- azaspiro[2,4] heptane (CIS, Enantiomer 2, E238)

[593] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E236, 25 mg) was separated into individual enantiomers by preparative chiral HPLC. Obtaining (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol- 3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E237, 7 mg) Enantiomer 1: retention time 6.2 min, 100% ee MS (m/z): 494.0 [MH]+ (1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E238, 7 mg) Enantiomer 2: retention time RET 8.0 min, 100% ee MS (m/z): 494.0 [MH]+.Example 239: (1R,3S)-5-(3-{[4-methyl-5-(4-methyl -1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride (CIS, Enantiomer 1, E239)

[594] (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E237, 7 mg) was dissolved in Et2O DCM and treated with 1.2 eq of 2N HCl in Et2O, obtaining (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (CIS, Enantiomer 1, E239, 7.6 mg).MS ( m/z): 494.0 [MH]+. Example 240: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (TRANS, E240)

[595] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazole (p191.63 mg, 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 mL), obtaining (1S,3S/1R,3R)-5-(3-{[4 -methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (TRANS, E240, 61 mg, y= 61%). NMR: 1H-NMR (Acetone-d6) δ: 8.04 (d, 1H), 7.81 (d, 1H), 7.63 (d, 2H), 7.36-7.44 (m, 2H), 4.06 (s, 3H), 3.39 (m, 2H), 2.96 (br. s., 5H), 2.26-2.39 (m, 1H), 2.012.05 (m, 3H), 1.66-1.79 (m, 1H), 1.42-1.53 (m, 1H ), 1.21-1.37 (m, 3H) MS (m/z): 480.4 [MH]+.Example 241: (1R,3S/1S,3R)-5-(3-{[4-methyl-5 -(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4 ]heptane (CIS, E241)

[596] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazole (p191, 40 mmol , 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 ml), obtaining (1R,3S/1S,3R)-5-(3-{[4 -methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl] -5- azaspiro [2,4]heptane (CIS, E241, 28 mg, y = 48%).NMR: 1H-NMR (Acetone-d6) δ: 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 4.02 (s, 3H), 3.19-3.37 (m, 2H), 2.70-2.76 (m, 2H), 2.61 (d, 1H), 2.44-2.57 (m, 3H) , 2.19-2.26 (m, 1H), 1.92-2.02 (m, 2H), 1.82-1.91 (m, 2H), 1.28 (m, 1H), 1.20 (m, 1H) MS (m/z): 480, 0 [MH]+.Examples 242 and 243: (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro 2,4] heptane (CIS, Enantiomer 1, E242) and (1S,3R)-5-(3- {[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptane (CIS, Enantiomer 2, E243)

[597] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E241.28 mg) was separated into individual enantiomers by preparative chiral HPLC. Obtaining (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E242, 9 mg) Enantiomer 1: retention time 10.6 min, 100% ee MS (m/z ): 480.0 [MH]+. (1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E243, 8 mg) Enantiomer 2: retention time 17.7 min, 100% ee MS (m/z): 480 .0 [MH]+.Example 244: (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazole -3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 1, E244)

[598] (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E242, 9 mg) was dissolved in Et2O/DCM and treated with 1.2 eq of 2N HCl in Et2O, obtaining (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (CIS, Enantiomer 1, E244, 10 mg). MS (m/z): 480.0 [MH]+. Example 245: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)- 4H-1,2,4-triazole -3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E245)

[599] The compound was prepared as in Example 1, reacting (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 50 mg , 0.207 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole (p192, 62 mg , 0.228 mmol), Na2CO3 (26 mg, 0.248 mmol) and Nal (37 mg, 0.248 mmol) in DMF (0.2 ml), obtaining (1S,3S/1R,3R)-5-(3-{ [4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl] -5- azaspiro[2,4]heptane (TRANS, E245, 46.7 mg, y= 47%). NMR: 1H-NMR (Acetone-d6) δ: 8.15 (s, 1H), 7.87 (s, 1H), 7.63 (d, 2H), 7.39 (br. s., 2H), 3.99 (s, 3H), 3.74 (s, 3H), 3.26 (br. s., 2H), 2.48-2.76 (m, 5H), 2.282.38 (m, 1H), 1.94-2.03 (m, 2H), 1.65-1.82 (m, 1H), 1.39-1.52 (m, 1H), 1.31 (br. s., 3H) MS (m/z): 477.4 [MH]+. Example 246: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H- 1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E246)

[600] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole (p192, 36 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{ [4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl] -5- azaspiro[2,4]heptane (CIS, E246, 31 mg, y=54%). NMR: 1H-NMR (Acetone-d6) δ: 8.13-8.17 (m, 1H), 7.86-7.89 (m, 1H), 7.607.65 (m, 2H), 7.36- 7.41 (m, 2H), 4.00 ( s, 3H), 3.71 (s, 3H), 3.08-3.24 (m, 2H), 2.71-2.76 (m, 1H), 2.57-2.65 (m,1H), 2.43-2.54 (m, 3H), 2.20- 2.26 (m, 2H), 1.952.04 (m, 3H), 1.78-1.87 (m, 2H), 1.26-1.32 (m, 1H), 1.19-124 (m, 1H) MS (m/z): 477 .5 [MH]+.Examples 247 and 248: (1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)- 4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E247) and (1R,3S)-5 -(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, Enantiomer 2, E248)

[601] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E246, 31 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC). Obtaining (1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, E247, 9.7 mg) Enantiomer 1: retention time 5.6 min, 96.2% ee MS (m/z): 477.0 [MH]+.(1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H -1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E248, 10 mg) Enantiomer 2: time retention 7.3 min, 100% ee MS (m/z): 477.0 [MH]+. Example 249: (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 2, E249) (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E248.10mg) was dissolved in Et2O/DCM and treated with 1.2 eq of 2N HCl in Et2O, obtaining if (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (CIS, Enantiomer 1, E249, 8.8 mg).MS (m/z): 477, 0 [MH]+. Example 250: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E250)

[602] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 35 mg , 0.15 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazole (p193, 30 mg, 0.15 mmol), Na2CO3 (19 mg, 0.18 mmol) and Nal (22 mg, 0.15 mmol) in DMF, (0.2 mL), obtaining (1R,3S/1S, 3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E250, 31 mg, y= 43%). NMR: 1H-NMR (Acetone-d6) δ: 7.61 (d, 1H), 7.54 (d, 2H), 7.22 (d, 2H), 6.51 (d, 1H), 4.15 (s, 3H), 3.56-3.60 (m, 3H), 3.25-3.39 (m, 2H), 2.89 (d, 1H), 2.73 (br. s., 1H), 2.62 (br. s., 2H), 2.50 (d, 1H), 2.13 -2.25 (m, 2H), 1.91-2.12 (m, 4H), 1,181.27 (m, 2H) MS (m/z): 477.4 [MH]+.Examples 251 and 252: (1S,3R) -5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[ 4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (CIS, Enantiomer 1, E251) and (1R,3S)-5-(3-{[4-methyl-5-(1- methyl- 1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS , Enantiomer 2, E252)

[603] (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS,E250, 31 mg) was separated into individual enantiomers by chiral preparative HPLC (SFC). Preparative Chromatography: Obtaining (1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E251, 8.6 mg) Enantiomer 1: retention time 6.6 min MS (m/z ): 477.4 [MH]+. (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E252, 8.6 mg) Enantiomer 2: retention time 9.0 min MS (m/z): 477 .4 [MH]+.Example 253: (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4 - triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride (CIS, Enantiomer 2, E253)

[604] (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E252, 8.6 mg) was dissolved in DCM and treated with 1.1 eq of 2N HCl in Et2O, obtaining (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane hydrochloride salt (CIS, Enantiomer 2, E253, 9 mg).MS (m/z): 477.4 [MH]+.Example 254: (1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl)-4-methyl-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E254)

[605] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 30 mg, 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-5-(furan-2-yl)-4-methyl-4H-1,2,4-triazole (p194, 34 mg, 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl) -4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS,E254, 19.4 mg, y= 32%).

[606] NMR: 1H-NMR (Acetone-d6) δ: 7.80-7.83 (m, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 7.03 (m, 1H), 6.67-6.70 (m , 1H), 3.79 (s, 3H), 3.11-3.28 (m, 2H), 2.70-2.76 (m, 1H), 2.57-2.67 (m, 1H), 2.44-2.56 (m, 3H), 2.20-2.25 (m, 2H), 1.89-2.02 (m, 2H) 1.79-1.87 (m, 2H), 1.78-1.87 (m, 2H), 1.46-1.55 (m, 1H), 1.25-1.31 (m, 1H), 1.17-1.24 (m, 1H) MS (m/z): 463.0 [MH]+ Example 255: (1R,3S/1S,3R)-5-(3-{[5-(furan-3-yl )-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E255)

[607] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-5-(furan-3-yl)-4-methyl-4H-1,2,4-triazole (p195, 34 mg, 0.132 mmol) , Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[5-(furan- 3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS ,E255, 27 mg, y= 45%). NMR: 1H-NMR (Acetone-d6) δ: 8.15-8.18 (m, 1H), 7.74-7.78 (m, 1H), 7.61 (d, 2H), 7.37 (d, 2H), 6.94-6.97 (m, 1H), 3.72 (s, 3H), 3.06-3.27 (m, 2H), 2.70-2.76 (m, 2H), 2.56-2.65 (m, 1H), 2.42-2.55 (m, 3H), 2.19-2.24 ( m, 1H), 1.92-2.00 (m, 2H), 1.81 (m, 2H), 1.24-1.30 (m, 1H), 1.17-1.24 (m, 1H) MS (m/z): 463.0 [MH ]+. Example 256: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, E256)

[608] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(thiophen-2-yl)-4H-1,2,4-triazole (p196, 36 mg 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl-5- (thiophen-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, E256, 29.7 mg, y= 50%).NMR: 1H NMR (Acetone-d6) δ: 7.66-7.71 (m, 1H), 7.60 (d, 3H), 7.33-7.41 (m, 2H), 7.22 -7.27 (m, 1H), 3.79 (s, 3H), 3.10-3.29 (m, 2H), 2.69-2.76 (m, 2H), 2.57-2.65 (m, 1H), 2.43-2.57 (m, 3H) , 2.19-2.25 (m, 1H), 1.92-2.03 (m, 2H), 1.771.87 (m, 2H), 1.25-1.30 (m, 1H), 1.17-1.23 (m, 1H) MS (m/z ): 479.0 [MH]+. Example 257: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-3-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E257)

[609] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 30 mg , 0.12 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(thiophen-3-yl)-4H-1,2,4-triazole (p197, 36 mg 0.132 mmol), Na2CO3 (15 mg, 0.144 mmol) and Nal (22 mg, 0.144 mmol) in DMF (0.135 mL), obtaining (1R,3S/1S,3R)-5-(3-{[4-methyl-5- (thiophen-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane (CIS, E257, 27.3 mg, y= 45%).NMR: 1H-NMR (Acetone-d6) δ: 7.95-7.98 (m, 1H), 7.66-7.71 (m, 1H), 7.577.64 (m, 3H ), 7.37 (d, 2H), 3.76 (s, 3H), 3.10-3.28 (m, 2H), 2.69-2.76 (m, 2H), 2.56-2.65 (m, 1H), 2.42-2.55 (m, 3H ), 2.19-2.26 (m, 1H), 1.92-2.02 (m, 2H), 1.771.87 (m, 2H), 1.28 (m, 1H), 1.20 (m, 1H) MS (m/z): 479 .0 [MH]+.Example 258: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrroyl-2-yl)-4H- 1 ,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E258)

[610] The compound was prepared as in Example 1, reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p14, 38 mg , 0.16 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazole (p198, 48 mg, 0.176 mmol), Na2CO3 (20 mg, 0.192 mmol) and Nal (29 mg, 0.192 mmol) in DMF (0.17 mL), obtaining (1R,3S/1S,3R)-5-(3 -{[4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl) phenyl]-5- azaspiro[2,4]heptane (CIS, E258, 33.2 mg, y= 42%).NMR: 1H-NMR (Acetone-d6) δ: 7.55-7.65 (m, 2H), 7.34 -7.40 (m, 2H), 6.916.97 (m, 1H), 6.47- 6.53 (m, 1H), 6.17-6.23 (m, 1H), 3.84 (s, 3H), 3.62 (s, 3H), 3.11 -3.29 (m, 2H), 2.68-2.76 (m, 2H), 2.61 (d, 1H), 2.43-2.57 (m, 3H), 2.20-2.25 (m, 1H), 1.78-2.01 (m, 4H) , 1.26-1.31 (m, 1H), 1.17-1.23 (m, 1H) MS (m/z): 476.02 [MH]+. Preparation 259: (1S,3S/1R,3R)-5(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (TRANS, p259)

[611] To a solution of (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, p13, 100 mg, 0.41 mmol) in THF (0.8 mL), in a vial, DIPEA (0.21 mL, 1.23 mmol) and 1-bromo-3-chloropropane (0.37 mL, 3.73 mmol) were added, the vial was sealed and the resulting mixture was stirred at 65°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with EA and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by FC on silica gel (elution with DCM/MeOH from 100/0 to 96/4), obtaining (1R,3S/1R,3R)-5- (3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (p259, TRANS, 75mg, y = 58%) as pale yellow oil. MS (m/z): 318.2 [MH]+. Example 259: (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)4H-1,2,4-triazole hydrochloride -3-yl]sufanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E259)

[612] A sealed container containing a mixture of (1S,3S/1R,3R)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS , p259, 40 mg, 0.13 mmol), 4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-thiol (p109, 31 mg , 0.16 mmol), Na2CO3 (17 mg, 0.16 mmol) and Nal (15 mg, 0.13 mmol) and DMF (0.2 ml) was stirred overnight at 60°C in a PLS apparatus. The mixture was diluted with EA, the organic phase was washed with water, dried with sodium sulfate and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with DCM/MeOH from 100/0 to 96/6) providing (1S.3S/1R,3R)-5-(3-{[4-methyl-5- (1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4] heptane (TRANS, 15 mg).

[613] This was dissolved in DCM (0.1 mL) and then 2N HCl/ether (eq 1.1) was added and the reaction mixture was concentrated under vacuum. The solid then obtained was triturated with ether and dried under vacuum at 45°C overnight, obtaining (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1-methyl -1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane ( TRANS, E259.15 mg, y = 22%).NMR: 1H NMR (DMSO-d6) δ:10.58 (br. s., 1H), 9.79 (s, 1H), 7.67 (m, 2H), 7.46 ( m, 2H), 3.90 (s, 3H), 3.50-3.70 (m, 4H), 3.16-3.40 (m, 6H), 3.00-3.12 (m, 1H), 2.37-2.48 (m, 1H), 1.80- 1.97 (m, 1H), 1.29-1.56 (m, 3H) MS (m/z): 481.4 [MH]+. Example 260: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H- 1,2,4-triazol- 3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, E260)

[614] The compound was prepared as in Example 1 by reacting (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 30 mg, 0.12 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,2,3-thiadiazole (p199.34 mg, 0.12 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL) obtaining (1R,3S/1S,3R)- 5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, E260, 6 mg, y= 9%). NMR: 1H NMR (CDCh) 5: 9.34 (s, 1H), 7.54 (d, 2H), 7.22 (d, 2H), 4.04 (s, 3H), 3.33 (d, 2H), 2.80-2.90 (m, 1H), 2.63-2.74 (m, 1H), 2.58 (br. s., 2H), 2.42-2.49 (m, 1H), 2.16 (d, 2H), 2.01 (br. s., 5H), 1.21 ( s, 2H) MS (m/z): 481.4 [MH]+. Preparation 260: (1R,3S)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p260)

[615] To a solution of (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 1, p15, 48 mg, 0.2 mmol) in THF (0.4 mL), in a vial, DIPEA (0.10 mL, 0.6 mmol) and 1-bromo-3-chloropropane (0.18 ml, 1.79 mmol) were added, the vial was sealed and the resulting mixture was stirred at 65°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with EA and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by FC on silica gel (elution with DCM/MeOH from 100/0 to 97/3), obtaining (1R,3S)-5-(3-chloropropyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p260, 40 mg, y = 62%) as pale yellow oil.MS (m/z): 318.2 [MH]+.Example 261: (1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4--yl)-4H-1,2 ,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E261)

[616] A sealed vial containing a mixture of (1R, 3S)-5-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, p260, 30 mg, 0.13 mmol), 4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazole-3-thiol (p109, 28 mg, 0. 14 mmol), Na2CO3 (17 mg, 0.16 mmol) and Nal (15 mg, 0.13 mmol) and DMF (0.2 mL) was stirred overnight at 60°C in a PLS apparatus. The mixture was diluted with EA, the organic phase was washed with water, dried with sodium sulfate and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with DCM/MeOH from 100/0 to 94/6) and then purified again by FC on an NH column (eluting with Cy/EA from 100/0 to 30/70). to give (1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl } propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (18 mg).

[617] The latter was dissolved in DCM (0.2 mL) and then 2N HCI / ether (eq 1.1) was added and the reaction mixture was concentrated under vacuum. The solid obtained was triturated with ether and dried under vacuum at 45°C overnight, yielding (1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazole hydrochloride) 4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E261, 19 mg, y = 28%) as a pale yellow solid. ), 7.39-7.48 (m, 2H), 3.87 (d, 3H), 3.65-3.76 (m, 1H), 3.39-3.47 (m, 1H), 2.94-3.32 (m, 6H), 2.62-2.71 (m , 1H), 2.19-2.44 (m, 2H), 1.94-2.15 (m, 3H), 1.271.52 (m, 2H) MS (m/z): 481.3 [MH]+.Example 262: (1 R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H- 1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride (CIS, Enantiomer 1, E262)

[618] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 30 mg, 0.12 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-4-methyl 1,2,3 thiadiazole(p200 , 34mg, 0.12 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL), obtaining (1R,3S)-5- (3-{[4-methyl-5-(4-methyl 1,2,3 thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (29 mg).

[619] The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (eq 1.1) was added and the reaction mixture was concentrated under vacuum. The solid thus obtained was triturated with ether and dried under vacuum at 45° C overnight, yielding (1R, 3S)-5-(3 - {[4-methyl-5-(4-methyl-1,2,3 -thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiometer 1, E262, 31 mg, y = 49%).NMR: 1H NMR (DMSO-d6) δ: 10.39-10.67 (m, 1H), 7.66 (d, 2H), 7.44 (d, 2H), 3.69 ( s., 1H), 3.51-3.59 (m, 3H), 3.37-3.47 (m, 1H), 2.93-3.29 (m, 5H), 2.80 (s, 3H), 2.61-2.72 (m, 1H) , 2.19-2.45 (m, 2H), 1.93-2.15 (m, 3H), 1.27-1.52 (m, 2H) MS (m/z): 495.3 [MH]+. Example 263: (1R, 3S)-5-[3-({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl] - 4H- 1,2, 4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E263)

[620] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 25 mg, 0.096 mmol), 3-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1,3-oxazol-2-yl) pyridine (P201, 34 mg, 0.1 mmol), Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.2 ml), giving (1R, 3S)-5-[ 3 -({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]-4H-1,2,4-triazol-3-yl}sulfanyl) propyl] -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E263, 34.2 mg, y = 66%).NMR: 1H NMR (Acetone-d6) δ : 9.29-9.36 (m, 1H), 8.77-8.80 (m, 1H), 8.678.69 (m, 1H), 8.44- 8.49 (m, 1H), 7.60-7.67 (m, 3H), 7.37-7.45 ( m, 2H), 3.97 (s, 3H), 3.20-3.35 (m, 2H), 2.61- 2.98 (m, 5H), 2.27-2.34 (m, 1H), 2.09-2.15 (m, 1H), 1.89- 2.03 (m, 4H), 1.33-1.40 (m, 1H), 1.23-1.29 (m, 1H).MS (m/z): 541.4 [MH]+.Example 264: (1R, 3S)-5 -[3 -({4-methyl-5-(6-(phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl}sulfanyl) propyl] -1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E264)

[621] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 25 mg, 0.096 mmol), 5-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-phenoxypyridine (P202, 37 mg, 0.1 mmol) , Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.2 ml) to give (1R, 3S)-5-(3 - {[4-methyl-5-(6 - phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E264, 27 mg, y = 49%).NMR: 1H NMR (Acetone-d6) δ: 8.45-8.50 (m, 1H), 8.16-8.22 (m, 1H), 7.607.66 (m, 2H ), 7.44- 7.52 (m, 2H), 7.34-7.42 (m, 2H), 7.20-7.32 (m, 3H), 7.14-7.20 (m, 1H), 3.70 (s, 3H), 3.11- 3.32 (m , 2H), 2.71-2.77 (m, 1H), 2.59-2.66 (m, 1H), 2.44-2.58 (m, 3H), 2.20-2.27 (m, 2H), 1.79-2.02 (m, 4H), 1.26 -1.33 (m, 1H), 1.21 (m, 1H) MS (m/z): 566.4 [MH]+. Example 265: (1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane dihydrochloride (CIS, Enantiomer 1, E265)

[622] (1R, 3S)-5-(3 - {[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl] sulfanyl} propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E264, 27 mg) was dissolved in MeOH and treated with 2.2 eq of 1N HCl in Et2O obtaining- if (1R, 3S)-5-(3 - {[4-methyl-5-(6-phenoxypyridin-3-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl} propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E265, 30.3 mg). MS (m/z): 566.4 [MH]+. Example 266: (1R, 3S)-5-[3 -({4-methyl-5- {[1,2,4] triazole [4,3 -a]pyridin-8-yl)- 4H- 1,2,4-triazol-3-yl}sulfanyl) propyl] -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane ( CIS, Enantiomer 1, E266)

[623] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 20 mg, 0.083 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}-4H-1, 2.4 -triazole (P203, 28 mg, 0.091 mmol), Na2CO3 (11 mg, 0.1 mmol) and Nal (15 mg, 0.1 mmol) in DMF (0.1 ml) obtaining (1R, 3S)- 5-{3-[(4-methyl-5-{[1,2,4]triazole [4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl) sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E266, 18.7 mg, y = 44%). NMR: 1H NMR (Acetone-d6) δ: 9.27-9.30 (m, 1H), 8.77-8.80 (m, 1H), 7.70-7.73 (m, 1H), 7.62 (d, 2H), 7.41 (d, 2H ), 7.19 (t, 1H), 3.68-3.71 (m, 3H), 3.30 (m, 2H), 2.52-2.76 (m, 5H), 2.13- 2.32 (m, 2H), 1.88-2.04 (m, 4H ), 1.30-1.36 (m, 1H), 1.24 (m, 1H) MS (m/z): 514.3 [MH]+.Example 267: (1R, 3S)-5-{3-[(4- methyl-5-{[1,2,4]triazol[4,3-a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4 -(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E267)

[624] (1R, 3S)-5-{3-[(4-methyl-5- {[1,2,4] triazolo [4,3-a]pyridin-8-yl}-4H- 1, 2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E266, 18.7 mg) was dissolved in DCM and treated with 1.1 eq of 2N HCl in Et2O obtaining (1R, 3S)-5-{3-[(4-methyl-5- {[1,2,4] triazolo [4, 3- a]pyridin-8-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS , Enantiomer 1, E267, 17 mg).MS (m/z): 514.3 [MH]+. Example 268: (1R, 3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3- a]pyridin-6-yl}-4H-1 hydrochloride ,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E268)

[625] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, p15, 25 mg, 0 .1 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazol[4,3-a]pyridin-6-yl}-4H-1,2 ,4-triazole (p204, 35 mg, 0.113 mmol), Na2CO3 (13 mg, 0.123 mmol) and Nal (18 mg, 0.123 mmol) in DMF (0.1 mL) obtaining (1 R,3S)-5 -{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl ]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (6.5 mg).

[626] The latter was dissolved in DCM and treated with 1.1 eq of 2M HCI in Et2O, then concentrated under reduced pressure, triturated with Et2O and dried under high vacuum, obtaining (1R,3S)-5- hydrochloride {3-[(4-methyl-5-{[1,2,4]triazol[4,3- a]pyridin-6-yl}-4H-1,2,4-triazol-3-yl)sulfanyl] propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E268 5.5 mg, y = 10%).NMR: 1H NMR (DMSO-d6) δ: 10.39-10.67 (m, 1H), 9.40 (s, 1H), 9.07 (s, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.67 (d, 2H), 7.46 (d, 2H), 3.65-3.77 (m, 4H), 2,943.48 (m, 7H), 1.95-2.46 (m, 5H), 1.28-1.54 (m, 2H) MS (m/z): 514.3 [MH ]+.Example 269: (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazol[4,3-a]pyridin-7-yl}- 4H- 1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E269)

[627] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 25 mg, 0 .1 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2 ,4-triazole (p205, 34 mg, 0.11 mmol) Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.113 mL) obtaining (1R, 3S) -5-{3- [(4-methyl-5- {[1,2,4] triazolo [4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl )sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E269, 25.4 mg, y = 49%). NMR: 1H NMR (Acetone-d6) δ: 9.16-9.25 (m, 1H), 8.67-8.72 (m, 1H), 8.078.12 (m, 1H), 7.60- 7.66 (m, 2H), 7.42-7.48 (m, 1H), 7.36-7.42 (m, 2H), 3.90 (s, 3H), 3.21-3.37 (m, 2H), 2.72-2.76 (m, 1H), 2.61-2.68 (m, 1H), 2.46 -2.58 (m, 3H), 2.21-2.28 (m, 1H), 2.10-2.13 (m, 1H), 1.94-2.05 (m, 2H), 1.83-1.94 (m, 2H), 1.271.32 (m, 1H), 1.22 (m, 1H) MS (m/z): 514.3 [MH]+.Example 270: (1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5- {3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a]pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl] propyl}-5- azaspiro[2,4]heptane (CIS, Enantiomer 1, E270)

[628] The compound was prepared as in Example 1, reacting (1S, 3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, p24, 26 mg, 0.1 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl - 5-{[1,2,4] triazole [4,3- a]pyridin-7-yl}-4 H -1, 2,4-triazole (p205, 34 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.113 mL) giving (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a] pyridin-7-yl}-4H- 1,2,4-triazol-3-yl)sulfanyl]propyl}-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E270, 24 mg, y = 45%). NMR: 1H NMR (DMSO-d6) δ: 9.38 (s, 1H), 8.68-8.74 (m, 1H), 8.15-8.20 (m, 1H), 7.60-7.66 (m, 1H), 7.47-7.53 (m , 1H), 7.34-7.39 (m, 1H), 7.27-7.34 (m, 1H), 3.73 (s, 3H), 3.17 (m, 2H), 2.75 (d, 1H), 2.36-2.48 (m, 4H ), 2.23 (s, 1H), 1.91-1.98 (m, 2H), 1.87 (d, 1H), 1.71-1.82 (m, 2H), 1.37 (m, 1H), 1.21 (m, 1H) MS (m /z): 532.3 [MH]+. Example 271: (1R,3S)-5-{3-[(4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H -1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E271)

[629] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 25 mg, 0.096 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1 ,2,4-triazole (P206, 32 mg, 0.1 mmol), Na2CO3 (13 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.2 ml), giving (1R, 3S )-5- {3-[(4-methyl-5- {3-methyl-[1,2,4] triazolo [4,3-a]pyridin-6-yl}-4H-1,2,4- triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E271.29.7 mg, y = 58%). NMR: 1H NMR (Acetone-d6) δ: 8.53-8.63 (m, 1H), 7.76-7.85 (m, 1H), 7.63 (s, 3H), 7.36-7.44 (m, 2H), 3.77 (s, 3H ), 3.16-3.35 (m, 2H), 2.81 (s, 3H), 2.72-2.77 (m, 1H), 2.59-2.68 (m, 1H), 2.46-2.56 (m, 3H), 2.21-2.28 (m , 2H), 1.83-2.03 (m, 4H), 1.27-1.32 (m, 1H), 1.19-1.25 (m, 1H) MS (m/z): 528.4 [MH]+.Example 272: (1R ,3S)-5-{3-[(5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-Triazol-3-yl)sulfanyl ]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E272)

[630] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, P15, 34 mg , 0.14 mmol), 3-[(3-chloropropyl)sulfanyl]-5-{1H-imidazole [4,5-b]pyridin-5-yl}-4-methyl-4H- 1,2,4 triazole (p207, 22 mg, 0.071 mmol), Na2CO3 (9 mg, 0.009 mmol) and Nal (10 mg, 0.007 mmol) in DMF (0.2 ml) giving (1R, 3S)-5-{3-[ (5- {1H - imidazole [4,5-b]pyridin-5-yl}-4-methyl-4H- 1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl] 5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E272, 16 mg, y = 44%).NMR: 1H NMR (DMSO-d6) δ: 13.01-13.19 (m, 1H) , 8.57 (s, 1H), 8.15-8.21 (m, 1H), 8.05 (s, 1H), 7.57-7.63 (m, 2H), 7.29-7.34 (m, 2H), 3.94-4.01 (m, 3H) , 3.08-3.22 (m, 2H), 2.66-2.76 (m, 1H), 2.36-2.50 (m, 4H), 2.21 (m, 1H), 1.82-1.98 (m, 3H), 1.72-1.81 (m, 2H), 1.23-1.29 (m, 1H), 1.15-1.20 (m, 1H) MS (m/z): 514.4 [MH]+.Example 273: (1R,3S)-5-[3-( {4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1 -[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (CIS, Enantiomer 1, E273)

[631] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 27 mg, 0 .11 mmol), 5-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)-1H- 1, 2.3 ,4-tetrazol (p208, 34 mg, 0.10 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (15 mg, 0.1 mmol) in DMF (0.2 ml) to obtain (1R , 3S)-5-[3-({4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-4H-1,2,4-triazol- 3-yl}sulfanyl)propyl]-1-[4-trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E273, 9.7 mg, y = 16%). NMR: 1H NMR (DMSO-d6) δ: 8.14 (d, 2H), 7.73 (d, 2H), 7.60-7.66 (m, 2H), 7.33-7.38 (m, 2H), 3.63 (s, 3H), 3.09-3.19 (m, 2H), 2.88-3.01 (m, 1H), 2.56-2.85 (m, 4H), 2.28 (m, 1H), 2.19 (br. s., 1H), 2.00-2.07 (m, 1H), 1.89-1.98 (m, 1H), 1.781.87 (m, 2H), 1.30-1.36 (m, 1H), 1.19- 1.25 (m, 1H)MS (m/z): 541.4 [MH ]+. Example 274: (1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4 hydrochloride -triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,4]heptane (CIS, Enantiomer 1, E274)

[632] Compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, P15, 30 mg, 0.12 mmol), 2-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)- 1,3,4- oxadiazole (p209, 47 mg, 0.14 mmol), Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL) giving (1R, 3S)-5 -[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]- 1-[4-(trifluoromethyl)phenyl]5-azaspiro[2,4]heptane (15 mg).

[633] The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (eq 1.1) was added and the reaction mixture was concentrated under vacuum. The solid obtained in this way was triturated with ether and dried under vacuum at 45°C overnight generating (1R, 3S)-5-[3 -({4-methyl-5-[4-(1,3,4- oxadiazol- 2-yl)phenyl]-4H-1,2,4-triazol- 3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS , Enantiomer 1, E274, 15 mg, y = 22%). NMR: 1H NMR (DMSO-d6) δ: 10.41-10.75 (m, 1H), 9.44 (s, 1H), 8.16-8.26 (m, 2H), 7.93-8.02 (m, 2H), 7.61-7.71 (m , 2H), 7.38-7.50 (m, 2H), 3.63-3.77 (m, 4H), 2.92-3.51 (m, 7H), 1.94- 2.70 (m, 5H), 1.26-1.53 (m, 2H) MS ( m/z): 541.4 [MH]+.Example 275: (1R,3S)-5-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazole -3- yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (CIS, Enantiomer 1 , E275)

[634] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, p15, 25 mg, 0 .1 mmol), 3-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl)-5-methyl-1,2 ,4-oxadiazole (p210, 39 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL) obtaining (1R, 3S)- 5-[3-({4-methyl-5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl} sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E275, 33 mg, y = 60%). NMR: 1H NMR (Acetone-d6) δ: 8.24 (d, 2H), 7.97 (d, 2H), 7.63 (d, 2H), 7.40 (d, 2H), 3.77 (s, 3H), 3.17-3.34 ( m, 2H), 2.72 (s, 3H), 2.60-2.70 (m, 1H), 2.48-2.60 (m, 3H), 2.23 (s, 1H), 2.11 (br. s., 1H), 1.95-2.03 (m, 2H), 1.84-1.95 (m, 3H), 1.30 (m, 1H), 1.23 (m, 1H) MS (m/z): 555.4 [MH]+.Example 276: (1R, 3S )-5-[3 -({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl) phenyl] - 4H- 1,2,4 -triazol-3-yl} sulfanyl) propyl] -1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4]heptane (CIS, Enantiomer 1, E276)

[635] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, P15, 25 mg , 0.1 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2 , 4-triazole (P211, 37 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 ml) to obtain (1R , 3S)-5-[3-({4-methyl- 5-[4-(4H- 1,2,4-triazol-4-yl) phenyl] -4H-1,2,4-triazol-3- yl}sulfanyl) propyl] -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E276, 36 mg, y = 67%).NMR: 1H NMR (Acetone -d6) δ: 8.96 (s, 2H), 7.95-8.01 (m, 2H), 7.87-7.94 (m, 2H), 7.58-7.64 (m, 2H), 7.35-7.41 (m, 2H), 3.74 ( s, 3H), 3.16-3.34 (m, 2H), 2.70-2.76 (m, 1H), 2.59-2.66 (m,1H), 2.42-2.57 (m, 3H), 2.19-2.26 (m, 1H), 2.072.11 (m, 1H), 1.80-2.03 (m, 4H), 1.26-1.31 (m, 1H), 1.21 (m, 1H) MS (m/z): 540.4 [MH]+.Example 277 : (1R, 3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H- 1,2,4-triazol-3-yl }sulfanyl) propyl] -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E277)

[636] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg , 0.096 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole (p212 , 35 mg, 0.1 mmol) Na2CO3 (12 mg, 0.115 mmol) and Nal (17 mg, 0.115 mmol) in DMF (0.15 mL) obtaining (1R,3S)-5-[3 -({ 4-methyl-5-(4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl) phenyl]-5- azaspiro[2,4]heptane (CIS, Enantiomer 1, E277, 31 mg, y = 60%).NMR: 1H NMR (Acetone-d6) δ: 8.19-8.25 (m, 2H), 8.11 (d, 1H), 7.92-7.97 (m, 2H), 7.62 (d, 2H), 7.37-7.44 (m, 3H), 3.76 (s, 3H), 3.20-3.34 (m, 2H), 2.47-2.72 (m, 6H), 2.28 (br. s., 1H), 1.86-2.02 (m, 4H), 1.33 (br. s., 1H), 1.24 (br. s., 1H) MS (m/z) : 540.4 [MH]+.Example 278: (1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]- hydrochloride 4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E278)

[637] (1R, 3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3 -yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E277, 31 mg) was dissolved in MeOH and treated with 1.1 eq. of 2N HCl in Et2O obtaining (1R, 3S)-5-[3 -({4-methyl-5-[4-(1,3-oxazol-2-yl] phenyl] - 4H-1,2, 4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E278, 30 mg).MS (m/z ): 540.4 [MH]+. Example 279: (1R, 3S)-5-[3 -({4-methyl-5-[3-(1,3-oxazol-2-yl) phenyl] -4H - 1,2,4-triazol-3-yl}sulfanyl) propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E279)

[638] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, p15, 25 mg, 0 .1 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazole (p239 , 37 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 ml) giving (1R, 3S)-5- [3 -({4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl) propyl] -1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, E279, 31 mg, y = 57%). NMR: 1H NMR (Acetone-d6) δ: 8.42-8.44 (m, 1H), 8.19-8.25 (m, 1H), 8.11 (d, 1H), 7.89- 7.94(m, 1H), 7.70-7.79 (m , 1H), 7.63 (d, 2H), 7.43 (d, 2H), 7.38 (d, 1H), 3.77 (s, 3H), 3.19- 3.38 (m, 2H), 2.64-3.04 (m, 6H), 2.28-2.37 (m, 2H), 1.932.05 (m, 3H), 1.35-1.41 (m, 1H), 1.25-1.30 (m, 1H) MS (m/z): 540.4 [MH]+. Example 280: 4-[4-methyl-5-({3 -[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E280)

[639] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 25 mg, 0. 1 mmol), 4- {5-[(3-chloropropyl)sulfanyl]-4-methyl-4H- 1,2,4-triazol-3-yl} benzamide (p213, 35 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 ml), giving 4-[4-methyl-5-({3-[(1R, 3S )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide-(CIS , Enantiomer 1, E280, 38.5 mg y=72%).NMR: 1H NMR (Acetone-d6) δ: 8.12 (d, 2H), 7.87 (d, 2H), 7.55-7.65 (m, 2H), 7.39 (d, 2H), 6.68-6.79 (m, 1H), 3.73 (s, 3H), 3.17-3.32 (m, 2H), 2.71-2.76 (m, 1H), 2.59-2.68 (m, 1H), 2.44-2.58 (m, 3H), 2.20-2.29 (m, 1H), 2.08-2.12 (m, 1H), 1.822.04 (m, 4H), 1.30 (m, 1H), 1.22 (m, 1H) MS (m/z): 516.4 [MH]+. Example 281: 4-[4-Methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl hydrochloride }sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E281)

[640] 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanil)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E280, 38.5 mg) was dissolved in DCM/Et2O and treated with 1.1 eq of 2N HCl in Et2O obtaining -se 4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptan- 5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]benzamide hydrochloric salt (CIS, Enantiomer 1, E281, 40.7mg). MS (m/z): 516.4 [MH]+.Example 282: 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5 -azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1, E282)

[641] The compound was prepared as in Example 1, reacting (1R,3S)-1-[4-(trifluoromethyl)phenyl]-4-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg , 0.103 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzonitrile (p214, 50 mg, 0.113 mmol, considered purity at 60%), Na2CO3 (13 mg, 0.123 mmol) and Nal (18 mg, 0.123 mmol) in DMF (0.1 mL), obtaining 4-[4-methyl-5({3-[(1R, 3S )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1, E282, 40 mg, y = 78%). NMR: 1H NMR (Acetone-d6) δ: 7.93-8.05 (m, 4H), 7.54-7.68 (m, 2H), 7.337.44 (m, 2H), 3.76 (s, 3H), 3.19-3.34 (m , 2H), 2.72-2.77 (m, 1H), 2.60-2.68 (m, 1H), 2.45-2.57 (m, 3H), 2.20- 2.28 (m, 1H), 2.08-2.13 (m, 1H), 1.81 -2.04 (m, 4H), 1.26-1.32 (m, 1H), 1.22 (m, 1H) MS (m/z): 498.4 [MH]+. Example 283: 4-[4-Methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl] hydrochloride propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1, E283)

[642] 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1, E282, 40 mg) was dissolved in MeOH/Et2O and treated with 1.1 eq of 2N HCl in Et2O obtaining 4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} hydrochloric salt sulfanyl)-4H-1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1, E283, 36.1 mg). MS (m/z): 498.4 [MH]+. Example 284: 1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5 hydrochloride -yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}etan-1-one (CIS, Enantiomer 1, E284)

[643] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, P15, 25 mg, 0. 1 mmol), 1-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl) ethan- 1-one (p215.34 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.113 mL), obtaining 1-{4-[4-methyl-5 -({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]phenyl} ethan-1-one (34.4 mg).

[644] The latter was dissolved in DCM/Et2O and treated with 2NHCl/ether (1.2 eq), providing 1-{4-[4-methyl-5-({3-[(1R,3S)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}etan-1- one (CIS, Enantiomer 1, E284, 34.5 mg, y = 62%). NMR: 1H NMR (DMSO-d6) δ: 10.14-10.44 (m, 1H), 8.12 (d, 2H), 7.88 (d, 2H), 7.65 (d, 2H), 7.38-7.48 (m, 2H), 3.68-3.74 (m, 1H), 3.64 (d, 3H), 3.38-3.47 (m, 1H), 3.21 (d, 6H), 2.65 (s, 3H), 2.20-2.45 (m, 2H), 1.92- 2.14 (m, 3H), 1.26-1.53 (m, 2H) MS (m/z): 515.4 [MH]+.Example 285: 4-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzene-1 - sulfonamide (CIS, Enantiomer 1, E285)

[645] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg , 0.1 mmol), 4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzene-1-sulfonamide (P216, 38 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 ml) giving 4-[4-methyl-5-({3 -[(1R, 3S)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol- 3- yl] benzene-1-sulfonamide (CIS, Enantiomer 1, E285, 32.9 mg, y = 60%).NMR: 1H NMR (Acetone) δ: 8.05 (s, 2H), 7.97 (s, 2H), 7.58 -7.66 (m, 2H), 7.32-7.42 (m, 2H), 6.70-6.76 (m, 1H), 3.74 (s, 3H), 3.26 (m, 2H), 2.79 (br. s., 2H), 2.45-2.70 (m, 4H), 2.21-2.26 (m, 1H), 1.81-2.02 (m, 4H), 1.29 (m, 1H), 1.21 (m, 1H) MS (m/z): 552.3 [MH]+.Example 286: 2- {4-[4-methyl-5-({3 -[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2,4] heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetonitrile (CIS, Enantiomer 1, E286)

[646] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg , 0.1 mmol), 2-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl) acetonitrile (p217, 31 mg , 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 ml) to give 2-{4-[4-methyl-5 -({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]phenyl}acetonitrile CIS, Enantiomer 1, E286, 27 mg, y = 55%). NMR: 1H NMR (Acetone-d6) δ: 7.79-7.85 (m, 2H), 7.60-7.66 (m, 4H), 7.367.43 (m, 2H), 4.11 (s, 2H), 3.71 (s, 3H ), 3.15-3.34 (m, 2H), 2.72-2.76 (m, 2H), 2.59-2.68 (m, 1H), 2.47-2.58 (m, 3H), 2.22-2.28 (m, 1H), 1.81-2.04 (m, 4H), 1,271.34 (m, 1H), 1.22 (m, 1H) MS (m/z): 512.3 [MH]+. Example 287: 2- {4-[4-methyl-5-({3 -[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl ]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]phenyl}acetamide (CIS, Enantiomer 1, E287)

[647] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantiomer 1, p15, 25 mg , 0.1 mmol), 2-(4-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}phenyl) acetamide (p218, (35 mg, 0.11 mmol), Na2CO3 (13 mg, 0.12 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.1 ml), yielding 2-{4-[4-methyl-5 -({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4- triazol-3-yl]phenyl}acetamide CIS, Enantiomer 1, E287, 31 mg, y = 61%). NMR: 1H NMR (DMSO-d6) δ: 7.58-7.68 (m, 4H), 7.50-7.56 (m, 1H), 7.417.47 (m, 2H), 7.29- 7.36 (m, 2H), 6.90-6.98 (m, 1H), 3.58 (s, 3H), 3.48 (s, 2H), 3.12 (d, 2H), 2.64-2.74 (m, 1H), 2.37-2.48 (m, 4H), 2.17-2.25 (m , 1H), 1.96 (d, 3H), 1.76 (s, 2H), 1.28 (m, 1H), 1.18 (m, 1H) MS (m/z): 530.4 [MH]+. Example 288: 3-[4-methyl-5-({3-[(1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E288)

[648] The compound was prepared as in Example 1 by reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (CIS, Enantiomer 1, p15, 25 mg, 0.103 mmol), 3-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzamide (p219, 35 mg, 0.113 mmol), Na2CO3 (13 mg , 0.123 mmol) and Nal (18 mg, 0.123 mmol) in DMF (0.1 mL) giving 3-[4 - methyl - 5-({3-[(1R, 3S)-1-[4- (trifluoromethyl) phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E288, 35 mg, y = 66% ).NMR: 1H NMR (Acetone-d6) δ: 8.27 (s, 1H), 8.08-8.15 (m, 1H), 7.88-7.95 (m, 1H), 7.59-7.72 (m,4H), 7.39 (d , 2H), 6.68-6.83 (m, 1H), 3.72 (s, 3H), 3.16-3.32 (m, 2H), 2.70-2.77 (m, 1H), 2.59-2.68 (m, 1H), 2.42-2.58 (m, 3H), 2.21-2.29 (m, 1H), 1.93-2.07 (m, 3H), 1.81-1.91 (m, 2H), 1.26-1.34 (m, 1H), 1.19-1.25 (m, 1H) MS (m/z): 516.4 [MH]+. Example 289: 3-[4-Methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl hydrochloride ]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E289)

[649] 3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl) -4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E288, 35 mg) was dissolved in Et2O and treated with 1.1 eq of 2N HCl in Et2O obtaining 3-[4 -methyl - 5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2, 4-triazol-3-yl] benzamide hydrochloric salt (CIS Enantiomer 1, E289, 31.5 mg). MS (m/z): 516.4 [MH]+. Example 290: 2-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]benzamide (CIS, enantiomer 1, E290)

[650] The compound was prepared as in Example 1, reacting (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, Enantomer 1, p15, 30 mg, 0.12 mmol), 2-{5-[(3-chloropropyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzamide (p220, 43 mg, 0.14 mmol) , Na2CO3 (15 mg, 0.14 mmol) and Nal (18 mg, 0.12 mmol) in DMF (0.2 mL), obtaining 2-[4-methyl-5-({3-[(1R , 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide ( 9 mg).

[651] The latter was dissolved in DCM (0.2 mL) and then 2N HCl/ether (eq 1.2) was added and the reaction mixture was concentrated under vacuum. The solid thus obtained was triturated with ether and dried under vacuum at 45° C overnight to obtain 2-[4-methyl-5-({3-[(1R,3S)-1-[4-( hydrochloride trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]benzamide (CIS, Enantiomer 1, E290, 9.7 mg, y = 22%).NMR: 1H NMR (DMSO-d6) δ: 10.40-11.03 (m, 2H), 7.30-8.02 (m, 7H), 6.87 (br. s , 1H), 3.60-3.82 (m, 3H), 3. 05-3.47 (m, 5H), 2.61-3.05 (m, 4H), 1.82-2.48 (s, 4H), 1.22-1.56 (m, 2H) MS (m/z): 516.4 [MH]+.Example 291: 1-{[4-methyl-5-(4-methyl -1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptan- 5-yl}propan-2-ol (CIS,E291) diastereometric mixture

[652] The compound was prepared as in Example 1, reacted with (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14.70 mg, 0.29 mmol), 1-chloro-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propan-2-ol (p240, 117 mg, 0.41 mmol), Na2CO3 (47 mg, 0.444 mmol) and Nal (67 mg, 0.444 mmol) in DMF (0.28 mL) giving 1 -{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-{1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl}propan-2-ol (CIS, E291, 13 mg, y = 9%) as diastereomeric mixture.NMR: 1H NMR (Acetone-d6) δ : 8.28-(s, 1H), 7.61 (d, 2H), 7.31-7.43 (m, 2H), 3.77 (d,3H), 3.52-3.59 (m, 1H), 3.41-3.49 (m, 1H), 3.11-3.24 (m, 2H), 2.57 (br. S., 2H), 2.43 (s, 3H), 2.20-2.28 (m,2H), 1.92-2.00 (m, 2H), 1.88-1.92 (m, 1H), 1,261.35 (m, 2H), 1.17-1.24 (m, 1H) MS (m/z): 494.4 [MH]+.Example 292: (1S, 3S/1R, 3R)-1- [2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 5-azaspiro[2,4]heptane (CIS, E292)

[653] (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, p23, 50 mg, 0.19 mmol) and 4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal (p247, 100 mg, 0.25 mmol), were dissolved in DCM ( 5 ml) and stirred for 15 min before adding NaBH (OAc) 3 (80 mg, 0.38 mmol). The reaction mixture was stirred at room temperature overnight. It was then diluted with water and DCM and extracted several times with DCM. The organic phase was evaporated and the residue was purified by FC on silica gel (eluent from DCM to MeOH) to obtain the compound (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl )phenyl] 5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane ( CIS, E292, 45 mg, y = 49%).NMR: 1H NMR (Acetone-d6) δ: 7.43-7.54 (m, 2H), 7.32 (m, 1H), 3.97 (m, 2H), 3.57 (s , 3H), 3.51 (d, 2H), 3.00-3.10 (m, 1H), 2.70-2.78 (m, 1H), 2.65 (d, 2H), 2.53-2.60 (m, 1H), 2.32-2.43 (m , 3H), 2.22-2.29 (m, 1H), 1.95-2.02 (m, 3H), 1.781.92 (m, 4H), 1.67-1.77 (m, 2H), 1.44- 1.53 (m, 2H), 1.32 -1.38 (m, 1H), 1.20-1.26 (m, 1H) MS (m/z): 481.1 [MH]+. Example 293 and Example 294: (1R, 3R)-1-[2-fluoro- 4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2 ,4]heptane (CIS, E293, Enantiomer 1) and (1S, 3S)-1-[2-fluoro- 4- (trifluoromethyl)phenyl] -5- {4-[4-methyl-5-(oxan-4 -yl)-4H-1,2,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane (CIS, E294, Enantiomer 2)

[654] (1S, 3S/1R, 3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]butyl}-5-azaspiro[2,4]heptane (CIS, E292, 40 mg) was separated into individual enantiomers by preparative chiral HPLC.

[655] (1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)- 4H-1,2, 4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane (CIS, E293, 11mg) Enantiomer 1: retention time 6.4 min, 100% ee MS (m/z): 481.5 [ MH]+.

[656] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)- 4H-1,2, 4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane (CIS, E294, 11mg) Enantiomer 2: RET time 8.5 min, 100% ee MS (m/z): 481.5 [ MH]+.Example 295: (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane (CIS, E295, Enantiomer 2)

[657] (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)- 4H-1,2, 4-triazol-3-yl]butyl}-5-azaspiro[2.4]heptane (CIS, E294, 11.5 mg) was treated with 1.1 eq of HCl in Et2O giving (1S,3S)-1-[2 -fluoro-4-(trifluoromethyl)phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-5- azaspiro hydrochloric salt [2.4] heptane (CIS, Enantiomer 2, E295 11.8 mg). MS (m/z): 481.1 [MH]+. Example 296: (1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, E296)

[658] For a solution of 4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butanal (p247, 135 mg, 0.57 mmol) and (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13, 137 mg, 0.57 mmol) in DCM (mL 4), the At RT and under a nitrogen atmosphere, sodium triacetoxyborohydate (mg 181, 0.86 mmol) was added in portions and the resulting reaction mixture was stirred overnight. A concentrated ammonium chloride solution was added, the mixture was diluted with DCM and the organic phase was washed with water, dried with sodium sulfate and the solvent removed under vacuum. The crude material was purified by FC ammonia (elution with DCM/MeOH from 100/0 to 95/5) to give (1S, 3S/1R, 3R)-5-{4-[4-methyl-5-(oxan- 4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, E296, 85 mg, y = 32%).NMR: 1H NMR (CDC3)δ: 7.53 (d, 2H), 7.15-7.21 (m, 2H), 4.07-4.17 (m, 2H), 3.52-3.59 (m, 2H), 3.51 (s , 3H), 2.84-2.96 (m, 1H), 2.75 (d, 4H), 2.55-2.66 (m, 2H), 2.47-2.55 (m, 2H), 2.05-2.17 (m, 4H), 1.84 (br .s., 4H), 1.59-1.74 (m, 3H), 1.451.56 (m, 1H), 1.22-1.29 (m, 1H), 1.08-1.15 (m, 1H) MS (m/z): 463 .5 [MH]+. Example 297 and Example 298: (1S, 3S or 1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4 -triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E297, Enantiomer 1) and (1R, 3R or 1S,3S)-5-{ 4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4 ]heptane (TRANS, E298, Enantiomer 2)

[659] (1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (TRANS, E296, 85 mg) was separated into the individual Enantiomers by preparative chiral HPLC.

[660] (1S, 3S or 1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E297, 24 mg) Enantiomer 1: Ret. 9.5 min MS (m/z): 463.5 [MH]+.

[661] (1R, 3R or 1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl} -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E298, 23 mg) Enantiomer 2: Ret. 12.1 min MS (m/z): 463.5 [MH]+.Example 299: (1S,3S/1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl )-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane chloride (TRANS, E299)

[662] (1S.3S or 1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E297, 24 mg) was dissolved in DCM and treated with 1.1 eq of 2N HCl in Et2O obtaining (1S, 3S or 1R,3R)-5-{4-[4-methyl-5-(oxan-4-yl salt)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl )phenyl]-5-azaspiro[2.4]heptane hydrochloric salt (TRANS Enantiomer 1, E299, 25mg). MS (m/z): 463.5 [MH]+. Example 300: (1R, 3R or 1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane hydrochloride (TRANS, E300, enantiomer 2)

[663] (1R, 3R or 1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E298, 23 mg) was dissolved in DCM and treated with 1.1 eq of 2N HCl in Et2O obtaining (1R, 3R or 1S,3S)-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2.4]heptani hydrochloric salt (TRANS, Enantiomer 2, E300, 24mg). MS (m/z): 463.5 [MH]+. Example 301: (1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole -3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane hydrochloride (CIS, E301) Step a:

[664] For a solution of 4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4 -triazole (p248, 62 mg, 0.27 mmol) in THF/H2O (mL 2.3/0.5) were subsequently added OsO4 (0.10 mL, 4% solution in water, 0.014 mmol) and NalO4 (173 mg , 0.81 mmol). The reaction mixture was stirred overnight at RT. Water was added and the mixture was extracted with DCM. The organic phase was dried with sodium sulfate and the solvent was removed in vacuo, yielding 4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2, 4-triazol-3-yl]butanal (35 mg) as colorless oil which was used as such in the next step. Step b:

[665] In a vial, a solution of 4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butanal (33 mg, from step a) and (1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, p14, 44 mg, 0.18 mmol) in DCM (0.5 mL) was stirred for 10 min at RT. Na(AcO)3BH (45 mg, 0.21 mmol) was added in portions and the resulting reaction mixture was stirred overnight at RT in a PLS apparatus. The mixture was diluted with DCM and washed with concentrated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and the solvent removed in vacuo. The residue was purified by FC on silica (elution with DCM/MeOH from 100/0 to 90/10), then further purified by FC ammonia (elution with EA/MeOH from 100/0 to 3/97) obtaining (1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (16 mg).Step c:

[666] (1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole -3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (16 mg) was dissolved in DCM (0.2 mL) then 2N HCl/ether (0.019 mL, 0.038 mmol) was added and the reaction mixture was concentrated in vacuo. The solid obtained was triturated with ether and dried under vacuum at 45°C overnight to obtain (1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1, 3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (CIS, E301 , 17 mg, y = 19%) as a pale yellow foam. NMR: 1H NMR (DMSO-d6) δ: 10.11-10.46 (m, 1H), 8.54 (s, 1H), 7.68 (d, 2H), 7.45 (d, 2H), 3.61-3.71 (m, 4H), 3.20 (br. s., 5H), 2.55-2.87 (m, 4H), 2.31-2.44 (m, 3H), 2.24 (m, 1H), 2.03- 2.15 (m, 1H), 1.71 (d, 4H) , 1.26-1.54 (m, 2H) MS (m/z): 460.5 [MH]+. Example 302: (1R,3S/1S,3R)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole -3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane hydrochloride (CIS, Enantiomer 1, E302) Step a:

[667] For a solution of 4-methyl-3-(4-methyl-1,3-oxazol-5-yl)-5-(pent-4-en-1-yl)-4H-1,2,4 -triazole (p248, 107 mg, 0.46 mmol) in THF/H2O (4ml/00.8 mL) OsO 4 (0.15 mL, 4% solution in water, 0.023 mmol) and NalO4 (295 mg, 1.38 mmol). The reaction mixture was stirred overnight at RT. Water was added and the mixture was extracted with DCM. The organic phase was dried with sodium sulfate and the solvent removed under vacuum, obtaining 4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2, 4-triazol-3-yl]butanal (107 mg) which was used raw in the next step. Step b:

[668] In a vial, a solution of 4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butanal (53 mg, from step a) and (1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, p15, 40 mg, 0.17 mmol) in DCM (0.6 mL) was stirred for 10 min at RT. Na(AcO)3 BH (73 mg, 0.35 mmol) was added in portions and the resulting reaction mixture was stirred at room temperature overnight in a PLS apparatus. The mixture was diluted with DCM and washed with concentrated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and the solvent removed in vacuo. The residue was purified by FC on the NH column (elution with EA/MeOH from 100/0 to 3/97) to give (1R,3S)-5-{4-[4-methyl-5-(4-methyl- 1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (29 mg) . Step c:

[669] (1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl ]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (29 mg) was dissolved in DCM (0.2 mL), then 2N HCl/ether (0.035 mL) was added and the reaction mixture was concentrated under vacuum. The solid obtained was triturated with ether and dried under vacuum at 45° C overnight, providing (1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazole) hydrochloride -5-yl)-4H-1,2,4-triazol-3-yl]butyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1, E302, 31 mg, y = 37%) as white solid. NMR: 1H NMR (DMSO-d6) δ: 10.26-10.57 (m, 1H), 8.55 (s, 1H), 7.68 (d, 2H), 7.45 (d, 2H), 3.64 (s, 3H), 2.88- 3.42 (m, 6H), 2.37-2.86 (m, 4H), 2.35 (s, 3H), 2.03-2.30 (m, 2H), 1.71 (d, 4H), 1.27-1.53 (m, 2H) MS (m /z): 460.4 [MH]+. Preparation 261: (1S,3S/1R,3R)-5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS)

[670] A mixture of (1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, p13, 100 mg, 0.41 mmol), (3 -bromopropoxy)(tert-butyl) dimethylsilane (0.143 mL, 0.615 mmol), TEA (0.171 mL, 1.23 mmol), Nal (12 mg, 0.082 mmol) in DMF (mL 2) was stirred at 50°C during night. The mixture was then diluted with brine and DCM, phases were separated and the aqueous phase was extracted twice with DCM. Combined organics were dried and concentrated under reduced pressure. Crude material was purified by FC on the NH column (eluent: Cy to 20% EtoAc), yielding (1S, 3S/1R, 3R)-5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, p261, 73 mg, y = 44%) as a colorless oil. MS (m/z): 414.6 [MH]+ Preparation 262: 3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propan-1-ol (TRANS)

[671] (1S,3S/1R,3R)-5-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, p261, 73 mg, 0.18 mmol) was dissolved in THF (1 mL) and treated with 1 m HCl (1 mL). The mixture was stirred at RT for 1h. 1 m NaOH was then added to raise the pH to 8 and the mixture was extracted with EtOAc. 1M NaOH was added until pH 10 and the aqueous phase was extracted again with DCM. Combined organics were dried and concentrated to obtain 3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-1-propanol ( TRANS, p262, 49 mg, y = 84%) as colorless oil. MS (m/z): 300.3 [MH]+. Preparation 263: 4-methyl-3-(methylsulfanyl)-5-(oxan-4-yl)-4H-1,2,4-triazole

[672] To a solution of 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole-3-thiol (p66, 500 mg, 2.5 mmol) in EtOH (3.75 mL ) iodomethane (187 uL, 3 mmol) was added dropwise. The resulting mixture was stirred at 80°C for 30'. Solvent was evaporated in vacuum; the residue was dissolved in 1M NaOH and extracted three times with DCM. Combined organics were dried and concentrated to obtain 4-methyl-3-(methylsulfanyl)-5-(oxan-4-yl)-4H-1,2,4-triazole (p263, 482 mg, y = 90%) as white solid. MS (m/z): 214.2 [MH]+ Preparation 264: 3-methanesulfonyl-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole

[673] To a solution of 4-methyl-3-(methylsulfanyl)-5-(oxan-4-yl)-4H-1,2,4-triazole (p263, 482 mg, 2.26 mmol) in DCM ( 6 mL) 3-chloroperbenzoic acid (1.17 g, 6.78 mmol) was added in portions. The resulting mixture was stirred at room temperature for 3h. EtOAc was then added until complete dissolution, followed by NaHCO3 ss. aqueous solution was extracted again with EtOAc and, combined organics were dried methanesulfonyl-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p264, 412 mg, y = 71%) as a white solid. MS (m/z): 246.2 [MH]+. Example 303: (1-S, 3S/1 R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl ]oxy}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, E303)

[674] To a solution of 3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propan-1-ol ( TRANS, p262, 49 mg, 0.16 mmol) in (mL 1.5), 3-methanesulfonyl-4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazole (p264, 39 0.16 mmol) was added followed by 60% NaH in mineral oil (9.6 mg, mmol) and the mixture was stirred in a PLS apparatus at 60 ° C for 4 hours. Additional was added (52 mg in 5 further additions) and the mixture was stirred for a total of 26 hrs. The reaction was cooled to 0°C with an ice bath and water was slowly added. Three times the mixture was extracted and with DCM, then twice with EyOAc. Combined organic products were dried and concentrated; Crude material was purified by FC on silica gel (eluent: DCM to DCM/MeOH 0:10) to obtain (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan- 4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, E303, 49 mg, y = 58%) as colorless gum. ), 3.44-3.54 (m, 2H), 3.40 (s, 3H), 2.90-3.01 (m, 1H), 2.72-2.76 (m, 2H), 2.53-2.66 (m, 5H), 2.18-2.30 (m , 1H), 1.94-2.02 (m, 2H), 1.81-1.86 (m, 3H), 1.61-1.70 (m, 1H), 1.37-1.46 (m, 1H), 1.25 (d, 1H), 1.20 (s , 1H) MS (m/z): 481.1 [MH]+. Example 304 and Example 305: (1S, 3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl ]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane ( TRANS, E304, Enantiomer 1) and (1R, 3R or 1S,3S)-5- (3-{[ 4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4] heptane (TRANS, E305, Enantiomer 2)

[675] (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, E303, 49 mg) was separated into the individual Enantiomers by preparative chiral HPLC.

[676] (1S, 3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy} propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, E304, 14 mg) Enantiomer 1: RET time 16.1 min, 100% ee MS (m/z): 465.5 [MH]+.

[677] (1R, 3R or 1S, 3S)-5-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]oxy}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.4] heptane (TRANS, E305, 11 mg) Enantiomer 2: RET time 19.4 min, 100% ee MS (m/z): 465.5 [MH]+. Preparation 265: benzyl-triphenyl-phosphonium bromide

[678] A solution of PPh3 (7.66 g, 29.23 mmol) and benzyl bromide (3.48 mL, 29.23 mmol) in toluene (mL 70) was refluxed overnight; the mixture was then cooled to RT and the resulting precipitate was collected by filtration, washed with pentane and dried under vacuum to obtain benzyl triphenyl phosium bromide (p265, g 12, y = 95%) as a white solid. . MS (m/z): 353.2 [M-Br]+ Preparation 266: tert-butyl-4 (phenylmethylidene) piperidine-1-carboxylate

[679] A suspension of benzyl-phosphonium triphenyl bromide (p265, 10.87g, 25.09 mmol) in THF (mL 70) was cooled with an ice bath and then dispersed in 60% NaH mineral oil (1.1 g, 27.6 mmol) was added. The suspension was stirred at 0°C for 10 minutes, then at RT for 45 min, the suspension turned yellow-orange.

[680] Tert-butyl 4-oxo-1-piperidinecarboxylate (5g, 25.09 mmol) dissolved in THF (30 mL) was added dropwise and the resulting reaction mixture was stirred at room temperature overnight. The mixture was then cooled to 0°C and diluted with water and EtOAc. The organic phase was separated and washed with ss NaHCOs, then dried and evaporated. The residual oil was treated with Et2O to precipitate the triphenylphosphoxide which was filtered. The solution was evaporated and the residue was purified by FC on silica gel (eluent of cHex to 10% EtOAct) to obtain the title compound tert-butyl-4(phenylmethylidene)piperidine-1-carboxylate (p266, 5.46 g, y = 79%) as white solid. MS (m/z): 274.2 [MH]+. Preparation 267: tert-butyl (2R/2S)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane-6-carboxylate

[681] Tetrabutylammonium bromide (150 mg, 0.46 mmol) was added to a mixture of tert-butyl - 4 (phenylmethylidene) piperidine-1-carboxylate (p266, 3G, 10.97 mmol) in CHCl3 (50 mL) and 50% aqueous NaOH (10 mL). The reaction mixture was stirred at RT for 3hrs and then over 30 mL of 50% aqueous NaOH was added. After 48 h, the reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM and the combined organics were dried and concentrated. The residue was purified by FC on silica gel (10% cHex AcOEt elution) to obtain tert-butyl(2R/2S)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane-6 -carboxylate (p267, 4G, y = quant) as colorless oil. (43) MS (m/z): 356.2 [MH]+ Preparation 268: (2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane

[682] To a stirred solution of tert-butyl (2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane-6-carboxylate (p267, 2 g, 5.6 mmol) in DCM (20 mL), TFA (4 mL) was added and the resulting solution was allowed to stir at RT for 1 h. The solvent was removed in vacuo and the residue was loaded onto an SCX cartridge, eluting with 1 M NH3 in MeOH to obtain the title compound (2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5 ]octane (p268 1.3 g) as pale yellow oil which was used as such in the next step. MS (m/z): 256.2 [M]+. Preparation 269: 1-[(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro [2.5] octan-6-yl] - 2,2,2 - trifluoroetan-1-one

[683] To a stirred solution of (2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octane (p268, 450 mg, 1.75 mmol) in DCM (mL 10) trifluoroacetic acid anhydride ( 0.364 mL) was added and the resulting solution was left stirring at room temperature overnight. It was then diluted with more DCM and washed with 1N NaOH. The organic solvent was dried and evaporated. The residue was purified by FC on silica gel (10% cHex AcOEt elution) to obtain 1-[(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro[2.5]octan-6 -yl]-2,2,2-trifluoroetan-1-one (p269, mg 550, y = 89%) as white solid. MS (m/z): 352.1 [M]+.Preparation 270: 2,2,2-trifluoro-1-[(1R/1S)-1-phenyl-6-azaspiro[2.5]octan-6-yl ] etan-1-one

[684] To a stirred solution of 1-[(2S/2R)-1,1-dichloro-2-phenyl-6-azaspiro [2.5] octan-6-yl] - 2,2,2 - trifluoroetan-1- one (p269, 550 mg, 1.56 mmol) in EtOH/H2O (10 mL/1 mL), Zn powder (560 mg, 8.58 mmol) was added. The resulting mixture was stirred at reflux overnight. Solid was filtered and washed with MeOH. The solution was concentrated and the residue was purified by FC on silica gel (Elution of cHex to 10% EtOAc) to obtain the title compound 2,2,2-trifluoro-1-[(1R/1S)-1-phenyl- 6-azaspiro [2.5] octan-6-yl] etan-1-one (p270, 130 mg, y = 29%) as colorless oil MS (m/z): 284.2 [MH]+ Preparation 271: (1R /1S)-1-phenyl-6-azaspiro [2.5]octane

[685] To a stirred solution of 2,2,2-trifluoro-1-{1-phenyl-6-azaspiro[2.5]octan-6-yl}etan-1-one (p270, 130 mg, 0.46 mmol ) in MeOH/H2O (mL 4/2 mL), K2CO3 (127 mg, 0.92 mmol) was added. The resulting solution was left stirring at RT for 1 h. MeOH was evaporated, then DCM and 1N NaOH were added and the product was extracted several times with DCM. The organic phase was dried and evaporated to obtain (1R/1S)-1-phenyl-6-azaspiro [2.5] octane (p271, 100 mg, 70% pure) as colorless oil which was used as such in the next step. MS (m/z): 188.2 [MH]+.Example 306: (1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4- triazol-3-yl]sulfanyl} propyl})-1-phenyl-6-azaspiro [2.5]octane (E306)

[686] The compound was prepared as in Example 1, reacting (1R/1S)-1-phenyl-6-azaspiro [2.5] octane (p271, 50mg, 0.267 mmol), 3-[(3-chloropropyl)sulfanyl] -4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (p148, 80 mg, 0.29 mmol), Na2CO3 (34 mg, 0 .32 mmol) and Nal (48 mg, 0.32 mmol) in DMF (0.2 mL) providing the title compound (1R/1S)-6 -(3-{[4-methyl-5-(4-methyl-1 , 3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro [2.5] octane (E306, 53 mg, y = 48% ). NMR: 1H NMR (Acetone-d6) δ: 8.28 (s, 1H), 7.12-7.34 (m, 5H), 3.75-3.86 (m, 3H), 3.30 (m, 2H), 2.45-2.70 (m, 4H ), 2.43 (s, 3H), 2.18-2.39 (m, 2H), 1.932.04 (m, 3H), 1.49-1.73 (m, 2H), 1.18-1.36 (m, 2H), 0.96-1.03 (m , 1H), 0.78-0.86 (m, 1H) MS (m/z): 424.1 [MH]+. Example 307 and Example 308: (1S or 1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane (E307, Enantiomer 1) and (1R or 1S)-6-(3-{[4-methyl-5-(4- methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane (E308, Enantiomer 2)

[687] (1R/1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-6-azaspiro [2.5] octane (E306, 44 mg) was separated into individual enantiomers by preparative chiral HPLC.

[688] Provides (1S or 1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3 -yl]-sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane (E307, 18 mg) Enantiomer 1: RET time 9.0 min, 100% ee MS (m/z): 424.5 [MH]+.

[689] (1R or 1S)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-6-azaspiro[2.5]octane (E308, 19 mg) Enantiomer 2: RET time 14.9 min, 100% ee MS (m/z): 424.5 [MH ]+. Example 309: (1S or 1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-6-azaspiro [2.5] octane hydrochloride (E309, Enantiomer 1)

[690] (1S or 1R)-6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3- yl]sulfanyl}propyl)-1-phenyl-6-azaspiro [2.5] octane (E307, 18 mg) was treated with 1.1 eq of HCl in Et2O giving (1S or 1R)-6-(3 - {[ 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl} propyl)-1-phenyl-6-azaspiro [ 2.5] octane (Enantiomer 1, E309, 18.6 mg). MS (m/z): 424.1 [MH]+. Preparation 272: N-benzyl-2-chloroacetamide

[691] 2-Chloroacetyl chloride (0.796 mL, 10 mmol) was added slowly and dropwise to a mixture of benzylamine (0.906 mL, 8.3 mmol) and TEA (1.4 mL, 10 mmol) in anhydrous DCM (8 ML) at 0°C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with NaHC > 3, NH4Cl and brine. Organic phase was separated, dried over Na2SO4 and concentrated to obtain N-benzyl-2-chloroacetamide (p272, 1.58 g, y = 98%) as gray solid. MS (m/z): 184.1 [MH]+.Preparation 273: [(benzylcarbamoyl)methyl]triphenylphosphanium chloride

[692] To a solution of N-benzyl-2-chloroacetamide (P272, 1.58 g, 8.17 mmol) in toluene (10 mL) was added triphenylphosphine (2.25 g, 8.58 mmol) and to reaction was stirred at reflux (110°C) overnight. A precipitate formed. The reaction was cooled to room temperature, Et2O was added and the suspension was filtered. The brown solid was washed with Et2O and dried under high vacuum to obtain [(benzylcarbamoyl)methyl]triphenylphosphanium chloride (P273, 3.26 g, y = 83%). MS (m/z): 410.4 [MH]+. Preparation 274: 1-benzyl-3-methylidenepiperidine-2,6-dione Step a:

[693] To a solution of [(benzylcarbamoyl) methyl] triphenylphosphanium chloride (P273, 2.76 g, 6.15 mmol) in MeOH (44 ml) at 0°C was added methoxysodium (831 mg, 15.38 mmol ) and the reaction was stirred at 0°C for 10'. Then the ice bath was removed and methyl acrylate (0.553 mL, 6.15 mmol) was added and the reaction was stirred at room temperature overnight. The day after the reaction was concentrated and the residue was dissolved in DCM and washed with water. The organic phase was dried under Na2SO4 and concentrated to obtain 1-benzyl-3-(triphenyl-α5-phosphanylidene)piperidine-2,6-dione (2.91 g) as a brown oil which was used crudely. in the next step. Step b:

[694] To a solution of 1-benzyl-3-(triphenyl-À52,6-dione (2.91 g, 6.28 mmol) in toluene (60 ml), 37% formaldehyde in water (0.374 ml, 5.02 mmol) and the reaction was stirred at RT for 2 h. EtOAc and water were added, the phases were separated, the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated. The crude material was purified by FC on silica gel (Cy eluent to 30% EtOAc) to obtain 1-benzyl-3-methylidenepiperidine-2,6-dione (P274, 400 mg, y = 30%) as a yellow oil. MS (m/z): 216.2 [MH]+. Preparation of 275 and 276: (1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro [2.5] octane-4,6-dione (TRANS, p275) and (1S, 3S/1R, 3R)-5-benzyl - 1-[4-(trifluoromethyl)phenyl] -5-azaspiro [2.5] octane-4,6-dione (CIS, p276)

[695] To a solution of {[4-(trifluoromethyl)phenyl] methylidene}hydrazine (p1, 350 mg, 1.86 mmol) in dioxane (mL 4), at 10 ° C, MnO2 (1.62 g, 50 mmol) was added in portions. The resulting mixture was stirred at RT for 30 min, then filtered through a pad of Celite, washed with dioxane and this solution was added to a solution of 1-benzyl-3-methylidene-piperidine-2,6-dione (P274, 400 mg, 1.86 mmol) in dioxane (1.4 mL). The resulting orange solution was stirred at room temperature overnight. Solvent was removed and crude material was purified by FC on the silica cartridge (elution of cHex to 30% EtOAc) to obtain: (1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl ]-5-azaspiro[2.5]octane-4,6-dione (TRANS, p275, mg 347, y = 45%) as a colorless gum and (1S,3S/1R,3R)-5-benzyl-1-[ 4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane-4,6-dione (CIS, p276, 186 mg, y = 21%) as wax. MS (m/z): 374.3 [MH] +.Preparation 277: (1R, 3S/1S, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.5]octane (TRANS)

[696] (1R, 3S/1S, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,5] octane-4,6-dione (TRANS, p275, 347 mg , 0.93 mmol) in THF (5 mL) and LiAIH41M in THF (1.86 mL, 1.86 mmol) was added dropwise. The resulting orange solution was heated at reflux (70°C) for 1 h. It was then cooled with an ice bath and quenched with Na2SO4 10 * H2O until gas evolution ceased. Filtered over a pad of celite washing with EtOAc, the solution was concentrated to obtain (1R, 3S/1S, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2 .5] octane (TRANS, P277, 260 mg, y = 60%) as a yellow oil which was used as such in the next step. MS (m/z): 346.4 [MH]+. Preparation 278: (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.5]octane (TRANS)

[697] (1R,3S/1S,3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, p277, 260 mg, 0.75 mmol) was dissolved in MeOH (3 mL) under N2 and Ammonium Formate (236 mg, 3.75 mmol) was added followed by Pd/C (25 mg). The resulting mixture was stirred at reflux for 1.5 hours.

[698] After cooling, it was filtered over a pad of Celite, the solvent was evaporated and the residue was divided between DCM and NaHC O3 (aqueous phase with pH ~8) and washed three times with DCM. Organic layers were combined, dried over a phase separator and concentrated. Crude material was purified with a C18 cartridge (water eluent for 30% ACN). Fractions containing the product were combined and volatile compounds were evaporated. The remaining water was basified and extracted several times with DCM. The combined organic phases were dried over Na2SO4 and concentrated to obtain (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5] octane (TRANS, p278, 50 mg , y = 26%) as a yellow oil.MS (m/z): 256.1 [MH]+.Preparation 279: (1S, 3S/1R, 3R)-5-benzyl-1 -[4-(trifluoromethyl )phenyl] 5- azaspiro [2.5] octane (CIS)

[699] (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,5] octane-4,6-dione (CIS, p276, 186 mg , 0.5 mmol) was dissolved in THF (3 mL) and 1 M LiAlH4 was added dropwise in THF (1 mL, 1 mmol). The resulting orange solution was heated at reflux (70°C) for 1 h. It was then cooled with an ice bath and quenched with Na2SO4 10*H2O until gas evolution ceased. Filtered over a pad of celite washing with EtOAc, the solution was concentrated to obtain (1R, 3S/1S, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2 .5] octane (CIS, p279, 153 mg, y= 62%) as a yellow oil which was used as such in the next step. MS (m/z): 346.4 [MH]+. Preparation 280: (1S, 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.5] octane (CIS)

[700] (1S, 3S/1R, 3R)-5-benzyl-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.5] octane (CIS, P279, 153 mg, 0.44 mmol) was dissolved in MeOH (2 ml) under N2 and ammonium formate (138 mg, 2.2 mmol) was added followed by Pd/C (15 mg). The resulting mixture was stirred at reflux for 1.5 hours.

[701] After cooling, it was filtered over a pad of Celite, the solvent was evaporated and the residue was divided between DCM and NaHCO3 (aqueous phase with pH ~7) and washed three times with DCM. The organic layers were combined, dried and concentrated. The crude material was purified with C18 cartridge (Water eluent to 30% ACN) and then purified by FC on silica cartridge (DCM eluent to MeOH) to obtain (1S, 3S/1R, 3R)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro [2.5] octane (CIS, p280, 47 mg, y = 36%) as a white solid. MS (m/z): 256.1 [MH]+ . Example 310: (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4- triazol-3-yl]salphanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, E310)

[702] The compound was prepared as in Example 1 by reacting (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.5] octane (TRANS, p278, 49 mg, 0.19 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4- triazole (p148, 57 mg, 0.21 mmol), Na2CO3 (24 mg, 0.228 mmol) and Nal (34 mg, 0.228 mmol) in DMF (0.2 ml) generating (1R,3S/1S,3R)-5- (3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]salphanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5- azaspiro[2.5]octane (TRANS, E310, 33 mg, y = 34%).NMR: 1H NMR (Acetone-d6) δ: 8.25-8.29 (m, 1H), 7.59- 7.64 (m, 2H), 7.437.52 (m, 2H), 3.81 (s, 3H), 3.31-3.47 (m, 2H), 2.44-2.55 (m, 3H), 2.42 (s, 3H), 2.25- 2.39 (m, 3H), 2.14-2.22 (m, 1H), 1.95-2.03 (m, 2H), 1.15-1.48 (m, 4H), 0.931.14 (m, 3H) MS (m/z): 492 .3 [MH]+. Example 311 and Example 312: (1R, 3S or 1S, 3R)-5-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl )-4H- 1,2,4-triazol-3-yl]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,5]octane (TRANS, E311, Enantiomer 1) and (1S, 3R or 1R, 3S)-5-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol- 3- yl] sulfanyl} propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro [2,5] octane (TRANS, E312, Enantiomer 2)

[703] (1R, 3S/1S, 3R)-5-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,5]octane (TRANS, E310, 33 mg) was separated into individual enantiomers by preparative chiral HPLC (SFC ).

[704] (1R,3S or 1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]salphanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, E311, 10 mg) Enantiomer 1: retention time 17.7 min, 100% ee MS (m/z): 492.4 [MH]+.

[705] (1S,3R or 1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]salphanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, E312, 10 mg) Enantiomer 2: Ret. 20.6 min, 100% ee MS (m/z): 492.5 [MH]+. Example 313: (1S,3R/1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4- triazol-3-yl]salphanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS, E313 )

[706] The compound was prepared as in Example 1 by reacting (1S, 3S/1R, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2.5] octane (CIS, P280, 46 mg, 0.18 mmol), 3-[(3-chloropropyl)sulfanyl]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole (P148 , (32 mg, 0.216 mmol) in DMF (0.2 ml), giving (1S, 3S/1R, 3R)-5-(3 - {[4- Methyl-5-(4-methyl-1, 3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl] sulfanyl} propyl)-1-[4-(trifluoromethyl)phenyl] 5-azaspiro [2,5] octane (CIS, E313, 23 mg, y = 25%).NMR: 1H NMR (Acetone-d6) δ: 8.27 (s, 1H), 7.62 (d, 2H), 7.48 (br. s., 2H), 3.81 (s, 3H), 3.40 (br. s., 2H), 2.48 (br. s., 3H), 2.42 (s., 3H), 2.34 (br. s., 3H), 2.21 (br. s., 1H), 1.97 (br. s., 2H), 1.16-1.49 (m, 4H), 0.94-1.15 (m, 3H) MS (m/z): 492.5 [MH]+. Example 314 and Example 315: (1S ,3S or 1R,3R)-5-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2, 4-triazol-3-yl ]sulfanyl}-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro [2,5] octane (CIS, E314, Enantiomer 1) and (1S, 3R or 1R, 3S)-5-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1 -[4-( trifluoromethyl)phenyl]-5-azaspiro [2,5] octane (CIS, E315, Enantiomer 2)

[707] (1S,3S/1R,3R)-5-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,5]octane (CIS, E313, 23 mg) was separated into individual enantiomers by preparative chiral HPLC.

[708] (1S.3s or 1 R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]salphanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS, E314, 9.6 mg) Enantiomer 1: Ret. 7.1 min, 100% ee MS (m/z): 492.5 [MH]+.

[709] (1R, 3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4 -triazol-3-yl]salphanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (CIS, E315, 7.9 mg) Enantiomer 2: ret. time. 8.5 min, 100% ee MS (m/z): 492.4 [MH]+ Preparation 281: 3-chloro-1-phenylpropan-1-ol

[710] To a stirred solution of 3-chloro-1-phenylpropan-1-one (7.80 g, 46.26 mmol) in THF (35 mL) and EtOH (35 mL), at -10°C and under a nitrogen atmosphere, sodium borohydride 2.20 g, 48.83 mmol) was added in portions over 10 min. The reaction mixture was stirred for a further 10 minutes at -5°C and then carefully poured into a stirred mixture of saturated ammonium chloride (85 ml) and ice (40 g). The mixture was extracted twice with ether, the organic phase was dried and the solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 95/5) to give the title compound 3-chloro-1-phenylpropan-1-ol (P281, 7.50 g , y = 95%) in the form of a pale yellow oil. NMR: 1H NMR (CDCh) 5: 7.39 (d, 5H), 4.91-5.01 (m, 1H), 3.70-3.83 (m, 1H), 3.59 (s, 1H), 2.20-2.32 (m, 1H), 2.11 (d, 1H) Preparation 282: (1-Bromo-3-chloropropyl) benzene

[711] A mixture of 3-chloro-1-phenylpropan-1-ol (P281, 7.50 g, 43.95 mmol) and 48% aqueous hydrobromic acid (98 mL) was stirred at RT for 3 hours, then poured cautiously into a mixture of potassium carbonate (27 g) and 180 g of ice. Potassium carbonate was cautiously added until neutral pH. The resulting mixture was extracted twice with ether, the organic phase was dried and the solvent removed in vacuo. The crude material was purified by FC on silica gel (eluting with Cy) affording (1-bromo-3-chloropropyl)benzene (P282, 7.49 g, y = 73%) as a colorless oil. NMR: 1H NMR (CDCl3) 5: 7.32-7.50 (m, 5H), 5.24 (m, 1H), 3.75 (m, 1H), 3.61 (m, 1H), 2 .67-2.80 (m, 1H), 2.45-2.58 (m, 1H) Preparation 283: 1,1-dimethyl-2-phenylcyclobutane-1,1-dicarboxylate

[712] A stirred solution of (1-bromo-3-chloropropyl)benzene (p282, (2.97 g, 22.52 mmol) and dimethyl malonate (2.97, 22.5 mmol) in anhydrous dioxane ( 60 mL) and under a nitrogen atmosphere was brought to 90°C, then 60% NaH (0.86 g, 21.49 mmol) was added cautiously in portions over 10 min and the reaction was heated to reflux. After 1 h, the reaction temperature was allowed to reach about 90°C and additional 60% NaH (0.86 g, 21.49 mmol) was added in portions over 10 min and The reaction mixture was refluxed and stirred overnight. After allowing the mixture to reach RT, it was filtered, the solid was washed with ether and the filtrate was concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 93/7) and then further purified with reverse FC (C18, eluting with MeCN + 0.1% formic acid/water + 0 formic acid .1% from 0/100 to 70/30) providing 1,1-dimethyl-2-phenylcyclobutane-1,1-dicarboxylate (P283, 2.36 g, y = 45%) as a colorless oil.NMR: 1H NMR (CDCl3) 5: 7.22-7.33 (m, 5H), 4.39 (m, 1H), 3.80 (s, 3H), 3.26 (s, 3H), 2.59-2 .76 (m, 2H), 2.16-2.34 (m, 2H) Preparation 284: methyl 2-phenylcyclobutane-1-carboxylate

[713] A stirred mixture of 1,1-dimethyl-2-phenylcyclobutane-1,1-dicarboxylate (P283, 2.17 g, 8.74 mmol), LiCl (0.79 g, 18.62 mmol) and water (0.17 ml) in DMSO (12 ml) was refluxed and stirred for 1.5 h. After cooling to room temperature, this mixture was diluted with ether (55 ml) and cyclohexane (23 ml), then washed sequentially with brine, water (3 times) and brine. The organic phase was dried and the solvent was removed under reduced pressure.

[714] The residue was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 97/3) to give methyl 2-phenylcyclobutane-1-carboxylate (P284, 1.07 g, y = 64 %) as a colorless oil.MS (m/z): 191.2 [MH]+.Preparation 285: methyl 2-phenyl-1-(prop-2-en-1-yl) cyclobutane-1- carboxylate

[715] To a solution of methyl 2-phenylcyclobutane-1-carboxylate (P284, 1.07 g, 5.62 mmol) in THF (14 ml) at -78°C under N2 was added dropwise , 1 M LHMDS/THF (7.3 mL, 7.30 mmol) and the reaction mixture was stirred at this temperature for 30 minutes. Allyl bromide (0.73 mL, 8.44 mmol) was then added dropwise and the reaction was allowed to reach RT and stirred overnight. The reaction mixture was treated with saturated aqueous NH4CI solution and diluted with EA. The organic phase was washed with water, dried and the solvent was removed under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 95/5) to obtain 2-phenyl-1-(prop-2-en- 1-yl) cyclobutane-1- methyl carboxylate (p285, 0.71 g, y = 55%) as a pale yellow oil. MS (m/z): 232.2 [MH]+. Preparation 286: methyl 1-(2-oxoethyl)-2-phenylcyclobutane-1-carboxylate

[716] A slow flow of O3 in O2 was passed through a cooled to -78°C solution of methyl 2-phenyl-1-(prop-2-en-1-yl) cyclobutane-1-carboxylate (p285.0 .71 g, 3.08 mmol) in DCM (10 ml) until a pale blue color persists (30 min). Excess O3 was purged by nitrogen bubbling and then a solution of TPP (0.89 g, 3.39 mmol) in DCM (2 mL) was added. The solution was allowed to reach 25°C and stirred for 2 h. The solvent was removed in vacuo and the crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 70/30) to give methyl 1-(2-oxoethyl)-2-phenylcyclobutane-1 - carboxylate (P286, 0.36 g, y = 51%) in the form of a colorless oil. MS (m/z): 233.2 [MH]+. Preparation 287: 6-benzyl-1-phenyl-6-azaspiro [3.4] octan-5-one

[717] To a solution of methyl 1-(2-oxoethyl)-2-phenylcyclobutane-1-carboxylate (P286, 360 mg, 1.55 mmol) and benzylamine (0.18 mL, 1.63 mmol) in THF ( 9.0 mL) sodium triacetoxyborohydride (493 mg, 2.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHO3. The mixture was extracted twice with DMC, the organic phase was dried and the solvent removed under reduced pressure. The residue was dissolved in THF (30 mL) and the resulting solution was refluxed for 8 h. The reaction mixture was concentrated under vacuum and the residue was purified by FC on the NH column (elution with Cy/EA from 100/0 to 70/30), then loaded onto an SCX cartridge (wash with MeOH and elution with 2N NH3/MeOH) providing a 6-benzyl-1-phenyl-6-azaspiro[3,4]octan-5-(p287, mg 124, y = 27%) as white foam. MS (m/z): 292 .3 [MH]+. Preparation 288: 6-benzyl-1-phenyl-6-azaspiro [3.4] octane

[718] To a stirred solution of 6-benzyl-1-phenyl-6-azaspiro [3.4] octane-5-one (p287, 124 mg, 0.43 mmol) in THF (4 ml), at 0 ° C and under a nitrogen atmosphere, 1M/THF LiAIH4 (0.55 mL, 0.55 mmol) was added dropwise. The ice bath was removed and the resulting reaction mixture was allowed to reach RT and then refluxed for 1 h. The mixture was then cooled to 0°C and quenched with Na2SO4*10H2O, diluted with EA, filtered over sodium sulfate and the solvent removed in vacuo to give 6-benzyl-1-phenyl-6-azaspiro [ 3.4] octane (P288, 120 Mg, y = quantity) which was used as such in the next step. MS (m/z): 278.3 [MH]+. Preparation 289:1-phenyl-6-azaspiro [3.4] octane

[719] For a solution of 6-benzyl-1-phenyl-6-azaspiro[3.4]octane (p288, 120 mg, 0.43 mmol) in MeOH (5 mL), HCOONH4 (164 mg, 2.60 mmol) and 10% Pd/C (52 mg) were added at RT and then the mixture was stirred at reflux for 2 hrs. The reaction mixture was filtered over a celite pad and the solvent removed under vacuum. The residue was dissolved in DCM, the solution was washed with saturated sodium bicarbonate, dried and the solvent removed in vacuo. The residue was dissolved in MeOH and the solution was loaded onto an SCX cartridge (wash with MeOH and elution with 2N/NH3 in MeOH) providing 1-phenyl-6-azaspiro [3.4] octane (p289, 63 mg, y = 78%) in the form of a colorless oil. MS (m/z): 188.2 [MH]+. Example 316: 6-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]-sulfanyl}propyl)-1-phenyl-6-azaspiro [3.4]octane (E316)

[720] The compound was prepared as in Example 1 by reacting 1-phenyl-6-azaspiro [3.4] octane (P289, 58 mg, 0.31 mmol), 3 -[(3-chloropropyl)sulfanyl] -4- methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H- 1,2,4-triazole (p148, 93 mg, 0.34 mmol), Na2CO3 (40 mg, 0.37 mmol ) and Nal (51 mg, 0.34 mmol) in DMF (0.35 ml) to give the title compound 6-(3-{[4-methyl-5-(4-Methyl-1,3-oxazole as diastereoisomeric mixture NMR: 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.30-7.38 (m, 2H), 7.18-7.26 (m, 3H), 3.67-3.72 (s, 3H) 3.54 (m, 1H) , 3.08-3.20 (m, 2H), 2.65-2.97 (m, 2H), 2.55 (s, 3H), 2.51 (d, 2H), 2.31-241 (m, 1H), 2.02-2.30 (m, 7H) , 1.94 (d, 2H). MS (m/z): 424.4 [MH]+ Example 317, Example 318, Example 319 and Example 320: (1R, 4S or 1S, 4R or 1S, 4S or 1R, 4R)-6-(3 - { [4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-phenyl-6-azaspiro [ 3,4] octane: E317 (Diastereomer 1 Enantiomer 1); E318 (Diastereomer 1 Enantiomer 1); E319 (Diastereomer 2 Enantiomer 1); E320 (Diastereomer 2 Enantiomer 2)

[721] 6-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl) -1-phenyl-6-azaspiro [3.4] octane (E316, 66 mg) was separated into individual enantiomers of each diastereoisomer by preparative chiral HPLC.

[722] 18 mg E317 (Diastereomer 1 Enantiomer 1): Ret. 10.1 min, 98.2% ee MS (m/z): 424.4 [MH]+.

[723] 23 mg E318 (Diastereoisomer 1 Enantiomer 2): Ret time. 11.9 min, 98.2% ee MS (m/z): 424.4 [MH]+.

[724] 2.3 mg E319 (Diastereisomer 2 Enantiomer 1): Ret time. 16.7 min, 100% ee MS (m/z): 424.4 [MH]+.

[725] 2 mg E320 (Diastereomer 2 Enantiomer 2): Ret time. 21 min, 100% ee MS (m/z): 424.4 [MH]+.Example 321: (1R, 4S or 1S, 4R or 1S, 4S or 1R, 4R)-6-(3 - {[4 -methyl-5- (4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl} propyl)-1-phenyl-6- azaspiro [3, 4] octane (E321, Diastereoisomer 1 Enantiomer 2)

[726] (1R, 4S or 1S.4R or 1S.4S or 1R, 4R)-6-(3 - {[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl] Sulfanyl} propyl)-1-phenyl-6-azaspiro [3.4] octane (E318, Diastereoisomer 1 Enantiomer 2, 23 mg) was treated with 1.1 eq of HCl in Et2O providing the corresponding hydrochloric salt (E321, Diastereoisomer 1 Enantiomer 2.24 Mg).MS (m/z): 424.4 [MH]+.

Biological Test Methods [3H]-Spiperone Binding Assay to Recombinant hD3 and hD4 Receptors

[727] CHO cells transiently transfected with human dopamine receptor type 3 or 4 (CHO-hD3 or CHO-hD4, respectively) were resuspended with 20 mM HEPES, 2 mM EDTA (pH 7.4), homogenized and centrifuged at 40 000 g (20 min, 4 °C). After resuspension, homogenization and centrifugation as above, the final pellet was resuspended in 20 mM HEPES, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA (pH 7.4) and aliquots were kept at - 80 °C. of [3H]-spiperone were performed in 96-deep well polypropylene plates in 50 mM Tris/HCl, 120 mM NaCl, 5 mM KCl, 5 mM MgCl2 (pH 7.4). Compounds of the invention were serially diluted in DMSO to 100-fold assay final concentrations (1% assay final DMSO). Displacement was performed in the presence of 0.3 nM [3H]-Spiperone. The reaction was initiated by addition of membrane suspension (4 μg and 12 μg of protein for CHO-hD3- and CHO-hD4 membranes, respectively) and lasted 90 or 100 min (for hD3 or hD4 membranes, respectively) at 23°C. in a final volume of 500 μl. Non-specific binding (NSB) was determined in the presence of 1 μ m Spiperone. The binding reaction was stopped by rapid filtration through GF/B filter plates previously soaked in 0.5% polyethylenimine (PEI) using a Packard cell harvester. After washing with ice-cold 0.9% NaCl, the plate was allowed to dry before adding Microscint 20 (50 μl/well, PerkinElmer). Radioactivity was counted with a TopCount (PerkinElmer). Data were analyzed by nonlinear regression analysis using GraphPad Prism 5.0 (GraphPad Software). Saturation binding experiments were performed in a similar way to competition binding experiments using radioligand concentrations ranging from 0.015 to 4.0 nM. Ref: Mackenzie RG et al. (1994). Characterization of the human dopamine D3 receptor expressed in transfected cell lines. Eur. J. Pharmacol., 266: 79-8 Binding assay of [125I]-70H-PIPAT to native rat D3 receptor on membranes from rat ventral striatum

[728] Frozen rat ventral striatal brain homogenates (Nucleus accumbens and Olfactory Tubercles), were prepared as described by Burris et al. (1994). [125I]-70H-PIPAT binding assay on D3 receptors was performed in 50 mM Tris-HCl (pH 7.0), 50 mM NaCl, 100 μM Gpp (NH) p (Guanosine 5'-[ β,Y—imido] triphosphate) and 0.02% BSA, that is, conditions that inhibit [125L]-7-OH-PIPAT binding to D2 and 5HT1A receptors. Compounds of the invention were serially diluted in DMSO to 100-fold assay final concentrations (1% assay final DMSO). Displacement experiments were performed in the presence of 0.2 nM [125I]-70H- PIPAT. The reaction, carried out in a final volume of 200 μl, was initiated by the addition of membrane suspension (about 20 μg/well of protein) and lasted 45 minutes at 37°C. Nonspecific binding (NSB) was determined in the presence of 1 μM SB277011A. The binding reaction was stopped by rapid filtration through GF/C filter plates previously soaked in 0.5% polyethylenimine (PEI) using a Packard cell harvester. After washing with ice-cold 50 mM Tris (pH 7.4) and addition of Microscint 20 (50 μl/well, PerkinElmer), radioactivity was counted with a TopcCount (PerkinElmer). Data were analyzed by nonlinear regression analysis using GraphPad Prism 5.0 (GraphPad Software). Ref: Burris, K.D.; Filtz, T.M.; Chumpradit, S.; Kung, M. P.; Foulon, C.; Flensler, J.G.; Kung, H.F.; Molinoff, P. B. Characterization of [125l](R)-trans-7- hydroxy-2-[N-propyl-N-(3'-iodo-2'- propenyl)amino]tetralin binding to dopamine D3 receptors in rat olfactory tubercle . J. Pharmacol. Exp. Ther. 1994, 268, 935-942.

Binding assay of [3H]-Spiperone to the hD2 recombinant receptor

[729] CHO cells stably expressing human dopamine receptor type 2, long variant (hD2L), coupled to Gα16 protein (CHO-Gα16-hD2L) were resuspended in 20 mM HEPES, 2 mM EDTA (pH 7, 4), homogenized and centrifuged at 40,000 g (20 min, 4°C). After resuspension, homogenization and centrifugation as above, the final pellet was resuspended in 20 mM HEPES, 100 mM NaCl, 10 mM MgCh2, 1 mM EDTA (pH 7.4) and aliquots were kept at -80 °C. [3H]-spiperone binding experiments were performed in 96-deep well polypropylene plates in 50 mM Tris/HCl, 120 mM NaCl, 5 mM KCl, 5 mM MgCh (pH 7.4). Compounds of the invention were serially diluted in DMSO to 100-fold assay final concentrations (1% assay final DMSO). Displacement was performed in the presence of 0.08 nM [3H]-Spiperone. The reaction was initiated by adding a membrane suspension (2 μg protein for CHO-hD2 membranes) and lasted 120 minutes at 23°C in a final volume of 1000 μl. Non-specific binding (NSB) was determined in the presence of 0.1 μM Spiperone. The binding reaction was stopped by rapid filtration through GF/B filter plates previously soaked in 0.5% polyethylenimine (PEI) using a Packard cell harvester. After washing with ice-cold 0.9% NaCl, the plate was allowed to dry before adding Microscint 20 (50μl/well, PerkinElmer). Radioactivity was counted with a TopCount (PerkinElmer). Data were analyzed by nonlinear regression analysis using GraphPad Prism 5.0 (GraphPad Software) or XLfit Version 5.2.0.0 (Copyright © 2006-2009 ID Business Solutions Ltd). Saturation binding experiments were performed in a similar way to competition binding experiments using radioligand concentrations ranging from 0.011 to 3.0 nM. Ref: Durcan MJ et al. (1995). Is Clozapine selective for the dopamine D4 receptor? Life Sciences, 57: 275-283.Petrus J.. Etal. (2001). Real-time analysis of dopamine: antagonist interactions at recombinant human D2long receptor upon modulation of its activation state. Brit. J. Pharmacol. 134.88 ± 97.

Functional assay of calcium in the recombinant hD2 receptor

[730] CHO cells stably expressing the human dopamine receptor type 2, long variant (hD2L), coupled to the Gα16 protein (CHO-Gα16-hD2L) were seeded in black-walled transparent base 384-well plates at a density of 8000 cells per well and grew overnight at 37°C. After washing with assay buffer (20 mM HEPES, 145 mM NaCl, 5 mM KCl, 5.5 mM glucose, 1 mM MgCh2 and 2 mM CaCl2, pH 7.4) containing 2.5 mM Probenecid, the cells were incubated with the Ca2+ cytoplasmic probe Fluo-4 AM at 1 μM (final concentration), 37°C for 60 min. Plates were washed three times as above and placed in a fluorometric imaging plate reader (FLIPR Tetra, Molecular Devices) to monitor cellular fluorescence (ex = 470-495 nm, em = 515-575 nm) before and after addition of different concentrations of test compounds. The compounds of the invention were dissolved in DMSO and diluted 200 times with assay buffer plus 0.01% Pluronic F-127. Cells were first exposed to test compounds for 10 min, then to a submaximal concentration of the dopamine hD2 receptor agonist (EC80, 50-140 nM). Fluorescence before compound addition (baseline) and before and after addition of agonist challenge was monitored. Peak Ca2+ stimulation was plotted (baseline subtracted) versus test compound concentration and the curve was fit using a four-parameter logistic equation (XLfit) to assess agonist/antagonist potency and maximum response. . Preparation 290: (1R, 3S)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane

[731] (1R, 3S)-[4-(trifluoromethyl)phenyl] - 5-azaspiro[2,4]heptane (P15, Enantiomer 1, 25 mg, 0.1 mmol) in dichloromethane (3 ml) was stirred at 0°C; Triethylamine (0.022 mL, 0.15 mmol) was added, followed by 4-methylbenzenesulfonyl chloride (21 mg, 0.11 mmol) and then the mixture was slowly warmed to room temperature and stirred at the same temperature for 1 h. DCM was added, washed with water and brine, then dried with Na2SO4, filtered and concentrated. The residue was chromatographed by FC on silica gel (eluent of 40% ethyl acetate cHext) yielding (1R, 3S)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]- 5-azaspiro[2,4]heptane (P290, 33 mg, y = 83%) as a white solid.

[732] The latter was suspended in 0.3 ml of EtOH and then heated until dissolved. After slow cooling to room temperature, crystallization was observed. Crystals were filtered and used for molecular and crystal structure determination by high-resolution crystal X-ray diffraction to determine absolute stereochemistry.

[733] X-ray data collection was carried out on a plate-shaped crystal of approximate dimensions 0.26x0.22x0.02 mm mounted in a glass capillary. X-ray intensities were measured on a Bruker Smart 20 system equipped with an APEXII CCD area detector.

[734] The structure was solved by direct methods using the Sir2011 program and was refined with the SHELXL-2014 program. Crystal data is reported below:

[735] The compound crystallizes in the chiral orthorhombic space group P212121. The asymmetric unit comprises four molecules. The Flack parameter for the present structure is 0.094 (322) by classical fit for all intensities and 0.064 (210) from 639 selected quotients (Parson's method) which strongly supports the present determination of absolute structure.

[736] According to absolute structure determination, the configuration is 1R, 3S. MS (m/z): 396.4 [MH]+ Preparation 291: (1S, 3R)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4] heptane

[737] (1R, 3S/1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (CIS, chiral preparative (SFC) to separate the enantiomers:

[738] (1R, 3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (1.1 g) Enantiomer 1: Ret Time. 7.9 min, 100% ee e

[739] (1S, 3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane (840 mg) Enantiomer 2: Ret Time. 10.2 min, 100% ee.

[740] (1S, 3R)-[4-(trifluoromethyl)phenyl] - 5-azaspiro[2.4]heptane (Enantiomer 2, 840 mg, 3.48 mmol) in dichloromethane (15 mL) was stirred at 0° W; Triethylamine 0.73 mL (5.22 mmol) was added, followed by 4-methylbenzenesulfonyl chloride (730 mg, 3.83 mmol) and then the reaction mixture was slowly warmed to room temperature and stirred at that temperature for 2 H. DCM was added, washed with water and brine, then dried with Na2SO4, filtered and concentrated. The residue was chromatographed by FC on silica gel (eluent of cHex 40% ethyl acetate) affording (1S, 3R)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (p291, 1.1 g, y = 80%) as a white solid.

[741] 100 mg of (1S, 3R)-5-(4-methylbenzenesulfonyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2,4]heptane were suspended in 1 mL of EtOH and then heated until dissolved. After slowly cooling to room temperature, the solution was left at room temperature for 3 days, after which crystallization was observed. Crystals were filtered and used for molecular and crystal structure determination by high-resolution crystal X-ray diffraction to determine absolute stereochemistry.

[742] X-ray data collection was carried out on a plate-shaped crystal of approximate dimensions 0.31x0.24x0.07 mm mounted in a glass capillary. X-ray intensities were measured on a Bruker Smart system equipped with an APEXII CCD area detector.

[743] The structure was solved by direct methods using the Sir2011 program and was refined with the SHELXL-2014 program. Crystal data is reported below:

[744] The compound crystallizes in the chiral orthorhombic space group P212121. The asymmetric unit comprises four molecules. The Flack parameter for the present structure is 0.000(199) by classical fit for all intensities and -0.005(57) from 1566 selected quotients (Parson's method) which strongly supports the present determination of absolute structure. According to absolute structure determination, the configuration is 1S, 3R.MS (m/z): 396.4 [MH]+.

[745] The compounds of the invention listed above have pKi values within the range of 7.0-10.5 at the dopamine D3 receptor. pKi results are only estimated to be accurate to about ±0.3-0.5.

[746] The compounds of the invention listed above have selectivity over D2 preferably greater than 10 times. The following Table reports the values of some of the Examples:

[747] All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as if fully described.

[748] It should be understood that the present invention encompasses all combinations of particular groups described above in this document.

[749] The application of which the present description and the claims form a part may be used as a basis for priority over any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process or use claims and may include, by way of example and without limitation, the following claims.

Claims (20)

1. COMPOUND OF FORMULA (I) OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, characterized by: Being a 3-6 membered saturated carbocyclic ring, and such ring may be substituted by one or more C1-4alkyl groups; B be a saturated 4-6 membered heterocyclic ring, in which one or two carbon atoms can be replaced by a heteroatom selected from at least one nitrogen or one oxygen and the bonding atom is always a nitrogen atom; such a ring may also be substituted on the carbon atoms or, possibly, on a different nitrogen atom, by one or more C1-4 alkyl groups; G be phenyl, biphenyl, naphthyl or pyridyl which may optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1- 4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, SF5, C(=O)NH2 and C(=O)(O)zR3; W be S, SO2, O, CHR2 or NR3; n be 0 or 1; m be 1 or 2; p be 1 or 2; z be, each independently, 0 or 1; R be hydrogen or C1-4alkyl or C1-4alkoxy; R1 is each independently hydrogen or F, C1-4alkyl, OH, or C1-4alkoxy; R2 is each independently hydrogen or F, C1-4alkyl, OH, or C1-4alkoxy; R3 is each independently hydrogen or C1-4alkyl; R4 is each independently hydrogen or C1-4alkyl, or -C(=O)Ci-4alkyl, -C(=O)Ci-4alkoxyCi-4alkyl, - C(=O)C3-6cycloalkyl; R5 is each independently hydrogen or Ci-4alkyl; R6 is each independently hydrogen or Ci-4alkyl; R7 is each independently halogen, Ci-4alkyl, OH, or Ci-4alkoxy; Gi be a 5-6 membered heteroaromatic group containing at least one nitrogen ring, which may be optionally substituted by i, 2 or 3 substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, amino, Ci- 4alkylamino, Ci-4alkyl, haloCi-4alkyl, haloCi-4alkoxy, Ci-4alkoxy, C(=O)NH2 and C(=O)(O)zR3; Y be phenyl or a moiety selected from the group consisting of: a 5-6 membered heteroaromatic group, an 8-ii membered heteroaromatic group, a monosaturated 3-7 membered carbocyclic group and an 8-ii bicyclic carbocyclic group members, and for any of these groups one or more ring carbons may be replaced by N(R4)z, O, S; Any of these groups may be optionally substituted by 1, 2 or 3 substituents selected from: halogen, cyano, hydroxyl, C1-4alkylamino, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl, haloC1-4alkoxy, oxo, -NHC( =O)C1-4alkyl, -NR5R6, SF5, (CH2)zC(=O)NR5R6, -C(=O)(O)zR3, C1-4alkylCN, -SO2NR5R6, Y', and OY';Y' be phenyl, or a 5-6 membered heteroaromatic group optionally substituted by 1 or 2 R7 groups. 2. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to claim 1, characterized by comprising formula (IA), wherein A and B of the compounds of formula (I) are selected from the following: and wherein G, G1, W, Y, n, m, p, z, R, R1 and R2 are as defined in claim 1. 3. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to claim 1, characterized by comprising formula (IB), wherein A and B of the compounds of formula (I) are selected from the following: and wherein G, G1, W, Y, n, m, p, z, R, R1 and R2 are as defined in claim 1. 4. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to claim 1, characterized in that it comprises a compound of formula (IIA) wherein G, G1, W, Y, n, m, p, z, R, R1 and R2 are as defined in claim 1. 5. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to claim 1, characterized in that it comprises a compound of formula (IIB) wherein G, G1, W, Y, n, m, p, z, R, R1 and R2 are as defined in claim 1. 6. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 5, characterized in that W is S and R, R1 and R2 are hydrogen. 7. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 6, characterized in that G is phenyl or pyridyl, optionally substituted by 1, 2, 3, 4 or 5, for example, 1 or 2 substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, amino, C1-4alkylamino, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C1-4alkoxy, -C(=O)NH2 and -C(=O )(O))zR3. 8. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 6, characterized in that G is phenyl or pyridyl, optionally substituted by 1, 2 or 3 independently selected groups of halo, C1-4alkyl and haloC1- 4alkyl. 9. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 8, characterized in that G is selected from: phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 2 ,4-difluorophenyl, 4-fluorophenyl, 2-trifluoromethyl-phenyl, 2-trifluoromethyl-4-fluorophenyl, or 3,5-dichlorophenyl. 10. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 9, characterized in that Gi is wherein Ra is H or C1-4alkyl, optionally, wherein Ra is C1-4alkyl, e.g. methyl. 11. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims i to i0, characterized in that Y is selected from the group consisting of: phenyl optionally substituted by one or two substituents selected from: cyano, -C (=O)NH2, sulfonamide, acetyl, -CH2CN, -CH2C(=O)NH2 and Y'; a 3-7 membered monosaturated carbocyclic group in which 0 or 1 or 2 carbon atoms are replaced by a heteroatom independently selected from O or NR3; an 8-membered bicyclic carbocyclic group, optionally substituted by one or more C1-4alkyl; a 5-6 membered heteroaromatic group optionally substituted by one or two substituents selected from: halogen, cyano, hydroxyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -(CH2)ZC(=O)N(R4R5 ), Y' and OY'; an 8-II membered heteroaromatic group in which i or 2 or 3 carbon atoms may be substituted by N, optionally substituted by one or more C1-4alkyl. 12. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims i to ii, characterized in that Y is phenyl substituted by i or 2 substituents selected from cyano, -CH2CN, -C(=O)R3, - (CH2)zC(=O)NR5R6, -SO2NH2 and Y', where Y' is selected from oxadiazolyl, tetrazolyl, triazolyl and oxazolyl, where Y' is optionally substituted by methyl; and wherein R3, R5, R6 and z are as defined in claim 1. 13. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 8, characterized in that Y is selected from pyridyl, pyrimidinyl and pyrazinyl, any groups thereof may be optionally substituted by 1 or 2 substituents selected from of: fluorine, cyano, C1-4alkyl, C1-4alkoxy, haloC1-4alkyl, and -C(=O)NR5R6; wherein Y is pyridyl optionally substituted by 1 or 2 substituents selected from: C1-4alkyl and C (= O) NH2; wherein, R5 and R6 are as defined in claim 1. 14. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to any one of claims 1 to 13, characterized in that the group -(CHR)n(CR1R2)m(CR1R2)pW- is 15. COMPOUND, according to claim 1, characterized in that it is selected from the group consisting of: (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(4-methyl- 1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 1 ); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl }-propyl)-1-[4 (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 1); (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl }-propyl)-1-phenyl-5- azaspiro[2.4]heptane (Enantiomer 2); (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl }-propyl)-1-phenyl-5- azaspiro[2.4]heptane (Enantiomer 2); (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS); (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 1); (1R,3S or 1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 2); (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 2); (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2 ,4-triazol-3yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1 ,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(4methyl-1,3-oxazol-5-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]-sulfanyl}propyl)-1-[2(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiomer 2); (1S,3R or 1R,3S)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); (1S,3S or 1R,3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5 -yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS, Enantiomer 1); (1S,3S/1R,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl- 5-(4-methyl-1,3-oxazol- 5-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS); (1R,3S/1S,3R)-1-(3,5-dichlorophenyl)-5-(3-{[4-methyl- 5-(4-methyl-1,3-oxazol- 5-yl)-4H -1,2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]-sulfanyl}propyl) -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1R,3R or 1S,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 1); (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 2); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H- 1,2,4-triazol-3-yl]-sulfanyl}propyl) -1- [4(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4-triazol-3-yl]-sulfanyl}-propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 1); (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (TRANS); (1S,3R or 1R,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 1); (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(oxan-4-yl)-4H-1,2,4- triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (Enantiomer 2); (1R,3S/1S,3R)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H1,2,4-triazol-3-yl )sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-{3-[(4-methyl-5-{8-oxabicyclo[3.2.1]octan-3-yl}-4H-1,2,4-triazol-3-yl)- sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 1); (1S,3S/1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1R,3R or 1S,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H- 1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 1); (1S,3S or 1R,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H- 1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (Enantiomer 2); (1R,3S/1S,3R)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4- (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-{3-[(5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl ]-5- azaspiro[2.4]heptane (Enantiomer 1); 1-{4-[4-methyl-5-({3-[(1R,3S/1S,R3)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethane-1-one (CIS); 1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl) -4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethane-1-one (CIS, Enantiomer 1); 1-{4-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl] propyl}sulfanyl)-4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethane-1-one (CIS); 1-{4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl) -4-methyl-4H-1,2,4-triazol-3-yl]piperidin-1-yl}ethane-1-one (CIS); 3-methoxy-1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]-heptane-5-yl ]propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}propan-1-one (CIS, Enantiomer 1); (1R,3S)-5-(3-{[5-(1-cyclopropanecarbonylpiperidin-4-yl)-4-methyl-4H1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 - (trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); N-{4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl] propyl}sulfanyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS); N-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl) -4H-1,2,4-triazol-3-yl]cyclohexyl}acetamide (CIS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(morpholine-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(morpholine-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1); 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]piperidin-2-one (CIS, Enantiomer 1); 6-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptano-5yl]propyl}sulfanyl)- 4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); 5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); 5-[5-({3-[(1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4-methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); 5-[5-({3-[(1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5- azaspiro[2.4]heptane-5-yl]propyl}-sulfanyl)-4- methyl-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); 5-[5-({3-[(1R,3S/1S,3R)-1-(4-fluorophenyl)-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)- 4-methyl-4H - 1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS); 1-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS); 4-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (TRANS); 1-methyl-4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); 4-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4 -methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1,2-dihydropyridin-2-one (CIS, Enantiomer 1); (1S,3S/1R,3S)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2-4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]- 5azaspiro[2.4]heptane (CIS, Enantiomer 2); (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,3- triazol-3-yl]sulfanyl}propyl)-5-azaspirol[2.4]heptane (CIS, Enantiomer 2); (1S,3S/1R,3R)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazole -3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S)-1-(2,4-difluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-5- azaspiro[2.4]heptane (CIS, Enantiomer 2); (1R,3S/1S,3R)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3 -yl]sulfanyl}propyl)-5- azaspiro[2.4]heptane (CIS); (1R,3S)-1-(4-fluorophenyl)-5-(3-{[4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]- sulfanyl}propyl)-5-azaspiro[2.4]heptane; (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5azaspiro[2.4]heptane (TRANS); (1R,3S/1S,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyridin-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-( 2-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1R,3S)-5-(3-{[4-methyl-5-(2-methylpyridin-3-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(2-methylpyridin-3- il)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[2-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R, 3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1 -[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyridin-2-yl)- 4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-( 3-{[5-(2,6-dimethylpyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl) phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[5-(2-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}-sulfanyl)propyl ]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-(3-{[5-(2-methoxypyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]pyridine-2-carbonitrile (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]pyridine-2-carbonitrile (CIS, Enantiomer 1); 5-[4-methyl-5-({3-[(1S,3S/1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); 5-[4-methyl-5-({3-[(1S,3S or 1R,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS); 5-[4-methyl-5-({3-[(1R,3R or 1S,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, Enantiomer 1); 5-[4-methyl-5-({3-[(1R,3S/1S,3R)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (TRANS, Enantiomer 2); 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS); 5-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4- methyl-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); 6-methyl-5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); 6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiomer 1); 6-[5-({3-[(1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4- methyl-4H-1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]pyridine-3-carboxamide (CIS, Enantiomer 1); 6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); N-methyl-6-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro-[2.4]heptane-5-yl]propyl} sulfanyl)-4H-1,2,4-triazol-3-yl]pyridine-2-carboxamide (CIS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (CIS, Enantiomer 1); (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiomer 1); (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrimidin-4-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1S,3S or 1R,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiomer 1); (1R,3R or 1S,R3)-5-(3-{[4-methyl-5-(pyrazin-2-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS, Enantiomer 2); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1-[4 -(trifluoromethyl)phenyl]-5- azaspiro[2.4]heptane (CIS, Enantiomer 2); (1S,3S/1R,3R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-(3-{[4-methyl-5-(pyrazin-2-yl)-4H-1, 2,4-triazol-3-yl]sulfanyl}propyl)-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(6-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(5-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(3-methylpyrazin-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); 5-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]propyl}sulfanyl)-4H- 1,2,4-triazol-3-yl]pyrazine-2-carboxamide (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(3-methyl-1,2-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl }-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl }-propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)- 4H-,1,2,4-triazol-3-yl] sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(1,3-thiazol-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S/1S,3R)5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl] -sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-4-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}- propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS,); (1R,3S)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrazol-5-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}- propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 2); (1R,3S/1S,3R)-5-(3-{[5-(furan-2-yl)-4-methyl-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[5-(furan-3-yl)-4-methyl-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-2-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(thiophen-3-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl)- 1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1S,3S/1R,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (TRANS); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS); (1R,3S)-5-(3-{[4-methyl-5-(1,2,3-thiadiazol-4-yl)-4H- 1,2,4-triazol-3-yl]sulfanyl}propyl )-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl ]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[2-(pyridin-3-yl)-1,3-oxazol-5-yl]-4H-1,2,4-triazole -3-yl}-sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-(3-{[4-methyl-5-(6-phenoxypyridin-3-yl)- 4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1- [4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3- a]pyridin-6-yl}-4H-1,2,4- triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3- a]pyridin-7-yl}-4H-1,2,4- triazol-3-yl)-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-5-{3-[(4-methyl-5-{[1,2,4]triazolo[4,3-a] -pyridin-7-yl}-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-{3-[(4-methyl-5-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-4H-1, 2,4-triazol-3-yl)sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-{3-[(5-{1H-imidazo[4,5-b]pyridin-5-yl}-4-methyl-4H-1,2,4-triazol-3-yl )-sulfanyl]propyl}-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-4H-1,2,4- triazol-3-yl}-sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4H-1,2,4-triazol-3- yl}-sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1);(1R,3S)-5-[3-({4-methyl- 5-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]- 1-[4-( trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[4-(4H-1,2,4-triazol-4-yl)phenyl]-4H-1,2,4-triazol- 3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[4-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl} sulfanyl)-propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S)-5-[3-({4-methyl-5-[3-(1,3-oxazol-2-yl)phenyl]-4H-1,2,4-triazol-3-yl} -sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]benzamido (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]benzonitrile (CIS, Enantiomer 1); 1-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptan-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]phenyl}ethane-1-one (CIS, Enantiomer 1); 4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]benzene-1-sulfonamide (CIS, Enantiomer 1); 2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]phenyl}acetonitrile (CIS, Enantiomer 1); 2-{4-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl )-4H-1,2,4-triazol-3-yl]phenyl}acetamide (CIS, Enantiomer 1); 3-[4-methyl-5-({3-[(1R,3S)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane-5-yl]-propyl}sulfanyl)-4H -1,2,4-triazol-3-yl]benzamido (CIS, Enantiomer 1); (1S,3S)-1-[2-fluoro-4-(trifluoromethyl)-phenyl]-5-{4-[4-methyl-5-(oxan-4-yl)-4H-1,2,4- triazol-3-yl)butyl}-5-azaspiro[2.4]heptane (Enantiomer 2); (1R,3S)-5-{4-[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)- 4H-1,2,4-triazol-3-yl]butyl} -1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane (CIS, Enantiomer 1); (1R,3S/1S,3R)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS); (1S,3R or 1R,3S)-5-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3 -yl]-sulfanyl}propyl)-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.5]octane (TRANS, Enantiomer 2) or a pharmaceutically acceptable salt thereof. 16. COMPOUND, according to claim 1, characterized by having the formula: or a pharmaceutically acceptable salt thereof. 17. COMPOUND, according to claim 1, characterized by having the formula: or a pharmaceutically acceptable salt thereof. 18. PHARMACEUTICAL COMPOSITION, characterized in that it comprises a compound, as defined in any one of claims 1 to 17, and a pharmaceutically acceptable carrier. 19. COMPOUND, according to any one of claims 1 to 17, characterized in that it is for use as a medicine. 20. COMPOUND according to any one of claims 1 to 17, characterized in that it is for use in treating a condition, wherein the condition is selected from: (i) substance abuse, optionally wherein the substance abuse is alcohol, cocaine, heroin or nicotine abuse; or (ii) a dyskinetic disorder, optionally wherein the dyskinetic disorder is Parkinson's disease, neuroleptic-induced parkinsonism or tardive dyskinesias; or (iii) cognitive impairment, optionally wherein the cognitive impairment is a memory disorder or Alzheimer's disease; or (iv) depression, anxiety, an eating disorder, sexual dysfunction, premature ejaculation, a sleep disorder, emesis, a movement disorder, an obsessive-compulsive disorder, amnesia, aggression, autism, vertigo, dementia, a rhythm disorder circadian or a gastric motility disorder, optionally wherein the gastric motility disorder is IBS; or (v) a psychotic condition, optionally wherein the psychotic condition is schizophrenia, a schizoaffective disorder, psychotic depression, mania, paranoid or a delusional disorder; or (vi) drug dependence, withdrawal symptoms from drugs of abuse or inhibition of opioid-induced tolerance, optionally wherein the drug is alcohol, cocaine, an opiate, nicotine or a benzodiazepine; or (vii) non-substance related disorders and addictive disorders, optionally where the disorder is a gambling disorder.