NZ543748A

NZ543748A - Heteroaryl amines as glycogen synthase kinase 3beta inhibitors (GSK3 inhibitors)

Info

Publication number: NZ543748A
Application number: NZ543748A
Authority: NZ
Inventors: Eddy Jean Edgard Freyen; Peter Jacobus Johan Buijnsters; Marc Willems; Werner Constant Joha Embrechts; Christopher John Love; Paul Adriaan Jan Janssen; Paulus Johannes Lewi; Jan Heeres; Jonge Marc Rene De; Lucien Maria Henricus Koymans; Hendrik Maarten Vinkers; Aken Koen Jeanne Alfons Van; Gaston Stanislas Marcell Diels
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2001-11-01
Filing date: 2002-10-29
Publication date: 2007-06-29

Abstract

Disclosed are compounds of formula (I), wherein the substituents R1, R2, R3, R4, X, Z and s are as defined in the specification. These compounds are used in the manufacture of medicaments for the treatment of diseases mediated through glycogen synthase kinase 3 (GSK3).

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 543748 54 3 748 *10050146991* Patents Form No. 5 Our Ref: HP225193 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Divisional Application from NZ 531853 HETEROARYL AMINES AS GLYCOGEN SYNTHASE KINASE 3BETA INHIBITORS (GSK3 INHIBITORS) We, JANSSEN PHARMACEUTICA N.V., a body corporate organised under the laws of Belgium of Turnhoutseweg 30, B-2340 Beerse, Belgium, hereby declare the invention, for which We pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page 1a) pt054516979 INTELLECTUAL PROPERTY OFFICE OF N.Z. 23 NOV 2005 RECEIVED 100682755_1 -la- HETEROARYL AMINES AS GLYCOGEN SYNTHASE KINASE 3BETA INHIBITORS (GSK3 INHIBITORS) 5 The present invention concerns a novel group of heterocyclic derivatives, their use as a medicine, their use for the manufacture of a medicament for the treatment of diseases mediated through glycogen synthase kinase 3; processes for their preparation and pharmaceutical compositions comprising them. 10 NZ 531853, from which this application is divided, relates to heterocyclic derivatives and their uses. WO 01/72745 describes 2-substituted 4-heteroaryl-pyrimidines useful in the treatment of proliferative disorders. 15 WO 98/41512 relates to substituted 2-anilinopyrimidines useful as protein kinase inhibitors. WO 95/09851 describes pyrimidineamine derivatives useful in the treatment of tumour diseases. WO 01/12621 describes inhibitors of c-JUN-N-terminal kinases and other protein 20 kinases. WO 01/60816 describes pyrimidine derivatives useful as kinase inhibitors. WO 97/19065 discloses substituted 2-anilinopyrimidines useful as p56Ick, p59f*n, ZAP-70 and protein kinase C inhibitors. WO 91/18887 discloses diaminopyrimidine compounds as inhibitors of gastric acid 25 secretion. WO 99/50250 concerns HIV inhibiting aminopyrimidine derivatives. US 5,516,775 concerns the use of 2-anilinopyrimidines as protein kinase C inhibitors. WO 95/09853 describes JV-phenyl-2-pyrimidineamine derivatives for the treatment of tumor diseases. 30 WO 98/18782 concerns 2-pyrimidineamine derivatives as selective protein tyrosine kinase inhibitors. EP 0,337,943 discloses iV-phenyl-iV-pyrixnidin-2-yl derivatives having herbicidal plant growth regulating activity. EP 0,164,204 concerns 2-aminopyrimidines which augment the immune respons. 35 EP 0,233,461 relates to 4,5,6-substituted 2-pyrimidineamines having anti-asthmatic activity. WO 00/62778 describes cyclic protein tyrosine kinase inhibitors. US 5,521,184 describes pyrimidine derivatives for the treatment of tumoral diseases. The present invention relates to compounds which are distinguishable from the prior art in structure, pharmacological activity, potency or selectivity. The present invention concerns a compound selected from the general formula (I) a jV-oxide, a phannaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein ring A is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; R1 is hydrogen; aryl; formyl; C]^alkylcarbony 1; Ci^alkyl; Ci^alkyloxycarbonyl; Ci-6alkyl substituted with formyl, C1 ^alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylcarbonyloxy; Ci^alkyloxyC 1 ^alkylcarbonyl optionally substituted with Ci^alkyloxycarbonyl; X is -NR1-; -NH-NH-; -N=N-; -0-; -C(=0)-; -C(=S)-; -O-C(O)-; -C(=0)-0-; -0-C(=0)-Ci^alkyl-; -C(=0)-0-Ci^alkyl-; -0-Ci^alkyl-C(=0)-; -C(=0)-C^alkyl-0-; -O-CCO^NR1-; -NR^CCK^-O-; -0-C(=0)-C(=0)-; -C(=0)-NR1-, -NR'-CC^O)-; -C(=S)-NR2-, -NR1-C(=S)-; -NR]-C(=0)-NR]-; -NR1-C(=S)-NR1-; -NR^S^-NR1-; -NR1-S(=0)2-NR1-; -CMalkyl-CC^-NR1-; -O-Ci^alkyl-CC^-NR1-; -Ci^alkyl-0-C(=0)-NR]-; -C,^alkyl-; -O-C^alkyl-; -Ci^alkyl-O-; -NR^Ci^alkyl-; -Ci^alkyl-NR1-; -NR^C^alkyl-NR1-; -NR^Ci^alkyl-Cs^cycloalkyl-; -C2^alkenyl-; -C2-6alkynyl-; -0-C2-6alkenyl-; -C2-6alkenyI-0-; -NR1-C2^alkenyl-; -C2-6alkenyl-NR1-; -NR1-C2-6alkenyl-NR1-; -NR1 -C2-6alkenyl-C3-7cycloalkyl-; -0-C2-6alkynyl-; -C2-6alkynyl-0-; -NR1-C2-6alkynyl-; ^^alkynyl-NR1-; -NR1-C2-6alkynyl-NR1-; -NR1-C2-6alkynyl-C3-7cycloalkyl-; -0-Ci-6alkyl-0-; -0-C2^alkenyl-0-; -0-C2-6alkynyl-0-; -CHOH-; -S-; -S(=0)-; -S(=0)2-; -SK^-NR1-; -SCK^-NR1-; -NR1-S(=0)-; -NR1-S(=0>2-; -S-Ci^alkyl-; -C^alkyl-S-; -S-C2-6alkenyl-; -C2^alkenyl-S-; -S-C2-6alkynyl-; -C2-6alkynyl-S-; -0-Ci^alkyl-S(=0)2- or a direct bond; Z is a direct bond, Ci_6alkanediyl, C2-6alkenediyl, C2-6alkynediyU -0-; -O-Ci^alkyl-; -S-; -C(=0)-; -C(=0)-Q-; -0-C(=0)-; -C(=S)-; -S(=0)-; -S(=0)2-; -NR1-; -NR^C,. 6alkyl-; -NR^CCK))-; -O-CH^-NR1-; -NR^O)-*}-; -NR^C^S)-; -S(=0)-NR]-; -S(=0)2-NR1-; -NR5-S(=0)-; -NR1-S(=0)2-; -NR^CO^NR1-; -NR1-C(=S)-NR1-; -NR1 -S(=0)-NR1 -; -NR^O^-NR1-; ,x—r- R intellectual property office of n.z 1 y MAR 2007 RECEIVED WO 03/037891 PCT/EP02/12077 -3- R2 is hydrogen, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyls R20, each of said groups representing R2 may optionally be substituted where possible with one or more substituents each independently being selected from =S; =0; R15; hydroxy, halo; nitre; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0)-; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0>; R15-S(=0>2-; R^; R5R6N-Ci ^alkyl; R^^-C^cycloalkyl; R5R6N-C1.fialkyloxy; R^N-QK))-; R5R6N-C(=S>; R5R6N-C(=0)-NH-; R5R<5N-C(=S)-NH-; R^K)),-; R^^-SC^n-NH-; R15-C(=S>; R15-C(=0)-NH-; R15-0-C(=0>NH-; R15-S(=0)n-NH-; R15-0-S(=0)n-NH-; R1s-C(=S)-NH-; R15-0-C(=S)-NH-; RnR,sN-Yla-; R17R18N-Y2-NR,6-Yr; Rls-Y2-NR19-Yi-; H-Y2-NR19-Yi-; R3 is hydrogen; hydroxy; halo; C^alkyl; Ci^alkyl substituted with cyano, hydroxy or -C(=0)R7; C2^alkenyl; C2^alkenyl substituted with one or more halogen atoms or cyano; C2-6alkynyl; C2^alkynyl substituted with one or more halogen atoms or cyano; Ci^alkyloxy; Ci^alkylthio; Ci^aikyloxycarbonyl; C i^alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Ci^alkyl)amino; polyhaloCi^alkyl; polyhaloCi^alkyloxy; polyhaloC i^alkylthio; R21; R21-Cj^alkyl; R21-0-; R2i-S-; R2,-C(=0)-; R2I-S(=0)p-; R7-S(=0)p-; R7-S(=0)p-NH-; R21-S(=0)p-NH-; R7-C(=0>; -NHC(=0)H; -C(=0)NHNH2; R7-C(=0)-NH-; R21-C(=0)-NH-; -C(=NH)R7; -C(=NH)R21; R4 is a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle or a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =S; =0; R1S; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0>; R1s-C(=0>0-; R15-0-C(=0>0-; -SO3H; R15-S(=0)-; R15-S(=0)2-; R5R6N; R^C^alkyl; R^^C^cycloalkyl; R^Ci^alkyloxy; R5R6N-C(=0>; R5R6N-C(=S>; R^-CCO^NH-; R5R6N-C(=S>NH-; R5R6N-S(=0)n-; R^-SC^n-NH-; R15-C(=S)-; R15-C(=0)-NH-; Rls-0-C(=0>NH-; R,5-S(=0)„-NH-; R15-0-S(=0)n-NH-; R15-C(=S)-NH-; R15-0-C(=S)-NH-; R17R1&N-Y,8-; R17R18N-Y2-NR16-Yi-; R15-Y2-NR19-Yr; H-Y2-NR19-Y!-; R5 and R6 each independently are hydrogen, R8, -Yi-NR9-Y2-NR10Rn, -Yi-NR9-YrR8, -Y^NRV0, or R5 and R6 may together with the nitrogen to which they are attached form a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14, or each of WO 03/037891 PCT/EP02/12077 said heterocycles may optionally be fused with a benzene ring, said benzene ring being optionally substituted with one or more substituents selected from R12, R13 and R14; R7 is Ci^alkyl, Ci^alkyloxy, amino, mono- or di(C i^alkyl)amino or polyhaloCi-6alkyl; R8 is Ci^alkyl; C2^alkenyl; C2-6alkynyl; a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said groups representing R8 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R9, R10 and Rn each independently are hydrogen or R8, or any two of R9, R10 and R11 may together be Ci^alkanediyl or C2^alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle together with the nitrogen atoms to which they are attached, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; R12, R13 and R14 each independently are hydrogen; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0>; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0>; R15-S(=0)2-; R15R16N-S(=0>; R15R16N-S(=0)2-; R17R18N-Yr; R17R1SN-Y2-NR16-Yr; R15-Y2-NR19-Yr; H-Y2-NR19-Yi-; 0x0, or any two of R12, R13 and R14 may together be Ci-6alkanediyl or C^alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered carbo — or heterocycle or an aromatic 4 to 8 membered monocyclic carbo — or heterocycle together with the atoms to which they are attached, or any two of R12, R13 and R14 may together be -0-(CH2)r-0- thereby forming a saturated, partially saturated or aromatic monocyclic 4 to 8 membered carbo — or heterocycle together with the atoms to which they are attached; R15 is Ci-galkyl, C2^alkenyl, C2^alkynyl, a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or WO 03/037891 PCT/EPO2/12077 -5- tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or ■with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said substituents representing R15 may optionally be substituted with one or more substituents selected from R12, R13 and R14; or each of said carbocycles or heterocycles may optionally be fused with a benzene ring, said benzene ring being optionally substituted with one or more substituents selected from R12, R13 and R14; R16, R17, R18 and R19 each independently are hydrogen or R15, or R17 and R18, or R15 and R19 may together be Ci^alkanediyl or C2^alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; or R17 and R18 together with R16 may be Ci^alkanediyl or C2-6a]kenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle together with the nitrogen atoms to which they are attached, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; R20 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; R21 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said carbocycles or heterocycles representing R21 may optionally be substituted with one or more substituents selected from R12, R13 and R14; Yla is -Y3-S(=0>Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S>Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0>Y4- or -Y3-C(=0)-0-Y4-; WO 03/037891 PCT/EP02/12077 -6- Yi or Y2 each independently are a direct bond, -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S>Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0)-Y4- or -Y3-C(=0)-0-Y4-; Y3 or Y4 each independently are a direct bond, Ci^alkanediyl, C2^alkenediyl or C2^alkynediyl; n is 1 or 2; m is 1 or 2; p is 1 or 2; r is 1 to 5; s is 1 to 3; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci-6alkyl, C3-7cycloalkyl, Ci_6alkyloxy, cyano, nitro, polyhaloC 1 ^alkyl and polyhaloCi ^alkyloxy; provided that -X-R2 and/or R3 is other than hydrogen; and provided that when r4—2. represents -Z is other than a direct bond or NH when R1 is hydrogen or methyl, s is 2, R3 is methoxy, and -X-R2 is methoxy; -Z-R4 is other than 3-pyridyl, 4-pyridyl or 4-pyridyl N-oxide when R1 is hydrogen or methyl, s is 1, R3 is 3-chloro or 4-methoxy, and -X-R2 is hydrogen; h—n \ V /j -Z-R4 is other than *—' n—' when R1 is hydrogen; -R3 and -X-R2 are other than hydrogen when R1 is hydrogen and -Z-R4 is 3-pyridyl or substituted 4-pyridyl; and provided that when represents |p NH then -R is other than pyridyl optionally substituted with methyl, pyridyl TV-oxide, 1-methyl-pyridinium, thienyl optionally substituted with one or two methyl groups, furanyl optionally substituted with one or two methyl groups, benzofuranyl, quinolinyl, indolyl, pyrrolyl optionally substituted with methyl, pyiimidinyl, phenothiazinyl; -7- and provided that the following compounds ch3 INTELLECTUAL PROPERTY OFFICE 0FN2. 8" MAY 2007 RECEIVED are not included. In particular, the present invention concerns a compound selected from r4—z x—R ^ w(r3)s (d, wherein: R1 is hydrogen; aryl; formyl; Ci-6alkylcarbonyl; Cj^alkyl; Ci-6alkyloxycarbonyl; Ci-6alkyl substituted with formyl, Ci^alkylcarbonyl, Ci^alkyloxycarbonyl, Ci-6alkylcarbonyloxy; Cj^alkyloxyCi^alkylcarbonyl optionally substituted with Ci. 6alkyloxycarbonyl; r4 Z x r2 s r3 2-tetrahydrofiirany] Lch2- nth- direct bond h 4-cn 2-thienyl -ch2- nh- direct bond H 4-cn h3c hjc-o-X^Kjj- -ch2- nh- direct bond h 4-cn 2,2-dimethyl-1,3 -dioxolan-4-yl -ch 2-nh- direct bond h 4-cn 1 -ethylpyrrolidin-2-yl -ch2- nh- direct bond h 4-cn 2-furanyl -ch2- nh- direct bond h 4-cn 3-quinolinyl -ch2- nh- direct bond h 4-cn QTO -ch2- nh- direct bond h 4-cn 4-moipholinyl -(ch2)2-nh- direct bond h 4-cn 1,3-benzodioxol-5-yl -ch2-m- direct bond H 4-cn -7a- R4 z X R2 s R3 4-methyl-1 -piperazinyl direct bond direct bond h 1 4-CN direct bond direct bond H 1 4-CN 4-morpholinyl direct bond direct bond h 1 4-CN 1 -methyl-1 if-imidazol-2-yl direct bond direct bond h 1 4-CN r^r n^n nh2 direct bond direct bond h 1 3-CF3 "*\y N direct bond direct bond h 1 3-CF3 ch3 direct bond -o-ch2-c6h5 1 4-CN 1-piperazinyl -fc=o>- -o-ch2-c6h5 1 4-CN i ch3 direct bond -0-ch2-c6h5 1 H ch ch3 direct bond -o-h 1 H a TV-oxide, a phaimaceutically acceptable addition salt, a quaternary amine or a sterochemically isomeric form thereof. The present invention also relates to the use of a compound for the manufacture of a medicament for the prevention or the treatment of diseases mediated through GSK3, said compound being a compound selected from the general formula (I') x—5T (I1) a TV-oxide, a pharmaceutical^ acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein ring A is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; R1 is hydrogen; aryl; formyl; Ci^alkylcarbonyl; Ci-6alkyl; C\^alkyloxycarbonyl; Ci^alkyl substituted with formyl, Ci^alkylcarbonyl, Ci.6alkyloxycarbonMl>N-rELLECTUAL PR0PERTY 0FF|C| of n.z. 19 MAR 2007 RECEIVE? D -7b- Ci-6alkylcarbonyloxy; C\^alkyloxyC\^alkylcarbonyl optionally substituted with C i ^alkyloxycarbonyl; X is -NR1-; -NH-NH-; -N=N-; -O-; -C(=0)-; -C(=S)-; -0-C(=0)-; -C(=0)-0-; -0-C(=0)-Ci -6alkyl-; -C(K))-0-C1^aIkyl-; -0-C^alkyl-C(=0)-; -C(=0)-C] ^alkyl-O-; -O-CCO^NR1-; -NR^CCOyO-; -0-C(=0)-C(=0)-; -C(=0)-NR1-, -NR'-CCO)-; -C(=S)-NR1-, -NR^C^S)-; -NR^QO^NR1-; -NR1-C(=S)-NR1-; -NR'-SCO^NR1-; -NR1-S(=0)2-NR1-; -Ci-galkyl-C^-NR1-; -0-Ci^alkyl-C(=0)-NR1-; -C^alkyl-O-CCOyNR1-; -Ci^alkyl-; -O-Ci^alkyl-; -Ci^alkyl-O-; -NR'-C^alkyl-; -C^alkyl-NR1-; -NR'-Cj^alkyl-NR1-; -NR1 -Ci_6alkyl-C3_7cycloaIkyl-; -C2-6alkenyl-; -C2-6alkynyl-; -0-C2-6alkenyl-; -C2-6alkenyI-0-; -NR1-C2-6alkenyl-; -C2-6aIkenyl-NR1-; -NR1-C2^alkenyl-NR1-; -NR1-C2-6alkenyl-C3-7cycloalkyl-; -0-C2-6alkynyl-; -C2-6alkynyl-0-; -NR1-C2^alkynyl-; -C2-6alkynyl-NR1-; -NR'^-^alkynyl-NR1-; intellectual property Of- fill 1 y MAR 2007 WO 03/037891 PCT/EP02/12077 -8- -NR1 -C2^alkynyl-C3.7cycloaIkyl-; -O-Ci^alkyl-O-; -0-C2-6alkenyl-0-; -O-Cs-ealkynyl-O-; -CHOH-; -S-; -S(=0>; -S(=0>2-; -S(=0>NR1-; -SCO^-NR1-; -NR,-S(=0>; -S-Cj^alkyl-; -Ci^alkyl-S-; -S-C2^alkenyl-; -C2^alkenyl-S-; -S-C2-6alkynyl-; -C2-6alkynyl-S-; -O-Cj_6alkyl-S(=0)2- or a direct bond; Z is a direct bond, Ci-6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Ci^alkyl-; -S-; -C(=0)-; -C(=0)-0-, -0-C(=0>; -C(=S)-; -S(=0)-; -S(=0)r; -NR1-; -NR'-Ci-ealkyl-; -NR'-CH))-; -0-C(=0>NR1-; -NR^OyO-; -NR'-C^S)-; -SCO^NR1-; -S(=0)2-NR1-; -NR^SCO)-; -NR'-SCO^s -NR'-CCK^-NR1-; -NR,-C(=S>NR1-; -NR'-S^-NR1-; -NR'-SCO^-NR1-; R2 is hydrogen, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, R20, each of said groups representing R2 may optionally be substituted where possible with one or more substituents each independently being selected from =S; =0; R15; hydroxy; halo; nitro; cyano; Rls-0-; SH; R15-S-; formyl; carboxyl; R1S-C(=0)-; Rls-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0)-; R15-S(=0>2-; R5R6N; R5R6N-Ci^alkyl; R5R6N-C3-7cycloalkyl; R5R6N-C]^alkyloxy; R5R6N-C(=0)-; R5R6N-C(=S>; R5R6N-C(=0)-NH-; R5R6N-C(=S>NH-; R5R6N-S(=0)„-; R5R6N-S(=0) n-NH-; R15-C(=S>; R15-C(=0)-NH-; R15-0-C(=0>NH-; R15-S(=0)„-NH-; RI5-0-S(=0)n-NH-; R15-C(=S>NH-; R15-0-C(=S)-NH-; R1?R1SN-Yla-; R17R18N-Y2-NR16-Yi-; R15-Y2-NR19-Yr; H-Y2-NR19-Y,-; R3 is hydrogen; hydroxy-, halo; Ci^alkyl; Ci^alkyl substituted with cyano, hydroxy or -C(=0)R7; C2^alkenyl; C2-6alkenyl substituted with one or more halogen atoms or cyano; C2-6alkynyl; C2-6alkynyl substituted with one or more halogen atoms or cyano; Ci^alkyloxy; Ci^alkylthio; Ci^alkyloxycarbonyl; Ci^alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Ci^alkyl)amino; polyhaloC 1 ^alkyl; polyhaloC 1 ^alkyloxy; polyhaloCj^alkylthio; R21; R21-Ci-6alkyl; R21-0-; R21-S-; R21-C(=0)-; R21-S(=0)p-; R7-S(=0)p-; R7-S(=0)p-NH-; R21-S(=0)p-NH-; R7-C(=0)-; -NHC(=0)H; -C(=0)NHNH2; R7-C(=0)-NH-; R2I-C(=0)-NH-; -C(=NH)R7; -C(=NH)R21; R4 is a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle or a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =S; =0; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0>0-; -S03H; R15-S(=0>; R15-S(=0)2-; R^; R^^Cj^alkyl; R^^Cj-ycycloalkyl; R^C^alkyloxy; R^-CCO)-; R5R6N-C(=S>; R^-C^-NH-; R5R6N-C(=S)-NH-; WO 03/037891 PCT/EP02/12077 -9- R^'N-SCOV; R5R6N-S(=0) n-NH-; R15-C(=S)-; R15-C(=0)-NH-; R15-0-C(=0)-NH-; R15-S(=0)n-NH-; R15-0-S(=0)n-NH-; R15-C(=S)-NH-; R15-0-C(=S>NH-; R17R18N-Yu-; R17R18N-Y2-NR16-Yr; R15-YrNR19-Yi-; H-Yr-NR19-Yi-; R5 and R6 each independently are hydrogen, R8, -Yi-NR9-Y2-NR1 'fc11, -Yi-NR9-Yi-R8, -Yi-NR^10, or R5 and R6 may together with the nitrogen to which they are attached form a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14, or each of said heterocycles may optionally be fused with a benzene ring, said benzene ring being optionally substituted with one or more substituents selected from R12, R13 and R14; R7 is Cj^alkyl, Ci^alkyloxy, amino, mono- or di(Ci^alkyl)amino or polyhaloC 1 ^alkyl; R8 is Ci^alkyl; C2^alkenyl; C2-6alkynyl; a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Cj^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said groups representing R8 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R9, R10 and R11 each independently are hydrogen or R8, or any two of R9, R10 and Rn may together be Ci^alkanediyl or C2-6alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle together with the nitrogen atoms to which they are attached, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; R12, R13 and R14 each independently are hydrogen; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0)-; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=OK>-; -SO3H; Rls-S(=0)-; R15-S(=0)2-; R15R16N-S(=0>; R15R16N-S(=0)2-; R17R18N-Yj-; R17R18N-Y2-NR16-YI-; R15-Y2-NR19-YI-; H-Y2-NR19-Yr; oxo, or WO 03/037891 PCT/EPO2/12077 -10- any two of R12, R13 and R14 may together be Cj^alkanediyl or C2^alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered carbo - or heterocycle or an aromatic 4 to 8 membered monocyclic carbo - or heterocycle together with the atoms to which they are attached, or any two of R12, R13 and R14 may together be -0-(CH2)r-0- thereby forming a saturated, partially saturated or aromatic monocyclic 4 to 8 membered carbo - or heterocycle together with the atoms to which they are attached; R15 is Ci-6alkyl, C2-6alkenyl, C2^alkynyl, a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said substituents representing R15 may optionally be substituted with one or more substituents selected from R12, R13 and R14; or each of said carbocycles or heterocycles may optionally be fused with a benzene ring, said benzene ring being optionally substituted with one or more substituents selected from R12, R13 and R14; R16, R17, R18 and R19 each independently are hydrogen or R15, or R17 and R18, or R15 and R19 may together be Cj^alkanediyl or C2-6alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; or R17 and R18 together with R16 may be Ci^alkanediyl or C2-6alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle together with the nitrogen atoms to which they are attached, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; R20 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; WO 03/037891 PCT/EP02/12077 -11- R21 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said carbocycles or heterocycles representing R21 may optionally be substituted with one or more substituents selected from R12, R13 and R14; Yi. is -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S)-Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0)-Y4- or —Y3-C(=0)-0-Y4-; Yj or Y2 each independently are a direct bond, -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S)-Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0>Y4- or -Y3-C(=0)-0-Y4-; Y3 or Y4 each independently are a direct bond, Ci^alkanediyl, C2-6alkenediyl or C2^alkynediyl; n is 1 or 2; m is 1 or 2; p is 1 or 2; r is 1 to 5; s is 1 to 3; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci-6alkyl, C3.7cycloalkyl, Ci-6alkyloxy, cyano, nitro, polyhaloCi^alkyl and polyhaloCj^alkyloxy; provided that -X-R2 and/or R3 is other than hydrogen. As used herein Cj.3alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl; CMalkyl 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 the groups defined for Ci.3alkyl and butyl; Ci-6alkyl 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 groups defined for Ci^alkyl and pentyl, hexyl, 2-methylbutyl and the like; Ci-ioalkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as the groups defined for Ci-^alkyl and heptyl, octyl, nonyl, decyl and the like; Ci^alkanediyl as a group or part of a group defines bivalent straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as methylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or WO 03/037891 PCT/EP02/12077 -12- 1,4-butylidene and the like; C2-6alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C2.ioalkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 10 carbon atoms containing a double bond such as the groups defined for C2^alkenyl and heptenyl, octenyl, nonenyl, decenyl and the like; C2^alkenediyl defines bivalent straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing one or more double bonds such as ethenediyl, propenediyl, butenediyl, pentenediyl, hexenediyl and the like; C2^alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; Cj-ioalkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 10 carbon atoms containing a triple bond such as the groups defined for C2-6alkynyl and heptynyl, octynyl, nonynyl, decynyl and the like; C2^alkynediyl defines bivalent straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as ethynediyl, propynediyl, butynediyl, pentynediyl, hexynediyl and the like; C^cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a monocyclic, bicyclic or tricyclic saturated carbocycle represents a ring system consisting of 1,2 or 3 rings, said ring system being composed of only carbon atoms and said ring system containing only single bonds; a monocyclic, bicyclic or tricyclic partially saturated carbocycle represents a ring system consisting of 1,2 or 3 rings, said ring system being composed of only carbon atoms and comprising at least one double bond provided that the ring system is not an aromatic ring system; a monocyclic, bicyclic or tricyclic aromatic carbocycle represents an aromatic ring system consisting of 1,2 or 3 rings, said ring system being composed of only carbon atoms; the term aromatic is well known to a person skilled in the art and designates cyclically conjugated systems of 4n' + 2 electrons, that is with 6,10,14 etc. rc-electrons (rule of HtLckel; n' being 1,2,3 etc.); a monocyclic, bicyclic or tricyclic saturated heterocycle represents a ring system consisting of 1,2 or 3 rings and comprising at least one heteroatom selected from O, N or S, said ring system containing only single bonds; a monocyclic, bicyclic or tricyclic partially saturated heterocycle represents a ring system consisting of 1,2 or 3 rings and comprising at least one heteroatom selected from O, N or S, and at least one double bond provided that the ring system is not an aromatic ring system; a monocyclic, bicyclic or tricyclic aromatic heterocycle represents an aromatic ring system consisting of 1,2 or 3 rings and comprising at least one heteroatom selected from O, N or S. WO 03/037891 PCT/EP02/12077 -13- Particular examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4,2,0]octanyl, cyclononanyl, cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl. Particular examples of monocyclic, bicyclic or tricyclic partially saturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclo-octenyl, bicyclo[4,2,0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl, 1 ,2,3,4-tetrahydronaphthalenyl, 1,2,3,4,4a,9,9a, 10-octahydro-anthracenyl. Particular examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are phenyl, naphthalenyl, anthracenyl. Particular examples of monocyclic, bicyclic or tricyclic saturated heterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl. Particular examples of monocychc, bicyclic or tricyclic partially saturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, indolinyl and the like. Particular examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, fiiropyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyraadnyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, WO 03/037891 PCT/EP02/12077 -14- isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, isoxazolotriazinyl, isothiazolo-triazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyL, carbazolyl, acridinyl, phenaanyl, phenothiazinyl, phenoxazinyl. Particular examples of 5-membered aromatic heterocycles are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl. As used herein before, 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 when two of said terms are attached to a sulfur atom. The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloCi ^alkyl as a group or part of a group is defined as mono- or polyhalosubstituted Cj^alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhalomethyl or polyhaloCi-6alkyl» they may be the same or different The term heterocycle as in the definition of for instance R4, R5, R6, R8 or R15 is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl also includes 2#-pyrrolyl. The hereinabove-mentioned carbocycles may be attached to the remainder of the molecule of formula (I) or (I') through any ring carbon as appropriate, if not otherwise specified. Thus, for example, when the partially saturated bicyclic carbocycle is WO 03/037891 PCT/EP02/12077 -15- 1,2,3,4-tetrahydronaphthalenyL, it may be 1,2,3,4-tetrahydronaphthalen-1 -yl, 1,2,3,4-tetrahydronaphthalen-2-yl and the like. The hereinabove-mentioned heterocycles may be attached to the remainder of the 5 molecule of formula (I) or (I') through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when the aromatic monocyclic heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like. When any variable (eg. R5, R6 etc.) occurs more than one time in any constituent, each 10 definition is independent Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms. 15 For therapeutic use, salts of the compounds of formula (I) or (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 20 invention. The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) or (I') are able to form. The latter can conveniently be 25 obtained 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, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-l,2,3-propanetricarboxylic, 30 methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 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. 35 The compounds of formula (I) or (I') containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for WO 03/037891 PCT/EPO2/12077 -16- example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. die 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, 5 dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, TV-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3 -propanediol, hydrabamine salts, and salts with amino acids such as, for example, argimne, lysine and the like. 10 Conversely the salt form can be converted by treatment with acid into the free acid form. The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) or (I') are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. 15 The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) or (I') are able to form by reaction between a basic nitrogen of a compound of formula (I) or (I') and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or 20 arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifhioroacetate and acetate. The counterion of choice can be introduced using ion 25 exchange resins. It will be appreciated that some of the compounds of formula (I) or (I') and their TV-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms. 30 The term "stereochemically isomeric forms" as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I) or (I'), and their TV-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of 35 compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (T) or (I') and their WO 03/037891 PCT/EP02/12077 -17- TV-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have 5 either the cis- or ^raws-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) or (I') are obviously intended to be embraced within the scope of this invention. 10 The TV-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 TV-oxide. Some of the compounds of formula (I) or (I') may also exist in their tautomeric form 15 (e.g. keto-enol tautomeric). Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. Whenever used hereinafter, the term "compounds of formula (1)" or "compounds of formula (I) or (I') is meant to also include their TV-oxide forms, their salts, their 20 quaternary amines and their stereochemically isomeric forms. Of special interest are those compounds of formula (I) or (I') which are stereochemically pure. Particular compounds are those compounds of formula (I) or (I') as defined hereinabove provided that the molecular mass of the compounds is at most 1000 u, in 25 particular at most 800 u, more in particular at most 700 u (u stands for unified atomic mass unit and equals 1.66xl0*27 kg). Particular compounds are also those compounds of formula (I) or (F) as defined hereinabove provided that when R3 is hydrogen then X is other than -C(=0)-NR1- or 30 -C(=S)-NR1-; and provided that when X is a direct bond and R2 is hydrogen than R3 is other than R7-C(=0)- with R7 representing amino or mono- or di(Ci^alkyl)amino; and provided that when X is a direct bond and R2 is hydrogen than R21 is other than a heterocycle; and provided that when R3 is hydrogen then R2 is other than a heterocycle. 35 Particular interesting compounds are those compounds of formula (I) or (I') as defined hereinabove, their TV-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein WO 03/037891 PCT/EP02/12077 -18- ring A is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; R1 is hydrogen; aryl; formyl; Ci^alkylcarbonyl; Cj^alkyl; Cj^alkyloxycarbonyl; Ci.6alkyl substituted with formyl, Ci-6alkylcarbonyl, Ci^alkyloxycarbonyl, Ci^alkylcarbonyloxy; Ci-galkyloxyCi^alkylcarbonyl optionally substituted with Ci^alkyloxycarbonyl; X is -NR1-; -NH-NH-; -N=N-; -0-; -C(=0)-; -C(=S>; -0-C(=0>; -C(=0)-0-; -0-C(=0)-C,-6alkyl-; -C(=0>0-C^alkyl-; -0-Ci^alkyl-C(=0>; -C(=0>Ci^alkyl-0-; -O-CCO^NR1-; -NR1-C(=0)-0-; -0-C(=0)-C(=0>; -CXOJ-NR1-, -NR^CCO)-; -C(=S)-NR1-, -NR1-C(=S>; -NR!-C(=0)-NR3-; -NRI-C(=S)-NR1-; -NR'-SC^Oy-NR1-; -NR1-S(=0)2-NR1-; -C^alkyl-CC^NR1-; -O-Ci^alkyl-q^NR1-; -Cwa]kyl-0-C(=0>NR1-; -C,^alkyl-; -O-Ci^alkyl-; -Cj^alkyl-O-; -NR^C^aliyl-; -Cj^alkyl-NR1-; -NR^i^alkyl-NR1-; -NR1 -Ci^alkyl-C3_7cycloalkyl-; -C2-6alkenyl-; -C2-6alkynyl-; -0-C2^alkenyl-; -C2-6alkenyl-0-; -NR1-C2-&alkenyl-; -Ci-ealkenyl-NR1-; -NR1-C2^alkenyl-NR1-; -NR1-C2-6alkenyl-C3.7cycloalkyl-; -0-C2-6alkynyl-; -C2-6alkynyl-0-; -NR1 -C2-6alkynyl-; -C2^alkynyl-NR1 -; -NR1-C2-6alkynyl-NR1-; -NR1-C2-6alkynyl-C3.7cycloalkyl-; -O-Cj-galkyl-O-; -0-C2^alkenyl-0-; -0-C2-6alkynyl-0-; -CHOH-; -S-; -S(=0)~; -S(=0)2-; -S^-NR1-; -SCKTh-NR1-; -NR^SCK))-; -NR]-S(=0)2-; -S-Ci^alkyl-; -Cj^alkyl-S-; -S-C2^alkenyl-; -C2-6alkenyl-S-; -S-C2^alkynyl-; -C2-6alkynyl-S-; -0-Ci-6alkyl-S(=0)2- or a direct bond; Z is a direct bond, Ci-galkanediyl, C2-6alke®ediylj C2-6alkynediyl; -0-; -O-Ci^alkyl-; -S-; -C(=0)-; -C(=0)-0-; -0-C(=0)-; -C(=S>; -S(=0>; -S(=0)2-; -NR1-; -NR^Cj^alkyl-; -NR^CCO)-; -O-CCO^NR1-; -NR^O^O-; -NR^^S)-; -SCOVNR1-; -SC^-NR1-; -NR^SCO)-; -NR1^^-; -NR^C^-NR1-; -NR1-C(=S)-NR1-; -NR^SCO^NR1-; -NR^SCO^-NR1-; R2 is hydrogen, Ci-ioalkyl, C2-ioalkenyl, C2-ioallcynyl5 R20, each of said groups representing R2 may optionally be substituted where possible with one or more substituents each independently being selected from =S; =0; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R1S-C(=0>; R15-0-C(=0>; R15-C(=0>0-; R15-0-C(=0K>s -SO3H; R15-S(=0)-; R15-S(=0)2-; R^; R^^-Cj^alkyl; R^Sf-C^cycloalkyl; R^^-Cj^alkyloxy; R5R6N-C(=0)-; R5R6N-C(=S)-; R5R6N-C(=0)-NH-; R^^-C^SJ-NH-; R5R6N-S(=0)n-; R^^-SCOJn-NH-; R15-C(=S>; R35-C(=0)-NH-; R15-0-C(=0)-NH-; R15-S(=0)n-NH-; R15-0-S(=0)n-NH-; R15-C(=S)-NH-; R15-0-C(=S)-NH-; R17R18N-Yia-; R17R18N-Y2-NR16-Yi-; R15-Y2-NR19-Yi-; H-YZ-NR19-^-; WO 03/037891 PCT/EP02/12077 -19- R3 is hydrogen; hydroxy; halo; Ci^alkyl; Ci^alkyl substituted with cyano, hydroxy or -C(=0)R7; C2-6alkenyl; C2^alkenyl substituted with one or more halogen atoms or cyano; C2^alkynyl; Cz-galkynyl substituted with one or more halogen atoms or cyano; Ci^alkyloxy; Cj^alkylthio; Ci^alkyloxycarbonyl; Cj^alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Ci^alkyI)amino; polyhaloCi^alkyl; polyhaloCi^alkyloxy, polyhaloC 1 -galkylthio; R21; R21-Cj^alkyl; R21-0-; R21-S-; R21-C(=0>; R21-S(=0)p-; R7-S(=0)p-; R7-S(=0)p-NH-; R21-S(=0)p-NH-; R7-C(=0>; -NHC(=0)H; -C(=0)NHNH2; R7-C(=0)-NH-; R21-C(=0)-NH-; -C(=NH)R7; -C(=NH)R21; R4 is a monocycHc, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle or a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from —S; =0; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0>0-; -S03H; R15-S(=0)-; R15-S(=0>2-; R5R6N; R^Cj^alkyl; R^^Cs-Tcycloalkyl; R5R6NC,.6alkyloxy; R5R6N-C(=0)-; R5R6N-C(=S)-; R5R6N-C(=0)-NH-; R5R6N-C(=S)-NH-; R5R6N-S(0)n-; R^-SC^n-KH-; R15-C(=S>; R15-C(=0>NH-; R15-0-C(=0)-NH-; Ris-S(=0)„-NH-; R1s-0-S(=0VNH-; R15-C(=S)-NH-; R15-0-C(=S>NH-; R17R18N-Yia-; R17R18N-Y2-NR16-Yr; R15-Y2-NR19-Y!-; H-Y2-NR19-Yr; R5 and R6 each independently are hydrogen, R8, - Yi -NR9-Y2-NR] °R! 1, -Yi-NR9-Y]-R8, -Y]-NR9R10; R7 is Ci^alkyl, Ci^alkyloxy, amino, mono- or di(Ci^alkyl)amino or polyhaloCi^alkyl; R8 is Ci^alkyl; C2-6alkenyl; C2-6alkynyl; a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said groups representing R8 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R9, R10 and R11 each independently are hydrogen or R8; WO 03/037891 PCT/EP02/12077 -20- Ru, R13 and R14 each independently are hydrogen; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0>; R1s-S(=0)2-; R15R16N-S(=0>; R15R16N-S(=0)2-; R17R,8N-Y,-; R17R18N-Y2-NR16-Y3-; R15-Y2-NR19-Y,-; H-Y2-NR19-Yi-; oxo; R15 is Ci^alkyl, C2^alkenyl, C2^alkynyl, a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Cj^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said substituents representing R15 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R16, R17, R18 and R19 each independently are hydrogen or R15; R20 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; R21 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said carbocycles or heterocycles representing R21 may optionally be substituted with one or more substituents selected from R12, R13 and R14; Yia is -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S)-Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Yj-0-C(=0>Y4- or-Y3-C(=0)-0-Y4-; Yi or Y2 each independently are a direct bond, -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0>Y4-, -Y3-C(=S>Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0>Y4- or -Y3-C(=0>0-Y4-; Y3 or Y4 each independently are a direct bond, Ci-6alkanediyl, C2^alkenediyl or C2^alkynediyl; WO 03/037891 PCT/EPO2/12077 -21- n is 1 or 2; m is 1 or 2; p is 1 or 2; r is 1 to 5; s is 1 to 3; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci-6alkyl, C3-7cycloalkyl, Ci-6alkyloxy, cyano, nitro, polyhaloCi^alkyl and polyhaloCi-6alkyloxy; provided that -X-R2 and/or R3 is other than hydrogen; and provided that when represents C i—n \ 3 then -Z is other than a direct bond or NH when R1 is hydrogen or methyl, s is 2, R3 is methoxy, and -X-R2 is methoxy; -Z-R4 is other than 3-pyridyl, 4-pyridyl or 4-pyridyl iV-oxide when R1 is hydrogen or methyl, s is 1, R3 is 3-chloro or 4-methoxy, and -X-R2 is hydrogen; — -Z-R4 is other than — n—' when R1 is hydrogen; -R3 and -X-R2 are other than hydrogen when R1 is hydrogen and -Z-R4 is 3-pyridyl or substituted 4-pyridyl; and provided that when represents ij\ —nh—then -R4 is other than pyridyl optionally substituted with methyl, pyridyl TV-oxide, 1-methyl-pyridinium, thienyl optionally substituted with one or two methyl groups, furanyl optionally substituted with one or two methyl groups, benzofuranyl, quinolinyl, indolyl, pyrrolyl optionally substituted with methyl, pyrimidinyl, phenothiazinyl; and provided that the following compounds WO 03/037891 PCT/EPO2/12077 -22- Br 1=1 are not included. Further interesting compounds are those compounds of formula (I) or (I') as defined hereinabove, their TV-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein ring A is pyridyl, pyrimidinyl or pyridazinyl; R1 is hydrogen; X is a direct bond, -O- or -O-Cj^alkyl-; Z is a direct bond, -NR1-, -NR^Ci^alkyl- or —C(=0)-; R2 is hydrogen or R20; R3 is hydrogen, halo, Ci-6alkyl, polyhaloCi^alkyl or cyano; R4 is a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle or a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from R15, R15-0-, R15-C(=0)- or halo; R15 is Cj^alkyl; a monocyclic, bicyclic or tricyclic saturated heterocycle; Ci-6alkyl substituted with a monocyclic, bicyclic or tricyclic aromatic carbocycle; R20 is a monocyclic, bicyclic or tricyclic aromatic carbocycle; s is 1 to 3; provided that -X-R2 and/or R3 is other than hydrogen; and provided that when \ represents then -Z-R4 is other than 3-pyridyl, 4-pyridyl or 4-pyridyl TV-oxide when s is 1, R3 is 3-chloro, and -X-R2 is hydrogen; WO 03/037891 PCT/EP02/12077 -23- -Z-R4 is other than ; -R3 and -X-R2 are other than hydrogen when -Z-R4 is 3-pyridyl or substituted 4-pyridyl; and provided that when then -R4 is other than pyridyl optionally substituted with methyl, pyridyl TV-oxide, 1 -methyl-pyridinium, thienyl optionally substituted with one or two methyl groups, furanyl optionally substituted with one or two methyl groups, benzofuranyl, quinolinyl, indolyl, pyrrolyl optionally substituted with methyl, pyrimidinyl, phenothiazinyl;. Also interesting compounds are those compounds of formula (I) or (T) as defined hereinabove provided that the compound is other than a) wherein X is -0-; R2 is Ci-ioalkyl, C2-ioalkenyl or C2-ioaIkynyl, said groups representing R2 may optionally be substituted; R3a is Ci.6alkyloxy; R3b is hydrogen, halo, optionally substituted Cj.ioalkyl, optionally substituted C2-ioalkenyl, optionally substituted C2-ioalkynyl, hydroxy, amino, mono -or di(Ci^alkyI)amino, Ci.6alkyl-C(=0)-NH-, Ci^alkyloxy, polyhaloCi_6alkyloxy, Ci^alkylthio, polyhaloC^alkylthio, aryloxy; R1 is hydrogen or Chalky] and Z-R4 is as defined hereinabove; b) wherein Z is Ci^alkanediyl, C2^alkenediyl, -C(=0)- or -C(=S)-; ring A is as defined hereinabove; R4 is monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle or a monocyclic, bicyclic or tricyclic aromatic heterocycle, said groups representing R4 may optionally be substituted; R1 is hydrogen; aryl; Ci^alkylcarbonyl; Ci^alkyl; Ci-6alkyloxycarbonyl; Cj^alkyl substituted with formyl, Cj^alkylcarbonyl, Ci^alkyloxycarbonyl, Ci^alkylcarbonyloxy; Ci^alkyloxyCi^alkylcarbonyl optionally substituted with WO 03/037891 PCT/EP02/12077 -24- Ci ^alkyloxycarbonyl; X is a direct bond or Ci^alkyl; R2, R3 and s are as defined hereinabove; c) x—r2 wherein X is a direct bond, -0-, -S-, -C(=0)-NH-s -C(=0)-0-; R2 is hydrogen, CF3, Ci-4alkyl; R3 is hydrogen, hydroxy, halo, CF3, CMalkyl, Ci-4alkyloxy, Ci^alkylthio, cyano, amino, aminocarbonyl, carboxyl, CMalkylcarbonyl; R1 is hydrogen or CMalkyl; R4, R3 and s are as defined hereinabove; d) x-r2 wherein z-r4 R4-Z represents indolyl-Cj-ioalkyl or Z is a direct bond, -Ci^alkyl-, -NR1-, -NH-NH-, -N=N-, -O-, -(C=0)-, -CHOH-, -S-, -S(=0>, -S(=0>r, -0-CMalkyl-, -NR^CMalkyl-, -S-CMalkyl- and R4 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, said groups representing R4 may optionally be substituted; R1 is hydrogen, aryl, Ci^alkylcarbonyl, Cj^alkyl, Ci-6alkyloxycarbonyl; X-R2 is hydrogen, hydroxy, Cj^alkyl, Ci-6alkyloxy, trihalomethyl, trihalomethyloxy, cyanoCi^alkyl; R3a is halo, Ci^alkyl, cyano, nitro, trihalomethyl, trihalomethyloxy or Ci-6alkyl substituted with cyano or aminocarbonyl; R3b is hydroxy, halo, Ci^alkyl, Ci^alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy; s is 0,1 or 2; e) x-r2 R4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 2-furyl, 5-methyl-2-furyl, 2,5-dimethyl-3-furyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuryl, JV-oxido-2-pyridyl, iV-oxido-3 -pyridyl, TV-oxido-4-pyridyl, lH-indol-2-yl, lH-indol-3-yl, 1 -methyl-lH-pyrrol-2-yl, 4-quinolinyl, l-methyl-pyridinium-4-yliodide; R1 is hydrogen or CMalkyl; X-R2, R3 and s are as defined hereinabove; WO 03/037891 PCT/EP02/12077 -25- f) wherein R4 is A^-methylpiperazinyl, piperidinyl, imidazolyl, triazolyl, benzimidazolyl, 4-phenyl-piperazin-l-yl wherein phenyl may optionally be substituted with Cioalkyl or Ci^alkyloxy or halo or trifluoromethyl, lH-imidazol-l-ylCi-3alkyl, lif-imidazol-1 -ylCi^alkyloxy, 1 if-imidazol-1 -ylC i .3alkylthio, morpholinylCi_3alkyl, morpholinylCi-3alkyloxy, morpholinylCi^alkylthio; X is a direct bond; R2 is hydrogen, Ci-3alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 2-furyl, 5-methyl-2-furyl, 2,5-dimethyl-3-furyl, 2-thienyL, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuryl, iV-oxido-2-pyridyl, 7V-oxido-3-pyridyl, Af-oxido-4-pyridyl, lif-indol-2-yl, 1 ii-indol-3-yl, 1-methyl-1 ii-pyrrol-2-yl, 4-quinolinyl, l-methyl-pyridinium-4-yliodide; R3 is hydrogen, Ci.3alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 2-furyl, 5-methyl-2-furyl, 2,5-dimethyl-3-furyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuryl, jty-oxido-2-pyridyl, N-oxido-3-pyridyl, N-oxido-4-pyridyl, 1 H-indol-2-yl, 1 .ff-indol-3-yl, 1-methyl-1 iif-pyirol-2-yI, 4-quinolinyl, l-methyl-pyridinium-4-yliodide; s is as defined hereinbove; R4 is pyridyl substituted with an optionally substituted monocyclic, bicyclic or tricyclic wherein R4 is 4-pyridyl substituted in position 3; R3a is hydrogen, halo, Ci-6alkyloxy or Ci^alkyl; R3b is as defined above for R3; i) g) wherein WO 03/037891 PCT/EP02/12077 -26- wherein R4 is 4-pyridyl substituted in position 3; R3a is hydrogen, halo, Ci-6alkyloxy or Cj^alkyl; X-R2 is as defined above; wherein R is halo, cyano, Ci^alkyloxy, polyhaloCi^alkyloxy, Ci^alkylthio, Cj^alkyl-S(=0>, Ci^alkyl-S(=0)2-, C^alkyl, polyhaloC i^alkyl, C i ^alkyloxycarbonyl, mono-or di(CMalkyl)aminocarbonyl, aminocarbonyl, poIyhaloCMalkylthio; R3b is hydrogen, halo, cyano, nitro, Ci^alkyl, Cj^alkyloxy, polyhaloCi^alkyl, Ci^alkyloxycarbonyl, CMalkylcarbonyl; R3c is hydrogen, halo or CMalkyl; R4 is 2-furanyl, 2-thienyl or 3-thienyl; wherein R is pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, pyridazinyl, or imidazolyl, each of said rings optionally substituted with one or more substituents selected from halo, cyano, aminocarbonyl, -C(=0)-0-R4, -C(=0)-R4, -S(=0)2-NR4 R4 , NR4 R4 , -O-R4 or CMalkyl optionally substituted with fluoro wherein R4 and R4 each independently represent hydrogen or Ci^alkyl optionally substituted with mono- or di(Ci-6alkyl)aniino; R1, R3 and s are as defined hereinabove; wherein R4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 2-pyrazinyl, 2-benzofuranyl, 2-pyridyl-A^-oxide, 3-pyridyl-iV-oxide, 4-pyridyl-N-oxide, 1 jff-indol-2-yl, 1 #-indol-3-yl, 1-methyl-1 H-pyrrol-2-yl, 4-quinolinyl, 4-pyridyl methyl iodide, dimethylaminophenyl; R1 is hydrogen or Chalky!; s is 1 to 3; X, R2 and R3 are as defined hereinabove. j) 1) x—r2 m) WO 03/037891 PCT/EPO2/12077 -27- "CrKf wherein R4 is 4-pyrazinyl, 1-methyl-li^-pyrrolyl, pyridyl optionally substituted with Cj^alkyl, pyridyl TV-oxide optionally substituted with Ci-6alkyl; X is -O-, -NR^OK)-, -NR^CX^O)-, -NR1-C(=S)-, -NR1-C(=0)-NR1-, -NR'-C^-NR1- or a direct bond; R2 is fluoro-substituted Q.ioalkyl, optionally substituted phenyl or naphthyl, optionally substituted phenylCj^alkyl, a monocyclic, bicyclic or tricyclic saturated carbocycle consisting of from 3 to 10 carbon atoms, a monocyclic, bicyclic or tricyclic partially saturated carbocycle consisting of from 3 to 10 carbon, Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle consisting of from 3 to 10 carbon atoms or a monocyclic, bicyclic or tricyclic partially saturated carbocycle consisting of from 3 to 10 carbon, a 5 or 6-membered heterocycle containing from 1 to 3 heteroatoms wherein the heteroatom is selected from O, N or S to which 5 or 6-membered heterocycle one or two benzene radicals may be fused, Ci^lkyl substituted by a 5 or 6-membered heterocycle containing from 1 to 3 heteroatoms wherein the heteroatom is selected from O, N or S to which 5 or 6-membered heterocycle one or two benzene radicals may be fused; R3 is nitro, R7-C(=0)-NH-; R21-C(=0)-NH-; s is as defined hereinabove. Further preferred compounds are those compounds of formula (I) or (I') wherein one of the following restrictions apply : a) X is a direct bond and R2 is hydrogen; b) R2 and R3 are other than hydrogen; c) R3 is hydrogen; d) Z is a direct bond. Also preferred compounds are those compounds of formula (I) or (I') wherein ring A is pyridyl, pyrimidinyl or pyridazinyl, in particular pyrimidinyl or pyridazinyl. Other preferred compounds are those compounds of formula (I) or (I') wherein ring A is pyridyl, pyrimidinyl or pyridazinyl; in particular pyrimidinyl or pyridazinyl; R1 is hydrogen; aryl; formyl; Ci^alkylcarbonyl; Ci-6alkyl; Ci-6alkyloxycarbonyl; Cj^alkyl substituted with formyl, Ci-6alkylcarbonyl, Ci^alkyloxycarbonyl, Cj^alkylcarbonyloxy; Ci^alkyloxyCi^alkylcarbonyl optionally substituted with Ci^alkyloxycarbonyl; WO 03/037891 PCT/EP02/12077 -28- X is -NR1-; -NH-NH-; -N=N-; -0-; -C(=0>; -C(=S)-; -0-C(=0>; -C(=0)-0-; -0-C(=0>C1^aIkyl-; -C(=0)-0-Ci^alkyl-; -0-Ci^alkyl-C(=0)-; -C(=0)-C,^alkyl-0-; -O-CCK^NR1-; -NR'-C(=0>0-; -0-C(0>C(=0>; -C(=0)-NR1-, -NR;-C(=0>; -C(=S)-NR2-, -NRJ-C(=S)-; -NRJ-C(=0)-NR)-; -NR'-CC^NR1-; -NR1 -S(=0)-NR1 -; -NR^SCO^-NR1-; -Ci^alkyl-CC^-NR1-; -0-C,^a!kyl-C(=0)-NR1 -; -C^altyl-O-C^-NR1-; -C^alkyl-; -O-Ci^alkyl-; -Cj^alkyl-O-; -NR'-Cj-^alkyl-; -Cj^alkyl-NR1-; -NR^Ci^alkyl-NR1-; -NR^-Ci-salkyl-C^cycloalkyl-; -C2-6alkenyl-; -C2-6alkynyl-; -0-C2^alkenyl-; -C2-6alkenyI-0-; -NR1-C2-6alkenyl-; -C2^alkenyl-NR1-; -NR1 -C2-6aIkenyl-NR1 -; -NR1-C2-6alkenyl-C3-7cycloalkyl-; -0-C2^alkynyl-; -C2-6aIkynyl-0-; -NR1-C2^alkynyl-; -C2-6alkynyl-NR1-; -NR1-C2^alkynyl-NR1-; -NR1 -C2^alkynyl-C3.7cycloalkyl-; -O-Ci^alkyl-O-; -0-C2-6alkenyl-0-; -0-C2.6aIkynyl-0-; -CHOH-; -S-; -S(=0)-; -S(=0)2-; -S(=0>NR!-; -SCO^-NR1-; -NR]-S(=0)-; -NR^SCOV; -S-Ci^alkyl-; -Ci^alkyl-S-; -S-C2^alkenyl-; -C2^alkenyl-S-; -S-C2^alkynyl-; -C2-6alkynyl-S-; -0-Ci^alkyl-S(=0)2- or a direct bond; Z is a direct bond, Ci-6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Ci^alkyl-; -C(=0)-; -C(=0)-0-; -0-C(=0>; -C(=S)-; -S(=0)-; -S(=0>2-; -NR1-; -NR^C,. ealkyl-; -NR'-CCO)-; -O-CCO^NR1-; -NR^OK)-; -NR1-C(=S>; -S^CO-NR1-; ^(O^-NR1-; -NR]-S(=0)-; -NR'-SCK)^-; -NR1-(C=0)-NR1-; -NR'-C^-NR1-; -NR^SCO^NR1-; -NR^S^O^-NR1-; R2 is hydrogen, Ci-ioalkyl, C2-ioaIkenyl, C2-ioalkynyl, R20, each of said groups representing R2 may optionally be substituted where possible with one or more substituents each independently being selected from =S; =0; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0)-; R15-0-C(=0)-; R15-C(=0>0-; R,5-0-C(=0>0-; -S03H; R15-S(=0>; R15-S(=0>2-; R^^; R^^-Ci^alkyl; R5R6N-C3.7cycloalkyl; R^-C^alkyloxy; R5aR6aN-C(=0)-; R5R6N-C(=S>; RsR6N-C(=0>NH-; R5R6N-C(=S>NH-; R'R'N-SCK)),,-; R^^N-SCOVNH-; R15-C(=S)-; R15-C(=0)-NH-; R15-0-C(=0)-NH-; R15-S(=0)n-NH-; R15-0-S(=0)n-NH-; R15-C(=S)-NH-; R15-0-C(=S)-NH-; RI7R,8N-Yu-; R17R18N-Y2-NR16-YX-; R15-Y2-NR19-Yi-; H-Y2-NR19-Y!-; R3 is hydrogen; hydroxy; halo; Cj^alkyl; Cj^alkyl substituted with cyano, hydroxy or -C(=0)R7; C2^alkenyl; C2^alkenyl substituted with one or more halogen atoms or cyano; C2^alkynyl; C2^alkynyl substituted with one or more halogen atoms or cyano; Ci^alkylthio; Ci^£tlkyloxycarbonyl; Cj^alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Ci-6aIkyI)amino; polyhaloCx^alkyl; polyhaloCi^alkylthio; R21; R21-Ci^alkyl; R21-0-; R21-S-; WO 03/037891 PCT/EP02/12077 -29- R21-C(=0>; R21-S(=0)p-; R7-S(=0)pS R7-S(=0)p-NH-; R21-S(=0)p-NH-; R7-C(=0)-; -NHC(=0)H; -C(=0)NHNH2; R7-C(=0>NH-; R2i-C(=0)-NH-; -C(=NH)R7; -C(=NH)R21; R4 is tetrahydrofuranyl, dihydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, triazinyl, moipholinyl, dioxolanyl or dioxanyl, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =S; =0; R15; hydroxy; halo; nitro; cyano; Rls-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0>; R15-C(=0>0-; R15-0-C(=0)-0-; -SOjH; R15-S(=0)-; RI5-S(=0>2-; R^'N; R5R6NCi-6aIkyI; R^^Cs-Tcycloalkyl; R^^NCi^alkyloxy; R5R6N-C(=0>; R5R6N-C(=S>; R^N-C^-NH-; R5R6N-C(=S)-NH-; R5R6N-S(=0)n-; R^^-SCO) „-NH-; R1S-C(=S)-; R15-C(=0>NH-; R15-0-C(=0>NH-; Rl5-S(=0) „-NH-; R15-0-S(=0)n-NH-; R15-C(=S)-NH-; RI5-0-C(=S)-NH-; R17R18N-Yia-; R17R18N-Y2-NR16-Yr; R15-Y2-NR19-Yj-; H-Y2-NR19-Yi-; R5 and R6 each independently are hydrogen, R8, -Yi-NR9-Y2-NR1 ^1, -Yi-NR9-Yi-R8, -Yj-NRV0, or R5a and R6a each independently are hydrogen, Ci^alkyl; C2.6alkenyl or C^alkynyl, each of said groups representing R5a and R6a may optionally be substituted with one or more substituents selected from R12, R13 and R14; R5 and R6 may together with the nitrogen to which they are attached form a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14, or each of said heterocycles may optionally be fused with a benzene ring, said benzene ring being optionally substituted with one or more substituents selected from R12, R13 and R14; R7 is Ci^alkyl, Cj^alkyloxy, amino, mono- or di(Ci-6alkyl)amino or polyhaloCi^alkyl; R8 is Ci^alkyl; C2^alkenyl; C2-6alkynyl; a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic WO 03/037891 PCT/EP02/12077 -30- saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said groups representing R8 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R9, R10 and R11 each independently are hydrogen or R8, or any two of R9, R10 and R11 may together be Ci^alkanediyl or C2-6alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle together with the nitrogen atoms to which they are attached, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; R12, R13 and R14 each independently are hydrogen; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; Ris-S-; formyl; carboxyl; R15-C(=0>; R15-0-C(=0>; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0)-; R15-S(=0)2-; R15R16N-S(=0)-; R15R16N-S(=0)2-; R17R18N-Yr; R17R18N-Y2-NR16-Yi-; R15-Y2-NR19-YI-; H-Y2-NR19-Yr; oxo, or any two of R12, R13 and R14 may together be Ci^alkanediyl or C2^alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered carbo - or heterocycle or an aromatic 4 to 8 membered monocyclic carbo - or heterocycle together with the atoms to which they are attached, or any two of R12, R13 and R14 may together be -0-(CH2)r-0- thereby forming a saturated, partially saturated or aromatic monocyclic 4 to 8 membered carbo - or heterocycle together with the atoms to which they are attached; R15 is Ci^alkyl, Cj^alkenyl, C2-6alkynyl3 a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Cj^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said substituents representing R15 may optionally be substituted with one or more substituents selected from R12, R13 and R14; or each of said carbocycles or heterocycles may optionally be fused with a benzene ring, said benzene ring being optionally substituted with one or more substituents selected from R12, R13 and R14; r16, gi8 gach independently are hydrogen or R15, or WO 03/037891 PCT/EP02/12077 -31- R17 and R18, or R15 and R19 may together be Ci^alkanediyl or C2^alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; or R17 and R18 together with R16 may be Ci^alkanediyl or C2-6alkenediyl thereby forming a saturated or partially saturated monocyclic 3 to 8 membered heterocycle or an aromatic 4 to 8 membered monocyclic heterocycle together with the nitrogen atoms to which they are attached, each of said heterocycles may optionally be substituted with one or more substituents selected from R12, R13 and R14; R20 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; R21 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said carbocycles or heterocycles representing R21 may optionally be substituted with one or more substituents selected from R12, R13 and R14; Yia is -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S)-Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0)-Y4- or-Y3-C(=0)-0-Y4-; Yi or Y2 each independently are a direct bond, -Y3-S(=0)-Y4-; -Y3-S(=0)2-Y4-, -Y3-C(=0)-Y4-, -Y3-C(=S)-Y4-, -Y3-0-Y4-, -Y3-S-Y4-, -Y3-0-C(=0>Y4- or -YrC(=0)-0-Y4-; Y3 or Y4 each independently are a direct bond, Ci-6alkanediyl, C2-6alkenediyl or C2^alkynediyl; n is 1 or 2; m is 1 or 2; p is 1 or 2; r is 1 to 5; s is 1 to 3; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci-6alkyl, C3-7cycloalkyl, Ci_6alkyloxy, cyano, nitro, polyhaloCi^alkyl and polyhaloCi^alkyloxy; WO 03/037891 PCT/EP02/12077 -32- provided that -X-R2 and/or R3 is other than hydrogen; and provided that R4 is other than optionally substituted pyridyl when ring A represents pyrimidinyl. Still other preferred compounds are those compounds of formula (I) or (I') wherein ring A is pyridyl, pyrimidinyl or pyridazinyl; in particular pyrimidinyl or pyridazinyl; R1 is hydrogen; aryl; formyl; Cj^alkylcarbonyl; Ci^alkyl; Cj^alkyloxycarbonyl; Ci^alkyl substituted with fonnyl, Cj^alkylcarbonyl, Ci^alkyloxycarbonyl, Ci.6alkylcarbonyloxy; Ci^alkyloxyCi^alkylcarbonyl optionally substituted with C i ^alkyloxy carbonyl; X is -NR1-; -0-; -C(=0)-; -0-C(=0)-; -C(=0>0-; -0-C(=0>Ci.6alkyl-; -C(=0)-0-Cj^alkyl-; -0-C^alkyl-C(=0>; -C(=0)-Ci.6alkyl-0-; -0-C(=0)-NR]-; -NR1-C(=0)-0-; -CCOy-NR1-, -NR1-^^))-; -Ci^alkyl-; -O-C^alkyl-; -Cj^alkyl-O-; -NR'-Ci^alkyl-; -Ci^alkyl-NR1-; -NR^Ci^alkyl-NR1-; -C2^alkenyl-; -C^alkynyl-; -0-C2-6alkenyl-; -C2^alkenyl-0-; -NR1 -C2^alkenyl-; -^^alkenyl-NR1 -; -NR1-^. ealkenyl-NR1-; -0-C2-6alkynyl-; -C2^alkynyl-0-; -NR1 -C2^alkynyl-; -C2^alkynyl-NR1-; -NR1-C2^alkynyl-NR1-; -0-Ci_6alkyl-0-; -0-C2^alkenyl-0-; -0-C2.6alkynyl-O-; -CHOH-; -S-; -S(=0)-; -S(=0)2-; -SCK^NR1-; -SC^-NR1-; -NR^SfK))-; -NR^SCK)^-; -S-Ci^alkyl-; -C]^alkyl-S-; -S-C2^alkenyl-; -C2^alkenyl-S-; -S-C2^alkynyl-; -C2^alkynyl-S-; or a direct bond; Z is a direct bond, Ci-galkanediyl, C2-6alkenediyl, C2_6alkynediyl; -0-; -O-Ci^alkyl-; -C(=0)-; -C(=0)-0-; -0-C(=0)-; -S(=0>; -S(=0)2-; -NR1-; -NR^C^alkyl-; -NR1-C(=0>; -O-QK^NR1-; -NR1C(=0)-0-; -S(=0)-NR1-; -SC^O^-NR1-; -NR^SCK))-; -NR1-S(=0)2-; R2 is hydrogen, Ci.i0alkyl, C2-ioalkenyl, C2-ioalkynyl, R20, each of said groups representing R2 may optionally be substituted where possible with one or more substituents each independently being selected from =0; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0)-; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0)-; R1s-S(=0)2-; R^; R^-Cj^alkyl; R^-Cj^alkyloxy; R5aR6aN-C(=0)-; R^^-SCK)),,-; R^-S^VNH-; R15-C(=0)-NH-; R3 is hydrogen; hydroxy; halo; Ci^alkyl; Ci.6alkyl substituted with cyano, hydroxy or -C(=0)R7; C^alkenyl; C^alkenyl substituted with one or more halogen atoms or cyano; C2^alkynyl; C2^alkynyl substituted with one or more halogen atoms or cyano; Cj^alkylthio; Ci^alkyloxycarbonyl; Cj^alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Ci^alkyl)amino; polyhaloCi^alkyl; polyhaloC i ^alkylthio; R21; R21-Ci^alkyl; R21-0-; R21-S-; WO 03/037891 PCT/EP02/12077 -33- R21-C(=0>; R21-S(=0)p-; R7-S(=0)pS R7-C(=0)-; -NHC(=0)H; -C(=0)NHNH2; R7-C(=0)-NH-; R21-C(=0>NH-; -C(=NH)R7; -C(=NH)R21; R4 is tetrahydrofuranyl, dihydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, triazinyl, moxpholinyl, dioxolanyl or dioxanyl, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =0; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; formyl; carboxyl; R15-C(=0)-; R15-0-C(=0>; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0)-; R15-S(=0>2-; R^^N; R5R6N-C1 ^alkyl; R^^-C^alkyloxy; R^R^-CCK))-; R5R6N-S(=0)n-; R15-C(=0)-NHs R5 and R6 each independently are hydrogen or R8; R5a and R6" each independently are hydrogen, Ci^alkyl; C2^alkenyl or C2-6alkynyl, each of said groups representing RSa and R6a may optionally be substituted with one or more substituents selected from R12, R13 and R14; R7 is Chalky!, Cj^alkyloxy, amino, mono- or di(Cj^alkyl)amino or polyhaloCi^alkyl; R8 is Ci^alkyl; C2^alkenyl; C2^alkynyl; a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Ci^alkyl substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said groups representing R8 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R12, R13 and R14 each independently are hydrogen; R15; hydroxy; halo; nitro; cyano; R15-0-; SH; R15-S-; fonnyl; carboxyl; R15-C(=0)-; R15-0-C(=0)-; R15-C(=0)-0-; R15-0-C(=0)-0-; -SO3H; R15-S(=0>; R15-S(=0)2S R15R16N-S(=0)-; R15R16N-S(=0>2-; R15 is Ci^alkyl, C2-6alkenyl, C2^alkynyl, a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; Chalky! WO 03/037891 PCT/EP02/12077 -34- substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle or with a monocyclic, bicyclic or tricyclic partially saturated carbocycle or with a monocyclic, bicyclic or tricyclic aromatic carbocycle or with a monocyclic, bicyclic or tricyclic saturated heterocycle or with a monocyclic, bicyclic or tricyclic partially saturated heterocycle or with a monocyclic, bicyclic or tricyclic aromatic heterocycle; each of said substituents representing R15 may optionally be substituted with one or more substituents selected from R12, R13 and R14; R16 is hydrogen or R15; R20 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle; R21 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said carbocycles or heterocycles representing R21 may optionally be substituted with one or more substituents selected from R12, R13 and R14; n is 1 or 2; m is 1 or 2; p is 1 or 2; s is 1 to 3; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci_6alkyl, C3.7cycloalkyl, Ci-6alkyloxy, cyano, nitro, polyhaloCj^alkyl and polyhaloCi^alkyloxy; provided that -X-R2 and/or R3 is other than hydrogen; and provided that R4 is other than optionally substituted pyridyl when ring A represents pyrimidinyl. Further preferred are those compounds of formula (I) or (I') wherein the compounds are compounds from one of the following formulae : 1) WO 03/037891 PCT/EP02/12077 -35- Also preferred are those compounds of formula (a-1) wherein one or where possible more, preferably all of the following restrictions apply : ~ * (a) s is 1 and said R substituent is placed at the para position compared to the NR linker; (b) s is 1 and said R3 substituent is placed at the para position of the NR1 linker and is other than Ci^alkyloxy or polyhaloCj^alkyloxy; (c ) X is other than a direct bond or C^aUcyl; (d) Z is other than S; (e) X-R2 is other than hydroxy, Ci^alkyl, Ci^alkyloxy, trihalomethyl, trihalomethyloxy, cyanoCi^alkyl, aminocarbonyl; (f) R4 is an optionally substituted 5-membered heterocycle with at least 2 nitrogen atoms; (g) R2 is other than hydrogen, Ci^alkyl, C2^alkenyl, C2^alkynyl, and X is other than O, S, C(=0), S(=0), S(=0>2, -NH-S(=0>, -NH-S(=0)2-, -NH-C(=0>; (h) R2 is other than hydrogen. Also preferred are those compounds of formula (a-2) wherein one or more, preferably all of the following restrictions apply (a) X is other than a direct bond or Ci-6alkyl; (b) R2 is other than hydrogen, trifluoromethyl or C^aUcyl; (c) X-R2 is other than hydroxy, Cj^alkyl, Ci-6alkyloxy, trihalomethyl, trihalomethyloxy, cyanoCi^alkyl, aminocarbonyl; WO 03/037891 PCT/EP02/12077 -36- (d) R4 is an optionally substituted 5-membered heterocycle. Further interesting compounds are those compounds of formula (I), (I'), (a-1) or (a-2) wherein R4 is an optionally substituted 5-membered heterocycle, in particular an optionally substituted imidazolyl or an optionally substituted triazolyl and/or wherein Z is a direct bond. Particular preferred compounds of formula (I) or (I') are selected from N2-(lif-inda2ol-5-yl)-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine; 4-[[4-(l-methyl-l#-imidazol-2-yl>2-pyrimidinyl]amino]-2-(phenylmethoxy)-benzonitrile; 4-[[4-(l-methyl-li?-imidaz°l-2-yl)-2-pyrimidinyl]amino]-benzonitrile; a TV-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof. Other preferred compounds of formula (T) or (I') are selected from N2-(6-moipholinyl-4-yl-pyridin-3-yI)-N4-(254,6-trimethyl-phenyl)-2,4- pyrimidinediamine; N2-(3H-benzimidazol-5-yl)-N4-(2,4,6-trimethyl-phenyl)-2,4-pyriinidinediamine; N2-(lH-indazol-6-yl)-N4-(2,4,6-trime1hyl-phenyl)-2,4-pyrimidinediamine; N2-(5-bromo-pyridin-2-yl)-N4-(2,456-trimethyl-phenyl)-2,4-pyrimidinediamine; N2-(6-methoxy-pyridin-3-yl)-N4-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N2-bexizothiazol-6-yl-N4-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N2-(lH-indazol-5-yl)-N4-(2,4,6-trimethyl-phenyI)-2,4-pyrimidinediamine; N2-(lH-ben2»triazol-5-yl)-N4-(2,4,6-trimethyl-phenyl)-2s4-pyriniidinediainine; N2-benzo[13]dioxol-5-yl-N4-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N2-(6-chIoro-pyridin-3-yI)-N4-(2,4,6-trimethyl-phenyl)-2>4-pyrimidinediamine; N2-(lH-indol-5-yI)-N4-(2,456-trimethyl-phenyl)-2,4-pyriinidinediamine; N2-quinolin-6-yl-N4-(254s6-trimethyl-phenyl)-2,4-pyiimidinediamine; 4-[4-[(benzo[l,3]dioxol-5-ylmethyl)-amino]-pyrimidin-2-ylamino]-benzonitrile; 4-[4-[(quinolin-3-methyl)-amino]-pyrimidin-2-ylamino]-benzonitrile; 4-[4-[(fiiran-2-yhnethyI)-amino]-pyrimidin-2-ylamino]-benzonitrile; 4-[4-[(thiophen-2-yhnethyI)-amino]-pyriinidin-2-ylaniino]-benzonitrile; a TV-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof. WO 03/037891 PCT/EP02/12077 -37- Compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) wherein Wj represents a suitable leaving group, such as for example a halo atom, e.g. chloro, bromo and the like, in the presence of a suitable solvent, such as for example N N-dimethylacetamide, acetonitrile, tetrahydrofuran, water, an alcohol, e.g. methanol, ethanol, isopropanol and the like, and optionally in the presence of a suitable acid, such as for example hydrochloric acid and the like. Alternatively, the above reaction may also be performed in the presence of a suitable solvent, such as for example toluene, a suitable catalyst, such as tris (dibenzylidene aceton)dipalladium (0), a suitable ligand such as for example 2,2-bis(diphenylphosphino)-l,l'-binaphthyl, and a suitable base, such as for example sodium tert.butoxide. Compounds of formula (I) can also be prepared by reacting an intermediate of formula (IV) wherein W2 represents a suitable leaving group, such as for example a halo atom, e.g. chloro and the like, with an intermediate of formula (V) in the presence of a suitable solvent, such as for example toluene, a suitable catalyst, such as tris (dibenzylidene aceton)dipalladium (0), a suitable ligand such as for example 2,2-bis(diphenylphosphino)-l,l'-binaphthyl, and a suitable base, such as for example sodium terLbutoxide. Compounds of formula (I) may also be prepared by reacting an intermediate of formula (VI), wherein W3 represents a suitable leaving group, such as a halo atom, e.g. chloro and the like, with an intermediate of formula (VH) in the presence of a suitable solvent, such as 1,4-dioxane or an alcohol, e.g. methanol, ethanol, isopropanol and the like, or water, optionally in the presence of a suitable acid, such as hydrochloric acid and the like, or a suitable base, such as for example JV^V-diisopropylethanamine. (II) (l) .x—r2 (R3), (D WO 03/037891 -38- PCT/EP02/12077 H-Z—R4 (VII) (I) Compounds of formula (I) wherein Z is C(=0), said compounds being represented by formula (I-a), may be prepared by reacting an intermediate of formula (VIE), wherein W4 represents a suitable leaving group, such as a halo atom, e.g. chloro and the like, or an alcoholate, such as methanolate, ethanolate and the like, with an intermediate of formula (IX) in the presence of a suitable solvent, such as for example an alcohol, e.g. methanol, ethanol and the like. .X—R2 , R' H-R4 c=o R4 (IX) (VIII) v,xv (l-a) Compounds of formula (I) wherein Z is a direct bond, said compounds being represented by formula (I-b), can be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (X) in the presence of a suitable catalyst, such as for example palladium tetrakis(triphenylphosphine), a suitable base, such as for example disodium carbonate, and a suitable solvent, such as for example acetonitrile and water. X—R HCk HO" B—R4 (X) (I-b) Compounds of formula (I) wherein Z is a direct bond and R4 represents 5-tetrazolyl, said compounds being represented by formula (I-c), can be prepared by reacting an intermediate of formula (XI) with sodium azide in the presence of a suitable salt, such as for example AyV-diethylethanamine hydrochloric acid salt, and a suitable solvent, such as for example l-methyl-2-pyirolidinone. WO 03/037891 PCT/EPO2/12077 -39- NaN, N •(r3)s (XI) (l-C) Compounds of formula (I) wherein Z is a direct bond and ring A is pyrimidinyl with the NR1 linker placed in position 2, said compounds being represented by formula (I-d), may be prepared by reacting an intermediate of formula (XX) with an intermediate of formula (XX3) in the presence of a suitable solvent, such as for example TV,TV-dimethylacetamide and a suitable base, such as for example sodium ethanolate. (R3)s (XX) (XXI) (I-d) In the above reaction, if R4 in a compound of formula (I-d) represents a heterocycle substituted with amino are aminocarbonyl, than R4 in an intermediate of formula (XXI) may represent a heterocycle substituted with -N=CH-N(CH3)2 or -C(=0)-N=CH-N(CH3)2. In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography. 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. The compounds of formula (I) may be converted to the corresponding TV-oxide forms following art-known procedures for converting a trivalent nitrogen into its TV-oxide form- Said TV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate 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. WO 03/037891 PCT/EP02/12077 -40- t.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. 5 Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can be converted into a compound of formula (I) wherein R is cyano, or wherein R is substituted with cyano, by reaction with a suitable cyano-introducing agent, such as sodium cyanide or CuCN, optionally in the presence of a suitable catalyst, such as for example tetrakis(triphenylphosphine)palladiuni and a suitable solvent, such as 10 AyV-dimethylacetainide or TVJV-dimethylformamide. A compound of formula (I) wherein R3 is cyano, or wherein R2 is substituted with cyano, can further be converted into a compound of formula (I) wherein R3 is aminocarbonyl, or wherein R2 is substituted with aminocarbonyl, by reaction with HCOOH, in the presence of a suitable acid, such as hydrochloric acid. A compound of formula (I) wherein R3 is cyano, or 15 wherein R2 is substituted with cyano, can also further be converted into a compound of formula (I) wherein R3 is tetiazolyl, or wherein R2 is substituted with tetrazolyl, by reaction with sodium azide in the presence of ammonium chloride and N, N -dimethylacetoacetamide. 20 Compounds of formula (I) wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R2 is substituted with mercapto, by reaction with disodium sulfide in the presence of a suitable solvent, such as, for example, 1,4-dioxane. 25 Compounds of formula (I) wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R2 is substituted with Cj^alkylthio, by reaction with a reagent of formula alkaline metal+ "S-Ci^alkyl, e.g. Na+ "S-Ci^alkyl, in the presence of a suitable solvent, such as dimethylsulfoxide. The latter compounds can further be converted into a compound of formula (I) wherein R2 is substituted with 30 Ci^alkyl-S(=0)-, by reaction with a suitable oxidizing agent, such as a peroxide, e.g. 3-chlorobenzenecarboperoxoic acid, in the presence of a suitable solvent, such as an alcohol, e.g. ethanol. Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, 35 can also be converted into a compound of formula (I) wherein R3 is Cj^alkyloxy, or wherein R2 is substituted with Ci^alkyloxy, by reaction with alcoholate salt, such as, WO 03/037891 PCT/EP02/12077 -41- for example, LiOCj^alkyl, in the presence of a suitable solvent, such as an alcohol, e.g. methanol. Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R3 is hydroxy, or wherein R2 is substituted with hydroxy, by reaction with a suitable carboxylate, e.g. sodium acetate, in a suitable reaction-inert solvent, such as, for example, dimethylsulfoxide, followed by treating the obtained reaction product with a suitable base, such as pyridine, and acetyl chloride. Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R3 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, or wherein R2 is substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, said substituents being represented by -L, by reaction with H-L in the presence of a suitable base, such as for example sodium hydroxide, dipotassium carbonate, sodium hydride, in the presence of a suitable solvent, such as, for example, 1,4-dioxane, N, TV-dimethylacetamide, jV,7V-dimethylformamide. Compounds of formula (I) wherein R3 is chloro, or wherein R2 is substituted with chloro, can be converted into a compound of formula (I) wherein R3 is fluoro, or wherein R2 is substituted with fluoro, by reaction with a suitable fluoride salt, such as for example potassium fluoride, in the presence of a suitable solvent, e.g. sulfolane. Compounds of formula (I) wherein X-R is hydrogen and wherein the R substituent positioned at the meta position compared to the NR1 linker, is halo, can be converted into a compound of formula (I) wherein said R3 substituent is replaced by X-R2 wherein X is other than a direct bond when R2 is hydrogen, by reaction with H-X-R2 in the presence of a suitable solvent, such as JV^V"-dimethylacetamide or WO 03/037891 PCT/EPO2/12077 -42- M^V-dimethylfoimainide optionally in the presence of a suitable base, such as for example NJV-diisopropylethanamine. Compounds of formula (I) wherein R2 is substituted with Ci-4alkyloxyCi-6alkyl, can be converted into a compound of formula (I) wherein R2 is substituted with hydroxyCi^alkyl, by dealkylating the ether in the presence of a suitable dealkylating agent, such as, for example, tribromoborane, and a suitable solvent, such as methylene chloride. Compounds of formula (I) wherein R3 or X-R2 are C]-6alkyloxycarbonyl, or wherein R2 is substituted with C i ^alkyloxycarbonyl, can be converted into a compound of formula (I) wherein R3 or X-R2 are aminocarbonyl, or wherein R2 is substituted with aminocarbonyl or mono- or di(C]^alkyl)aminocarbonyl, by reaction with a suitable agent such as ammonia, NH2(Ci-6alkyl), AlCH3[N(Ci-6alkyl)2]Cl optionally in the presence of a suitable acid, such as for example hydrochloric acid, and in the presence of a suitable solvent such as an alcohol, e.g. methanol; tetrahydrofuran; AyV-diisopropylethane. Compounds of formula (I) wherein R3 is hydrogen or wherein R2 is unsubstituted, can be converted into a compound wherein R3 is halo or wherein R2 is substituted with halo, by reaction with a suitable halogenating agent, such as, for example Br2 or l-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2^,2]octane bis[tetrafluoroborate], in the presence of a suitable solvent, such as tetrahydrofuran, water, acetonitriie, chloroform and optionally in the presence of a suitable base such as NjAT-diethylethanamine. Compounds of formula (I) wherein R3 or -X-R2 are Ci^alkyloxycarbonyl or wherein R2 is substituted with Ci^alkyloxycarbonyl, can be converted into a compound of formula (I) wherein R3 or X-R2 are hydroxymethyl or wherein R2 is substituted with hydroxymethyl, by reaction with a suitable reducing agent, such as for example LiAlEU. Compounds of formula (I) wherein -X-R2 is -O-CHHoptionally substituted)phenyl may be converted into a compound of formula (I) wherein -X-R2 represents OH, by reaction with a suitable reducing agent, such as H2, 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, ethanol and the like, or XW-dimethylacetamide. WO 03/037891 PCT/EPO2/12077 -43- Compounds of formula (I) wherein -X-R2 represents OH, may be converted into a compound of formula (I) wherein -X-R2 represents -O-Xi-R2, by reaction with Wi-Xj- a R wherein Wi represents a suitable leaving group, such as for example a halo atom, e.g. chloro, and wherein -O-Xj represents those linkers falling under the definition of X which are attached to the phenyl ring via a O atom (in said definition Xi represents that part of the linker wherein the O atom is not included), in the presence of a suitable base, such as for example dipotassium carbonate, and a suitable solvent, such as for example JV^-dimethylacetamide. Compounds of formula (I) wherein R3 is nitro, or wherein R2 is substituted with nitro, may be converted into a compound of formula (I) wherein R3 is amino or wherein R2 is substituted with amino, by reaction with a suitable reducing agent, such as for example H2, in the presence of a suitable catalyst, such as for example palladium on charcoal, a suitable catalyst poison, such as for example a thiophene solution, and a suitable solvent, such as fen- example an alcohol, e.g. methanol, ethanol and the like. Compounds of formula (I) wherein R2 is substituted with NH2, can be converted into a compound of formula (I) wherein R2 is substituted with NH-S(=0)2-NR5R6, by reaction with Wi-S(=0)2-NR5R6 wherein W] represents a suitable leaving group such as for example a halo atom, e.g. chloro, in the presence of a suitable solvent, such as for example JV^-dimethylacetamide and a suitable base, such as for example A^-diethylethanamine. Some of the compounds of formula (I) and some of the intermediates in the present invention may 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 as selective crystallization or chromatographic techniques, e.g. counter current distribution, 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 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 WO 03/037891 PCT/EPO2/12077 -44- 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 5 formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography 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, such as 10 those described in WO 99/50250, WO 00/27825 or EP 0,834,507. Intermediates of formula (II) wherein R1 is hydrogen, said intermediates being represented by formula (Il-a), can be prepared by reducing an intermediate of formula (XII) in the presence of a suitable reducing agent, such as for example H2, a suitable 15 catalyst, such as for example palladium on charcoal, a suitable catalyst poison, such as for example a thiophene solution, and a suitable solvent, such as for example tetrahydrofuran or an alcohol, e.g. methanol, ethanol and the like, y—1 reduction J \ \^J—NOz —NHj 7 Z I* (XII) ("-a) Intermediates of formula (ID) can be prepared by reacting an intermediate of formula 20 (Xm) wherein Wi is as defined hereinabove, with an intermediate of formula (XIV) in the presence of a suitable solvent, such as for example acetonitrile or dioxane, and optionally in the presence of a suitable base, such as for example AfTV-diisopropyl ethanamine. .w. V \ + h—x—r2 w W'" x " \ /\ 3, V), (Ill) (XIII) (XIV) 25 Intermediates of formula (IV) can be prepared by reacting an intermediate of formula (XV) wherein W2 is as defined hereinabove, with an intermediate of formula (XVI) wherein W2 is as defined hereinabove. WO 03/037891 PCT/EP02/12077 -45- + K4-W2 {TV"1 \ (XVI) H ■w2 I (iv) (XV) Intermediates of formula (XVI) can be prepared by reacting an intermediate of formula (XVII) with a leaving group introducing agent of formula (XVTCT) wherein W2 represents the leaving group and R represents the remaining of the leaving group introducing agent, such as for example POCI3. R*—OH + W2 R »- ^—W2 (XVII) (XVIII) (XVI) Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (XIX) wherein W3 is as defined hereinabove, with an intermediate of formula (ID) in the presence of a suitable solvent, such as for example an alcohol, e.g. methanol, ethanol, isopropanol and the like, and a suitable acid, such as for example hydrochloric acid. .X-R2 i x_r2 <^h ♦ m (m) W! ^ Intermediates of formula (VH3) wherein ring A is pyrimidinyl with the NR1 linker in position 2 and W4 represents an alcoholate, i.e. Ci^alkylO-, said intermediates being represented by formula (Wl-a), may be prepared by reacting an intermediate of formula (XX) with an intermediate of formula (XXII) in the presence of a suitable solvent, such as for example /^-dimethylacetamide. Xt-R2 „ fCre-M "VtrC ♦ w — % /-TR2 oc.-.aftyi (XX) (XXII) (VIM-a) J ntermediates of formula (XXH) can be prepared by reacting an intermediate of formula (XXHI) with l,l-diethoxy-iV,jV-dimethyl-methanamine. WO 03/037891 PCT/EPO2/12077 -46- \z-°v / JL^OC,-^! ♦ ^0>"< — "^VSjAocn ■6alkyl (XXIII) (XXII) Intermediates of formula (XX) can be prepared by reacting an intermediate of formula (V) with cyanamide in the presence of a suitable solvent, such as for example diglyme. NC NH2 - H2N (V) (XX) Intermediates of formula (XXI) can be prepared by reacting an intermediate of formula (XXIV) with 1,1-diethoxy-JV^-dimelhyl-methanamine. V - ^ O (XXIV) (XXI) The compounds of formula (I) or (I') inhibit Glycogen synthase kinase 3 (GSK3), in particular glycogen synthase kinase 3 beta (GSK3p). They are selective Glycogen synthase kinase 3 inhibitors. Specific inhibitory compounds are superior therapeutic agents since they are characterized by a greater efficacy and lower toxicity by virtue of their specificity. Synonyms for GSK3 are tau protein kinase I (TPK I), FA (Factor A) kinase, kinase FA and ATP-citrate lysase kinase (ACLK). Glycogen synthase kinase 3 (GSK3), which exists in two isoforms, i.e. GSK3a and GSK3P, is a proline-directed serine/threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase. However, it has been demonstrated that GSK3 phosphoiylates numerous proteins in vitro such as glycogen synthase, phosphatase inhibitor 1-2, the type-II subunit of cAMP-dependent protein kinase, the G-subunit of phosphatase-1, ATP-citrate lyase, acetyl coenzyme A carboxylase, myelin basic protein, a microtubule-associated protein, a neurofilament protein, an N-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous polyposis coli tumor supressor protein, tau protein and (3-catenin. WO 03/037891 PCT/EP02/12077 -47- The above-indicated diversity of proteins which may be phosphorylated by GSK3 implies that GSK3 is implicated in numerous metabolic and regulatory processes in cells. GSK3 inhibitors may therefore be useful in the prevention or treatment of diseases mediated through GSK3 activity such as bipolar disorder (in particular manic depression), diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Down syndrome, myotonic dystrophy, Parkinsonism-dementia complex of Guam, aids related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) (late complication of viral infections in the central nervous system), inflammatory diseases, cancer, dermatological disorders such as baldness, neuronal damage, schizophrenia, pain, in particular neuropathic pain. GSK3 inhibitors can also be used to inhibit sperm motility and can therefore be used as male contraceptives. In particular, the compounds of the present invention are useful in the prevention or treatment of Alzheimer's disease, diabetes, especially type 2 diabetes (non insulin dependent diabetes). The major neuropathological landmarks in Alzheimer's disease are neuronal loss, the deposition of amyloid fibers and paired helical filaments (PHF) or neurofibrillary tangles (NFT). Tangle formation appears to be the consequence of accumulation of aberrantly phosphorylated tau protein. This aberrant phosphorylation destabilizes neuronal cytoskeleton, which leads to reduced axonal transport, deficient functioning and ultimately neuronal death. The density of neurofibrillary tangles has been shown to parallel duration and severity of Alzheimer's disease. Reduction of the degree of tau phosphorylation can provide for neuroprotection and can prevent or treat Alzheimer's disease or can slow the progression of the disease. As mentioned hereinabove, GSK3 phosphorylates tau protein. Thus compounds having an inhibitory activity for GSK3 may be useful for the prevention or the treatment of Alzheimer's disease. Tnsulin regulates the synthesis of the storage polysaccharide glycogen. The rate-limiting step in the glycogen synthesis is catalyzed by the enzym glycogen synthase. It is believed that glycogen synthase is inhibited by phosphorylation and that insulin WO 03/037891 PCT/EP02/12077 -48- stimulates glycogen synthase by causing a net decrease in the phosphorylation of this enzym. Thus, in order to activate glycogen synthase, insulin must either activate phosphatases or inhibit kinases, or both. It is believed that glycogen synthase is a substrate for glycogen synthase kinase 3 and 5 that insulin inactivates GSK3 thereby promoting the dephosphorylation of glycogen synthase. In addition to the role of GSK3 in insulin-induced glycogen synthesis, GSK3 may also play a role in insulin resistance. It is believed that GSK3 dependent Tnsnlin Receptor Substrate-1 phosphorylation contributes to insulin resistance. 10 Therefore, GSK3 inhibition may result in the increased deposition of glycogen and a concomitant reduction of blood glucose, thus mimicing the hypoglycemic effect of insulin GSK3 inhibition provides an alternative therapy to manage insulin resistance commonly observed in non insnlin dependent diabetes mellitus and obesity. GSK3 inhibitors may thus provide a novel modality for the treatment of type 1 and type 2 15 diabetes. GSK3 inhibitors, in particular GSK3P inhibitors, may also be indicated for use in the prevention or the treatment of pain, in particular neuropathic pain. After axotomy or CCI, neuronal cells die through an apoptotic pathway and the morphological changes correlate with the onset of hyperalgesia and/or allodynia. The induction of apoptosis is probably triggered by a reduced supply of neurotrophic factors as the time course of neuronal loss is positively altered by administration of neurotrophins. GSK, in particular GSK3P, has been shown to be involved in the initiation of the apoptotic cascade and trophic factor withdrawal stimulates the GSK3P apoptosis pathway. In view of the above, GSK3P inhibitors might reduce signals of and even prevent levels of neuropathic pain. Due to their GSK3 inhibitory properties, particularly their GSK3P inhibitory properties, 30 the compounds of formula (I) or (I'), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, are useful to prevent or treat GSK3 mediated diseases, in particular GSK3P mediated diseases, such as bipolar disorder (in particular manic depression), diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with 35 Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Down WO 03/037891 PCT/EP02/12077 -49- syndrome, myotonic dystrophy, Parkinsonism-dementia complex of Guam, aids related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) (late complication of viral infections in the central nervous system), inflammatory diseases, cancer, dennatological disorders such as baldness, neuronal damage, schizophrenia, pain, in particular neuropathic pain. The present compounds are also useful as male contraceptives. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals suffering from disease mediated through GSK3, in particular GSK3P, or they may be useful to prevent warm-blooded animals to suffer from disease mediated through GSK3, in particular GSK3J3. More in particular, the compounds of the present invention may be useful in the treatment of warmblooded animals suffering from Alzheimer's disease, diabetes, especially type 2 diabetes, cancer, inflammatory diseases or bipolar disorder. In view of the above described pharmacological properties, the compounds of formula (I) or any subgroup thereof^ their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms, may be used as a medicine. In particular, the present compounds can be used for the manufacture of a medicament for treating or preventing diseases mediated through GSK3, in particular GSK3P. More in particular, the present compounds can be used for the manufacture of a medicament for treating or preventing Alzheimer's disease, diabetes, especially type 2 diabetes, cancer, inflammatory diseases or bipolar disorder. In view of the utility of the compounds of formula (I) or (I'), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from diseases mediated through GSK3, in particular GSK3p, more in particular a method of treating or preventing Alzheimer's disease, diabetes, especially type 2 diabetes, cancer, inflammatory diseases or bipolar disorder. Said method comprises the administration, preferably oral administration, of an effective amount of a compound of formula (I) or (I'), a TV-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a possible stereoisomeric form thereof, to warm-blooded animals, including humans. The present invention also provides compositions for preventing or treating diseases mediated through GSK3, in particular GSK3p, comprising a therapeutically effective amount of a compound of formula (I) or (I') and a pharmaceutically acceptable carrier WO 03/037891 PCT/EP02/12077 -50- or diluent The compounds of the present invention or any subgroup thereof 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 amount of the particular compound, optionally in addition 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 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 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 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 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, hi the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined 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. The compounds of die 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 WO 03/037891 PCT/EP02/12077 -51- powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation 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 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. The present compounds are orally active compounds, and are preferably orally administered. The exact dosage, the therapeutically effective amount and frequency of administration depends on the particular compound of formula (I) or (I') used, the particular condition being treated, the severity of the condition 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 subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. When used as a medicament to prevent or treat Alzheimer's disease, the compounds of formula (I) or (I') may be used in combination with other conventional drugs used to combat Alzheimer's disease, such as galantamine, donepezil, rivastigmine or tacrine. Thus, the present invention also relates to the combination of a compound of formula (I) or (I') and another agent capable of preventing or treating Alzheimer's disease. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I'), and (b) another agent capable of preventing or treating Alzheimer's disease, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of Alzheimer's disease. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. WO 03/037891 PCT/EP02/12077 -52- When used as a medicament to prevent or treat type 2 diabetes, the compounds of formula (I) or (I') may be used in combination with other conventional drugs used to combat type 2 diabetes, such as glibenclamide, chlorpropamide, gliclazide, glipizide, gliquidon, tolbutamide, metformin, acarbose, miglitol, nateglinide, repaglinide, acetohexamide, glimepiride, glyburide, tolazamide, troglitazone, rosiglitazone, pioglitazone, isaglitazone. Thus, the present invention also relates to the combination of a compound of formula (I) or (I') and another agent capable of preventing or treating type 2 diabetes. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I'), and (b) another agent capable of preventing or treating type 2 diabetes, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of type 2 diabetes. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. When used as a medicament to prevent or treat cancer, the compounds of formula (I) or (I') may be used in combination with other conventional drugs used to combat cancer such as platinum coordination compounds for example cisplatin or carboplatin; taxane compounds for example paclitaxel or docetaxel; camptothecin compounds for example irinotecan or topotecan; anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine; anti-tumour nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine; nitrogen mustard or nitrosourea alkylating agents for example cyclophosphamide, chlorambucil, carmustine or lomustine; anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin or idarubicin; HER2 antibodies for example trastzumab; and anti-tumour podophyllotoxin derivatives for example etoposide or teniposide; and antiestrogen agents including estrogen receptor antagonists or selective estrogen receptor modulators preferably tamoxifen, or alternatively toremifene, droloxifene, faslodex and raloxifene; aromatase inhibitors such as exemestane, anastrozole, letrazole and vorozole; differentiating agents for example retinoids, vitamin D and DNA methyl transferase inhibitors for example azacytidine; kinase inhibitors for example flavoperidol and imatinib mesylate or farnesyltransferase inhibitors for example R115777. Thus, the present invention also relates to the combination of a compound of formula (I) or (I') and another agent capable of preventing or treating cancer. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (!'), and (b) another agent capable of preventing or treating cancer, as a combined preparation for simultaneous, separate or sequential use WO 03/037891 PCT/EP02/12077 -53- in the prevention or treatment of cancer. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. When used as a medicament to prevent or treat bipolar disorder, the compounds of formula (I) or (I') may be used in combination with other conventional drugs used to combat bipolar disorder such as atypical antipsychotics, anti-epileptica, benzodiazepines, lithium salts, for example olanzapine, risperidone, carbamazepine, valproate, topiramate. Thus, the present invention also relates to the combination of a compound of formula (I) or (I') and another agent capable of preventing or treating bipolar disorder. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I'), and (b) another agent capable of preventing or treating bipolar disorder, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of bipolar disorder. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. When used as a medicament to prevent or treat inflammatory diseases, the compounds of formula (I) or (I') may be used in combination with other conventional drugs used to combat inflammatory diseases such as steroids, cyclooxygenase-2 inhibitors, non-steroidal-apti-infl ammatoiy drugs, TNF- a antibodies, such as for example acetyl salicylic acid, bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen, naproxen, 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, methylprednisolone, prednisolone, prednisone, triamcinolone, celecoxib, rofecoxib, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine. Thus, the present invention also relates to the combination of a compound of formula (I) or (I') and another agent capable of preventing or treating inflammatory diseases. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I')» and (b) another agent capable of preventing or treating inflammatory diseases, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of inflammatory WO 03/037891 PCT/EPO2/12077 -54- disorders. The different drags may be combined in a single preparation together with pharmaceutically acceptable carriers. Experimental part 5 Hereinafter, "DIPE" is defined as diisopropyl ether, "DMA" is defined as 7\^-dimethylacetamide, "DMF" is defined as A^-dimethylformamide. A. Preparation of the intermediate compounds 10 Example A1 Reaction under Argon atmosphere. 2,4,6-Trimethylaniline (0.0678 mol) was added to 2,4-dichloropyrimidine (0.0664 mol) in 1,4-dioxane (100 ml). 1 -methylethyl)- ethaneamine (A^-diisopropylethanamine) (0.083Omol) was added. The reaction mixture was stirred and refluxed for 4 days and the solvent was evaporated. The residue 15 was dissolved in CH2CI2, washed with a saturated NaHCC>3 solution, then dried (Na2S04), filtered and the solvent was evaporated to give 17.1 g solid residue. This solid was dissolved in CH2Cl2:hexane (1:1; 150 ml), and the resulting solution was concentrated to 100 ml, then filtered. The residue was purified by column chromatography on KP-Sil (eluent: CH2C12). The desired fractions were collected and 20 the solvent was evaporated. The less polar fraction was stirred in CH2C12 for 3 hours and filtered, yielding 0.44 g 4-chloro-7\^2,4,6-trimethylphenyl)-2-pyrimidinamine. A second fraction was recrystallized from acetonitrile, filtered off and dried, yielding 2-chloro-A^2,4,6-trimethyl-phenyl)-4-pyrimidinamine (intermediate 1). F.yamp1e AO. 25 A mixture of 4-[(4-hydroxy-2-pyrimidinyl)amino]-benzonitrile (0.12 mol) in POCI3 (90 ml) was stirred and refluxed under Argon for 20 minutes. The reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated by filtration. The solid was suspended in 500 ml water, and the pH of the suspension was adjusted to neutral by adding a 20% NaOH solution. The solid was again separated by filtration, 30 suspended in 200 ml 2-propanone, and 1 L methylene chloride was added. The mixture was heated till all solid had dissolved. After cooling to room temperature, the aqueous layer was separated, and the organic layer was dried over magnesium sulfate. During removal of the drying agent by filtration, a solid formed in the filtrate. Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g of 35 4-[(4-chloro-2-pyrimidinyl)amrno]-benzonitrile (intermediate 2). WO 03/037891 -55- PCT/EPO2/12077 F.vample A3 a) The preparation of intermediate 3 "n A mixture of 4-amino-2-(2-phenylethoxy)benzonitrile (0.012 mol) in 1,1-oxybis [2-methoxyethane] (50 ml) was stirred at 100°C, cyanamide (1 ml) was added dropwise. The reaction mixture was stirred at 100°C for 30 minutes and at room temperature overnight Extra cyanamide (1ml) was added and the reaction mixture was stirred at 100°C for 24 hours. Extra cyanamide (1ml) was added and the reaction mixture was stirred further at 100°C for 24 hours. The solvent was evaporated. The residue (6.3 g) was purified by high-performance liquid chromatography over Hypeiprep C18 HS BDS (eluent: (0.5% NH4AC in H20/CH3CN 90/10)/MeOH/CH3CN 75/25/0; 0/50/50; 0/0/100). The first fraction was collected and the solvent was evaporated, yielding 1.36g (42.6%) of intermediate 3. b) The preparation of intermediate 4 Cyanamide (0.0444 mol) was added portionwise at 80°C to a solution of 4-amino-2-(phenylmethoxy)-benzonitrile hydrochloric acid (1:1) (0.0444 mol) in l,r-oxybis[2-methoxyethane] (90 ml). The mixture was stirred at 100°C for 3 hours, cooled to room temperature and poured out into ice water. The precipitate was filtered. The filtrate was evaporated. The residue was taken up in CH2CI2 and crystallized. The precipitate was filtered off and dried, yielding 12.5 g of intermediate 4 (90%) 9mp. 132°C). F.vample A4 a) The preparation of intermediate 5 0 1 1,1 -Diethoxy-AyV-dimethylmethanamine (0.153 mol) was added over 15 minutes to ethyl 2-oxopropanoate (0.153 mol) at room temperature while vigorously stirring. The temperature was kept below 30°C. The reaction mixture was heated to 80°C for 24 o WO 03/037891 PCT/EP02/12077 -56- hours. The residue was purified by distillation, yielding 9.8 g (37.4%) of intermediate 5. F.v ample A 5 To a solution of intermediate 3 (0.00477 mol) in DMA (30 ml), intermediate 5 (0.0057 5 mol) was added. The reaction mixture was stirred for 1 hour at room temperature and overnight at 100°C. This mixture was again stirred at 100°C for 24 hours and then cooled to room temperature. The residue was poured out in a saturated NaCl-solution (300 ml), filtered and washed with H2O. The precipitate was dissolved in 2-propanone and this solution was concentrated in vacuum. The obtained solid was crystallized from 10 EtOH, filtered and dried at 40°C under vacuum, yielding 0.64 g (35.8%) of intermediate 6. Example A 6 a) The preparation of intermediate 7 1 -(1 -Methyl- lif-imidazol-2-yl)ethanone (0.0028 mol) in 1,1-diethoxy-iV^V-dimethylmethanamine (10 ml) was stirred and refluxed for 12 hours; then allowed to 15 cool to room temperature. The precipitate was filtered off and dried (50°C, vacuum), yielding 0.42 g (82.3%) of intermediate 7. A mixture of 5-acetyl-3-pyridinecarboxamide in DMF/DMA (100 ml) was stirred at 80°C overnight. The precipitate was filtered off and dried (vacuum), yielding 4g of intermediate 8. 20 B. Preparation of the final r.r>mpounds Example B1 The preparation of compound 1 The preparation of intermediate 6 b) The preparation of intermediate 8 WO 03/037891 PCT/EP02/12077 -57- A suspension of 6-bromo-23'-bipyridine (0.00042 mol), tris (dibenzylidene aceton)dipalladium (0) (0.0085 mmol), 2,2-bis(diphenylphosphino)-1,1'-binaphthyl (0.0128 mmol) and sodium tert butoxide (0.00051 mol) in toluene (4 ml) was degassed withN2. 3-(Trifluoromethyl)-benzenamine (0.00051 mol) was added while stirring at room temperature. The resulting reaction mixture was stirred for 18 hours at 90 °C. The reaction mixture was washed with water (1 ml), then filtered through Extrelut and the filtrate was evaporated, yielding 0.027 g of compound 1. Example B2 a) The preparation of compound 2 A mixture of methanol (4 ml), water (4 ml) and HCl/2-propanol (0.2 ml) was added to a mixture of intermediate 2 (0.000242 mol) and lif-indazol-5-amine (0.000242 mol). The reaction mixture was stirred overnight at 60 °C. The desired compound was isolated and purified by high performance liquid chromatography over RP C-18 (eluent: (0.5% NH4OAC in H20/CH3CN 90/10)/CH30H/CH3CN 70/15/15; 0/50/50; 0/0/100). The desired fractions were collected and the solvent was evaporated, yielding 0.017 g of compound 2. b) The preparation of compound 3 A mixture of intermediate 2 (0.000325 mol), 3-quinolinemethanamine (0.000357 mol) and i^-diisopropylethanamine (0.0005 mmol) in 1,4-dioxane (4 ml) was stirred at 95 °C for 3 days. The solvent was evaporated and the residue was taken up in methylene chloride. Water (1 ml) was added. The mixture was stirred for 30 minutes; then extracted through Extrelut. The Extrelut was washed twice with methylene chloride. The extract was purified by high performance liquid chromatography over silica gel (eluent: methylene chloride/methanol 100/0; 90/10). The desired fractions were collected and the solvent was evaporated, yielding 0.048 g of compound 3. cn WO 03/037891 PCT/EP02/12077 -58- P.yamp1fi"R3 c) The preparation of compound 4 A mixture of intermediate 6 (0.002 mol) and piperazine (0.002 mol) in methanol (15 ml) was stirred at room temperature for 1 day; then stirred at 50°C for 1 day. The solvent was evaporated. The residue was dissolved in CH2Cl2/MeOH (95/5) and washed with H2O. The separated organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CI^Ck/MeOH 92.5/7.5). The desired fractions were collected and the solvent was evaporated. The residue was stirred in diethyl ether. The precipitate was filtered off, washed and dried (50°C, vacuum), yielding 0.32g of compound 4. F.vample ft4 d) The preparation of compound 5 A mixture of 6-chloro-jV-(2,3-dichlorophenyI)-3-pyridazinamine (0.00037 mol) and palladium tetrakis(triphenylphosphine) (0.000018 mol) in acetonitrile (10 ml) was stirred (and degassed) under N2 atmosphere and heated to 90 °C. A solution of 3-pyridinylboronic acid (2 equiv, 0.00074 mol) in 0.4 M Na2CC>3 in H2O (10 ml) (previously degassed under N2) was added dropwise and the resulting reaction mixture was stirred for 18 hours under N2 atmosphere. The mixture was filtered warm and the filter residue was washed with CH3CN (1 ml). The filtrate was diluted with CH2CI2 (4 ml), then filtered/dried through Extrelut and the filtrate was evaporated. The residue was purified by preparative column chromatography. The product fractions were collected and the solvent was evaporated, yielding 0.027 g of compound 5. Example B5 a) The preparation of compound 6 NaOEt (0.68g) was added to a solution of intermediate 4 (0.01 mol) in DMA (25 ml) h WO 03/037891 -59- PCT/EP02/12077 The reaction mixture was stirred at room temperature for 1 hour. Intermediate 4 (0.01 mol) was dissolved in DMA (5 ml) and EtOH (15 ml). This solution was added dropwise to the reaction mixture at room temperature. The mixture was stirred at room temperature for 2 hours; then gently heated to 100°C and stirred for 3 days at this temperature. This fraction was purified by high performance liquid chromatography over hyperprep CI 8 (0.5% NH4OAC in H20/CH3CN 90/10yCH3CN 63/37; 25/75; 0/100). The desired fractions were collected and the solvent was evaporated. The residue was suspended in DIPE and stirred overnight. The precipitate was filtered off and dried (40t>C, vacuum), yielding 1.34g (35%) of compound 6. b) The preparation of compound 37 A mixture of guanidine, [3-(trifiuoromethyl)phenyl]-, mononitrate (250 mg), intermediate 8 (220 mg), sodium methanolate (0.05g) and methoxyethanol (20 ml) was stirred at 110°C for 1 day. The temperature was raised to 160°C overnight The reaction mixture was colled, the solvent was evaporated and the residue was suspended in aceton. The precipitate was filtered off, washed and dried (vacuum), yielding 248,1 mg of compound 37. Example B6 The preparation of compound 7 in methanol and DMA (50 ml) was hydrogenated at 50°C with Pd/C 10% (1 g) as a catalyst After uptake of hydrogen (1 equiv), the catalyst was filtered off and the mixture was concentrated till 100 ml. The formed precipitate was filtered off, washed with DIPE and dried, yielding 2.6 g of compound 7. (compound 8) (0.013 mol) (prepared according to Example B5) WO 03/037891 PCT/EP02/12077 -60- Tables 1 to 4 list the compounds of formula (I) which were prepared according to one of the above examples. Table 1: ch3 Co. No. Ex. No. R4 Physical data 9 B2a KK) 10 B2a li/-benzimidazol-5-yl 11 B2a liJ-indazol-6-yl 12 B2a 5-bromo-2-pyrimidinyl H20(1:1) 13 B2a 5-bromo-2-pyridinyl 14 B2a 6-methoxy-3-pyridinyl 15 B2a 6-benzothiazolyl 2 B2a l-ff-indazol-5-yl 16 B2a 17?-benzotriazol-5-yl 17 B2a 1,3-benzodioxol-5-yl 18 B2a 6-chloro-3-pyridinyl 19 B2a l#-indol-5-yl 20 B2a 6-quinolinyl WO 03/037891 PCT/EP02/12077 Co. No. Ex. No. R4 Z 21 B2b 2-tetrahydrofuranyl -ch2-nh- 22 B2b 2-thienyl -ch2-nh- 23 B2b -ch2-nh- 24 B2b 2,2-dimethyl-1,3-dioxolan-4-yI -ch2-nh- 25 B2b 1 -ethylpyrrolidin-2-yl -ch2-nh- 26 B2b 2-furanyl -ch2-nh- 3 B2b 3-quinolinyl -ch2-nh- 27 B2b cro-i -ch2-nh- 28 B2b 4-morpholinyl -(CH2)2-NH- 29 B2b 1,3-benzodioxol-5-yl -ch2-nh- 30 B2b 4-methyI-1 -piperazinyl direct bond 31 B2b direct bond 32 B2b 4-morpholinyl direct bond 33 B5a 1 -methyl-1 i/-imidazol-2-yl direct bond 5 WO 03/037891 PCT/EP02/12077 Co. No. Ex. No. R4 ~(D~ R3a R3b Physical data 34 ch3 Vf" n^n 4- CeHia H 5 B4 3-pyridinyl hCH 2-C1 3-C1 35 B4 3-pyridinyl l-CH 3-CF3 H 1 B1 3-pyridinyl 3-CF3 H 36 B5b rr n^n nh, 3-CF3 H 37 B5b 3-CF3 H Co. No. Ex. No. R4 Z X-R2 R3 Physica 1 data 6 B5a CH3 ib* -O-CHs-CfiHs 4-CN 4 B3 1-piperazinyl ■(C=0)- -0-CH2-C6H5 4-CN 8 B5a CV* f f ch3 ib* -O-CHz-CeHs H WO 03/037891 -63- PCT/EP02/12077 Co. No. Ex. No. R4 Z X-R2 R3 Physica 1 data 7 B6 r r ch3 ib* -O-H H *db = direct bond C. Pharmacolofrical Example The pharmacological activity of the present compounds was examined using the 5 following test GSK3beta assays were performed at 25°C in a 100 fil reaction volume of 25mM Tris (pH 7.4) containing 10 mM MgCh, 1 mM DTT, 0.1 mg/ml BSA, 5% glycerol and containing 19 nM GSK3P, 5 pM biotinylated phosphorylated CREB peptide, 1 jiM 10 ATP, 2nM ATP-P33 and a suitable amount of a test compound of formula (I) or (F). After one hour, the reaction was terminated by adding 70 (il of Stop mix (1 mM ATP, 18 mg/ml streptavidin coated PVT SPA bead pH 11.0). The beads to which the phosphorylated CREB peptide is attached were allowed to settle for 30 minutes and the radioactivity of the beads was counted in a microtiterplate scintillation counter and 15 compared with the results obtained in a control experiment (without the presence of a test compound) in order to determine the percentage of GSK3(3 inhibition. The IC50 value, i.e. the concentration (M) of the test compound at which 50 % of GSK3fi is inhibited, was calculated from the dose response curve obtained by performing the above-described GSK3P assay in the presence of different amounts of the test 20 compound- Table 5 lists pICso values (-log IC50 (M)) obtained in the above-described test for the present compounds. Table 5 25 Comp. No. pICs# 22 5.74 24 5.36 25 5.72 26 5.81 2 6.28 17 5.30 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 03/037891 -64- PCT/EP02/12077 Comp. No. pICso 20 5.44 6 7.01 4 5.53 33 7.11 Claims 1. A compound selected from -65 X—R intellectual property office of n.z. 8 - MAY 2007 RECEIVED (r)s (i) wherein: R1 is hydrogen; aryl; formyl; Ci^alkylcarbonyl; Ci^alkyl; Ci^alkyloxycarbonyl; Ci. 6alkyl substituted with fonnyl, CMalkylcarbonyl, Ci^alkyloxycarbonyl, Ci-6alkylcarbonyloxy; C\^alkyloxyCi^alkylcarbonyl optionally substituted with Ci-6alkyloxycarbonyl; R4 z X R2 s R3 2-tetrahydrofuranyl -ch2- nh- direct bond h 1 4-cn 2-thienyl -ch2- nh- direct bond h 1 4-cn H3(^ h3c—o— -ch2- nh- direct bond h 1 4-cn 2,2-dimethyl-1,3-dioxolan-4-yl -ch2- nh- direct bond h 1 4-cn 1 -ethylpyrrolidin-2-yl -ch2- nh- direct bond h 1 4-cn 2-furanyl -ch2- nh- direct bond h 1 4-cn 3-quinolinyl -ch2- nh- direct bond h 1 4-cn cro' -ch2- nh- direct bond h 1 4-cn 4-morpholinyl -(ch2)2-nh- direct bond h 1 4-cn 1,3-benzodioxol-5-yl -ch2- nh- direct bond h 1 4-cn 4-methyl-1 -piperazinyl direct bond direct bond h 1 4-cn direct bond direct bond h 1 4-cn 4-morpholinyl direct bond direct bond h 1 4-cn 1 -methyl-1 //-imidazol-2- yi direct bond direct bond h 1 4-cn -66- R4 z X R*;s;R3;fY;direct bond direct bond;H;1;3-CF3;-V;direct bond direct bond;H;1;3-CFs;Os.;CH,;direct bond;-O-CH2-QH5;1;4-CN;1-piperazinyl;-(C=0)-;-O-CHz-CgHs;1;4-CN;qn;CHj direct bond;-0-CH2-C6H5;1;H;X -;direct bond;-O-H;1;H;a //-oxide, a pharmaceutical^ acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.;2. A compound as claimed in claim 1 wherein the compound is 4-[[4-(l-methyl-l.ff-imidazol-2-yl)-2-pyrimidinyl]ainino]-2-(phenylmethoxy)-benzonitrile;;4-[[4-(l -methyl- li/-imidazol-2-yl)-2-pyrimidinyl] amino] -benzonitrile; a TV-oxide, a pharmacerutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof;3. A compound as claimed in claim 1 wherein the compound is 4-[4-[(benzo[ 1 >3]dioxol-5-ylmethyl)-amino]-pyrimidin-2-ylamino] -benzonitrile; 4-[4-[(qdnolin-3-methyl)-aijiino]-pyrixrudin-2-ylamino3-ben2onitrile; 4-[4-[(furan-2-ylmethyl)-amino]-pyrimidin-2-yIamino]-benzonitiile; 4-[4-[(thiophen-2-ylmethyl)-amino]-pyrimidin-2-ylamino]-benzonitrile;;a TV-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof.;4. A compound as claimed in any one of claims 1 to 3 for use as a medicine.;5. The use of a compound for the manufacture of a medicament for the prevention or the treatment of a disease mediated through GSK3, said compound being a compound as claimed in any one of claims 1 to 3.;intellectual property office of m.z;13 MAS 2007;! «FCFIVFn;• ';-67-;6. The use of a compound as defined in any one of claims 1 to 3 for the manufacture of a medicament for the prevention or the treatment of bipolar disorder (in particular manic depression), diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Down syndrome, myotonic dystrophy, Parkinsonism-dementia complex, of Guam, aids related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) (late complication of viral infections in the central nervous system), inflammatory diseases, cancer, dermatological disorders, neuronal damage, schizophrenia, pain.;7. The use of a compound as claimed in claim 6 for the prevention or the treatment of Alzheimer's disease, diabetes, cancer, inflammatory diseases or bipolar disorder.;8. A pharmaceutical composition comprising a phaimaceuticaJly acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 3.;9. A process for preparing a pharmaceutical composition as claimed in claim 8 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1 to 3 is intimately mixed with a pharmaceutically acceptable carrier.;10. A process for preparing a compound as claimed in claim 1, characterized by a) by reacting an intermediate of formula (II) with an intermediate of formula (III) in the presence of a suitable solvent and optionally in the presence of a suitable acid,;with Wj representing a suitable leaving group, and s, Z, R1, R2, R3, R4 and X as defined in claim 1;;intellectual property office of m.z;1 ^ MAR 2007;Rpnpi\/pn;-6S-;15;b) by reacting an intermediate of formula (II) with an intermediate of formula (HI) in the presence of a suitable solvent, a suitable catalyst, a suitable ligand and a suitable base;.X—R2 R4—Z. —R2;\=N;(HI);(II);(0;5 with W] representing a suitable leaving group, and s, Z, R1, R2, R3, R4 and X as defined in claim 1;;c) reacting an intermediate of formula (IV) with an intermediate of formula (V) in the presence of a suitable solvent, a suitable catalyst, a suitable ligand and a suitable base, rA ^ ,X—R2 R*~ ■w2 v=n (V) (IV) (I) 10 with W2 representing a suitable leaving group, and s, Z, R1, R2, R3, R4 and X as defined in claim 1; d) reacting an intermediate of formula (VI) with an intermediate of formula (VII) in the presence of a suitable solvent and optionally in the presence of a suitable acid or a suitable base w, x—R2 R4—z x—R2 (VI) (VII) (I) < A ) i with W3 representing a suitable leaving group, and s, Z, R , R , R , R and X as defined in claim 1; e) reacting an intermediate of formula (VIII) with an intermediate of formula (IX) in the presence of a suitable solvent piSraALtSfEBivomctS 1 \ 3 MAS 2007 j IrECEIVPO- -69- X—R2 + H—R4 (VIII) {DC) (l-a) with W4 representing a suitable leaving group, and s, Rl, R2, R5, R4 and X as defined in claim 1; f) reacting an intermediate of formula (VI) with an intermediate of formula (X) in the 5 presence of a suitable catalyst, a suitable base and a suitable solvent w, .x—R? HO^ 4 + —R hot (R )i (X) (VI) (j-b) with W3 representing a suitable leaving group, and s, R1, R2, R3, R4 and X as defined in claim 1; g) reacting an intermediate of formula (XX) with an intermediate of formula (XXI) in 10 the presence of a suitable solvent and a suitable base x—R2 (XX) (XXI) with s, R1, R2, R3, R4 and X as defined in claim 1; 0-d) or, if desired, converting compounds of formula (1) into each other following art-known 15 transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment 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, 20 if desired, preparing stereochemically isomeric forms, quaternary amines or N-oxide forms thereof. [Intellectual pro^rtv ^ of w / Jaqssen Pharmaceutics N.V, \ a MAR 2007 </div>