AU2007213744A1 - Piperidine derivatives as CXCR3 receptor antagonists - Google Patents

Description

WO 2007/090836 PCT/EP2007/051123 -1 PIPERIDINE DERIVATIVES AS CXCR3 RECEPTOR ANTAGONISTS Field of the invention 5 The present invention concerns piperidine derivatives having CXCR3 receptor antagonistic properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of a disease mediated through activation of the CXCR3 receptor. 10 Background prior art US 3,125,578 describes 2,6-dioxo-piperidine derivatives having anticholinergic activity. WO 95/11234 relates to N-derivatives of dexetimide suitable for PET studies and 15 SPECT studies of muscarinic receptors. Description of the invention The compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity and/or pharmacological potency. 20 One aspect of the present invention relates to a compound of formula R3 Y N RI-N) R2 a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof, wherein 25 X represents N or CH; Y represents a direct bond, CH 2 -C(=O) wherein the CH 2 is attached to the N of the piperidine ring, C(=O) or S(=0)p; p represents an integer of value 1 or 2; RI represents CH(R 4 )-aryl or CH(R 4 )-heteroaryl; 30 R2 represents aryl 2 or heteroaryl; R3 represents hydrogen, C1.

6 alkyl, polyhaloC1.

6 alkyl, CI 6 alkyloxy, aryll, aryll-NH-, heteroaryl, heteroaryl-NH-, C 3

.

7 cycloalkyl, amino or mono or di(C1.

4 alkyl)amino; R4 represents hydrogen or C1 4 alkyl; WO 2007/090836 PCT/EP2007/051123 -2 R and R6 each independently represent hydrogen, or C1.

6 alkyl optionally substituted with hydroxyl; or

R

5 and R6 together with the nitrogen to which they are attached form a monocyclic heterocycle selected from piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, 5 each of said rings optionally substituted with C1 4 alkyl; aryl represents unsubstituted naphthyl; or phenyl or naphthyl, each of said phenyl or naphthyl substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo, hydroxyl, CI 6 alkyl,

C

1

.

6 alkyloxy, C 1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, 10 polyhaloCI 6 alkyl, polyhaloCI.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -,

CI

4 alkyl-SO 2 -, R6R N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino,

C

1

.

4 alkylcarbonylamino, aryll, aryl CI 4 alkyloxy, arylloxy, or arylC(=O)-; aryll represents phenyl or phenyl substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, hydroxyl, C1.

6 alkyl, CI.

6 alkyloxy, 15 C 1

.

6 alkyloxycarbonyl, CI.

6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloCI.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, aminocarbonyl, mono-or di(Ci 4 alkyl)aminocarbonyl, amino, or mono-or di(Ci 4 alkyl)amino; aryl 2 represents phenyl or naphthyl, each of said rings optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent 20 independently selected from halo, hydroxyl, CI 6 alkyl, CI 6 alkyloxy,

C

1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -,

CI

4 alkyl-SO 2 -, R6R N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino,

C

1

.

4 alkylcarbonylamino, aryll, aryl CI 4 alkyloxy, arylloxy, or arylC(=O)-; 25 heteroaryl represents a monocyclic heterocycle selected from pyrrolinyl, imidazolinyl, pyrazolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; or a bicyclic heterocycle selected from indolyl, indolizinyl, isoindolyl, indolinyl, 30 benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, benzoxadiazolyl, benzoxazolyl, benzthiazolyl, each of said monocyclic or bicyclic heterocycles optionally being substituted with at least one substituent, in particular one, two or three substituents, 35 each substituent independently selected from halo, hydroxyl, CI 6 alkyl,

CI.

6 alkyloxy, CI 6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2

-,

WO 2007/090836 PCT/EP2007/051123 -3 C1.

4 alkyl-SO 2 -, R6R N-C(=0)-, amino, mono-or di(CI 4 alkyl)amino or

C

1

.

4 alkylcarbonylamino. The present invention also relates to the use of a compound of formula (I) for the 5 manufacture of a medicament for preventing or treating a disease mediated through activation of the CXCR3 receptor, in particular for treating a disease mediated through activation of the CXCR3 receptor, more in particular for preventing or treating an inflammatory disease, even more in particular for treating an inflammatory disease. 10 As used hereinbefore or hereinafter C1 4 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; CI 6 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for C1 4 alkyl and pentyl, hexyl, 15 2-methylbutyl and the like; C 3

.

7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As used hereinbefore, the term (=0) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety 20 when two of said terms are attached to a sulfur atom. The term halo is generic to fluoro, chloro, bromo and iodo. As used hereinbefore or hereinafter, polyhaloC1.

6 alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1.

6 alkyl, for example methyl substituted with one or more fluoro 25 atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atoms are attached to a C1.

6 alkyl group within the definition of polyhaloC1.

6 alkyl, they may be the same or different. The term heteroaryl, e.g. in the definition of R 1 or R2, is meant to include all the 30 possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl. The aryl, aryll, aryl 2 or heteroaryl listed in the definitions of the substituents of the compounds of formula (I) (see for instance R1, R2 and Ri) as mentioned hereinbefore or 35 hereinafter may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when heteroaryl is pyridyl, it may be for instance 3-pyridyl or 4-pyridyl.

WO 2007/090836 PCT/EP2007/051123 -4 When any variable occurs more than one time in any constituent, each definition is independent. 5 For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present 10 invention. The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained 15 by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, 20 ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form. The compounds of formula (I) containing acidic protons may be converted into their 25 therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to also comprise the therapeutically active non-toxic metal or amine addition salt forms (base addition salt forms) which the compounds of formula (I) are able to form. Appropriate base addition salt forms 30 comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, 35 diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, WO 2007/090836 PCT/EP2007/051123 -5 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form. 5 The term salt also comprises the quaternary ammonium salts (quaternary amines) which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted C 1

.

6 alkylhalide, arylhalide, 10 C 1

.

6 alkylcarbonylhalide, arylcarbonylhalide, or arylCi 6 alkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as for example C1.

6 alkyl trifluoromethanesulfonates, C1.

6 alkyl methanesulfonates, and C1.

6 alkylp-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, 15 acetate, triflate, sulfate, sulfonate. The counterion of choice can be introduced using ion exchange resins. The term solvate comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, 20 alcoholates and the like. The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide. 25 It will be appreciated that some of the compounds of formula (I) and their N-oxides, salts, and solvates may contain one or more centers of chirality and exist as stereochemically isomeric forms. 30 The term "stereochemically isomeric forms" as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, salts, solvates, or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all 35 diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts or solvates, substantially free, i.e. associated with less than 10%, preferably less than 5%, in WO 2007/090836 PCT/EP2007/051123 -6 particular less than 2% and most preferably less than 1% of the other isomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer. When a compound of formula (I) is specified as (RS), this means that the compound is 5 a mixture, in particular a racemic mixture, of the (R) and (S) isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen) -stereochemistry at said double bond. The terms cis, trans, R, S, E and Z 10 are well known to a person skilled in the art. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention. Following CAS-nomenclature conventions, when two stereogenic centers of known 15 absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R *,R * ] or [R *,S*], where the first R * is always specified as the reference center and [R *,R *] indicates centers with the same chirality and [R *,S*] 20 indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S-[R*,S*]. If "a" and "P" are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the "a" position of the mean plane determined by 25 the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated "a", if it is on the same side of the mean plane determined by the ring system, or "P", if it is on the other side of the mean plane determined by the ring system. 30 The compounds of (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said 35 diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula WO 2007/090836 PCT/EP2007/051123 -7 (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said 5 compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula (I) are intended to be 10 included within the scope of the present invention. The scope of the present invention also embraces all possible polymorphic forms which the compounds of formula (I) are able to form. 15 Whenever used hereinafter, the term "compounds of formula (I)" or any subgroup thereof, is meant to also include their N-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds of formula (I) which are stereochemically pure. 20 Whenever used hereinbefore or hereinafter that substituents can be selected each independently out of a list of numerous definitions, all possible combinations are intended which are chemically possible. A first interesting embodiment of the present invention are those compounds of 25 formula (I) wherein X represents N or CH; Y represents C(=O) or S(=0)p; p represents an integer of value 1 or 2; RI represents CH(R 4 )-aryl or CH(R 4 )-heteroaryl; 30 R2 represents aryl 2 or heteroaryl; R3 represents hydrogen, C1.

6 alkyl, C1.

6 alkyloxy, aryll, aryll-NH-, amino or mono or di(CI 4 alkyl)amino; R4 represents hydrogen or C1.

4 alkyl; R and R6 each independently represent hydrogen, or C1.

6 alkyl optionally substituted 35 with hydroxyl; or WO 2007/090836 PCT/EP2007/051123 -8

R

5 and R6 together with the nitrogen to which they are attached form a monocyclic heterocycle selected from piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each of said rings optionally substituted with C1 4 alkyl; aryl represents unsubstituted naphthyl; or phenyl or naphthyl, each of said phenyl or 5 naphthyl substituted with at least one substituent, each substituent independently selected from halo, hydroxyl, CI.

6 alkyl, CI.

6 alkyloxy, CI.

6 alkyloxycarbonyl,

C

1

.

6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C1.

4 alkyl-SO 2 -, R 6

R

5 N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino, C 1

.

4 alkylcarbonylamino, aryll, arylI CI 4 alkyloxy, arylloxy, or 10 aryl 1 C(=O)-; aryll represents phenyl or phenyl substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, hydroxyl, C1.

6 alkyl, CI.

6 alkyloxy,

C

1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloCI.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, aminocarbonyl, mono-or 15 di(Ci 4 alkyl)aminocarbonyl, amino, or mono-or di(Ci 4 alkyl)amino; aryl 2 represents phenyl or naphthyl, each of said rings optionally substituted with at least one substituent, each substituent independently selected from halo, hydroxyl,

C

1

.

6 alkyl, C 1

.

6 alkyloxy, CI 6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, 20 C1.

4 alkyl-SO 2 -, R6R N-C(=O)-, amino, mono-or di(C1.

4 alkyl)amino,

C

1

.

4 alkylcarbonylamino, aryll, aryl CI 4 alkyloxy, arylloxy, or arylC(=O)-; heteroaryl represents a monocyclic heterocycle selected from pyrrolinyl, imidazolinyl, pyrazolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, 25 pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; or a bicyclic heterocycle selected from indolyl, indolizinyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, benzoxadiazolyl, benzoxazolyl, benzthiazolyl, 30 each of said monocyclic or bicyclic heterocycle optionally being substituted with at least one substituent, each substituent independently selected from halo, hydroxyl,

CI.

6 alkyl, CI.

6 alkyloxy, CI 6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1 .4alkyl S02-, R6R N-C(=O)-, amino, mono-or di(CI 4 alkyl)amino or C1.

4 alkylcarbonylamino. 35 WO 2007/090836 PCT/EP2007/051123 -9 A second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents C(=O). 5 A third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents S(=O)p, in particular S(=0)2. A fourth interesting embodiment of the present invention are those compounds of 10 formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents CH 2 -C(=O). A fifth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting 15 embodiment wherein X represents CH. A sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein X represents N. 20 A seventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein aryl represents unsubstituted naphthyl; or phenyl or naphthyl, each of said phenyl or naphthyl substituted with one, two or three substituents, 25 preferably one or two substituents, each substituent independently selected from halo, hydroxyl, C 1

.

6 alkyl, C1.

6 alkyloxy, CI 6 alkyloxycarbonyl, C 1

.

6 alkylcarbonyloxy,

C

1

.

6 alkylthio, polyhaloC 1

.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -,

CI

4 alkyl-SO 2 -, R6R N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino,

C

1

.

4 alkylcarbonylamino, aryll, aryl CI 4 alkyloxy, arylloxy, or arylC(=O)-. 30 An eighth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 represents CH(R 4 )-aryl, in particular wherein R 1 represents

CH(R

4 )-aryl wherein aryl represents unsubstituted naphthyl; or phenyl or naphthyl, 35 each of said phenyl or naphthyl substituted with one or two substituents, each substituent independently selected from halo, hydroxyl, CI 6 alkyl, Ci 6 alkyloxy,

C

1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI.

6 alkyl, WO 2007/090836 PCT/EP2007/051123 -10 polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1

.

4 alkyl-SO 2 -, R 6 R'N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino, C 1

.

4 alkylcarbonylamino, aryll, arylCI 4 alkyloxy, arylloxy, or aryl 1 C(=O)-. 5 A ninth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 represents CH(R 4 )-aryl wherein aryl represents phenyl substituted with at least one substituent, preferably one or two substituents, each substituent independently selected from halo, hydroxyl, C1.

6 alkyl, CI.

6 alkyloxy, 10 C 1

.

6 alkyloxycarbonyl, CI.

6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloCI.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1

.

4 alkyl-SO 2 -, R 6 R'N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino, C 1

.

4 alkylcarbonylamino, aryll, arylC 1

.

4 alkyloxy, arylloxy, or aryl 1 C(=O)-; more in particular wherein R 1 represents CH(R 4 )-aryl wherein aryl represents phenyl substituted with one or two substituents selected from halo or 15 C1.

6 alkyl, preferably halo. Preferably, R 1 represents 4-halobenzyl, in particular 4 bromobenzyl or 4-chlorobenzyl. A tenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting 20 embodiment wherein R 1 represents CH(R 4 )-aryl wherein aryl represents naphthyl optionally substituted with at least one substituent, preferably one or two substituents, each substituent independently selected from halo, hydroxyl, CI 6 alkyl, C1.

6 alkyloxy,

C

1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloCI.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1

.

4 alkyl-SO 2 -, R 6 R'N-C(=O)-, 25 amino, mono-or di(Ci 4 alkyl)amino, C 1

.

4 alkylcarbonylamino, aryll, arylC 1

.

4 alkyloxy, arylloxy, or aryl 1 C(=O)-; in particular wherein R 1 represents CH(R 4 )-aryl wherein aryl represents unsubstituted naphthyl. An eleventh interesting embodiment of the present invention are those compounds of 30 formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 represents CH(R 4 )-aryl with aryl representing substituted phenyl wherein phenyl when carrying 1 substituent, is substituted preferably in position 3 or 4, or when carrying 2 substituents, is substituted preferably in position 3 and 4. Preferred substituents are halo, in particular bromo or chloro. 35 A twelfth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting WO 2007/090836 PCT/EP2007/051123 -11 embodiment wherein R 1 represents CH(R 4 )-heteroaryl; in particular wherein R 1 represents CH(R 4 )-heteroaryl wherein heteroaryl represents pyrrolinyl, imidazolinyl, pyrazolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, each of said heterocycles 5 optionally being substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo, hydroxyl, CI 6 alkyl,

C

1

.

6 alkyloxy, C 1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1 .4alkyl S02-, R6R'N-C(=O)-, amino, mono-or di(CI 4 alkyl)amino or C1.

4 alkylcarbonylamino or 10 wherein R 1 represents CH(R 4 )-heteroaryl wherein heteroaryl represents pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; each of said heterocycles optionally being substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo, hydroxyl, CI.

6 alkyl, CI.

6 alkyloxy, CI.

6 alkyloxycarbonyl, 15 C 1

.

6 alkylcarbonyloxy, CI.

6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C1.

4 alkyl-SO 2 -, R 6 R'N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino or CI 4 alkylcarbonylamino or wherein R 1 represents CH(R 4

)

heteroaryl wherein heteroaryl represents a bicyclic heterocycle selected from indolyl, indolizinyl, isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, 20 benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridnyl, pteridinyl, benzoxadiazolyl, benzoxazolyl, benzthiazolyl, each of said bicyclic heterocycles optionally being substituted with at least one substituent, in particular one, two or three substitunets, each substituent independently selected from halo, hydroxyl, CI 6 alkyl, 25 C 1

.

6 alkyloxy, CI.

6 alkyloxycarbonyl, CI.

6 alkylcarbonyloxy, CI.

6 alkylthio, polyhaloCi.

6 alkyl, polyhaloC1.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1

.

4 alkyl S02-, R6R'N-C(=O)-, amino, mono-or di(CI 4 alkyl)amino or C1.

4 alkylcarbonylamino. A thirteenth interesting embodiment of the present invention are those compounds of 30 formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 represents CH(R 4 )-heteroaryl and the ring system representing heteroaryl is optionally substituted with one or two substituents, preferably one substituent. 35 A fourteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 represents CH(R 4 )-heteroaryl wherein heteroaryl represents WO 2007/090836 PCT/EP2007/051123 -12 thienyl, benzofuranyl, benzoxadiazolyl, each of said rings optionally substituted with halo. A fifteenth interesting embodiment of the present invention are those compounds of 5 formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R2 represents aryl 2 ; in particular wherein R 2 represents aryl2 wherein aryl2 represents phenyl optionally substituted with at least one substituent, in particular one or two substituents, each substituent independently selected from halo, hydroxyl, C 1

.

6 alkyl, C 1

.

6 alkyloxy, CI 6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, 10 C1.

6 alkylthio, polyhaloC1.

6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -,

CI

4 alkyl-SO 2 -, R6R N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino, C1.

4 alkylcarbonylamino, aryll, aryl 1 C1.

4 alkyloxy, arylloxy, or aryl 1 C(=O)-; more in particular wherein R2 represents phenyl optionally substituted with one or two halo atoms. 15 A sixteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R2 represents phenyl substituted with one substituent, said substituent preferably being placed in position 2, 3 or 4, or wherein R2 represents 20 phenyl substituted with two substituents, said substituents preferably being placed in position 2 and 4. Preferably, said substituents are halo, in particular fluoro. A seventeenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting 25 embodiment wherein R3 represents hydrogen, CI 6 alkyl, CI 6 alkyloxy, aryll, aryll-NH-, heteroaryl, heteroaryl-NH-, amino, C 3

.

7 cycloalkyl or polyhaloC1 6 alkyl; in particular R3 represents CI.

6 alkyl, aryll, aryll-NH- or heteroaryl-NH-. An eighteenth interesting embodiment of the present invention are those compounds of 30 formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein heteroaryl in the definition of R3 represents a monocyclic heterocycle selected from pyrrolinyl, imidazolinyl, pyrazolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 35 piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; each of said monocyclic heterocycles optionally being substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo, hydroxyl, WO 2007/090836 PCT/EP2007/051123 -13

C

1

.

6 alkyl, C 1

.

6 alkyloxy, C 1

.

6 alkyloxycarbonyl, C 1

.

6 alkylcarbonyloxy, C 1

.

6 alkylthio, polyhaloC1.

6 alkyl, polyhaloC1.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1

.

4 alkyl S02-, R6R'N-C(=O)-, amino, mono-or di(CI 4 alkyl)amino or C1.

4 alkylcarbonylamino; or wherein R3 represents a bicyclic heterocycle selected from indolyl, indolizinyl, 5 isoindolyl, indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, benzoxadiazolyl, benzoxazolyl, benzthiazolyl, each of said bicyclic heterocycles optionally being substituted with at least one substituent, in particular one, two or three substituents, each substituent 10 independently selected from halo, hydroxyl, CI 6 alkyl, CI 6 alkyloxy,

C

1

.

6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloC1.

6 alkyl, polyhaloC1.

6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1

.

4 alkyl-SO 2 -, R 6 R'N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino or CI 4 alkylcarbonylamino. More in particular, heteroaryl in the definition of R3 represents thienyl, isoxazolyl, pyridyl or pyrimidinyl, 15 each of said cycles optionally substituted with halo. A nineteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 4 represents hydrogen. 20 A twentieth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 4 represents C1 4 alkyl. 25 A twenty first interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore wherein aryl represents phenyl, optionally substituted with halo. A twenty second interesting embodiment of the present invention are those compounds 30 of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein one or more, preferably all, of the following restrictions apply: a) aryl represents phenyl substituted with at least one substituent, in particular 1 or 2 substituents, each substituent independently selected from halo or C1.

6 alkyl; b) aryl represents phenyl optionally substituted with halo; 35 c) R 2 represents aryl 2 ; d) aryl 2 represents phenyl optionally substituted with one or two halo atoms; WO 2007/090836 PCT/EP2007/051123 -14 e) heteroaryl represents thienyl, isoxazolyl, pyridyl, pyrimidinyl, benzofuranyl or benzoxadiazolyl, each of said ring systems optionally being substituted with halo; f) X is CH; g) p is 2. 5 A twenty third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting R -N X embodiment wherein the carbon atom carrying the R2 and the moiety has the R configuration, i.e. compounds having the following formula R3 Y N 1 R) (I-A) R -N 10 R2 a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof. A twenty fourth interesting embodiment of the present invention are those compounds 15 of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting R -N X embodiment wherein the carbon atom carrying the R2 and the moiety has the S configuration, i.e. compounds having the following formula R3 Y N I ( (I-B) R -N a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically 20 isomeric form thereof or a solvate thereof. Preferred compounds of formula (I) are selected from the following compounds: WO 2007/090836 PCT/EP2007/051 123 -15 N I N Ra 2b R I R 3 yR2 R 2bStereodescriptor/ ____ ___ ____ __ ___ ____ ___ __ ____ ___ ___Salt I-H C=O H H *(RS) I -- CH 3 C=O H H *(RS) I -- NH 2 0=5=0 H H *(RS) Br ~-C=0 H H*() 14 r 0L<O-cH3 C=0 H H *(RS)

I-CH

3 C=0 H H *(RS) I)1)y -CH 3 C=0 H H*() F &: I y -CH 3 C=0 H H *(RS) Br)(_________ y -CH 3 C=0 H H *(RS) I, -CH 3 C=0 H H (S Br H 3 C ( Iol -CH 3 C=0 H H *(RS) Br_________ CH3 *(RS) y -CH 3 C=0 H H Br ____________ H13C *(RS) y -CH 3 C=0 H H Brj___________ *(RS)

\/-CH

3 C=0 H H 0N -CH 3 C=0 H H *(RS) WO 2007/090836 PCT/EP2007/051123 -16 R R' Y R2a R2b Stereodescriptor/ Salt Br

-NH

2

-CH

2 -C(=O)- H H *(RS) Br

-CH

3 C(=O) H H *(R); .HCl B

-CH

3 C(=O) F F *(RS); HCl salt B -CH 2

CH

3 C=O H H *(RS) B -NH 2 C=O H H *(RS) Br C=O H H *(R); HCl salt Br C=O H H *(RS) CH3 H BrI C=O H H *(RS) BrH 0 Br F\/ C=O H H *(RS) F Ho0 B -NH 2 -- H H *(S); fumarate salt a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof. In particular preferred compounds of formula (I) are selected from the following 5 compounds: R 3 R Y N I N * 2a 2b R IR3 Y R2 R2b Stereodescriptor/ Salt B -CH 3 C=O H H *(RS) WO 2007/090836 PCT/EP2007/051123 -17 R R' Y R2 R2b Stereodescriptor/ Salt Br C=O H H *(RS) -CH3 C=O H H *(RS) F*(RS) I -CH 3 C=O H H *(RS) F Y -CH 3 C=O H H *(RS) Br( Br -NH 2

-CH

2 -C(=O)- H H *(RS) Br

-CH

3 C(=O) H H *(R); .HCl Br

-CH

3 C(=O) F F *(RS); HCl salt B -CH 2

CH

3 C=O H H *(RS) B -NH 2 C=O H H *(RS) Br C=O H H *(R); HCl salt Br N C=O H H *(RS) CH3 H3 N-. B C=O H H *(RS) Bri 0 BrN C=O H H *(RS) H F Br "F-- C=O H H *(RS) Ho0 1111 11I Br

-NH

2

-

H H *(S); fumarate salt a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof. The present invention also relates to a compound of formula WO 2007/090836 PCT/EP2007/051123 -18 R 3 1 Y I N HN X R2 wherein R2, Ri, X and Y are as defined for a compound of formula (I). The present invention also relates to a compound of formula H N i- (IV) R -N

X

5 R2 wherein R 1 , R2, X and Y are as defined for a compound of formula (I). In general, compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W1 represents a suitable 10 leaving group, such as for example halo, e.g. bromo and the like, in the presence of a suitable base, such as for example NN-diethylethanamine or N,N-diisopropylethanamine, and a suitable solvent, such as for example N,N-dimethylformamide, dichloromethane or an alcohol, e.g. methanol and the like. R3 R3 Y Y N N + R--W

R

1 -Nr- HN R R R2 R2 15 Compounds of formula (I) wherein the R 4 substituent in the definition of R 1 represents hydrogen, said R 1 being represented by Ria-CH 2 and said compounds being represented by formula (I-a), can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III') wherein Ria represents aryl or heteroaryl, in the presence of a suitable reducing agent, such as for example NaBH(OAc) 3 , a suitable acid, such as 20 for example acetic acid, and a suitable solvent, such as for example dichloromethane.

WO 2007/090836 PCT/EP2007/051123 -19 R3 R3 HN X+ Ria R1a N X R2 0 \ / R (11)' (1-a) Compounds of formula (I) wherein Y-R 3 is as defined in claim 1 but other than -S0 2

-NH

2 , -C(=O)-NH-aryll, -C(=O)-NH-heteroaryl, said Y-R 3 being represented by Y-R3a, and said compounds being represented by formula (I-b), can also be prepared by 5 reacting an intermediate of formula (IV) with an intermediate of formula (V), wherein

W

2 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, an alcoholate, e.g. C1.

6 alkyl-O-, or a carboxylate, e.g. C1.

6 alkyl-C(=O)-O- (CH 3 C(=O)-O-) or polyC1.

6 alkyl-C(=O)-O- (CF 3 -C(=O)-O-), optionally in the presence of a suitable base, such as for example NN-diethylethanamine, NN-diisopropylethanamine 10 or K 2 C0 3 , and optionally in the presence of a suitable solvent, such as for example tetrahydrofuran, dichloromethane or an alcohol, e.g. ethanol and the like.

R

3 a I Y NN RI- X+ R 3a -Y-W2 I R

R

1 -N R R-N (IV) (V) (1-b) Compounds of formula (I) wherein R3 represents NH 2 and Y represents S(=0) 2 , said compounds being represented by formula (I-c), can be prepared by reacting an 15 intermediate of formula (IV) with S(=0) 2

-(NH

2

)

2 , in the presence of a suitable solvent, such as for example pyridine.

NH

2 o=s=0 HN N RI-N + S(=0) 2

-(NH

2

)

2 i Ri-N X VJR Qx, (IV) (I-c) Compounds of formula (I) wherein Y-R 3 represents C(=O)-NH-aryll or C(=O)-NH heteroaryl, said Y-R3 being represented by C(=O)-NH-R3b wherein R3b represents aryll 20 or heteroaryl, and said compounds being represented by formula (I-d), can be prepared WO 2007/090836 PCT/EP2007/051123 -20 by reacting an intermediate of formula (IV) with an intermediate of formula (VI) in the presence of a suitable solvent, such as for example dichloromethane.

R

3 b HN c=o NN R--N X + R 3 b-N=C=O 1 R1-N R-N

RX

(IV) (v1) (1-d) Compounds of formula (I) wherein Y represents C(=O) and R3 represents NH 2 , said 5 compounds being represented by formula (I-e), can be prepared by reacting an intermediate of formula (IV) with isocyanatotrimethylsilane in the presence of a suitable solvent, such as for example dioxane.

NH

2 C=O H N N Risocyanatotrimethylsilane R1-N R -N RR2 R (IV) (I-e) Compounds of formula (I) wherein the ring moiety of the R2 substituent is substituted 10 with R 5

R

6 N-C(=O)-, said R2 substituent being represented by -R 2 a-C(=O)-NR5R 6 and said compounds being represented by formula (I-f-1), or compounds of formula (I) wherein the ring moiety of the R 1 substituent is substituted with R 5

R

6 N-C(=O)-, said R 1 substituent being represented by -Ra-C(=O)-NR5R 6 and said compounds being represented by formula (I-f-2), can be prepared by reacting an intermediate of formula 15 (XXXIII-a) or (XXXIII-b) wherein W 2 represents a suitable leaving group, such as for example halo, e.g. chloro, or 1H-imidazolyl or azide and the like, with a suitable base of formula R5 RNH in the presence of a suitable solvent, such as for example dioxane or an alcohol, e.g. ethanol, methanol and the like.

WO 2007/090836 PCT/EP2007/051123 -21 R3 R3 Y YI I N N RI-N X Q + NHR 5 R -4 R-N X R~a Ra O 1R 6

R

5 N 0 O w2 (XXXII-a) R3 R3I Y N N 0 O Ria-N X+ NHR 5

R

6 -- 6 5 Ria-N (1-f-2) (XXxIII-b) The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions. 5 The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate 10 inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper oxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo peroxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. 15 tert.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents. Compounds of formula (I) wherein the R 1 or the R2 substituent is substituted with 20 methoxy, can be converted into a compound of formula (I) wherein the R1 or R2 substituent is substituted with hydroxyl, by reaction with a suitable dealkylating agent, WO 2007/090836 PCT/EP2007/051123 -22 such as for example BBr 3 , in the presence of a suitable solvent, such as for example dichloromethane or an alcohol, e.g. methanol and the like. Compounds of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is 5 substituted with carboxyl, can be converted into a compound of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is substituted with -C(=O)-NRR 6 , by reaction with a suitable amine HNR5 R in the presence of a suitable solvent, such as for example dichloromethane, a suitable coupling agent, such as diimidazolylcarbonyl or carbodiimides, e.g. diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3 10 ethylcarbodiimide, N,N'-dicyclohexylcarbodiimide, and optionally a suitable base, such as for example NN-diisopropylethanamine. This conversion can also be achieved by first converting the carboxylic acid into an acylhalide by reaction with SOCl 2 optionally in the presence of a suitable solvent, such as for example toluene, dichloromethane followed by the above-described reaction. 15 Compounds of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is substituted with nitro, can be converted into a compound of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is substituted with amino, by reaction with a suitable reducing agent, such as for example H 2 , in the presence of a suitable catalyst, 20 such as for example platina on charcoal, a suitable catalyst poison, such as for example a thiophene solution, V 2 0 5 , and a suitable solvent, such as for example tetrahydrofuran. Compounds of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is substituted with nitro, can be prepared from the unsubstituted compound by reaction 25 with HNO 3 . Compounds of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is substituted with amino, can be converted into a compound of formula (I) wherein the ring moiety of the R 1 or the R2 substituent is substituted with CI 6 alkylcarbonylamino, 30 by reaction with a suitable anhydride O(C(=O)-C1.

6 alkyl) 2 or a suitable acyl chloride

CI

6 alkyl-C(=O)-Cl in the presence of a suitable solvent, such as for example dichloromethane, and a suitable base, such as for example NN-diisopropylethanamine. The compounds of formula (I) and some of the intermediates in the present invention 35 contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such WO 2007/090836 PCT/EP2007/051123 -23 as selective crystallization or chromatographic techniques, e.g. counter current distribution, chiral liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts 5 or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically 10 isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography or SCF (Super Critical 15 Fluid) chromatography, in particular using a chiral stationary phase. Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures. 20 Intermediates of formula (II) can be prepared by deprotecting an intermediate of formula (VII) wherein P represents a suitable protecting group, such as for example

C

6

H

5

-CH

2 -0-C(=O)- or benzyl, with H 2 in the presence of a suitable catalyst, such as for example palladium on charcoal, and a suitable solvent, such as for example an alcohol, e.g. methanol and the like. R 3 R3 Y Y N N N /_ P-N X HN X R2 R2 25 (V11) (II) Intermediates of formula (VII) wherein Y-R 3 represents Y-R a as defined hereinbefore, said intermediates being represented by formula (VII-a), can be prepared by reacting an intermediate of formula (VIII) with an intermediate of formula (V) optionally in the presence of a suitable base, such as for example NN-diethylethanamine or NN 30 diisopropylethanamine, and optionally in the presence of a suitable solvent, such as for example tetrahydrofuran or dichloromethane.

WO 2007/090836 PCT/EP2007/051123 -24

R

3 a Y NN + R -Y-W 2 O P-N P-N XR (Vi1) (V) (VI-a) Intermediates of formula (VIII) can be prepared by reducing an intermediate of formula (IX) with a suitable reducing agent, such as for example trihydro(tetrahydrofuran) boron (borane-tetrahydrofuran complex), in the presence of a suitable solvent, such as 5 for example tetrahydrofuran. H H N ~ reduction N P-N P-N \ / R2 \ / R2 (IX) (ViII) Intermediates of formula (IX) can be prepared by reacting an intermediate of formula (X) with an intermediate of formula (XI) wherein W 3 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, in the presence of a suitable 10 base, such as for example NN-diethylethanamine or NN-diisopropylethanamine, and a suitable solvent, such as for example NN-dimethylformamide. 0 H 00 H N N H-N +P-W3 P-N R2 R2 (X) (XI) (IX) Intermediates of formula (X) can be prepared by debenzylating an intermediate of formula (XII) in the presence of H 2 , a suitable catalyst, such as for example palladium 15 on charcoal, and a suitable solvent, such as for example an alcohol, e.g. methanol and the like in case X represents CH. The debenzylation of an intermediate of formula (XII) can also be performed in the presence of 1-chloroethylcarbonochloridic acid ester and a suitable solvent, such as for example dichloroethane followed by the addition of an alcohol, e.g. methanol and the like, preferably at elevated temperature.

WO 2007/090836 PCT/EP2007/051123 -25 0 H 0 0 NN O HN N \/ R2 R (XI1) (x) Intermediates of formula (X) wherein X represents N, said intermediates being represented by formula (X-a), can also be prepared by reacting an intermediate of formula (XIII) with a suitable acid, such as for example hydrochloric acid and the like, 5 in the presence of a suitable solvent, such as for example an alcohol, e.g. 2-propanol and the like. 0 0 N 0 N HN N \ / R2 (X111) (X-a) Intermediates of formula (XII) wherein X represents CH, said intermediates being represented by formula (XII-a), can be prepared by reacting an intermediate of formula 10 (XIV) with a suitable acid, such as for example a mixture of H 2

SO

4 and acetic acid. CN N R2 2 I R CN (XIV) (X1I-a) Intermediates of formula (XII) wherein X represents N, said intermediates being represented by formula (XII-b), can be prepared by reacting an intermediate of formula (XV) with a suitable base, such as for example NaOtertBu, in the presence of a suitable 15 solvent, such as for example tetrahydrofuran.

H

2 N 0 H 0 10 NN N NO 2 N R R2 0 1 (x11-b) (XV) C 1

-

4 alkyl(XIb Intermediates of formula (XIV) can be prepared by reacting an intermediate of formula (XVI) with CH 2 =CH-CN, in the presence of a suitable catalyst, such as for example TritonB, and a suitable solvent, such as for example dioxane.

WO 2007/090836 PCT/EP2007/051123 -26 CN + CH 2 =CH-CN 2 N CN ICN (XVI) (XIV) Intermediates of formula (XVI) can be prepared by reducing an intermediate of formula (XVII) with a suitable reducing agent, such as for example H 2 , in the presence of a suitable catalyst, such as for example palladium on charcoal or Rhodium on charcoal, a 5 suitable catalyst poison, such as for example a thiophene solution, and a suitable solvent, such as for example an alcohol, e.g. methanol and the like. The reaction can also be performed with NaBH 4 as reducing agent in the presence of a suitable solvent, such as for example an alcohol, e.g. 2-propanol and the like. N R 2 NO2 CN ICN (XV11) (XVI) 10 Intermediates of formula (XVII) can be prepared by reacting an intermediate of formula (XVIII) with an intermediate of formula (XIX) in the presence of a suitable base, such as for example NaOCH 3 , and in the presence of a suitable solvent, such as for example an alcohol, e.g. methanol and the like. NO + C CN N- R2 + '~ ICN (XV111) (XIX) (XV11) 15 Intermediates of formula (XV) can be prepared by reacting an intermediate of formula (XX) with NH 3 in the presence of a suitable coupling agent, such as for example 1,1 '-carbonylbis- 1H-imidazole, and in the presence of a suitable solvent, such as for example dichloromethane. HO

H

2 N 0 0 N NO

NH

3 0 0 0 (xx) 4aiky1 (XV)

C

1

-

4 aikyl 20 Intermediates of formula (XX) can be prepared by hydrolyzing an intermediate of formula (XXI) with a suitable base, such as for example NaOH, in the presence of a suitable solvent, such as for example dioxane.

WO 2007/090836 PCT/EP2007/051123 -27 HO

C

1

-

4 alkyl-0 0 0 S N N 2 N N 2 R O O (XX) C 1

-

4 alkyl (XXI) C 1

-

4 alkyl Intermediates of formula (XXI) can be prepared by reacting an intermediate of formula (XXII) with an intermediate of formula (XXIII) wherein W 4 represents a suitable leaving group, such as for example halo, e.g. bromo and the like, in the presence of a 5 suitable base, such as for example NaH and a suitable solvent, such as for example N,N-dimethylformamide.

C

1

-

4 alkyl-O 0 N. N-- RF2+

C

1- 4alkyl N NO R (XXII) C 1

-

4 alkyl (XXII) (XXI) 1-4alky1 Intermediates of formula (XXII) can be prepared by reacting an intermediate of formula (XXIV) with an intermediate of formula (XXV) wherein W 5 represents a 10 suitable leaving group, such as for example halo, e.g. bromo and the like, in the presence of a suitable base, such as for example NN-diethylethanamine, and a suitable solvent, such as for example dichloromethane. 0 N \-/ NH + OC1-4aikyi N N R 0-C

\-

4 lky -3 Nj :

W

5 0 0 (XXIV) (XXII) C 1

-

4 alkyl (XXV) Intermediates of formula (XIII) can be prepared by reacting an intermediate of formula 15 (XXVI) with a suitable base, such as for example Na tertBuO, in the presence of a suitable solvent, such as for example tetrahydrofuran.

C

1

-

4 alkyl I H 00 U 0 0 0 N O N NO

NH

2 O N NO R2 (XXVI) (XIII) Intermediates of formula (XXVI) can be prepared according to the procedures described for intermediates of formula (XV).

WO 2007/090836 PCT/EP2007/051123 -28 Intermediates of formula (VIII) wherein P represents benzyl and X represents CH, said intermediates being represented by formula (VIII-a), can also be prepared by cyclizing an intermediate of formula (XXXIV) with a suitable acid, such as for example HBr in 5 the presence of a suitable solvent, such as for example H 2 0. H N

NHBH

2 N OH HBr N N N 2. (XXXIV) (VIII-a) Intermediates of formula (XXXIV) can be prepared by reacting an intermediate of formula (XXIX) with trihydro(tetrahydrofuran)-boron in a suitable solvent, such as for example tetrahydrofuran.

NHBH

2 N N N OC 1

-

6 alkyl N OH R2 0 P3" 2 10 (XXIX) (XXXIV) Intermediates of formula (IV) can be prepared by reacting a final compound of formula (I) wherein Y-R 3 represents C1- 6 alkyloxycarbonyl, said final compound being represented by formula (I-g), with a suitable acid, such as for example HBr and the like. 15

O-CI-

6 alkyl H O=C N (IV) (1-g) Compounds of formula (I-g) can be prepared according to the procedures described above for the compounds of formula (I) starting from an intermediate of formula (II) and (III). 20 Intermediates of formula (IV) can also be prepared by reacting an intermediate of formula (XXVII) with a suitable reducing agent, such as for example BH 3 .THF, in the presence of a suitable solvent, such as for example tetrahydrofuran.

WO 2007/090836 PCT/EP2007/051123 -29 H N H N 0 PR -N X 2 R -N X-,R R2 (IV) (XXVII) Intermediates of formula (XXVII) can be prepared by reacting an intermediate of formula (XXVIII) with an intermediate of formula (III) in the presence of a suitable solvent, such as for example NN-dimethylformamide, and a suitable base, such as for 5 example NN-diethylethanamine. H H N 0 N HN X W 1 - R -N X R2 2 (XXRlll) (XXRll) Intermediates of formula (XXVIII) wherein X represents CH, said intermediates being represented by formula (XXVIII-a), can be prepared by reacting an intermediate of formula (XXIX) with H 2 , in the presence of a suitable catalyst, such as for example 10 palladium on charcoal, and a suitable solvent, such as for example an alcohol, e.g. methanol and the like. After the initial hydrogenation for debenzylation, the reaction can further be performed using Raney Ni as catalyst for the cyclization. Alternatively, the reaction can also be performed by using Raney Ni as first catalyst for the cyclisation reaction followed by debenzylation with palladium on charcoal as catalyst. H N 0 ON N 01

C

1

-

6 alkyI 0 15 (X(IX) (XXVIIl-a) Intermediates of formula (XXIX) can be prepared by reacting an intermediate of formula (XXX) with an intermediate of formula (XXXI) in the presence of a suitable solvent, such as for example xylene, and a suitable base, such as for example an alcoholate, e.g. sodium methanolate. This reaction can also be performed in the 20 presence of a suitable catalyst, such as Triton B, and a suitable solvent, such as for example dioxane.

WO 2007/090836 PCT/EP2007/051123 -30 ON O, N 2+ C1-0alk N C 1

-

6 alkyl 0 R 0 (XXX) (XXXI) (XXIX) Pharmacological part 5 The compounds of formula (I) and any subgroup thereof show CXCR3 receptor antagonistic properties. Such CXCR3 antagonists can inhibit binding of one or more chemokines (e.g., CXC-chemokines, such as IP-10, MIG and/or I-TAC) to CXCR3 receptor. 10 Chemokines (contraction of "chemotactic cytokines") are most important regulators of leukocyte trafficking. This biological role is exerted by interacting - on target cells with seven-transmembrane-domain receptors that are coupled to heterodimeric G proteins.Chemokines are mainly grouped into 4 major families (C-C; C-X-C; C and

C-X

3 -C family) dependent on whether the two conserved cysteine residues (represented 15 by C) near the amino terminus are separated by a single amino acid (represented by X) (C-X-C), are adjacent (C-C), have a missing cysteine pair (C) or are separated by three amino acids (C-X 3 -C). The CXCR3 chemokine receptor is a G protein coupled receptor also known as 20 CD183.The CXCR3 receptor is mainly expressed on activated or stimulated T lymphocytes, Natural Killer cells (NK cells), malignant B lymphocytes, endothelial cells, thymocytes and plasma cells. The selective expression of the CXCR3 receptor makes it a suitable target for intervention to interrupt inappropriate T cell trafficking. 25 Ligands which act through the CXCR3 receptor are the CXC chemokines I-TAC (interferon-inducible T cell alpha-chemoattractant), IP-10 (interferon-inducible protein 10) and MIG (monokine induced by gamma-interferon); I-TAC having the highest receptor affinity. 30 Clinical indications for intervening in, in particular inhibiting, inappropriate T-cell trafficking via interaction with the CXCR3 receptor are : (1) inflammatory or allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g. to penicillin, cephalosporins), insect sting allergies; inflammatory bowel diseases, such as Crohn's disease, colitis (e.g. ulcerative WO 2007/090836 PCT/EP2007/051123 -31 colitis), ileitis and enteritis; vaginitis; psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g. necrotizing, cutaneous, and hypersensitivity vasculitis); spondyloarthropathies; scleroderma; respiratory allergic diseases such as asthma, 5 allergic rhinitis, obstructive pulmonary disease (COPD), hypersensitivity lung diseases, hypersensitivity pneumonitis, interstitial lung diseases (ILD) (e.g. idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), idiopathic pneumonia; and the like, (2) autoimmune diseases, such as arthritis (e.g. rheumatoid arthritis, psoriatic arthritis, 10 juvenile rheumatoid arthritis, polyarthritis, spondyloarthropathy), multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, diabetes (including diabetes mellitus and juvenile onset diabetes), Sjogren's syndrome, glomerulonephritis and other nephritides, autoimmune thyroid disorders, such as e.g. thyroiditis, and the like; 15 (3) graft rejection (including allograft rejection (e.g. cardiac, renal and lung rejection), xenograft rejection and graft-v-host disease), and (4) other diseases in which undesired inflammatory responses are to be inhibited (e.g. atherosclerosis, restenosis, cytokine- induced toxicity, myositis (including polymyositis, dermatomyositis), neurodegenerative diseases, Alzheimer's disease, 20 encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, conjunctivitis, otitis, retinopathy (e.g. retinopathy of prematurity, diabetic retinopathy), retinal vein occlusion, macular degeneration (e.g. age-related macular degeneration), hemangiomas, chronic obstructive pulmonary disease, sinusitis and Behcet's syndrome. 25 Reference therefore is made to Arimili et al, Immunological Reviews, 2000, vol 177, 43-5 1; Xanthou et al., Eur. J.Immunol., 2003, vol 33, 2927-2936; WO 01/16114 and WO 02/85861; which are incorporated herein by reference. Due to their CXCR3 receptor antagonistic activity, the compounds of formula (I), their 30 N-oxides, pharmaceutically acceptable salts, stereochemically isomeric forms or solvates are useful for the treatment or prevention, in particular for the treatment, of a disease or condition mediated through the activation of the CXCR3 receptor. In view of the above-described pharmacological properties, the compounds of formula 35 (I), their N-oxides, pharmaceutically acceptable salts, stereochemically isomeric forms and solvates, may be used as a medicine. In particular, the present compounds can be used for the manufacture of a medicament for treating or preventing a disease mediated WO 2007/090836 PCT/EP2007/051123 -32 through activation of the CXCR3 receptor, in particular for treating a disease mediated through activation of the CXCR3 receptor. More in particular, the compounds of the invention can be used for the manufacture of a medicament for treating or preventing, preferably treating, a CXCR3 mediated inflammatory or allergic disease, a CXCR3 5 mediated autoimmune disease, a CXCR3 mediated graft rejection, other CXCR3 mediated diseases in which undesired inflammatory responses are to be inhibited.Even more in particular, the compounds of the invention can be used for the manufacture of a medicament for treating or preventing (1) inflammatory or allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g. to penicillin, 10 cephalosporins), insect sting allergies; inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis; vaginitis; psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g. necrotizing, cutaneous, and hypersensitivity vasculitis); spondyloarthropathies; scleroderma; respiratory allergic diseases such as asthma, 15 allergic rhinitis, obstructive pulmonary disease (COPD), hypersensitivity lung diseases, hypersensitivity pneumonitis, interstitial lung diseases (ILD) (e.g. idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), idiopathic pneumonia; and the like; (2) autoimmune diseases, such as arthritis (e.g. rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, polyarthritis, 20 spondyloarthropathy), multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, diabetes (including diabetes mellitus and juvenile onset diabetes), Sjogren's syndrome, glomerulonephritis and other nephritides, autoimmune thyroid disorders, such as e.g. thyroiditis, and the like; (3) graft rejection (including allograft rejection (e.g. cardiac, renal and lung rejection), xenograft rejection and graft-v-host disease), 25 and (4) other diseases in which undesired inflammatory responses are to be inhibited (e.g. atherosclerosis, restenosis, cytokine- induced toxicity, myositis (including polymyositis, dermatomyositis), neurodegenerative diseases, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, conjunctivitis, otitis, retinopathy (e.g. retinopathy of prematurity, diabetic retinopathy), retinal vein 30 occlusion, macular degeneration (e.g. age-related macular degeneration), hemangiomas, chronic obstructive pulmonary disease, sinusitis and Behcet's syndrome.Further, the compounds of the invention can be used for the manufacture of a medicament for treating or preventing rheumatoid arthritis, inflammatory bowel diseases such as Crohn's disease and colitis, allograft rejection (e.g. cardiac, renal, lung 35 allograft rejection), multiple sclerosis, COPD, glomerulonephritis, allergic contact dermatitis, lupus, psoriasis, atherosclerosis, Sjogren's syndrome, autoimmune thyroid disorders. Preferably, the present compounds can be used for treating or preventing, WO 2007/090836 PCT/EP2007/051123 -33 especially treating, rheumatoid arthritis, inflammatory bowel diseases such as Crohn's disease and colitis, allograft rejection (e.g. cardiac, renal, lung allograft rejection). In view of the utility of the compounds of formula (I), there is provided a method of 5 treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease mediated through activation of the CXCR3 receptor, in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease mediated through activation of the CXCR3 receptor. Said methods comprise the administration 10 of an effective amount of a compound of formula (I), a N-oxide form thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof, to a warm-blooded mammal, including a human. The present invention also provides compositions for preventing or treating a disease 15 mediated through activation of the CXCR3 receptor, in particular for treating a disease mediated through activation of the CXCR3 receptor. Said compositions comprise a therapeutically effective amount of a compound of formula (I), a N-oxide form thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof, and a pharmaceutically acceptable carrier or diluent. 20 The compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, an effective 25 amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by 30 parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the 35 case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral WO 2007/090836 PCT/EP2007/051123 -34 compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions 5 may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined 10 with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. 15 The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry 20 powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds. The compounds of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye 25 drops are suitable for the administration of the present compounds. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary 30 dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. 35 The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition WO 2007/090836 PCT/EP2007/051123 -35 being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated 5 subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by 10 weight, even more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition. 15 The compounds of formula (I) may also be used in combination with other conventional anti-inflammatory or immunosuppressive agents, such as steroids, cyclooxygenase-2 inhibitors, non-steroidal-anti-inflammatory drugs, TNF- a antibodies, such as for example acetyl salicylic acid, bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen, naproxen, 20 naproxen sodium, tiaprofen acid, flurbiprofen, mefenamic acid, nifluminic acid, meclofenamate, indomethacin, proglumetacine, ketoprofen, nabumetone, paracetamol, piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, beclomethasone dipropionate, betamethasone, beclamethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylpredniso lone, prednisolone, prednisone, 25 triamcinolone, celecoxib, rofecoxib, valdecoxib, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine, antilymphocytory immunoglobulines, antithymocytory immunoglobulines, azathioprine, cyclosporine, tacrolimus substances, ascomycin, rapamycin, muromonab-CD3. 30 Thus, the present invention also relates to the combination of a compound of formula (I) and another anti-inflammatory or immunosuppressive agent. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I), and (b) another anti-inflammatory or immunosuppressive compound, as a combined preparation for simultaneous, separate or sequential use in 35 the treatment of a disease mediated through activation of the CXCR3 receptor. The different drugs in such products may be combined in a single preparation together with pharmaceutically acceptable carriers. Alternatively, such products may comprise, for WO 2007/090836 PCT/EP2007/051123 -36 example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing another anti-inflammatory or immunosuppressive compound. Such a product may have the advantage that a physician can select on the basis of the diagnosis of the patient to be 5 treated the appropriate amounts of each component and the sequence and timing of the administration thereof. The following examples are intended to illustrate the present invention. 10 Experimental Part Hereinafter, "THF" means tetrahydrofuran, "DMF" means NN-dimethylformamide, "DIPEA" means N-ethyl-N-(1-methylethyl)-2-propanamine. A number of compounds were purified by reversed phase high-performance liquid 15 chromatography using one of the methods below (indicated in the compound procedure with method A and method B). HPLC method A The product was purified by high-performance liquid chromatography (RP18 BDS 8 m 20 250 g; I.D. 5 cm). Three mobile phases (mobile phase A: 90 % of a 0.5 % NH 4 0Ac solution + 10 % CH 3 CN; mobile phase B: CH 3 0H; mobile phase C: CH 3 CN) were employed. First, 75 % A and 25 % B with a flow rate of 40 ml/min was hold for 0.5 minutes. Then a gradient was applied to 50 % B and 50 % C in 41 minutes with a flow rate of 80 ml/min. Then a gradient was applied to 100 % C in 20 minutes with a flow 25 rate of 80 ml/min and hold for 4 minutes. HPLC method B The product was purified by high-performance liquid chromatography (RP18 BDS 8 m 250 g; I.D. 5 cm). Three mobile phases (mobile phase A: a 0.25 % NH 4

HCO

3 solution; 30 mobile phase B: CH 3 0H; mobile phase C: CH 3 CN) were employed. First, 75 % A and 25 % B with a flow rate of 40 ml/min was hold for 0.5 minutes. Then a gradient was applied to 50 % B and 50 % C in 41 minutes with a flow rate of 80 ml/min. Then a gradient was applied to 100 % C in 20 minutes with a flow rate of 80 ml/min and hold for 4 minutes. 35 A. Preparation of the intermediate compounds Example Al WO 2007/090836 PCT/EP2007/051123 -37 a) Preparation of intermediate 1 0 'I, H 0 N O I 0 N 0 Carbonochloridic acid phenylmethyl ester (0.116 mol) was added dropwise to a stirring mixture of 3-phenyl-[3,4'-bipiperidine]-2,6-dione (0.1 mol), DMF (300 ml) and Et 3 N (0.3 mol). The reaction mixture was stirred for 18 hours at room temperature. The mixture was poured out into cold water (1 L). The product was extracted with diethyl 5 ether (2 x 1 L). The combined organic layers were dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was stirred in diethyl ether (200 ml), filtered off, washed, and then dried (vacuum, 50'C). Yield: 29 g of intermediate 1. b) Preparation of intermediate 2 0 0 N I N A mixture of intermediate 1 (0.00246 mol) in THF (20 ml; p.a., dried on molecular 10 sieves) was stirred. Trihydro(tetrahydrofuran)-boron (12.3 ml; IM in THF) was added slowly and the reaction mixture was stirred and refluxed under N 2 atmosphere for 6 hours. The reaction mixture was cooled to room temperature and poured slowly into 1 N HCl (125 ml). Stirring was continued for 1 hour and then diethyl ether (50 ml) was added. Stirring was continued for 30 minutes. NaHCO 3 was added to the separated 15 water layer till pH 8. This mixture was extracted with CH 2 Cl 2

/CH

3 0H 90/10. The separated organic layer was dried (MgSO 4 ), filtered, and the solvent was evaporated. Yield: 0.96 g of intermediate 2. c) Preparation of intermediate 3 0 0 O CH 3 N A solution of intermediate 2 (0.00253 mol) and Et 3 N (1 ml) in CH 2 Cl 2 (15 ml; p.a.) was 20 stirred on an ice-bath. Carbonochloridic acid, ethyl ester (0.0028 mol) was added and WO 2007/090836 PCT/EP2007/051123 -38 the reaction mixture was stirred at 0 0 C for 30 minutes and at room temperature for 18 hours. An aqueous NaHCO 3 solution (25 ml, half saturated) was added to the reaction mixture and stirring was continued for 15 minutes. The separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by 5 Sipan flash column chromatography over silica gel (eluent: CH 2 Cl 2

/CH

3 0H 99.7/0.3). The product fractions were combined, the solvent was evaporated and co-evaporated with CH 3 0H and toluene. Yield: 0.42 g of intermediate 3 (36.8 %). d) Preparation of intermediate 4 H0N O O CH 3 N A solution of intermediate 3 (0.0009 mol) in CH 3 0H (50 ml; p.a.) was hydrogenated 10 with Pd/C 10% (0.1 g) as a catalyst. After uptake of H 2 (1 equiv.), the catalyst was filtered off and the filtrate was evaporated. Yield: 0.28 g of intermediate 4 (98 %). Example A2 a) Preparation of intermediate 5 O N CH3 N Acetic acid, anhydride (5 ml) was added to a stirred solution of intermediate 2 (0.00819 15 mol) in THF (20 ml; p.a.). The reaction mixture was stirred for 18 hours at room temperature. The solvent was evaporated. Xylene was added and the mixture was evaporated again on the rotary evaporator. The residue was purified over silica gel on a glass filter (eluent: CH 2 Cl 2

/CH

3 0H 98/2). The product fractions were collected and the solvent was evaporated. Toluene was added and co-evaporated on the rotary 20 evaporator. Yield: 1.2 g of intermediate 5.

WO 2007/090836 PCT/EP2007/051123 -39 b) Preparation of intermediate 6 HN0

CH

3 N A solution of intermediate 5 (0.0028 mol) in CH 3 0H (50 ml) was hydrogenated with Pd/C 10% (0.5 g) as a catalyst. After uptake of H 2 (1 equiv.), the catalyst was filtered off and the filtrate was evaporated. Yield: 0.56 g of intermediate 6. 5 Example A3A Preparation of intermediate 7 N N Br A solution of final compound 9 (0.00045 mol) in HBr (10 ml; 48% p.a.) was stirred and refluxed for 2 hours, and was then stirred at room temperature overnight. The solvent was evaporated and co-evaporated with toluene. The remaining residue was stirred in

CH

2 Cl 2 (20 ml) and an aqueous NaHCO 3 solution (15 ml, saturated) was added. 10 Stirring was continued for 18 hours. The organic layer was separated, dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over a RediSep 12g cartridge (eluent: CH 2 Cl 2

/(CH

3 0H/NH 3 ) from 100/0 to 93/7). The product fractions were combined and the solvent was evaporated. Yield: 0.13 g of intermediate 7 (69.9 %). 15 Example A3(B) a) Preparation of intermediate 8 N 0 N OICH 3 Reaction under N 2 atmosphere. Xylene (206 L) was poured into a 500-L RVS reactor, previously flushed with N 2 gas. ca-Phenyl-1-(phenylmethyl)-4-piperidineacetonitrile (60 kg) was added and this mixture was heated to reflux temperature. The solution was 20 distilled azeotropically using a water separator, until it was free of water. N 2 gas was let in. The mixture was cooled to ± 65 'C. CH 3 0Na 30% (9.3 kg, 51.6 mol) was added dropwise at ± 65 'C. 2-Propenoic acid methyl ester (26.7 kg, 310 mol) was added WO 2007/090836 PCT/EP2007/051123 -40 dropwise at ± 65 'C over a 30-minutes period. The addition container was flushed with xylene (20 L). The reaction mixture was stirred for 4-6 hours at ± 70 'C, then it was cooled to room temperature. NaCl (5.2 kg) and water (133 L) were added and the mixture was stirred for at least 15 minutes. The layers were allowed to separate slowly. 5 The organic layer was separated, treated with NaCl (2.6 kg) in water (67 L) and stirred for at least 15 minutes. The layers were allowed to separate slowly. The organic layer was separated, dried (Na 2

SO

4 , 5 kg), filtered over a cotton bag, and the filtrate's solvent was evaporated (in vacuo; container temperature: 100 C). Yield: 71.7 kg of intermediate 8 (92%). 10 b) Preparation of intermediate 9 HN H N 0 Intermediate 8 (max. 0.01mol) was dissolved in CH 3 0H (200 ml) and this solution was hydrogenated at room temperature with Pd/C 10% (q.s.) as a catalyst. After uptake of

H

2 (1 equiv), the catalyst was filtered off and the filtrate (containing debenzylated starting material intermediate 8) was hydrogenated further at room temperature with 15 Raney Nickel (1 g) as a catalyst. After uptake of H 2 (2 equiv), the catalyst was filtered off and the filtrate was evaporated. Toluene was added and co-evaporated on the rotary evaporator. Methanol was added, then co-evaporated. Yield: 1.45 g of intermediate 9 (56.1%). c) Preparation of intermediate 10 N H N 0 Br 20 1-Bromo-4-(chloromethyl)benzene (0.00035 mol) was added to a shaking solution of intermediate 9 (0.00019 mol) in Et 3 N (0.2 ml) and DMF, (4 ml; p.a.). The reaction mixture was shaken further for 18 hours at room temperature, then for 40 minutes at 55 'C. The solvent was evaporated. The residue was purified by reversed-phase high performance liquid chromatography (Column: Xterra Prep MS C18, Length: 10 cm, 25 I.D.: 19 mm, particle size: 5 pm; eluent: (0.2 % NH 4

HCO

3 in H 2 0)/CH 3 0H/CH 3 CN gradient). The product fractions were combined and the solvent was evaporated.

WO 2007/090836 PCT/EP2007/051123 -41 Methanol was added and co-evaporated on the rotary evaporator, yielding intermediate 10. d) Preparation of intermediate 7 N H N Br

BH

3 .THF (30 ml; IM in THF) was added to crude intermediate 10 (2 g). When initial 5 foaming stopped, the reaction mixture was heated to reflux temperature, then stirred and refluxed for 18 hours. The mixture was allowed to cool to room temperature. Then it was poured into a stirred mixture of concentrated HCl (20 ml) and ice (40 g). This mixture was stirred for 3 hours. The resultant solution was cooled on an ice- bath. Solid KOH was added portionwise until pH > 9. This mixture was extracted with CH 2 Cl 2 . 10 The separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. Toluene was added and co-evaporated on the rotary evaporator. Yield: ± 1.8 g of intermediate 7 (crude yield). Intermediate 7 can be converted into different final compounds as described in example Bl. 15 Example A4 a-i) Preparation of intermediate 11 N F F N

CH

3 0Na (0.0170 mol) was added to a solution of 1-(phenylmethyl)-4-piperidinone (0.0163 mol) and 2,4-difluorobenzeneacetonitrile (0.0327 mol) in CH 3 0H, dry (50 ml) under argon, and the mixture was stirred under reflux for 4 hours. Then, the reaction mixture was cooled to room temperature and poured into ice (200 g). The resulting 20 mixture was extracted with ethyl acetate. The separated organic layer was dried (Na 2

SO

4 ), filtered and the solvent was evaporated in vacuum. Yield: 5.3 g of intermediate 11. a-2) Preparation of intermediate 11 N F F N

CH

3 0Na (47.2 ml, 0.26 mol; 30 % in CH 3 0H) was added to a stirring solution of 2,4 25 difluorobenzeneacetonitrile (39.7 g, 0.259 mol) and 1-(phenylmethyl)-4-piperidinone WO 2007/090836 PCT/EP2007/051123 -42 (24.5 g, 0.129 mol) in CH 3 0H (250 ml; p.a.) under N 2 atmosphere. The reaction mixture was stirred and refluxed for 18 hours. The solvent was evaporated and the residue was stirred in 250 ml ice-H 2 0. The product was extracted 2x with CH 2 Cl 2 . The combined organic layers were dried (MgSO 4 ), filtered and the solvent was evaporated. 5 The residue was filtered over silica (eluent: CH 2 Cl 2 /MeOH 99.5/0.5). The pure fractions were combined and the solvent was evaporated and co-evaporated with toluene. Yield: 27.6 g of intermediate 11. b-i) Preparation of intermediate 12 N F F N NaBH 4 (0.0245 mol) was added to a solution of intermediate 11 (0.0163 mol) in 10 2-propanol (20 ml). The mixture was stirred under reflux for 4 hours, and cooled to room temperature. Then, a mixture of water and ice (200 ml) was added, and extracted with dichloromethane. Extract was dried over Na 2

SO

4 , filtered and concentrated in vacuum. The residue was purified by Flash chromatography (eluent: hexane/ethyl acetate 4/1). The product fractions were collected and the solvent was evaporated. 15 Yield: 3.464 g of intermediate 12 (65 %; 2-(1-benzyl-4-piperidinyl)-2-(2,4 difluorophenyl)acetonitrile). b-2) Preparation of intermediate 12 N F F N A solution of intermediate 11 (27 g, 0.083 mol) in a thiophene solution (2 ml) and

CH

3 0H (250 ml; p.a.) was hydrogenated over Pd/C 10 % (3 g, catalyst). After the 20 calculated amount of H 2 (1 equivalent) was taken up, the catalyst was filtered off. The filtrate was evaporated and co-evaporated with 1,4-dioxane. The residue was used as such in the next step. Yield: Intermediate 12 (residue).

WO 2007/090836 PCT/EP2007/051123 -43 c) Preparation of intermediate 13 N 0-CHT 3 qN 0 F F A solution of intermediate 12 (0.083 mol; residue) and methyl acrylate (9 ml, 0.1 mol) in 1,4-dioxane (250 ml; p.a., dried on molecular sieves) was stirred under N 2 atmosphere on an ice-bath. When stirring became difficult, Triton-B (1 ml; catalyst) was added and the reaction mixture was continued stirring on the ice-bath for 5 minutes 5 and then at room temperature for 3 days. Then more methyl acrylate (3 ml) and Triton B (0.5 ml) were added and the reaction mixture was continued stirring for 18 hours at room temperature. The solvents were evaporated. The residue was filtered over silica (eluent: CH 2 Cl 2

/CH

3 0H 99/1). The desired fractions were combined and evaporated and co-evaporated with toluene. Yield: 32 g of intermediate 13 (93.5 %) 10 d) Preparation of intermediate 14 BH 2 NH OH N / F F

BH

3 .THF (1 M in THF; 100 ml; 0.1 mol) was added to intermediate 13 (residue; 11.9 g; 0.0288 mol). After the initial foaming, the reaction mixture was heated. The mixture was stirred and refluxed for 20 hours. Then the solvent was evaporated and co evaporated with toluene. Yield: Intermediate 14 (residue). 15 e) Preparation of intermediate 15 H NN F F

H

2 0 (1 ml) was added dropwise to intermediate 14 (residue; 0.0288 mol) (exothermic reaction). HBr 48 % (25 ml) was added dropwise (exothermic) and more HBr 48 % (75 ml) was added slowly. The mixture was stirred and heated on an oil-bath at 110 'C for 150 minutes and was then stirred for 18 hours at room temperature. The precipitate 20 was filtered off and was washed with a small amount of HBr 48 %. The filtrate was WO 2007/090836 PCT/EP2007/051123 -44 added dropwise to a stirring mixture of 50 % NaOH (100 ml) and crushed ice while cooled on an ice-bath. After the addition, the mixture was stirred for 1 hour and then the product was extracted (pH water layer > 9) with CH 2 Cl 2 . The separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated and co-evaporated 5 with toluene. The crude residue (intermediate 15) was used as such in the next reaction. f) Preparation of intermediate 16 O yCH3 NN F F A solution of intermediate 15 (1 g; 0.0027 mol) and acetic anhydride (15 ml) was stirred for 18 hours at 60 'C. The solvent was evaporated and co-evaporated with toluene. The residue was stirred in a half saturated aqueous NaHCO 3 solution and the 10 product was extracted with CH 2 Cl 2 . The separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by flash chromatography over silica (eluent: CH 2 Cl 2 /MeOH from 99/1 till 98/2 till 97/3). The desired fractions were combined and the solvent was evaporated and co-evaporated with MeOH. The product was crystallized from Et 2 0, filtered off, washed with Et 2 0 15 and dried (vacuum, 50 C). Yield: 0.24 g of intermediate 16. g) Preparation of intermediate 17 O CH 3 HN F F A solution of intermediate 16 (0.24 g; 0.00058 mol) in MeOH (100 ml; p.a.) was hydrogenated at room temperature with Pd/C 10 % (0.05 g) as a catalyst. After uptake of H 2 (1 equiv), the catalyst was filtered off and the filtrate was evaporated. Yield: 20 Intermediate 17. The residue was used as such in the next reaction.

WO 2007/090836 PCT/EP2007/051123 -45 B. Preparation of the final compounds Example BI a) Preparation of compound 1 0) BrN A solution of intermediate 7 (0.000109 mol) in formic acid, butyl ester (1 ml) was stirred at 100 'C for 4 hours. Then the solution was allowed to cool to room 5 temperature. The volatiles were evaporated and the residue was purified by Flash Tube (eluent: CH 2 Cl 2

/CH

3 0H 90/10). The product fractions were collected, stirred in

CH

2 Cl 2

/CH

3 0H 90/10, filtered and washed. The filtrate was evaporated. Yield: 0.016 g of compound 1 (33.3 %). b) Preparation of compound 2 0 CH 3 N N Br" 10 A solution of intermediate 7 (0.00012 mol) in THF (2 ml; p.a.) was stirred. Acetic acid, anhydride (0.2 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in CH 2 Cl 2 (3 ml). This solution was washed with an aqueous NaHCO 3 solution (half saturated) and the organic layer was separated. The organic layer was filtered and dried over an 15 Isolute HM-N filter and the filtrate was evaporated. Yield: 0.050 g of compound 2 (90.8%). 0 c) Preparation of compound 3 0 /CH3 S N Br A solution of intermediate 7 (0.000109 mol) and Et 3 N (0.1 ml) in CH 2 Cl 2 (3 ml; p.a.) was stirred. Methanesulfonylchloride (0.00012 mol) was added and the reaction 20 mixture was stirred at room temperature for 18 hours. An extra amount of Et 3 N (0.2 ml) WO 2007/090836 PCT/EP2007/051123 -46 and methanesulfonylchloride (0.00013 mo 1) was added and the reaction mixture was stirred further at room temperature for 24 hours. Na 2

CO

3 (2 ml; 10% aqueous solution) was added and the reaction mixture was stirred vigorously for 15 minutes. The organic layer was separated, dried (MgSO 4 ), filtered and the solvent was evaporated. The 5 residue was purified by flash tube (eluent: CH 2 Cl 2

/CH

3 0H 90/10). The product fraction was isolated, stirred in CH 2 Cl 2

/CH

3 0H 90/10, filtered (removal of silica) and washed. The filtrate was evaporated. Yield: 0.019 g of compound 3 (35.5 %). d) Preparation of compound 4 0 CH 3 BrN A solution of intermediate 7 (0.000109 mol) and Et 3 N (0.1 ml) in CH 2 Cl 2 (3 ml; p.a.) 10 was stirred. Propanoylchloride (0.00012 mol) was added and the reaction mixture was stirred at room temperature for 18 hours. Na 2

CO

3 (1.5 ml; 10% aqueous solution) was added and stirring was continued for 5 hours. The organic layer was separated, dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by Flash Tube (eluent: CH 2 Cl 2

/CH

3 0H 90/10). The product fraction was isolated, stirred in 15 CH 2 Cl 2

/CH

3 0H 90/10, filtered and washed (removal of silica). The filtrate was evaporated and co-evaporated with CH 3 0H. Yield: 0.033 g of compound 4 (64.5 %). e) Preparation of compound 5 N Y N BrN Benzoylchloride (0.00012 mol) was added to a stirring solution of intermediate 7 (0.000109 mol) and Et 3 N (0.1 ml) in CH 2 Cl 2 (4 ml). The reaction mixture was stirred 20 for 4 days at room temperature. MeOH (1 ml) was added and the solvent was evaporated. The residue was purified by flash column chromatography over a flash tube (eluent: CH 2 Cl 2

/CH

3 0H 90/10). The product fractions were collected and stirred in

CH

2 Cl 2

/CH

3 0H 90/10, filtered to remove the silica gel and the filtrate was evaporated. Yield: 0.030 g of compound 5 (53.2 %). 25 WO 2007/090836 PCT/EP2007/051123 -47 f) Preparation of compound 6 0"//O

S-NH

2 N Br N Reaction in a sealed tube. A mixture of intermediate 7 (0.000109 mol) and sulfamide (0.00011 mol) in pyridine (2 ml; p.a.) was stirred for 18 hours at 120 'C. The mixture was allowed to cool to room temperature. The solvent was evaporated. The residue was purified by reversed-phase high-performance liquid chromatography (method B). The 5 product fractions were collected and the solvent was evaporated. Methanol was added and co-evaporated on the rotary evaporator (2 x). Yield: 0.0084 g of compound 6 (15.6%). H g) Preparation of compound 8 Br N O Isocyanatobenzene (0.00012 mol) was added to a solution of intermediate 7 (0.000109 10 mol) in CH 2 Cl 2 (3 ml; p.a.), stirred at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The solvent was evaporated. The residue was purified by flash tube (eluent: CH 2 Cl 2

/CH

3 0H 90/10). The desired fraction was isolated, stirred in CH 2 Cl 2

/CH

3 0H 90/10, filtered to remove the silica gel, and the filtrate was evaporated. Yield: 0.037 g of compound 8 (63.7 0) 15 h) Preparation of compound 29 O NH 2 N N Br" A solution of intermediate 7 (0.000109 mol, 0.045 g) and isocyanatotrimethylsilane (0.00015 mol, 0.02 ml) in 1,4-dioxane (3 ml, dried on molecular sieves) was stirred at 90 'C in a sealed tube for 20 hours. A saturated aqueous solution of NH 4 Cl (1 ml) was added. The solvent was evaporated. The residue was stirred in saturated aqueous 20 solution of NaHCO 3 (2 ml). The product was extracted with CH 2 Cl 2 /MeOH (90/10).

WO 2007/090836 PCT/EP2007/051123 -48 The separated organic layer was evaporated. The residue was purified by high performance liquid chromatography (method A). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in CH 2 Cl 2 (5 ml) and a half saturated aqueous solution of NaHCO 3 (0.5 ml). The mixture was stirred for 12 minutes 5 and the bi-phasic solution was dried over an Isolute HM-N filter. The filter was washed four times with CH 2 Cl 2 (5 ml). The filtrate was evaporated. Yield: 0.007g of compound 29(14.1 %). i) Preparation of compound 30 NN BrNN Cyclopropanecarbonyl chloride (0.014 ml, 0.0002 mol) was added to a stirring solution 10 of intermediate 7 (0.05 g, 0.0001 mol) in CH 2 Cl 2 (3 ml, p.a.) and Et 3 N (0.025 ml, 0.0002 mol) and the mixture was stirred at room temperature for 48 hours. NH 3 in

CH

3 0H (7 N, 1 ml) was added to the reaction mixture. The solvent was evaporated. The residue was purified by reversed phase high-performance liquid chromatography (method B). The desired fractions were collected and the solvent was evaporated and 15 co-evaporated 2 times with CH 3 0H. Yield: 0.045 g of compound 30 (77.2 0) i) Preparation of compound 31 0 H 3 0 -IIN, S

CH

3 N Br" Dimethylsulfamoyl chloride (0.013 ml, 0.0001 mol) was added to a stirring solution of intermediate 7 (0.045 g, 0.0001 mol) in CH 2 Cl 2 (5 ml, p.a.) and DIPEA (0.2 ml, 0.0012 mol). The mixture was stirred at room temperature for 18 hours. The reaction mixture 20 was washed with a half saturated aqueous NaHCO 3 solution. The separated organic layer was evaporated. The residue was purified by flash tube (eluent: CH 2 Cl 2

/CH

3 0H 93/7). The desired product fractions were collected then stirred with some

CH

2 Cl 2

/CH

3 0H (90/10). The mixture was filtered and the filter residue was washed. The combined filtrates were evaporated. The residue was purified by reversed phase 25 high performance liquid chromatography (method B). The desired fractions were WO 2007/090836 PCT/EP2007/051123 -49 collected and the solvent was evaporated and and co-evaporated 3 times with CH 3 0H. Yield: 0.015 g of compound 31 (26.4 0) k) Preparation of compound 35 O N N Br N 3-Isocyanatopyridine (0.018 g, 0.0002 mol) was added to a stirring solution of 5 intermediate 7 (0.05 g, 0.0001 mol) in CH 2 Cl 2 (3 ml, p.a.) and then stirred at room temperature for 20 hours. NH 3 in CH 3 0H (7 N, 1 ml) was added to the reaction mixture. The solvent was evaporated. The product was purified by reversed phase high performance liquid chromatography (method B). The desired fractions were collected and the solvent was evaporated and co-evaporated 3 times with CH 3 0H. Yield: 0.048 g 10 of compound 35 (74.4 %). 1) Preparation of compound 36 F NO F N BrNNF Trifluoroacetic acid anhydride (1 ml) was added to intermediate 7 (0.064 g, 0.000154 mol). The reaction mixture was stirred at room temperature for 4 days. The solvent was evaporated and the residue was stirred in CH 2 Cl 2 . The organic layer was washed with 15 an aqueous saturated NaHCO 3 solution, was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified over a Flash Tube (eluent: CH 2 Cl 2 /MeOH 94/6). The product fraction was isolated and stirred in CH 2 Cl 2 /MeOH 94/6. The silica was filtered off and was washed. The filtrate was evaporated, yielding 0.029 g of compound 36 (36.8 %). 20 WO 2007/090836 PCT/EP2007/051123 -50 m) Preparation of compound 37 N N N N A mixture of intermediate 7 (0.00109 mol, 0.045 g), 2-chloropyrimidine (0.00011 mol, 0.0126 g), K 2 C0 3 (0.00011 mol, 0.0152 g) and EtOH (4 ml, p.a.) was stirred at 85 'C in a sealed tube for 18 hours. The solvent was evaporated. The residue was stirred in

H

2 0 and the product was extracted with CH 2 Cl 2 . The separated organic layer was dried 5 (MgSO 4 ), filtered off and the solvent was evaporated. The product was purified by high-performance liquid chromatography (method B). The desired fractions were combined and the solvent was evaporated and co-evaporated with MeOH. Yield: 0.0223 g of compound 37 (41.6 %). n) Preparation of compound 38 0 N NH 2 Br" 10 2-Chloroacetamide (0.014 g, 0.0002 mol) was added to a stirring solution of intermediate 7 (0.05 g, 0.0001 mol) in CH 2 Cl 2 (3 ml) and Et 3 N (0.025 ml, 0.0002 mol), and was then stirred at room temperature for 18 hours. The solvent was evaporated. The residue was purified by reversed phase high performance liquid chromatography (method B). The desired product fractions were collected and the solvent was 15 evaporated, and co-evaporated 2 times with CH 3 0H. Yield: 0.028 g of compound 38 (49.2%). Example B2 Preparation of compound 9 O O CH 3 BrNN A solution of intermediate 4 (0.00079 mol) and Et 3 N (0.001 mol) in CH 2 Cl 2 (10 ml; 20 p.a.) and CH 3 0H (10 ml; p.a.) was stirred. 1-Bromo-4-(chloromethyl)benzene (0.0010 WO 2007/090836 PCT/EP2007/051123 -51 mol) was added and the reaction mixture was kept stirring at room temperature for 18 hours. Then CH 2 Cl 2 (20 ml), H 2 0 (20 ml) and an aqueous saturated solution of NaHCO 3 (20 ml) were added successively. Stirring was continued for 1 hour. The separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. 5 The residue was purified by column chromatography over a RediSep 12g cartridge (eluent: CH 2 Cl 2

/(CH

3 0H/NH 3 ) from 100/0 to 96/4). The product fractions were collected and the solvent was evaporated. Yield: 0.24 g of compound 9 (62.5 %) Example B3 Preparation of compound 13 0 CH 3 Br NN N Br 10 A mixture of intermediate 6 (0.000175 mol) and DIPEA (0.2 ml) in DMF (4 ml; p.a.) was shaken at room temperature. 1 -Bromo-4-(bromomethyl)-2-fluorobenzene (0.000244 mol) was added and the resultant reaction mixture was shaken for 18 hours at room temperature. The solvent was evaporated. The residue was purified by reversed-phase high-performance liquid chromatography (Column: Xterra Prep MS 15 C18, Length: 10 cm, I.D.: 19 mm, particle size: 5 tm; eluent: (0.2 % NH 4

HCO

3 in

H

2 0)/CH 3 0H/CH 3 CN gradient). The product fractions were collected and the solvent was evaporated. CH 3 0H was added and co-evaporated on the rotary evaporator (2 x). Yield: Compound 13 (8.4 %). 20 Example B4 Preparation of compound 23 0 CH 3 BrN .HC A solution of intermediate 6 (0.0014 mol) and DIPEA (0.28 ml) was stirred in CH 2 Cl 2 (10 ml; p.a.). 1-Bromo-4-(chloromethyl)benzene ( 0.0015 mol) was added and the reaction mixture was stirred further for 18 hours at room temperature. Et 3 N (0.5 ml) was added and the mixture was stirred at room temperature for 24 hours. The reaction 25 mixture was washed with H 2 0 and NaHCO 3 (aqueous saturated solution). The WO 2007/090836 PCT/EP2007/051123 -52 separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:

CH

2 Cl 2

/CH

3 0H from 99/1 to 98/2). The product fractions were combined, the solvent was evaporated and co-evaporated with CH 3 0H. The product was turned into its HCl 5 salt in 2-propanol (10 ml) by addition of HCl/2-propanol (0.25 ml; 6 N). The solvent was evaporated and the residue was triturated in diethyl ether. The product was filtered off, washed and dried (vacuum, 50 'C). Yield: 0.309 g of compound 23 (44.9 %). Example B5 Preparation of compound 24 and compound 25 H H N O0 N Br Br R S 10 .HCl .HCl Compound 8 (0.0013 mol) was separated into its enantiomers by supercritical fluid chromatography over an AD-H column (isocratic elution: 35 % CO 2 / 65% methanol + 0.1 % 2-propanol; flow: 50 ml/min; column oven: 40 'C; Nozzle pressure: 100 bar). Two product fraction groups were collected and their solvent was evaporated. Each 15 residue was dissolved in diethyl ether and converted into the hydrochloric acid salt (1:1) with HCl (6 N)/2-propanol. Each salt was filtered off, washed with diethyl ether and dried (vacuum, 55 'C). Yield: 0.19 g of compound 24 and 0.22 g of compound 25. Example B6 Preparation of compound 26 and compound 27 N O < CH 3 BN O < CH 3 N N Br" Br I R| 20 .HCl .HCl Compound 2 (0.0006 mol) was separated into its enantiomers by supercritical fluid chromatography over an AD-H column (eluent gradient: C0 2 / 10-40 % methanol; the gradient of 10-40 % methanol was applied in steps of 1.6 % / minute and the final condition was hold for 4.5 minutes; flow: 50 ml/min; column oven: 40 'C; Nozzle 25 pressure: 100 bar). Two product fraction groups were collected and their solvent was evaporated. Each residue was dissolved in 2-propanol and converted into the WO 2007/090836 PCT/EP2007/051123 -53 hydrochloric acid salt (1:1) with HCl (6 N)/2-propanol. Each salt was filtered off and triturated under diethyl ether, filtered off and dried. Yield: 0.079 g of compound 26 and 0.104 g of compound 27. 5 Example B7 Preparation of compound 39 and compound 40 0 0 NH, NH, N N Br Br N N S R fumarate-salt fumarate-salt Compound 38 (1.8 g) was separated into its enantiomers by supercritical fluid chromatography over an AD-H column (20 x 250 mm) (eluent: isocratic elution : 60 %

CO

2 / 40 % MeOH with 0.2 % 2-propanol; flow: 50 ml/min; column oven: 40 'C; 10 Nozzle pressure: 100 bar). Fraction "A" was the first enantiomer to be eluted from the column under given preparative enantiomeric separation method. The fraction "A" product fractions were combined and the solvent was evaporated. The residue was dissolved in EtOH (25 ml), and fumaric acid was added. Stirring was continued for 2 hours and then the solvent was evaporated. The residue was stirred in Et 2 0. The 15 precipitate was filtered off, washed 3 x with Et 2 0 and dried at 50 'C (vacuum). Yield: Compound 39 (S, OR: +). Fraction "B" was the second enantiomer to be eluted from the column under given preparative enantiomeric separation method. The fraction "B" product fractions were combined and the solvent was evaporated. The residue was dissolved in EtOH (25 ml), and fumaric acid was added. Stirring was continued for 1 20 hour and then the solvent was evaporated. The residue was stirred in Et 2 0. The precipitate was filtered off, washed 3 x with Et 2 0 and dried at 50 'C (vacuum). Yield: compound 40 (R,OR: -).

WO 2007/090836 PCT/EP2007/051123 -54 Example B8 Preparation of compound 41 O yCH 3 Br N Br N _

F

.HC F Acetic acid (0.053 ml) was added to a stirring mixture of intermediate 17 (residue; 0.00058 mol), 4-bromobenzaldehyde (0.14 g; 0.00075 mol) and sodium triacetoxyborohydride (0.369 g; 0.00174 mol) in CH 2 Cl 2 (10 ml; p.a.). The reaction 5 mixture was continued stirring for 18 hours at room temperature. Then a HCl solution (1 N, 2.5 ml) was added and stirring was continued vigorously for 1 hour. Then a half satured aqueous K 2 C0 3 solution (10 ml) was added. The organic layer was separated and was washed with H 2 0. Then the separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified over a RediSep 10 cartridge (eluent: CH 2 Cl 2 /(MeOH/NH 3 7 N) from 100/0 till 99/1 till 98/2 till 97/3). The desired fractions were combined and the solvent was evaporated. The product was converted into its HCl-salt in 2-propanol using HCl/2-propanol (6 N; 0.5 ml). The solvents were evaporated and the residue was triturated in Et 2 0. The precipitate was filtered off, washed with Et 2 0 and dried (50 'C; vacuum). Yield: 0.21 g of compound 15 41 (68.8 %; HCl-salt). Table 1 lists the compounds of formula (I) which were prepared according to one of the above examples (Ex. No.) WO 2007/090836 PCT/EP2007/051123 -55 Table 1 R N R3 N I N * 2a 2b R2a R2b Stereodescrip Comp. Exp. R y tor/ No. No. Salt/Analyt. data 1 B.a -HC=O H H *(RS) _________ Br 2 Bl.b -CH 3 C=O H H *(RS) 3 Bl.c -CH 3 O=S=O H H *(RS) Brj) 4 Bl.d Br -CH 2

CH

3 C=O H H *(RS) 5 Bl.e Br C=O H H *(RS) 6 Bl.f Br -NH 2 O=S=O H H *(RS) 8 Bl.g Br L N C=O H H *(RS) 9 B2 Br LONCH3 C=O H H *(RS) 10 B3 -CH 3 C=O H H *(RS) 11 B3 I-CH 3 C=O H H *(RS) 12 B3 -CH 3 C=O H H *(RS) 13 B3 -CH 3 C=O H H *(RS) 14 B3 -CH 3 C=O H H *(RS) 15 B3 -CH 3 C=O H H *(RS) Cl C WO 2007/090836 PCT/EP2007/051123 -56 R2a R2b Stereodescrip Comp. Exp. R y tor/ No. No. Salt/Analyt. data F 16 B3 Br -CH 3 C=O *(RS) _________ B 17 B3 HB -CH 3 C=O H H *(RS) 18__ B3__Br -CH3_C=OHH_*(RS H3 H H *(RS) 18 B3 *

-CH

3 C=O Br **(RS) 20 B3 CH3 C=O H H *(RS) 21 B3Br -H3 C= H H *(RS) 22 B3 0 -CH 3 C=O *(RS) H H 20 B3 B -CH 3 C=O *(RS) B-NH H H 21 B3 B\ C=O *(RS) 23 B3 Br -CH 3 C=O H H *(RS) 23 B4 B-H C=O H H *(R); HClsalt 24 B5 N- C= H H *(R); HCl salt 25 B6 -C3 C=O H H *(S); HCl salt 26 B6 I~" -CH 3 =O H H *S;HCl salt Br 28 B3 I t- -CH 3 c=o H H *(RS) 29 B1.h I ~~-NH 2 c=o H H *(RS) 30 B1I cJ H H *(RS) 31 B1.j -N(CH 3

)

2 o=s=o H H *(RS) 32 B1.k LlN-(iq C=O H H *(RS) WO 2007/090836 PCT/EP2007/051123 -57 R2a R2b Stereodescrip Comp. Exp. R Y tor/ No. No. Salt/Analyt. data CH3 HH H 33 Bl.k Br C=O *(RS) Br) 0

H

3 C 34 Bl.k B r\/ C=O H H *(RS) 35 Bl.k Br C=O H H *(RS) 36 B1.1 B-CF 3 C=O H H *(RS) 37 Blm Br db H H *(RS) Ho0 38 Bl.n B -NH 2 ._I_ _. H H *(RS) Br H 39 B7 -H~~-_ H H *(S); OR:+, 39rB -NH 2 I rH fumarate salt 40 B7 -H~~-_ H H *(R); OR:, 40 B7 -NH 2 I rH fumarate salt 41 Br

-CH

3 C=O F F .HCl OR means optical rotation; db means direct bond C. Analytical Part 5 LCMS conditions General procedure A The HPLC gradient was supplied by an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 C) and 10 DAD detector. Flow from the column was split to a MS detector. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3kV and the source temperature was maintained at 140 'C. Nitrogen was used as 15 the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

WO 2007/090836 PCT/EP2007/051123 -58 General procedure B The LC gradient was supplied by an Acquity UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55 'C) and diode-array detector (DAD). Flow from the column was split to a MS detector. The MS detector 5 was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 'C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system. 10 Procedure 1 In addition to general procedure A: Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 tm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile 15 phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 1 minute, 100 % B for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 [[1 was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization 20 mode. Procedure 2 In addition to general procedure A: Reversed phase HPLC was carried out on a Chromolith (4.6 x 25 mm) with a flow rate of 3 ml/min. Three mobile phases (mobile 25 phase A: 95 % 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 96 % A, 2 % B and 2 % C, to 49 % B and 49 % C in 0.9 minutes, to 100 % B in 0.3 minutes and hold for 0.2 minutes. An injection volume of 2 [[1 was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode. 30 WO 2007/090836 PCT/EP2007/051123 -59 Procedure 3 In addition to general procedure A: Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 tm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70 % methanol + 30 % H 2 0; mobile phase B: 0.1 % formic 5 acid in H 2 0/methanol 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 12 minutes. An injection volume of 10 [[l was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode. 10 Procedure 4 In addition to general procedure A: Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 tm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient 15 condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and 99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 [[l was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode. 20 Procedure 5 In addition to general procedure B: Reversed phase UPLC was carried out on a bridged ethylsiloxane/silica (BEH) C18 column (1.7 jam, 2.1 x 50 mm) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1 % formic acid in H 2 0/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95 % A to 25 5 % A, 95 % B in 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 [[l was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

WO 2007/090836 PCT/EP2007/051123 -60 Procedure 6 In addition to general procedure A: Column heater was set at 60 'C. Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 tm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM 5 ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50 % B and 50 % C in 6.5 minutes, to 100 % B in 0.5 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 [[l was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative 10 ionization mode. Table 2 : Analytical data (Retention time in minutes; MH+ means the protonated mass of the compound). (When a compound is a mixture of isomers which give different peaks in the LCMS 15 method, only the retention time of the main component is given in the LCMS table). Comp. No. [MH+] Retention time Procedure 1 441 6.58 1 2 455 5.77 1 3 491 6.71 1 4 469 6.94 1 5 517 7.15 1 6 492 6.43 1 7 484 6.98 1 8 532 7.02 1 9 485 6.84 1 10 411 6.41 1 11 429 6.76 1 12 429 6.69 1 13 473 6.85 1 14 445 7.05 1 15 445 7.28 1 16 473 6.89 1 17 469 6.83 1 18 469 6.65 1 19 483 6.88 1 WO 2007/090836 PCT/EP2007/051123 -61 Comp. No. [MH+] Retention time Procedure 20 417 6.49 1 21 495 6.95 1 22 419 6.43 1 23 455 (free base) 1.11 2 24 532 (free base) 7.47 3 25 532 (free base) 7.47 3 26 455 (free base) 6.29 3 27 455 (free base) 6.26 3 28 455 6.69 4 29 456 6.2 4 30 481 6.89 4 31 568 1.15 5 32 533 0.88 5 33 551 6.57 4 34 538 6.82 4 35 520 1.05 5 36 509 7.17 4 37 491 7.00 6 38 470 6.59 4 39 470 (free base) 6.60 4 40 470 (free base) 6.58 4 41 491 (free base) 7.72 3 Optical rotation The optical rotation was measured using a polarimeter. [a]D20 indicates the optical 5 rotation measured with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 20 'C. Behind the actual value the concentration and solvent of the solution which was used to measure the optical rotation are mentioned.

WO 2007/090836 PCT/EP2007/051123 -62 Table 3 : Optical rotation Comp. ID20 concentration solvent 24 -78.350 C = 3.51 mg/5 ml CH 3 0H 25 +86.850 C = 4.145 mg/5 ml CH 3 0H 26 -60.440 C = 4.55 mg/5 ml CH 3 0H 27 +60 C = 5.75 mg/5 ml CH 3 0H D. Pharmacological example CXCR3 receptor inhibition was examined in a [ 35 1GTPyS exchange assay 5 The exchange of guanosine 5 '-[ 3 5 S]triphosphate was measured on membranes of human CXCR3-transfected CHO cells. [ 35 S]GTPyS exchange assays were performed in 96-well plates with 10 tg of membrane protein/well using basic flashplates (Perkin Elmer). Compounds were dissolved in DMSO and diluted with incubation buffer to yield required concentrations with 9% DMSO. Incubation buffer is composed of 20 10 mM HEPES, 100 mM NaCl, 3 tM GDP and 1 mM MgCl 2 , pH 7.4. Membrane incubation buffer is incubation buffer supplemented with 14.3 [tg/ml saponin. Compound, membranes, hI-TAC (interferon-inducible T-cell alpha chemoattractant) and [ 3 5 S]GTPyS were added in a total volume of 200 1tl. First, 20 [[1 of the appropriate compound dilution and 140 [[1 membranes from CXCR3-CHO cells were dissolved in 15 membrane incubation buffer and pre-incubated for 30 minutes at 30'C. Then, 20 1tl of hI-TAC dissolved at 30 nM in incubation buffer was added to the membranes and the mixture containing 1% of DMSO was incubated for another 30 minutes at 30'C. Finally, 20 [[1 [ 35 S]GTPyS (-1119 Ci/mmol, Amersham) dissolved at 2.5 nM in incubation buffer was added. After 1 minute shaking and 30 minutes incubation at 20 30'C, flashplates were centrifuged for 5 minutes at 2500 rpm at room temperature. Flashplate bound radioactivity was determined by liquid scintillation counting. Basal GTPyS-binding was measured in 8 wells with membranes incubated in the same volume with 1% DMSO, without I-TAC. Maximal GTPyS-binding was measured in 8 wells with membranes incubated with 1% DMSO and 3 nM I-TAC. The IC 50 value is 25 calculated as the molar concentration of the test compound, which inhibits 50% of specific I-TAC-induced GTPyS-binding. IC 50 values were calculated using non-linear regression in Graphpad Prism.

WO 2007/090836 PCT/EP2007/051123 -63 Table 4 reports pIC 5 o values obtained in the above-described test for compounds of formula (I). pIC 5 o defines -log IC 50 wherein IC 50 is the molar concentration of the test compound which inhibits 50 % of specific I-TAC-induced GTPyS-binding. 5 Table 4 Comp. No. pIC 5 o 1 7.0 2 6.9 3 6.0 4 6.7 5 6.4 6 6.7 7 6.1 8 7.2 9 6.5 10 6.6 11 6.8 12 6.8 13 7.3 14 6.5 15 6.7 16 6.9 17 6.9 18 6.7 19 6.4 20 6.1 21 6.5 22 6.8 23 6.7 24 7.5 25 5.2 26 7.0 27 5.6 28 5.5 29 6.7 WO 2007/090836 PCT/EP2007/051123 -64 Comp. No. pIC 5 o 30 6.7 31 6.1 32 7.3 33 7.3 34 7.2 35 7.5 36 6.1 37 5.5 38 7.1 39 7.2 40 6.1 41 7.2

Claims (24)

1. A compound of formula R3 Y N RI-N) R2 a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically 5 isomeric form thereof or a solvate thereof, wherein X represents N or CH; Y represents a direct bond, CH

2 -C(=O) wherein the CH 2 is attached to the N of the piperidine ring, C(=O) or S(=0)p; p represents an integer of value 1 or 2; 10 RI represents CH(R 4 )-aryl or CH(R 4 )-heteroaryl; R2 represents aryl 2 or heteroaryl; R3 represents hydrogen, C1. 6 alkyl, polyhaloCI 6 alkyl, CI 6 alkyloxy, aryll, aryll-NH-, heteroaryl, heteroaryl-NH-, C 3 . 7 cycloalkyl, amino or mono or di(C1. 4 alkyl)amino; R 4 represents hydrogen or C1 4 alkyl; 15 R and R6 each independently represent hydrogen, or C1. 6 alkyl optionally substituted with hydroxyl; or R 5 and R6 together with the nitrogen to which they are attached form a monocyclic heterocycle selected from piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of said rings optionally substituted with C1 4 alkyl; 20 aryl represents unsubstituted naphthyl; or phenyl or naphthyl, each of said phenyl or naphthyl substituted with at least one substituent, each substituent independently selected from halo, hydroxyl, CI. 6 alkyl, CI. 6 alkyloxy, CI. 6 alkyloxycarbonyl, C 1 . 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C1. 4 alkyl-SO 2 -, R 6 R 5 N-C(=O)-, amino, mono-or 25 di(Ci 4 alkyl)amino, C 1 . 4 alkylcarbonylamino, aryll, arylI CI 4 alkyloxy, arylloxy, or aryll C(=O)-; aryll represents phenyl or phenyl substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, hydroxyl, C1. 6 alkyl, CI. 6 alkyloxy, C 1 . 6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI. 6 alkyl, 30 polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, aminocarbonyl, mono-or di(Ci 4 alkyl)aminocarbonyl, amino, or mono-or di(Ci 4 alkyl)amino; aryl 2 represents phenyl or naphthyl, each of said rings optionally substituted with at least one substituent, each substituent independently selected from halo, hydroxyl, WO 2007/090836 PCT/EP2007/051123 -66 C 1 . 6 alkyl, C 1 . 6 alkyloxy, C 1 . 6 alkyloxycarbonyl, C 1 . 6 alkylcarbonyloxy, C 1 . 6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1 . 4 alkyl-SO 2 -, R6R N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino, C 1 . 4 alkylcarbonylamino, aryll, aryl C 1 . 4 alkyloxy, arylloxy, or arylC(=O)-; 5 heteroaryl represents a monocyclic heterocycle selected from pyrrolinyl, imidazolinyl, pyrazolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; or a bicyclic heterocycle selected from indolyl, indolizinyl, isoindolyl, indolinyl, 10 benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, benzoxadiazolyl, benzoxazolyl, benzthiazolyl, each of said monocyclic or bicyclic heterocycles optionally being substituted with at least one substituent, each substituent independently selected 15 from halo, hydroxyl, C1. 6 alkyl, CI 6 alkyloxy, CI 6 alkyloxycarbonyl, C 1 . 6 alkylcarbonyloxy, CI 6 alkylthio, polyhaloCI 6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, HO-SO 2 -, C 1 . 4 alkyl-SO 2 -, R 6 R 5 N-C(=O)-, amino, mono-or di(Ci 4 alkyl)amino or CI 4 alkylcarbonylamino. 20 2. A compound according to claim 1 wherein Y represents C(=O) or S(=O)p and R3 represents hydrogen, C1 6 alkyl, CI 6 alkyloxy, aryll, aryl 1 -NH-, amino or mono or di(Ci 4 alkyl)amino.

3. A compound according to claim 1 or 2 wherein Y represents C(=O). 25

4. A compound according to claim 1 wherein Y represents CH 2 -C(=O).

5. A compound according to any one of the preceding claims wherein X represents CH. 30

6. A compound according to any one of the preceding claims wherein R 1 represents CH(R 4 )-aryl.

7. A compound according to claim 6 wherein aryl represents phenyl substituted with 35 one or two substituents, each substituent independently selected from halo, hydroxyl, C 1 . 6 alkyl, C 1 . 6 alkyloxy, CI 6 alkyloxycarbonyl, CI 6 alkylcarbonyloxy, C 1 . 6 alkylthio, polyhaloCI. 6 alkyl, polyhaloCI 6 alkyloxy, cyano, nitro, carboxy, WO 2007/090836 PCT/EP2007/051123 -67 HO-SO 2 -, CI 4 alkyl-SO 2 -, R6R'N-C(=O)-, amino, mono-or di(C1. 4 alkyl)amino, C 1 . 4 alkylcarbonylamino, aryll, arylCI 4 alkyloxy, arylloxy, or arylC(=O)-.

8. A compound according to any one of claims 1 to 5 wherein R 1 represents CH(R 4 ) 5 heteroaryl.

9. A compound according to any one of the preceding claims wherein R2 represents aryl 2 .

10 10. A compound according to claim 9 wherein aryl 2 represents phenyl optionally substituted with one or two halo atoms.

11. A compound according to any one of the preceding claims wherein R 3 represents CI 6 alkyl, aryll, aryll-NH-, or heteroaryl-NH-. 15

12. A compound according to claim 1 wherein aryl represents phenyl substituted with one or two substituents, each substituent independently selected from halo or C 1 . 6 alkyl; aryll represents phenyl optionally substituted with halo; R 2 represents aryl 2 wherein aryl 2 represents phenyl optionally substituted with one or two halo 20 atoms; heteroaryl represents thienyl, isoxazolyl, pyridyl, pyrimidinyl, benzofuranyl or benzoxadiazolyl, each of said ring systems optionally being substituted with halo; X is CH; p is 2.

13. A compound according to claim 1 wherein the compound is selected from: R Y N I N * 2a 2b 25 R R R3 Y R 2 a R 2 b Stereodescriptor/ Salt B -H C=O H H *(RS) B -CH 3 C=O H H *(RS) BrO~ WO 2007/090836 PCT/EP2007/051 123 -68 RiR' Y R 2 a R 2 b Stereodescriptor/ ____ ___ ____ __ ___ ____ ___ __ ____ ___ ___Salt I -NH 0=5= H H*(RS) Br 2 =0= H H*() I L<ONH C=0 H H *(RS) I-CH 3 C=0 H H *(RS) I)1) y -CIA 3 C=O H H*() F &: y -CH 3 C=0 H H *(RS) Br(D Cl y -CH 3 C=0 H H *(RS) I, -CH 3 C=0 H H (S Brb__________ I3)( l -CH 3 C=0 H H *(RS) Br CH3 *(RS) y -CH 3 C=0 H H Br ____________ H13C *(RS) y-CH 3 C=0 H H Brj___________ *(RS) \/-CH 3 C=0 H H 0N---CH 3 C=0 H H *(RS) Br -NH 2 -CH 2 -C(=0)- H H *(RS) Br-CH 3 C(=0) H H *(R); .HCl Br-CH 3 C(=0) F F *(RS); HCl I-CH 2 CH 3 C=0 H H *(RS) I-NH 2 C=0 H H *(RS) WO 2007/090836 PCT/EP2007/051123 -69 R R' Y R 2 a R 2 b Stereodescriptor/ Salt Br C=O H H *(R); HCi salt BrOC=O H H *(RS) N CH3 H Br / C=O H H *(RS) H3C BH 0 Br LLN C=O H H *(RS) IBrF C=O H H *(RS) Ho0 B -NH 2 -- H H *(S); fumarate salt Br H a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof.

14. A compound according to claim 1 wherein the compound is selected from: R Y N I N * 5 R2a R2b R R3 Y R 2 a R 2 b Stereodescriptor/ Salt Br -CH3C=O H u *(RS) Br ~C=O H H *(RS) -CH3 C=O H H *(RS) C -CH 3 C=O H H *(RS) r -CH 3 C=O H H *(RS) B -NH 2 -CH 2 -C(=O)- H H *(RS) WO 2007/090836 PCT/EP2007/051123 -70 R' Y R 2 a R 2 b Stereodescriptor/ Salt Br -CH 3 C(=O) H H *(R); .HCl Br -CH 3 C(=0) F F *(RS); HCl salt B -CH 2 CH 3 C=O H H *(RS) B -NH 2 C=O H H *(RS) C=O H H *(R); HCl salt Br C=O H H *(RS) CH3 N N Bri \. / C=O H H *(RS) H3C Hr 0 Br C=O H H *(RS) H- F Br "F C=O H H *(RS) Ho0 Br -NH 2 -- H H *(S); fumarate salt a N-oxide thereof, a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof or a solvate thereof.

15. A compound according to any one of the preceding claims for use as a medicine. 5

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims I to 14. 10

17. A process of preparing a composition as claimed in claim 16 characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any one of claims 1 to 14.

18. Use of a compound for the manufacture of a medicament for preventing or treating 15 a disease mediated through activation of the CXCR3 receptor wherein the compound is a compound according to any one of claims I to 14. WO 2007/090836 PCT/EP2007/051123 -71

19. Use of a compound as claimed in claim 18 for the manufacture of a medicament for treating a disease mediated through activation of the CXCR3 receptor.

20. Use of a compound according to claim 18 or 19 wherein the disease mediated 5 through activation of the CXCR3 receptor is rheumatoid arthritis, inflammatory bowel disease, allograft rejection, multiple sclerosis, COPD, glomerulonephritis, allergic contact dermatitis, lupus, psoriasis, atherosclerosis, Sjogren's syndrome, autoimmune thyroid disorder. 10

21. Use according to claim 20 wherein the disease mediated through activation of the CXCR3 receptor is rheumatoid arthritis, Crohn's disease, colitis, allograft rejection.

22. A compound of formula R 3 Y I N HN X R2 15 wherein R2, R3, X and Y are as defined in claim 1.

23. A compound of formula H N 1-/ (IV) R -N X R2 wherein R , R2, X and Y are as defined in claim 1. 20

24. A process of preparing a compound as defined in claim 1 characterized by a) reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W 1 represents a suitable leaving group, in the presence of a suitable base and a suitable solvent, WO 2007/090836 PCT/EP2007/051123 -72 R3 R3 I I Y Y N N + R0W1 HN X-N with R 1 , R 2 , R 3 , X and Y as defined in claim 1; b) reacting an intermediate of formula (II) with an intermediate of formula (III') wherein Ria represents aryl or heteroaryl, in the presence of a suitable reducing 5 agent, a suitable acid and a suitable solvent, R3 R3 I I NN + Ria R HN - R N (II)' (1-a) with R 2 , R 3 , X and Y as defined in claim 1; c) reacting an intermediate of formula (IV) with an intermediate of formula (V), wherein W 2 represents a suitable leaving group, optionally in the presence of a 10 suitable base and optionally in the presence of a suitable solvent, R 3 a II N Y N + R 3 a -Y-W 2 - ~ RI-N X + - R -N X \- R2 \-/ R2 (IV) (V) (1-b) with R 1 , R 2 , X and Y as defined in claim 1 and Y-R 3 a corresponding to Y-R 3 as defined in claim 1 but other than -S0 2 -NH 2 , -C(=O)-NH-aryll, -C(=O)-NH heteroaryl; 15 d) by reacting an intermediate of formula (IV) with S(=0) 2 -(NH 2 ) 2 in the presence of a suitable solvent, WO 2007/090836 PCT/EP2007/051123 -73 NH 2 o=s=o I RI-N + S=0)2(NH22 O=S-N H N + R b-NC=O R-N X (IV) (I-c) with R 1 , R2 and X as defined in claim 1; e) reacting an intermediate of formula (IV) with an intermediate of formula (VI) in the presence of a suitable solvent, R 3 b HN c=o HI NN -N R -N R 1 + R 3 bN=C=O \-/ R \-/ R2 5 (IV) (v1) (1-d) with R 1 , R2 and X as defined in claim 1, and Rib representing aryll or heteroaryl; f) reacting an intermediate of formula (IV) with isocyanatotrimethylsilane in the presence of a suitable solvent, NH 2 C=O HN N isocyanatotrimethylsilane N R 1 -N R -N x R - R2 R2 (IV) (l-e) 10 with R 1 , R2 and X as defined in claim 1, g) reacting an intermediate of formula (XXXIII-a) or (XXXIII-b) wherein W 2 represents a suitable leaving group, with a suitable base of formula R5 RNH in the presence of a suitable solvent, WO 2007/090836 PCT/EP2007/051123 -74 R3 R3 Y YI I N N RI-N+ NHR 5 R - 4- RQ-N O R 6 R 5 N W2 (xxx111 I-a) R3 R3I YY Y IN N 0 0+ NH 5 R 6 1 >RaN O Ra- X+ NHR R 6 R65 Ria-N X_ (1-f-2) (XXxIII-b) with X, Y, R3, R and R6 as defined in claim 1 and wherein -R2a-C(=0)-NR 5 R 6 represents a R 2 substituent wherein the ring moiety is substituted with R 5RN-C(=O)- and wherein -Ra-C(=O)-NR 5 R 6 represents a R 1 substituent wherein 5 the ring moiety is substituted with R 5 R 6 N-C(=O)-; or, if desired, converting compounds of formula (I) into each other following art known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment 10 with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; or, if desired, preparing stereochemically isomeric forms, quaternary amines, solvates or N-oxide forms thereof. 15