ZA200206402B

ZA200206402B - Novel compounds.

Info

Publication number: ZA200206402B
Application number: ZA200206402A
Authority: ZA
Inventors: Peter Hansen; Lars Pettersson
Original assignee: Astrazeneca Ab
Priority date: 2000-02-25
Filing date: 2002-08-12
Publication date: 2003-11-12
Also published as: ZA200206665B; ZA200206404B; SE0000620D0

Description

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

US 5789402 describes certain indole deriatives which are said to be useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems, particularly those relating to the serotonin 1 4 receptor and those relating to the uptake of serotonin.

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 amine 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 neulrophil-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 lo and 18 (MIP-1a and MIP-18).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR.1, CCR2,

CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCRS8, CCRY9, CCR10, CXCR1,

CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug 4 development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those previously mentioned. ¢

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

RA OH a

R N2

RRR WR

4 6

R R ® wherein,

R represents either a group 3

Xy 2 Fn 1 Z

Sf JE 2

OF a group

H

N

1

N_ . mis 0, 1,2 0r3; each R! independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

C;-Cg cycloalkyl, C;-Cq alkoxy, C,-Cgq alkoxycarbonyl, C;-Cg haloalkyl,

C;-Cg¢ haloalkozry, -NRR!?, C3-Cg cycloalkylamino, C;-Cg alkylthio, C;-Cg alkylcarbonyl, C;-C4 alkylcarbonylamino, sulphonamido (-SC,NH,),

CC alkylsulphonyl, -C(ONR''R", NRPC(O)-@TH),R', phenyl, or C1-Cg alkyl optionally substituted by carboxyl or C;-Cg alkoxycarbonyl; pisQOorl;

X represents an oxygen or sulphur atom or a CH,, CH(CHj3), CCH,, CH,O, CH,NH, . NH or carbonyl! group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH,0, CH,NH or NH group, then ‘ Y represents a CH group; 7! represents a bond or a group (CHy)q where q is 1 or 2; 7? represents a bond or a group CH,, with the proviso that Z! and 7? do not both simultaneously represent a bond;

Q represents an oxygen or sulphur atom or a group CH, or NH; 2

R” represents a group 0

RE on T= \ [ J" oy [ ;

LK

: HN” TCH, Jig

HN CH,

O y

PIS or © HC N° of . nis0, 1 or 2; each R’ independently represents a Cy-Cg alkyl, C,-Cg¢ alkoxycarbonyl, -CH,OH or . 15 carboxyl group; 1:8 R>, RS and R” each independently represent a hydrogen atom or a C,-Cg alkyl ’ group, or R®, RS, R® and R” to gether 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’, RS 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;

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 Cy-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;-Cg¢ alkoxycarbonyl; rR? represents a hydrogen atom or a C;-Cg alkyl group; rR represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl, C,-Cq alkoxy or C;-Cg¢ alkoxycarbonyl; rR? represents carboxyl, C;-Cg alkylcarbonyl, Cy-Cg alkoxycarbonyl,

C,-Cy alkoxycarbonylC;-Cq alkyl or a group -NR''R'S, -NHSO,CH;, -NHC(O)CHs, -CONR'R', -NHC(ONR!'R®, -0C(ONR'R'®, -OCH,C(O)NR!TR?,

NHC(©O)OR!” or -OR' : tis 0, 1, 2 or 3; each R'S independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

C3-C4 cycloalkyl, Cq-Cg alkoxy, C,-Cq alkoxycarbonyl, C{-Cg4 haloalkyl,

C;-Cq haloalkoxy, NRY¥R%, C3-C¢ cyclozlkylamino, C;-Cgq alkylthio,

C;-C; alkylcarbonyl, Cy-Cq alkylcarbonylamino, sulphonamide (-SO,NH,),

C,-Cg alkylsulphonyl, -C(O)NR?'®*?, -NR*C(O)NE),R*, phenyl, or C;-Cy alkyl optionally substituted by carboxyl or C;-Cg¢ alkoxycarbonyl;

R'7 and R'® each independently represent (i) a hydrogen atom, (ii) a 5- to 6- membered saturated or unsaturated ring which may comprise at least one heteroatom : chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a C;-Cgq alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C;-Cg¢ alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one e substituent selected from halogen, methyl and trifluoromethyl, or

R'7 and R!® together with the nitrogen atom to which they are attached form a 4-to 7- : membered saturated heterocycle; 5 RY represents a hydrogen atom, or a C-Cgq alkyl group optionally substituted by carboxyl or C;-Cg alkoxycarbonyl;

R'”" is defined as for R!” above except that R'" does not represent a hydrogen atom;

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

RY and R% to gether with the nitrogen atom to which they are attached form a do to T- membered saturated heterocycle;

R?! and R? each independently represent a hydrogen atom or a Cy~Cq¢ alkyl group optionally substituted by C;-Cg4 alkoxycarbonyl; visOQorl;

RZ represents a hydrogen atom or a C;-Cg alkyl group; and r* represents a hydrogen atom, or a C;-Cq alkyl group optionally substituted by carboxyl, C;-Cg alkoxy or C;-Cq alkoxycarbonyl, provided that when X is an oxygen atom or a group CH,, Y is CH, 7! and 72 each represent a group CH, and Q is an oxygen atom, then R? is other than an unsubstituted indolyl group; or a pharmaceutically acceptzble 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.

In one aspect of the present invention, there is provided a compound of general formula

RCH a ’ Le

RY R° a : wherein,

R represents a group : yrs p hn (" tT L f

SAN mis@, 1,2 or 3; each R} independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

C5-Cg cycloalkyl, C;-Cq alkoxy, C;-Cq alkoxycarbonyl, C;-Cg haloalkyl, =

C,-Cg haloalkoxy, -NR’R'?, C,-Cj cycloalkylarnino, C;-Cy alkylthio, . C1~Cg alkylcarbonyl, C;-Cg alkylcarbonylamino, sulphonamido, C;-Cg alkylsulphonyl, 10 .C(O)NR!'R2, NRPC(0)-NH),R phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C;-Cg alkoxycarbonyl; pisOorl;

X represents an oxygen or sulphur atom or a CH,, CH(CHj3), OCH,, CH,0, CH,NH,

NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CHO, CEHLNH or NH group, then

Y represents a CH group; 7! represents a bond or a group (CHy)q where gis 1 or 2; z? represents a bond or a group CH,, with the proviso that z! and 7? do not both simultaneously represent a bond;

Q represents an oxygen or sulphur atom or a group CH, or NH; rR? represents a group 15

Ge

‘ nis0,1 or 2; : each R’ independently represents a C;-Cq alkyl, C;-Cg4 alkoxycarbonyl, -CH,0H or ’ carboxyl group;

RY, Rr’, R® and R” each independently represent a hydrogen atom or a C;-Cg alkyl group, or R*, RS, 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, oor rR, R® and R’ each represent a hydrogen atom and R* and R10 gether with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;

R® represents a hydrogen atom, a C;-Cgq alkyl group or is linked to R* as defined above;

R’ and R!? each independently represent a hydrogen atom or a C4-Cgq allyl aroun, or

Rr’ and R'® together with the nitrogen atom to which they are attached form 2 4- to 7- membered saturated heterocycle; | oo

R'! and R'? each independently represent a hydrogen atom or a C-Cgq alkyl group optionally substituted by C,-Cq alkoxycarbonyl; jl represents a hydrogen atom or a C;-Cg alkyl group;

RM represents a hydrogen atom, or a C;-Cg4 alkyl group optionally substituted by carboxyl, C;-Cq alkoxy or C,-Cg¢ alkoxycarbonyl;

RY represents carboxyl, Ci-Cg alkylcarbonyl, C;-Cg4 alkoxycarbonyl,

C,-Cy alkoxycarbonylCy-Cg 2lkyl or a group -NR''R'®, -NHSO,CH,, -NHC(O)CH,, c(©©NR'R'E, -NHCONR!R'S, -oc(O)NR'R!®, -oCH,C(ONR'R',

NHCO)CR! or -OR'; tis 0, 1, 2 or 3; each R'® independently represents halogen, cyano, nitro, carboxyl, hydroxyl, ) C;-Cg cycloalkyl, C;-Cq alkoxy, C,-C4 alkoxycarbonyl, C;-C4 haloalkyl,

C;-Cg haloalkoxy, -NR'R?, C4-C cycloelkylemino, C;-Cg alkylthio,

C,-Cg alkylcarvonyl, C,-Cy alkylcarbonylamino, suiphonamido (-SO,INHj,),

C,-Cg alkylsulphonyl, -C(O)NRHR%, NRZco)m), RY, phenyl, or C(~Cg alkyl optionally substituted by carboxyl or C;-Cg alkoxycarbonyl;

RY and R'® each independently represent (i) a hydrogen atom, (ii) a 5- to 6- " membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at : least one substituent selected from halogen, methyl and triftuoromethyl, or - 5 (ii) a Cy-Cq4 alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C;-Cg alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or

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

RY represents a hydrogen atom, or a C-Cg alkyl group optionally substituted by carboxyl or C,-Cg alkoxycarbonyl;

R'7" is defined as for R' above except that R'” does not represent a hydrogen atom;

R* and R?® each independently represent a hydrogen atom or a C;-Cy alkyl group, or

RY 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 1-Ce alicyl group optionally substituted by C;-Cg4 alkoxycarbonyl; visQorl; -

RZ represents a hydrogen atom or a C;-Cg alkyl group; and

Rr represents a hydrogen atom, or a C-Cg alkyl group optionally substituted by carboxyl, C;-Cg alkoxy or Cy-C¢ alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof. ) In another aspect of the invention, there is provided a compound of general formula

ROH

Le ~g2

RR a wherein, - R represents a group

Xo ~~ (R), of J § i

SAN mis 0, 1,2o0r3; each R' independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

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

C,-Cg haloalkoxy, NR°R'?, C5-Cg cycloalkylamino, C;-Cg4 alkylthio,

Cy-Cg alkylcarbonyl, C;-Cgq alkylcarbonylamine, sulphonamido, C;-Cg4 alkylsulphonyl, -CONR''RY, NRPC(0)-(NH),R™, phenyl, or C,-Cg alkyl optionally substituted by carboxyl or C;-Cq alkoxycarbonyl; pisQorl; | | as

X represents an oxygen or sulphur atom or a CH,, CH(CH3), OCH,, CH,0, CH,NH,

NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided oo | . that when X represents an oxygen or sulphur atom or a CH,O, CH,NH or NH group, then

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

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

R? represents a group

O

. HI neX 3

WO o a Jil ® HN” CH,

SOPRECE nisQ, 1 or2; } each R> independently represents a C;-Cq alkyl, C,-Cg¢ alkoxycarbonyl, -CH,OH or carboxyl group; a RY, 150 R® and'R each independently represent a hydrogen. atom or a C;-Cg alkyl - group, or. RY, R’, R® and R’ together represent a C4-C; alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or rR’, R® and R” each represent a hydrogen atom and R* and R® together with the carbon atoms to which they are atiached form a 5- to 6-membered saturated carbocycle;

RS represents a hydrogen atom, a C;-Cgy alkyl group or is linked to R? as defined above;

R’ and R'? each independently represent 2 hydrogen atom or a C;-Cg alkyl group, or rR’ and R10 together with the nitrogen atom to which they are attached form a 4- to 7- 1s membered saturated heterocycle;

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

RM represents a hydrogen atom, or a C;-Cg4 alkyl group optionally substituted by . carboxyl, C-Cg alkoxy or C;-Cg alkoxycarbonyl; provided that when X is an oxygen atom or a group CH,, Y is CH, 7! and 7° each : represent a group CH, and Q is an oxygen atom, then R? is other than an unsubstituted 5s indolyl group; or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect of the invention, there is provided a compound of general formula

RY OH

LSE

| RR a) wherein,

R represents a group ~ 5 mis 0,1,2or3; each R! mdependently represents halogen, —— nitro, carboxyl, hydroxyl,

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

C,-Cg haloalkoxy, -NR°R', C3-C¢ cycloalkylamino, C,-Cg alkylthio,

C;-C¢ alkylcarbonyl, C;-Cg alkylcarbonylamino, sulphonamide, C;-Cg4 alkylsulphonyl, 2 -CONR'R?, NR"C(0)-(NH),R", phenyl, or C;-Cq alkyl optionally substituted by carboxyl or C-C¢ alkoxycarbonyl; pisOor 1; } Q represents an oxygen or sulphur atom or a group CH, or NH;

R? represents a group

O eX . 3

R"™ HN NT) : 16

X

HN" TCH, bie

HN CH,

O

’ PI] or © HC N

IH .

RY, Rr’, R® and R” each independently represent a hydrogen atom or a C-Cg alkyl group, or R®, RS, R® and R” to gether 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, © sor R’, RS 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;

RS represents a hydrogen atom, a C1-Cgq alkyl group or is linked to rR? as cefined above;

R® 2nd 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;

RM and R!? each independently represent a hydrogen atom or a C4-Cg alkyl group optionally substituted by C;-Cg4 alkoxycarbonyl; . 15 RY represents a hydrogen atom or a C;-Cg alkyl group;

RM represents a hydrogen atom, or a Cy-Cg alkyl group optionally substituted by ) carboxyl, C;-Cg alkoxy or C;-Cg¢ alkoxycarvonyl;

RY represents carboxyl, C;-Cq alkylcarbonyl, C{-Cq alkoxycarbonyl,

CC alkoxycarbonylC;-Cg alkyl or a group -NRVR®, -NHSO,CH;, -NHC(C)CH;,

-CONRRY, -NHCONR'TR', -0Cc(ONR!R', -OCH,C(ONRIR®, -NHC©@)OR!” or -oR!7"; tis 0,1, 2 or 3; * each R? 6 independently represents halogen, cyano, nitro, carboxyl, hydroxyl,

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

C,-Cg haloalkoxy, -NR''R?®, C;-Cg eyeloalkylarnine, C;-Cy alkylthio,

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

C;-Cg alkylsulphonyl, -C(ONR?'R*, -NRZC(O)(NH),R?*, phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C,-Cg4 alkoxycarbonyl;

R'7 and R'® each independently represent (i) a hydrogen atom, (ii) a 5- to 6- membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a C;-Cq alkyl group optionally substituted by at least one substituent selected from 1s halogen, trifluoromethyl, carboxyl, C{-Cg4 alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or

RY and R'E 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;

R!7" is defined as for R!7 above except that RY” does not represent a hydrogen atom;

R'® and R?® each independently represent a hydrogen atom or a C;-Cg alkyl group, or 35 RY and R% together with the nitrogen atom to which they are attached form a 4- io 7- : membered saturated heterocycle;

R?! and R? each independently represent 2 hydrogen atom or a C;-Cg alkyl group optionally substituted by C;-Cg¢ alkoxycarbonyl; visQorl; r% represents a hydrogen atom or a C;-Cg alkyl group; and

R* represents a hydrogen atom, or a C;-C¢ alkyl group optionally substituted by - carboxyl, C;-Cg alkoxy or C;-Cg4 alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof.

The integer m is preferably 0, 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), Ci-Cg, preferably C;-C,, alkoxycarbonyl (e.g. methoxycarbenyl or ethoxycarbonyl), C;-Cg, preferably C;-C,, haloalkyl (e.g. triflucromethyl),

C,-Cs, preferably C;-C,, haloalkoxy (e.g. trifluoromethoxy), NRR?,

C;3-Cq cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C1-Cg, preferably C;-C,, alkylthio (e.g. methylthio or ethylthio),

C;-Cg, preferably Ci-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, oo n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl.or : n-hexylcarbonyl), C;-Cg, preferably C;-Cy, alkylcarbonylamino (e.g. - methylcarbonylamino or ethylcarbonylamine), sulphonamido,

C1-Ce, preferably C1-C,, alkylsuiphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(ONR! R12, NR CO) NE,R phenyl, or

C1-Cy, preferably C1-Cy, 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

C4-Cy, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl). ) Most preferably, each Rr! independently represents halogen (particularly chlorine or ] fluorine), cyano, nitro, C;-Cq alkoxy (especially methoxy), C1-Cg alkylcarbonyl (especially methylcaroonyl) or C;-Cq4 alkylcarbonylamino (particularly methylcarbonylamino).

Preferably X represents an oxygen atom or a CH,, OCH,, CH,0, NH or carbonyl group.

Preferably Y represents a nitrogen atom or CH group. 5s Preferred combinations of X - Y include O - CH, OCH, - CH, NH - CH, CH,O - CH,

CH, -N, C(O) -N and CH, - CH.

Preferred combinations of Y, 7! and 7? include: bond cH, (CHa),

Q preferably represents an oxygen atom.

Each rR’ independently represents a C,-Cg, preferably C;-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C;-Cg, preferably is Cy-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), -CH,OH or carboxyl group. [iis preferred that rR? represents a methyl, methoxycarbonyl, ethoxycarbonyl, -CH,OH or carboxyl group.

RY, rR, R® and R7 each independently represent a hydrogen atom or a Cy-Cg, preferably

C;-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl ; or n-hexyl), or RY, R’, R°and R to gether 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 (e.g. cyclohexyl or preferably cyclopentyl), or R’, RS and R7 each represent a hydrogen atom and R* and R® to gether with the carbon atoms to which they are attached form a 5- to . 6-membered saturated carbocycle (preferably cyclopentyl). : R® represents a hydrogen atom, a C,-Cg, preferably C,-Cy, alkyl group (e.g. methyl, ethyl, 5s n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to R's defined above.

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

C1-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or rR’ and R'% to gether 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 hydro gen 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.

RB represents a hydrogen atom or a C;-Cyg, preferably C;-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-peniyl or n-hexyl).

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

Cy-Cy4, alkoxycarbonyl. } RY represents carboxyl, C;-Cg, preferably C;-C,, alkylcarbonyl (e.g. methylcarbonyi, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), Cy-Cg, preferably C;-Cy, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C;-Cg¢ alkoxycarbonylC,-Cg alkyl, preferably

C;-C4 alkoxycarbonylC;-C, alkyl (e.g. methoxycarbonylmethyl or methoxycarbonylethyl), . ora group -NR''R'®, -NHSO,CH;, -NHC(C)CH;, -C(ONR'R!, -NEHC(O)NR!'RY, -OC(O)NR'R!3, _0CH,c(O)NR'R!®, -NHC(©O)OR! or -OR!". .

Itis preferred that rR" represents C;-C, alkoxy (especially methoxy), C;-C, alkylcarbony! (especially methylcarbonyt or ethylcarbonyl), C;-C,4 alkoxycarbonylCq-C, alkyl (particularly methoxycarbonylmethyl or methoxycarbonylethyl), -NHC(C)CHj, -C(ONR'R®, -NHSO,CH; or -NHC(O)NR''R'®, 0 BachR!® independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C5-C cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C,-Cg, preferably C;-C,, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C4-Cg, preferably C;-Cy, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C;-Cg, preferably C;-Cy, haloalkyl (e.g. trifluoromethyl),

Cy-Cg, preferably Cy-Cy, haloalkoxy (e.g. trifluoromethoxy), NR¥R?, - C3-C4 cycloalkylamino (e.g. cyclopropylamino, cyclobutylamine, cyclopentylamino or cyclohexylamino), C;-Cg, preferably C,-C,, alkylthio (e.g. methylthio or ethylthic),

C,-Cy, preferably C,-Cy, alkylcarbony! (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or mn-hexylcarbonyl), Cy-Cg, preferably Ci-Cy, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamine), sulphonamide,

C,-Cs, preferably C;-Cy, alkylsulphonyl (e.g. methylsulphonyl, ethylsuiphonyl, n-propylsulphonyl, isopropylsuiphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsufphonyl), -C(ONRY'R%, NR*C(O)-(NH),R%, phenyl, or

Cy-Cg, preferably Cy-Cy, 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;-Cy, alkoxycarbonyl (e.g. methoxycarbony! or ethoxycarbonyl).

Preferably, each Rr’ independently represents halogen (particularly chlorine or fluorine), . hydroxyl, cyano, C;-C, alkoxy (especially methoxy), C,-C, alkoxycarbonyl! (especially methoxycarbonyl), C;-C, haloalkyl (especially trifluoromethyl), C;-C, alkylcarbonyl ) (particularly methylcarbonyl), phenyl or C;-C,4 alkyl (e.g. methyl or tert-butyl).

R'7 and R'® each independently represent (i) a hydrogen atom, (ii) a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom (e.g. one, two or three heteroatoms independently) chosen from nitrogen, oxygen and sulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), the ring being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g.

Co fluorine, chlorine, bromine or icdine), methyl and trifluoromethyl, or (iii) 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 at least one substituent (e.g. one, two or three substituents independently) selected from - - halogen (e.g. fluorine, chlorine, bromine or iodine), triflucromethyl, carboxyl,

C,-Cs, preferably C1-C,, alkoxycarbonyl, especially methoxycarbonyl, and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom (e.g. one, two or three heteroatoms independently) chosen from nitrogen, oxygen and sulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), the ring being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. flucrine, chlorine, bromine or iodine), methyl and trifluoromethyl, or 2s RY andR'® together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).

RY represents a hydrogen atom or a C1-Cg, preferably C,-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally

Claims

1. A compound of general formula

RA. OH A R? : R R a. RY R° ™ wherein, R represents a group Xe ®), rl NUN mis0,1,2o0r3; 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'®, C,-C¢ cycloalkylamino, C;-Cg alkylthic, . C1-Cg alkylcarbonyl, C,-Cg alkylcarbomylamino, sulphonamide, C;-Cg4 alkylsulphonyl, -C(O)NR!R!?, NRPc©)-aER"Y, phenyl, or C;-Cq4 alkyl optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl; pisOor 1; X represents an oxygen or sulphur atom or a CH,, CH(CHj3), OCH,, CH,0, CH,NH, NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH,0, CH,NH or NH group, then Y represents a CH group; z! 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 Zz! and 7? do not both ‘ simultaneously represent a bond, Q represents an oxygen or sulphur atom or a group CH, or NH; Rr? represents a group

WQ 01/62729 PCT/SEO1/00404

. C ~ H,C A \ © OU O on o en, Roa: or (J why B® H 5 nis0,1or2; each R’ independently represents a C;-Cg alkyl, C;-Cg4 alkoxycarbonyl, -CH,OH or carboxyl group; : RY, rR, R® and R” each independently represent a hydrogen atom or a C,-Cg alkyl group, or RY, Rr, R® and R7 together represent a C,-C4 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 R” each represent a hydrogen atom and R* and R® 10 gether with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle; R® represents a hydrogen atom, a C;-Cgq alkyl group or is linked to R* 2s defined above; R® and R' each independently represent a hydrogen atom or a C;-Cg alkyl group, or is RP andR'%to gether 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,-Cgq alkoxycarbonyl; Rr represents a hydrogen atom or a C;-Cg alkyl group; and

Rr represents a hydrogen atom, or a C{-Cg¢ alkyl group optionally substituted by . carboxyl, C1-C¢ alkoxy or C1-Cg alkoxycarbonyl; provided that when X is an oxygen atom or a group CH,, Y is CH, Zz! and 7? each ’ represent a group CH, and Q is an oxygen atom, then Ris other than an unsubstituted indolyl group; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, wherein X represents an oxygen atom or a CH,, OCH,, CH,0, NH or carbonyl group.

3. A compound according to claim 1 or 2, wherein Y represents a nitrogen atom or CH group.

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 I to 4, wherein rR? represents a group 0 yg HIN I\ : > ICD or H,C N H

6. A compound of formula (I), or a pharmaceutically acceptable salt or selvate thereof, as defined in claim 1 being selected from: 1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-y1]-3-(1H-indol-7-yloxy)-propan-2-ol, 1-(7-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin- 1-yl}-2-hydroxy-propoxy} -indol-1-y1)- ethanone, 1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yi]-3-( 1 H-indol-7-yloxy)-propan-2-ol,

1-(7-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]}-2-hydroxy-propoxy } -indol-1-yl}- : ethanone, 1-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol, 1-(7-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy }~indol-1-yl)- ethanone, 1-[3-(3,4-Diflucro-phenoxy)-pysrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol, 1-(7-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin- 1-y1]-2-hydroxy-propoxy} -indol-1-y1)- ethanone, 1-(7-{3-[4-(3,4-Dichlorc-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy} -indol-1-yl)- ethanone, 1-(7-{3-[4-(4-Chloro-phenoxy) _piperidin-1 -yl}-2-hydroxy-propoxy }-indol-1-yl)- ethanone, N-(3-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-y1}-2-hydroxy-propoxy} -naphthalen- 2-yl)-acetamide, and N-(3-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} -naphthalen-2- yl)-acetamide.

7. 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-H a wherein R is as defined in formula (I"), with 2 compound of general formula oR a, RR qm) wherein Q, rR? rR? rR’, RS, R and RS are as defined in formula (IM); or (b) reacting a compound of general formula

Ro R R R av" wherein R, 1:8 : 5 RS, R” and R® are as defined in formula @™, with a compound of general formula L'-Q-R (v9 wherein L' represents a hydrogen atom or an activating group and Q and R? are as defined in formula (I"); and optionally thereafter converting the compound of formula (I") to a further compound of formula (I"); and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I").

8. A pharmaceutical composition comprising a compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed iri any one of claims 1 to 6 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 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 6 with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A compound of formula (I"), or a pharmaceutically-acceptable sali or solvate thereof, as claimed in any one of claims 1 to 6 for use in therapy.

11. Use of a compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in therapy.

PCT/SE01/60404

12. Useofa compound of formula (I"), or 2 pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.

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

14. Useofa compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease.

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

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 6 in the manufacture of a medicament for use in treating multiple sclerosis.

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 6 in the manufacture of a medicament for treating an inflammatory disease in a patient suffering from, or at risk of, said disease.

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 6 in the manufacture of a medicament for treating an airways disease in a patient suffering from, or at risk of, said disease. AMENDED SHEET

) 168 PCT/SEG1/00404

19. 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 claims 1 to 6, and said method comprising administering said substance or composition.

20. A substance or composition for use in a method of treating rheumatoid arthritis, 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 6, and said method comprising administering said substance or composition.

21. A substance or composition for use in a method of 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 6, and said method comprising administering said substance or composition.

22. A substance or composition for use in a method of 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 6, and said method comprising administering said substance or composition.

23. A substance or composition for use in a method of 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 6, and said method comprising administering said substance or composition. :

24. 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 6, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.

25. A substance or composition for use in a method of treating an airways disease in a patient suffering from, or at risk of, said disease, said substance or composition comprising a AMENDED SEIEET

169 PCT/SEQ1L/00404 compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.

26. A compound according to any one of claims 1 to 6, or 10, substantially as herein described and illustrated.

27. A process according to claim 7, substantially as herein described and illustrated.

28. A composition according to claim 8, substantially as herein described and illustrated.

29. A process according to claim 9, substantially as herein described and illustrated.

30. Use according to any one of claims 11 to 18, substantially as herein described and illustrated.

31. A substance or composition for use in a method of treatment according to any one of claims 19 to 25, substantially as herein described and illustrated.

32. A new compound, a new process for the preparation of a compound, a new composition, a new process for the preparation of a composition, a new use of a compound as claimed in any one of claims 1 to 6, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET