ZA200106858B - Novel compounds. - Google Patents

Description

NOVEL COMPOUNDS

The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. E oo

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 characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the

NH-proximal pair of cysteine residues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and

MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1a and 1B (MIP-10. and MIP-1B).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, 33 CCR2A, CCR2B, CCR3, CCR4, CCRS5, CCR6, CCR7, CCR8, CCRY, CCR10, CXCR1,

CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

Certain piperidinyl derivatives and piperazinyl derivatives are known from U.S. Patents

Nos. 3787 419, 4 559 349 and 5 210 086 for use respectively as central nervous system depressants, antipsychotic agents and as oj-adrenoreceptor antagonists. s In accordance with the present invention, there is therefore provided a compound of general formula

R'— (Q),—T— CRRY— Wex— R* _/ Co wherein: rR! represents a C1-C3 alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C1-Cg alkoxy, C;-Cg alkylthio and

C1-Cg alkoxycarbonyl groups, or rR! represents a 3- to 10-membered saturated or unsaturated ring system which may comprise up to two ring carbon atoms that form carbonyl groups and which may comprise

Is up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one or more substituents independently selected from halogen atoms, and cyano, nitro, hydroxyl, C;-Cg alkyl, C3-Cg cycloalkyl,

C1-Cp alkoxy, C;-Cg alkoxycarbonyl, C1-Cg haloalkyl, C;-Cg haloalkoxy, NRRS,

C3-Cg cycloalkylamino, C;-Cg alkylthio, C1-Cs alkylthioC1-Cg alkyl, 2 C1-C alkylcarbonylamino, -C(O)NR'R®, sulphonamido (-SO,NHy), (d1)C;-Cg alkylsulphonamido, phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R’-substituted C1-Cg alkyl or Cy-Cg alkoxy groups; misQOorl;

Qrepresents a group OCH;, C;-C4 alkylene or C-C4 alkenylene;

T represents a group C(O)NH, or when mis 0, T may additionally represent a bond or a group NH, or when m is 1 and Q represents C1-C4 alkylene, T may additionally represent a group NH;

nis 1,2,3 or 4; each R? independently represents a hydrogen atom or a C1-Cy alky! group; each R’ independently represents a hydrogen atom or a C1-C4 alkyl group;

V represents a nitrogen atom;

W represents a nitrogen atom or a group CH;

X represents an oxygen atom or a group C(O), CH(OH), NH or N(C;-Cg alkyl), + provided that when W represents a nitrogen atom, then X represents C(O); rR? represents a phenyl group optionally substituted by one or more substituents independently selected from halogen atoms, and amino, nitro, cyano, sulphonyl (-SO3H), to sulphonamido (-SO2NHy), C1-Cg alkyl, C-Cg haloalkyl, C;-Cg haloalkoxy and c 1-Cg alkylsulphonyl groups;

Rr’ and RC each independently represent a hydrogen atom or a C1-Cg alkyl or

B® hydroxyC;-Cg alkyl group, or rR’ and RO together with the nitrogen atom to which they are _ attached form a 4- to 7-membered saturated heterocyclic ring; i R’ and R® each independently represent a hydrogen atom or a C1-Cg alkyl group; and rR’ represents a hydroxyl or NR'R® group; : with the provisos that i (a) whenmis OQ, Tis CONH, nis 2, 3 or 4 and each Rr? and Rr represents hydrogen, W is

CH, X is C(O) or CH(OH) and R! represents a substituted 3- to 10-membered unsaturated ring system, then the one or more substituents in the ring system do not include hydroxyl, halogen, C1-Cg alkoxy or C}-Cg haloalkoxy, and (b) when Wis N, X is C(O), Rr represents 3-trifluoromethylphenyl, mis O and T is a bond, then R! and (CR?R?), taken together do not represent a C1-Cg alkyl group, and (c) when W is CH, X is O, nis 2 or 3 and each R? and rR represents hydrogen, m is 0 and

Tis NH, then R! does not represent a group

NS CONH,

J or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Further, the alkyl moieties in a dialkylamino, di(hydroxyalkyl)amino or dialkylsulphonamido substituent group may be the same or different. rR! represents a C-Cj, preferably C1-Cy, alkyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from cyano, hydroxyl, C-Cg, preferably C;-Cy, alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C;-Cg, preferably C1-Cy, alkylthio (e.g. methyl-, ethyl-; propyl-, butyl-, pentyl- or hexylthio) and C;-Cg, preferably C;-Cy4, alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl) groups, or

Rr! represents a-3- to -10-membered- saturated or unsaturated ring system’ comprising up to two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms 1s independently selected from nitrogen, oxygen and sulfur, the ring system being optionally “substituted by. one or more (e.g. one, two, three or four) substituents independently selected from halogen atoms (fluorine, chlorine, bromine or iodine), and cyano, nitro, hydroxyl,

C1-Cg alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or SE hexyl), C3-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl),

Cy-Cg alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy),

C1-Cs alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C;-Cg haloalkyl (e.g. trifluoromethyl), C;-Cg haloalkoxy (e.g. trifluoromethoxy), -NR’RS, C3-Cg cycloalkylamino (cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexylamino), C;-Cg alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio), Cy-Cg alkylthioC;-Cg alkyl (e.g. methylthiomethyl),

C1-Cs alkylcarbonylamino (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylcarbonylamino), -C(O)NR'R®, sulphonamido (-SO,NH,), (d)Cy-Cg alkylsulphonamido (e.g. (di)methylsulphonamido or (di)ethylsulphonamido), phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl,

furanyl, and C(O)R’-substituted C1-Cg alkyl or C1-Cg alkoxy groups, the alkyl and alkoxy moieties being as defined above. . The 3- to 10-membered saturated or unsaturated ring system in the group rR! may be : monocyclic, or polycyclic comprising 2 or more fused rings, examples of which include { cyclobutyl, cyclopentyl, cyclohexyl, norbornylenyl, adamantyl, piperidyl, phenyl, +. haphthyl, naphthyridinyl, 1,3-benzodioxolyl, pyrazolyl, furanyl, pyridyl, thienyl, benzoxazolyl, benzothiazolyl, chromonyl, imidazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, : thiazolopyrimidinyl, pyrimidinedione, pyrazinyl, pyridazinyl, purinyl, quinoxalinyl, . thiazolyl, isothiazolyl and 2,4-dioxo-3,4-dihydro-quinazolinyl.

Preferably, R! represents a C-Cjg alkyl group optionally substituted by one or two substituents independently selected from cyano, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio - and C;-C4 alkoxycarbonyl groups, or wr R! represents a 3- to 10-membered saturated or unsaturated ring system comprising up to . two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms +. independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one, two or three substituents independently selected from halogen atoms, and cyano, nitro, hydroxyl, C1-C4 alkyl, C3-Cg cycloalkyl, C;-Cy4 alkoxy,

C1-C4 alkoxycarbonyl, C1-C3 haloalkyl, Cy-Cj haloalkoxy, NRRS,

C3-Cg cycloalkylamino, C;-Cy alkylthio, C1-Cj4 alkylthioCy-Cy alkyl,

C1-C4 alkylcarbonylamino, -C(O)NR'R®, phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R’-substituted C1-C4 alkyl -or 25. Cy-Cy4 alkoxy groups.

Preferably Q represents a group OCH, C-Cj alkylene or Cp-Cs alkenylene.

Each R? independently represents a hydrogen atom or a C-Cy alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl) group, and is especially a hydrogen atom.

Each rR independently represents a hydrogen atom or a C)-Cy4 alkyl (e.g. methyl, ethyl, propyl, isopropy! or butyl) group, and is especially a hydrogen atom.

Preferably nis 2 or 3.

X preferably represents an oxygen atom or a group C(O) or NH. rR? represents a phenyl group optionally substituted by one or more (e. g. one, two, three or four) substituents independently selected from halogen atoms (fluorine, cholorine, bromine or iodine), and amino, nitro, cyano, sulphonyl (-SO3H), sulphonamido (-SO,NH»),

C1-Cé, preferably C;-Cy, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), C1-Cg, preferably C;-Cy, haloalkyl (e.g. trifluoromethyl), C;-Csg, preferably C-Cy, haloalkoxy (e.g. trifluoromethoxy) and C 1-Cé, preferably C;-Cy, alkylsulphonyl (e.g. methyl-, ethyl-, 1s propyl, butyl-, pentyl- or hexylsulphonyl) groups.

Preferably, rR? represents a phenyl group optionally substituted by one or two halogen atoms, particularly chlorine atoms. 0 R and R® each independently represent a hydrogen atom or a C;-Cg, preferably C;-Cy, "alkyl or hydroxyC;-Cg, preferably C;-Cy, alkyl group, or rR and R® together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring. The alkyl moiety in each case may, for example, be a methyl, ethyl, propyl, butyl, pentyl or hexyl group. In the hydroxyalkyl group, the hydroxyl group may be attached to any suitable carbon atom of the alkyl moiety.

R’ and R® each independently represent a hydrogen atom or a C;-Cg, preferably C;-Cy4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) group. Preferably, R’ and R® each independently represent a hydrogen atom or a methyl group.

rR’ represents a hydroxyl or, preferably, -NR°R® group.

Examples of particularly preferred compounds of the invention include: 4-Chloro-N-{2-[4~(3,4-dichlorophenoxy)- 1-piperidinyl]ethy} }-2- [2-(dimethylamino)-2- oxoethoxy]benzamide,

N-{2-{4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-ethoxybenzamide hydrochloride, % + N-{2-[4-(3,4-Dichlorophenoxy)--piperidinyl]ethyl }-4-isopropoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl }-4-ethoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-(trifluoromethoxy)benzamide hydrochloride, oo

N-{ 2-[4-( 3,4-Dichlorophenoxy)-1-piperidinylJethy! }-4-methoxybenzamide,

Lo N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-(trifluoromethoxy)benzamide in " hydrochloride, a R N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl }-2-furamide hydrochloride, 1s N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2-phenylacetamide hydrochloride,

N -{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyllethyl } -3-methoxybenzamide hydrochloride, % 4 3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyljethyl } benzamide hydrochloride, i N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-fluorobenzamide, ~~ N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-fluorobenzamide hydrochloride,

N-{2-[4-(3 »4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-hydroxybenzamide hydrochloride,

N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinylJethyl } -3-[2-(methylamino)-2- oxoethoxy]benzamide hydrochloride, co 2-[3-{2-[4-(4-Fiuorobenzoyl)-1 -piperidinyljethyl}-2,4-dioxo-3,4-dihydro-1(2H)- quinazolinyl]-N,N-dimethylacetamide hydrochloride, to 2s N-{2-[4-(3,4-Dichlorobenzoyl)-1-piperazinyl]ethyl }-3-methoxybenzamide hydrochloride, 3,4-Dichloro-N-{2-[4-(3,4-dichlorobenzoyl)-1 -piperazinyl]ethyl }benzamide, . 4-Chloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl } -2- [2-(dimethylamino)-2- oxoethoxy]benzamide hydrochloride,

N~7~-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl Jethyl}-5-methyi[1,3]thiazolo[4,5- d]pyrimidine-2,7-diamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl} -9-methyl-9H-purin-6-amine,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-1,3-benzothiazol-2-amine,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl}ethyl}-1,3-benzoxazol-2-amine, 6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }-2-pyrazinamine, 6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl}-3-pyridazinamine, 6-({2-{4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl }amino)-1 ,3-dimethyl-2,4(1H,3H)- pyrimidinedione,

N-{1-[4-(3,4-Dichlorophenoxy)-piperidin-1 -ylmethyl]-2-methyl-propyl }-4-methyl- benzamide, hydrochloride salt,

N-{1-[4-(3,4-Dichloro-phenoxy)-piperidin-1 -ylmethyl]-2-methyl-propyl}-3-methoxy- benzamide, hydrochloride salt,

N-{2-[4-(3,4-Dichloroanilino)- 1-piperidinyl]ethyl } -3-methoxybenzamide dihydrochloride, : -N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-N-(3-methoxybenzyl)amine dihydrochloride, 3-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-6-methoxy-2,4( 1H,3H)- quinazolinedione,

N-{2-[4-(3 ,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-3-fluorobenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl}ethyl }benzamide, 4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl } benzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-methoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-methoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinylJethyl }-3-methoxybenzamide,

N-{2-{4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-nitrobenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-methylbenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl } -3-(trifluoromethyl)benzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl }-3,5-dinitrobenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-iodobenzamide, 4-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide, 4-Bromo-N-{2-{4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-methylbenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-nitrobenzamide, 3-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyljethyl } benzamide, 3,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyljethyl }benzamide,

N-{2-[4~(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-fluorobenzamide, s 24-Dichloro-N-{2-[4-(3 4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl }-3-methylbenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } -4-iodobenzamide, ~ 4-Chloro-N- {2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }-3-nitrobenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jethyl } -4-methyl-3-nitrobenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl } -2-fluoro-5- Lo (trifluoromethyl)benzamide, . N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-3-(trifluoromethox y)benzamide, . 3,5-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide, ) N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-4-(trifluoromethyl)benzamide, 3-Cyano-N-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinyl]ethyl }benzamide, . 2-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl}-5-methoxybenzamide,

PA N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethy! }-2-furamide, p 3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)- 1 -piperidinyl]ethyl }benzamide, 2-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-3,5-difluorobenzamide, 2,3-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl}benzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-2-naphthamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl }-2-(methylsulfanyl)nicotinamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-fluoro-6- : .25 (trifluoromethyl)benzamide, . N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2,4-difluorobenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl ethyl }-2-thiophenecarboxamide,

N-{2-[4-(3 4-Dichlorophenoxy)-1 -piperidinyljethyl }-2-quinoxalinecarboxamide,

Methyl 4-({2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl}amino)-4-oxobutanoate,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinylJethyl } bicycio[2.2.1]hept-5-ene-2- carboxamide,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyi]ethyl } cyclobutanecarboxamide,

N-{2-{4-(3,4-Dichlorophenoxy)- 1-piperidinylJethyl } -2-methoxyacetamide, 5s N-{2-[4-(3,4-Dichlorophenoxy)- 1 -piperidinyl]ethyl }cyclohexanecarboxamide, (E)-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } -3-phenyl-2-propenamide, 2-Chloro-N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl } nicotinamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jethyl }-2-phenylacetamide,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyljethyl } cyclopentanecarboxamide, 10 N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyljethy! }-2-phenoxyacetamide, -

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }benzamide, :

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl } -3-(trifluoromethyl)benzamide, 4-(tert-Butyl)-N-{2-[4-(4-chlorobenzoyl)- 1-piperidinyl]ethyl } benzamide,

N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }-4-methylbenzamide, 15. N-{2-{4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl } -4-nitrobenzamide,

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-3-methylbenzamide,

N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }-4-methyl-3-nitrobenzamide,

N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }-3-cyanobenzamide,

N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }-2-furamide,

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-3-nitrobenzamide,

N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }-2-naphthamide,

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-2-(methylsulfanyl)nicotinamide,

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl } -2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3- thiazole-4-carboxamide, 2s N~2~-Cyclopropyl-N~4~-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinylJethyl }-2,4- pyrimidinediamine, 2-{[4-({2-[4-(3,4-Dichlorophenoxy)- i -piperidinyl]ethyl }amin 0)-2-pyrimidinylJamino}-1- ethanol, 2-[[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } amino)-2- pyrimidinyl}j(methyl)amino]-1-ethanol,

N~4~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-N~2~-phenyl-2,4- pyrimidinediamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethy! }-2-(methylsulfanyl)-4-pyrimidinamine,

N~4~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl }-6-methyl-2 4-pyrimidinediamine, 5s N~4~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-N~2~,6-dimethyl-2,4- . - pyrimidinediamine, : w+ --2-Chloro-N~4~-cyclopropyl-N~6~-{2-[4-(3,4-dichlorophenoxy)- 1 -piperidinylJethyl }-4,6- pyrimidinediamine, :

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-phenyl-2-pyrimidinamine,

N-2~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethy] } -N~4~ N~4~ 6-trimethyl-2,4- . pyrimidinediamine, ve N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-(trifluoromethyl)-2- si pyrimidinamine, 34 N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-(propylsulfanyl)-2-pyrimidinamine, | N~2~-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-N~4~-phenyl-2,4- pyrimidinediamine, w . N~4~-Cyclopropyl-N~2~-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl }-2,4- s pyrimidinediamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }[ 1 ,8Inaphthyridin-2-amine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-4-(3-pyridinyl)-2-pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyi } -4,6-dimethoxy-2-pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } -4-(3-furyl)-2-pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jethyl } - 1-methyl- 1H-pyrazolo[3,4- : 25 d]pyrimidin-4-amine, : : N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }- | H-purin-6-amine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jethy! } -5-methylthieno[2,3-d]pyrimidin-4- amine, : N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-7-methylthieno[3,2-d] pyrimidin-4- amine,

. N-{ 2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }-2-thiophenecarboxamide,

N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl)ethyl} -2-quinoxalinecarboxamide,

N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl}bicyclo[2.2.1 Jhept-5-ene-2-carboxamide,

N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl}cyclohexanecarboxamide, 5s (E)-N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }-3-phenyl-2-propenamide,

N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }-2-phenoxyacetamide, (E)-N-{2-[4-(4-Chlorobenzoy}l)-1 -piperidinyl]ethyl } -3-(4-nitrophenyl)-2-propenamide, 2-(1-Adamantyl)-N-{ 2-{4-(4-chlorobenzoyl)-1 -piperidinyl]ethyl }acetamide, (4-Chlorophenyl)(1-{ 2-[(2-fluoro-4,5-dimethoxybenzyl)amino]ethy] }-4- piperidinyl)methanone, (4-Chlorophenyl)(1-{2-[(3 +4,5-trimethoxybenzyl)aminojethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{ 2-[(3-nitrobenzyl)amino]ethyl } -4-piperidinyl)methanone, (4-Chlorophenyl){ 1- [2-(isobutylamino)ethyl]-4-piperidinyl }methanone, 4-[({2-[4-(4-Chlorobenzoyl)-1 -piperidinyljethy}} amino)methyl]-4-ethylhexanenitrile, (4-Chlorophenyl)(1-{ 2-[(7-hydroxy-3,7-dimethyloctyl)aminoJethyl }-4- piperidinyl)methanone, (4-Chlorophenyl)[ 1-(2-{ [(6-nitro-1 .3-benzodioxol-5-yl)methylJamino }ethyl)-4- piperidinylJmethanone, [1-(2-{[(5-Chloro-1,3-dimethyl-1 H-pyrazol-4-yl)methyl}amino }ethyl)-4-piperidinyl](4- chlorophenyl)methanone, (4-Chlorophenyl)[1-(2-{ [3-nitro-4-(2-pyridinylsulfanyl)benzyl}amino yethyl)-4- piperidinyljmethanone, (4-Chlorophenyl)[1-(2-{ [(E)-3-(4-nitrophenyl)-2-propenyl}amino }ethyl)-4- piperidinyl]methanone, 2s (4-Chlorophenyl){1-[2-({ [5-(3-nitrophenyl)-2-furyl}methyl }amino)ethyl]-4- piperidinyl }methanone, (4-Chlorophenyl)[1-(2-{ [5-nitro-2-(2-pyridinylsulfanyl)benzyl amino }ethyl)-4- piperidinyljmethanone, 6-[({ 2-[4-(4-Chlorobenzoyl)-1 -piperidinylJethyl }amino)methyl]-2- (methylsulfanyhnicotinonitrile,

{1-[2-({[5-Chloro-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-ylJmethyl }amino)ethyl}-4- piperidinyl }(4-chlorophenyl)methanone, (4-Chlorophenyl)[1-(2-{ [3-(methylsulfanyl)butyl]amino} ethyl)-4-piperidinyl]Jmethanone, (4-Chlorophenyl)[1-(2-{ [(4-phenyl-4-piperidinyl)methyl]amino }ethyl)-4- piperidinyljmethanone, (4-ChlorophenyD){1-(2-{[(1-phenyl-1 H-pyrazol-5-yl)methyl]amino }ethyl)-4- ) #.. «piperidinyllmethanone,

Ethyl 3-[({2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl } - amino)methyl]cyclohexanecarboxylate, : :

N-{4-[({2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }amino)methyljphenyl J acetamide, (4-Chlorophenyl)(1-{ 2-[(2,5-difluorobenzyl)amino]ethyl }-4-piperidinyl)methanone, ine (4-Chlorophenyl)(1-{ 2-[(4-nitrobenzyl)amino]ethyl }-4-piperidinyl)methanone, #% (4-Chlorophenyl)(1-{ 2-[(2,6-dichlorobenzyl)amino]ethyl }-4-piperidinyl)methanone, % (4-Chlorophenyl)(1-{ 2-[(2-pyridinylmethyl)amino] ethyl}-4-piperidinyl)methanone, (4-Chlorophenyl)[1-(2-{ [(3-methyl-2-thienyl)methyl]amino} ethyl)-4- piperidinylJmethanone, #- (4-Chlorophenyl)(1-{2- [(3-hydroxy-4-methoxybenzyl)amino]ethyl }-4- + piperidinyl)methanone, 3-[({2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl} amino)methyl]-4H-chromen-4-one, [1-(2-{[(5-Chloro-1,3-dimethyl- 1H-pyrazol-4-yl)methyl]amino }ethyl)-4-piperidinyl](4- chlorophenyl)methanone, (4-Chlorophenyl)[1-(2-{ [(2,6-dichloro-4-pyridinyl)methylJamino }ethyl)-4- piperidinyl]methanone, (4-Chlorophenyl)[1-(2-{[(2-pheny]-1 H-imidazol-4-yl)methylJamino }ethyl)-4- =~ oo 25. piperidinyl]Jmethanone, : (4-Chlorophenyl)[1-(2-{[(5 -ethyl-2-thienyl)methyl}amino} ethyl)-4-piperidinyllmethanone, .{4-Chlorophenyl)[1-(2-{ [(2-chloro-3-quinolinyl)methyl]amino) ethyl)-4- piperidinyl}Jmethanone, Sn (4-Chlorophenyl)[1-(2-{ [(6-methyl-2-pyridinyl)methyl]amino }ethyl)-4- tr piperidinylJmethanone,

oo 14 (4-Chlorophenyl)(1-{2- [(3-quinolinylmethyl)amino]ethyl } -4-piperidinyDmethanone, 4-[({2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }Jamino)methyl]-1,5 -dimethyl-2-phenyl- 1,2-dihydro-3H-pyrazol-3-one, (4-Chlorophenyl)(1-{ 2-[(4-pyridinylmethyl)amino]ethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{ 2-[(3-hydroxy-4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{ 2-[(3,5-difluorobenzyl)amino]ethyl }-4-piperidinyl)methanone, (1-{2-[(2-Chloro-6-fluorobenzyl)amino)ethyl }-4-piperidinyl)(4-chlorophenyl)methanone, [1-(2-{[(4-Bromo-1 H-pyrazol-3-yl)methylJamino} ethyl)-4-piperidinyl}(4- chlorophenyl)methanone, : 3-[({2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl } ami no)methyl]-6,7-dimethyl-4H- chromen-4-one, : 2-{2-[( {2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }amino)methyl] -4-nitrophenoxy }acetic acid, (4-Chlorophenyl)[ 1-(2-{ [(1-methyl- IH-benzimidazol-2-yl)methyl]amino }ethyl)-4- is piperidinyl)methanone, . (4-Chlorophenyl)[ 1-(2-{ [(2,4-dimethoxy-5-pyrimidinyl)methylJamino }ethyl)-4- piperidinylJmethanone,

N-{2-[4-(3,4-Dichlorophenoxy)- 1 -piperidinyl]ethyl }-4-(methyl amino)benzamide, 4-Chloro-N-{2-[4-(3 ,4-dichlorophenoxy)-1 -piperidinyl}ethyl}-3-methoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-3-methoxy-4-methylbenzamide, 3-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl}4-methoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-1 ,3-benzodioxole-5-carbox amide, 4-Amino-N-{2-[4-(3 ,4-dichlorophenoxy)-1 -piperidinyl]ethyl}-3-methoxybenzamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl])ethyl} -3-fluoro-4-methoxybenzamide, 2s 5-Bromo-N-{ 2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl)ethyl }-2-furamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-3-methyl-2-furamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyllethyl}-4,5-dimethyl-2-furamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl }-7-ethoxy- 1-benzofuran-2- carboxamide,

IS

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-5-methoxy-1-benzofuran-2- } carboxamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-7-methoxy-1-benzofuran-2- carboxamide, 5s N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(4-fluorophenyl)acetamide, * N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(2-methoxyphenyl)acetamide, % - N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methylphenyl)acetamide, ' N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyllethyl } -2-(2-methylphenyl)acetamide, 2-(3-Bromophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } acetamide, 2-(2-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } acetamide, : 2-(4-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } acetamide, «z- N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-[2- (trifluoromethyl)phenyl]acetamide, #t 2-(3-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinylJethyl } acetamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(3,4-dimethoxyphenyl)acetamide, # N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(4-methoxyphenyl)acetamide, ¢ N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2-(3,4-dichlorophenyl)acetamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyllethyl }-2-(3-fluoro-4- methoxyphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl} -2-(4-ethoxyphenyl)acetamide, 2-(1,3-Benzodioxol-5-yl)-N-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinyl)ethyl } acetamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-[4- oe (dimethylamino)phenyl]acetamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } -2-(4-methylphenyl)acetamide, 2s N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(3,4-difluorophenyl)acetamide, . N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-2-(3-methoxyphenyl)acetamide, * ~N-{2-[{4-(3:4-Dichlorophenoxy)-1-piperidinyljethyl } -4-phenylbutanamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-3-phenylpropanamide, =~

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-(3-methoxyphenyl)propanamide, 2-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyljethyl}-1,3-thiazole-4-carboxamide,

2-(Acetylamino)-N-{2-{4-(3,4-dichlorophenoxy)- 1 -piperidinyl]ethyl }-1,3-thiazole-4- . carboxamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } -2-(4-pyridinyl)-1,3-thiazole-4- carboxamide, : 5s N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2,4-dimethyl-1,3-thiazole-5- carboxamide,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl ethyl }-2,5-dimethyl-1,3-oxazole-4- carboxamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-1H-imidazole-4-carboxamide,

N-{2-[4-(3,4-Chlorophenoxy)-1-piperidinyl]Jethyl }-3-methoxybenzamide, hydrochloride salt,

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propy!} -1-methyl-1H-pyrazolo[3,4- ) d]pyrimidin-4-amine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl Jpropyl }-2,6-dimethoxy-4-pyrimidinamine, 1s N~4~-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}propyl }-N~2~ N~2~-dimethyl-2,4- pyrimidinediamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl propyl} -2-[(methylsulfanyl)methyl}-4- pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propyl }-2-(methylsulfanyl)-6- (trifluoromethyl)-4-pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinylJpropyl }-5-methoxy-2-(methylsulfanyl)-4- pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyljpropyl }-6-methyl-2-(methylsulfanyl)-4- pyrimidinamine, 2s N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl } -5-methoxy-2-methyl-4- pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jpropyl } -2-(ethylsulfany})-6-methy}l-4- pyrimidinamine,

N~2~-Cyclopropyl-N~4~-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyllpropyl }-2,4- pyrimidinediamine,

2-{[4-({3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyi] propyl}amino)-2-pyrimidinylJamino}-1- ) ethanol, 2-[{4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }amino)-2- pyrimidinyl](methyl)amino]-1-ethanol,

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-2-(methylsulfanyl)-4- pyrimidinamine, 4 , N~4~-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-6-methyl-2,4- pyrimidinediamine,

N~4~-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl propyl } -N~2~,6-dimethyl-2,4- pyrimidinediamine, EE

N-{3-[4-(3,4-Dichiorophenoxy)-1 -piperidinyl]propyl}-4-phenyl-2-pyrimidinamine, . wy N~2~-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl}propyl }-5-fluoro-2,4-pyrimidinediamine, «. N~2~-{3-[4~(3,4-Dichiorophenoxy)-1-piperidinyl]propyl }-N~4~N ~4~,6-trimethyl-2,4- 4 pyrimidinediamine, }

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]jpropyl }-4~(trifluoromethyl)-2- pyrimidinamine, : # N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl}-4-(propylsulfanyl)-2- pyrimidinamine,

N~2~-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propyl }-N~4~-phenyl-2 4- pyrimidinediamine,

N~2~-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propyl }-N~4~,6-dimethyl-2,4- pyrimidinediamine, ’

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl}[1,8]naphthyridin-2-amine, 2-{[2-({3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl } amino)-4-pyrimidinylJamino}-1- 25 . ethanol, . 2-[[2-({3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl Jpropyl } amino)-4- SE ’ .pyrimidinyl](methyl)amino]-1-ethanol,

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl}propyl }-4-(3-pyridinyl)-2-pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propy! } -4-(3-thienyl)-2-pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-2-pyrimidinamine, oo

18 i

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl}propyl }-4,6-dimethoxy-2-pyrimidinamine, ,

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propyl }-4-(3-furyl)-2-pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-4-(2-thienyl)-2-pyrimidinamine,

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propyl }-1H-purin-6-amine,

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyljpropy! } -5-methylthieno[2,3-d] pyrimidin-4- amine,

N-{3-[4-(3.4-Dichlorophenoxy)- 1-piperidinyl}propy! }-7-methylthieno[3,2-d]pyrimidin-4- amine,

N~7~-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propy} }-5-methyl[1,3]thiazolo[4,5- d]pyrimidine-2,7-diamine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinylJpropy! } -9-methyl-9H-purin-6-amine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl propyl }-2-pyridinamine, . 5-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl }-2-pyridinamine, 6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl }-2-pyridinamine, . 1s. N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}propyl} -6-methyl-2-pyridinamine,

N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinylJpropy! }-1,3-benzothiazol-2-amine,

N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-1,3-benzoxazol-2-amine, 6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)- 1-piperidinylJpropyl }-2-pyrazinamine, 6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl }-3-pyridazinamine, 6-({3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }amino)-1,3-dimethyl-2,4(1H,3H)- pyrimidinedione,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2,6-dimethoxy-4-pyrimidinamine,

N~4~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl} -N~2~ N~2~-dimethy}-2,4- pyrimidinediamine, 2s N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl } -2-[(methylsulfanyl)methyl}-4- pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-5-methoxy-2-(methylsulfanyl)-4- pyrimidinamine,

N-{2-{4-(3,4-Dichlorophenoxy)- 1-piperidinyi}ethyl }-6-methyl-2-(methylsulfanyl)-4- pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl } -5-methoxy-2-methyl-4- pyrimidinamine, and )

N~4~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-6-methyl-N~2~-phenyl-2,4- pyrimidinediamine. . . -The present invention further provides a process for the preparation of a compound of +, ~ formula (I) which comprises (1) when T represents a group C(O)NH, reacting a compound of general formula . R'-(Q)_-coL' - B wherein L! represents a leaving group (e.g. a hydroxyl or halide, such as chloride, group) pel .and Rr! , mand Q are as defined in formula (I), with a compound of general formula ’ HN— CRF— Wx R* _/ am i 1s or an acid addition salt thereof (e.g. trifluoroacetate) wherein n, rR? R>, V,W, X and rR? i . are as defined in formula (I); or (ii) when T represents a group C(O)NH and W represents a nitrogen atom, reacting a compound of general formula

R'— (Q),—T— oR — WH — Ww wherein rR! m,Q,T,n, R?, R> and V are as defined in formula (I), with a compound of general formula

B | LAx-R* wherein L? represents a leaving group (e.g. a halogen atom) and X and rR? are as defined in formula (I); or

(iii) when T represents a group NH and m is 0, reacting a compound of general formula :

R'-1* (vp : wherein 1? represents a leaving group (e.g. a halogen atom) and R! is as defined in formula (I), with a compound of formula (I) as defined in (i) above; or (iv) when T represents a group NH, m is 1 and Q represents C1-C4 alkylene, reacting a compound of general formula

R'-(CH,),-CHO (VID wherein pis 0, 1,2 or 3 and R! is as defined in formula (I), with a compound of formula (I) as defined in (i) above; or (v) when T represents a bond and m is 0, reacting a-compound of general formula .

R-CRR, LY (vim wherein Lt represents a leaving group such as a halogen atom (e.g. chlorine) and n, R!, Rr? . 1s andR> are as defined in formula (I), with a compound of general formula iN Wer / (IX) wherein W, X and R* are as defined in formula (I); and optionally after (i), (ii), (iii), (iv) or (v) converting the compound of formula Dtoa further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).

The processes of the invention may conveniently be carried out in a solvent, €.g. an organic solvent such as dimethylformamide or dichloromethane at a temperature of, for example, 15°C or above such as a temperature in the range from 20 to 100°C.

Compounds of formula (IIT) in which W represents a nitrogen atom may be prepared by reacting a compound of general formula

HN— (CRR)—V NH 2 n \ / .

X) in which n, R?, R> and V are as defined in formula (I) with a compound of formula (V) as defined above.

Compounds of formula (X) can be prepared by reacting piperazine with a compound of general formula

H,N— (CR*R%)—L°® 2 (CR'R i XD = wherein L’ represents a halogen atom such as a bromine atom and n, rR? and rR are as defined in formula (I). ts ’ .

Compounds of formula (I) in which W represents a group CH and X represents an oxygen atom may be prepared by reacting a compound of general formula (XI in which rR? is as defined in formula (I), with a compound of formula (XI).

Compounds of formula (XII) may be prepared by reacting 4-piperidinol with a compound of general formula (XIII), rR*.om, wherein RY is as defined in formula (I), in the presence of a coupling agent such as diethyl azodicarboxylate and triphenylphosphine and in a solvent such as benzene or tetrahydrofuran at a temperature typically in the range from 20 to 30 °C.

NU ,

Compounds of formula (III) in which W represents a group CH and X represents a group

C(O) may be prepared by reacting a compound of general formula

0 w_— 4

Rv) wherein Rr is as defined in formula (I), with a compound of formula XD.

Compounds of formula (III) in which W represents a group CH and X represents a group s CH(OH) may be prepared by reducing/hydrogenating a corresponding compound of formula (IIT) in which X represents C(O) using techniques known in the art.

Compounds of formula (III) in which W represents a group CH and X represents a group

NH may be prepared by reacting a compound of general formula

H

HN N, 2 .

R XV) in which rR? is as defined in formula (I), with a compound of formula (XI).

Compounds of formula (XV) may be prepared by reacting 4-piperidone with a compound of general formula (XVI), R*-NH,, wherein rR? is as defined in formula (I), in the presence is of areducing agent such as sodium cyanoborohydride or sodium borohydride and in a solvent such as methanol or benzene at a temperature typically in the range from to 90 °C.

Compounds of formula (II) in which W represents a group CH and X represents a group 20 N(C;-Cg alkyl) may be prepared by alkylating a corresponding compound of formula (IIT) in which X represents a group NH, using techniques conventional in the art.

Compounds of formula (IV) may be prepared by reacting a compound of formula (II) with a compound of formula (X).

23 CL

Compounds of formulae II, V, VI, VII, VIII, IX, XI, XII, XIV and XVI are either commercially available, are well known in the literature or may be prepared easily using known techniques.

Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) in which rR! represents an alkoxy-substituted phenyl group can be converted to compounds of formula (I) in which rR! ” represents a hydroxy-substituted phenyl group by reaction with boron tribromide in a solvent such as dichloromethane. Further, compounds of formula (D) in which X represents

C(O) can be converted to compounds of formula (D in which X represents CH(OH) by reaction with triethylsilane and trifluoroacetic acid in a solvent such as dichloromethane.

It will be appreciated by those skilled in the art that in the processes of the present = invention certain functional groups such as hydroxyl or amino groups in the starting : reagents or intermediate compounds may need to be protected by protecting groups. Thus, ¢« the preparation of the compounds of 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. McOmie, Plenum Press (1973) and Protective

Groups in Organic Synthesis’, 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-

Interscience (1991).

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, * hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, ‘methanesulphonate or p-toluenesulphonate.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers

+ of the compounds of formula (I) and mixtures thereof including racemates. The use of i tautomers and mixtures thereof also form an aspect of the present invention.

The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR1 and/or CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).

Examples of these conditions are: (1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, ) allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis: acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and serofoulous rhinitis; seasonal rhinitis including 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 ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease,

Sjogren’s syndrome and systemic sclerosis: (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus,

Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;

.(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn’s disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., 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 7. syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; and : } . . . (6) (allograft rejection) acute and chronic following, for example, transplantation of i kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host

Br disease.

Thus, the present invention provides a compound of formula (I), or a pharmaceutically- ~~ acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. = In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture 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 construed accordingly. . The invention also provides a method of treating an inflammatory disease in a patient - suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary . with the compound employed, the mode of administration, the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (D) compound/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 %w (per cent by weight), more preferably from 0.05 to 80 Tow, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition. . "The present invention also provides a pharmaceutical composition comprising a compound } of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (D,ora pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols 2s and dry powder formulations; or systemically, e.g. 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.

Example 1 : 4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(dimethylamino)-2- oxoethoxy}benzamide cl so, “0 lo} go AT oo

HN a ci (i) tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate , Diethyl azodicarboxylate (12.6ml) was added to a solution of triphenylphosphine (20.8g) in 0 tetrahydrofuran (300ml) at 0° C. After 15 minutes 3,4-dichlorophenol (12.9g) was added, after a further 10 minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (14.5g) in tetrahydrofuran (100ml) was added dropwise over 0.5 hour. The solution was stirred at . room temperature for 5 hours and concentrated to a small volume. The residue was : a partitioned between ether and brine. The organic phase was separated, dried and 1s evaporated to a gum. Purification by chromatography (ethyl acetate : isohexane 95:5) gave the sub-titled product as an oil (20g).

MS: APCI(+ve): 246 (M-BOC+2H) (ii) 4-(3,4-Dichlorophenoxy)piperidine

The product from step (i) was dissolved in dichloromethane (200ml) and trifluoroacetic acid (100ml) was added. After 18 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (16.2g). (iii) tert-Butyl 2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethylcarbamate

The product from step (ii) (6.55g) was dissolved in DMF (50ml) and triethylamine (7.9m)) was added. tert-Butyl 2-bromoethylcarbamate (4.3 g) in DMF (5m) was added and the solution stirred at room temperature for 3 days. Ethyl acetate and water were added, the organic phase separated, dried and evaporated to a gum. Purification by chromatography (dichloromethane : methanol 95:5) gave the sub-titled product as a gum (5.7g).

MS: APCI(+ve): 389(M+H) (iv) 2-{4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethylamine trifluoroacetate

The product from step (iii) was dissolved in dichloromethane (200ml) and trifluoroacetic acid (100ml) added. After 18hrs at room temperature the solvent was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (5.72).

MS: APCI(+ve): 290(M+H) v) 2-(Dimethylamino)-2-oxoethyl 4-chloro-2-[2-(dimethylamino)-2- oxoethoxy]benzoate

A mixture of 4-chloro-2-hydroxybenzoic acid (5g), Cs,CO; (17.5 g) and 2-chloro-N,N- dimethylacetamide (6.6g) was stirred and heated at 70 °C for 3 hours. Water and ethyl acetate were added, the organic phase separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate : methanol, 9:1) to give the sub-titled product as a solid (8.0g).

MS: APCI(+ve) 343(M+H) 2s Melting point: 140-141 °C (vi) 4-Chloro-2-[2-(dimethylamino)-2-oxoethoxy}benzoic acid

The product from step (v) (1.0g) was dissolved in a 2 : 1 water : methanol mixture (15mi) and LiOH.H,0 added. After 2 hours 2M aqueous HCI solution and ethyl acetate were added, the organic phase separated, dried and concentrated to give the sub-titled product as a solid (1.2g).

MS: APCI(+ve) 258(M+H) 5s Melting point: 141-142 °C (vii) 4-Chloro-N -{2-[4-(3,4-dichlorophenoxy)-1-piperidinyllethyl}-2-[2- - (dimethylamino)-2-oxoethoxy]benzamide :

The product from step (vi) (0.3g) and N,N-carbonyldiimidazole (0.19g) were dissolved in

DMF (20ml) and the solution stirred at room temperature for 1 hour. .The product from step (iv) (0.42g) and triethylamine (0.32ml) were added. After 20 hours water and ether sw. Were added, the organic phase separated, dried and concentrated to a gum which was purified by chromatography (dichloromethane : methanol, 93:7) to give the titled product as a solid (0.38g). : MS: ESI 528.12 M+H) n NMR: (DMSO) 9.17 (t, 1H), 7.88 (d, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 7.24 (d, 1H), tec 7.13 (dd, 1H), 6.99 (dd, 1H), 5.11 (s, 2H), 4.32 (m, 1H), 3.42 (m, 2H), 2.99 (s, 3H), 2.88 (s, 3H), 2.73 (m, 2H), 2.50 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H), 1.59 (m, 2H).

Melting point: 139-40 °C

Example 2

N -(2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl}-3-ethoxybenzamide : hydrochloride cl 0

J Uns

H

~ 0 h

The product of Example 1 step (iv) (0.4g) was dissolved in DMF (10m) , PyBrop (0.541g), 3-ethoxybenzoic acid ( 0.167g ) and N,N-di-isopropylethylamine (0.5g) were added. After

18 hours at room temperature chloroform and aqueous NaHCO; solution were added. The . organic phase was separated, dried and concentrated to leave a gum which was purified by chromatography ( ethyl acetate : methanol 97:3) to give an oil. Addition of 1.0M ethereal hydrogen chloride solution gave the titled product as a solid (0.14g).

MS: ESI 437.14 (M+H) 'H NMR: §(DMSO) 8.87 (bs, 1H), 7.50 (m, 3H), 7.40 (m, 2H), 7.06 (m, 2H), 4.83 / 4.62 (m, 1H), 4.08 (q, 2H), 3.67 (m, 3H), 3.47 (m, 1H), 3.17 (m, 3H), 2.20 (m, 2H), 2.03 (m, 2H), 1.34 (t, 3H) :

Melting point: 191-193 °C

Example 3 ] : N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-d-isopropoxybenzamide

OCLs cl YL

IPN

1s Prepared by the same method as Example 2 using 4-isopropoxybenzoic acid without the ~ addition of 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid (0.12).

MS: ESI 451.14 (M+H) » IH NMR: §(DMSO) 8.22 (t, 1H), 7.8 (m, 2H), 7.49 (d, 1H), 7.25 (d, 1H), 7.00 (m, 3H), : 4.7 (m, 1H), 4.45 (m, 1H), 3.36 (m, 2H), 2.73 (m, 2H), 2.48 (m, 2H), 2.29 ( m, 2H), 1.91 (m, 2H), 1.60 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H)

Melting point: 113-15 °C 2s Example 4

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-ethoxybenzamide ci “NY ’ H oN

Prepared by the same method as Example 2 using 4-ethoxybenzoic acid without the : addition of 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid (0.1g). £5

MS: ESI437.14 (M+H) : "HNMR: (DMSO) 8.22 (t, 1H), 7.79 (d, 2H), 7.49 (d, 1H), 7.25 (d, 1H), 7.00 (m, 3H), 4.5 (m, 1H), 4.07 (q, 2H), 3.37 (q, 2H), 2.73 (m, 2H), 2.47 (m, 2H), 2.30 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H), 1.34 (t, 3H)

Melting point: 118-20 °C

Example 5

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamide hydrochloride

F

BORG UN J or al NN Oo

H

Prepared by the same method as Example 2 using 3-trifluoromethoxybenzoic acid to give the titled product as a solid (0.12g).

MS: ESI 477.09 (M+H)

HNMR: 3(DMSO) 10.42 (bs, 1H), 9.11 (bm, 1H), 8.0 (d, 1H), 7.88 (s, 1H), 7.6 (m, 3H), 7.37 (m, 1H), 7.06 (m, 1H), 4.70 (m, 1H), 3.71 (m, 3H), 3.48 (d, 1H), 3.20 (m, 4H), 2.2 (m, 4H)

Melting point: 180-82 °C 2s Example 6

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}ethyl}-4-methoxybenzamide cl o o]

XT Tl

H oo”

Prepared by the same method as Example 2 using 4-methoxybenzoic without the addition of 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid (0.11g).

MS: ES1423.12 (M+H) "HNMR: 6(DMSO) 8.42 (t, 1H), 7.81 (m, 2H), 7.49 (d, 1H), 7.25 (d, 1H), 6.98 (s, 3H), 4.4 (m,1H), 3.8 (s, 3H), 3.35 (q, 2H), 2.73 (m, 2H), 2.47 (m, 2H), 2.30 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H)

Melting point: 110-12 °C

Example 7 + N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}ethyl}-4-(trifluoromethoxy)benzamide hydrochloride ct RQ fo) ) C Ne

Cl OL ke lo

F

Prepared by the same method as Example 2 using 4-trifluoromethoxybenzoic acid to give the titled product as a solid (0.19g).

MS: ES1477 (M+H) 0 HNMR: (DMSO) 10.5 (bs, 1H), 9.06 (m, 1H), 8.07 (dd, 2H), 7.55 (t, 1H), 7.49 (d, 2H), 7.36 (dd, 1H), 7.10-7.02 (m, 1H), 4.72 (m, 1H), 3.70 (m, 3H), 3.47 (d, 1H), 3.14 (m, 2H), 2.25 (m, 2H), 2.02 (m, 2H)

Melting point: 184-187 °C 2s Example 8

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide hydrochloride

BOROPN

0)

H \ J.

Prepared by the same method as Example 2 using furan-2-carboxylic acid to give the titled . product as a solid (0.14g).

MS: ESI 383.09 (M+H)

H NMR: DMSO) 10.43 (bm, 1H), 8.76 (t, 1H), 7.87 (s, 1H), 7.55 (t, 1H), 7.36 (dd, 1H), 7.21 (d, 1H), 7.06 (m, 1H), 6.64 (dd, 1H), 4.83-4.61 (m, 1H), 3.65 (m, 3H), 3.45 (d, 1H), . 3.08 (m, 4H), 2.1 (m, 4H) : , Melting point: 225-28 °C

Example 9

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jethyl}-2-phenylacetamide hydrochloride ; cl Ne

H

Prepared by the same method as Example 2 using phenylacetic acid to give the titled product as a solid (0.12g). :

MS: ESI407 (M+H) 0 IH NMR: (DMSO) 10.28 (bm, 1H), 8.46 (bm, 1H), 7.56 (t, 1H), 7.3 (m, 6H), 7.10 (m, 1H), 4.81/4.58 (m, 1H), 3.58 (d, 1H), 3.46 (m, 4H), 3.10 (m, 4H), 2.15 (m, SH) «Melting point: 135-38 °C

Example 10 2s N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide hydrochloride

ARS eve]

Oo

The product of Example 1 step (iv) (2.0g) was dissolved in dichloromethane (490ml), triethylamine (1.85ml) and 3-methoxybenzoyl chloride (0.66g) were added. After 72 hours at room temperature, water was added, the organic phase separated, dried and concentrated 5s toagum. The product was dissolved in dichloromethane and treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.88g).

MS: ESI 423.12 (M+H) 'H NMR: 8(DMSO) 10.6-10.5 (m, 1H), 9.92 (s, 1H), 7.54 (m, 3H), 7.38 (m, 2H), ~~ 10 7.08 (m, 2H), 4.84/4.62 (m 1H), 3.82 (s, 3H), 3.45 (m, 8H), 2.27 (m, 4H).

Melting point: 72-73 °C

Example 11 3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide hydrochloride cl OL Cl 0] : Oo

The product of Example 1 step (iv) (0.15g) was dissolved in DMF (3ml), N,N-di- isopropylethylamine (0.3ml) and 3-chlorobenzoyl chloride (0.054m)) were added. After 2 hours at room temperature, water and ethyl acetate were added, the organic phase separated dried and concentrated. The residue was purified by chromatography (dichloromethane : methanol, 95:5) to give an oil which was dissolved in ether and 1.0M ethereal hydrogen chloride solution added to give the titled product as a solid (0.12g).

MS: ESI 427.07 (M+H)

'H NMR: O(DMSO0) 8.42 (t, 1H), 7.94-7.84 (m, 2H), 7.49 (d, 1H), 7.29 (m, 3H), 6.98 (dd, 1H), 4.44 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.48 (m, 2H), 2.29 (bt, 2H), 1.92 (m, 2H), 1.60 (m, 2H)

Melting point: 118 °C : 3 .. Example 12 ” N-{2-{4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl}-4-fluorobenzamide

TL $ Cl 0 . 0] * Prepared by the same method as Example 11 using 4-fluorobenzoyl chloride without the 10= - addition of 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid ~(0.1g).

MS: ESI 411.10 (M+H) 7 "HNMR: 3(DMSO) 10.46 (bs, 1H), 9.04 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.58 (m, 3H), 15- 7.36 (dd, 1H), 7.05 (m, 1H), 4.84/4.60 (m, 1H), 3.69 (m, 3H), 3.48 (bd, 1H), 3.20 (m, 4H), 2.15 (m, 4H)

Melting point: 192 °C :

Example 13

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl}-3-fluorobenzamide hydrochloride

Ls

F OL Jes 0) “ o

Prepared by the same method as Example 11 using 3-fluorobenzoyl chloride to give the titled product as a solid (0.09g). 2s MS: ESI411.10 (M+H)

8% NMR: 8(DMSO) 10.67 (bs, 1H), 9.06 (s, 1H), 7.80 (m, 2H), 7.55 (m, 2H), } 7.40 (m, 2H), 7.05 (m, 1H), 4.84/4.63(m, 1H), 3.70 (m, 3H), 3.28 (m, 3H), 2.20 (m, 4H)

Melting point: 225 °C 5s Example 14

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyllethyl}-3-hydroxybenzamide : hydrochloride

OW a aaeVes

Oo

Oo

The product of Example 10 (0.15g) was dissolved in dichloromethane (10ml) and a solution of 1.0M BBr; in dichloromethane (4ml) added. After 16 hours at room } temperature the solvent was removed by evaporation, methanol was added and the solution concentrated. The residue was dissolved in 2M aqueous HC solution, concentrated to i dryness and the residue triturated under ether to give the titled product as a solid (0.1 g). 15. MS: ESI409.10 (M+H) 'n NMR: (DMSO) 9.98-9.4 (bs, 2H), 8.71 (t, 1H), 7.6 (dd, 1H), 7.4-7.2 (m, 4H), 7.05 (m, 1H), 6.95 (dd, 1H), 4.65 (m, 1H), 3.40 (m, 8H), 2.0 (m, 4H)

Melting point: 83-4 °C

Example 15 : N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-[2-(methylamino)-2- oxoethoxylbenzamide hydrochloride

HN”

Isao SVa ot “ey 2s (i) [1-(2-Aminoethyl)-4-piperidinyl}(4-chlorophenyl)methanone trifluoroacetate

To a solution of (4-chlorophenyl)(4-piperidinyl)methanone hydrochloride (2.5g) and tert- butyl 2-bromoethylcarbamate (2.1g) in DMF was added triethylamine (2.9g), after 72 hours at room temperature water and ether were added. The organic phase was separated, dried and concentrated. The residue was dissolved in dichloromethane (40 ml), trifluoroacetic s acid (10ml) added and the solution left for 20 hours. Evaporation of the solvent gave a ~ sticky solid which was triturated under ether to give the sub-titled product as a solid (2.5g). (ii) N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-methoxybenzamide hydrochloride :

The product of step (i) (2.5g) was dissolved in dichloromethane (20ml), triethylamine (0.75ml) and 3-methoxybenzoyl chloride (0.276g) were added. After 16 hours, water was

Ge added, the organic phase separated, dried and concentrated to a gum. Purification by & . chromatography (ethyl acetate) gave a gum, which was treated with 1.OM ethereal % ,, hydrogen chloride solution to give the sub-titled product as a solid (0.3g).

MS: ES1401.16 (M+H) 'H NMR: 8(DMSO) 10.3 (bm, 1H), 8.95 (t, 1H), 8.0 (m, 2H), 7.6 (m, 2H), 7.5 (m, 2H), - - 74( 1H), 7.05 (m, 1H), 3.8 (s, 3H), 3.68 (m, 4H), 3.28 (m, 5H), 2.0 (m, 4H).

Melting point: 196-7 °C (iii) N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-hydroxybenzamide hydrochloride

Prepared by the method of Example 14 using the product of step (ii) above (0.24g) to give the sub-titled product as a solid (0.20g).

MS: ESI387.14 (M+H) 'n NMR: DMSO) 8.62 (t, 1H), 8.05 (dd, 2H), 7.6 (dd, 2H), 7.25 (m, 3H), 6.95 (m, 1H), 4.26 (m, 9H), 2.0 (m, 4H)

Melting point: 90-91 °C

(iv) N-{2-{4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-[2-(methylamino)-2- . oxoethoxylbenzamide hydrochloride

The product of step (iii) above (0.10g) was dissolved in DMF (3ml), Cs,CO; (0.23g) and 2-chloro-N-methylacetamide (0.26g) were added and the mixture heated at 80° C for 16 5s hours. The mixture was cooled to room temperature, water and ethyl acetate were added and the organic phase separated. Evaporation of the solvent gave a gum which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.0592).

MS: ESI 458.18 (M+H) 0 IH NMR: §(DMSO) 10.6-10.2 (bm, 1H), 8.95 (bm, 1H), 8.1 (m, 2H), 7.55 (m, 8H), 7.14 (bd, 1H), 4.54 (s, 2H), 4.0 (m, 1H), 3.4 (m, 8H), 2.65 (d, 3H), 2.0 (m, 4H)

Melting point: 69-70 °C }

Example 16 . 15 2-[3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H)- quinazolinyl]-N,N-dimethylacetamide hydrochloride

F. ho

ONO

YT 0 3-{2-[4-(4-Fluorobenzoyl)- 1 -piperidinyl]Jethyl}-2,4( 1H,3H)-quinazolinedione was dissolved in DMF (5ml) and NaH ( 60% dispersion in mineral oil) added. After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and the solution stirred at room temperature for 16 hours. Water and ethyl actetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane : methanol 95:5) gave an oil which was treated with 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid(0.015 g).

MS: ESI 481.22 (M+H) 'H NMR: §DMSO) 8.08 (m,3H), 7.76 (t, 1H), 7.40 (t, 2H), 7.32 (m, 2H), 5.05 (s, 2H), 4.36 (m, 1H), 3.76 (m, 3H), 3.39 (m, 2H), 3.15 (s, 3H), 2.87 (s, 3H), 2.02 (m, 2H), s 1.81 (m, 2H), 1.28 (m,2H)

Melting point: 245-246 °C

Example 17

N -{2-[4-(3,4-Dichlorobenzoyl)-1-piperazinyljethyl}-3-methoxybenzamide hydrochloride ; pps cl Nr

H

(i) tert-Butyl 2-(1-piperazinyl)ethylcarbamate

A mixture of benzaldehyde (21g) and 1-(2-aminoethyl)piperazine (25.8 g) was stirred and ¥ heated under a Dean and Stark water separator for 20 hours. The cooled solution was treated portionwise with di-tert-butyldicarbonate (48g), stirred for 72 hours and concentrated. The residue was treated with IM aqueous KHSO, solution (220ml), stirred for 24hours, ether was added and the organic phase separated. The aqueous phase was treated with 2M NaOH solution, dichloromethane was added and the organic phase separated. The combined organic phase was washed with brine, dried and concentrated to give the sub-titled product as an oil (30g).

MS: APCl(+ve ) 230( M+H) 'n NMR 8 (CDCl) 3.43 (t, 4H), 2.8 (t, 2H ), 2.45 (m, 6H), 1.5 (s, 9H). (ii) tert-Butyl 2-[4-(3,4-dichlorobenzoyl)-1-piperazinyljethylcarbamate

The product from step (i) above (3 g) was dissolved in pyridine (12ml), 3,4-dichlorobenzoyl chloride (2.05g) was added and the mixture stirred at room temperature for 18 hours. A solid was collected by filtration and purified by chromatography (dichloromethane : } methanol : 0.880 NH,OH, 90:9:1) to give the sub-titled product as an oil (3.59g).

MS: APCI(+ve ) 364( M+H) 'H NMR & (CDCl) 7.33 (m, 3H), 7.04 (m, 1H), 6.76 (bs, 1H), 3.86 (s, 3H), 3.55 (gq, 2H), 3.45 (t, 4H), 2.61 (t, 3H), 2.46 (t, 4H), 1.46 (s, 9H) (iii) [4-(2-Aminoethyl)-1-piperazinyl](3,4-dichlorophenyl)methanone trifluoroacetate

The product from step (ii) above (3.3g) was dissolved in dichloromethane (50m) and trifluoroacetic acid (10ml) added. After 16 hours at room temperature the solvent was ] removed to give the sub-titled product as an oil (5.92). .

MS: APCI(+ve ) 264( M+H) (iv) N-{2-{4-(3,4-Dichlorobenzoyl)-1-piperazinyl]ethyl}-3-methoxybenzamide hydrochloride

The product from step (iii) above (0.15g) was dissolved in pyridine (2ml) and 3-methoxybenzoyl chloride (0.064g) added. After 16 hours at room temperature, water and ethyl acetate were added, the organic phase separated, dried and concentrated to an oil.

Purification by chromatography (dichloromethane : methanol, 95:5) gave an oil which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.043g).

MS: ESI 436.12 (M+H) 'n NMR: §(DMSO) 8.8 (bt, 1H), 7.34 (m, 2H), 7.43 (m, 4H), 7.14(m, 1H), 3.82(s, 3H), 3.48 (m,12H)

Melting point: 230 °C

Example 18 3,4-Dichloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinylethyl}benzamide

Cl Cl : Q i cl (po os H : A solution of benzaldehyde (5.3g) and 1-(2-aminopiperazine) (6.45g) in toluene (100ml) was heated under a Dean and Stark water separator for 4 hours. The solution was cooled to room temperature and triethylamine (5.05g) added. A solution of 3,4-dichlorobenzoyl s chloride (10.48g) in toluene (50ml) was added dropwise, the solution stirred at room temperature for 18 hours and water added. The organic phase was separated, dried and concentrated to a residue which was treated with IN aqueous KHSO, solution (65ml). The ~ mixture was stirred vigorously for 4 hours, ether was added, the aqueous phase separated and NaOH added. CHCl; was added, the organic phase separated, dried and concentrated . 10 toa gum. Purification by chromatography (dichloromethane : triethylamine, 95:5) gave the titled product as a foam (0.25g).

MS: ESI 474.03 (M+H) y NMR: §(DMSO) 8.8 (bt, 1H), 7.34 (m, 2H), 7.43 (m, 4H), 7.14 (m, 1H), 3.82 (s, 3H), : “1s 3.48 (m, 12H) 3

Example 19 4-Chloro-N -{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}-2-[2-(dimethylamino)-2- oxoethoxy]benzamide hydrochloride pel

N

(J -" & cl

The product of Example 26 step (ii) (0.3g), 3,4-dichlorobenzoyl chloride (0.1g) and triethylamine (0.15g) were dissolved in dichloromethane (15ml). After 20 hours at room temperature water was added, the organic phase separated, dried and evaporated to give a - gum. Purification by chromatography (dichloromethane : methanol, 20:1) gave a solid which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.1g).

MS: ESI 541.11 (M+H) 'H NMR §DMSO-D6) 9.54 (t, 1H), 7.91 (d, 1H), 7.74 (m, 2H), 7.43 (m, 2H), 7.18 (d, 1H), 5.12 (s, 2H), 3.2-3.8 (m, 12H), 2.99 (s, 3H), 2.88 (s,3H).

Melting point: 226-7 °C.

Example 20

N~7~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methyl[1,3]thiazolo[4,5- } d]pyrimidine-2,7-diamine cl ea . H to} nS ars 2 ay" = 1s MS: APCI(+ve) 453 (M+1)

Example 21

N -{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl}-9-methyl-9H-purin-6-amine

CN

8 =N

HN

Ny

LL re (o} cl

MS: APCI(+ve) 421 (M+1)

Example 22

N -{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzothiazol-2-amine

Hs

N Y

ISS

@ o je ’ cl .. MS: APCI(+ve) 422 (M+1)

Example 23

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzoxazol-2-amine | °

H 0

N

Ie

N

@ cl’ 0 cl :

MS: APCI(+ve) 406 (M+1)

Example 24 6-Chloro-N -{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrazinamine

!

A ae 0

DOS cl

MS: APCI(+ve) 403 (M+1) oo

Example 25 6-Chloro-N-{2-[4-(3 4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-pyridazinamine .

ZN ci

Ar

T

® ct

MS: APCI(+ve) 403 (M+1)

Example 26 6-({2-[4-(3 4-Dichlorophenoxy)-1-piperidinylJethyl}amino)-1,3-dimethyl-2,4(1H,3H)- pyrimidinedione

NN

A

0= ™N NH

N

0

Or ci

MS: APCI(+ve) 427 (M+1) :

Example 27 ei N={ 1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl }-4-methyl- benzamide, hydrochloride

Xr ~N o

NA

(iN -{1-{4-(3,4-Dichlorophenoxy)-piperidine-1-carbonyl]-2-methyl-propyl}-acetamide

N-Boc Valine (1.13g) was dissolved in dichloromethane (5 ml) and EDC (0.99g) added, lo after 5 min the product according to Example 1 step (ii) (1.44g) in dichloromethane (5 ml) was added in one portion. After 3 hours at room temperature, aqueous sodium bicarbonate solution and ethyl acetate were added. The organic phase was separated and the solvent removed to give the sub-titled compound as an oil (1.57 8) which was used in the next step without further purification. (ii) 2-amino-1-[4-(3,4-dichlorophenoxy)-piperidine-1-yl]-3-methyl-butan-1-one

The product of step (i) (1.57 g) was dissolved in dichloromethane (14 ml) and trifluoroacetic acid (4 ml) added. After 2 hours at room temperature the solvent was removed, ethyl acetate and 2N aqueous NaOH solution were added to give pH 8.0. The organic phase was separated and concentrated to give the sub-titled product as an oil (1.24 g) which was used in the next step without further purification.

(iii) 1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl}-2-methyl-propylamine

The product of step (ii) (1.12g) was dissolved in THF (10 ml) and Borane/THF complex (22.7 ml) added. The mixture was heated under reflux for 2 hours and cooled. The solvent - was evaporated, the product dissolved in methanol (Sml) and 50% aqueous HCI solution - added. The mixture was heated to 70°C for 1 hour and cooled to room temperature. The solvent was removed, ethyl acetate and 2N aqueous NaOH solution were added to give pH 9.0. The organic phase was separated and the solvent evaporated to give the sub-titled compound as an oil (0.98 g) which used without further purification. (iv) N-{1-{4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl}-4-methyl- benzamide, hydrochloride ~The product of step (iii) (0.2g) was dissolved in.dichloromethane (5ml), triethylamine (0.126 ml) and 4-methylbenzoyl chloride (0.097 ml) were added. After 2 hours at room temperature, ethyl acetate and aqueous NaHCO; solution were added, the organic phase separated and the solvent removed to leave an oil. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH40Ac,q (0.1%) to 95%

MeCN//NH4OAc,q (0.1%)) gave a gum. Addition of 1.0M ethereal hydrogen chloride solution gave the titled product as a solid (0.104 g).

Melting point: 131-132°C

MS: ESI450 (M+H) 'H NMR: §(DMSO) 8.45 (t, 1H), 7.00-7.90 (m, TH), 4.79 (br s, 1H), 4.24-4.30 (mn, 1H), 3.10-3.42 (m, SH), 2.36 (s, 3H), 1.88-2.40 (m, 5H), 0.92 (t, 6H)

Example 28

N-{ 1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-ylmethy}]-2-methyl-propyl}-3-methoxy- benzamide, hydrochloride

Or ~~ © cl WY

The product according to Example 27 step (iii) dissolved in dichloromethane (4 ml), triethylamine (0.090 ml) and 3-methoxybenzoy! chloride (0.077 ml) were added. After 2 hours at room temperature, NaHCO; was added, the product extracted with ethyl acetate, 5. ‘the combined organic extracts dried with Na;SO, and concentrated. Purification with reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4OAc,q (0.1%) to 95%

MeCN//NH4OAc,q (0.1%)) gave a gum. The product was dissolved in methanol and treated with 1.0M ethereal Hydrogen chloride solution to give the product as a solid (0.045 g). = MS: ESI465 (M+H) git 'H NMR: §(DMSO) 8.58-8.63 (m, 1H), 7.01-7.58 (m, 6H), 4.80 (br s, 1H), 4.23-4.59 : (m, 1H), 3.83 (s, 3H), 3.04-3.60 (m, 4H), 1.89-2.14 (m, SH), 0.85 (m, 6H)

Example 29 2 N-{2-[4-(3,4-Dichloroanilino)-1-piperidinyl]ethyl}-3-methoxybenzamide dihydrochloride

QW ! o) NY) or

Oo

N

(i) tert-Butyl 4-(3,4-dichloroanilino)-1-piperidinecarboxylate

A solution of 3,4-dichloroaniline (5g), N-tert-butoxycarbonyl-4-piperidone (11 7g), sodium triacetoxyborohydride (19.7g) and acetic acid (7ml) in dichloroethane (150ml) was stirred for 16 hours. 2M NaOH solution and ether were added, the organic phase separated, dried and concentrated. The residue was triturated under an isohexane : ethyl acetate, 4:1 mixture and the sub-titled product collected as a solid (7.25g).

MS: APCI(+ve) 345 (M+H)

Claims (4)

1. A compound of general formula R'— (Q),—T— RR — Wx R* ) | / 0 wherein: R! represents a C1-Cj3 alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C;-Cg alkoxy, C;-Cg alkylthio and C1-Ce alkoxycarbonyl groups, or R! represents a 3- to 10-membered saturated or unsaturated rin g system which may comprise up to two ring carbon atoms that form carbonyl groups and which may comprise up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one or more substituents independently selected from halogen atoms, and cyano, nitro, hydroxyl, Ci-Cg alkyl, C3-Cg cycloalkyl, 1s C-Cg alkoxy, C;-C alkoxycarbonyl, C-Cg haloalkyl, C;-Cg haloalkoxy, -NR°R®, C3-Cg cycloalkylamino, C;-Cg alkylthio, C1-Cs alkylthioC-Cg alkyl, C;-Cg alkylcarbonylamino, -CCO)NR'R®, sulphonamido, (di)C-Cg alkylsulphonamido, phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R-substituted C1-Cs alkyl or C;-Cg alkoxy groups; misOorl; Q represents a group OCH,, C;-C4 alkylene or Cp-Cy4 alkenylene; T represents a group C(O)NH, or when mis 0, T may additionally represent a bond or a group NH, or when m is 1 and Q represents C1-C4 alkylene, T may additionally represent a group NH; 2s nis 1,2,3or4; each R? independently represents a hydrogen atom or a C1-C4 alkyl group; each rR independently represents a hydrogen atom or a C1-C4 alkyl group; V represents a nitrogen atom; i

W represents a nitrogen atom or a group CH; X represents an oxygen atom or a group C(O), CH(OH), NH or N(C;-Cg alkyl), provided that when W represents a nitrogen atom, then X represents C(O); rR represents a phenyl group optionally substituted by one or more substituents independently selected from halogen atoms, and amino, nitro, cyano, sulphonyl, sulphonamido, Cy-Cg alkyl, C1-Cg haloalkyl, C;-Cg haloalkoxy and C1-Cg alkylsulphonyl groups; rR’ and RS each independently represent a hydrogen atom or a C;-Cg alkyl or hydroxyC}-Cg alkyl group, or R> and RS together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R’ and R® each independently represent a hydrogen atom or a C;-Cg alkyl group; and rR’ represents a hydroxyl or NR'R® group; } with the provisos that (a whenmisO, Tis CONH, nis 2, 3 or 4 and each R? and rR? represents hydrogen, W is }

ts. CH, X is C(O) or CH(OH) and Rr! represents a substituted 3- to 10-membered unsaturated ring system, then the one or more substituents in the ring system do not include hydroxyl, halogen, C;-Cg alkoxy or C1-Ce haloalkoxy, and (b) when Wis N, X is C(O), r? represents 3-trifluoromethylphenyl, misOandTisa bond, then R! and (CR?RY), taken together do not represent a C1-Cs alkyl group, and (¢) when WisCH, X is O, n is 2 or 3 and each rR? and R® represents hydrogen, m is 0 and T is NH, then rR! does not represent a group NS CONH, J or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, wherein rR! represents a Cy-Cjq alkyl group optionally substituted by one or two substituents independently selected from cyano, hydroxyl, C;-C4 alkoxy, C;-C4 alkylthio and C1-C4 alkoxycarbonyl groups, or

R! represents a 3- to 10-membered saturated or unsaturated ring system comprising up to two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one, two or three substituents independently selected from halogen atoms, s and cyano, nitro, hydroxyl, C;-Cy4 alkyl, C3-Cg cycloalkyl, C;-C4 alkoxy, C}-C4 alkoxycarbonyl, C;-C3 haloalkyl, C1-Cj haloalkoxy, -NR°R®, C3-Cg cycloalkylamino, C1-Cy4 alkylthio, C;-Cy4 alkylthioC;-Cy4 alkyl, C-C4 alkylcarbonylamino, -C(O)NR'RS, phenyl, phenylamino, nitrophenyl, pyridyl, : pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R’-substituted C1-C4 alkyl or 10 Cy-C4 alkoxy groups. :

3. A compound according to claim 1 or claim 2, wherein m is 1 and Q represents a group OCH,, C;-Cj alkylene or C»-Cj3 alkenylene. 15 4. A compound according to any one of claims 1 to 3, wherein T represents a group - C(O)NH. : )

5. A compound according to any one of the preceding claims, wherein n is 2 or 3.

6. A compound according to any one of the preceding claims, wherein V represents a nitrogen atom and W represents a group CH. :

7. A compound according to any one of the preceding claims, wherein X represents an oxygen atom or a group C(O) or NH.

8. A compound according to any one of the preceding claims, wherein r* represents a phenyl group optionally substituted by one or two halogen atoms.

9. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 being selected from:

4-Chloro-N-{2-[4-(3 s4-dichlorophenoxy)- 1 -piperidinyl]ethyl )-2- [2-(dimethylamino)-2- . oxoethoxy]benzamide, . N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl }-3-ethoxybenzamide hydrochloride, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }4-isopropoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-4-ethoxybenzamide, N-{ 2-[4-(3,4-Dichlorophenoxy)- I-piperidinyl]ethyl} -3-(trifluoromethoxy)benzamide . hydrochloride, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl)ethyl }-4-methoxybenzamide, . N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-(trifluoromethoxy)benzamide

10 . hydrochloride, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-furamide hydrochloride, N-{2-[4~(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-phenylacetamide hydrochloride, . N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinylJethyl }-3-methoxybenzamide hydrochloride, 3-Chloro-N-{ 2-[4-(3,4-dichlorophenoxy)-1 -piperidinyljethyl }benzamide hydrochloride, 1s N-{ 2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-fluorobenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-3-fluorobenzamide hydrochloride, . N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl}-3-hydroxybenzamide hydrochloride, - N-{2-[4-(4-Chlorobenzoy})-1 -piperidinyljethyl }-3-[2-(methylamino)-2- oxoethoxy]benzamide hydrochloride, 2-[3-{ 2-[4-(4-Fluorobenzoyl)-1 -piperidinyl]ethyl }-2,4-dioxo-3,4-dihydro-1 (2H)- quinazolinyl]-N,N-dimethylacetamide hydrochloride, N-{2-[4-(3 »4-Dichlorobenzoyl)-1 -piperazinyljethyl }-3-methoxybenzamide hydrochloride, 3,4-Dichloro-N-{2- [4-(3,4-dichlorobenzoyl)-1 -piperazinyl]ethyl }benzamide, 4-Chloro-N-{2- [4-(3,4-dichlorobenzoyl)-1 -piperazinyljethyl }-2-[2-(dimethylamino)-2- 25s oxoethoxy]benzamide hydrochloride, N~7~-{2-[4-(3 ;4-Dichlorophenoxy)-1 -piperidinyl}ethyl }-5 -methyl[1,3]thiazolo[4,5- d}pyrimidine-2,7-diamine, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-9-methyl-9H-purin-6-amine, N-{2-[4-(3 ,4-Dichlorophenoxy)- 1 -piperidinyljethyl}-1 ,3-benzothiazol-2-amine, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-1 ,3-benzoxazol-2-amine,

6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinyljethyl }-2-pyrazinamine, 6-Chloro-N-{2-[4-(3 ,A-dichlorophenoxy)- 1-piperidinyl]ethyl }-3-pyridazinamine, 6-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }amino)- 1,3-dimethyl-2,4(1H,3H)- pyrimidinedione, : N-{1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl } -4-methyl- benzamide, hydrochloride salt, : N-{1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl }-3-methoxy- * benzamide, hydrochloride salt, N-{2-[4-(3,4-Dichloroanilino)-1-piperidinyl]ethyl }-3-methoxybenzamide dihydrochloride, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-N-(3-methoxybenzyl)amine dihydrochloride, : > 3-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}ethyl }-6-methoxy-2,4(1H,3H)- ’ quinazolinedione,

. N-{2-{4-(3,4-Dichlorophenoxy)-1-piperidinyl}jethyl }-3-fluorobenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }benzamide, 4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } benzamide, oe : N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-4-methoxybenzamide, ’ N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-methoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}ethyl }-3-methoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-nitrobenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-2-methylbenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-(trifluoromethyl)benzamide, N-{2-{4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3,5-dinitrobenzamide, N-{2-[4-(34-Dichlorophenoxy)-1-piperidinylJethyl }-2-iodobenzamide, 4-Cyano-N-{2-[4-(3,4-dichlorophenoxy)- 1 -piperidinyljethyl }benzamide, 4-Bromo-N-{2- [4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } benzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-methylbenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-4-nitrobenzamide, 3-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyljethyl } benzamide, 3,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyllethyl }benzamide,

- N-{2-[4-(3.4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-4-fluorobenzamide, . 2,4-Dichloro-N-{ 2-[4-(3,4-dichlorophenoxy)- 1-piperidinyl]ethyl }benzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-3-methylbenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-iodobenzamide, 4-Chloro-N-{2-[4-(3 s4-dichlorophenoxy)-1 -piperidinyl]ethyl }-3-nitrobenzamide, - N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-methyl-3-nitrobenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-2-fluoro-5- * (trifluoromethyl)benzamide, . N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl} ~3~(trifluoromethoxy)benzamide, 3,5-Dichloro-N-{2-[4-(3 ,4-dichlorophenoxy)-1-piperidinyl] ethyl }benzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-4-(trifluoromethyl)benzamide, 3-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1 -piperidinyljethyl }benzamide, } 2-Bromo-N-{2-[4-(3 ,4-dichlorophenoxy)-1 -piperidinyl]ethyl} -5-methoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-2-furamide, }

15. 3-Chloro-N-{ 2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide, 2-Chloro-N-{ 2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl }benzamide, - N-{2-{4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-3,5-difluorobenzamide, . 2,3-Dichloro-N-{ 2-[4-(3,4-dichlorophenoxy)-1 -piperidinyljethyl }benzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl}-2-naphthamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl} -2-(methylsulfanyl)nicotinamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-fluoro-6- (trifluoromethyl)benzamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyljethyl }-2,4-difluorobenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-thiophenecarboxamide, 2s N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl} -2-quinoxalinecarboxamide, Methyl 4-({ 2-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]ethyl} amino)-4-oxobutanoate, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }bicyclo[2.2. 1Jhept-5-ene-2- carboxamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }cyclobutanecarboxamide, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-2-methoxyacetamide,

N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }cyclohexanecarboxamide, (E)-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-phenyl-2-propenamide, 2-Chloro-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]Jethyl } nicotinamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-2-phenylacetamide, : 5s N- {2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }cyclopentanecarboxamide, : N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2-phenoxyacetamide, N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }benzamide, N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl } -3-(trifluoromethyl)benzamide, 4-(tert-Butyl)-N-{2-[4-(4-chlorobenzoyl)- 1-piperidinyl]ethyl } benzamide, N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-4-methylbenzamide, oe N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl } -4-nitrobenzamide, .. N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-3-methylbenzamide,

4. N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl } -4-methyl-3-nitrobenzamide, , N-{ 2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl}-3-cyanobenzamide, : N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl }-2-furamide, : N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-nitrobenzamide, - # N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-2-naphthamide, : 7 N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl ethyl }-2-(methylsulfanyl nicotinamide, N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3- thiazole-4-carboxamide, N~2~-Cyclopropyl-N~4~-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinyl ethyl }-2,4- pyrimidinediamine, i : 2-{[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }amino)-2-pyrimidinyl Jamino}-1- ethanol, 2s 2-[[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }Jamino)-2- SE pyrimidinyl](methyl)amino]-1-ethanol, : N~4~-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-N~2~-phenyl-2,4- pyrimidinediamine, : ~ N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl}ethyl } -2-(methylsulfanyl)-4-pyrimidinamine, N~4~-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl } -6-methyl-2,4-pyrimidinediamine, i

162 i N~4~-{2-[4-(3,4-Dichiorophenoxy)-1 -piperidinyl]ethyl}-N~2~,6-dimethyl-2,4- pyrimidinediamine, 2-Chloro-N~4~-cyclopropyl-N~6~-{2-[4-(3 ;4-dichlorophenoxy)-1 -piperidinyl]ethyl }-4,6- pyrimidinediamine, 5s N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl } -4-phenyl-2-pyrimidinamine, N~2~-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyllethyl}-N~4~ N~4~,6-trimethyl-2,4- . pyrimidinediamine, ~ N-{2-[4-(3 4-Dichlorophenoxy)-1 -piperidinyl]ethyl} -4-(trifluoromethyl)-2- pyrimidinamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl} -4-(propylsulfanyl)-2-pyrimidinamine, N~2~-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-N~4~-phenyl-2,4- pyrimidinediamine, . N~4~-Cyclopropyl-N~2~-{2-[4-(3 ,4-dichlorophenoxy)-1 -piperidinyl}ethyl }-2,4- pyrimidinediamine,

N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}[1 ,8Inaphthyridin-2-amine, N-({2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyljethyl } -4-(3-pyridinyl)-2-pyrimidinamine, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-2-pyrimidinamine, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]jethyl } -4,6-dimethoxy-2-pyrimidinamine, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-4-(3-furyl)-2-pyrimidinamine,

N-{ 2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyllethyl }- 1 H-purin-6-amine, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-5-methylthieno[2,3-d]pyrimidin-4- amine,

2s N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-7-methylthienof3,2-d]pyrimidin-4- amine, N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }-2-thiophenecarboxamide, N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethy] }-2-quinoxalinecarboxamide, N-{2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl}bicyclo[2.2. 1]hept-5-ene-2-carboxamide,

N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethy} }cyclohexanecarboxamide,

(E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-3-phenyl-2-propenamide, N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }-2-phenoxyacetamide, (E)-N-{2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl} -3-(4-nitrophenyl)-2-propenamide, 2-(1-Adamantyl)-N-{2-[4-(4-chlorobenzoyl)- 1 -piperidinyljethyl }acetamide, (4-Chlorophenyl)(1-{ 2-[(2-fluoro-4,5-dimethoxybenzyl)amino]ethyl }-4-

piperidinyl)methanone, oe

{(4-Chlorophenyl)(1-{ 2-[(3,4,5-trimethoxybenzyl)amino]ethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{2-[(3-nitrobenzyl)amino]ethyl }-4-piperidinyl)methanone,

(4-Chlorophenyl){ 1-[2-(isobutylamino)ethyl]-4-piperidinyl }methanone,

4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyllethyl} amino)methyl}-4-ethylhexanenitrile, (4-Chlorophenyl)(1-{2-[ (7-hydroxy-3,7-dimethyloctyl)amino]ethyl }-4- piperidinyl)methanone,

«+ (4-Chlorophenyl)[1-(2-{[(6-nitro-1 ,3-benzodioxol-5-yl)methyljamino) ethyl)-4- piperidinylJmethanone,

[1-(2-{[(5-Chloro-1,3-dimethyl-1 H-pyrazol-4-yl)methyl]Jamino} ethyl)-4-piperidinyl](4-

- chlorophenyl)methanone,

; (4-Chlorophenyl)[1-(2-{ [3-nitro-4-(2-pyridinylsulfanyl)benzylJamino }ethyl)-4-

, piperidinyljmethanone, (4-Chlorophenyl)[1-(2-{ [(E)-3-(4-nitrophenyl)-2-propenylJamino }ethyl)-4-

piperidinyl]methanone,

(4-Chlorophenyl){ 1-[2-({ [5-(3-nitrophenyl)-2-furyljmethyl } amino)ethyl]-4- piperidinyl }methanone, 0 (4-Chlorophenyl)[1-(2-{ [5-nitro-2-(2-pyridinylsulfanyl)benzyllamino }ethyl)-4- piperidinyljmethanone,

6-[({2-[4-(4-Chlorobenzoyl)- 1-piperidinyl]ethyl } amino)methyl]-2- ° (methylsulfanyl)nicotinonitrile, oo {1-[2-({[5-Chloro-1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl]methyl} amino)ethyl]-4- piperidinyl} (4-chlorophenyl)methanone, (4-Chlorophenyl)[1-(2-{[3-(methylsulfanyl)butyl}amino} ethyl)-4-piperidinyllmethanone,

164 x (4-Chlorophenyl)[1-(2-{ [(4-phenyl-4-piperidinyl)methyljamino }ethyl)-4- . piperidinylJmethanone, (4-Chlorophenyl)[1-(2-{[(1-phenyl-1 H-pyrazol-S-yl)methylJamino } ethyl)-4- piperidinyl}methanone, 5s Ethyl 3-[({ 2-[4-(4-chlorobenzoyl)-1 -piperidinyl]ethyl}- amino)methyl]cyclohexanecarboxylate, . N-{4-[({2-[4-(4-Chlorobenzoy])-1 -piperidinyl]ethyl }amino)methyl] phenyl }acetamide, (4-Chlorophenyl)(1-{ 2-[(2,5-difluorobenzyl)amino]ethyl} -4-piperidinyl)methanone, . (4-Chlorophenyl)(1-{ 2-{(4-nitrobenzyl)aminojethy] }-4-piperidinyl)methanone,

(4-Chlorophenyl)(1-{ 2-[(2,6-dichlorobenzyl)amino]ethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{ 2-[(2-pyridinylmethyl)amino]ethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)[1-(2-{ [(3-methyl-2-thienyl)methyl] amino }ethyl)-4- R piperidinyl]Jmethanone, (4-Chlorophenyl)(i-{ 2-[(3-hydroxy-4-methoxybenzyl)amino]ethyl }-4- .

piperidinyl)methanone, - 3-[({2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl} amino)methyl}-4H-chromen-4-one, . [1-(2-{[(5-Chloro-1,3-dimethyl-1 H-pyrazol-4-yl)methyl}amino }ethyl)-4-piperidinyl}(4- . Chlorophenyl)methanone, (4-Chlorophenyl)[1-(2-{ [(2,6-dichloro-4-pyridinyl)methyl]amino }ethyl)-4- piperidinylJmethanone, (4-Chlorophenyl)[1-(2-{ [(2-phenyl-1 H-imidazol-4-y)methyl)amino }ethyl)-4- piperidinylJmethanone, (4-Chlorophenyl)[1-(2-{ [(5-ethyl-2-thienyl)methylJamino }ethyl)-4-piperidinyl}methanone, (4-Chlorophenyl)[1-(2-{ [(2-chloro-3-quinolinyl)methyl] amino }ethyl)-4- 2s piperidinyl]Jmethanone, (4-Chlorophenyl)[1-(2-{ [(6-methyl-2-pyridinyl)methyl]amino }ethyl)-4- piperidinylJmethanone, (4-Chlorophenyl)(1-{2- [(3-quinolinylmethyl)aminojethyl }-4-piperidinyl)methanone, 4-[({2-[4-(4-Chlorobenzoyl)-1 -piperidinyl]ethyl }amino)methyl]-1 ,3-dimethyl-2-phenyl- 1,2-dihydro-3H-pyrazol-3-one,

(4-Chlorophenyl)(1-{2-[(4-pyridinylmethyl)amino]ethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{2-[(3-hydroxy-4-nitrobenzyl)amino]ethyl }-4-piperidinyl)methanone, (4-Chlorophenyl)(1-{2- [3 ,5-difluorobenzyl)amino]ethyl }-4-piperidinyl)methanone, (1-{2-[(2-Chloro-6-fluorobenzyl)amino]ethyl }-4-piperidinyl)(4-chlorophenyl)methanone, 5s [1-(2-{[(4-Bromo-1H-pyrazol-3-yl)methyl]amino} ethyl)-4-piperidinyl}(4- chlorophenyl)methanone, 3-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl }amino)methyl]-6,7-dimethyl-4H- chromen-4-one, 2-{2-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyljethyl} amino)methyl]-4-nitrophenoxy } acetic acid, _ . a : (4-Chlorophenyl)[1-(2-{ [(1-methyl-1 H-benzimidazol-2-yl)methyl}amino} ethyl)-4- ; piperidinyljmethanone, (4-Chloropheny)[1-(2-{[(2,4-dimethoxy-5-pyrimidinyl)methylJamino }ethyl)-4- : piperidinyljmethanone, oo

15. N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-4-(methylamino)benzamide, 4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl }-3-methoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl } -3-methoxy-4-methylbenzamide, 3-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl }-4-methoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl }-1,3-benzodioxole-5-carboxamide, 4-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl }-3-methoxybenzamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3 -fluoro-4-methoxybenzamide, 5-Bromo-N-{2-[4-(3,4-dichlorophenoxy)- 1-piperidinyl]ethyl }-2-furamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl }-3-methyl-2-furamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-4,5-dimethyl-2-furamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-7-ethoxy-1-benzofuran-2- carboxamide, - : : ’ N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-5-methoxy-1-benzofuran-2- carboxamide, N-{2-[4-(3,4-Dichiorophenoxy)-1-piperidinyl]ethyl }-7-methoxy-1-benzofuran-2- carboxamide, Co

" N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(4-fluorophenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(2-methoxyphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(3-methylphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-I-piperidinyl]ethyl }-2-(2-methylphenyl)acetamide, : 2-(3-Bromophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } acetamide, 2-(2-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]jethyl } acetamide, 2-(4-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl } acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyllethyl }-2-[2- (trifluoromethyl)phenyl]acetamide, : 2-(3-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinylJethyl } acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(3,4-dimethoxyphenyl)acetamide,

. N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(4-methoxyphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyljethyl }-2-(3,4-dichlorophenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(3-fluoro-4- methoxyphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(4-ethoxyphenyl)acetamide, 2-(1,3-Benzodioxol-5-yl)-N-{2-[4-(3 A4-dichlorophenoxy)- 1-piperidinyl}ethyl }acetamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2-[4- (dimethylamino)phenyl]acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(4-methylphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyllethyl } -2-(3,4-difluorophenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl }-2-(3-methoxyphenyl)acetamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]jethyl } -4-phenylbutanamide, N-{2-[4-(3.4-Dichlorophenoxy)-1-piperidinyl]ethyl }-3-phenylpropanamide, 2s N-{2-[4-(3,4-Dichlorophenoxy)-i-piperidinyl]ethyl } -3-(3-methoxyphenyl)propanamide, 2-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl }-1,3-thiazole-4-carboxamide, 2-(Acetylamino)-N-{2-[4-(3,4-dichlorophenoxy)--piperidinyllethyl }-1,3-thiazole-4- carboxamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyljethyi }-2-(4-pyridinyl)-1,3-thiazole-4- carboxamide,

N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl}ethyl }-2,4-dimethyl-1,3-thiazole-5- carboxamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-2,5-dimethyl-1,3-oxazole-4- carboxamide, N-{2-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]ethyl }-1 H-imidazole-4-carboxamide, N-{2-[4-(3,4-Chlorophenoxy)-1-piperidinyl]ethyl } -3-methoxybenzamide, hydrochloride salt, N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl propyl }- 1-methyl- 1H-pyrazolo[3,4- d]pyrimidin-4-amine, N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-2,6-dimethoxy-4-pyrimidinamine, N~4~-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-N~2~,N~2~-dimethyl-2,4-

_.. pyrimidinediamine,

5. N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-2-[(methylsulfanyl)methyl]-4- + pyrimidinamine, : :

15s. N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl propyl }-2-(methylsulfanyl)-6- (trifluoromethyl)-4-pyrimidinamine, : N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-5-methoxy-2-(methylsulfanyl)-4- - pyrimidinamine, N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-6-methyl-2-(methylsulfanyl)-4- pyrimidinamine, N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl Jpropyl }-5-methoxy-2-methyl-4- pyrimidinamine, Se N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }-2-(ethylsulfanyl)-6-methyl-4- pyrimidinamine, N~2~-Cyclopropyl-N~4~-{ 3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl }-2,4- : : pyrimidinediamine, . 2-{[4-({3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl}propyl }amino)-2-pyrimidinylJamino }-1- ethanol, 2-[[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl }amino)-2- So Co pyrimidinyl](methyl)amino]-1-ethanol,

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-2-(methylsulfanyl)-4- : pyrimidinamine, N~4~-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-6-methyl-2,4- oo pyrimidinediamine, N~4~-{3-[4-(3 ;4-Dichlorophenoxy)-1 -piperidinyl]propyl }-N ~2~,6-dimethyl-2 4- pyrimidinediamine, N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-4-phenyl-2-pyrimidinamine, N~2~-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-5-fluoro-2,4-pyrimidinediamine, N=~2~-{ 3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-N ~4~N~4~ 6-trimethyl-2,4- pyrimidinediamine, N-{ 3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-4-(trifluoromethyt)-2- pyrimidinamine, . N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-4-(propylsulfanyl)-2- pyrimidinamine, N~2~-{3-[4-(3 ;/4-Dichlorophenoxy)-1 -piperidinyl]propyl } -N~4~-phenyl-2,4- pyrimidinediamine, N~2~-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl}-N ~4~,6-dimethyl-2,4- pyrimidinediamine, N-{3-[4-(3,4-Dichlorophenoxy)- 1 -piperidinyl]propyl }[1 ,8]naphthyridin-2-amine, 2-{[2-({3-[4-(3 »4-Dichlorophenoxy)-1 -piperidinyl]propyl} amino)-4-pyrimidinylJamino}-1- ethanol, 2-[[2-({3-[4-(3 ,4-Dichlorophenoxy)-1 -piperidinyl]propyl }amino)-4- pyrimidinyl]}(methyl)amino]-1-ethanol, N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl}propyl }-4-(3-pyridinyl)-2-pyrimidinamine, 2s N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinylipropyl} -4~(3-thienyl)-2-pyrimidinamine, N-{3-[4-(3,4-Dichlorophenoxy)- | -piperidinyl]propyl } -2-pyrimidinamine, N-{3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propy} }-4,6-dimethoxy-2-pyrimidinamine, N-{ 3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-4-(3-furyl)-2-pyrimidinamine, N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-4-(2-thienyl)-2-pyrimidinamine, N-{ 3-[4~(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl}-1 H-purin-6-amine,

N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-5-methylthieno[2,3-d]pyrimidin-4- amine, N-{3-[4-(3.4-Dichlorophenoxy)-1 -piperidinyljpropy! }-7-methylthieno[3,2-d)pyrimidin-4- "amine, N~7~-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-5-methyl[ 1,3]thiazolo[4,5- djpyrimidine-2,7-diamine, N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-9-methyl-9H-purin-6-amine, CN- {3-[4-(3,4-Dichlorophenoxy)- 1-piperidinyl]propyl }-2-pyridinamine, 5-Chloro-N-{3-[4-(3,4-dichlorophenoxy)- 1-piperidinyl]propyl}-2-pyridinamine, 6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1 -piperidinyl]propyl}-2-pyridinamine, N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl }-6-methyl-2-pyridinamine, N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl}-1,3-benzothiazol-2-amine,

. N-{3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]}propyl}-1,3-benzoxazol-2-amine, 6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)- 1-piperidinyl]propyl}-2-pyrazinamine, 6-Chloro-N-(3-{4-(3,4-dichlorophenoxy)- 1-piperidinylJpropyl }-3-pyridazinamine. 6-({3-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]propyl}amino)-1,3-dimethyl-2,4(1 H,3H)- pyrimidinedione, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-2,6-dimethoxy-4-pyrimidinamine, N~4~-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-N~2~,N~2~-dimethyl-2,4- pyrimidinediamine, N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl } -2-[(methylsulfanyl)methyl]-4- pyrimidinamine, N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinylJethyl } -5-methoxy-2-(methylsulfany)-4- pyrimidinamine, 2s N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl }-6-methyl-2-(methylsulfanyl)-4- pyrimidinamine, : N-{2-[4-(3,4-Dichlorophenoxy)-1 -piperidinylJethyl}-5-methoxy-2-methyl-4- pyrimidinamine, and N~4~-{2-{4-(3,4-Dichlorophenoxy)-1 -piperidinyl]ethyl}-6-methyl-N~2~-phenyl-2 4- pyrimidinediamine.

10. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises (1) when T represents a group C(O)NH, reacting a compound of general formula R'-(Q),,-coL’ Im (In ‘wherein L! represents a leaving group (e.g. a hydroxyl or halide, such as chloride, group) and rR! m and Q are as defined in formula (I), with a compound of general formula / HN— (CR*R)—V ~~ W—x—R* _/ (Im or an acid addition salt thereof (e.g. trifluoroacetate) wherein n, RZ, R>, V,W, X and rR? are as defined in formula (I); or (1) when T represents a group C(O)NH and W represents a nitrogen atom, reacting a

15. compound of general formula /\ R'— (Q,—T— (CRR)—V NH Iv) wherein rR, m,Q,T,n, R?, R> and V are as defined in formula (D, with a compound of general formula L2-x-rR* wm wherein L2 represents a leaving group (e.g. a halogen atom) and X and R* are as defined in formula (I); or (iit) when T represents a group NH and m is 0, reacting a compound of general formula R'-L> (vp wherein 1} represents a leaving group (e.g. a halogen atom) and Rr! is as defined in formula (I), with a compound of formula (ill) as defined in (i) above; or

(iv) when T represents a group NH, mis 1 and Q represents C1-Cy alkylene, reacting a compound of general formula R'-(CH,),-CHO VID whereinpis0, 1,2 or3 and rR! is as defined in formula (I), with a compound of formula (III) as defined in (i) above; or (v) when T represents a bond and m is 0, reacting a compound of general formula : R-(CRRY,1* (vip wherein L? represents a leaving group such as a halogen atom (e.g. chlorine) and n, rR , rR? ’ and R° are as defined in formula (I), with a compound of general formula aN W ~x—R* / (X) wherein W, X and rR? are as defined in formula (I); and optionally after (i), (ii), (iii), (iv) or (v) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).

11. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. A process for the preparation of a pharmaceutical composition as claimed in claim 11 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 with a pharmaceutically acceptable adjuvant, diluent or carrier.

PCT/SE00/00563

13. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 for use in therapy.

14. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in the manufacture of a medicament for use in therapy.

15. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.

16. A substance or composition for use in a method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.

17. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 9 in the manufacture of a medicament for use in asthma.

18. A compound as claimed in claim 1 or claim 9, substantially as herein described and illustrated.

19. A process as claimed in claim 10 or claim 12, substantially as herein described and illustrated.

20. A composition as claimed in claim 11, substantially as herein described and illustrated.

21. A compound for use in therapy as claimed in claim 13, substantially as herein described and illustrated. AMENDED SHEET

PCT/SE00/00563

22. Use as claimed in claim 14 or claim 15 or claim 17, substantially as herein described and illustrated.

23. A substance or composition for use in a method of treatment as claimed in claim 16, substantially as herein described and illustrated.

24. A new compound. a new process for producing a compound or a composition, a new use of a compound of formula (I) as defined in any one of claims 1 to 9, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET