MXPA06005427A - Novel compounds - Google Patents

Abstract

The invention provides compounds of formula (I) wherein m, R1, n, R2, q, X, Y, Z, t, R3, R4, R5, R6, R7 and R8 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Description

NOVEL COMPOUNDS DESCRIPTION OF THE INVENTION The present invention relates to novel compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies, such as rheumatoid arthritis and atherosclerosis. These small, secreted molecules are a growing superfamily of 8-14 kDa proteins characterized by a conserved configuration of four cysteines. The chemokine superfamily can be divided into two main groups that exhibit structural configurations, characteristics, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These differ on the basis of a single amino acid insertion between the pair close to NH of the cysteine residues and a sequence similarity. The C-X-C chemokines include several chemoattractants and potent activators of neutrophils, such as interleukin-8 (? L-8) and the activating peptide of REF: 172599 neutrophils 2 (NAP-2). CC chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils, such as the human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Normal, Expressed and Secreted T Cells, Regulated with Activation), eotaxin and the inflammatory proteins of macrophages la and lß (MlP-la and MlP-lß). Studies have shown that the actions of chemokines are mediated by sub-families of receptors coupled to the G protein, among which are the designated receptors CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents that modulate these receptors would be useful in the treatment of disorders and diseases, such as those mentioned above. According to the present invention, therefore, a compound of the formula is provided where m is O, 1, 2, 3 or 4; each R1 independently represents halogen, cyano, hydroxyl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or sulfonamido; X represents a bond, -CH2- or -0-, Y represents a bond, -CH2- or -0- and Z represents a bond -0-, -NH- or -CH2-, with the condition that only one of X, Y and Z can represent a link at any time and with the proviso that X and Y do not represent both simultaneously -0-; n is 0, 1 or 2; each R2 independently represents halogen, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; q is 0 or 1; t is O, 1, 2, 3, 4 or 5; each R3 independently represents halogen, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (O) NR ^ R12, -CH2NHC (0) R13, -NHS02R14, -S02NR15R16, -CH2-R17, alkylcarbonyl from 1 to 6 carbon atoms, phenylcarbonyl, cycloalkyl of 3 to 6 carbon atoms or a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, C 1-6 alkoxy, phenyl and a 5- to 10-membered, saturated or unsaturated heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulfur, each group is optionally substituted by at least one substituent selected from halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; R4, R5, Rd, R7 and R8 each independently represent hydrogen, halogen, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; R9 and R10 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms; R11 and R12 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms or R11 and R12 together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring, which may be optionally substituted by at least one substituent selected from hydroxyl; R 13 and R 14 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms; and R15 and R16 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms or R15 and R16 together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring, which may be optionally substituted by at least one substituent selected from hydroxyl; R17 is a 5- to 7-membered saturated heterocyclic ring containing at least one nitrogen atom, the ring which may be optionally substituted by one or more oxo groups; or a pharmaceutically acceptable salt or solvate thereof. In the context of the present specification, unless otherwise stated, an alkyl, alkenyl or alkynyl substituent group or a portion in a substituent group may be linear or branched. A haloalkyl substituent group will comprise at least one halogen atom, for example one, two, three or four halogen atoms. In the ring substituted by R2, R2 can be attached to any carbon atom of the appropriate ring that includes the carbon atom of (CH2) q. Also, in the definition of R3, it should be understood that the 5- to 10-membered, saturated or unsaturated heterocyclic ring system may have alicyclic or aromatic properties. An unsaturated ring system will be partially or completely unsaturated. Further, when R11 and R12 or R15 and R16 represent a heterocyclic ring, saturated from 4 to 7 members, it should be understood that only the heteroatom present is the nitrogen atom to which R11 and R12 or R15 and R16 are attached. In one embodiment of the invention, m is 0 or 1, particularly 1.

Each R1 independently represents halogen (for example chlorine, fluorine, bromine or iodine), cyano, hydroxyl, alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tere-butyl, n-pentyl or n-hexyl), haloalkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example trifluoromethyl or pentafluoroethyl), alkoxy of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methoxy, ethoxy, n-propoxy or n-butoxy) or sulfonamido. In one embodiment of the invention, each R1 independently represents halogen, alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms or haloalkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. In another embodiment, each R1 independently represents fluorine, chlorine, methyl or trifluoromethyl, particularly chlorine. The combinations of X and Y of particular interest include one or more of any of the following: In one embodiment of the invention, X and Y have the meanings shown below: The combinations of X, Y and Z of particular interest include one or more of any of the following: In one embodiment of the invention, Z represents -0- or -CH2-. In one embodiment of the invention, X, Y and Z have the meanings shown below: Each R independently represents halogen (for example chlorine, fluorine, bromine or iodine), alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl) , isobutyl, tere-butyl, n-pentyl or n-hexyl) or haloalkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example trifluoromethyl or pentafluoromethyl). In one embodiment of the invention, n is 0 or n is 1 and R2 represents halogen, particularly fluorine. In one embodiment of the invention, t is 0 or 1 or 2 or 3 or 4 or 5 or a combination of two or more thereof. In another embodiment, t is 1, 2 or 3. Each R3 independently represents halogen (eg, chlorine, fluorine, bromine or iodine), cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0 NRUR12, -CH2NHC (0) R13, -NHS02R14, ~ S02NR15R16, -CH2-R17, alkylcarbonyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl) , n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), phenylcarbonyl, cycloalkyl of 3 to 6 carbon atoms, preferably 5 to 6 carbon atoms (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or a group selected from alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, n-pentyl or n- hexyl), alkenyl having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms (for example ethenyl, prop-1-en ilo, prop-2-enyl, but-1-enyl, pent-1-enyl, hex-1-enyl or 2-methyl-pent-2-enyl), alkynyl of 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms (for example ethinyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, pent-1-yl, penta-1,3-diinyl or hex-1-ynyl), alkoxy 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), phenyl and a 5 to 6, 7, 8, 9 or 10 membered heterocyclic ring system, saturated or unsaturated comprising at least one ring heteroatom (eg, one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulfur, each group is optionally substituted by at least one substituent (for example one, two, three or four substituents independently) selected from halogen (for example chlorine, fluorine, bromine or iodine), cyano, hydroxyl, carboxylalkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), alkoxy of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy) and alkoxycarbonyl from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms (for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl or n-hexoxycarbonyl). The 5 to 10 membered heterocyclic ring system saturated or unsaturated in R3 can be monocyclic or polycyclic (for example bicyclic), examples of which include pyrrolidinyl, morpholinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrrolyl , furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl, pyridinyl and combinations of two or more of any of them. In one embodiment of the invention, each R3 independently represents halogen, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0) NRX1R12, -CH2NHC (0) R13, -NHS02R14, -S02NR15R16, - CH2R17, alkylcarbonyl of 1 to 4 carbon atoms, phenylcarbonyl, cycloalkyl of 5 to 6 carbon atoms or a group selected from alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 atoms carbon, alkoxy of 1 to 4 carbon atoms, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclic ring system comprising at least one ring heteroatom (for example one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulfur (such as isoxazoline, pyrrolyl, morpholinyl, piperidinyl or oxadiazolyl), each group is optionally substituted by at least one substituent (for example one, two, three or four substituents independently) selected from halogen, cyano, hydroxyl , carbonyl, carboxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and alkoxycarbonyl of 1 to 4 carbon atoms. In one embodiment of the invention, each R3 independently represents halogen, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0) NR? AR12, -CH2NHC (0) R13, -NHS02R14, -S02NR15R16 , alkylcarbonyl of 1 to 4 carbon atoms, phenylcarbonyl, cycloalkyl of 5 to 6 carbon atoms or a group selected from alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms carbon, alkoxy of 1 to 4 carbon atoms, phenyl and a saturated or unsaturated 5-6 membered heterocyclic ring system comprising at least one ring heteroatom (for example one, two, three or four ring heteroatoms independently) selected of nitrogen, oxygen and sulfur (such as isoxazolyl, pyrrolyl, morpholinyl, piperidinyl or oxadiazolyl), each group is optionally substituted by at least one substituent (for example one, two, three or four substituents independently) selected from halogen, cyano, hydroxyl , carboxyl or, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and alkoxycarbonyl of 1 to 4 carbon atoms. In another embodiment, each R3 independently represents fluorine, chlorine, bromine, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0) NR R12, -CH2NHC (0) R13, -NHS02R14, -CH2 -R17, methylcarbonyl, ethylcarbonyl, phenylcarbonyl, cyclohexyl or a group selected from alkyl of 1 to 4 carbon atoms, ethenyl, ethinyl, methoxy, ethoxy, phenyl and a 5-6 membered heterocyclic ring system, saturated or unsaturated comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen (such as isoxazolyl, pyrrolyl, morpholinyl, piperidinyl or oxadiazolyl), each group is optionally substituted by one, two or three substituents independently selected from halogen (particularly fluorine), hydroxyl, alkyl of 1 to 4 carbon atoms (particularly alkyl of 1 to 2 carbon atoms) and alkoxycarbonyl of 1 to 2 carbon atoms. R4, R5, R6, R7 and R8 each independently represent hydrogen, halogen (for example chlorine, fluorine, bromine or iodine), alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or haloalkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (eg, trifluoromethyl or pentafluoroethyl). In one embodiment of the invention, R 4, R 5, R 6, R 7 and R 8 each independently represent a hydrogen atom or a methyl group.

In another embodiment of the invention, R4, R5, R and R7 each represent a hydrogen atom and R8 represents a methyl group. In one embodiment of the invention, R4, R5, R6, R7 and R8 each represent a hydrogen atom. R9 and R10 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl). In one embodiment of the invention, R9 and R10 each represent hydrogen. R11 and R12 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -pentyl or n-hexyl) or R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring (for example pyrrolidinyl or piperidinyl) which can be optionally substituted by at least one substituent (for example one, two or three substituents independently) selected from hydroxyl. In one embodiment of the invention, R11 and R12 each independently represent hydrogen or alkyl of 1 to 4 carbon atoms or R11 and Ra2 together with the nitrogen atom to which they are attached form a heterocyclic, saturated ring of 5 to 6 members on the which can optionally be substituted by one or two hydroxyl groups. In another embodiment, R11 and R12 each independently represent hydrogen or alkyl of 1 to 2 carbon atoms or R11 and R12 together with the nitrogen atom to which they are attached form a 5-membered saturated, heterocyclic ring which can optionally be substituted by a hydroxyl group. R13 and R14 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -pentyl or n-hexyl), particularly methyl. R 15 and Rld each independently represent hydrogen or alkyl of 1 to β carbon atoms, preferably 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -pentyl or n-hexyl) or R15 and R16 together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring (for example pyrrolidinyl or piperidinyl) which can be optionally substituted by at least a substituent (eg, one, two or three substituents independently) selected from hydroxyl. R17 is a 5- to 7-membered saturated heterocyclic ring containing at least one (for example one or two) nitrogen atom, the ring may optionally be substituted by one or more (for example one or two) oxo groups. In one embodiment, R17 is a 5- to 7-membered, saturated heterocyclic ring containing two nitrogen atoms and the ring that is substituted by two oxo groups (e.g., imidazolin-2,4-dione). In one embodiment of the invention: m is 0, 1, 2, 3 or 4; each R1 independently represents halogen, cyano, hydroxy, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or sulfonamido (-S02NH2); X represents a bond, -CH2- or -O-, Y represents a bond, -CH2 or -O- and Z represents a bond, -O-, -NH- or -CH2 with the condition that only one of X, Y and Z can represent a link at any time and with the proviso that X and Y do not represent both simultaneously -0-; n is 0, 1 or 2; each R2 independently represents halogen, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; q is 0 or 1; t is O, 1, 2, 3, 4 or 5; each R3 independently represents halogen, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (O) NR1XR12, -CH2NHC (0) R13, -NHS02R14, -S02NR15R16, alkylcarbonyl of 1 to 6 carbon atoms , phenylcarbonyl, cycloalkyl of 3 to 6 carbon atoms or a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to ß carbon atoms, alkoxy of 1 to 6 carbon atoms, phenyl and a 5- to 10-membered, saturated or unsaturated heterocyclic ring system comprising at least one heteroatom of the ring selected from nitrogen, oxygen and sulfur, each group is optionally substituted by at least one substituent selected from halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and -alkoxycarbonyl from 1 to 6 carbon atoms; R4, R5, Rd, R7 and R8 each independently represent hydrogen, halogen, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; R9 and R10 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms; R11 and R12 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms or R11 and R12 together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring which can be optionally substituted by minus one substituent selected from hydroxyl; R 13 and R 14 each independently represent hydrogen or alkyl of 1 to β carbon atoms; and R15 and R16 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms or R15 and R16 together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring which can be optionally substituted by at least one substituent selected from hydroxyl; or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention: m is 1; R1 represents halogen (particularly chlorine); X represents a bond, -CH2- or -O-, Y represents a bond, -CH2- or -O- and Z represents -CH2- or -O-, with the proviso that X, Y and Z are different from each other; n is 0; q is 1; t is 0, 1, 2, 3, 4 or 5; each R3 independently represents fluorine, chlorine, bromine, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0) NR1: LR12, -CH2NHC (0) R13, -NHS02R14, -CH2-R17, methylcarbonyl, ethylcarbonyl, phenylcarbonyl, cyclohexyl or a group selected from alkyl of 1 to 4 carbon atoms, ethenyl, ethinyl, methoxy, ethoxy, phenyl and a ring system 5 to 6 membered heterocyclic, saturated or unsaturated comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen, each group is optionally substituted by one or two substituents independently selected from halogen (particularly fluorine), hydroxyl, 1 to 2 carbon atoms and alkoxycarbonyl of 1 to 2 carbon atoms; R4, R5, Rd, R7 and R8 each independently represent hydrogen; R9 and R10 each independently represent hydrogen; R11 and R12 each independently represent hydrogen or methyl or R11 and R12 together with the nitrogen atom to which they are attached form a 5-membered saturated, heterocyclic ring which can be optionally substituted by a hydroxyl group; R13 and R14 each independently represent methyl; and R17 is a 5- to 7-membered heterocyclic ring containing 2 nitrogen atoms and the ring which is substituted by two oxo groups. Examples of the compounds of the invention include: (2S) -1- (5-chloro-1'JJ, 3i? -spiro [1-benzofuran-2, '-piperidin] -1'-yl) -3 hydrochloride - (2-methoxyphenoxy) propan-2-ol, 2-. { [(2S) -3- (5-Chloro-1'H, 3i-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} phenol, (2S) -1- (5-chloro-l 'if, 3 H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- ( 2-hydroxyethoxy) -phenoxy] propan-2-ol, 2- (2 { [(2S) -3- (5-chloro-1'E, 3H-spiro [l-benzofuran-2, 4-trifluoroacetate] '-piperidine] -1' -yl) -2-hydroxypropyl] -oxi.}. phenyl) -N-methylacetamide (salt), (3S) -l- [(2- { [(2S) -3- (5-chloro-l, 3ff-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropyl] oxy} phenyl) -acetyl] pyrrolidin-3-ol, N- (2- { [(2S) -3- (5-chloro-l 'i?, 3i? -spiro [1-benzofuran-2,4'-piperidin] -1' -yl-2-hydroxypropyl ] oxyabenzyl) acetamide, 2- (2- { [(2S) -3 ~ (5-chloro-l ?, 3-f-spiro [l ~ benzofuran-2,4'-piperidin] -1 '-il) - 2-hydroxypropyl] oxy.} -4-methoxyphenyl) -N-methylacetamide, 2- (2 { [(2S) -3- (5-chloro-1H, 3H-spiro [1] -trifluoroacetate] benzofuran-2,4 '-piperidin-1'-yl) -2-hydroxypropyl] -oxi.} -4-hydroxyphenyl) -N-methylacetamide (salt), 2- (4- { [(2S) - 3- (5-chloro-1i?, 3i? -spiro [1-benzofuran-2,4'-piperid in] -1 '-yl) -2-hydroxypropyl] oxy} -2-methoxyphenyl) -JV- ethylacetamide, bis (trifluoroacetate) of (2S) -1- (2-amino-5-oxyphenoxy) -3- (5-chloro-l 'if3f-spiro [l-benzofuran-2 , 4'-piperidin] -1'-yl) propan-2-ol, N- (2 { [(2S) -3- (5-chloro-l-2, 3 H-spiro] trifluoroacetate -benzofuran-2,4 '-piperidine] -1'-yl) -2-hydroxypropyl] -oxi.} -4-hydroxyphenyl) methanesulfonamide, trifluoroacetate of N ~ (2- { [(2S) -3- (5-chloro-l 'H, 3 H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] -oxi.} -4-methoxyphenyl) methanesulfonamide, (2S) -1- (4 ~ bromo-2-fluorophenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) propan-2-ol (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-ethynylphenoxy) propan-2-ol (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2,4-dichloro-3, 5) -dimethylphenoxy) propan-2-ol, (2S) -1- (4-chloro-2-isoxazol-5-ylphenoxy) -3- (5-chloro-1'H, 3H-spiro [l-benzofuran-2, 4 '-piperidine] -1' -yl) propan-2-ol, (4- { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy-phenyl) (phenyl) -ethanone, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (2,3, 4, β-tetrachlorophenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1'-yl) -3 - (2-cyclohexyl-5-methylphenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1-yl ) -3-phenoxypropan-2-ol, (2S) -1- (2-bromophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2], 4 '-piperidine] -1' -yl) propan-2-ol, 2-. { [(2S) ~ 3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxijbenzaldehyde, 5-tert-butyl- 2-. { [(2S) -3- (5-chloro-l 'H, 3 H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} ~ benzaldehyde, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (1,1 ': 3' , l "-terphenyl-2'-yloxy) ropan-2-ol, 1- (2- { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2 , 4 '-piperidine] -1' -yl) -2-hydroxypropyl] oxy} .5-methoxyphenyl) -ethanone, 1- (5-bromo-2- { [(2S) -3- (5 -chloro-L 'H, 3 H-spiro [1-benzofuran-2,4'-piperidin] -1' -yl) -2-hydroxypropyl] oxy} phenyl) -ethanone, (2S) -1- (4 -chloro-2-isopropyl-5-methylphenoxy) -3- (5-chloro-1'H, 3H-spiro [l-benzofuran-2, '-piperidin] -1'-yl) propan-2-ol, ( 2S) -l ~ (5 ~ chloro-l'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2,3-dimethyl-4-nitrophenoxy) propan -2-ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2,4-dichlorophenoxy) ) propan-2-ol, (2E) -3- (4- { [(2S) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -l'-yl) -2-hydroxypropyl] oxy] -3-ethoxyphenyl) ethyl acrylate, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2, 4 '-piperidin] -1 '-il) -3- (2-methyl-3-nitrophenoxy) propan-2-ol, 5-chloro-2-. { [(2S) -3- (5-chloro-l 'H, 3 H-spiro [1-benzofuran-2,' -piperidin] -1 '-yl) -2-hydroxypropyl] oxy} -benzaldehyde, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2-fluorophenoxy) propan-2 -ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-fluorophenoxy) propan-2 -ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (4-fluorophenoxy) propan-2 -ol, (2S) -1- (2-chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 -ol, (2S) -1- (3-chlorophenoxy) -3- (5-chloro-l 'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) ropan-2 -ol, (2S) -1- (4-chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 -ol, (2S) -1- (3-bromophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 -ol, (2S) -1- (4-bromophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 -ol, (2S) -1- (2-tert-butyl-5-methylphenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1 ' -il) propan-2-o 1, (2S) -1- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -l'-yl) -3- [2- (trifluoromethyl) phenoxy] propan -2-ol, 1- (2-. { [(2S) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} -4,5-dimethoxyphenyl) ethanone, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- [2 , 3, 5, 6-tetrafluoro-4- (trifluoromethyl) -phenoxy] -propan-2-ol, (2S) -1- (4-chloro-3-ethylphenoxy) -3- (5-chloro-l'H , 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran] -2,4 '-piperidin] -1' -yl) -3- [3- (2, 5-dimethyl-lH-pyrrol-1-yl) phenoxy] propan-2-ol, (2S) -1- ( 5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (hydroxymethyl) phenoxy] propan-2-ol, (2S) - 1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (2-hydroxyethyl) phenoxy] propan-2-ol , 3- . { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropyl] oxy} benzonitrile, 2-. { [(2S) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} benzonitrile, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1 '-yl) -3- (2-morpholin-4-ylphenoxy) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1' -il) -3- (2, 3- difluoro-6-nitrophenoxy) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3 H-spiro [l-benzofuran-2,4'-piperidin] -l'-il) -3 - (2,3,6-trichlorophenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -l'- il) -3- (4-fluoro-2-methoxyphenoxy) propan-2-ol, 5-chloro-2-. { [(2S) -3- (5-chloro-l 'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} -3-methylbenzaldehyde, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2, '-piperidin] -l'-yl) -3- [4- (4-methylpiperidin -l-il) -2-nitrophenoxy] propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1 '- il) -3- (2, -dichloro-3, 5-dimethyl-6-nitrophenoxy) -propan-2-ol, 1- (3,5-dichloro-2- { [(2S) -3- ( 5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropyl] oxy} phenyl) -propan-1-one, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-lyl) -3- (4-ethylphenoxy) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2-ethylphenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-ethylphenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-morpholin-4-ylphenoxy) propan-2-ol , (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- [2- (5-methyl-1, 3, 4-oxadiazol-2-yl) phenoxy ] propan-2-ol, 4-. { [(2S) -3- (5-Chloro-1'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxijbenzonitrile, (2S) -1- (5-chloro-l 'H, 3 # -spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (pyrrolidin-1-ylsulfonyl) phenoxy] -propan-2 -ol, l- (2- { [(2S) -3- (5-chloro-l, 3-spiro [l-benzofuran-2,4'-piperidin] -1 '-il) -2 -hydroxypropoxy] benzyl.}. imidazoline-2,4-dione, (2S) -. {2-chloro-5- [3- (5-chloro-1i?, 3i? -spiro [1-benzof] acid ran-2, '-piperidin] -1'-yl) -2-hydroxypropoxy] phenoxy], acetic acid (2S) - { 2,4-dichloro-5- [3- (5-chloro-l) 'H, 3H ~ spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropoxy] phenoxy] acetic acid, and pharmaceutically acceptable salts and solvates of any of them. further provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined above, which comprises the steps consisting of n (a) reacting a compound of the formula wherein m, R1, n, R2, q, X, Y and Z are as defined in formula (I), with a compound of the formula wherein t, R3, R4, R5, Rd, R7 and R8 are as defined in formula (I); or (b) reacting a compound of the formula wherein m, R1, n, R2, q, X, Y, Z, R4, R5, Rd, R7 and R8 are as defined in formula (I), with a compound of the formula (V) wherein t and R3 are as defined in formula (I), in the presence of a suitable base (e.g., triethylamine or potassium carbonate); .o (c) when t is at least one and a group R3 represents -NHS02R14, reacting a compound of the formula where t 'is O, 1, 2, 3 or 4, R3' is as defined for R3 in formula (I) different from -NHS02R14 and rn, R1, n, R2, q, X, Y, Z, R4, R5, R6, R7 and R8 are as defined in formula (I), with a compound of the formula wherein L represents a leaving group (for example a halogen atom, such as chlorine) and R14 is as defined in formula (I), in the presence of a suitable base (e.g., pyridine); (D) where t is at least 1 and one group R3 represents -CH2 ~ R17, where R17 is a heterocyclic ring, saturated 5 to 7 members containing two nitrogen atoms and the ring is substituted by two oxo groups, to react a compound of the formula where t 'is 0, 1, 2, 3 or 4, R3' is as defined for R3 in formula (I) different from -CH2-R17, and m, R1, n, R2, q, X, Y, Z, R4, R5, Rd, R7 and R8 are as defined in formula (I), with a glycinate alkyl (e.g. ethyl glycinate) in the presence of a reducing agent (eg NaCNBH), and subsequently with a metal isocyanate (e.g., potassium isocyanate); and optionally after (a), (b), (c) or (d), forming a pharmaceutically acceptable salt or solvate. The methods of the invention can be conveniently carried out in a solvent, for example an organic solvent such as an alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene) or tetrahydrofuran, dimethylformamide, N-methylpyrrolidinone, dichloromethane or acetonitrile at a temperature of, for example, 0 ° C or higher, such as a temperature in the range of 0, 5, 10, 15 or 20 ° C to 100, 110 or 120 ° C. The compounds of the formula (II), (III), (IV), (V), (VI), (VII) and (VIII) are either commercially available, are known in the literature or can be prepared using known techniques. Those skilled in the art will appreciate that in the methods of the present invention, certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. In this way, the preparation of the compounds of the formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is described in "Protective Groups in Organic Chemistry", edited by J. W. F. McOie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3- edition, T..

Greene and P. G. M. Wuts, iley-Interscience (1999). The compounds of formula (I) above may be converted 'to a pharmaceutically acceptable salt or solvate thereof, preferably a salt of addition of acid such as hydrochloride, hydrate bro, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. The compounds of the formula (I) can exist in stereoisomeric forms. It will be understood that the invention includes the use of all geometric and optical isomers (including atropisomers) of the compounds of the formula (I) and mixtures thereof, including racemates. The use of tautomers and mixtures thereof also forms an aspect of the present invention. Enantiomerically pure forms are particularly desired. The compounds of the formula (I) have activity as pharmaceutical agents, in particular as modulators of the activity of chemokine receptors (especially the chemokine receptor MlP-la) and can be used in the treatment of autoimmune diseases., inflammatory, proliferative and hyperproliferative and uniologically mediated diseases that include the rejection of transplanted organs or tissues and the acquired immunodeficiency syndrome (AIDS). Examples of these conditions are: (1) (the respiratory tract) diseases of the airways that include chronic obstructive pulmonary disease (COPD, for its acronym in English) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic asthma and various powders, particularly chronic or inveterate asthma (eg, delayed asthma and hyper-sensitivity of the airways); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and rhinitis medicamentosa; Membranous rhinitis that includes croupy, fibrinous, pseudomematous rhinitis, and scrofulous rhinitis; seasonal rhinitis that includes rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including alkylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, Sjogren's syndrome, and systemic sclerosis; (3) (skin) psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigus bullosum, epidermolysis bullosa, urticaria, angioderma, vasculitis, erythema, cutaneous eosinophilia, uveitis, alopecia areata and conjunctivitis vernal; (4) (gastrointestinal tract) celiac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies, which have effects far from the intestine, for example, migraine, rhinitis and eczema; (5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fasciitis, hypertension syndrome IgE, lepromatous leprosy, Sezary syndrome and idiopathic purple thrombocytopenia; (6) (allograft rejection) acute and chronic after, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; • and chronic graft versus host disease; (7) cancers, especially non-small cell lung cancer (NSCLC) and squamous sarcoma; (8) diseases in which angiogenesis is associated with elevated levels of chemokines; and (9) cystic fibrosis, stroke, reperfusion injury to the heart, brain, peripheral limbs, and sepsis. In this manner, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above for use in therapy. In a further aspect, the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above in the preparation of a medicament for use in therapy. . In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be considered accordingly. The invention also provides a method for treating an inflammatory disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined earlier in this document. The invention still further provides a method for treating an airway disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof. , as defined earlier in this document. For the therapeutic uses mentioned above, the dosage administered will, of course, vary with the compound used, the mode of administration, the treatment desired and the indicated disorder. The daily dosage of the compound of the formula (I) can be in the range of 0.001 mg / kg to 30 mg / kg. The compounds of the formula (I) and the pharmaceutically acceptable salts and solvates thereof can be used by themselves but will generally be administered in the form of a pharmaceutical composition in which the compound of the formula (I) / salt / solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% (percent by weight), more preferably from 0.05 to 80% by weight, still more preferably from 0.10 to 70% by weight and even more preferably from 0.10 to 70% by weight. 50% by weight, of active ingredient, all percentages by weight are based on the total composition. The present invention also provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a method for the preparation of a pharmaceutical composition of the invention, which comprises mixing a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined hereinbefore, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions can be administered topically (for example to the skin or lung and / or airways) in the form of, for example, creams, solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally. The invention will now be further explained by reference to the following illustrative examples, in which the XH NMR spectra were recorded on a Varian Unity Inova 400 device. The central solvent peak of chloroform-d (dH 7.27 ppm), acetone-de (dH 2.05 ppm), DMSO-e (dH 2.50 ppm) or methanol-d4 (dH 4.87 ppm) were used as internal standard. Low-resolution mass spectra and accurate mass determination were recorded in a Hewlett-Packard 1100 CL-MS system equipped with APCI / ESI ionization chambers. All commercial solvents and reagents were laboratory grade and were used as received. The nomenclature used for the compounds was generated with ACD / Name and ACD / Name Batch. The abbreviations or terms used in the examples have the following meanings: DMF-V ^ N-dimethylformamide THF tetrahydrofuran DME 1,2-dimethoxyethane Examples Intermediate compound: 5-Chloro-3H-spiro [l-benzofuran-2,4'-piperidine] Method A: This compound was prepared as described by Effland, R. C; Gardner, B. A; Strupcze ski, J., J. Heterocyclic Chem., 1981, 18, 811-814.

Method B: i) l-oxa-6-azaspiro [2.5] octane-6-carboxylic acid 1,1-dimethylethyl ester Potassium t-butoxide (31 g) was added to a stirred suspension of trimethylsulfoxonium iodide (60.8 g) in 1 ml. , 2-dimethoxyethane (250 ml) at 20 ° C. After 1 hour, the mixture was added dropwise over 30 minutes to a stirred solution of 4-1-oxo-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (50 g) in 1,2-dimethoxyethane (50 ml). at 0 ° C. After a further 2 hours, water (500 ml) was added and the mixture was extracted with tert-butyl-methyl ether (2 x 500 ml). The organic extracts were washed separately with a saturated solution of sodium bicarbonate (250 ml), combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was co-evaporated with toluene (100 ml) to provide the subtitle compound (43.25 g, 81%) as a solid.

NMR-XH (400 MHz, CDC13): d 1.46 (9H, s), 1.43-1.48 (2H, m), 1.75-1.84 (2H,), 2.69 (2H, s), 3.38-3.47 (2H, m) 3.70-3.75 (2H, m). ii) 5-chlorospiro [l-benzofuran-2,4'-piperidin] -1'-carboxylic acid 1,1-dimethylethyl ester A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 106.6 ml) was added drop dropwise over 15 minutes to a stirred solution of 2-bromo-4-chloro-1-fluorobenzene (42.5 g) in anhydrous tetrahydrofuran (250 ml) at 0 ° C under nitrogen. After an additional 15 minutes, a solution of l-oxa-6-azaspiro [2.5] octane-6-carboxylic acid 1,1-dimethylethyl ester (43.2 g) in anhydrous tetrahydrofuran (50 ml) was added followed by a bromide complex. of copper (1) -dimethyl sulfoxide (0.4 g). The mixture was stirred at 40 ° C for 18 hours, cooled to 20 ° C, diluted with water (300 ml) and extracted with tert-butyl-methyl ether (2 x 300 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was dissolved in 1,2-dimethoxypropane (200 ml). Potassium tert-butoxide (22.8 g) was added and the mixture was stirred at 40 ° C for 16 hours, then at 50 ° C for 24 hours. Additional potassium tert-butoxide (5.7 g) was added and stirring continued at 50 ° C for 2 hours, then at 55 ° C for 4 hours. Water (500 ml) was added and the mixture was extracted with tert-butyl-methyl ether (2 x 300 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide the subtitle compound (47.45 g, 67%) as an oil.

RMN-1 !! (400 MHz, CDC13): d 1.47 (9H, s), 1.67 (2H, td), 1.85-1.93 (2H,), 2.94 (2H, s), 3.39 (2H, td), 3.65-3.80 (2H, m), 6.67 (ÍH, d), 7.06 (1H, d), 7.10 (ÍH, s). iii) 5-Chlorospiro [l-benzofuran-2,4'-piperidine] The concentrated hydrochloric acid (23 ml) was added to a solution of 1,1-dimethyl ester of 5-chlorospiro acid [1-benzofuran-2, 4 '-piperidine] -1'-carboxylic acid (46.43 g) in tetrahydrofuran (230 ml). The mixture was stirred at 50 ° C for 6 hours, cooled to 20 ° C, diluted with water (230 ml) and extracted with tert-butyl methyl ether (2 x 230 ml). The aqueous phase was adjusted to pH > 10 by the addition of a 50% by weight sodium hydroxide solution and extracted with tert-butyl-methyl ether (3 x 300 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was dissolved in tetrahydrofuran (240 ml), concentrated hydrochloric acid (12 ml) was added and the mixture was stirred at 20 ° C for 16 hours. The precipitated solid was filtered and dissolved in water (100 ml). The solution was adjusted to pH > 10 by the addition of a 50% by weight sodium hydroxide solution and extracted with tert-butyl methyl ether (3 x 100 ml) to give the title compound (13.3 g, 45%) as a solid.

RMN-1 !! (400 MHz, CDC13): d 1.69-1.76 (2H, m), 1.83-1.87 (2H, m), 2.78-2.84 (2H, m), 2.98-3.03 (4H, m), 6.65 (HI, d) , 7.04 (ÍH, d), 7.13 (1H, s). APCI-MS: m / z 224/6 [M + H] +.

EXAMPLE 1 (2S) -1- (5-Chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -3- (2-methoxyphenoxy) propan- 2-ol Step I: (2S) -2- [(2-M-toxyphenoxy)] oxirane A mixture of (2S) -oxiran-2-ylmethyl-3-nitrobenzenesulfonate (777 mg, 3.0 mmol), 2-methoxyphenol (372.5 mg, 3.0 mmol) and Cs2CO3 (1.3 g, 4.0 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-30% ethyl acetate in 40-60 petroleum spirit) to give the subtitle compound (425 mg).

NMR-aH (CDC13, 400 MHz): d 7.08-6.88 (m, 4H); 4.26 (dd, < J = 3. 6, 11.4 Hz, 1H); 4.08 (dd, J = 5.4, 11.4 Hz, 1H); 3.90 (s, 3H); 3.43 (m, 1H); 2.92 (t, J = 4.8 Hz, ÍH); 2.77 (dd, J = 2. 7, 5.0 Hz, 1H). APCI-MS: m / z 222 (MH +).

Step II: (2S) -1- (5-Chloro-l'fl, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2-methoxyphenoxy) propan-2 -ol A mixture of 5-chloro-3ff-spiro [1-benzofuran-2,4'-piperidine] (150 mg, 0.67 mmol) and (2S) -2 - [(2-methoxyphenoxy) methyl] oxirane ( 121 mg, 0.67 mmol) in ethanol (2 mL) was stirred at 80 ° C overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (0-1% methanol in dichloromethane, 0.2% NH 4 OH) to give the title compound (190 mg).

X-NMR (CDCl 3, 400 MHz): d 7.10 (m, 1 H); 7.05 (dd, J = 2.3, 8.5 Hz, ÍH); 6.98-6.93 (m, 2H); 6.90 (, 2H); 6.67 (d, J = 8.5 Hz, 1H); 4.18 (, ÍH); 4.05 (d, J = 5.0 Hz, 2H); 3.88 (s, 3H); 2.98 (s, 2H); 2.84 (m, 1H); 2.75 (m, ÍH); 2.60 (m, 4H); 1.99 (m, 2H); 1.80 (m, 2H). APCI-MS: m / z 403 (MH +).

Example 2 2-. { [(2S) -1- (5-Chloro-1'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropylJoxy} phenol To a solution of (2S) -1- (5-chloro-l 'H, 3i-spiro [1-benzofuran-2,4'-piperidin] -1'-yl)' -3- (2-methoxyphenoxy) propan-2-ol (180 mg, 0.444 mmol) in dichloromethane (4 L) was added a solution of 1M BBr3 in CH2C12 (1.32 mL, 1.32 mmol) at 0 ° C. After the addition was complete, the reaction mixture was stirred at 0 ° C for 1.5 hours. Methanol (1 mL) was added and the reaction mixture was stirred at 0 ° C for 10 minutes and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed successively with aqueous NaHCO3 and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give the title compound (150 mg).

NMR-XH (CD3OD, 400 MHz): d 7.14 (m, ÍH); 7.04 (dd, J = 2.4, 8.5 Hz, ÍH); 6.94 (m, ÍH); 6.85-6.74 (m, 3H); 6.65 (d, J = 8.5 Hz, ÍH); 4.18 (m, ÍH); 4.04 (dd, J = 4.0, 9.9 Hz, ÍH); 3.95 (dd, J = 5.9, 9.9 Hz, ÍH); 3.04 (s, 2H); 2.79-2.57 (m, 6H); 2.00-1.82 (m, 4H). APCI-MS: m / z 390 (MH +).

EXAMPLE 3 (2S) -1- (5-Chloro-l'ff, 3ff-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (2-hydroxyethoxy) hydrochloride ) phenoxy] propan-2-ol A mixture of 2-. { [(2S) -3- (5-chloro-1i?, 3i? -spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} phenol (50 mg, 0.128 mmol), chloroethanol (103 mg, 1.28 mmol) and K2CO3 (207 mg, 1.5 mmol) in DMF (1.5 mL) was stirred at 83 ° C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and H20. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-2.5% methanol in dichloromethane, 0.2% NH4OH) to give the title compound (40 mg).

RMN-1 !! (CD3OD, 400 MHz): d 7.13 (m, ÍH); 7.06-6.97 (m, 3H); 6.94-6.90 (m, 2H); 6.65 (d, J = 8.5 Hz, ÍH); 4.17 (m, ÍH); 4.10-4.03 (m, 3H); 3.96 (dd, J = 6.2, 9.9 Hz, 1H); 3.89-3.85 (m, 2H); 3.02 (s, 2H); 2.76-2.56 (, 6H); 1.98-1.78 (m, 4H). APCI-MS: m / z 434 (MH +).

EXAMPLE 4 2- (2 { [(2S) -3- (5-Aloro-1-yl), 3-T-spiro [l-benzofuran-2,4'-piperidine] -1'-yl trifluoroacetate -2-hydroxypropyl] oxy} phenyl) -i-methylacetamide (salt) Step 1: Jtf-Methyl-2-. { 2- [(2S) -oxiran-2-ylmethoxy] phenyl} acetamide A mixture of 2- (2-hydroxyphenyl) -N-methylacetamide (1.00 g, 6.1 mmol) prepared according to a known procedure (Bernd, Peschke, Eur. J. Med. Chem., 2000, 35, 599- 618), (25) -oxiran-2-ylmethyl-3-nitrobenzene sulfonate (1.58 g, 6.1 mmol) and cesium carbonate (2.37 g, 7.3 mmol) in 1-methylpyrrolidin-2-one (15 ml) was stirred at room temperature. atmosphere throughout the night. The mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were dried with sodium sulfate, the volatiles were removed in vacuo. The residue was purified by recrystallization from ethyl acetate / heptane; (390 mg) of the subtitle compound were obtained.

X-NMR (CDC13, 400 MHz): d 7.30-7.23 (m, 2H); 7.00-6.96 (m, ÍH); 6.89 (d, J = 8.3 Hz, ÍH); 5.97 (broad s, ÍH); 4.37 (dd, J = 2.6, 11.1 Hz, 1 H); 4.05-3.99 (m, 1H); 3.58 (broad s, 2H); 3.41-3.36 (m, 1H); 2.94 (t, J = 4.4 Hz, ÍH); 2.86-2.83 (m, ÍH); 2.75 (d, J = 4.9 Hz, 3H). APCI-MS: m / z 222 (MH +).

Step II: 2- (2- { [(2S) -3- (5-sloro-l'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) trifluoroacetate -2-hydroxypropyl] oxy} phenyl) -N-methylasetamide A mixture of N-methyl-2-. { 2- [(2S) -oxiran-2-methoxy] phenyl} acetamide (23 mg, 0.1 mmol) and 5-chloro-3 H-spiro [l-benzofuran-2,4'-piperidine] (22 mg, 0.1 mmol) in ethanol (15 mL) was heated to reflux overnight , the volatile products were removed in vacuo. The residue was purified by means of HPLC (acetonitrile / water, trifluoroacetic acid 0.1%) and gave (25 mg) of the subtitle compound.

X-NMR (CDC13, 400 MHz): d 7.63-7.52 (m, 3); 7.44 (dd, J = 2.1, 8.5 Hz, 1H); 7.37-7.28 (m, 2H); 7.08 (d, J = 8.5 Hz, ÍH); 4.82-4.72 (m, 1H); 4.46-4.35 (m, 2H); 4.10-3.96 (m, 2H); 3.96-3.69 (, 6H); 3.47 (broad s, 2H); 3.05 (s, 3H); 2.63-2.45 (m, 4H). APCI-MS: m / z 445 (MH +).

Example 5 (3S) -1- [(2- { [(2S) -3- (5-Chloro-1H, 3i? -spiro [l-benzofuran-2,4'-piperidine] -1 ' -yl) -2-hydroxypropyl] oxy} phenyl) acetyl] -pyrrolidin-3-ol Step 1: (3S) -1- [(2-Hydroxyphenyl) acetyl] irrolidin-3-ol A mixture of (2-hydroxyphenyl) acetic acid (304 mg, 2.0 mmol) and N ^ N-carbonyldiimidazole (405 mg, 2.5 mmol) in DMF (5 mL) was stirred at room temperature for 45 minutes. A solution of (3S) -pyrrolidin-3-ol (435 mg, 5.0 mmol) in DMF (1.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H20. The organic layers were dried over Na 2 SO 4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-3% methanol in dichloromethane) to give the subtitle compound (205 mg).

RMN-1 !! (CD3OD, 400 MHz): d 7.68 (s, 1H); 7.13-7.03 (, 3H); 6.77 (, ÍH); 4.40 (m, 1H); 3.80-3.45 (m, 6H); 2.10-1.84 (m, 2H). APCI-MS: m / z 222 (MH +).

Step II: (3S) -1- ( { 2- [(2S) -Oxiran-2-ylmethoxy] phenyl}. Acetyl) pyrrolidin-3-ol A mixture of (2S) -oxiran-3-nitrobenzene sulfonate 2-ylmethyl (228 mg, 0.88 mmol), (3S) -l - [(2-hydroxyphenyl) acetyl] pyrrolidin-3-ol (196 mg, 0.88 mmol) and CS2CO3 (344 mg, 1.05 mmol) in DMF (5%). mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel / (0-3% methanol in dichloromethane) to provide the subtitle compound (35 mg).

NMR-XH (CD3OD, 400 MHz): d 7.26-7.15 (m, 2H); 6.97-6.88 (m, 2H); 4.48-4.30 (, 2H); 3.94-3.45 (m, 8H); 2.86 (t, J. = .8 Hz, ÍH); 2.73 (m, ÍH); 2.16-1.86 (, 2H). APCI-MS: m / z 278 (MH +).

Step III: (3S) -1- [(2- { [(2S) -3- (5-Chloro-1'H, 3H-spiro [l-benzofuran-2, '-piperidin] -l'- il) -2-hydroxypropyl] oxy} phenyl) acetyl] -pyrrolidin-3-ol A mixture of 5-chloro-3'-spiro [1-benzofuran-2,4'-piperidine] (26 mg, 0.115 mmol ) and (3S) ~ 1- ( { 2- [(2S) -oxiran-2-ylmethoxy] phenyl}. acetyl) pyrrolidin-3-ol (32 mg, 0.115 mmol) in ethanol (2 L) it was stirred at 80 ° C overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (0-2% methanol in dichloromethane, 0.2% NH 4 OH) to give the title compound (33 mg).

RMN-1 !! (CD3OD, 400 MHz): d 7.24 (, ÍH); 7.19 (d, J = 7.3 Hz, ÍH); 7.14 (s, 1H); 7.05 (dd, J = 2.0, 8.5 Hz, ÍH); 6.97 (d, J = 8.2 Hz, 1H); 6.91 (t, J = 7.3 Hz, 1H); 6.65 (d, J = 8.5 Hz, ÍH); 4.46 (m, 0.5H); 4.42 (, 0.5H); 4.15 (m, 1H); 4.05 (m, ÍH); 3.97 (dd, J = 5.9, 9.8 Hz, ÍH); 3.75-3.47 (m, 6H); 3.00 (s, 2H); 2.74-2.52 (m, 6H); 2.14-1.80 (m, 6H). APCI-MS: m / z 501 (MH +).

Example 6 N- < 2-. { [< 2S) -3- (5-Chloro-1H.3H-spiroyl-benzofuran-2,4'-piperidine] -1'-yl-2-hydroxypropyl] oxy} benzyl) acetamide Step I: N- (2-Hydroxybenzyl) asetamide 2-methoxybenzylamine (822 mg, 6.0 mmol) in methanol (10 L) was treated with acetic anhydride (613 mg, 6.0 mmol) at room temperature for 2 hours. The volatile products were removed in vacuo. The residue was dissolved in CH2C12, cooled to 0 ° C, a 1M solution of BBr3 in CH2C12 (12 L, 12.0 mmI) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature overnight, cooled to 0 ° C, methanol (3 mL) was added and after 10 minutes, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous NaHCO3 and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-50% ethyl acetate in petroleum alcohol) to provide the subtitle compound (400 mg).

NMR-XH (CD3OD, 400 MHz): d 7.16-7.06 (, 2H); 6.81-6.74 (, 2H); 4.18 (s, 2H); 1.99 (s, 3H). APCI-MS: m / z 166 (MH +).

Step II: N-. { 2- [(2S) -Oxiran-2-ylmethoxy] benzyl} acetamide A mixture of N- (2-hydroxybenzyl) acetamide (382 mg, 2.31 mmol), (2S) -oxiran-2-yl ethyl 3-nitrobencenesulfonate (599 mg, 2.31 mmol) and Cs2C03 (901 mg, 2.77 mmol) in DMF (5 L) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-80% ethyl acetate in petroleum alcohol) to provide the subtitle compound (333 mg).

RMN-1 !! (CDCl 3, 400 MHz): d 7.32-7.22 (, 2H); 6.95 (m, ÍH); 6.87 (, ÍH); 6.34 (broad s, ÍH); 4.55-4.354 (m, 3H); 4.03 (dd, J = 5.1, 11.2 Hz, ÍH); 3.39 (m, ÍH); 2.95 (m, ÍH); 2.86 (, 1H); 1.98 (s, 3H). APCI-MS: m / z 222 (MH +).

Step III: N- (2- { [(2S) -3- (5-Chloro-l '. 3 H-spiro [l-benzofuran-2,4'-piperidin] -1' -yl-2-hydroxypropyl ] oxy] benzyl acetamide A mixture of 5-chloro-3J? -spiro [1-benzofuran-2,4'-piperidine] (64 mg, 0.284 mmol) and N- { 2 ~ [( 2S) -oxiran-2-ylmethoxy] benzyl.} Acetamide (63 mg, 0.284 mmol) in ethanol (1.5 L) was stirred at 80 ° C overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (0-1% methanol in dichloromethane, 0.2% NHOH) to give the title compound (85 mg).

X-NMR (CD30D, 400 MHz): d 7.28-7.21 (, 2H); 7.14 (s, ÍH); 7.04 (dd, J = 2.2, 8.4 Hz, 1H); 6.97 (d, J = 8.1 Hz, 1H); 6.91 (t, J = 7.4 Hz, 1H); 6.65 (d, J = 8.5 Hz, ÍH); 4.39 (s, 2H); 4.18 (m, ÍH); 4.09 (dd, J = 3.9, 9.8 Hz, ÍH); 3.98 (dd, J "= 5.9, 9.8 Hz, ÍH), 3.02 (s, 2H), 2.79-2.58 (m, 6H), 1.99-1.80 (m, 7H), APCI-MS: m / z 445 (MH + ).

Example 7 2- (2- { [(2S) -3- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4-piperidin] -1'-yl) -2-hydroxypropyl ] oxi.} -4- ethoxy-enyl) -N-methylacetamide from Step I: 2- (2, -Dimethoxyphenyl) -2-methylacetamide A mixture of (2,4-dimethoxyphenyl) acetic acid (577 mg, 3.0 mmol) and N, N-carbonyldiimidazole (608 mg, 3.75 mmol) in DMF (10 L) was stirred at room temperature for 45 minutes, 40% aqueous methyl amine (4.5 mL) was added and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was dried over Na 2 SO, filtered and concentrated. The residue was purified by means of flash chromatography on silica gel (0-80% ethyl acetate in petroleum alcohol) to provide the subtitle compound (460 mg).

RMN-1 !! (CDC13, 400 MHz): d 7.12 (d, J = 7.8 Hz, 1H); 6.48 (m, 2H); 5.64 (broad s, ÍH); 3.83 (s, 3H); 3.81 (s, 3H); 3.25 (s, 2H); 2.73 (d, J = 4.8 Hz, 3H). APCI-MS: m / z 210 (MH +).

Step II: 2- (2-Hydroxy-4-methoxyphenyl) -27-methylacetamide To a solution of 2- (2,4-dimethoxyphenyl) -N-ethylacetamide (445 mg, 2.12 mmol) in CH2C12 (10 L) was slowly added a solution of 1M BBr3 in CH2C12 (6.4 mL, 6.4 mmol). After the addition was complete, the reaction mixture was stirred at 0 ° C for 2.5 hours, methanol (2 mL) was added and after 15 minutes, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous NaHCO3 and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-5% methanol in dichloromethane) to provide the subtitle compound (16 mg) together with 2- (4-hydroxy-2-ethoxyphenyl) - ÍV-methylacetamide (30 mg). 2- (4-Hydroxy-2-methoxyphenyl) -.-V-methylacetamide: NMR-XH (CDC13, 400 MHz): d 6.87 (d, J = 8.2 Hz, 1H); 6.56 (d, J = 2.6 Hz, ÍH); 6.38 (dd, J = 2.7, 8.4 Hz, 1H); 6.08 (broad s, 1H); 3.78 (s, 3H); 3.49 (s, 2H); 2.83 (d, J = 4.8 Hz, 3H). APCI-MS: m / z 182 (MH +). 2- (4-Hydroxy-2-methoxyphenyl) -W-methylacetamide: NMR-XH (CDCl3, 400 MHz): d 6.97 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 2.4 Hz, ÍH) , 6.44 (dd, J = 8.2, 2.4 Hz, ÍH), 5.92 (d, J = 4.4 Hz, 1H), 3.76 (s, 3H), 3.48 (s, 2H), 2.76 (d, J = 4.8 Hz, 3H). APCI-MS: m / z 182 (MH +).

Step III: 2- { 4-Methoxy-2- [(2S) -oxiran-2-ylmethoxy] phenyl} -W-methylacetamide A mixture of 2- (2-hydroxy-4-methoxyphenyl) -N-methylacetamide (15 mg, 0.076 mmol), 3-nitrobenzenesulfonate from (2S) -oxiran-2-ylmethyl (20 mg, 0.076 mmol) and Cs2C03 (30 mg, 0. 091 mmol) in DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by means of flash chromatography on silica gel '(0-100% ethyl acetate in petroleum alcohol) to provide the subtitle compound (18 mg).

NMR-XH (CDC13, 400 MHz): d 7.17 (d, J = 8.2 Hz, ÍH); 6.52-6.46 (m, 2H); 5.90 (broad s, 1H); 4.33 (dd, J = 2.6, 11.1 Hz, ÍH); 3.97 (dd, J = 5.2, 11.1 Hz, 1H); 3.80 (s, 3H); 3.49 (s, 2H); 3.36 (m, ÍH); 2.93 (t, J = 4.7 Hz, ÍH); 2.82 (dd, J = 2.6, 4.7 Hz, 1H); 2.74 (d, J = 4.9 Hz, 3H). APCI-MS: m / z 252 (MH +).

Step IV: 2- (2- { [(2S) -3- (5-Chloro-1H, 32? -spiro [l-benzofuran-2,4'-piperidin] -1 '-il) - 2-hydroxypropyl] ox.} -4-methoxyphenyl) -N-methylacetamide A mixture of 5-chloro-3β-spiro [1-benzofuran-2, '-piperidine] (16 mg, 0.0716 mmol) and the 2-. { 4-methoxy-2- [(2S) -oxiran-2-ylmethoxy] phenyl} -N-methylacetamide (18 mg, 0.0716 mmol) in ethanol (1 L) was stirred at 80 ° C overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (0-1% methanol in dichloromethane, 0.2% NH4OH) to give the title compound (16 mg).

RMN-1 !! (CD3OD, 400 MHz): d 7.23 (s, 1H); 7.20 (d, J = 8.3 Hz, ÍH); 7.14 (dd, J = 2.2, 8.5 Hz, ÍH); 6.73 (d, J = 8.5 Hz, 1 HOUR); 6.65 (d, J = 2.4 Hz, ÍH); 6.59 (dd, J = 2.4, 8.3 Hz, ÍH); 4.25 (m, ÍH); 4.14 (dd, J = 3.9, 9.7 Hz, 1H); 4.05 (dd, J = 5.7, 9.7 Hz, ÍH); 3.88 (s, 3H); 3.55 (s, 2H); 3.11 (s, 2H); 2.86-2.64 (m, 9H); 2.03 (, 2H); 1.94 (m, 2H). APCI-MS: m / z 475 (MH +).

EXAMPLE 8 2- (2 { [(2S) -3- (5-Chloro-1H, 3 H-spiro [l-benzofuran-2,4'-piperidin] -1 'yl) -2-trifluoroacetate -hydroxypropyl] oxy.} -4-hydroxy enyl) -iV-methylacetamide (salt) To a solution of 2- (2- { [(2S) -3- (5-chloro-1 H, 3H -spiro [l-benzofuran-2, '-piperidin] -1'-yl) -2-hydroxypropyl] -oxi.} -4-methoxyphenyl) -N-methylacetamide (12 mg, 0.025 mmol) in CH2C12 (1 mL ) a solution of 1M BBr3 in CH2C12 ((0.075 L) was added slowly at 0 ° C. After the addition was complete, the reaction mixture was stirred at 0 ° C for 80 minutes, 0.3 mL of methanol was added and After 10 minutes, the volatiles were removed in vacuo and the residue subjected to HPLC (CH3CN 10-55% in H20, CF3C02H 0.1%) to give the title compound (7 mg).

RMN-1 !! (CD3OD, 400 MHz): d 7.20 (s, 1H); 7.10 (m, 1H); 7.01 (d, J = 8.1 Hz, ÍH); 6.74 (, ÍH); 6.43 (s, 1H); 6.39 (dd, J = 2.0, 8.1 Hz, ÍH); 4.40 (m, ÍH); 4.00 (, 2H); 3.69 (m, 2H); 3.53-3.34 (, 6H); 3.13 (s, 2H); 2.69 (s, 3H); 2.29- 2.06 (m, 4H). APCI-MS: m / z 461 (MH +).

Example 9 2- (4- { [(2S) -3- (5-Chloro-1'H, 3ff-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2- hydroxypropyl] oxy.} -2-methoxyphenyl) -N-methylacetamide Step I: 2-. { 2-Methoxy-4- (2S) -oxiran-2-ylmethoxy] -iV-methylacetamide A mixture of (2S) -oxiran-2-ylmethyl 3-nitrobenzenesulfonate (37 mg, 0.143 mmol), 2- (4- hydroxy-2-methoxyphenyl) -N-methylacetamide (28 mg, 0.143 mmol) and cesium carbonate (58 mg, 0.178 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-1% methanol in CH2C12) to give the subtitle compound (21 mg).

RMN-1 !! (CDC13, 400 MHz): d 7.12 (d, J = 8.3 Hz, ÍH); 6.55 (d, "= 2.3 Hz, ÍH), 6.48 (dd, J = 2.3, 8.0 Hz, ÍH), 5.58 (s broad, ÍH), 4.26 (dd, J = 2.9, 11 Hz, 1H), 3.95 ( dd, J = . 8, 11.0 Hz, ÍH); 3.82 (s, 3H); 3.42 (s, 2H); 3.36 (m, 1H); 2. 93 (t, J = 4.7 Hz, ÍH); 2.77 (dd, J = 2.6, 4.9 Hz, ÍH); 2.74 (d, J = 4.9 Hz, 3H). APCI-MS: m / z 252 (MH +).

Step II: 2- (4- { E (2S) -3- (5-Chloro-l 'ff ^ H-spiro l-benzo uran-2,4' -piperidine] -1 '-il) -2 -hydroxypropyl] oxy.} -2-m toxyphenyl) -limetiacetamide A mixture of 5-chloro-3H-spiro [1-benzofuran-2,4'-piperidine] (16 mg, 0.071 mmol) and 2- . { 2-methoxy-4- [(2S) -oxiran-2-ylmethoxy] -W-methylacetamide (18 mg, 0.071 mmol) in ethanol (2 mL) was stirred at 80 ° C overnight. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel (0-1% methanol in CH2C12, 0.2% NH4OH) to give the title compound (20 mg).

NMR-aH (CD3OD, 400 MHz): d 7.7.13 (s, ÍH); 7.07 (d, J = 8.3 Hz, ÍH); 7.04 (dd, J = 1.9, 8.5 Hz, 1H); 6.65 (d, J = 8.5 Hz, ÍH); 6.58 (d, J = 2.2 Hz, 1H); 6.51 (dd, J = 2.2, 8.3 Hz, ÍH); 4.16-4.09 (m, 1H); 4.01 (dd, J = 4.1, 9.7 Hz, ÍH); 3.93 (dd, J = 5.8, 9.7 Hz, ÍH); 3.80 (s, 3H); 3.40 (s, 2H); 3.00 (s, 2H); 2.78-2.52 (m, 9H); 1.98-1.78 (m, 4H). APCI-MS: m / z 475 (MH +).

Example 10 Bis (trifluoroacetate) of (2S) -1- (2-amino-5-methoxyphenoxy) -3- (5-sloro-l'H / 3H-spiro [l-benzofuran-2,4'-piperidine] - 1 '-il) -propan-2-ol (salt) Step I: N- (2-Hydroxy-4-methoxy-nyl) acetamide 2-nitro-5-methoxyphenol (prepared from 3-ethoxyphenol, RJ Maleski, Synthetic Communications, 1993, 23, 343-348) (48.5 g , 0.287 mol) dissolved in THF (1.5 L) was hydrogenated at room temperature overnight with 10% palladium on carbon (10 g) until 20.3 L of hydrogen were consumed. After filtration and evaporation, the residue was suspended in degassed water (1.7 L) and acetic anhydride (42.5 mL) was added with stirring. The mixture was heated at 60 ° C for 1 hour and then cooled to room temperature. The volatiles were removed in vacuo and the solid was washed thoroughly with water and dried in vacuo to give brick-red crystals (41.7 g, 80%).

RMN-1 !! (400 MHz, CDC13): d 8.98 (s, ÍH); 7.34 (broad s, 1H); 6.81 (d, 1H); 6.58 (d, ÍH); 6.44 (dd, ÍH); 3.78 (s, 3H); 2.26 (s, 3H).

Step II: 2T-. { 4-Methoxy-2 [(2S) oxiran-2-ylmethoxy] phenyl} cetamide N- (2-hydroxy-4-methoxyphenyl) acetamide (18.12 g, 0.1 mol) and (2S) -oxiran-2-ylmethyl 3-nitrobenzenesulfonate (25.92 g, 0.1 mol) were dissolved in dry DMF (75 L) and stirred under nitrogen (N2) in an ice bath. Cesium carbonate (35.8 g, 11 mol) was added and stirring under N2 continued at room temperature overnight. The mixture was poured into ethyl acetate (1 L) and water (250 L). The organic phase was washed with water (3 x 250 mL), dried over Na 2 SO 4, filtered and concentrated in vacuo to give a crude, orange solid product. (29 g), which was recrystallized from ethanol (100 mL) and washed with ether to give white crystals. More white crystals of the mother liquor were obtained after evaporation and recrystallization of 2-propanol. Total yield 15 g (63%).

NMR-aH (CDCl 3): d 8.22 (d, 1H); 7.64 (broad s, ÍH); 6.53 (dd, ÍH); 6.50 (d, ÍH); 4.34 (dd, ÍH); 3.92 (dd, ÍH); 3.79 (s, 3H); 3.38 (m, ÍH); 2.96 (t, ÍH); 2.78 (dd, ÍH); 2.20 (s, 3H).

Step III: N- (2-. {E (2S) -3- (5-Chloro-1H, 3H-spiro [l-benzofuran-2, '-piperidin] -1' -il) -2- hydroxypropyl] oxy.} -4-methoxyphenyl.} acetamide A mixture of 5-chloro-3i? -spiro [l-benzofuran2,4'-piperidine] (200 mg, 0.894 mmol) and? t-. { 4-methoxy-2 [(2S) -oxiran-2-ylmethoxy] phenyl] acetamide (212 mg, 0.894 mmol) in ethanol (5 mL) was stirred at 80 ° C overnight. They were removed in vacuo and the residue was purified by flash chromatography on silica gel (0-2% methanol in dichloromethane, 0.2% NH4OH) to give the title compound (400 mg).

NMR-XH (CD3OD, 400 MHz): d 7.74 (d, J = 8.9 Hz, 1H); 7.13 (m, 1H); 7.04 (dd, J = 2.3, 8.5 Hz, ÍH); 6.65 (d, J = 8.5 Hz, ÍH); 6.61 (d, J = 2.7 Hz, 1H); 6.51 (dd, J = 2.7, 8.8 Hz, ÍH); 4.17 (, ÍH); 4.08 (dd, J = 3.4, 10.0 Hz, ÍH); 3.98 (dd, J = 6.3, 9.9 Hz, 1H); 3.79 (s, 3H); 3.03 (s, 2H); 2.72 (m, 4H); 2.62 (, 2H); 2.15 (s, 2H); 1.95 (m, 2H); 1.84 (, 2H). APCI-MS: m / z 461 (MH +).

Step IV: Bis (trifluoroacetate) of (2S) -1- (2-amino-5-methoxyphenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1 '-il) -propan-2-ol (salt) A solution of N- (2- { [(2S) -3- (5-chloro-l' H, 3H ~ spiro [l-benzofuran -2,4'-piperidin] -l'-yl) -2-hydroxypropyl] -oxi.} -4-methoxyphenyl) acetamide (0.23 g, 0.5 mmol) in aqueous 1M HCl (10 mL) was heated with reflux for 5 hours. The reaction mixture was then concentrated in vacuo and purified by means of HPLC to give a colorless solid (0.175 g, 54%).

NMR-1H (400 MHz, d6-DMSO): d 7.28 (s, 1H), 7.15 (dd, J = 8.5, 2. 3 Hz, 2H), 7.07 (broad s, 1H), 6.78 (d, J = 8.5 Hz, ÍH), 6.67 (s, 1H), 6.53 (d, J = 8.6 Hz, ÍH), 6.09 (s, 1H) ), 4.33 (m, 1H), 4.02 (m, 2H), 3.72 (s, 3H), 3.66-3.22 (, 6H), 3.11 (s, 2H), 2.22-1.95 (, 4H). APCI-MS: m / z 419 (MH +).

EXAMPLE 11 27- (2 { [(2S) -3- (5-Chloro-1H, 3H-Spiro Trifluoroacetate El-benzofuran-2,4'-piperidine] -1'1) -2- hydroxypropyl] oxy} 4-hydroxyphenyl) ethanesulfonamide (salt) Step I N- (2-. {E (2S) -3- (5-sloro-l'H, 3H-spiro [l-benzofuran-2 , 4 '-piperidin] -1' -yl) -2-hydroxypropyl] oxy} -4-hydroxyphenyl) asetamide To a cold (0 ° C) solution of the N- (2- { [(2S) -3- (5-chloro-1 'JJ, 3-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropyl] oxy] -4-methoxyphenyl) acetamide (cf. Example 10) (380 mg, 0.82 mmol) in dichloromethane (8 mL) was slowly added a 1M solution of boron tribromide (BBr3) in dichloromethane (2.47 mL, 2.47 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was cooled to 0 ° C and methanol (2 mL) was slowly added with stirring for 10 minutes. The volatile products were removed in vacuo. The residue was dissolved in a large volume of ethyl acetate, washed successively with an aqueous solution of sodium hydrogen carbonate (NaHCO 3) and water. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by flash chromatography on silica gel (0-3% methanol in dichloromethane, 0.2% NH40H) to give the title compound ( 155 mg).

NMR-XH (CD3OD, 400 MHz): d 7.57 (d, J = 8.7 Hz, 1H); 7.14 (m, ÍH); 7.04 (dd, J = 2.3, 8.5 Hz, 1H); 6.66 (d, J = 8.5 Hz, 1H); 6.48 (d, J = 2.5 Hz, 1H); 6.32 (dd, J = 2.5, 8.6 Hz, ÍH); 4.17 (m, ÍH); 4.06 (dd, J = 3.4, 9.8 Hz, ÍH); 3.93 (dd, J = 6.2, 9.8 Hz, 1H); 3.03 (s, 2H); 2.70 (, 4H); 2.59 (m, 2H); 2.13 (s, 3H); 1.95 (m, 2H); 1.84 (m, 2H). APCI-MS: m / z 447 (MH +).

Step II: Bis (trifluoroacetate) of 4-amino-3-. { E (2S) -3- (5-chloro-1H, 3H-spiro-l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} phenol (salt) N- (2- { [(2S) -3- (5-chloro-l '?, 3i? -spiro [1-benzofuran-2,4'-piperidin] -1'-yl ) -2-hydroxypropyl] oxy} -4-hydroxyphenyl) acetamide (135 mg, 0.3 mmol) was stirred in 1M hydrochloric acid (3 mL) at 100 ° C for 2 hours. The reaction mixture was concentrated in vacuo. After purification by means of preparative HPLC, the subtitle compound was obtained as a white amorphous solid (150 mg). 1 H-NMR (MeOH-dff, 400 MHz): d 7.21 (broad s, 1H); 7.18 (d, J = 8.8 Hz, ÍH); 7.11 (dd, J = 2.0, 8.4 Hz, 1H); 6.74 (d, J = 8.4 Hz, 1H); 6.62 (d, J = 2.4 Hz, 1H); 6.49 (dd, J = 2.4, 8.8 Hz, 1H); 4.58-4.49 (, ÍH); 4.13 (d, J = 4.8 Hz, 2H); 3.8-3.6 (m, 2H); 3.6-3.4 (m, 2H); 3.48 (d, J = 13.2 Hz, 1H); 3.45 (d, J = 13.2 Hz, 1H); 3.16 (s, 2H); 2.31-2.17 (m, 4H) APCI-MS: m / z 405 (MH +).

Step III: To a stirred solution of bis (trifluoroacetate) of 4-amino-3-. { [(2S) -3- (5-chloro-l 'i?, -3ÍÍ-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} Phenol (43 mg, 0.11 mmol) in dichloromethane (10 ml) was added pyridine (100 μl).

The mixture was cooled to 0 ° C and methanesulfonyl chloride (12 mg, 0.11 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo and purified by means of HPLC being preparative to give a colorless solid (24 mg, 37%).

RMN-1 !! (400 MHz, d &-DMSO): d 9.63 (s, ÍH), 9.53 (s broad, 1H), 8.53 (s, ÍH), 7.30 (s, 1H), 7.16 (dd, J = 8.5, 1.8 Hz , 1H), 7.05 (d, J = 8.5 Hz, ÍH), 6.79 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 2.1 Hz, ÍH), 6.37 (dd, J = 8.5, 2.4 Hz , 1H), 6.00 (s broad, ÍH), 4.34 (broad s, 1H), 3.89 (m, 2H), 3.64-3.15 (m, 8H), 3.11 (s, 1H), 2.86 (s, 3H), 2.23-2.00 (m, 4H). APCI-MS: m / z 483 (MH +).

EXAMPLE 12 N- (2 { [(2S) -3- (5-chloro-1 H, 3 H-spiro-l-benzofuran-2,4'-piperidine] -1'-yl) trifluoroacetate -hydroxypropyl] oxy.} -4-methoxyphenyl) me anosulfonamide (salt) A 'a stirred solution of (2S) -1- (2-amino-5-methoxyphenoxy) -3- (5-chloro) bis (trifluoroacetate) -l 'H, 3-spiro [1-benzofuran-2,4-piperidin] -1'-yl) propan-2-ol (65 mg, 0.1 mmol) in dichloromethane (10 ml) is added pyridine (50 μl) . The mixture was cooled to 0 ° C and methanesulfonyl chloride (11.4 mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature overnight and washed with water (10 ml). The solvent was removed in vacuo. Purification by means of the semi-preparative HPLC produced a colorless solid (9 mg, 15%).

X-NMR (400 MHz, d5-DMSO): d 9.58 (broad s, HI), 9.49 (broad s, HI), 8.63 (s, ÍH), 7.29 (s, 1H), 7.16 (m, 2H), 6.79 (, 1H), 6.62 (d, J = 2.6 Hz, ÍH), 6.54 (dd, J = 8.7, 2.5 Hz, ÍH), 6.01 (s broad, ÍH), 4.35 (s broad, ÍH), 4.05-3.89 (m, 2H), 3.75 (s, 3H), 3.67-3.15 (m, 6H), 3.10 (s, 2H), 2.87 (s, 3H), 2.24-1.95 (m, 4H). APCI-MS: m / z 497 (MH +).

Example 13 (2S) -1- (4-Bromo-2-fluorofinoxy) -3- (5-chloro-1'H, 3H-spiroEl-benzofuran-, 4'-piperidin] -1'-yl) propan- 2-ol A slurry of 4-bromo-2-fluorophenol (100 μL, 0.5 M in dimethylformamide), 3-nitrobenzene sulfonate (2S) -oxiran-2-ylmethyl (100 uL, 0.5 M in dimethylformamide) and cesium carbonate (13 mg, 0.04 mmol) was stirred at room temperature overnight and then partitioned between water and dichloromethane. The organic phase was evaporated and the crude (2S) -2 [(4-bromo-2-fluorophenoxy) methyl] oxirane, resulting, was dissolved in ethanol (400 uL) and the 5-chloro-3H-spiro [l-] was added. benzofuran-2, 4-piperidine] (100 uL, 0.5 M in dimethylformamide). The mixture was heated to reflux overnight and the solvent was evaporated. The purification was carried out on a C18 column with acetonitrile / water, 0.1% trifluoroacetic acid as the mobile phase. The pure fractions were collected, pooled and evaporated to provide the title compound as the trifluoroacetate salt. APCI-MS m / z: 471 [MH +] The following Examples 14 to 64 were prepared by methods analogous to the method described in Example 13.

Example 14 (2S) -1- < 5-Claro-l'H, 3H-spiroEl-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-ethynyl enoxi) propan-2-ol APCI-MS m / z: 398 [ MH +] Example 15 (2S) -1- (5-Chloro-1H, 3H-spiro El-benzofuran-2,4'-piperidin] -1'-yl) -3- (2,4-dichloro-3) , 5-dimethylphenoxy) propan-2-ol APCI-MS m / z: 470 [MH +] Example 16 (2S) -1- (4-Chloro-2-isoxazol-5-ylphenoxy) -3- (5-chloro- l'H, 3 H-spiroEl-ben.zofuran-2,4 '-piperidin] -1' -il) propan-2-ol APCI-MS m / z: 475 [MH +] Example 17 (4-. {E (2S) -3- (5-Chloro-l 'H, 3 H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropyl] oxy] phenyl) (phenyl) methanone APCI-MS m / z: 478 [MH +] Example 18 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2,3,4,6- t chloroform enoxi) propan-2-ol APCI-MS m / z: 510 [MH +] Example 19 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidxn] -1 '-yl) -3- (2-cyclohexyl-5-methylphenoxy) propan-2-ol APCI-MS m / z: 470 [MH +] Example 20 (2S) -1- (5-Chloro-1H, 3H-spiro-l-benzofuran-2,4'-piperidxn] -1'-yl) -3-phenoxpropan-2-ol APCI-MS m / z: 374 [MH +] Example 21 (2S) -1- (2-Bromophenoxy) -3- (5-chloro-1H, 3H-spiro-l-benzofuran-2,4'-piperidine] -1'-yl ) propan-2-ol APCI-MS m / z: 453 [MH +] Example 22 2-. { E (2S) -3- (5-Chloro-1 H, 3 H-spiro El-benzofuran-2,4'-piperidin] -1'-l) -2-hydroxypropyl] oxy} benz ldehyde APCI-MS m / z: 402 [MH +] Example 23 5-tera-Butyl-2-. { (2S) -3- (5-Chloro-1'H, 3H-spiroEl-benzofuran-2,4'-piper din] -1'-yl) -2-hydroxypropyl] oxy} benzaldehxdo APCI-MS m / z: 458 [MH +] Example 24 (2S) -1- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-piperidin] -l'-yl) -3- (1,1 ': 3', l " -terphenyl-2'-yloxy) propan-2-ol APCI-MS m / z: 526 [MH +] Example 25 l- (2- { (2S) -3- (5-Chloro-1H, 3H-spiroEl-benzofuran-2 / 4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy .}. -5-methoxy nyl) ethanone APCI-MS m / z: 446 [MH +] Example 26 1- (5-Bromo-2-. {E (2S) -3- (5-chloro-1 H, 3 H-spiro El-benzo uran-2 , 4 '-piperidine] -1' -yl) -2-hydroxypropyl] oxy} phenyl) ethanone APCI-MS m / z: 495 [MH +] Example 27 (2S) -1- (4-Chloro-2-isopropyl-5-methyl-enoxy) -3- (5-chloro-1'H, 3H-spiro [1-benzofuran-2,4'-piperidine] -1 '-il) propan-2-ol APCI-MS m / z: 464 [MH +] Example 28 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1 '-yl) -3- (2,3-dxmethyl-4-) nitrophenoxy) propan-2-ol APCI-MS m / z: 447 [MH +] Example 29 (2S) -1- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-piperidxn] -1'-yl) -3- (2,4-dichlorophenoxy) propan-2 ol APCI-MS m / z: 442 [MH +] Example 30 (2?) -3- (4- { (2S) -3- (5-Chloro-l 'H, 3 H-spiro El-benzofuran-2, 4' -pxperxdin] -1 '-il) Ethyl 2-hydroxypropyl] oxy.}. 3-methoxyphenyl) acrylic acid APCI-MS m / z: 502 [MH +] Example 31 (2S) -1- (5-Clo or-l'H, 3H-spiro [ l-benzofuran-2,4 '-piperidin] -1' -yl) -3- (2-methyl-3-nitrophenoxy) ropan-2-ol APCI-MS m / z: 433 [MH +] Example 32 5-Chloro-2-. { E (2S) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} benzaldehxdo APCI-MS m / z: 436 [MH +] Example 33 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-pxperidin] -1'-yl) -3- (2-fluorophenoxy) pepan-2 ol APCI-MS m / z: 392 [MH +] Example 34 (2S) -1- (5-Chloro-1H, 3H-spiro-l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-fluoro enoxi) ropan-2 ol APCI-MS m / z: 392 [MH +] Example 35 (2S) -1- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-piperidin] -1'-yl) -3- (4-fluorophenoxy) propan-2-ol APCI -MS m / z: 392 [MH +] Example 36 (2S) -1- (2-Chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzo-uran-2,4'-piperidin] ] -! '-il) propan-2-ol APCI-MS m / z: 408 [MH +] Example 37 (2S) -1- (3-Chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) propan-2 ol APCI-MS m / z: 408 [MH +] Example 38 (2S) -1- (4-Chloroxy) -3- (5-sloro-l 'H, 3H-spiroEl-benzofuran-2,4'-piperidin] -1'-yl) propan-2-ol APCI-MS-m / z: 408 [MH +] Example 39 (2S) -1- (3-Bromophenoxy) -3- (5-chloro-1'H, 3H-spiro [1-benzofuran-2,4'-pxperidin] -1'-yl) propan-2 ol APCI-MS m / z: 453 [MH +] Example 40 (2S) -1- (4-Bromophenoxy) -3- < 5 ~ chloro-l'H, 3H-spxro [l-benzofuran-2,4'-piperidin] -1'-yl) propan-2-ol APCI-MS m / z: 453 [MH +] Example 41 (2S) -1- (2-tert-Butyl-5-methylphenoxy) -3- (5-chloro-l'H, 3H-spiro El-benzofuran-2,4'-piperidin] -1'-yl) propan-2 ol APCI-MS m / z: 444 [MH +] Example 42 (2S) -l- (5-Chloro-1'H, 3H-spiro [l-benzofuran-2,4'-piperxdin] 1'-yl) -3- E2- (trifluoromethyl) phenoxy] propan-2 -ol APCI-MS m / z: 442 [MH +] Example 43 l- (2-. {E (2S) -3- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4 '-piperidin] -1'-yl) -2-hydroxypropyl] oxy] -4,5-dimethoxyphenyl) ethanone APCI-MS m / z: 476 [MH +] Example 44 (2S) -1- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-piperxdin] 1'-1) -3- [2,3,5,6-tetrafluoro-4 - (trxfluoromethyl) phenox] -propan-2-ol APCI-MS m / z: 514 [MH +] Example 45 (2S) -l- (4-Chloro-3-ethylphenoxy) -3- (5-sloro-l 'H, 3 H-spiro tl-benzofuran-2,4'-pxperidin] -1'-yl) propan -2-ol APCI-MS m / z: 436 [MH +] Example 46 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1 ' -yl) -3- [3- (2, 5-dimethyl-lH-pyrrol-l-yl) phenoxy] ropan-2-ol APCI-MS m / z: 467 [MH +] Example 47 (2S) -1- (5-Chloro-1H, 3H-spiro El-benzof ran-2,4'-piperidin] -1'-yl) -3- [2- (hydroxymethyl) phenoxy] propan -2-ol APCI-MS m / z: 404 [MH +] Example 48 (2S) -1- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (2-hydroxyethyl) phenoxy] propan -2-ol APCI-MS m / z: 418 [MH +] Example 49 3-. { E (2S) -3- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-pxperidin] -1'-yl) -2-hydroxypropyl] oxy} benzonxtrile APCI-MS m / z: 399 [MH +] Example 50 2-. { [(2S) -3- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4 '-pxperidin] -1' -xl) -2-hydroxypropyl] oxy} benzonitrile APCI-MS m / z: 399 [MH +] Example 51 (2S) -1- (5-Chloro-1H, 3H-spiro El-benzofuran-2,4'-piperidin] -l'-yl) - 3- (2-morpholin-4-ylphenoxy) propan-2-ol APCI-MS m / z: 459 [MH +] Example 52 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2,3-difluoro-6-) nitro enoxi) propan-2-ol APCI-MS m / z: 455 [MH +] Example 53 (2S) -1- (5-Chloro-l 'H, 3 H-spiro El-benzofuran-2,4'-piperidin] -1' -xl) -3- (2, 3, 6-trichlorofenoxi) ropan-2-ol APCI-MS m / z: 476 [MH +] Example 54 (2S) -1- (5-Chloro-1H, 3H-spiro [l-bensofuran-2,4'-pxperidin] -1 '-yl) -3- (4-fluoro-2-methoxyphenoxy) ropan-2-ol APCI-MS m / z: 422 [MH +] Example 55 5-Chloro-2-. { [(2S) -3- (5-chloro-1H, 3H-spiro El-benzof ran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxx} -3-methylbenzaldehxdo APCI-MS m / z: 450 [MH +] Example 56 (2S) -1- (5-Chloro-1H, 3 H-spiro [l-benzofuran-2,4 '-pxperidin] -1' -il) - 3- E4- (4-methylpiperidin-1-yl) -2-nxtro enoxi] propan-2-ol APCI-MS m / z: 517 [MH +] Example 57 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidxn] -1 '-yl) -3- (2,4-disloro-3, 5-dimethyl-6-nitrophenoxy) propan-2-ol APCI-MS m / z: 514 [MH +] Example 58 l- (3,5-Dichloro-2- { [(2S) -3- (5-chloro-l 'H, 3 H-spiroEl-benzofuran-2,4'-piperidine] -1' -il ) -2-hydroxypropyl] oxy} phenyl) propan-1-one APCI-MS m / z: 498 [MH +] Example 59 (2S) -l- (5-Chloro-1H, 3H-spiro-l-benzofuran-2,4'-piperxdin] -1'-yl) -3- (4-etxlfenoxy) ropan-2-ol APCI-MS m / z: 402 [MH +] Example 60 (2S) -1- (5-Chloro-1'H, 3H-spiro [l-benzofuran-2,4'-piperxdxn] -1 '-yl) -3- (2-ethyl enoxy) ropan-2 -ol APCI-MS m / z: 402 [MH +] Example 61 (2S) -1- (5-Chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl ) -3- (3-ethylphenoxy) propan-2-ol APCI-MS m / z: 402 [MH +] Example 62 (2S) -1- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-piperidine] -1 '-xl) -3- (3-morpholin-4-ylphenoxy) 2-ol APCI-MS m / z: 459 [MH +] Example 63 (2S) -1- (5-Chloro-l 'H, 3 H-spiro l-benzofuran-2,4'-piperidxn] -1'-yl) -3- E2- (5-? Aethyl-1 , 3, 4-oxadiazol-2-yl) phenoxy] propan-2-ol APCI-MS m / z: 456 [MH +] Example 64 4-. { (2S) -3- (5-Chloro-1H, 3H-spiroEl-benzofuran-2,4'-pxperidin] -1'-l) -2-hydroxypropyl] oxy} benzonitrile APCI-MS m / z: 399 [MH +] Example 65 (2S) -1- (5-chloro-1H, 3H-spiro-l-benzofuran-2,4'-piperxdxn] -1'-yl) -3- E2- (pyrrolidin-1-ylsulfonyl) phenoxy ] propan-2-ol Step I: 2- (pyrrolidin-1-ylsulfonyl) enol To a solution of 4-tert-butyl-2-methoxybenzenesulfonyl chloride (258 mg, 0.99 mmol) in DMF (6 ml) was added. pyrrolidine (70 mg, 0.99 mmol) and the solution was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was dissolved in xylene (10 ml) and then added to a mixture of A1C13 (525 mg, 3.39 mmol) in xylene (5 ml). The resulting mixture was stirred for 18 hours at 70 ° C. After cooling, the mixture was poured into ice water, stirred and extracted with ether (2 x 30 ml). The ether layer was dried over sodium sulfate, filtered and concentrated to provide 120 mg of the subtitle compound.

NMR ^ H (400 MHz, D20): d 7.64 (1H, m); 7.41 (ÍH, m); 6.95 (2H, m); 3.22 (4H, m); 1.85 (4H, m) APCI-MS m / z: 228.1 [MH +] Step II: 1- (. {2- (2R) -oxxran-2-ylmethoxy] phenxyl} sulfonyl) pyrrolidine Prepared from 2- (pyrrolidin-1-ylsulfonyl) phenol as described in Example 1 , Step 1. APCI-MS m / z: 284.2 [MH +] Step III: (2S) -1- (5-sloro-l'H, 3H-spiro El-benzofuran-2,4'-piperidin] -1 ' -yl) -3- [2- (pyrrolidin-1-ylsulfonyl) phenoxy] propan-2-ol was prepared from 1- (. {2- 2- [(2R) oxiran-2-ylmethoxy] phenyl}. sulfonyl) pyrrolidine as described in Example 1, Step 2.

NMR-XH (400 MHz, D20): d 7.83 (1H, m); 7.55 (ÍH, m); 7.16 (H, s); 7.09 (3H, m); 6.75 (ÍH, d; J = 9 Hz); 4.57 (ÍH, m); 4.18 (2H, m); 3.7 (ÍH, m); 3.59 (2H, m); 3.35 (6H,); 3.10 (1H, M); 2.33 (2H, m); 2.14 (2H, m); 1.80 (4H, m). APCI-MS m / z: 507 [MH +] Example 66 l- (2-. {E (2S) -3- (5-chloro-1H, 31? -spiroEl-benzofuran-2,4'-p perxdxn] -1'-1) -2- hidroxxpropoxx] bencil.}. imidazolin-2, 4-dione Step I: 2 - [(2S) -oxxran-2-ylmethoxy] benzaldehyde Salicylaldehyde (486 mg, 3.99 mmol) and (2S) -oxiran-2-ylmethyl 3-nitrobencenesulfonate (900 mg, 3.47 mmol) were dissolved in DMF (5 ml) and Cs2CO3 (1.28 g, 3.94 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Water (100 ml) was added and the mixture was extracted with DCM (2 x 50 ml). The combined organic extracts were washed with water (2 x 50 ml). The volatiles were removed in vacuo to provide the subtitle compound (76%, 710 mg), which was used directly in the next step. APCI-MS: m / z 179 (MH +).

Step II: 2-. { (2S) -3- (5-chloro-1H, 3H-es? Iro [l-benzo-uran-2,4'-pxperidin] 1'-yl) -2-hydroxypropyl] oxy} benzaldehxdo A mixture of 5-chloro-3i? -spiro [l-benzofuran-2,4'-piperidine] (889 mg, 3.99 mmol) and 2- [(2S) -oxiran-2-ylmethoxy] benzaldehyde (710 mg, 3.99 mmol) in EtOH (30 ml) was heated at 80 ° C for 12 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (silica gel, HC2Cl2: MeOH, 10: 1) to give the subtitle compound (60%, 933 mg) APCI-MS: m / z 402 (MH +).

Step III: N ~ (2- {E (2S) -3- (5-chloro-l ?, 3 H-spiro El-benzof ran-2, 4 '-pxperidxn] -1' -il) -2 - hydroxypropyl] oxx.} benzaldehyde) ethyl glycinate A mixture of 2-. { [(2S) -3- (5-Chloro-1'J ?, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} Benzaldehyde (933 mg, 2.41 mmol) and ethyl glycinate hydrochloride (335 mg, 2.41 mmol) and NaCNBH 4 (302 mg, 4.28 mmol) in EtOH / THF (1: 1, 30 mL) was stirred at room temperature at pH 4 (adjusted by the addition of acetic acid) for 1.5 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (silica gel, CH2Cl2: MeOH, 10: 1) to give the subtitle compound (37%, 435 mg). APCI-MS: m / z 490 (MH +).

Step IV: 1- (2- {E (2S) -3- (5-sloro-l 'H, 3H-spiro El-benzofuran-2,4'-piperidin] -1' -il) -2- hydroxypropoxy] benzyl.}. imidazoline-2,4-dione N- (2- {[[2S) -3- (5-chloro-1'2, 3ff-spiro [l-benzofuran-2, 4 ' -piperidin] -l-yl) -2-hydroxypropyl] oxy} .benzaldehyde) ethyl glycinate (435 mg, 0.89 mmol) was dissolved in 1M HCl (0.975 mL) and KOCN (109 mg, 1.33 mmol) was added. The reaction mixture was heated at 90 ° C for 10 minutes, concentrated HCl (1.11 ml) was added and the reaction mixture was heated at 100 ° C for 0.5 hours.The volatiles were removed in vacuo and the residue was purified. by flash chromatography (silica gel, CH2Cl2: MeOH, 10: 1) and HPLC to give the title compound (35%, 152 mg).

NMR-XH (400 mM acetone d6f): d 7.28-7.34 (, 2H); 6.92-7.19 (m, 4H); 6.67-6.73 (m, ÍH); 4.55-4.60 (m, 2ü); 3.95-4.5 (m, 3H); 3.80-3.85 (m, 2H); 3.05-3.15 (m, 2H); 2.65-2.85 (m, 6H); 1.56-1.95 (m, 4H). APCI-MS: m / z 486 (MH +).

Example 67 Acid (2S) -. { 2-Aloro-5- [3- (5-sloro-l'ff, 3H-spiro-l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxxpropoxx] phenoxy} Step I: (2S) -2- E (4-Aloro-3-methoxyphenoxy) methyl] oxirane The sodium nitrite (5 g) in water was added to a solution of 2-chloro-5-amino-anisole (10%). g) in sulfuric acid (3%, 50 ml) at 50 ° C. It was stirred for 1 hour and then heated to reflux for 1 hour. The solution was cooled and extracted with ethyl acetate, which was dried (Na2SO4) and concentrated in vacuo. To the resulting gum was added (2S) -oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.6 g) and cesium carbonate (2 g) in THF (10 ml) and the mixture was stirred at 50 ° C for the entire night. The mixture was concentrated, water was added and extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and the volatiles were removed in vacuo. Purification by column chromatography (ethyl acetate: isohexanes 1: 4) gave the title compound as an orange solid (0.42 g). GCMS: m / z 214 (MH +).

Step II: acid (2S) -. { 2-Aloro-5- [3- (5-chloro-l'H, 3ff-spiro [l-benzofuran ~ 2,4'-piperidine] -1'-l) -2-hydroxypropox] phenoxy} acetic A mixture of 5-chloro-3H-spiro [1-benzofuran-2,4-piperidine] (0.6 g) and (2S) -2- [(4-chloro-3-methoxyphenoxy) methyl] oxirane (1 g) in ethanol (10 mL) was stirred at 60 ° C overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography (ethyl acetate: isohexanes: ethanol, 1: 1: 0 to 20: 0: 1) to give a gum (0.6 g). The gum was dissolved in DCM (10 ml) and treated with BBr3 (1M in DCM; 2 mL) at room temperature for 1 hour. Methanol (1 ml) was added and stirred for 1 hour, then concentrated in vacuo to leave the phenol intermediate. This phenol (0.6 g) was added to a mixture of potassium carbonate (0.5 g) and methyl bromoacetate (0.24 g) in THF (10 ml) and heated to reflux for 4 hours. The mixture was cooled and methanol (10 ml) was added followed by lithium hydroxide (20 mg). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. Methanol (2 ml) was added and the mixture was filtered and the filtrate was purified by means of the reverse phase HPLC (Xterra, 75-5% aqueous ammonia gradient (0.2% aqueous) in acetonitrile) to provide the title as a white solid (49 mg).

NMR-XH (CDC13, 400 MHz): d 7.30 (d, ÍH); 7.23 (s, ÍH); 7.1 (dd, ÍH); 6.74 (d, 1H); 6.54-6.57 (, 2H); 4.71 (s, 2H); 3.90-4.02 (m, 2H); 3.82 (tt, ÍH); 3.00 (s, 2H); 2.50-2.80 (, 6H); 1.70-1.90 (m, 4H). APCI-MS: m / z 480 (M-H +) Example 68 Acid (2S) -. { 2,4-dichloro-5- [3- (5-chloro-l'ff, 32? -spiro [l-benzofuran-2,4'-piperidin] -1 '-yl) -2-hydroxypropoxy] phenoxy} acetic Step I: (2, 4-dichloro-5-hydroxyphenoxy) methyl acetate A mixture of 4,6-dichlororesorcinol (2 g), potassium carbonate (1.54 g) and methyl bromoacetate (1.71 g) in DMF (10 ml) ) was heated at 80 ° C for 24 hours. The resulting mixture was cooled and water (200 ml) was added. The solid (bis-alkylated product) was filtered, then the aqueous layer was acidified with aqueous HCl, which was extracted with ether and the organic products were dried and concentrated in vacuo. Purification by reverse phase HPLC (Xterra, 95-5% ammonia gradient (0.2% aqueous) in acetonitrile) afforded the subtitle compound (0.65 g) as a solid. APCI-MS: m / z 250 (M + H ~) Step II: Acid (2S) -. { 2,4-dichloro-5- [3 (5-chloro-l'H, JH-spiroEl-benzofuran-2,4'-piperidin] 1'-l) -2-hydroxypropoxy] phenoxy} -acetic A mixture of (2S) -oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.4 g), methyl (2,4-dichloro-5-hydroxyphenoxy) -acetate (0.39 g) and Cs2C03 (0.58 g) in DMF (2 ml) was stirred at room temperature overnight. Water was added and the methyl ester of (2,4-dichloro-5-oxiranylmethoxy-phenoxy) -acetic acid (0.22 g) was isolated by means of filtration and dried in vacuo. The 5-chloro-3? -spiro [l-benzofuran-2,4'-piperidine] (0.16 g) in ethanol (5 ml) was added and heated at 70 ° C for 2 hours. The mixture was allowed to cool and water (1 ml) was added followed by LiOH (2 equivalents). It was stirred for 3 hours. Reverse phase HPLC (Xterra, 95-5% ammonia gradient (0.2% aqueous): acetonitrile) afforded the title compound (0.1 g) as a white solid.

NMR-XH (DMSO 300 MHz) d 7.40 (s, ÍH); 7.22 (d, J = 2.1Hz, 1H); 7.09 (dd, J = 8.5, 2.3Hz, ÍH); 6.75 (d, J = 8.5Hz, ÍH); 6.64 (s, ÍH); 4.93 (s, 1H); 4.22 (s, 2H); 4.01-3.85 (m, 3H); 2.99 (s, 2H); 2.66-2.35 (m, 6H); 1.87-1.67 (m, 4H). APCI-MS: m / z 514 (M-H +) Chemistry test of THP-1 Introduction The assay measures the chemotactic response produced by the chemokine MlP-la in the monocytic cell line of human THP-1. The compounds are evaluated for their ability to suppress the chemotactic response at a standard concentration of the chemokine MlP-la.

Methods Culture of THP-1 cells Cells are thawed rapidly at 37 ° C frozen aliquots and resuspended in a 25 cm flask containing 5 ml of RPMI-1640 medium supplemented with Glutamax ™ and 10% thermally inactivated fetal bovine serum. without antibiotics (RPMI + 10% HIFCS). On day 3, the medium is discarded and replaced by a fresh medium. THP-1 cells are cultured in a normal manner in RPMI-1640 medium supplemented with 10% thermal inactivated fetal bovine serum and Glutamax ™ but without antibiotics. The optimal growth of the cells requires that they be evacuated every 3 days and that the minimum density of the subculture be 4 x 105 cells / ml.

Chemotaxis Assay The cells are removed from the flask and washed by centrifugation in RPMI + 10% HIFCS + Glutamax ™. The cells are then resuspended at 2 × 10 7 cells / ml in fresh medium (RPMI + 10% HIFCS + Glutamax ™) to which calcein-AM (5 μl of stock solution at 1 ml is added to give a final concentration of 5 × 10_dM). After gentle mixing, the cells are incubated at 37 ° C in a CO 2 incubator for 30 minutes. The cells are then diluted to 50 ml with the medium and washed twice by centrifugation at 400 x g. The labeled cells are then resuspended at a cell concentration of 1 x 10 7 cells / ml and incubated with an equal volume of MlP-la antagonist (final concentration of 10"10M to 10_6M) for 30 minutes at 37 ° C in a humidified CO 2 incubator Chemotaxis is performed using 96-well chemotaxis plates Neuroprobe ™ using 8 μm filters (no of cat 101-8) Thirty microliters of the chemoattractant supplemented with various concentrations of antagonists or vehicle is added to the bottom wells of the plate in triplicate.The filter is then carefully placed on top and, then, 25 μl of cells previously incubated with the corresponding concentration of antagonist or vehicle are added to the filter surface. The plate is then incubated for 2 hours at 37 ° C in a humidified C02 incubator. The cells that remain on the surface are then removed by adsorption and the whole silver is centrifuged at 2000 rpm for 10 minutes. The filter is then removed and the cells that have migrated to the lower wells are quantified by the fluorescence of the calcein-AM associated with the cells. Cell migration is then expressed in fluorescence units after subtraction of the reagent model and the values are standardized at% migration by comparing the fluorescence values with that of a known number of labeled cells. The effect of the antagonists is calculated as% inhibition when the number of emigrated cells is compared with the vehicle.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula characterized in that m is 0, 1, 2, 3 or 4; each R1 independently represents halogen, cyano, hydroxyl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or sulfonamido; X represents a bond, -CH2- or -O-, Y represents a bond, -CH2- or -O- and Z represents a bond -O-, -NH- or -CH2-, with the proviso that only one of X , Y and Z can represent a link at any time and with the proviso that X and Y do not represent both simultaneously -0-; n is 0, 1 or 2; each R2 independently represents halogen, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; q is 0 or 1; t is 0, 1, 2, 3, 4 or 5; each R3 independently represents halogen, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0) NRuR12,
2. -CH2NHC (0) R13, -NHS02R14, -S02NR15R16, -CH2-R17, alkylcarbonyl 1 to 6 carbon atoms, phenylcarbonyl, cycloalkyl of 3 to 6 carbon atoms or a group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, phenyl and a 5- to 10-membered, saturated or unsaturated heterocyclic ring system comprising at least one ring heteroatom selected from nitrogen, oxygen and sulfur, each group is optionally substituted by at least one substituent selected from halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and alkoxycarbonyl of 1 to 6 carbon atoms; R4, R5, Rd, R7 and R8 each independently represent hydrogen, halogen, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 6 carbon atoms; R9 and R10 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms; R11 and R12 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms or R11 and R12 together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring, which may be optionally substituted by at least one substituent selected from hydroxyl; R 13 and R 14 each independently represent hydrogen or alkyl of 1 to 6 carbon atoms; and R 15 and R each independently represent hydrogen or alkyl of 1 to 6 carbon atoms or R 15 and Rld together with the nitrogen atom to which they are attached form a heterocyclic, saturated 4- to 7-membered ring, which may be substituted optionally by at least one substituent selected from hydroxyl; R17 is a 5- to 7-membered saturated heterocyclic ring containing at least one nitrogen atom, the ring which may be optionally substituted by one or more oxo groups; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to claim 1, characterized in that X and Y have the meanings shown in the following table:
3. 3. A compound according to claim 1 or claim 2, characterized in that Z represents -0- or -CH2-.
4. 4. A compound according to any of claims 1 to 3, characterized in that q is 1.
5. 5. A compound according to any of claims 1 to 4, characterized in that m is 1 and R1 represents halogen.
6. 6. A compound according to any of claims 1 to 5, characterized in that each R3 independently represents halogen, cyano, nitro, hydroxyl, -C (0) H, -NR9R10, -CH2C (0) NR R12, ~ CH2NHC ( 0) R13, -NHS02R14, -S02NR15R16, -CH2-R17, -CH2-R17, alkylcarbonyl of 1 to 4 carbon atoms, phenylcarbonyl, cycloalkyl of 5 to 6 carbon atoms or a group selected from alkyl of 1 to 4 atoms of carbon, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclic ring system comprising one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulfur, each group being optionally substituted by one, two, three or four substituents independently selected from halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and alkoxycarbonyl of 1 to 4 carbon atoms;
7. 7. A compound according to claim 6, characterized in that the saturated or unsaturated 5-6 membered heterocyclic ring system is isoxazolyl, pyrrolyl, morpholinyl, piperidinyl or oxadiazolyl).
8. 8. A compound according to claim 1, characterized in that it is selected from: (2S) -1- (5-chloro-1-f, 3iT-spiro [1-benzofuran-2,4'-piperidin] hydrochloride] -1 '-il) -3- (2-methoxyphenoxy) propan-2-ol, 2-. { [(2S) -3- (5-chloro-l'ff, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} phenol, (2S) -1- (5-chloro-1i?, 3i? -spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (2-hydrochloride -hydroxyethoxy) -phenoxy] propan-2-ol, 2- (2 { [(2S) -3- (5-chloro-1'H, 3H-spiro [l-benzofuran-2, 4 '] trifluoroacetate -piperidine] -1 '-yl) -2-hydroxypropyl] -oxi.}. phenyl-N-methylacetamide (salt), (3S) -l- [(2- {[(2S) -3- (5 -chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropyl] oxy] phenyl) -acetyl] -pyrrolidin-3-ol, N - (2- { [(2S) -3- (5-chloro-l 'ff, 3i? -spiro [1-benzofuran-2,4'-piperidin] -1' -yl-2-hydroxypropyl] oxy .}. benzyl) acetamide, 2- (2- { [(2S) -3- (5-chloro-1-yl, 3-y-spiro [l-benzofuran-2,4'-piperidine] -1 ' -yl) -2-hydroxypropyl] oxy.} -4-methoxyphenyl) -N-ethylacetamide, 2- (2 { [(2S) -3- (5-chloro-l '/ J, 3) trifluoroacetate .ff-spiro [l-benzofuran-2,4'-piperidin] -1'yl) -2-hydroxypropyl] -oxi.} -4-hydroxyphenyl) -W-methylacetamide (salt), 2- (4- { [(2S) -3- (5-chloro-l'H, 3i-spiro [l-benzofuran-2, 4 '-piperid in] -1 'il) -2-hydroxypropyl] oxy} -2-methoxyphenyl) -N-methylacetamide, bis (trifluoroacetate) of (2S) -1- (2-amino-5-methoxyphenoxy) -3- (5-chloro-l'i?, 3i? -spiro [l- benzofuran-2,4 '-piperidine] -1' yl) propan-2-ol, N- (2 { [(2S) ~ 3 ~ (5-chloro-1 H, 3 H-spiro [trifluoroacetate]] l-benzofuran-2,4 '-piperidin] -1'-yl) -2-hydroxypropyl] -oxi.} -4-hydroxyphenyl) methanesulfonamide, trifluoroacetate of IV- (2- { [(2S) -3 - (5-chloro-l 'H, 3 H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] -oxi.} -4-methoxyphenyl) ethanesulfonamide, (2S ) -1- (-bromo-2-fluorophenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) propan-2-ol (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1' -yl) -3- (3-ethynylphenoxy) propan-2-ol , (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (2,4-dichloro-3, 5 -dimethylphenoxy) propan-2-ol, (2S) -1- (4-chloro-2-isoxazol-5-ylphenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2, 4 '-piperidine] -V -il) propan-2-o l, (4- { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy. phenyl) (phenyl) -methanone, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- ( 2,3,4,6-tetrachlorophenoxy) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3 H-spiro [l-benzofuran-2,' -piperidin] -l'-il ) -3- (2-cyclohexyl-5-methylphenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] - 1 '-yl) -3-phenoxypropan-2-ol, (2S) -1- (2-bromophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2, 4' - piperidin] -1 '-yl) propan-2-ol, 2-. { [(2S) -3- (5 ~ chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} benzaldehyde, 5-tert-butyl-2-. { [(2S) -3- (5-chloro-1H, 3H-spiro El-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} benzaldehyde, (2S) -1- (5-chloro-l 'H, 3 H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (1, 1': 3 ' , l "-terphenyl-2'-yloxy) propan-2-ol, 1- (2 { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2 , 4 '-piperidine] -1' -yl) -2-hydroxypropyl] oxy} .5-methoxyphenyl) -ethanone, 1- (5-bromo-2- { [(2S) -3- (5 -chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} phenyl) -ethanone, (2S) -1- (4 -chloro-2-isopropyl-5-methylphenoxy) -3- (5-chloro-1'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (2,3-dimethyl-4-nitrophenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (2,4-dichlorophenoxy) pepan-2 ol, (2E) -3- (4- { [(2S) -3- (5-chloro-l 'H, 3 H-spiro [1-benzofuran-2,' -piperidin] -l'-il) -2-hydroxypropyl] oxy.} - 3-methoxyphenyl) ethyl acrylate, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1 '-il) -3- (2-methyl-3-nitrophenoxy) propan-2-ol, 5-chloro-2-. { [(2S) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} -benzaldehyde, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2-fluorophenoxy) ropan-2 -ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-fluorophenoxy) propan-2 -ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (4-fluorophenoxy) propan-2 -ol, (2S) -1- (2-chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 -ol, (2S) -1- (3-chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 -ol, (2S) -1- (4-chlorophenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2, '-piperidin] -1'-yl) propan-2 ol, (2S) -1- (3-bromophenoxy) -3- (5-chloro-1'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) propan-2 ol, (2S) -1- (4-bromophenoxy) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2, '-piperidin] -1'-yl) propan-2-ol (2S) -1- (2-tert-butyl-5-methylphenoxy) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1'-yl propan-2-ol, ( 2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (trifluoromethyl) phenoxy] propan-2 ol, 1- (2-. { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} -4,5-dimethoxyphenyl) ethanone, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2 , 3, 5, 6-tetrafluoro-4- (trifluoromethyl) -phenoxy] -propan-2-ol, (2S) -1- (4-chloro-3-ethylphenoxy) -3- (5-chloro-l'H , 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran] -2, 4 '-piperidin] -l'-yl) -3- [3- (2, 5-dimethyl-lH-pyrrol-l-yl) phenoxy] ropan-2-ol, (2S) -1- ( 5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (hydroxymethyl) phenoxy] propan-2-ol, (2S) - 1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (2-hydroxyethyl) phenoxy] ropan-2-ol , 3-. { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} benzonitrile, 2-. { [(2S) -3- (5-chloro-1H, 3H-spiro [1-benzofuran-2], 4'-piperidine] -1 '-yl) -2-hydroxypropyl] oxy} benzonitrile, (2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (2-morpholin-4-ylphenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2, 3) difluoro-6-nitrophenoxy) propan-2-ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1'-yl) -3 - (2, 3, 6-trichlorophenoxy) propan-2-ol, (2S) -1- (5-chloro-l 'H, 3 H-spiro [l-benzofuran-2,4'-piperidine] -1' - il) -3- (4-fluoro-2-methoxyphenoxy) propan-2-ol, 5-chloro-2-. { [(2S) -3- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} -3-methylbenzaldehyde, (2S) -1- (5 ~ chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1' -il) -3- [4- (4- methylpiperidin-1-yl) -2-nitrophenoxy] propan-2-ol, (2S) -1- (5-chloro-1'H, 3H-spiro [l-benzofuran-2,4'-piperidine] -1 ' -yl) -3- (2,4-dichloro-3,5-dimethyl-6-nitrophenoxy) -propan-2-ol, 1- (3,5-dichloro-2- { [(2S) -3 - (5-chloro-1'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxy} phenyl) -propan-1-one, ( 2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -l'-yl) -3- (4-ethylphenoxy) propan-2-ol, ( 2S) -1- (5-chloro-l 'H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (2-ethylphenoxy) ropan-2-ol, ( 2S) -1- (5-chloro-l 'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-ethylphenoxy) propan-2-ol, ( 2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- (3-morpholin-4-ylphenoxy) propan-2 -ol, (2S) -1- (5-chloro-1H, 3H-spiro [l-benzofuran-2,4'-piperidin] -1'-lyl) -3- [2- (5-methyl- l, 3, 4-oxadiazole-2-i l) phenoxy] propan-2-ol, 4-. { [(2S) -3- (5-chloro-l 'H, 3H-spiro [1-benzofuran-2,4'-piperidin] -1'-yl) -2-hydroxypropyl] oxijbenzonitrile, (2S) -1- (5-chloro-l 'H, 3 # -spiro [l-benzofuran-2,4'-piperidin] -1'-yl) -3- [2- (pyrrolidin-1-ylsulfonyl) phenoxy] -propan-2 -ol, l- (2- { [(2S) -3- (5-chloro-1iJ, 3i? -espirotl-benzofuran-2,4'-piperidin] -1'-yl) -2- hydroxypropoxy] benzyl.}. imidazoline-2,4-dione, (2S) -. {2-chloro-5- [3- (5-chloro-1-HT, 3 H-spiro [1-benzofuran-2, '-piperidin] -1' -yl) -2-hydroxypropoxy] phenoxy] acetic acid (2S) - { 2,4-dichloro-5- [3- (5-chloro-1-yl, 3H -spiro [1-benzofuran-2,4'-piperidin] -l'-yl) -2-hydroxypropoxy] phenoxy] acetic acid, and pharmaceutically acceptable salts and solvates of any of them
9. 9. A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to claim 1, characterized in that it comprises the steps consisting of, (a) reacting r a compound of the formula wherein m, R1, n, R2, q, X, Y and Z are as defined in formula (I), with a compound of the formula wherein t, R3, R4, R5, R6, R7 and R9 are as defined in formula (I); or (b) reacting a compound of the formula wherein m, R1, n, R2, q, X, Y, Z, R4, R5, R6, R7 and R8 are as defined in formula (I), with a compound of the formula wherein t and R3 are as defined in formula (I), in the presence of a suitable base; or (c) when t is at least one and a group R3 represents -NHS02R14, reacting a compound of the formula where t 'is 0, 1, 2, 3 or 4, R3' is as defined for R3 in formula (I) different from -NHS02R14 and m, R1, n, R2, q, X, Y, Z, R4 , R5, R6, R7 and R8 are as defined in formula (I), with a compound of the formula wherein represents a leaving group and R is as defined in formula (I), in the presence of a suitable base; (d) where t is at least 1 and a group R3 represents -CH2-R17, where R17 is a heterocyclic ring, saturated from 5 to 7 members that contains 2 nitrogen atoms and the ring is substituted by two oxo groups, react a compound of the formula where t 'is 0, 1, 2, 3 or 4, R3' is as defined for R3 in formula (I) different from -CH2-R17, and m, R1, n, R2, q, X, Y, Z, R4, R5, R6, R7 and R8 are as defined in formula (I), with an alkyl glycinate in the presence of a reducing agent and subsequently with a metal isocyanate; and optionally after (a), (b) or (c), forming a pharmaceutically acceptable salt or solvate.
10. 10. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
11. 11. A process for the preparation of a pharmaceutical composition according to claim 10, characterized in that it comprises mixing a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 with a pharmaceutically acceptable adjuvant, diluent or carrier.
12. 12. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 characterized in that it is for use in therapy.
13. 13. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 in the preparation of a medicament for the treatment of diseases or conditions in humans, in the which modulates the activity of chemokine receptors. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 in the preparation of a medicament for use in the treatment of rheumatoid arthritis. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 in the preparation of a medicament for use in the treatment of pulmonary disease, obstructive , chronic 16. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8 in the preparation of a medicament for use in the treatment of asthma. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 8 in the preparation of a medicament for use in the treatment of multiple sclerosis. 18. A method for treating an inflammatory disease, characterized in that it comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof in accordance with any of the claims 1 to 8. 19. A method for treating an airway disease, characterized in that it comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any of claims 1 to 8.