ZA200209904B - Novel compounds. - Google Patents

Description

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NOVEL COMPOUNDS

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

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins 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 1p (MIP-1o and MIP-1p). . 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,

CCR2A, CCR2B, CCR3, CCR4, CCRS, CCR6, CCR7, CCR8, CCRY, CCR10, CXCRI, . 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.

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In accordance with the present invention, there is therefore provided a compound of general formula

RL NT R 5 R J

NG Pd SON) ~< AR

SE on a son ~ @ s wherein mis 0, 1,2o0r3; each R' independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

C3-Cg cycloalkyl, C;-Cg alkoxy, C;-Cq alkoxycarbonyl, C,-Cg4 haloalkyl,

C-Cg¢ haloalkoxy, NERY, C;3-Cg cycloalkylamino, C;-C alkylthio, 10 C;-Cg alkylcarbonyl, C;-Cgq alkylcarbonylamino, sulphonamido (-SO,NH,),

C,-Cg alkylsulphonyl, -C(O)NR''R'?, -NR"C(0)-(NH),R", phenyl, or C;-Cq alkyl optionally substituted by carboxyi or C;-Cg alkoxycarbonyi; pisUorl;

Zz! represents a bond or a group (CH,), where q is 1 or 2; 7? represents a bond or a group CH,, with the proviso that 7! and Z* do not both simultaneously represent a bond;

Q represents an oxygen or sulphur atom or a group CH, or NH;

R? represents a group

RY

Ten nis 0,1 or2; ‘ each R independently represents a C-Cg alkyl, C;-C¢ alkoxycarbonyl, -CH,OH or - carboxyl group;

RY, R’, R® and R” each independently represent a hydrogen atom or a C;-Cg alkyl group, Or R?, Rr, R® and R’ together represent a C|-C, alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R’, R® and R” each represent a hydrogen atom and R* and R® together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle; , r® represents a hydrogen atom, a Cy-Cg alkyl group or is linked to R* as defined s above;

R® and R' each independently represent a hydrogen atom or a C;-Cg alkyl group, or

R’ and rR" together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;

R'! and R'? each independently represent a hydrogen atom or a C;-Cg alkyl group to optionally substituted by C;-C¢ alkoxycarbonyl; rR" represents a hydrogen stom or a C;-Cg alkyl group; rR" represents a hydrogen atom, or a C;-Cg¢ alkyl group optionally substituted by carboxyl, C,-Cg alkoxy or C,-C¢ alkoxycarbonyl;

RY represents carboxyl, C;-Cg4 alkoxy, C,-Cg alkylcarbonyl, C;-Cg4 alkoxycarbonyl, 1s C;-Cg alkoxycarbonylC,-Cg alkyl ora group -NR''R'®, -NIISO,CH;, -C(ONR''R"S,

NHC(O)NR'"R'®, -0C(O)NR''R'®, -OCH,C(O)NR''R'®, -NHC(O)OR' or

NHC(O)R*’; tis 0,1, 2 or 3; each R!® independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

C3-Cg cycloalkyl, C,-Cg alkoxy, C;-Cg4 alkoxycarbonyl, C,-Cg4 haloalkyl,

C,-Cg haloalkoxy, -NR*'R*?, C3-C¢ cycloalkylamino, C,-Cj alkylthio,

C,-Cg alkylcarbonyl, C-Cq alkylcarbonylamino, sulphonamido (-SO,NH,),

C,-Cg alkylsulphonyl, -C(O)NRZR**, -NR*C(O)(NH),R?S, phenyl, or C;-C; alkyl optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl;

R'” and R'® each independently represent a hydrogen atom, or a C,-Cg alkyl group . optionally substituted by carboxyl or C,-Cg4 alkoxycarbonyl, or R!7 and R"® together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated ’ heterocycle; rR" represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl,

/ N

RY represents a group C-Cq alkyl, C,-Cq alkenyl, C;3-Cq cycloalkyl, adamantyl,

Cs5-Cg cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents ‘ independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C;-C alkyl,

Ci-Cg alkoxy, C,-Cg alkylthio, C-Cg alkylcarbonyl, C-C, alkoxycarbonyl, phenyl! and _NHC(0)-R*’;

R*' and R** each independently represent a hydrogen atom or a C;-Cyg alkyl group, or

R*! and R* together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;

R™ and R* each independently represent a hydrogen atom or a C-Cg alkyl group optionally substituted by C,-Cg alkoxycarbonyl; visOor 1; n> represents a hydrogen atom or 2 C=C alkyl aroun:

R% represents a hydrogen atom. or a C;-Cg alkyl group optionally substituted by carboxyl, C,-Cq alkoxy or C;-C alkoxycarbonyl; and

RY’ represents a C,-Cg alkyl, amino (-NH,) or phenyl group; 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. When R’ and R'° (or R' and R'E, or R*! and R%) represent a saturated heterocycle, it should be understood that the only heteroatom present is the nitrogen atom to which R’ and R'? (or R'7 and R'E, or R? and rR) are attached. In the definition of rR, it should be noted that the saturated or unsaturated 5- to 2s 10-membered heterocyclic ring system may be aliphatic or aromatic.

The integer m is preferably 1 or 2.

Each R' independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C;-C¢ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C;-Cg, preferably C;-C,, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C,-Cg, preferably C,-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C;-Cg, preferably C;-Cy, haloalkyl (e.g. trifluoromethyl), . C,-Cg, preferably C,-C,, haloalkoxy (e.g. trifluoromethoxy), NR°R'?, 5s C3-Cg cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C;-Cg, preferably C;-C,, alkylthio (e.g. methylthio or ethylthio),

C,-Cq, preferably C,-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C,-Cg, preferably C;-C,, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,

C.-C, preferably C;-C,, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR''R'%, -NR"C(0)-(NH),R", phenyl, or

C,-C, preferably C;-C,, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or C;-Cg, preferably

C,-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).

Most preferably, each R' independently represents halogen (particularly chlorine or fluorine), cyano, nitro, C;-Cg alkoxy (especially methoxy), C;-Cg alkylcarbonyl (especially methylcarbonyl) or C,-Cg alkylcarbonylamino (particularly methylcarbonylamino). Each R' especially represents a halogen atom.

Q preferably represents an oxygen atom. 2» EachR’ independently represents a C;-Cg, preferably C,-Cy, alkyl (e.g. methyl, ethyl, . n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-penty! or n-hexyl), C,-C, preferably

C,-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), -CH,OH or carboxyl group. It is preferred that rR’ represents a methyl, methoxycarbonyl, ethoxycarbonyl, -CH,OH or carboxy! group.

RY, R’, R® and R” each independently represent a hydrogen atom or a C,-Cg, preferably

C,-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or RY, Rr’, Rand R’ together represent a C;-C, alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle ‘ s {e.g cyclohexyl! or preferably cyclopentyl), or R’, R® and R7 each represent a hydrogen atom and R” and R® together with the carbon atoms tc which they are attached form a 5- to 6-membered saturated carbocycle (preferably cyclopentyl).

R® represents a hydrogen atom, a Cy-Cg, preferably C,-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to R* as defined above.

R® and R'? each independently represent a hydrogen atom or a C,-Cg, preferably

C.-C, alkyl oromn (eo methyl ethyl n-propyl isopropyl, n-butyl, isobutyl, tert-butyl, n-pentvl or n-hexyl), or R’ and R'° together with the nitrogen atom to which they are attached form a 4- to 7-itnembered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).

R'! and R'? each independently represent a hydrogen atom or a C;-Cg, preferably

C;-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C,-Cg, preferably C;-C,, alkoxycarbonyl substituent group. rR" represents a hydrogen atom or a C;-Cg, preferably C,-C,, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

RY represents a hydrogen atom, or a C;-Cg, preferably C,-C,, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl, C;-Cg, preferably C;-Cy, alkoxy or C,-Cg, preferably

C,-C4, alkoxycarbonyl.

RY represents carboxyl, C;-Cg, preferably C;-C,, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C-Cg, preferably C,-C,, alkylcarbonyl (e.g. methylcarbonyl, ‘ ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or 5s n-hexylcarbonyl), C;-Cq, preferably C,-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C;-Cg alkoxycarbonylC;-Cg alkyl, preferably

C,-C, alkoxycarbonylC,-C, alkyl (e.g. methoxycarbonylmethyl or methoxycarbonylethyl), ora group -NR''R'®, NHSO,CH;, -C(O)NR''R'®, -NHC(O)NR''R'?, -0C(O)NR''R'®, -OCH,C(O)NR''R®, -NHC(0)OR" or -NHC(O)R*". :

It is preferred that Rr! represents C;-C4 alkoxy (especially methoxy), C;-C, alkylcarbonyl (especially methylcarbonyl or ethylcarbonyl), C;-C4 alkoxycarbonylC-C, alkyl (particularly methoxycarbonylmethyl or methoxycarbonylethyl), _C(O)NR!R®, -NHSO,CH;, -NHC(O)NR''R'® or, especially, -NHC(O)R™,

Is

Fach R'® independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C;-Cg, preferably C;-Cy, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C;-Cq, preferably C;-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C,-Cg, preferably C;-C,, haloalkyl (e.g. trifluoromethyl),

C,-Cq, preferably C,-C,, haloalkoxy (e.g. trifluoromethoxy), NR*'R%,

C3-Cg cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C;-Cq, preferably C;-C,, alkylthio (e.g. methylthio or ethylthio),

C;-Cq, preferably C,-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, 2s n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or . n-hexylcarbonyl), C,-Cg, preferably C;-Cy, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,

C,-Cs, preferably C,-Cy, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), _C(O)NRZR* NR*C(0)-(NH),R*, phenyl, or

C;-Cq, preferably C,-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxy! or C,-Cg, preferably

C-Cy, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). 5s Preferably, cach R'e independently represents halogen (particularly chlorine or fluorine), : cyano, Cy-Cy4 alkoxy {especially methoxy), C,-C, alkoxycarbonyl! {especially methoxycarbonyl), C,-C, haloalkyl (especially trifluoromethyl), C;-C, alkylcarbonyl (particularly methylcarbonyl), phenyl or C;-C, alkyl (e.g. methyl or tert-butyl). vw Rand R'® each independently represent a hydrogen atom or a C;-Cy, preferably

C,-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or, more preferably,

C,-Cg, preferably C-C,, alkoxycarbonyl, especially methoxycarbonyl, or R'” and R'® together wilh (he nilivgen stom to which they are attached form 2 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).

RY represents a hydrogen atom or a C-Cg, preferably C,-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or, more preferably, C,-Cs, preferably C,-C,, alkoxycarbonyl, especially methoxycarbonyl. rR represents a group C,-Cg, preferably C,-Cs, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-penty! or n-hexy!), C,-Cg, preferably

C,-Cy, alkenyl, C5-Cq4 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), 2s adamantyl, Cs-Cg cycloalkenyl, phenyl! or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom (e.g. one, two, three or four ) heteroatoms) selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from nitro, hydroxyl, oxo, halogen (e.g. fluorine, chlorine, bromine or iodine), carboxyl,

Cy-Cg, preferably C,-Ca, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,

tert-butyl, n-pentyl or n-hexyl), C;-Cg, preferably C,-C,, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C;-Cg, preferably C;-Cy,, alkylthio (e.g. methylthio or ethylthio),

C,-Cq, preferably C,-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, . n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C,-C, preferably C,-C,, alkoxycarbonyl (e.g. methoxycarbonyl or : ethoxycarbonyl), phenyl and _NHC(0)-R?".

The saturated or unsaturated 5- to 10-membered heterocyclic ring system may be monocyclic or polycyclic (e.g. bicyclic) and may comprise up to four heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of ring systems that may be used include pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl. is R*! and R* each independently represent a hydrogen atom or a C;-Cg, preferably

C,-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,’ n-pentyl or n-hexyl), or R*! and R?? together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).

R* and R?* each independently represent a hydrogen atom or a C;-Cg, preferably

C,-Cy4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C{-Cg, preferably C;-C4, alkoxycarbonyl substituent group. : - R> represents a hydrogen atom or a C,-Cg, preferably C,-C,, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

R*® represents a hydrogen atom, or a C;-Cg, preferably C;-C,, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl, C,-Cy, preferably C,-Cy, alkoxy or C;-Cg, preferably

C4-Cy, alkoxycarbonyl.

RY represents a C-Cg, preferably C,-C,, alkyl group (e.g. methyl, ethyl, n-propyl, . isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amine or phenyl group.

Preferred compounds of the invention include:

N-[2-(3-{[1-(3,4-dichlorobenzylpiperidinyl Jaminohydroxypropoxy)phenyl jacetamide,

N-[5-chloro-2-(3- {[1-(3,4-dichlorobenzyl)-4-piperidinylJamino}-2- hydroxypropoxy)phenyl]acetamide,

N-[2-(3- {[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyl]acetamide,

N-[4-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinylJamino} -2-hydroxypropoxy)[1,1'- hipheny!l-2.ylacetamide,

N-[3-acetyl-2-(3- {[1-(3,4-dichlorobenzyl)-4-piperidinyl Jamino } -2-hydroxypropoxy)- 5-mcthylphenyljacctamide,

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinylJamino} -2-hydroxypropoxy)-4- fluorophenyl]acetamide,

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino } -2-hydroxypropoxy)-5- fluorophenyl]acetamide,

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]Jamino} -2-hydroxypropoxy)-5- cyanophenyljacetamide,

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyllamine} -2-hydroxypropoxy)phenyl]- acetamide,

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amin0} -hydroxypropoxy)phenyl]- isobutyramide, -

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinylJamino}-2 -hydroxypropoxy)phenyl]-2-2- dimethyl-propiomanide,

N-[5-chloro-2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyljacetamide,

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyl]acetamide,

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]Jamino}-2-hydroxypropoxy)-4- . methylphenyl]acetamide, :

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl amino} -2-hydroxypropoxy)-4- fluorophenyl]acetamide,

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinylJamino}-2-hydroxypropoxy)-5- cyanophenyl]acetamide,

N-(2-{[(2S)-3-({-[(4-Chlorophenyl)methyl]-4-piperidinyl } amino)-2- hydroxypropyl]oxy}phenyl)acetamide bi(trifluoroacetate), 'N-(2-{(2R)-3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide,

N-(2-{[3-({1-[(4-Chlorophenyl)methyl]-4-piperidinyl } amino)-2-hydroxy-2- methylpropylloxy}phenyl)acetamide,

N-(2-{(2S)-3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy }-phenyl)-acetamide,

N-{2-[((2S)-3-{[1-(4-Fluorobenzyl)-4-piperidinylJamino}-2- hydroxypropyl)oxy]phenyl} acetamide,

N-{2-[((2S)-3-{[1-(4-Chlorobenzyl)-4-piperidinyl Jamino}-2-hydroxypropyl)oxy]-4- fluorophenyl}acetamide,

N-{4-fluoro-2-[((2S)-3-{[1-(4-fluorobenzyl)-4-piperidinylJamino} -2- hydroxypropyl)oxy]phenyl} acetamide,

N-{2-[((2S)-3-{[(39)-1 ~(4-Chlorobenzyl)pyrrolidiny!] amino} -2-hydroxypropyl)oxy]-. 4-fluorophenyl} acetamide,

N-{2-[((25)-3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl]amino} -2-hydroxypropyl)oxy]- : 4-fluorophenyl} acetamide,

N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]acetamide,

N-[2-(3-{[1-(4-Chlorobenzy!)-4-piperidinyl]Jamino}-2-hydroxy-2-methylpropoxy)-4- fluorophenyljacetamide, .

N-{4-Fluoro-2-(3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino} -2-hydroxy-2- methylpropoxy)phenyljacetamide,

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]Jamino } -2-hydroxypropoxy)-4- methylphenyl]acetamide, :

N-{2-(3- {[1-{4-Fluorobenzyl)-4-piperidinyljamino} -2-hydroxypropoxy)-4- methylphenyijacetamide,

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinylJamino}-2- hydroxypropoxy)phenyllbenzamide,

N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyllbenzamide,

N-[2-(3-{[(3S)-1-(4-Chlorobenzyl)pyrrolidinyl]amino} -2- hydroxypropoxy)phenyllbenzamide,

N-[2-(3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinylJamino} -2- hydroxypropoay phenyl jbenzamide, is N-[2-(3-{[!-(4-Bromobenzy!)-4-piperidinyl]aminc}-2- hydroxypropoxy)phenyljbenzamide,

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide,

N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide,

N-[2-(3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl]lamino } -2-hydroxy-2- methylpropoxy)phenyl]benzamide,

N-{2-(3-{[1-(4-Bromobenzyl)-4-piperidinyl]amino } -2-hydroxy-2- methylpropoxy)phenyl]benzamide,

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino } -2-hydroxypropoxy)-4- methoxyphenyl]acetamide, i

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino }-2-hydroxypropoxy)-6- fluorophenyl]acetamide,

N-[2-Fluoro-6-(3-{[1-(4-fluorobenzy!)-4-piperidinylJamino}-2- hydroxypropoxy)phenyljacetamide,

2-(3-{[1-(4-Chlorobenzyl)-4-piperidinylJamino}-2-hydroxy-2-methylpropoxy)-N- methylbenzamide,

N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino}-2-hydroxy-propoxy} -phenyl)- . benzamide,

N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-benzamide,

N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyl)- benzamide,

N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6- methyl-phenyl)-acetamide,

N-(2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- phenyl)-acetamide,

N-(2- {3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy} - phenyl)-acetamide,

N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy }-phenyl)-acetamide,

N-(2- {3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide,

N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino}-2-hydroxy-2-methy]l- propoxy}-phenyl)-acetamide, 2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide, 2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy } -N-methyl- benzamide, 2-{3-[1 -(4-Chloro-benzyl)-piperidin-4-ylamino] -2-hydroxy-propoxy}-N-methyl- benzamide, 2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy }-N-methyl- benzamide, 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(4-bromo-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide,

3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(3-chloro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy} -phenyl)-amide, 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-{1-(3-fluoro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide, ‘

N-(2-{3-[1-(4-Bromo-benzyi)-piperidin-4-ylamino}-2-hydroxy-propoxy } -plienyl)- acetamide,

N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} - phenyl)-acetamide,

N-(2-{3-[1-(3,4-Ditluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyt)- acetamide, and

N-(2-{3-[1 ~(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyl)- acetamide.

The present invention furicr provides a process for the preparation of a compound of i5 formula (I) as defincd above which comprises (a) reacting a compound of general formula ; Na

Fo Le A 7 z'7 NH, (RY) " (II) wherein m, n, z', z’, R' and R? are as defined in formula (I), with a compound of general formula 0._R 4 ~~ 2

CER OR

4 6 -

RR (IIT) . 2 54 55 pb 7 8 . wherein Q, R”, R', R™, R", R" and R" are as defined in formula (I); or (b) reacting a compound of general formula

R) Na R* ] R® i ’ m

JEN

R% SE 0 ®) R aw) wherein m, n, z, 72 rR! rR’, rR? R>, RS, rR’ and Rr? are as defined in formula (I), with a compound of general formula 1 2

L' -Q-R Vv) wherein L' represents a hydrogen atom or a leaving group (e.g. Li when Q is CH,) and Q and R? are as defined in formula @); or (c) reacting a compound of general formula ~N2 1 N Zz

ES

1

R3 z Oo (Rn (VD) wherein m, n, z! 72 Rr! and R> are as defined in formula (I), with a compound of general ts formula

HOR’ 4

HN Np2

ROR vp wherein Q, rR’, RY, Rr’, RS, R’ and R® are as defined in formula (1); and optionally after (a), (b) or (c) 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).

The process of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as an alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene) or acetonitrile at a temperature of, for example, 15°C or above such as a temperature in the range from 20 to 120°C. .

Compounds of formulae (II), (IIL), IV), (V), (VI) and (VII) 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, a compound of formula (I) in which RY represents -NHC(O)CHj can be converted to a further compound of formula (I) in which RP represents -N1, by a hydrolysis reaction in the presence of hydrochloric acid. 1s It will be appreciated by those skilled in the art that in the process of the present invention certain functional groups such as hydroxy! 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.

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 . tautomers and mixtures thereof also form an aspect of the present invention. Preferred . . s optical isomers are the (S)-enantiomers. Co

The compounds of formula (IT) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially MIP-1a chemokine receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative to 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) 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 scrofoulous 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 diseasc, ulcerative colitis, food-related allergies which have effects remote from the gut, €.g., migraine, rhinitis and eczema; (5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired

Immunodeficiency Syndrome (A1DS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; (7) cancers, especially non-small cell lung cancer (NSCLC) and squamous sarcoma; (8) diseases in which angiogenesis is associated with raised chemokine levels (e.g.

NSCLC); and (9) cystic fibrosis, stroke, re-perfusion injury in the heart, brain, peripheral limbs and sepsis.

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.

Inthe 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. )

The invention still further provides a method of treating an airways disease in a patient 1s 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 daily dosage of the compound of formula (I) may be in the range from 0.001 mg/kg to 30 mg/kg.

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 (I) 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 %w,

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 : sof formula (I), or a pharmaccutically acceptable salt or solvate thereof, as hereinbefore defined, in associaiion wilh a pharinaceutically 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 (I), or a 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 oi to the skin) inthe form of solutions, suspensions. heptafinoraalkane nernsnle

QLLVW AYO UL WU aL ondid) dad HAO JULIE OF SUILILILLL, BE CAEEISEE ES te Liepiidliiningg LALIT IL AIA ts 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, in which '"H NMR spectra were recorded on Varian Unity Inova 400. The central solvent peak of chloroform—d (3; 7.27 ppm) were used as internal standard. Low resolution mass spectra and accurate mass determination were recorded on a Hewlett-

Packard 1100 LC-MS system equipped with APCI /ESI ionisation chambers. 2s All solvents and commercial reagents were laboratory grade and used as received.

The nomenclature used for the compounds was generated with ACD/IUPAC Name Pro. )

Examples 1-16

Starting material: 1-(3 ,4-Dichlorobenzyl)-4-piperidinylamine i) tert-Butyl 4-piperidinylcarbamate

Di-tert-butyl-dicarbonate (11.6g, 53.16mmol) was added to a solution of 1-benzyl-4- piperidinamine (13.10g, 68.84mmol) in dichloromethane (100ml) and triethylamine (2ml) and the solution was stirred at room temperature for 2 hrs. Water was added to the solution s and the organic layer was separated, dried over natrium sulphate, filtered and concentrated.

The resulting residue was taken up into ethanol. Palladium hydroxide 20% (500mg) was added to the solution and the mixture was hydrogenated (parr apparatus) over 50psig hydrogen for 48 hrs. The mixture was filtered over a pad of celite. The solid was washed with two portions of hot ethanol and concentrated in vacuo to give 8.85g product.

APCI-MS: m/z 201[MH+] "HNMR (400MHz, CD;0D) 6 2.97-3.39(1H, m), 3 (2H, m), 2.55-2.62 (2H, m), 1.8-1,84 (2H,dd), 1.42 (94, s), 1.27-1.37 (2H,m) is ii) 1-(3,4-Dichlorobenzyl)-4-piperidinylamine 1,2-dichloro-4-(chloromethyl)benzene (390mg, 1.99mmol) ) was added to a solution of tert-butyl 4-piperidinylcarbamate (400mg, 2.0mmol) in DMF (25ml) and triethylamine (2ml). The solution was stirred at room temperature for 3hrs and then concentrated in vacuo. To the solution of the solid in dichloromethane was added (30ml) trifluoroacetic acid (6ml) was added and stirred at room temperature for 2hrs. The solution was diluted with dichloromethane and washed with two portions of water. The combined water washings were treated with 2M NaOH to pH 10 and extracted with ether. The ether was dried (Na, S0O,), filtered and evaporated to leave a yellow residue (300mg, 1.16mmol). 2s APCI-MS: m/z 259[MH+] . "HNMR (400MHz, CD5;0D) 3 7.41(1H, d), 7.36 (1H, br d), 7.13 (1H, dd), 3.42 (2H, s), 2.97-3.01 (1H, m), 3 (2H, m), 2.55-2.62 (2H, m), 1.41-1.55 (2H,dd), 1.31-1.54 (2H,m)

Example 1

N-[2-(3-{[1-(3,4-dichlorobenzylpiperidinyl]aminohydroxypropoxy)phenyl]acetamide

The mixture of N-Acetyl-2-(2,3-epoxypropoxy)aniline (120mg, 0,58mmol) and the above starting material (150mg, 0,58mmol) in ethanol (10ml 99.5%) was refluxed for 3hrs. The solvent distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluant: dichloromethane/methanol 15:1) to give 108mg of the title compound as a gum. Addition of 1.0M ethereal HCI solution gave a white solid product.

APCI-MS:m/z 466[MH'] io 'HNMR (400MHz, CD,0D) &§ 8.0 (1H, dd,), 7.5 (1H, d), 7.45 (1H d), 7.23 (1H, dd), 6.89- 7.08 (4H, m), 4.15 (1H, m), 3.9-4.1 (2H, m), 3.40 (2H, S), 2.97-3.11 (1H, m), 3 (2H, m), 2.55-2.68 (2H, m), 1.39-1.55 (2H,dd), 1.31-1.44 (2H,m), 2.17 (3H, s).

The following compounds wore synthesised by methods analogous fo the method 1s described in Example 1.

Example 2

N-[5-chloro-2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyljacetamide

APCI-MS: m/z 500[MH"]

Example 3

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- 2s methylphenyl]acetamide

APCI-MS: m/z 480[MH"]

Example 4

N-[4-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)[1,1'- biphenyl}-3-yl]acetamide

APCI-MS: m/z 542[MH"]

Example 5 ~~ N-[3-acetyl-2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyljacetamide ‘10 APCI-MS: m/z 522[MH"]

Example 6

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amine}-2-hydroxypropoxy)-4- fluorophenyljacetamide

APCI-MS: nv/z 484[MH"]

Example 7

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- fluorophenyl]acetamide

APCI-MS: m/z 484[MH"]

Example 8

N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinylJamino}-2-hydroxypropoxy)-5- ‘ cyanophenyl]acetamide

APCI-MS: m/z 491[MH"]

Example 9 :

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl}- acetamide

APCI-MS: m/z 432[MH"]

Example 16

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amin0}-hydroxypropoxy)phenyl]- isobutyramide

APCI-MS: m/z 460[MH")

Example 11

N-[2-(3-{]1-(4-chlorobenzyl)-4-piperidinyljamino}-2-hydroxypropoxy)phenyl}-2-2-

APCI-MS: m/z 474[MH"]

Example 12

N-[5-chloro-2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]Jamino}-2- hydroxypropoxy)phenyljacetamide

APCI-MS: m/z 466[MH")

Example 13

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyljacetamide '

APCI-MS: m/z 446[MH")

Example 14

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]Jamino}-2-hydroxypropoxy)-4- methylphenyljacetamide

APCI-MS: m/z 446[MH"]

Example 15

N-{2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- fluorophenyl}acetamide

APCI-MS: m/z 450[MH"]

Example 16

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl}]amino}-2-hydroxypropoxy)-5- cyanophenyljacetamide

APCI-MS: m/z 457[MH"]

Starting Materials for Examples 17 to 63.

Epoxide: A

N-{2-[(28)Oxiranylmethoxy]phenyl}acetamide ) (2S)-2-[(2-nitrophenoxy)methyl]oxirane (1.17 g, 6 mmol) was dissolved in ethyl acetate (50 ml). Platinum on charcoal (0.50 g) was added, and the mixture was stirred in the atmosphere of hydrogen for 3 h at room temperature and atmospheric pressure. The catalyst was filtered and washed on the filter with ethyl acetate (10 ml). Acetic anhydride : (1.23g, 1.13. ml, 12 mmol) and ethyldi(i-propyl)amine (1.55 g, 2.05 ml, 12 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 3 h, then washed with 1M NaOH (2 x 50 ml) and brine (2 x 50 ml), and dried with Na,SO,.

Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (from 25 to 75 %) afforded the title compound (0.74 g, 3.57 mmol, 60 %) as colourless crystals. "H-NMR (400MHz, CDCL,): & 8.36 (m, 1H), 7.89 (br. S, 1H), 6.8 — 7.0 (m, 3H), 4.35 (dd, : so WL J=2350=113)395(dd, 1H, J=597=17113,330(m, 1H),295(, 1H J=48), 2.78(dd, 111, J =2.7, J =4.8),2.22 (s, 311).

APCI-MS: m/z 208 [MH']

Epoxide: B 1) [(2R)-2-Methyloxiranyl]methyl-4-methylbenzenesulfonate (S)-2-methyl-glycidol (0,10g, 1.13mmol), dimethylaminopyridine (0.5mg, 3.8umol) in triethylamine (2ml) was cooled on an ice bath and tosyl chloride (0.217g, 1.14mmol) was added in portions during 10 min. The flask was sealed and kept at —10°C over night. The reaction mixture was evaporated and the residue was stirred with dry diethylether (2 Sm), 1s The solid was filtered off and washed with diethylether ( 3 x 1m). The filtrate was dried and concentrated in vacuo. The crude product was purified on silica (Ileptane/EtOAc 1:2) to give 145mg (53%) of the subtitle compound. 'H-NMR (400MHz, CDCL,): § 7.80 (2H, d, J8.4Hz), 7.36 (2H, d, J8.1Hz), 4.04 (1H, d,

J10.7Hz), 3.95 (1H, 4, J10.7Hz), 2.70 (1H, d, J4.7Hz), 2.64 (1H, d, J4.6Hz), 2.46 (3H, s), 1.36 3H, s). ii) N-2-{[(2R)-2-Methyloxiranyl]methoxy}phenyl)acetamide

To 2-acetamidophenol (90.5mg, 0.598mmol) and cesium carbonate( 234mg, 0.718mmol) 35 was added [(2R)-2-methyloxiranyl]methyl 4-methylbenzene-sulfonate (145mg, 0.598mmol) dissolved in DMF (1ml). The mixture was stirred at room temperature for four hours and then partitioned between ethyl-acetate and water. After extraction the combined organic phases were dried and concentrated in vacuo. The residue was purified on silica (Heptane/EtOAc 3:1 — 2:1) to give 63mg (48%) of the title compound.

'H-NMR (400MHz, CDC1,): 3 8.38-8.31 (1H, m), 8.02 (1H, bs), 7.04-6.97 (2H, m), 6.93- 6.86 (1H, m), 4.11 (1H, d, J10.9Hz), 4.01 (1H, d, J10.9Hz), 2.95 (1H, d, J4.7Hz), 2.78 (1H, d, J4.7Hz), 2.21 (3H, 5), 1.48 (3H, 5). s Epoxide: C i) [(2S)-2-Methyloxiranyljmethyl-3-nitrobenzenesulfonate

To an oven-dried 1000 ml three-necked flask was added powdered activated molecular sieves (8.0 g, 4A) and CH, Cl, (440 ml, dried over molecular sieves). D-(-)-Diisopropyl tartrate (3.0 ml, 14.2 mmol) and 2-methyl-2-propan-1-ol (20 ml, 240 mmol) was added and the mixture was cooled to ~20°C. Titanium tetraisopropoxide (3.5 ml, 11.9 mmol) was added with a few ml of CH,Cl, and the mixture was stirred at —20°C for 30 minutes.

Cumene hydroperoxide (75 ml, approx. 430 mmol) was added dropwise over 1.5 hours maintaining the temperature at 20°C. The mixture was stirred at this temperature over night. Trimethylphosphite (40 ml, 340 mmol)was added dropwise over 5 hours maintaining ts the temperature at —20°C. Triethylamine (50 ml, 360 mmol) and DMAP (3.48 g, 28.5 mmol) was added followed by a solution of 3-nitrobenzenesulphony] chloride (47 g, 212 mmol) in CH,Cl, (400 ml). The temperature was raised to —10°Cand the mixture was stirred at this temperature over night. After removing the external cooling, the reaction mixture was filtered through celite®. The organic phase was washed with 10% tartaric acid (500 ml), saturated NaHCO, (300 ml) and brine (300 ml). The organic phase was dried (MgSO0,) and evaporated to give ca 150 g of a yellow oil. The crude material was chromatographed (1 kg silica, Heptane/EtOAc 100:0 to 50:50 gradually increased polarity) to give 48.8 g (84%) of the sub-title compound as a yellow oil. The compound was pure enough to use further without any additional purification. i "H-NMR (400 MHz, CDCl,): O 8.79-8.75 (1H, m); 8.52 (1H, ddd, J 1.1 2.3 8.3 Hz); 8.25 (1H, ddd,/J 1.1 1.8 7.8 Hz); 7.81 (1H, t, J 8.5 Hz); 4.28 (1H, d, J 11.3 Hz); 4.05 (1H, d, J 11.3 Hz); 2.73 (1H, d, J 4.4 Hz); 2.67 (1H, d, J 4.4 Hz); 1.56 (3H, 5) ii) V-(2-{[(25)-2-Methyloxiranyllmethoxy}phenyl)acetamide

In a flask was added the compound obtained in a) (24.57 g, 90 mmol), 2-acetamido-phenol (13.59 g, 90 mmol), Cs,CO, (35.1 g, 108 mmol, powdered anhydrous) and DMF (90 ml).

The flask was sealed and the mixture was stirred with a magnetic stirrer at room temperature for 2 hours. A heavy precipitate was formed, and the starting materials were s converted in 2 hours The mixture was partitioned between EtQOAc/water (400 + 400 ml).

The organic phase was collected and the aqueous phase was washed with EtOAc (2 x 200 ml). The combined organic phases were washed with water (200 ml), 1M NaOH (2 x 200 ml) and brine (150 mi). The organic solution was dried over Na,SO,, and conceniraied in vacuo after filtration. The crude material was purified on silica (Heptane/EtOAc 5:1 to 1:1, gradually increasing the polarity), eluting 18.5 g (92%) of the sub-title compound. The optical purity was 97.4 %, according to chiral HPLC (Chiralpak ™, iso-hexane/iso- propanol 95:5). "H-NMR (400 MHz. CDCL): 1M 839-832 (1H, m): 8.00 (1H, bs): 7.05-6.97 (2H. m); 6.95- is 6.88 (1H, m); 4.12 (1H, d, AB, J 11.0 Hz); 4.02 (1H, d, AB, J 11.0 Hz); 2.96 (1H, d, J 4.6

Hz), 2.79 (1H, d, J4.8 Hz); 2.22 (3H, 5); 1.49 (3H, 5)

Epoxide: D

N-{4-Fluoro-2-[(28)oxiranylmethoxy]phenyl}acetamide was prepared from (2S5)-2-[(5-fluoro-2-nitrophenoxy)methyl]oxirane according to the method described for Epoxide: A.

APCI-MS: m/z 226 [MH+] 'H-NMR (400MHz, CDCl): 6 8.30 (dd, 1H, J = 5.2, J = 9.0), 7.71 (br. S, 1H), 8.6 — 8.8 2s (m,2H),4.36 (dd, 1H,J=2.3,J=113),390(dd, 1H,J=6.3, J=11.3),3.40 (m, 1H), 297(t, 1H, J =4.4),2.78 (dd, IH, J=2.7, J = 4.8), 2.21 (s, 3H). .

Epoxide: E

N-{2-[(2-Methyl-2-oxiranyl)methoxy]phenyl}benzamide

A mixture of N-(2-hydroxyphenyl)benzamide (159 mg, 0.75 mmol), 2-(chloromethyl)-2- methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70 — 75 °C for 6 h. After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2x5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na,SO,, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethy] acetate (ethyl acetate from 25 to 50 %) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62 %).

APCI-MS: m/z 284 [MH+] "H-NMR (400MHz, CDCL): 8 8.68 (br. S, 1H), 8.54 (m, 1H), 7.94 (m, 2H), 7.4 — 7.6 (m, : 3H), 7.07 (m, 2H), 6.92 (m, 1H), 4.19 (d, 1H, J = 10.7), 4.06 (4, 1H, J 10.7), 2.92 (4, 1H, J =4.6),2.78 (d, 1H, J = 4.6).

Epoxide: F

N-Methyl-2-[(2-methyl-2-oxiranyl)methoxy]benzamide was prepared from 2-hydroxy-N-methylbenzamide (prepared according to Cohen et al, J.

Am. Chem. Soc.,1998, 20, 6277 - 6286.) according to the method described for N-{2-[(2- methyl-2-oxiranyl)methoxy}phenyl} benzamide.

APCI-MS: m/z 284 [MH+] 'H-NMR (400MHz, CDCL,): & 8.68 (br. S, 1H), 8.54 (m, 1H), 7.94 (m, 2H), 7.47.6 (m, 3H), 7.07 (m, 2H), 6.92 (m, 1H), 4.19 (d, 1H, J = 10.7), 4.06 (d, 1H, J 10.7),2.92 (d, 1H, J =4.6),2.78 (d, 1H, J = 4.6), 1.51 (s, 3H).

Epoxide: G

N-[4-Methyl-2-(2-oxiranylmethoxy)phenyl]acetamide

A mixture of N-(2-hydroxy-4-methylphenyl)acetamide (10 g, 60 mmol), 2- (bromomethyljoxirane (9.86 g, 72 mmol, 6.0 ml) and potassium carbonate (16.8 g, 120 mmol) in DMF (100 ml) was heated at 55 °C for 2 h. Then the reaction mixture was diluted with ethyl acetate and washed with aq. HCI (1.5 %), aq. sat. NaHCO, and brine.

Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 35 to 70 %) afforded the title compound (5.65 g, 25 mmol, 43 %).

APCLI-MS: m/z 222 [MH+] "H-NMR (400MHz, CDCl): 6 8.20 (d, 1H, J = 8.2), 7.78 (br. 5, 1H), 6.79 (d, 1H, J = 8.2), 6.70 (s, 1H), 4.32 (dd, 1H, J = 2.5, J = 11.4),3.93 (dd, LH, J = 5.9, J = 11.4), 3.38 (m, 1H), 2.94 (t, 1H, J = 4.8),2.77(dd, 1H, J = 2.7, J = 4.8), 2.29 (s, 3H), 2.19 (s, 3H).

Epoxide: H

N-[4-Methoxy-2-(2-oxiranylmethoxy)phenyl]acetamide

Was prepared from N-(2-hydroxy-4-methoxyphenyl)acetamide according to the method described for N14 methyl-2-(2-oviranyImethoxy)phenvllacetamide using cesium carbonate is instead of potassium carbonate.

APCI-MS: m/z 238 [MH+] "H-NMR (400MHz, CDCl): § 8.20 (d, 1H, J = 8.8), 7.62 (br. s, 1H), 6.4 — 6.6 (m, 2H), 6.70 (s, 1H), 4.32 (dd, 1H,J = 2.5, J=11.3),391 (dd, 1H,J= 6.1, J = 11.3),3.77 (s, 3H), 3.37 (m, 1H), 2.94 (t, 1H,J = 4.8), 2.76 (dd, I1H,J = 2.7, J = 4.8), 2.18 (s, 3H).

Epoxide: I i) 2-Amine-3-fluorophenol

To a stirred solution of 2,6-difluoronitrobenzene (1100mg, 6.9mmol) in dry methanol (20ml) was added a solution of sodium (180mg, 7.8mmol) in dry methanol ( 8 ml). The solution was stirred overnight. After concentration, water was added and the solution was ‘extracted with ether, dried over MgSO,, filtered and concentrated to a yellow residue (870mg.5.08 mmol). To the solution of the yellow residue in dichloromethane (10 ml) boron tribromide (1M in dichloromethane, 10 ml) was added and stirred at room temperature overnight. Water was then added and the solution stirred for further 60 min.

The organic phase was separated and the water phase was extracted with ether. The combined organic phase were dried over MgSO, filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and s neutralised with 6M HCl and extracted with ether, dried over MgSO, and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with

EtOAc:Heptane: 1:3 as eluant to give the product ( 720mg, 4.6mmol) which was directly suspended with palladium-charcoal (140mg) in water-ethanol (30ml). Sodium borohydride (530mg) was added over a period of 5 min and the suspension was stirred at room to temperature (1h). The catalyst was removed by filtration through a Celite pad. The filtrate was acidified with 6M hydrochloric acid to destroy any residual borohydride, neutralised with 2 M sodium hydroxide, and then extracted with ether. The ethereal extracts were dried over MgSO, and evaporated.

APCI-MS: m/z 128.2 [MH*] ii) N-[2-Fluoro-6-(2-oxiranylmethoxy)phenyl]acetamide

To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) in water-methanol (10 ml) acetic acid anhydride was added until all 2-amino-3-fluorophenol was consumed.

The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide.

To a mixture of N-(2-fluoro-6-hydroxyphenyl)acetamide (399mg, 2.36mmol) and potassium carbonate (652mg, 4.72mmol) in DMF (5 ml) epibromohydrin (388 mg, 2.8mmol) was added and the mixture was stirred at 70°C for 3hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by RP- HPLC (10- 40 % CH3CN) to give the desired product as a solid (242 } mg,1.08mmol).

APCI-MS: m/z 226 [MH+]

‘H-NMR (400MHz, CDCl): 0 7.15 (m, 1H), 6.87 (br. s, 1H), 6.6 - 6.8 (m, 2H), 4.30 (dd, 1H,J=23,J=11.3),393 (dd, 1H,J =5.7,J=11.3),3.34 (m, 1H), 2.91 (t, IH, J = 4.4), 2.75 (dd, 1H, J = 2.8, J = 4.8), 2.20 (br. 5, 3H). s Epoyxide: J

N-(2-Oxiranylmethoxy-phenyl)-benzamide

To a stirred solution of N-(2-Hydroxy-phenyl)-benzamide (0.81g, 3.80 mmol), and cesium carbonate (1.61g, 4.94 mmoi) in acetonitriie was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between to dichloromethane and water. After evaporation of the organic solvent the residue was crystallised from petroleum ether and diethy! ether yielding (0.741g, 73%).

APCI-MS: m/z 227[MH’ "H-NMR (400 MHz, CCL): 8 R 65 (hs, 1H), R.55 (hs, 1H). 7.94 (d. 2H), 7.53 (m. 3H), 7.08 (bs, 2H), 6.96 (bs, 1H), 4.42 (d, 1H), 4.02, (m, 1H), 3.41 (bs, 1H), 2.96 (s, 1H), 2.80 (s, 1H).

Epoxide: K

N-Methyl-2-oxiranylmethoxy-benzamide

To a solution of 2-Hydroxy-N-methyl-benzamide (0.5g, 3.31 mmol prepared according to

Cohen, Seth Metal J. Am. Chem. Soc., (1998), 120(25), 6277-6286.) and cesium carbonate (2.16g, 6.62mmol) in acetonitrile was added epibromohydrin (0.274mi, 3.31mmol). The mixture was heated at 50°C for 2 hours and then after cooling to room temperature partitioned between water(50 ml)and dichloromethane (100ml). The 2s dichloromethane was dried and evaporated . Chromatography (EtOAc) gave 0.43g (64%) of the product as a solid. -

APCI-MS: m/z 208[MH"]

'H -NMR (400 MHz, CDCl): 8 8.20 (dd, 1H), 7.85 (bs, 1H), 7.42 (m, 1H), 7.11 (m, 1H), 6.95 (dd, 1H), 4.46 (dd, 1H), 4.11 (dd, 1H), 3.41 (m, 1H), 3.02 (d, 3H), 2.97 (t, 1H), 2.84 (dd, 1H). 5s Epoxide: L

N-(2-Methyl)-6-oxiranylmethoxy-phenyl)-acetamide

A mixture of 3-methyl-2-acetamidophenol (0.165g, 1 mmol), and epichlorohydrin (1.84g, 20mmol) was stirred at 70°C to afford a clear solution. Triethylbenzylammonium chloride (0.15g, 1 mmol) was then added and stirring was continued at 125°C for 15 minutes. After cooling to room temperature 1M NaOH solution was added and the solution was extracted with dichloromethane. The organic extract was washed with water and dried. After evaporation of the dichloromethane the resulting brownish oil was purified through silica chromatography 50-70% EtOAc in heptane yielding the product as a colourless oil (0.12g, 0.54mmol).

APCI-MS: m/z 208[MH"]

Epoxide: M 3,5 Dimethyl-1-H-pyrrole-2-carboxylic acid (2-oxiranylmethoxy-phenyl)-acetamide

The compound was prepared from 3,5 Dimethyl-1-H-pyrrole-2-carboxylic acid-(2-phenyl)- acetamide (300 mg, 1.3 mmol) analogously to that described for Epoxide: L.

APCI-MS: m/z 287 [MH'] "H-NMR (400 MHz, CDCL,): § 8.46 (m,1H), 8.31 (m,1H), 6.99 (m,2H), 6.87 (m,1H), 5.85(m,1H), 4.34(m; 1H), 3.92 (m, 1H), 3.36 (m,1H), 2.91 (m,2H), 2.71 (m,1H), 2.47 (m, . 3H), 2.25 (m,3H). (i) 3,5 Dimethyl-1-H-pyrrole-2-carboxylic acid (2-phenyl)-acetamide 2-Aminofenol ( 545mg, 5 mmol), 3,5 dimethyl-1-H-pyrrole-2-carboxylic acid (ii) (695mg, 5 mmol) and HATU (1900mg, 5 mmol) were stirred in DMF (20 ml).

Diisopropylethylamine was added to pH 8. The mixture was stirred overnight and then concentrated. The residue was purified on C18 ( acetonitrile/water 10/90 to 40/60 with 0.5% trifluoroacetic acid ) to give the title compound ( 550 mg, 48% ). s APCI-MS: m/z 231 [MH] "H-NMR (400MHz, CDCl, ): 8 9.22 (s,1H), 7.63 (s, 1H), 7.11(m, 2H), 7.03 (m, 1H), 6.88 (m,1H), 5.88 (s, 1H), 2.44 (s,1H), 2.24 (5,1H). (ii) 3,5 Dimethyl-1-H-pyrrole-2-carboxylic acid

To a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich ) (504mg, 3 mmol ) in

THF/H,0/MeOH (5:1:1, 30ml ) was added NaOH ( 480 mg, 12 mmol ) in H,0 ( 12 ml).

The mixture was stirred at 75° C overnight. The homogeneous mixture was washed with ether. To the aqueous layer was added a saturated aqueous KHSO, solution until the pH wage ahont 3. The solution was then extracted with dichloromethane. The extracts were is dried over MgSO, and evaporated. The residue was purified on silica (ethylacetate /methanol 90/10} te give the title compound ( 375 mg, 90 % ).

H-NMR (400MHz, CDCl, ): & 8.75(s,1H), 5.83(s,1H), 2.25(s,1H), 2.38 (s,1H).

Amine: N 1-(4-Chlorobenzyl)-piperidineamine 1-Chloro-4-(chloromethyl)benzene (1.61 g, 10 mmol) was added to a stirred solution of tert-butyl 4-piperidinylcarbamate (2.02 g. 10.1 mmol) and triethylamine (10 ml) in dry

DMF (100 ml). The solution was stirred at room temperature overnight and then the solvent was removed in vacuo. The residue was taken in dichloromethane (150 ml) and trifluoroacetic acid (30 ml) was added. After stirring at room temperature for 3 h, the . solution was diluted with dichloromethane (150 ml), and extracted with water (2 x 150 ml).

The pH of the combined aqueous extracts was adjusted to 10 by addition of 2 M NaOH.

The solution was extracted with ether (3 x 100 ml). Drying with sodium sulfate and evaporation of the solvent afforded the title compound as yellowish oil (1.91 g, 8.5 mmol, ‘H-NMR (400MHz, CDCl,): § 7.2 7.3 (m, 4H), 3.41 (s, 2H), 2.76 (m, 2H), 2.63 (m, 1H), 1.98 (m, 2H), 1.76 (m, 2H), 1.3 ~ 1.6 (m, 4H).APCL-MS: m/z 225 [MH]

Amine: O (38)-1-(4-Chlorobenzyl)-3-pyrrolidinamine was prepared according the method described for Amine: N from tert-butyl (3S)pyrrolidinylcarbamate.

APCI-MS: m/z 211 [MH+] "H-NMR (400MHz, CDCl): § 7.2 — 7.3 (m, 4H), 5.55 (d, 2H), 3.49 (m, 1H), 2.66 (m, 2H), 2.41 (m, 1H), 2.29 (dd, 1H), 2.18 (m, 1H), 1.68 (br. 5, 2H), 1.48 (m, 1H). )

Amine: P (3R)-1-(4-Chlorobenzyl)-3-pyrrolidinamine

Was prepared according the method described for Amine: N from tert-butyl (3R)pyrrolidinylcarbamate. oo

APCI-MS: m/z 211 [MH+] 'H-NMR (400MHz, CDCl,): § 7.2 - 7.3 (m, 4H), 5.55 (d, 2H), 3.49 (m, 1H), 2.66 (m, 2H), 2.41 (m, 1H), 2.29 (dd, 1H), 2.18 (m, 1H), 1.68 (br. s, 2H), 1.48 (m, 1H).

Amine: Q . 3-(4-Chlorophenoxy)piperidine tert-Butyl 3-hydroxy-1-piperidinecarboxylate (1.85 g, 9.18 mmol, prepared according to

Costa et al., J. Med. Chem. 1992, 35, 4334 — 4343) (1.85 g, 9.18 mmol) and triphenyl phosphine (2.41 g, 9.18 mmol) were dissolved in dry THF (25 ml) under nitrogen. The solution was cooled to 0 °C and a solution of 4-chloropheno] (1.18 g, 9.18 mmol) in dry

THF (10 ml) was added followed by diethyl azodicarboxylate (1.60 g, 9.18 mmol, 1.45 ml). After 15 minutes the reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo, the residue stirred with ether/n- heptane (1 : 2, 50 ml) mixture. The solid triphenyl phosphine oxide was filtered off, the s solution washed with aq. NaOH (1M, 3 x 75 ml) Evaporation of the solvent and flash chromatography on silica gel with ethyl acetate/n-heptane (ethyl acetate from 5 to 25 %) afforded the BOC-protected subtitle compound, which was dissolved in dichloromethane (20ml). Trifluoroacetic acid (10 mi) was added, and the reaction mixture was stirred overnight at room temperature. The solution was concentrated in vacuo and the product to was purified by flash chromatography on silica gel (MeOH/CHCI,/NH,, 100: 100 : 1) to afford colourless oil (0.23 g, 12%).

APCI-MS: m/z 212 [MH+] "H-NMR (400MHz. CCL): § 7.19 (m, 2H), 6.84 (m_ 2H), 425 (m_ 1H) 3.17 (m. 1H), 2.7 —2.9(m, 4H). 1.97 (m, 1H), 1.7 - 1.9 (m, 2H), 1.53 (m, 1H).

Amine: R : 1-(4-Bromobenzyl)-4-piperidinylamine

To a solution of 4-bromo benzylbromide (1.0g, 4.1mmol) in dichloromethane (20ml) and diisopropyletylamine (1ml) was added tert-butyl 4-piperidinylcarbamate (1.0g, 5.0mmo]l).

The solution was then stirred at room temperature over night. The solvent was evaporated and 25 ml of 50% TFA in dichloromethane was added to the resulting white solid. The mixture was then stirred at room temperature for 2h and then evaporated to dryness. The resulting solid was dissolved in water and extracted with toluene. After removal of the 2s toluene the water phase was made basic with 1M NaOH giving a pH of 13. The water phase was then extracted with dichloromethane 3 times and the combined extracts were : dried and then evaporated to give the pure product as a slightly yellow oil (0.96g, 3.6mmol)

APCI-MS: m/z 269[M+]

"H-NMR (400 MHz, CDCl): 7.42 (d, 2H), 7.18 (d, 2H), 3.43 (s, 2H), 2.78 (m, 3H), 2.43 (bs, 2H), 2.10 (t, 2H), 1.82 (m, 2H), 1.44 (m, 2H).

The following Amines (S, T, U) were synthesised by methods analogous to the method 5s described for Amine R.

Amine: S 1-(3,4-Difluorobenzyl)-4-piperidinylamine

APCI-MS: m/z 227[MH"]

Amine: T 1-(3-Chloro-4-fluorobenzyl)-4-piperidinylamine is APCI-MS: m/z 243[MH"]

Amine: U 1-(4-Fluorobenzyl)-4-piperidinylamine

APCI-MS: m/z 209[MH"]

Example 17 :

N-(2-{[(25)-3-({-[(4-Chlorophenyl)methyl]-4-piperidinyl}amino)-2- hydroxypropyl]Joxy}phenyl)acetamide bi(trifluoroacetate) . A solution of 1-(4-chlorobenzyl)-piperidine amine (0.80 g, 3.57 mmol) and N-{2- [(25)oxiranylmethoxy]phenyl}acetamide (0.74 g, 3.57 mmol) in ethanol (50 ml, 99.5 %) was refluxed for 4h. The solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC (Kromasil C18 column; eluant: [acetonitrile + 0.1 %

TFA/water + 0.1 % TFA]) to afford colourless solid (1.158 g, 1.75 mmol, 49 %).

APCI-MS: m/z 432 [MH]

Example 18

N-(2-{(2R)-3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino}-2-hydroxy-2-methyl- s propoxy}-phenyl)-acetamide 1-(4-chlorobenzyl)-4-piperidinamine (62mg, 0.276mmol) and N-(2-{[(2R)-2- methyloxiranyijmethoxy jphenyi)acetamide (6 img, 0.276mmoi) in ethanoi (i.5mi) was stirred in a sealed vial at 80°C for 4 hours. The reaction mixture was diluted with water and to purified by reversed phase HPLC to give 130mg (70%) of the title compound as a ditrifluoroacetate after lyophilisation. The optical purity was determined to 86% ee, by chiral HPLC on a Chiralpak AD-column.

APCI-MS: m/z446 1 [M+]

Example 19

N-(2-{[3-({1-[(4-Chlorophenyl)methyl]-4-piperidinyl}amino)-2-hydroxy-2- methylpropyljoxy}phenyl)acetamide

Prepared by analogy to the method described in Example 18 from racemic epoxide.

APCI-MS: m/z 446.1 [M+]

Example 20 2s N-(2-{(25)-3-[1-(4-Chloro-benzyl)-piperidin-4-ylamine}-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide :

Prepared according to the method described in Example 18 from N-(2-(((25)-2- methyloxiranyl)methoxy)phenyl)acetamide, >98% yield was obtained.

APCI-MS: m/z 446.1 [M+]

General Procedure (Examples 21-43)

To a solution of the amine in EtOH (0.1 M, 0.2 ml) a solution of the epoxide in DMSO (0.1 5s M, 0.2 ml) was added. The reaction mixture was heated at 80 °C for 24 h.

Example 21

N-{2-[((28)-3-{[1-(4-Fluorobenzyl)-4-piperidinyljamino}-2- hydroexypropyDoxy]phenyl}acetamide

APCI-MS: m/z 416 [MH+]

Example 22

N-{2-[((28)-3-{[1-(4-Chlorobenzyl)-4-piperidinyllamino}-2-hydroxypropyl)oxy]-4- fluorophenyl}acetamide

APCI-MS: m/z 450 [MH+]

Example 23

N-{4-fluoro-2-[((2S)-3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropyl)oxy]phenyl}acetamide -

APCI-MS: m/z 434[MH+]

Example 24

N-{2-[((25)-3~{[(35)-1-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl}acetamide APCI-MS: m/z 436 [MH+]

Example 25

N-{2-[((25)-3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl}acetamide

APCI-MS: 1v/z 436 [MII]

Example 26

N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- io methylpropoxy)phenyl]acetamide

APCI-MS: m/z 430 [MH+]

Example 27 1s N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl}amino}-2-hydroxy-2-methylpropoxy)-4- fluorophenyljacctamide

APCI-MS: m/z 464 [MH+]

Example 28

N-[4-Fluoro-2-(3-{[1-(4-fluorobenzyl)-4-piperidinyljamino}-2-hydroxy-2- methylpropoxy)phenyljacetamide

APCI-MS: m/z 448 [MH+] oo

Example 29

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyljamino}-2-hydroxypropoxy)-4- methylphenyljacetamide APCI-MS: m/z 446 [MH+]

Example 30

N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methylphenyl]acetamide 3 .

APCI-MS: m/z 430 [MH+]

Example 31

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide APCL-MS: m/z 494 [MH+]

Example 32

N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyl]amineo}-2- . hydroxypropoxy)phenyl]benzamide

APCI-MS: m/z 478 [MH+]

Example 33

N-[2-(3-{[(35)-1-(4-Chlorobenzyl)pyrrolidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide

APCI-MS: m/z 480 [MH+] : Example 34

N-[2-(3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide APCI-MS: m/z 480 [MH+]

Example 35

N-[2-(3-{[1-(4-Bromobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyljbenzamide

APCI-MS: m/z 540 [MH+] iixampie 36

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinylj]amino}-2-hydroxy-2- methylpropoxy)phenyljbenzamide

APCI-MS: m/z 508 [MH+]

Example 37 1s N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinyljamino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide

APCI-MS: m/z 492 [MH+]

Example 38

N-[2-(3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxy-2- methyipropoxy)phenyljbenzamide

APCI-MS: m/z 494 [MH] )

Example 39 :

N-[2-(3-{[1-(4-Bromobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide

APCI-MS: m/z 554 [MH+]

Example 40

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methoxyphenyl]acetamide s :

APCI-MS: m/z 462 [MH+]

Example 41

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-6- fluorophenyl]acetamide

APCI-MS: m/z 450 [MH+]

Example 42

N-[2-Fluoro-6-(3-{[1-(4-fluorobenzyl)-4-piperidinyljamino}-2- hydroxypropoxy)phenyl]acetamide

APCI-MS: m/z 434 [MH+]

Example 43 2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-/V- methylbenzamide

APCI-MS: m/z 446 [MH+] : Example 44

N-(2-{3-[1-(3,4-Dichlore-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide

To a solution of N-(2-Oxiranylmethoxy-phenyl)-benzamide (0.2ml, 0.1M in DMSO) was added (0.2ml, 0.1M in EtOH) of 1-(3,4-Dichloro-benzyl)-piperidin-4-ylamine. The resulting mixture was heated at 75-80°C for 24hours. The ethanol was removed and the product was purified with preparative LC/MS.

APCI-MS: m/z 529[MH™]

The foiiowing Exampies 45-63 were synthesised by methods analogous to the method described in Example 44.

Example 45

N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-benzamide is APCI-MS: m/z 513[MH"]

Example 46

N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide.

APCI-MS: m/z 496[MH"]

Example 47

N-(2-{3-[1-(3,4-Dichlore-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- 2s phenyl)-acetamide

APCI-MS: m/z 481[MH"]

Example 48

N-(2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- phenyl)-acetamide

APCI-MS: m/z 430[MH]

Example 49

N-(2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino}-2-hydroxy-2-methyl-propoxy}- phenyl)-acetamide

APCI-MS: m/z 490[M+]

Example 50

N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy}- phenyl)-acetamide :

APCI-MS: m/z 481[MH"]

Example 51

N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide

APCI-MS: m/z 464[MH"]

Example 52 2s N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino}-2-hydroxy-2-methyl-propexy}- . phenyl)-acetamide

APCI-MS: m/z 448[MH]

Example 53

2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide

APCI-MS: m/z 476[M’]

Example 54 2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzaniide

APCI-MS: m/z 467[M"]

Example 55 2-{3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide

APCI-MS: m/z 432[MH"]

Example 56 2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide

APCI-MS: m/z 416]MH"]

Example 57 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(4-bromo-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS: m/z 456[MH")

Example S8

3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(3-chloro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS: m/z 512[MH"]

Example 59 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(3-fluoro-benzyl)-piperidin-4- ylamino}-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS: m/z 495[MH']

Example 60

N-(2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide

APCI-MS: m/z 476[M"]

Example 61

N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-acetamide

APCI-MS: m/z 450[MH"]

Example 62 | :

N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- . acetamide

APCI-MS: m/z 434[MH"]

Example 63

N-(2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide

APCI-MS: m/z 416]MH"]

THP-1 Chemotaxis Assay iniroduction

The assay measured the chemotactic response elicited by MIP-1c chemokine in the human monocytic cell line THP-1. The compounds of the Examples were evaluated by their ability to depress the chemotactic response to a standard concentration of MIP-1a chemokine.

Methods 1s Culture of THP-1 cells

Cells were thawed rapidly at 37°C from frozen aliquots and resuspended in a 25 cm flask containing 5 ml of RPMI-1640 medium supplemented with Glutamax and 10% heat inactivated fetal calf serum without antibiotics (RPMI+10%HIFCS). At day 3 the medium is discarded and replaced with fresh medium.

THP-1 cells are routinely cultured in RPMI-1640 medium supplemented with 10% heat inactivated fetal calf serum and giutamax but without antibiotics. Optimal growih of the cells requires that they are passaged every 3 days and that the minimum subculture density 1s 4x10+5 cells/ml.

Chemotaxis assay .

Cells were removed from the flask and washed by centrifugation in

RPMI+10%HIFCS+glutamax. The cells were then resuspended at 2x10+7 cells/ml in fresh medium (RPMI+10%HIFCS+glutamax) to which was added calcein-AM (5 pl of stock solution to 1 ml to give a final concentration of 5x107°M). After gentle mixing the cells were incubated at 37°C in a CO, incubator for 30 minutes. The cells were then diluted to 50 ml with medium and washed twice by centrifugation at 400xg. Labelled cells were then resuspended at a cell concentration of 1x10+7 cells/ml and incubated with an equal volume of MIP-1a antagonist (10M to 10M final concentration) for 30 minutes sat 37°C in a humidified CO, incubator.

Chemotaxis was performed using Neuroprobe 96-well chemotaxis plates employing 8 pm filters (cat no. 101-8). Thirty microlitres of chemoattractant supplemented with various concentrations of antagonists or vehicle were added to the lower wells of the plate in triplicate. The filter was then carefully positioned on top and then 25ul of cells preincubated with the corresponding concentration of antagonist or vehicle were added to the surface of the filter. The plate was then incubated for 2 hours at 37°C in a humidified

CO; incubator. The cells remaining on the surface were then removed by adsorption and the whole plate was centrifuged at 2000 rpm for 10 minutes. The filter was then removed 1s and the cells that had migrated to the lower wells were quantified by the fluorescence of cell associated calcein-AM. Cell migration was then expressed in fluorescence units after subtraction of the reagent blank and values were standardized to % migration by comparing the fluorescence values with that of a known number of labelled cells. The effect of antagonists was calculated as % inhibition when the number of migrated cells were compared with vehicle.

Claims (36)

1. A compound of general formula weft vf Rr’ RS R RT ; X z' SAE R . Rs HRY “OH 0 wherein mis0,1,2or3; each R! independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-Cg cycloalkyl, C,-Cg alkoxy, C;-Cg alkoxycarbonyl, C,-Cg haloalkyl, 10 C;-Cg haloalkoxy, -NR’R'®, C3-C cycloalkylamino, C;-Cg alkylthio, C,-Cs alkylcarbonyl, C,-Cg alkylcarbonylamino, sulphonamido, C,-Cg alkylsulphonyl, -CONR''R", -NR"’C(0)-(NH),R"*, phenyl, or C;-C alkyl optionally substituted by carboxy! or C;-Cg alkoxycarbonyl; pisOorl; Zz! represents a bond or a group (CH,), where qis 1 or2; 7? represents a bond or a group CH,, with the proviso that Zz! and 72 do not both simultaneously represent a bond; Q represents an oxygen or sulphur atom or a group CH, or NH; R® represents a group R'S ; nis0, 1 or2; each R’ independently represents a C;-Cg alkyl, C;-Cg alkoxycarbonyl, -CH,0H or carboxyl group;

RY, R’,R®and R’ each independently represent a hydrogen atom or a C;-Cg alkyl group, or RY, Rr, R® and R’ together represent a C,-C,4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or Rr’, RS and R7 each represent a hydrogen atom and R* and R® together with the carbon s atoms to which they are attached form a 5- to 6-membered saturated carbocycle; RS represents a hydrogen atom, a C,-Cg alkyl group or is linked to R* as defined above;

R® and R'® each independently represent a hydrogen atom or a C;-Cg alkyl group, or R’ and R"? together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;

R'! and R'? each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C;-C¢ alkoxycarbonyl; rR" represents a hydrogen atom or a C;-Cg4 alkyl group;

rR" represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl, C{-Cg alkoxy or C-Cg alkoxycarbonyl;

rR" represents carboxyl, C,-Cq alkoxy, C;-Cg alkylcarbonyl, C;-Cg4 alkoxycarbonyl, C-Cg alkoxycarbonylC;-Cg alkyl or a group NR'RS, -NHSO,CHj3;, -C(O)NR''R"®, -NHC(O)NR''R'®, -0C(O)NR''R'®, -0CH,C(O)NR'R'®, NHC(0)OR" or _NHC(O)R?,

» tis 0, 1,2 or 3; :

each R'® independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

C3-Cg cycloalkyl, C;-Cg alkoxy, C;-Cg4 alkoxycarbonyl, C;-C¢ haloalkyl,

C,-Cg haloalkoxy, NR?'R%, C;-Cg cycloalkylamino, C{-Cg alkylthio,

C,-Cg alkylcarbonyl, C;-Cg4 alkylcarbonylamino, sulphonamido, C;-Cg alkylsulphonyl, 2» -C(ONR®R*, -NR*™C(0)(NH),R*, phenyl, or C,-Cg alkyl optionally substituted by carboxyl or C-Cg¢ alkoxycarbonyl;

R'” and R'® each independently represent a hydrogen atom, or a C,-C alkyl group optionally substituted by carboxyl or C;-C¢ alkoxycarbonyl, or R' and R'® together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;

Rr" represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl or C;-C¢ alkoxycarbonyl; R* represents a group C,-Cg alkyl, C,-Cq alkenyl, C5-C¢ cycloalkyl, adamantyl, Cs-Cg cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic s ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C;-Cg alkyl, C,-Cq alkoxy, C;-C¢ alkylthio, C,-Cq alkylcarbonyl, C-Cq alkoxycarbonyl, phenyl and _NHC(0)-R”; R*! and R** each independently represent a hydrogen atom or a C-Cg alkyl! group, or R*! and R® together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; R? and R* each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C,-C alkoxycarbonyl; visOorl; R% represents a hydrogen atom or a C,-Cy alkyl group: R* represents a hydrogen atom, or a C,-Cq alkyl group optionally substituted by carboxyl, C,-Cg¢ alkoxy or C-Cg¢ alkoxycarbonyl; and Rr” represents a C-Cg alkyl, amino (-NH;) or phenyl group; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, wherein m is i or 2.

3. A compound according to claim 2, wherein each R' represents a halogen atom.

4. A compound according to any one of claims 1 to 3, wherein Q represents an oxygen atom.

5. A compound according to any one of claims 1 to 4, wherein rR" represents a group 0 -NHC(O)R®.

6. A compound according to claim 5, wherein, in R%, the saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, is pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidiny], thienyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.

7. A compound according to any one of claims 1 to 6, wherein each R'® independently represents halogen, cyano, C;-C,4 alkoxy, C,-C, alkoxycarbonyl, C,-C, haloalkyl, to C,-C4 alkylcarbonyl, phenyl or C;-C, alkyl.

8. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1 being selected from: N-[2-(3-{[1-(3,4-dichlorobenzylpiperidinylJaminohydroxypropoxy)phenyljacetamide, (5 N-[5-chloro-2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyljamino}-2- hydroxypropoxy)phenyl]acetamide, N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinylJamino } -2-hydroxypropoxy)-5- methylphenyljacetamide, N-[4-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino } -2-hydroxypropoxy)[1,1'- biphenyl]-3-yllacetamide, N-[3-acetyl-2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)- 5-methylphenyl]acetamide, N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)-4- fluorophenyl]acetamide, N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinylJamino}-2-hydroxypropoxy)-5- fluorophenyljacetamide, N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinylJamino} -2-hydroxypropoxy)-5- cyanophenyl]acetamide, N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinylJamino} -2-hydroxypropoxy)phenyl]- acetamide,

N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amin0 } -hydroxypropoxy)phenyl]- 1sobutyramide, N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]Jamino}-2-hydroxypropoxy)phenyl]-2-2- dimethyl-propiomanide, N-{5-chloro-2-(3-{[1-(4-chlorobenzyl)-4-piperidinyi]amino} -2- hydroxypropoxy)phenyl]acetamide, N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinylJamino} -2-hydroxypropoxy)-5- methyiphenyijacetamde, N-[2-(3-{[1-(4-chlorobenzy!)-4-piperidinylJamino} -2-hydroxypropoxy)-4- methylphenyl]acetamide, N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl amino} -2-hydroxypropoxy)-4- fluorophenyllacetamide, N-[2-(3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)-5- cvanaphenyllacetamide.

N-(2-{[(2S)-3-({-[(4-Chlorophenyl)methyl |-4-piperidinyl }amino)-2- hydroxypropylloxy}phenylacetamide bi(trifluoroacetate), N-(2-{(2R)-3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide, N-(2-{[3-({ 1-[(4-Chlorophenyl)methyl]-4-piperidinyl} amino)-2-hydroxy-2- methylpropyl]oxy}phenyl)acetamide, N-(2-{(25)-3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy }-phenyl)-acetamide, N-{2-[((2S)-3-{[1-(4-Fluorobenzyl)-4-piperidinyl Jamino } -2- hydroxypropyl)oxy]phenyl} acetamide, N-{2-[((2S)-3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl}acetamide, N-{4-fluoro-2-[((2S)-3-{[1-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropyl)oxy]phenyl}acetamide, N-{2-[((2S)-3-{[(35)-1-(4-Chlorobenzyl)pyrrolidinylJamino} -2-hydroxypropyl)oxyl- 4-fluorophenyl}acetamide,

N-{2-[((25)-3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinylJamino} 2-hydroxypropyl)oxy]- 4-fluorophenyl} acetamide, N-[2-(3- {[1-(4-Fluorobenzyl)-4-piperidinylJamino} -2-hydroxy-2- methylpropoxy)phenyljacetamide, N-[2~(3- {[1-(4-Chlorobenzyl)-4-piperidinylJamino} -2-hydroxy-2-methylpropoxy)-4- fluorophenyl]acetamide, N-[4-Fluoro-2-(3- {[1-(4-fluorobenzyl)-4-piperidinyl]amino} -2-hydroxy-2- methylpropoxy)phenyl]acetamide, N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinylJamino}-2-hydroxypropoxy)-4- methylphenyl]acetamide, N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinylJamino}-2-hydroxypropoxy)-4- methylphenyl]acetamide, N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinylJamino} -2- hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[1-(4-Fluorobenzyl)-4-piperidinylJamino}-2- hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[(3S)-1-(4-Chlorobenzyl)pyrrolidinylJamino}-2- hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl]Jamino} -2- hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[1-(4-Bromobenzyl)-4-piperidinyl Jamino}-2- hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide, N-[2-(3-{[1 -(4-Fluorobenzy1)-4-piperidinyl] amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide, N-[2-(3-{[(3R)-1-(4-Chlorobenzyl)pyrrolidinyl ]amino }-2-hydroxy-2- methylpropoxy)phenyl]benzamide, N-[2-(3- {[1-(4-Bromobenzyl)-4-piperidinylJamino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide,

N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinylJamino -2-hydroxypropoxy)-4- methoxyphenyl]acetamide, N-[2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino } -2-hydroxypropoxy)-6- fluorophenyl]acetamide, N-[2-Fluoro-6-(3-{[1-(4-fluorobenzyl)-4-piperidinyllamino} -2- hydroxypropoxy)phenyl]acetamide, 2-(3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-N- methyibenzamide, N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyl)- benzamide, N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-benzamide, : N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino}-2-hydroxy-propoxy} -pheny})- henzamide. 1s N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino J-2-hydroxy-propoxy } -6- methyl-phenyl)-acctamide, N-(2- {3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino}-2-hydroxy-propoxy} -6-methyl- phenyl)-acetamide, N-(2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy } - phenyl)-acetamide, N-(2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy }-phenyl)-acetamide, N-(2- {3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino}-2-hydroxy-2-methyl- propoxy }-phenyl)-acetamide, N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy }-phenyl)-acetamide, 2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino}-2-hydroxy-propoxy} -N-methyl- benzamide, 2-{3-[1-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy } -N-methyl- benzamide,

2-{3-[1-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -N-methy]l- benzamide, 2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -N-methyl- benzamide, 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(4-bromo-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide, 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(3-chloro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide, 3,5-Dimethyl-1H-pyrrole-2-carboxylic acid (2-{3-[1-(3-fluoro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide, N-(2-{3-[1-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy } -phenyl)- acetamide, N-(2-{3-[1-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} - phenyl)-acetamide, N-(2-{3-[1-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy } -phenyl)- acetamide, and N-(2-{3-[1-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyl)- acetamide.

9. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises, (a) reacting a compound of general formula R' cS J 7 1 RY), Z NH, ay wherein m, n, z!, 72, R! and R? are as defined in formula (D), with a compound of general formula oR 4 >< ~_ Rr? 7 (IID

. 2 4 55 6 7 8 . wherein Q,R™, R",R", R", R" and R" are as defined in formula (I); or (b) reacting a compound of general formula 5 I i rR? RS (R Ji I 1 | RR ZZ 1

NN . PS ee (Rn R av)

. 1 52 51 53 54 5 6 7 8 . . whereinm,n,Z ,Z",R",R",R,R",R",R and R" are as defined in formula (I), with a compound of general formula L'-Q-R* (VW) wherein L! represents a hydrogen atom or a leaving group and Q and R” arc as defined in formula (I); or (c) reacting a compound of general formula ZN2 ~~ N™ ~z LY L = NF ~ Zz" So (R) " (VD wherein m, n, z} 72, R! and R? are as defined in formula (1), with a compound of general formula HOR’ q HN Nn? .

wherein Q, Rr, RY R>, RS, R” and R® are as defined in formula (I); and optionally after (a), (b) or (c) 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).

10. 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 8 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A process for the preparation of a pharmaceutical composition as claimed in claim 10 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 8 with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. A compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 for use in therapy.

13. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament 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 8 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.

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 8 in the manufacture of a medicament for use in treating rheumatoid arthritis.

16. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease.

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 8 in the manufacture of a medicament for use in treating asthma.

18. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use In treating multiple sclerosis.

19. A method of treating an inflammatory disease in a patient suffering from, or at risk of. 1s 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 claimed in any one of claims 1 to 8.

20. A method of treating an airways 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 claimed in any one of claims 1 io 8.

60 PCT/SE01/01377

16. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease.

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 8 in the manufacture of a medicament for use in treating asthma.

18. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating multiple sclerosis.

19. A method of preventing an inflammatory disease in a subject at risk of said disease, which comprises administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8.

20. A method of preventing an airways disease in a subject at risk of said disease, which comprises administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8. :

21. A substance or composition for use in a method for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claim 1 to 8, and said method comprising administering said substance or composition.

22. A substance or composition for use in a method for treating rheumatoid arthritis, said substance or composition comprising a compound of formula (I), or a AMENDED SHEET f

61 PCT/SE01/01377 pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8, and said method comprising administering said substance or composition.

23. A substance or composition for use in a method for treating chronic obstructive pulmonary 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 8, and said method comprising administering said substance or composition.

24. A substance or composition for use in a method for treating asthma, 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 8, and said method comprising administering said substance or composition.

25. A substance or composition for use in a method for treating multiple sclerosis, 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 8, and said method comprising administering said substance or composition.

26. A substance or composition for use in a method of treating inflammatory disease in a subject 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 8, and said method comprising administering a therapeutically effective amount of said substance or composition to the subject.

27. A substance or composition for use in a method of treating an airways disease in a subject 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 8, and said method comprising administering a therapeutically effective amount of said substance or composition to the AMENDED SHEET f

] 62 PCT/SE01/01377 subject.

28. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8, in the manufacture of a preparation for treating an inflammatory disease in a subject suffering from, or at risk of said disease.

29. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8, in the manufacture of a preparation for treating an airways disease in a subject suffering from, or at risk of, said disease.

30. A compound according to claim 1, substantially as herein described and illustrated.

31. A process according to claim 9, or claim 11, substantially as herein described and illustrated.

32. A composition according to claim 10, substantially as herein described and illustrated.

33. A substance or composition for use in a method of treatment according to claim 12, or any of claims 21 to 27, substantially as herein described and illustrated.

34. Use according to any of claims 13 to 18, or 28, or 29, substantially as herein described and illustrated.

35. A method according to claim 19, or claim 20, substantially as herein described and illustrated.

36. A new compound; a new process for preparing a compound; a new process for preparing a composition; a new composition; a substance or composition for a new use in a method of treatment; a new use of a compound of formula (I), or a pharmaceutically AMENDED SHEET ¢

: | 63 PCT/SE01/01377 acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8; or a new non- therapeutic method of treatment, substantially as herein described.

AMENDED SHEET !