AU2002363176A1

AU2002363176A1 - Heteroaryl amines as glycogen synthase kinase 3Beta inhibitors (GSK3 inhibitors)

Info

Publication number: AU2002363176A1
Application number: AU2002363176A
Authority: AU
Inventors: Peter Jacobus Johannes Antonius Buijnsters; Marc Rene De Jonge; Gaston Stanislas Marcella Diels; Werner Constant Johan Embrechts; Eddy Jean Edgard Freyne; Jan Heeres; Paul Adriaan Jan Janssen; Lucien Maria Henricus Koymans; Paulus Joannes Lewi; Christopher John Love; Koen Jeanne Alfons Van Aken; Hendrik Maarten Vinkers; Marc Willems
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2001-11-01
Filing date: 2002-10-29
Publication date: 2003-07-10
Anticipated expiration: 2022-10-29

Description

HETEROARYL AMINES AS GLYCOGEN SYNTHASE KINASE 3BETA INHIBITORS (GSK3 INHIBITORS)

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.

WO 01/72745 describes 2-substituted 4-heteroaryl-pyrimidines useful in the treatment of proliferative disorders.

WO 98/41512 relates to substituted 2-aniliήopyrimidines 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 kinases.

WO 01/60816 describes pyrimidine derivatives useful as kinase inhibitors.

WO 97/19065 discloses substituted 2-anilinopyrimidines useful as p56^Ick, p59^fyn,

ZAP-70 and protein kinase C inhibitors. WO 91/18887 discloses diammopyrimidine compounds as inhibitors of gastric acid 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 N-phenyl-2-pyrimidineamine derivatives for the treatment of tumor diseases.

WO 98/18782 concerns 2-pyrimidineamine derivatives as selective protein tyrosine kinase inhibitors.

EP 0,337,943 discloses N-phenyl-N-pyrimidin-2-yl derivatives having herbicidal plant growth regulating activity. EP 0, 164,204 concerns 2-aminopyrimidines which augment the immune respons.

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 of formula

a N-oxide, a pharmaceutically 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; Cι.₆alkylcarbonyl; Ci-βalkyl; Cι.₆alkyloxycarbonyl; Cι-₆alkyl substituted with formyl, C_.^alkylcarbonyl, Cι_₆alkyloxycarbonyl,

Ci-_όalkylcarbonyloxy; Cι_₆alkyloxyC₁_₆alkylcarbonyl optionally substituted with

Ci-₆alkyloxycarbonyl; X is -ΝR¹-; -ΝH-ΝH-; -N=N-; -O-; -C(=O)-; -C(=S)-; -O-C(=O)-; -C(=O)-O-;

-O-C(=O)-Cι_₆alkyl-; -C(=O)-O-Cι.₆alkyl-; -O-Cι.₆alkyl-C(=O)-; -C(=O)-C₁.₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹-C(-O)-O-; -O-C(=O)-C(=O)-;

-C(=O)-NR¹-, -NR¹-C(=O)-; -C(=S)-NR¹-, -NR¹-C(=S)-; -NR¹-C(=O)-NR¹-;

-NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; -Cι_₆alkyl-C(=O)-NR¹-;

-O-C₁.₆alkyl-C(=O)-NR¹-; -C₁.₆alkyl-O-C(=O)-NR¹-; -Cι.₆alkyl-; -O-d-ealkyl-;

-Ct-ealkyl-O-; -NR^Ci-galkyl-; -C_.-ealkyl-NR¹-; -NR^Ci^alkyl-NR¹-; -NR'-C.-ealkyl-C^cycloalkyl-; -C₂.₆alkenyl-; -C₂.₆alkynyl-; -O-C₂.₆alkenyl-;

-C₂.₆alkenyl-O-; -NR¹-C₂.₆alkenyl-; -C^alkenyl-NR¹-; -NR¹-C₂.₆alkenyl-NR¹-;

-NR¹-C₂-₆alkenyl-C₃.₇cycloalkyl-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-;

-NR^C^alkynyl-; -C^alkynyl-NR¹-; -NR¹-C₂.₆alkynyl-NR¹-;

-NR¹-C₂-₆alkynyl-C₃.₇cycloalkyl-; -O-Cι_₆alkyl-O-; -O-C₂.₆alkenyl-O-; -O-C₂-₆alkynyl-O-; -CHOH-; -S-; -S(=O)-; -S(=O)₂-; -S(=O)-NR¹-; -S(=O)₂-NR¹-;

-NR¹-S(=O)-; -NR¹-S(-O)₂-; -S-Cj.₆alkyl-; -d-ealkyl-S-; -S-C₂.₆alkenyl-;

-C₂.₆alkenyl-S-; -S-C₂_₆alkynyl-; -C₂.₆alkynyl-S-; -O-C₁.₆alkyl-S(=O)₂- or a direct bond; Z is a direct bond, Ci-^alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O- -ealkyl-; -S-; -C(=O)-; -C(=O)-O-; -O-C(= )-; -C(=S)-; -S(=O)-; -S(=O)₂-; -NR¹-; -NR^d.

₆alkyl-; -NR^C^O)-; -O-C(=O)-NR¹-; -NR^O O-; -NR¹-C(=S)-; -S(=O)-NR¹-; -S(=O)₂-NR¹-; -NR^!-S(=O)-; -NR^Sf^O)^; -NR^C^-NR¹-; -NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; R² is hydrogen, Ci-ioalkyl, C₂_₁₀alkenyl, C₂.ιoalkynyl, R²⁰, each of said groups representing R² may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹ -S(=O)-; R¹⁵-S(=O)₂-; R^SR

R^^-d-ealkyl; R⁵R°N-C₃-₇cycloalkyl; R⁵R°N-d-₆alkyloxy; R⁵R°N-C(=O)-;

R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(-S)-NH-; R⁵R°N-S(=O)_n-;

R⁵R⁶N-S(-O)„-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-;

R¹⁵-S(=O)_n-NH-; R¹⁵-O-S(=O)„-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yia-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y.-; H-Y₂-NR¹⁹-Y_r;

R³ is hydrogen; hydroxy; halo; Ci-βalkyl; d-₆alkyl substituted with cyano, hydroxy or

-C(=O)R⁷; C₂.₆alkenyl; C₂.₆alkenyl substituted with one or more halogen atoms or cyano; C₂_₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; d-₆aιkyloxy; Ci.₆alkylthio; d-ealkyloxycarbonyl; d-₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(C₁.₆alkyl)amino; polyhaloCι-₆alkyl; polyhaloCι_₆alkyloxy; polyhalod-ealkylthio; R²¹; R²¹-Cι_₆alkyl; R²¹-O-; R²¹-S-;

R²¹-C(=O)-; R²¹-S(=O)p-; R⁷-S(=O)_p-; R⁷-S(=O)_p-NH-; R²¹-S(=O)_p-NH-;

R⁷-C(-O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-NH-;

-C(=NH)R⁷; -C(=NH)R²¹ ; R 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;

=O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-;

R¹⁵-S(=O)₂-; R⁵R°N; R^d-ealkyl; R⁵R°NC₃.₇cycloalkyl; R⁵R^C_walkyloxy;

R^sR°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-;

R⁵R°N-S(=O)_n-; R⁵R°N-S(=O) „-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-;

R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O)„-NH-; R¹⁵-O-S(=O)„-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Y ; R¹⁵-Y₂-NR¹⁹-Yι-;

H-Y₂-NR¹⁹-Y_!-; R⁵ and R⁶ each independently are hydrogen, R⁸, -Y₁-NR⁹-Y₂-NR¹⁰R¹¹, -Y₁-NR⁹-Yι-R⁸,

-Yi-NR^¹⁰, or R and R 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; R is Cι_₆alkyl, Cι.₆alkyloxy, amino, mono- or di(Cι_₆alkyl)amino or polyhaloCι.₆alkyl; R is d_₆alkyl; 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; Cι-₆alkyl 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 pf 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 Cι.₆alkanediyl 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; R , R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R^ls-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(0)-; R¹⁵-S(=O)₂-; R¹⁵R¹⁶N-S(=O)-;

R¹⁵R¹⁶N-S(=O)₂-; R¹⁷R¹⁸N-Y ; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y ; H-Y₂-NR¹⁹-Yι-; oxo, or any two of R¹², R¹³ and R¹⁴ may together be d-ealkanediyl or C₂.₆alkenediyl 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 -O-(CH₂)_r-O- 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 d_₆alkyl₅ 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; Cι.₆alkyl 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 R ⁷ and R ⁸, or R¹⁵ and R¹⁹ may together be d-βalkanediyl 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

17 151 • 1 (.

R and R together with R may be d-₆alkanediyl 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; R 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;

91

R 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; Y is -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-, -Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y3-O-Y₄-, -Y3-S-Y4-, -Y₃-O-C(=O)-Y₄- or-Y₃-C(=O)-O-Y₄-; Yi or Y₂ each independently are a direct bond, -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-,

-Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y3-O-Y4-, -Y₃-S-Y₄-, -Y₃-O-C(=O)-Y₄- or

-Y₃-C(=O)-O-Y₄-; Y₃ or Y₄ each independently are a direct bond, C₂_₆alkenediyl or

C₂.₆alkynediyl; 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 _₆alkyl and polyhalod-βalkyloxy; provided that -X-R² and/or R³ is other than hydrogen; and provided that when

represents 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 N-oxide when R¹ is hydrogen or methyl, s is 1, R is 3 -chloro or 4-methoxy, and -X-R is hydrogen;

H— N -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 then

-R⁴ is other than pyridyl optionally substituted with methyl, pyridyl N-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

are not included.

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

R¹ is hydrogen; aryl; formyl; d.₆alkylcarbonyl; Ci-βalkyl; d_₆alkyloxycarbonyl; d-βalkyl substituted with formyl, d.₆alkylcarbonyl, Cι_₆alkyloxycarbonyl,

Cι-₆alkylcarbonyloxy; Cι.₆alkyloxyCι_₆alkylcarbonyl optionally substituted with

Cι_₆alkyloxycarbonyl; X is -ΝR¹-; -ΝH-ΝH-; -N=N-; -O-; -C(=O)-; -C(=S)-; -O-C(=O)-; -C(=O)-O-;

-O-C(=O)-Cι_₆alkyl-; -C(O)-0-Cι_₆alkyl-; -O-Cι.₆alkyl-C(-O)-;

-C(=O)-Cι.₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹-C(=O)-O-; -O-C(=O)-C(=O)-;

-C(=O)-NR¹-, -NR¹-C(=O)-; -C(=S)-NR¹-, -NR^!-C(=S)-; -NR¹-C(=O)-NR¹-;

-NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; -Cι.₆alkyl-C(=O)-NR¹-; -O-Cι_₆alkyl-C(=O)-NR¹-; -Cι_₆alkyl-O-C(=O)-NR¹-; -Cι.₆alkyl-; -O-Cι_₆alkyl-;

-Cι.₆alkyl-O-; -NR^d-ealkyl-; -Ci-galkyl-NR¹-; -NR^d-ealkyl-NR¹-; -C₂.₆alkenyl-; -C₂.₆alkynyl-; -O-C₂.₆alkenyl-;

-C₂.₆alkenyl-O-; -NR¹-C₂.₆alkenyl-; -d-ealkenyl-NR¹-; -NR¹-C₂.₆alkenyl-NR¹-;

-NR¹-C₂.₆alkenyl-C₃.₇cycloalkyl-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-; -NR¹-C₂.₆alkynyl-; -C^alkynyl-NR¹-; -NR¹-C₂.₆alkynyl-NR¹-; -NR¹-C₂.₆alkynyl-C₃.₇cycloalkyl-; -O-Cι.₆alkyl-O-; -O-C₂.₆alkenyl-O-; -O-C₂.₆alkynyl-O-; -CHOH-; -S-; -S(=O ; -S(=O)₂-; -SfK^-NR¹-; -S(=O)₂-NR¹-; -NR^!-S(=O)-; -NR¹-S(=O)₂-; -S-d_₆alkyl-; -Cι.₆alkyl-S-; -S-C₂.₆alkenyl-; -C₂.₆alkenyl-S-; -S-C₂_₆alkynyl-; -C₂_₆alkynyl-S-; -O-Cι.₆alkyl-S(=O) - or a direct bond;

Z is a direct bond, Ci_6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Cι.₆alkyl-;

-S-; -C(=O)-; -C(=O)-O-; -O-C(=O)-; -C(=S)-; -S(=O)-; -S(=O)₂-; -NR¹-; -NR¹-C(=O)-; -O-C(=O)-NR¹-; -NR¹C(=O)-O-; -NR¹-C(=S)-;

-S(=O)-NR¹-; -S(=O)₂-NR¹-; -NR¹-S(=O)-; -NR¹-S(=O)₂-; -NR¹-(C=O)-NR¹-; -NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-;

R² is hydrogen, Cι-ιoalkyl, C₂_ι₀alkenyl, C₂_ι₀alkynyl, R²⁰, each of said groups representing R may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°N-C₃.₇cycloalkyl; R⁵R°N-C(=O)-;

R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)_n-;

R⁵R°N-S(=O)„-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-;

R¹⁵-S(=O)_n-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y ; H-Y₂-NR¹⁹-Y ;

R³ is hydrogen; hydroxy; halo; Cι_₆alkyl; Cι_₆alkyl substituted with cyano, hydroxy or

-C(=O)R ; C₂.₆alkenyl; C _₆alkenyl substituted with one or more halogen atoms or cyano; C .₆alkynyl; C₂_₆alkynyl substituted with one or more halogen atoms or cyano; Cι_₆alkyloxy; Cι_₆alkylthio; Cι_₆alkyloxycarbonyl; Cι.₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι_₆alkyl)amino; polyhaloCι_₆alkyl; polyhaloCι_₆alkyloxy; polyhaloCι_₆alkylthio; R²¹; R²¹-Cι.₆alkyl; R²¹-O-; R²¹-S-;

R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-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;

=O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(-O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-;

R¹⁵-S(=O)₂-; R^^; R^^Ci-galkyl; R⁵R°NC₃.₇cycloalkyl; R⁵R^C_walkyloχy;

R⁵R°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R⁶N-C(=S)-NH-; R⁵R°N-S(=O)_n-; R⁵R°N-S(=O) _n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O) „-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Y_la-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y ; H-Y₂-NR¹⁹-Yι-; R⁵ and R⁶ each independently are hydrogen, R⁸, -Yι-NR⁹-Y₂-NR¹⁰R^π, -Yι-NR⁹-Yι-R⁸, -Yι-NR⁹R¹⁰, 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

19 1 being optionally substituted with one or more substituents selected from R , R and R¹⁴; R⁷ is Cι_₆alkyl, Cι_₆alkyloxy, amino, mono- or di(Cι_₆alkyl)amino or polyhaloCι-₆alkyl; R⁸ is Cι.₆alkyl; 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; Cι_₆alkyl 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 R¹¹ may together be Cι_₆alkanediyl 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-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R¹⁵R¹⁶N-S(=O)-;

R¹⁵R¹⁶N-S(0)₂-; R¹⁷R¹⁸N-Y_!-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yι-; H-Y₂-NR¹⁹-Yι-; oxo, or any two of R¹², R¹³ and R¹⁴ may together be Cι.₆alkanediyl or C₂.₆alkenediyl 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 -O-(CH₂)_r-O- 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-βalkyl, 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; Cι_₆alkyl 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 R , R ³ and R¹⁴; R¹⁶, R¹⁷, R¹⁸ and R¹⁹ each independently are hydrogen or R¹⁵, or R¹⁷ and R¹⁸, or R¹⁵ and R¹⁹ may together be Cι.₆alkanediyl 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 R¹ ; or R¹⁷ and R¹⁸ together with R¹⁶ may be Cι_₆alkanediyl 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; Y_la is -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-, -Y₃-C(-O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-,

-Y₃-S-Y₄-, -Y₃-O-C(=O)-Y₄- or-Y₃-C(=O)-O-Y₄-; Yi or Y₂ each independently are a direct bond, -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-,

-Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-, -Y₃-S-Y₄-, -Y₃-O-C(=O)-Y₄- or

-Y₃-C(=O)-O-Y₄-; Y₃ or Y₄ each independently are a direct bond, Cι_₆alkanediyl, C₂.₆alkenediyl or

C₂.₆alkynediyl; 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-βalkyl, C .₇cycloalkyl, Ci-βalkyloxy, cyano, nitro, polyhaloCι_₆alkyl and polyhaloCι.₆alkyloxy; provided that -X-R² and/or R³ is other than hydrogen.

As used herein Cι-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; Cι_₄alkyl 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 Cι_₃alkyl and butyl; Cι_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 and pentyl, hexyl, 2-methylbutyl and the like; Cι_ι₀alkyl 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 Cι-₆alkyl and heptyl, octyl, nonyl, decyl and the like; Cι_₆alkanediyl 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 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_ι₀alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 10 carbon atoms containing a double bond such as the groups defined for C₂.₆alkenyl and heptenyl. octenyl, nonenyl, decenyl and the like; C₂.₆alkenediyl 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; C₂.₆alkynyl 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; C _ι₀alkynyl 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; C₂.₆alkynediyl 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; C₃. 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. π-electrons (rule of Huckel; 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. 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 monocyclic, bicyclic or tricyclic partially saturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydroberιzofuranyl. 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, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, fhienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, 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, phenazinyl, 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 (=O) 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; polyhaloCι-₆alkyl as a group or part of a group is defined as mono- or polyhalosubstituted Cι-₆aιkyl, 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 2H-pyrrolyl.

The hereinabove-mentioned carbocycles may be attached to the remainder of the molecule of formula (I) or (F) through any ring carbon as appropriate, if not otherwise specified. Thus, for example, when the partially saturated bicyclic carbocycle is 1,2,3,4-tetrahydronaphthalenyl, it may be 1,2,3,4-tetrahydronaphthalen-l-yl, l,2,3,4-tetrahydronaphthalen-2-yl and the like.

The hereinabove-mentioned heterocycles may be attached to the remainder of the molecule of formula (I) or (F) 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, R etc.) occurs more than one time in any constituent, each definition is independent.

Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) or (F) 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 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 (F) are able to form. The latter can conveniently be 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, 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.

The compounds of formula (I) or (F) 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 example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine. diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1 ,3 -propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) or (P) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) or (F) are able to form by reaction between a basic nitrogen of a compound of formula (I) or (F) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or 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, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

It will be appreciated that some of the compounds of formula (I) or (F) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I) or (F), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) or (F) and their N-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 either the cis- or trαπs-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 (F) are obviously intended to be embraced within the scope of this invention.

The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.

Some of the compounds of formula (I) or (F) may also exist in their tautomerie form (e.g. keto-enol tautomerie). 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 (I)" or "compounds of formula (I) or (F) is meant to also include their N-oxide forms, their salts, their quaternary amines and their stereochemically isomeric forms. Of special interest are those compounds of formula (I) or (F) which are stereochemically pure.

Particular compounds are those compounds of formula (I) or (F) as defined hereinabove provided that the molecular mass of the compounds is at most 1000 u, in particular at most 800 u, more in particular at most 700 u (u stands for unified atomic mass unit and equals 1.66χl0^"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(=O)-ΝR¹- or -C(=S)-ΝR¹-; and provided that when X is a direct bond and R² is hydrogen than R³ is other than R⁷-C(-O)- with R⁷ representing amino or mono- or di(Cι-₆alkyl)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. Particular interesting compounds are those compounds of formula (I) or (F) as defined hereinabove, their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein ring A is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

R¹ is hydrogen; aryl; formyl; Cι_₆alkylcarbonyl; Cι_₆alkyl; Cι-₆alkyloxycarbonyl;

Cι-₆alkyl substituted with formyl, Cι.₆alkylcarbonyl, Cι.₆alkyloxycarbonyl,

Cι-₆alkylcarbonyloxy; Cι.₆alkyloxyCι_₆alkylcarbonyl optionally substituted with Cι-₆alkyloxycarbonyl;

X is -NR¹-; -NH-NH-; -N=N-; -O-; -C(0)-; -C(=S)-; -O-C(=O)-; -C(=O)-O-;

-O-C(=O)-Cι.₆alkyl-; -C(=O)-O-Cι_₆alkyl-; -O-Cι.₆alkyl-C(=O)-;

-C(=O)-Cι_₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹-C(=O)-O-; -O-C(=O)-C(=O)-;

-CC ^-NR¹-, -NR^C^O)-; -C(=S)- R¹-, -NR^C^S)-; -NR¹-C(=O)-NR¹-; -NR¹-C(=S)-NR¹-; -NR^S^O NR¹-; -NR^S^O^-NR¹-; -d.₆alkyl-C(=O)-NR¹-;

-O-Cι_₆alkyl-C(=O)-NR¹-; -Cι.₆alkyl-O-C(=O)-NR¹-; -Cι.₆alkyl-; -O-Cι.₆alkyl-;

-Cι_₆alkyl-O-;

-NR^d-ealkyl-C^cycloalkyl-; -C₂_₆alkenyl-; -C₂.₆alkynyl-; -O-C₂.₆alkenyl-;

-C₂.₆alkenyl-O-; -NR^C^alkenyl-; -C₂.₆alkenyl-NR¹-; -NR¹-C₂.₆alkenyl-NR¹-; -NR¹-C₂.₆alkenyl-C₃_₇cycloalkyl-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-;

-NR^C^alkynyl-; -d-ealkynyl-NR¹-; -NR^C^alkynyl-NR¹-;

-NR¹-C₂.₆alkynyl-C₃.₇cycloalkyl-; -O-Cι_₆alkyl-O-; -O-C₂.₆alkenyl-O-;

-O-C₂.₆alkynyl-O-; -CHOH-; -S-; -S(=O)-; -S(=O)₂-; -S(=O)-NR¹-; -S(=O)₂-NR¹-;

-NR^!-S(=O)-; -NR¹-S(=O)₂-; -S-d-βalkyl-; -Cι_₆alkyl-S-; -S-C₂.₆alkenyl-; -C₂.₆alkenyl-S-; -S-C₂.₆alkynyl-; -C₂.₆alkynyl-S-; -O-Cι_₆alkyl-S(^:=O) - or a direct bond; Z is a direct bond, Ci_6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Ci-βalkyl-;

-S-; -C(=O)-; -C(=O)-O-; -O-C(=O)-; -C(=S ; -S(=O)-; -S(=O)₂-; -NR¹-; -S(=O)-NR¹-; -S(=O)₂-NR¹-; -NR^J-S(=O)-; -NR¹-S(=O)₂-; -NR¹-(C=O)-NR¹-;

-NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; R² is hydrogen, Cι-ι₀alkyl, C₂.ι₀alkenyl, C₂_ιoalkynyl, R²⁰, each of said groups representing R may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-;

R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R⁶N;

R^-CLgalkyl; R⁵R°N-C₃.₇cycloalkyl; R⁵R⁶N-Cι^alkyloxy; R⁵R°N-C(=O)-;

R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(-O)_n-;

R⁵R°N-S(=O)_n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O)_n-NH-; R¹⁵-O-S(-O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-;

R¹⁷R¹⁸N-Yi_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Y_!-; R¹⁵-Y₂-NR¹⁹-Yι-; H-Y₂-NR¹⁹-Yι-; R³ is hydrogen; hydroxy; halo; Cι_₆alkyl; Cι_₆alkyl substituted with cyano, hydroxy or -C(=O)R⁷; C₂.₆alkenyl; C₂.₆alkenyl substituted with one or more halogen atoms or cyano; C₂.₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; Cι_₆alkyloxy; Cι.₆alkylfhio; Cι.₆alkyloxycarbonyl; Cι.₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι.₆alkyl)amino; polyhaloCι-₆alkyl; polyhaloCι.₆alkyloxy; polyhaloCi _₆alkylthio; R²¹; R²¹-Cι.₆alkyl; R²¹-O-; R²¹-S-; R²¹-C(=O)-; R²¹-S(=O)_p-; R⁷-S(=O)_p-; R⁷-S(=O)_p-NH-; R²¹-S(=O)_p-NH-; R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-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; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-;

R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°NCι.₆alkyl; R⁵R°NC₃.₇cycloalkyl; R⁵R^C_walkyloxy; R⁵R°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)„-; R⁵R°N-S(=O)_n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O) _n-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yι-;

H-Y₂-NR¹⁹-Yι-; R⁵ and R⁶ each independently are hydrogen, R⁸, -Yι-NR⁹-Y₂-NR¹⁰R^π, -Yι-NR⁹-Yι-R⁸,

-Yι-NR⁹R¹⁰; R⁷is Cι_₆alkyl, Cι-₆alkyloxy, amino, mono- or di(Cι.₆alkyl)amino or polyhaloCι.₆alkyl; R⁸ is Cι_₆alkyl; 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; Cι_₆alkyl 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; R¹², R¹³ and R¹⁴ each independently are hydrogen; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O ; R¹⁵-S(=O)₂-; R¹⁵R¹⁶N-S(=O)-; R¹⁵R¹⁶N-S(=O)₂-; R¹⁷R¹⁸N-Yι-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y_r; H-Y₂-NR¹⁹-Y ; oxo;

R¹⁵ is Ci.₆alkyl, 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; Cι-₆alkyl 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;

90

R 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;

91 • •

R 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;

Y is -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-, -Y₃-C(=O)-Y₄-_ -Y₃-C(=S)-Y₄-, -Y3-O-Y.-,

-Y3-S-Y4-, -Y₃-O-C(=O)-Y₄- or-Y₃-C(=O)-O-Y₄-; Yi or Y₂ each independently are a direct bond, -Y₃-S(=^:O)-Y -; -Y₃-S(=O)₂-Y₄-, -Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-₅ -Y₃-S-Y₄-, -Y₃-O-C(=O)-Y₄- or -Y₃-C(=0)-O-Y₄-;

Y₃ or Y₄ each independently are a direct bond, Cι.₆alkanediyl, C₂.₆alkenediyl or C₂.₆alkynediyl; 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, Cι_6alkyl, C₃. cycloalkyl, Ci-6alkyloxy, cyano, nitro, polyhaloCι-₆alkyl and polyhaloCι.₆alkyloxy; provided that -X-R² and/or R³ is other than hydrogen; and provided that when

represents then

-Z is other than a direct bond or NH when R is hydrogen or methyl, s is 2, R is methoxy, and -X-R 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;

-Z-R⁴ is other than 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 then

-R⁴ is other than pyridyl optionally substituted with methyl, pyridyl N-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 are not included.

Further interesting compounds are those compounds of formula (I) or (F) as defined hereinabove, their N-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-Cι_₆alkyl-; Z is a direct bond, -ΝR¹-, -ΝR^Ci^alkyl- or -C(=O)-; R² is hydrogen or R²⁰;

R³ is hydrogen, halo, Cι.₆alkyl, polyhaloCi-_δalkyl 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 R ⁵,

R¹⁵-O-₅ R¹⁵-C(=O)- or halo; R¹⁵ is Cι_₆alkyl; a monocyclic, bicyclic or tricyclic saturated heterocycle ; Cι.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 N-oxide when s is 1, R³ is 3 -chloro, and -X-R² is hydrogen;

-R and -X-R are other than hydrogen when -Z-R is 3 -pyridyl or substituted 4-pyridyl; and provided that when

-R⁴ is other than pyridyl optionally substituted with methyl, pyridyl N-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 (P) as defined hereinabove provided that the compound is other than

wherein

9 9

X is -O-; R is Cι_ι₀alkyl, C₂_ιoalkenyl or C₂.ι₀alkynyl, said groups representing R may optionally be substituted; R^3a is Cι_₆alkyloxy; R³ is hydrogen, halo, optionally substituted Cι_ι₀alkyl, optionally substituted C .ι₀alkenyl, optionally substituted C₂_ι₀alkynyl. hydroxy, amino, mono -or di(Cι_₆alkyl)amino, Cι_₆alkyl-C(=O)-ΝH-,

Cι_₆alkyloxy, polyhaloCι-₆alkyloxy, Cι_₆alkylthio, polyhaloCι.₆alkylthio, aryloxy; R¹ is hydrogen or Cι_₆alkyl and Z-R⁴ is as defined hereinabove;

wherein Z is Cι_₆alkanediyl, C₂_₆alkenediyl, -C(=O)- 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 R may optionally be substituted; R¹ is hydrogen; aryl; Cι_₆alkylcarbonyl; Cι_₆alkyl; Cι_₆alkyloxycarbonyl; Cι.₆alkyl substituted with formyl, Cι.₆alkylcarbonyl, Cι_₆alkyloxycarbonyl,

Cι_₆alkylcarbonyloxy; Cι.₆alkyloxyCι.₆alkylcarbonyl optionally substituted with Cι_₆alkyloxycarbonyl; X is a direct bond or Cι.₆alkyl; R², R³ and s are as defined hereinabove;

wherein

X is a direct bond, -O-, -S-, -C(=O)-NH-, -C(=O)-O-; R² is hydrogen, CF₃, C_Malkyl;

•_>

R is hydrogen, hydroxy, halo, CF₃, C_Malkyl, Cι.₄alkyloxy, Ci^alkylthio, cyano, amino, aminocarbonyl, carboxyl, Cι-₄aιkylcarbonyl; R¹ is hydrogen or C_Malkyl; R⁴, R³ and s are as defined hereinabove;

wherein

R⁴-Z represents indolyl-Cι-ιoalkyl or Z is a direct bond, -Cι_₆alkyl-, -NR¹-, -NH-NH-, -N=N-, -O-, -(C=O)-, -CHOH-, -S-, -S(=O)-, -S(=O)₂-, -O-d-₄alkyl-, -NR^d^alkyl-,

-S-Cι_₄alkyl- and R⁴ is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, said groups representing R⁴may optionally be substituted; R¹ is hydrogen, aryl, Cι-₆alkylcarbonyl.

Cι_₆alkyl, Cι_₆alkyloxycarbonyl; X-R is hydrogen, hydroxy, Cι_₆alkyl, Cι_₆alkyloxy, trihalomethyl, trihalomethyloxy, cyanoCι_₆alkyl; R^3a is halo, Cι-₆aιkyl. cyano, nitro, trihalomethyl, trihalomethyloxy or Cι_₆alkyl substituted with cyano or aminocarbonyl;

R is hydroxy, halo, Cι_₆alkyl, C_halky loxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy; s is 0, 1 or 2;

wherein

R 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, N-oxido-2-pyridyl, N-oxido-3 -pyridyl, N-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 Cι-₃alkyl; X-R², R³ and s are as defined hereinabove; wherein

R⁴ is N-methylpiperazinyl, piperidinyl, imidazolyl, triazolyl, benzimidazolyl, 4-phenyl-piperazin-l-yl wherein phenyl may optionally be substituted with Cι_₃alkyl or Cι_₃alkyloxy or halo or trifluoromethyl, lH-imidazol-l-ylCι-₃alkyl, lH-imidazol-l-ylCi.₃alkyloxy, lH-imidazol-l-ylCι-₃alkylthio, morpholinylCι_₃alkyl, morpholinylCι-₃alkyloxy, morpholinylCι-₃alkylthio; X is a direct bond; R is hydrogen, Ci^alkyl, 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-fhienyl, 5-methyl-2-thienyl, 2-phenothiazinyl. 4-pyrazinyl, 2-benzofuryl, N-oxido-2-pyridyl, N-oxido-3-pyridyl, N-oxido-4-pyridyl, lH-indol-2-yl, 1 H-indol-3-yl,

1 -methyl- 1 H-pyrrol-2-yl, 4-quinolinyl, l-methyl-pyridinium-4-yliodide; R³ is hydrogen, 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-fhienyl, 5-methyl-2-thienyl. 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuryl, N-oxido-2-pyridyl, N-oxido-3 -pyridyl, N-oxido-4-pyridyl, 1 H-indol-2-yl, 1 H-indol-3-yl, 1 -methyl- 1 H-pyrrol-2-yl, 4-quinolinyl, l-methyl-pyridinium-4-yliodide; s is as defined hereinbove;

R⁴ is pyridyl substituted with an optionally substituted monocyclic, bicyclic or tricyclic

9 ^ saturated heterocycle consisting of from 3 to 7 atoms, and X, R , R and s are as defined hereinabove;

wherein R⁴ is 4-pyridyl substituted in position 3; R^3a is hydrogen, halo, Cι_₆alkyloxy or Cι-₆alkyl; R^3b is as defined above for R³; i) wherein R is 4-pyridyl substituted in position 3; R 3a^a i <s hydrogen, halo, Cι-₆alkyloxy or

Cι-₆alkyl; X-R is as defined above;

wherein R^3a is halo, cyano, Cι_₄alkyloxy, Cι.₄alkylthio, C alkyl-S(=O)-, d-₄alkyl-S(=O)₂-₅ C_Malkyl, polyhaloCι_₄alkyl, Cι_₄alkyloxycarbonyl, mono-or di(Cι-₄alkyl)aminocarbonyl, aminocarbonyl, polyhaloC_Malkylthio; R^3b is hydrogen, halo, cyano, nitro, Cι-₄alkyloxy, polyhaloCι_₄alkyl, Cι.₄alkyloxycarbonyl, R^3c is hydrogen, halo or Ci^alkyl; R⁴ is 2-furanyl, 2-thienyl or 3-fhienyl;

herein 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(=O)-O-R^4', -C(=O)-R^4', -S(=O)₂-NR⁴ R^4", NR⁴ R^4", -O-R⁴ or Cι_₆alkyl optionally substituted with fluoro wherein R⁴ and R⁴ each independently represent hydrogen or Cι.₆alkyl optionally substituted with mono- or di(Cι_₆alkyl)amino; 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-fhienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 2-pyrazinyl, 2-benzofuranyl, 2-pyridyl-N-oxide, 3-pyridyl-N-oxide, 4-pyridyl-N-oxide, 1 H-indol-2-yl, 1 H-indol-3-yl,

1-methyl-l H-pyrrol-2-yl, 4-quinolinyl, 4-pyridyl methyl iodide, dimethylaminophenyl; R¹ is hydrogen or Cι.₃alkyl; s is 1 to 3; X, R² and R³ are as defined hereinabove. m) wherein R is 4-pyrazinyl, 1 -methyl- lH-pyrrolyl, pyridyl optionally substituted with Cι-₆alkyl, pyridyl N-oxide optionally substituted with Cι.₆alkyl; X is -O-, -ΝR¹-C(=O)-O-, -NR^C^O)-, -NR¹-C(=S)-, -NR¹-C(=O)-NR¹-, -NR¹-C(=S)-NR¹- or a direct bond; R² is fluoro-substituted Cι_ι₀alkyl, optionally substituted phenyl or naphthyl, optionally substituted phenylCι_₆alkyl, 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, Cι_₆alkyl 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, Cι-₆lkyl 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(=O)-NΗ-; R²¹-C(=O)-NH-; s is as defined hereinabove.

Further preferred compounds are those compounds of formula (I) or (F) wherein one of the following restrictions apply : a) X is a direct bond and R is hydrogen; b) R² and R³ are other than hydrogen; c) R is hydrogen; d) Z is a direct bond.

Also preferred compounds are those compounds of formula (I) or (F) wherein ring A is pyridyl, pyrimidinyl or pyridazinyl, in particular pyrimidinyl or pyridazinyl.

Other preferred compounds are those compounds of formula (I) or (F) wherein ring A is pyridyl, pyrimidinyl or pyridazinyl; in particular pyrimidinyl or pyridazinyl;

R¹ is hydrogen; aryl; formyl; Ci_₆alkylcarbonyl; Cι_₆alkyl; Cι-₆alkyloxycarbonyl; Ci-galkyl substituted with formyl, Cι_₆alkylcarbonyl, Cι.₆alkyloxycarbonyl, Cι-₆alkylcarbonyloxy; Cι_₆alkyloxyCι.₆alkylcarbonyl optionally substituted with Cι-₆alkyloxycarbonyl; X is -NR¹-; -NH-NH-; -N=N-; -O-; -C(=O)-; -C(=S)-; -O-C(=O)-; -C(=O)-O-;

-O-C(=O)-Cι.₆alkyl-; -C(=O)-O-Cι.₆alkyl-; -O-Cι.₆alkyl-C(=O)-;

-C(=O)-Cι.₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹-C(=O)-O-; -O-C(=O)-C(=O)-;

-CCO^NR¹-, -NR^C^O)-; -C(=S)-NR¹-, -NR¹-C(=S)-; -NR¹-C(=O)-NR¹-; -NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; -Cι.₆alkyl-C(=O)-NR¹-;

-O-Cι.₆alkyl-C(=O)-NR¹-; -Cι.₆alkyl-O-C(=O)-NR¹-; -Cι.₆alkyl-; -O-Cι_₆alkyl-;

-Cι_₆alkyl-O-; -Ci-ealkyl-NR¹-;

-NR¹-Cι.₆alkyl-C₃_₇cycloalkyl-; -C₂_₆alkenyl-; -C₂.₆alkynyl-; -O-C₂_₆alkenyl-;

-C₂.₆alkenyl-O-; -NR¹-C₂.₆alkenyl-; -d-ealkenyl-NR¹-; -NR¹-C₂.₆alkenyl-NR¹-; -NR¹-C₂.₆alkenyl-C₃.₇cycloalkyl-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-;

-NR¹-C₂.₆alkynyl-; -d-ealkynyl-NR¹-; -NR¹-C₂.₆alkynyl-NR¹-;

-NR^C^ealkynyl-Cs^cycloalkyl-j -O-Ci-ealkyl-O-j -O-C^alkenyl-O-;

-O-C₂.₆alkynyl-O-; -CHOH-; -S-; -S(=O>; -S(=O)₂-; -S(=O)-NR¹-; -S(-O)₂-NR¹-;

-NR^S^O)-; -NR¹-S(=O)₂-; -S-Cι_₆alkyl-; -d.₆alkyl-S-; -S-C₂.₆alkenyl-; -C₂.₆alkenyl-S-; -S-C₂_₆alkynyl-; -C₂_₆alkynyl-S-; -O-Cι.₆alkyl-S(=O)₂- or a direct bond; Z is a direct bond, Ci-6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Cι_₆alkyl-;

-C(=O)-; -C(=O)-O-; -O-C(=O)-; -C(=S)-; -S(=O)-; -S(=O)₂-; -NR¹-; -NR^C_..

₆alkyl-; -NR¹-C(=O)-; -O-C(=O)-NR¹-; -NR¹C(=O)-O-; -NR^!-C(=S)-; -S(=O)-NR¹-; -S(=O)₂-NR^J-; -NR¹-S(=O)-; -NR¹-S(=O)₂-; -NR¹-(C=O)-NR¹-; -NR¹-C(=S)-NR¹-;

-NR¹-S(=O)-NR¹-; -NR¹-S(-O)₂-NR¹-; R² is hydrogen, Cι.ι₀alkyl, C₂.ιoalkenyl, C₂.ιoalkynyl, R²⁰, each of said groups representing R may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-;

R¹⁵-C(-O)-O-; R¹⁵-0-C(O)-0-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N;

R⁵R°N-Cι.₆alkyl; R⁵R°N-C₃.₇cycloalkyl; R⁵R°N-Cι.₆alkyloxy; R^5aR^6aN-C(=O)-;

R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)_n-;

R⁵R°N-S(=O)_n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O)„-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-;

R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y ; H-Y₂-NR¹⁹-Yι-; R³ is hydrogen; hydroxy; halo; Cι_₆alkyl; Ci-βalkyl substituted with cyano, hydroxy or

-C(=O)R⁷; C₂.₆alkenyl; C₂_₆alkenyl substituted with one or more halogen atoms or cyano; C₂.₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; Cι.₆alkylthio; Cι_₆alkyloxycarbonyl; Cι.₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι_₆alkyl)amino; polyhaloCι.₆alkyl; polyhaloCι_₆alkylthio;

R²¹; R²¹-Cι.₆alkyl; R²¹-O-; R²¹-S-; R²¹-C(=O)-; R²¹-S(=O)_p-; R⁷-S(=O)_p-; R⁷-S(=O)_p-NH-; R²¹-S(=O)_p-NH-; R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-NH-; -C(=NH)R⁷; -C(=NH)R²¹ ; R is tetrahydrofuranyl, dihydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, triazinyl, morpholinyl, dioxolanyl or dioxanyl, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R -O-; SH; R -S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-;

R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°NCι_₆alkyl; R⁵R°NC₃.₇cycloalkyl; R⁵R°NCι.₆alkyloxy;

R⁵R°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(-S)-NH-;

R⁵R°N-S(=O)„-; R⁵R°N-S(=O)„-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-;

R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O) „-NH-; R¹⁵-O-S(=O)„-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Y_ia-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yι-;

-Yι-NR⁹R¹⁰, or R^5a and R^6a each independently are hydrogen, Cι-₆alkyl; C₂_₆alkenyl or C₂.₆alkynyl, each of said groups representing R^5a and R^6a 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 R , 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;

R⁷is Cι_₆alkyl, Cι-₆alkyloxy, amino, mono- or di(Cι_₆alkyl)amino or polyhaloCι.₆alkyl; R⁸ is Cι-₆alkyl; 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; Cι_₆alkyl 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 R¹¹ may together be Cι.₆alkanediyl or C .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-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R¹⁵R¹⁶N-S(=O)-; R¹⁵R¹⁶N-S(=O)₂-; R¹⁷R¹⁸N-Yι-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y_!-; H-Y₂-NR¹⁹-Yι-; oxo, or any two of R¹², R¹³ and R¹⁴ may together be Cι-₆alkanediyl or C₂.₆alkenediyl 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 -O-(CH₂)_r-O- 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 Cι_₆alkyl, 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; Cι_₆alkyl 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-βalkanediyl 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

19 1 may optionally be substituted with one or more substituents selected from R , R and R¹⁴; or

R¹⁷ and R¹⁸ together with R¹⁶ may be Cι_₆alkanediyl 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;

90

91

R 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; Y is -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-, -Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-,

-Y₃-S-Y₄-, -Y₃-O-C(=O)-Y₄- or-Y₃-C(=O)-O-Y₄-; Yi or Y₂ each independently are a direct bond, -Y₃-S(=O)-Y₄-; -Y₃-S(= )₂-Y₄-,

-Y₃-C(=O)-Y₄-₅ -Y₃-C(=S)-Y₄-, -Y -O-Y₄-, -Y₃-S-Y₄-, -Y₃-O-C(=O)-Y₄- or

-Y₃-C(=O)-O-Y₄-; Y₃ or Y each independently are a direct bond, Cι-₆alkanediyl, C₂_₆alkenediyl or

C₂.₆alkynediyl; 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, Cι_6alkyl, C₃.₇cycloalkyl, Cι_6alkyloxy, cyano, nitro, polyhaloCι_₆alkyl and polyhaloCι.₆alkyloxy; 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 (F) wherein ring A is pyridyl, pyrimidinyl or pyridazinyl; in particular pyrimidinyl or pyridazinyl; R¹ is hydrogen; aryl; formyl; Cι_₆alkylcarbonyl; Cι_₆alkyl; Cι-₆alkyloxycarbonyl; Cι_₆alkyl substituted with formyl, Ci-βalkylcarbonyl, Cι_₆alkyloxycarbonyl, Ci.₆alkylcarbonyloxy; Cι-₆alkyloxyCι_₆alkylcarbonyl optionally substituted with Cι_₆alkyloxycarbonyl;

X is -NR¹-; -O-; -C(=O)-; -O-C(=O>; -C(=O)-O-; -O-C(=O)-Cι.₆alkyl-; -C(=O)-O- Cι-₆alkyl-; -O-Cι.₆alkyl-C(=O)-; -C(=O)-d.₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹- C(=O)-O-; -CCO^N ¹-, -NR¹-C(=O)-; -Cι.₆alkyl-; -O-Cι_₆alkyl-; -Cι.₆alkyl-O-; -C₂.₆alkenyl-; -C₂_₆alkynyl-; -O-C₂.₆alkenyl-; -C₂.₆alkenyl-O-; -NR¹-C₂.₆alkenyl-; -C₂.₆alkenyl-NR¹-; -NR¹-C₂. ealkenyl-NR¹-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-; -NR¹-C₂.₆alkynyl-; -C₂.₆alkynyl- NR¹-; -NR¹-C₂.₆alkynyl-NR¹-; -O-Cι_₆alkyl-O-; -O-C₂.₆alkenyl-O-; -O-C₂.₆alkynyl- O-; -CHOH-; -S-; -S(=O)-; -S(=O)₂-; -SC ^-NR¹-; -S(=O)₂-NR¹-; -NR¹-S(=O)-; -NR¹-S(=O)₂-; -S-Cι-₆alkyl-; -d_₆alkyl-S-; -S-C₂.₆alkenyl-; -C₂-₆alkenyl-S-; -S-C₂.₆alkynyl-; -C₂_₆alkynyl-S-; or a direct bond;

Z is a direct bond, Ci_6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Cι_₆alkyl-;

-C(=O)-; -C(=O)-O-; -O-C(=O)-; -S(=O)-; -S(=O)₂-; -NR¹-; -NR^d-ealkyl-; -NR¹-

C(=O)-; -O-C(=O)-NR¹-; -NR¹C(=O)-O-; -S(=O)-NR¹-; -S(=O)₂-NR¹-;

-NR^!-S(=O)-; -NR¹-S(=O)₂-; R² is hydrogen, Cι-ι₀alkyl, C₂_ι₀alkenyl, C₂_ι₀alkynyl, R²⁰, each of said groups representing R² may optionally be substituted where possible with one or more substituents each independently being selected from =O; R ; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-;

R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°N-Cι_₆alkyl; R -d-ealkyloxy; R^5aR^6aN-C(=O)-; R⁵R°N-S(=O)_n-;

R⁵R°N-S(=O) „-NH-; R¹⁵-C(=O)-NH-; R³ is hydrogen; hydroxy; halo; Cι_₆alkyl; Cι.₆alkyl substituted with cyano, hydroxy or

-C(=O)R⁷; C₂.₆alkenyl; C₂_₆alkenyl substituted with one or more halogen atoms or cyano; C₂.₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; Cι.₆alkylthio; Cι_₆alkyloxycarbonyl; Cι.₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι_₆alkyl)amino; polyhaloCι_₆alkyl; polyhaloCι_₆alkylthio;

R²¹; R²¹-Cι.₆alkyl; R²¹-O-; R²¹-S-; R²¹-C(=O)-; R²¹-S(-O)_p-; R⁷-S(=O)_p-; R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂;

R⁷-C(=O)-NH-; R²¹-C(=O)-NH-; -C(=NH)R⁷; -C(=NH)R²¹ ; R⁴ is tefrahydrofuranyl, dihydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, triazinyl, morpholinyl, dioxolanyl or dioxanyl, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =O; R ⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O ; R¹⁵-O-C(=O)-;

R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N; R^-d-ealkyl; R⁵R⁶N-C₁^₅alkyloxy; R^5aR^6aN-C(=O)-; R⁵R°N-S(=O)„-;

R¹⁵-C(=O)-NH-; R⁵ and R each independently are hydrogen or R ; R⁵ and R^6a each independently are hydrogen, Cι-₆alkyl; C₂.₆alkenyl or C₂-₆alkynyl, each of said groups representing R^5a and R ^a may optionally be substituted with one or more substituents selected from R¹², R¹³ and R¹⁴;

R is Cι-₆alkyl, Cι-₆alkyloxy, amino, mono- or di(Cι.₆alkyl)amino or polyhaloCι_₆alkyl; R is Cι_₆alkyl; 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; Cι.₆alkyl 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 R 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-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-;

R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R¹⁵R¹⁶N-S(=O)-;

R¹⁵R¹⁶N-S(=O)₂-; R¹⁵ is Cι-₆alkyl, 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; Cι.₆alkyl 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;

90

91

R 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

91 representing R 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, Cf-βalkyloxy, cyano, nitro, polyhaloCι_₆alkyl and polyhaloCι-₆alkyloxy; provided that -X-R² and/or R³ is other than hydrogen; and provided that R is other than optionally substituted pyridyl when ring A represents pyrimidinyl.

Further preferred are those compounds of formula (I) or (F) wherein the compounds are compounds from one of the following formulae :

1)

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 R substituent is placed at the para position of the NR linker and is other than Cι_₆alkyloxy or polyhaloCι_₆alkyloxy;

(c ) X is other than a direct bond or Cι_₆alkyl;

(d) Z is other than S;

(e) X-R² is other than hydroxy, Cι_₆alkyl, Cι_₆alkyloxy, trihalomethyl, trihalomethyloxy, cyanoCι_₆alkyl, aminocarbonyl; (f) R⁴ is an optionally substituted 5 -membered heterocycle with at least 2 nitrogen atoms;

(g) R² is other than hydrogen, Cι-₆alkyl, C₂.₆alkenyl, C₂.₆alkynyl, and X is other than O,

S, C(=O), S(=O), S(=O)₂, -NH-S(=O)-, -NH-S(=O)₂-, -NH-C(=O)-;

(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 Cι_₆alkyl;

(b) R² is other than hydrogen, trifluoromethyl or Cι-₄alkyl; (c ) X-R² is other than hydroxy, Cι_₆alkyl, Cι.₆alkyloxy, trihalomethyl, trihalomethyloxy, cyanoCi-βalkyl, aminocarbonyl; (d) R⁴ is an optionally substituted 5-membered heterocycle.

Further interesting compounds are those compounds of formula (I), (F), (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 (F) are selected from

N²-(lH-indazol-5-yl)-N⁴-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine; 4- [[4-( 1 -methyl- 1 H-imidazol-2-yl)-2-pyrimidinyl] amino] -2-(phenylmethoxy)- benzonitrile;

4- [[4-( 1 -methyl- 1 H-imidazol-2-yl)-2-pyrimidinyl] amino] -benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof.

Other preferred compounds of formula (I) or (F) are selected from

Ν²-(6-morpholinyl-4-yl-pyridin-3-yl)-Ν⁴-(2,4,6-trimethyl-phenyl)-2,4- pyrimidinediamine;

N²-(3Η-benzimidazol-5-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N²-(lH-indazol-6-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(5-bromo-pyridin-2-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(6-methoxy-pyridin-3-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-benzothiazol-6-yl-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(lH-indazol-5-yl)-N⁴-(2₅4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N²-(lH-benzotriazol-5-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-benzo[l,3]dioxol-5-yl-N⁴-(2₅4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(6-chloro-pyridin-3-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N -(lH-indol-5-yl)-N -(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-quinolin-6-yl-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; 4- [4- [(benzo [1,3] dioxol-5-ylmethyl)-amino] -pyrimidin-2-ylamino] -benzonitrile;

4-[4-[(quinolin-3-methyl)-amino]-pyrimidin-2-ylamino]-benzonitrile;

4- [4- [(furan-2-ylmethyl)-amino] -pyrimidin-2-ylamino] -benzonitrile;

4- [4- [(thiophen-2-ylmethyl)-amino] -pyrimidin-2-y lamino] -benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof. Compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) wherein Wi 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 NN-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 (IN) 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)- 1 , 1 '-binaphthyl, and a suitable base, such as for example sodium tert.butoxide.

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 (Nil) 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 N,N-diisopropylethanamine. Compounds of formula (I) wherein Z is C(=O), said compounds being represented by formula (I-a), may be prepared by reacting an intermediate of formula (NIII), 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.

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.

(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 N-N-diethylethanamine hydrochloric acid salt, and a suitable solvent, such as for example l-methyl-2-pyrrolidinone.

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 (XXI) in the presence of a suitable solvent, such as for example

N,N-dimethylacetamide and a suitable base, such as for example sodium ethanolate.

(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(=O)-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 N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate 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. 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.

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 R³ 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)palladium and a suitable solvent, such as N,N-dimethylacetamide or N,N-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 R is aminocarbonyl, or wherein R 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 wherein R² is substituted with cyano, can also further be converted into a compound of formula (I) wherein R³ is tetrazolyl, or wherein R² is substituted with tetrazolyl, by reaction with sodium azide in the presence of ammonium chloride and N, N -dimethylacetoacetamide.

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.

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 Cι.₆alkylthio, by reaction with a reagent of formula alkaline metal^{4" "}S-Cι_₆alkyl, e.g. Νa^{+ "}S-Cι-₆alkyl, 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 C₁.₆alkyl-S(=O)-, 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, can also be converted into a compound of formula (I) wherein R³ is Cι-₆alkyloxy, or wherein R² is substituted with Cι_₆alkyloxy, by reaction with alcoholate salt, such as, for example, LiOCι.₆alkyl, 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

9 ■ wherein R 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 R is halo, or wherein R 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 R 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, NN-dimethylacetamide, NN-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 R 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-R² is hydrogen and wherein the R³ substituent positioned at the meta position compared to the ΝR¹ 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 N,N-dimethylacetamide or N,N-dimethylformamide optionally in the presence of a suitable base, such as for example N,N-diisopropylethanamine.

Compounds of formula (I) wherein R² is substituted with can be converted into a compound of formula (I) wherein R is substituted with hydroxyCι_₆alkyl, 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.

" 9 9 Compounds of formula (I) wherein R or X-R are Cι.₆alkyloxycarbonyl, or wherein R is substituted with Cι_₆alkyloxycarbonyl, 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(Cι_₆aιkyl)aminocarbonyl, by reaction with a suitable agent such as ammonia, ΝH₂(Cι_₆alkyl), AlCH₃[N(Cι.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; N,N-diisopropylethane.

Compounds of formula (I) wherein R is hydrogen or wherein R 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-l,4-diazoniabicyclo[2,2,2]octane bis[tetrafluoroborate], in the presence of a suitable solvent, such as tetrahydrofuran, water, acetonitrile, chloroform and optionally in the presence of a suitable base such as N,N-diethylethanamine.

Compounds of formula (I) wherein R³ or -X-R² are Cι_₆alkyloxycarbonyl or wherein R² is substituted with Cι.₆alkyloxycarbonyl, 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 LiAlH-_t.

Compounds of formula (I) wherein -X-R² is -O-CH₂-(optionally 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 NN-dimethylacetamide. Compounds of formula (I) wherein -X-R² represents OH, may be converted into a compound of formula (I) wherein -X-R² represents -O-Xι-R²'by reaction with W1-X1- R² wherein Wi represents a suitable leaving group, such as for example a halo atom, e.g. chloro, and wherein -O-Xi 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 N,N-dimethylacetamide.

Compounds of formula (I) wherein R is nitro, or wherein R is substituted with nitro, may be converted into a compound of formula (I) wherein R is ammo or wherein R 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 for example an alcohol, e.g. methanol, ethanol and the like.

Compounds of formula (I) wherein R² is substituted with ΝH₂, can be converted into a compound of formula (I) wherein R² is substituted with NH-S(=O)₂-NR⁵R⁶, by reaction with Wι-S(=O)₂-NR⁵R⁶ wherein Wi 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 N,N-dimethylacetamide and a suitable base, such as for example N,N-diethylethanamine.

Some of the compounds of formula (I) and some of the intermediates in the present in- vention 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 isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, 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 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 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, rreedduuccttiioonn

(XII) (ll-a)

Intermediates of formula (III) can be prepared by reacting an intermediate of formula (XIII) 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 N,N-diisopropylethanamine.

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 (XNI) wherein W₂ is as defined hereinabove.

Intermediates of formula (XVI) can be prepared by reacting an intermediate of formula

(XVII) with a leaving group introducing agent of formula (XVIII) wherein W₂ represents the leaving group and R represents the remaining of the leaving group introducing agent, such as for example POCl₃. R^OH + W₂ R *^{► 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 (III) 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.

Intermediates of formula (VIII) wherein ring A is pyrimidinyl with the NR¹ linker in position 2 and W₄ represents an alcoholate, i.e. Cι_₆alkylO-, said intermediates being represented by formula (VHI-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 exam le N,N-dimethylacetamide.

(XX) P^") (Vlll-a) T ntermediates of formula (XXII) can be prepared by reacting an intermediate of formula (XXIII) with l,l-diethoxy-N,N-dimethyl-methanamine.

(XXIII) (XXII)

Intermediates of formula (XX) can be prepared by reacting an intermediate of formula (V) with cyanarnide in the presence of a suitable solvent, such as for example diglyme.

(V) (XX) Intermediates of formula (XXI) can be prepared by reacting an intermediate of formula imethyl-methanamine.

(XXIV) (XXI)

The compounds of formula (I) or (F) inhibit Glycogen synthase kinase 3 (GSK3), in particular glycogen synthase kinase 3 beta (GSK3β). 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. GSK3α and GSK3β, is a proline-directed serine/threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase. However, it has been demonstrated that GSK3 phosphorylates 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 β-catenin. The above-indicated diversity of proteins which may be phosphorylated by GSK3 implies that GS 3 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.

Insulin 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 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 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 Insulin Receptor Substrate- 1 phosphorylation contributes to insulin resistance. 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 insulin dependent diabetes mellitus and obesity. GSK3 inhibitors may thus provide a novel modality for the treatment of type 1 and type 2 diabetes.

GSK3 inhibitors, in particular GSK3β 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 GSK3β, has been shown to be involved in the initiation of the apoptotic cascade and trophic factor withdrawal stimulates the GSK3β apoptosis pathway.

In view of the above, GSK3β inhibitors might reduce signals of and even prevent levels of neuropathic pain.

Due to their GSK3 inhibitory properties, particularly their GSK3β inhibitory properties, the compounds of formula (I) or (F), 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 GSK3β mediated diseases, 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, Νiemann 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. 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 GSK3β, or they may be useful to prevent warm-blooded ammals to suffer from disease mediated through GSK3, in particular GSK3β. 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 GSK3β. 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 (F), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded ammals, including humans, to suffer from diseases mediated through GSK3, in particular GSK3β, 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 admimstration, preferably oral administration, of an effective amount of a compound of formula (I) or (F), a N-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 GSK3β, comprising a therapeutically effective amount of a compound of formula (I) or (F) and a pharmaceutically acceptable carrier 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 admimstration. 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 admimstration, 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. In 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 the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for admimstration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry 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 (F) 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 (F) 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 (F) 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 (F), 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. When used as a medicament to prevent or treat type 2 diabetes, the compounds of formula (I) or (F) 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 (F) 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 (F), 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 (F) 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 frastzumab; 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 Rl 15777.

Thus, the present invention also relates to the combination of a compound of formula (I) or (F) 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 (F), and (b) another agent capable of preventing or treating cancer, as a combined preparation for simultaneous, separate or sequential use 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 (F) 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 (F) 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 (F), 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 (F) may be used in combination with other conventional drugs used to combat inflammatory diseases such as steroids, cyclooxygenase-2 inhibitors, non- steroidal-anti-inflammatory drugs, TNF- α 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 (F) 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 (F), 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 disorders. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.

Experimental part

Hereinafter, "DIPE" is defined as diisopropyl ether, "DMA" is defined as N,N-dimethylacetamide, "DMF" is defined as N,N-dimethylformarnide.

A. Preparation of the intermediate compounds Example Al

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). N,N-di(l-methylethyl)- ethaneamine (N,N-diisopropylethanamine) (0.0830mol) was added. The reaction mixture was stirred and refluxed for 4 days and the solvent was evaporated. The residue was dissolved in CH C1₂, washed with a saturated ΝaHCO₃ solution, then dried (Na₂SO₄), filtered and the solvent was evaporated to give 17.1 g solid residue. This solid was dissolved in CH₂Cl :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 the solvent was evaporated. The less polar fraction was stirred in CH₂C1₂ for 3 hours and filtered, yielding 0.44 g 4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine. A second fraction was recrystallized from acetonitrile, filtered off and dried, yielding 2-chloro-N-(2,4,6-trimethyl-phenyl)-4-pyrimidinamine (intermediate 1 ).

Example A2 A mixture of 4-[(4-hydroxy-2-pyrimidinyl)amino]-benzonitrile (0.12 mol) in POCl₃ (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% ΝaOH solution. The solid was again separated by filtration, 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 4-[(4-cUoro-2-pyτimidinyl)amino]-benzonitrile (intermediate 2). Example A3 a) The preparation of intermediate 3

A mixture of 4-amino-2-(2-phenylethoxy)benzonitrile (0.012 mol) in l,l'-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 (6.3g) was purified by high-performance liquid chromatography over Hyperprep C18 HS BDS (eluent : (0.5% NH₄Ac in H₂O/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,l'-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 CH₂C1₂ and crystallized. The precipitate was filtered off and dried, yielding 12.5 g of intermediate 4 (90%) 9mp. 132°C).

Example A4 a) The preparation of intermediate 5

l,l-Diethoxy-N,N-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 hours. The residue was purified by distillation, yielding 9.8 g (37.4%) of intermediate 5.

Example A5

The preparation of intermediate 6

To a solution of intermediate 3 (0.00477 mol) in DMA (30 ml), intermediate 5 (0.0057 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 EtOH, filtered and dried at 40°C under vacuum, yielding 0.64 g (35.8%) of intermediate 6.

Example A6 a) The preparation of intermediate 7

l-(l-Methyl-lH-imidazol-2-yl)ethanone (0.0028 mol) in l,l-diefhoxy-N,N- dimethylmethanamine (10 ml) was stirred and refluxed for 12 hours; then allowed to cool to room temperature. The precipitate was filtered off and dried (50°C, vacuum), yielding 0.42 g (82.3%) of intermediate 7.

b) The preparation of intermediate 8

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. B. Preparation of the final compounds Example BI The preparation of compound 1

A suspension of 6-bromo-2,3'-bipyridine (0.00042 mol), tris (dibenzylidene aceton)dipalladium (0) (0.0085 mmol), 2,2-bis(diphenylphosphino)-l,l'-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 lH-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% NΗ₄OAC in H₂O/CH₃CN 90/10)/CH3OH/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 NN-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. Example B3 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 (MgSO₄), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent : CH₂Cl₂/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.

Example B4 d) The preparation of compound 5

A mixture of 6-chloro-N-(2,3-dichlorophenyl)-3-pyridazinamine (0.00037 mol) and palladium tetrakis(triphenylphosphine) (0.000018 mol) in acetonitrile (10 ml) was stirred (and degassed) under Ν₂ atmosphere and heated to 90 °C. A solution of 3-pyridinylboronic acid (2 equiv, 0.00074 mol) in 0.4 M Na₂CO₃ 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 CH₂C1 (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). 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 C18 (0.5% NH₄OAc in H₂O/CH₃CN 90/10)/CH₃CN 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 (40°C, vacuum), yielding 1.34g (35%) of compound 6.

b) The preparation of compound 37

A mixture of guanidine, [3-(trifluoromethyl)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

(compound 8) (0.013 mol) (prepared according to Example B5)

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. Tables 1 to 4 list the compounds of formula (I) which were prepared according to one of the above examples.

Table 1:

Table 2:

Table3:

*db = direct bond

C. Pharmacological Example

The pharmacological activity of the present compounds was examined using the following test.

GSK3beta assays were performed at 25 °C in a 100 μl reaction volume of 25mM Tris (pH 7.4) containing 10 mM MgCl_2; 1 mM DTT, 0.1 mg/ml BSA, 5% glycerol and containing 19 nM GSK3β, 5 μM biotinylated phosphorylated CREB peptide , 1 μM 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 μl 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 compared with the results obtained in a control experiment (without the presence of a test compound) in order to determine the percentage of GSK3β inhibition. The IC₅₀ value, i.e. the concentration (M) of the test compound at which 50 % of GSK3β is inhibited, was calculated from the dose response curve obtained by performing the above-described GSK3β assay in the presence of different amounts of the test compound.

Table 5 lists pIC₅₀ values (-log IC₅₀ (M)) obtained in the above-described test for the present compounds.

Table 5

Claims

1. A compound of formula

a N-oxide, a pharmaceutically 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; Cι_₆alkylcarbonyl; Cι.₆alkyl; Cι_₆alkyloxy carbonyl; Cι_₆alkyl substituted with formyl, Cι-₆alkylcarbonyl, Cι_₆alkyloxycarbonyl, Cι_₆alkylcarbonyloxy; Ci.₆alkyloxyCi_₆alkylcarbonyl optionally substituted with Cι-₆alkyloxycarbonyl;

X is -ΝR¹-; -ΝH-ΝH-; -N=N-; -O-; -C(=O)-; -C(=S)-; -O-C(=O)-; -C(=O)-O-; -O-C(=O)-Cι.₆alkyl-; -C(=O)-O-Cι.₆alkyl-; -O-Cι_₆alkyl-C(=O)-; -C(=O)-d.₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹-C(=O)-O-; -O-C(=O)-C(=O)-; -C(=O)-NR¹-, -NR^J-C(=O)-; -C(=S)-NR¹-, -NR^!-C(=S)-; -NR¹-C(=O)-NR¹-; -NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; -Cι.₆alkyl-C(=O)-NR¹-; -O-Cι_₆alkyl-; -Cι.₆alkyl-O-; -C₂.₆alkenyl-; -C₂.₆alkynyl-; -O-C₂_₆alkenyl-; -C₂.₆alkenyl-O-; -NR^d-ealkenyl-; -C₂.₆alkenyl-NR¹-; -NR¹-C₂.₆alkenyl-NR¹-; -NR¹-C _₆alkenyl-C₃.₇cycloalkyl-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-;

-NR'-C^alkynyl-; -C₂.₆alkynyl-NR¹-; -NR¹-C₂.₆alkynyl-NR¹-; -NR¹-C₂.₆alkynyl-C₃-₇cycloalkyl-; -O-Cι_₆alkyl-O-; -O-C₂.₆alkenyl-O-; -O-C₂.₆alkynyl-O-; -CHOH-; -S-; -S(=O)-; -S(=O)₂-; -S(=O)-NR^J-; -S(=O)₂-NR¹-; -NR^Sf^O)-; -NR¹-S(=O)₂-; -S-Cι.₆alkyl-; -d.₆alkyl-S-; -S-C₂.₆alkenyl-; -C .6alkenyl-S-; -S-C₂.₆alkynyl-; -C₂.₆alkynyl-S-; -O-Cι-₆alkyl-S(=O)₂- or a direct bond; Z is a direct bond, Cl_6alkanediyl, C2-6alkenediyl, C2-6^alkynediyl; -O-;

-O-Cι.₆alkyl-; -S-; -C(=O)-; -C(=O)-O-; -O-C(=O)-; -C(=S)-; -S(=O)-; -S(=O)₂-; -NR¹-; -O-C(=O)-NR¹-; -NR¹C(=O)-O-; -NR¹-C(=S)-; -S(=O)-NR¹-; -S(=O)₂-NR¹-; -NR^S^O)-; -NR¹-S(=O)₂-;

-NR^C^-NR¹-; -NR¹-C(=S)-NR¹-; -NR^SH^-NR¹-; -NR^S^O^-NR¹-; R² is hydrogen, Ci.ioalkyl, C₂.ι₀alkenyl, C₂.ι₀alkynyl, R²⁰, each of said groups representing R² may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O ; R¹⁵-C(=O)-0-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°N-Cι.₆alkyl; R⁵R⁶N-C₃.₇cycloalkyl; R⁵R°N-Cι.₆alkyloxy; R⁵R°N-C(=O ; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)_n-; R⁵R°N-S(=O) _n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-;

R¹⁵-S(=O)_n-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y_!-; H-Y₂-NR¹⁹-Y_.-;

•_>

R is hydrogen; hydroxy; halo; Cι_₆alkyl; Cι_₆alkyl substituted with cyano, hydroxy or

-C(=O)R⁷; C₂.₆alkenyl; C _₆alkenyl substituted with one or more halogen atoms or cyano; C₂_₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; Cι_₆alkyloxy; Cι_₆alkylthio; Cι.₆alkyloxycarbonyl; Cι_₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι_₆alkyl)amino; polyhaloCι_₆alkyl; polyhaloCι_₆alkyloxy; polyhaloCι_₆alkylthio; R²¹; R²¹-Cι.₆alkyl; R²¹-O-; R²¹-S-;

R²¹-C(0)-; R²¹-S(=O)_p-; R⁷-S(=O)_p-; R⁷-S(=O)_p-NH-; R²¹-S(=O)_p-NH-; R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-NH-;

=O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl;

R¹⁵-C(=O ; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-;

R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°NCι.₆alkyl; R⁵R°NC₃.₇cycloalkyl; R⁵R°NCι.₆alkyloxy;

R⁵R°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)_n-; R⁵R°N-S(=O) „-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-;

R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O) _n-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-;

R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yι-;

H-Y₂-NR¹⁹-Yι-; R⁵ and R⁶ each independently are hydrogen, R⁸, -Yι-NR⁹-Y₂-NR¹⁰R^π, -Yι-NR⁹-Y R⁸, -Yι-NR⁹R¹⁰, or

R and R 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 Cι_₆alkyl, Cι.₆alkyloxy, amino, mono- or di(Cι_ alkyl)amino or polyhaloCι_₆alkyl; R⁸ is Cι_₆alkyl; 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; Cι_₆alkyl 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 R¹¹ may together be Cι-₆alkanediyl 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-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R¹⁵R¹⁶N-S(=O)-; R¹⁵R¹⁶N-S(=O)₂-; R¹⁷R¹⁸N-Y ; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y ; H-Y₂-NR¹⁹-Y ; oxo, or any two of R¹², R¹³ and R¹⁴ may together be Cι_₆alkanediyl or C₂.₆alkenediyl 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 -O-(CH₂)_r-O- 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 Cι_₆alkyl, 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; Cι_₆alkyl 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 R ⁵ 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 Cι-₆alkanediyl 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, R ³ and R¹⁴; or R¹⁷ and R¹⁸ together with R¹⁶ may be Ci-₆alkanediyl 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;

90 R 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; 1 R 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; Yι_a is -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y₄-, -Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-,

-Y3-S-Y4-, -Y₃-O-C(=O)-Y₄- or-Y₃-C(=O)-O-Y₄-; Yi or Y₂ each independently are a direct bond, -Y₃-S(=O)-Y -; -Y₃-S(=O)₂-Y -, -Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-, -Y₃-S-Y₄-_. -Y₃-0-C(=O)-Y₄- or

C₂.₆alkynediyl; 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, Cι_6alkyl, C₃_ cycloalkyl, Ci-βalkyloxy, cyano, nitro, polyhaloCi .₆alkyl and polyhaloCι_₆alkyloxy;

9 ' provided that -X-R and/or R is other than hydrogen; and provided that when

represents then

1 '

-Z is other than a direct bond or NH when R is hydrogen or methyl, s is 2, R is methoxy, and -X-R 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, R is 3 -chloro or 4-methoxy, and -X-R is hydrogen;

-Z-R⁴ is other than when R¹ is hydrogen;

represents then

are not included.

2. A compound as claimed in claim 1 wherein ring A is pyridyl, pyrimidinyl or pyridazinyl.

3. A compound as claimed in claim 2 wherein

-C(=O)-; -C(=O)-O-; -O-C(=O)-; -C(=S)-; -S(=O)-;

₆alkyl-; -NR^C^O)-; -O-C(=O)-NR¹-; -NR¹C(=O)-O-; -NR¹-C(=S)-; -S(=O)-NR¹-; -S(=O)₂-NR¹-; -NR¹-S(=O)-; -NR¹-S(=O)₂-; -NR^CO^NR¹-; -NR¹-C(=S)-NR¹-;

-NR¹-S(=O)-NR¹-; -NR¹-S(=O)₂-NR¹-; R² is hydrogen, d-ioalkyl, C₂_₁₀alkenyl, C₂-ιoalkynyl, R²⁰, each of said groups representing R² may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-;

R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N;

R⁵R°N-Cι-₆alkyl; R⁵R°N-C₃.₇cycloalkyl; R⁵R°N-Cι.₆alkyloxy; R^5aR^6aN-C(=O)-;

R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)„-;

R⁵R°N-S(=O) _n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-; R¹⁵-S(=0)_n-NH-; R¹⁵-O-S(=O)„-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-;

R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yι-; H-Y₂-NR¹⁹-Yι-; R³ is hydrogen; hydroxy; halo; Cι_₆alkyl; Cι.₆alkyl substituted with cyano, hydroxy or

-C(=O)R⁷; C₂.₆alkenyl; C₂_₆alkenyl substituted with one or more halogen atoms or cyano; C₂.₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; Cι_₆alkylthio; Cι_₆alkyloxycarbonyl; Cι_₆alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι_₆alkyl)amino; polyhaloCι-₆alkyl; polyhaloCι_₆alkylthio;

R²¹; R²¹-Cι_₆alkyl; R²¹-O-; R²¹-S-; R²¹-C(=O)-; R²¹-S(=O)_p-; R⁷-S(=O)_p-; R⁷-S(=O)_p-NH-; R²¹-S(=O)_p-NH-;

R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-NH-;

-C(=NH)R⁷; -C(-NH)R²¹ ; R⁴ is tetrahydrofuranyl, dihydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, pyrimidinyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, triazinyl, morpholinyl, dioxolanyl or dioxanyl, each of said heterocycles optionally being substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O>; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-;

R¹⁵-S(-O)₂-; R⁵R°N; R⁵R°NCι.₆alkyl; R⁵R°NCι-₆alkyloxy;

R⁵R°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-;

R⁵R°N-S(=O)„-; R⁵R°N-S(=O)„-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-;

R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O) _n-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Y ;

H-Y₂-NR¹⁹-Yι-; R^5a and R^6a each independently are hydrogen, Cι.₆alkyl; C₂.₆alkenyl or C .₆alkynyl, each of said groups representing R^5a and R^6a may optionally be substituted with one or more substituents selected from R¹², R¹³ and R¹⁴; provided that R⁴ is other than optionally substituted pyridyl when ring A represents pyrimidinyl.

4. A compound as claimed in any one of claims 1 to 3 wherein the compound has the following formula

5. A compound as claimed in any one of claims 1 to 3 wherein the compound has the following formula

6. A compound as claimed in any one of claims 1 to 5 wherein R⁴ is a 5-membered aromatic heterocycle optionally being substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-;

R⁵R°NCι.₆alkyl; R⁵R^C₃-₇cycloalkyl; R⁵R°NCι.₆alkyloxy; R⁵R°N-C(=O)-;

R⁵R°N-C(-S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)„-; R⁵R°N-S(=O) _n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-;

R¹⁵-S(=O)„-NH-; R¹⁵-O-S(=O)„-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-;

R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yι-; H-Y₂-NR¹⁹-Y .

7. A compound as claimed in claim 6 wherein Z is a direct bond.

8. A compound as claimed in claim 1 wherein the compound is

9 A

N -(lH-indazol-5-yl)-N -(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine; 4-[[4-(l-methyl-lH-imidazol-2-yl)-2-pyrimidinyl]amino]-2-(phenylmethoxy)- benzonitrile; 4- [[4-( 1 -methyl- 1 H-imidazol-2-yl)-2-pyrimidinyl] amino] -benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof.

9. A compound as claimed in claim 1 wherein the compound is Ν²-(6-morpholinyl-4-yl-pyridin-3-yl)-Ν⁴-(2,4,6-trimethyl-phenyl)-2,4- pyrimidinediamine;

N²-(3Η-benzimidazol-5-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(lH-indazol-6-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(5-bromo-pyridin-2-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N²-(6-methoxy-pyridin-3-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-benzotMazol-6-yl-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-(lH-indazol-5-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N²-(lH-benzotriazol-5-yl)-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

N²-benzo[l,3]dioxol-5-yl-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

9 A

N -(lH-indol-5-yl)-N -(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine; N²-quinolin-6-yl-N⁴-(2,4,6-trimethyl-phenyl)-2,4-pyrimidinediamine;

4- [4- [(benzo [ 1 ,3] dioxol-5 -ylmethyl)-amino] -pyrimidin-2-ylamino] -benzonitrile;

4- [4- [(quinolin-3 -methyl)-amino] -pyrimidin-2-ylamino] -benzonitrile;

4- [4- [(furan-2-ylmethyl)-amino] -pyrimidin-2-ylamino] -benzonitrile;

4- [4- [(thiophen-2-ylmethyl)-amino] -pyrimidin-2-ylamino] -benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof.

10. A compound as claimed in any one of claims 1 to 9 for use as a medicine.

11. 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 of formula of formula (F)

R¹ is hydrogen; aryl; formyl; Cι_₆alkylcarbonyl; Cι.₆alkyl; Cι-₆alkyloxycarbonyl;

Cι_₆alkyl substituted with formyl, Cι_₆alkylcarbonyl, d-₆alkyloxycarbonyl,

Cι-₆alkylcarbonyloxy; Cι.₆alkyloxyCι_₆alkylcarbonyl optionally substituted with Cι_₆alkyloxycarbonyl;

X is -ΝR¹-; -ΝH-ΝH-; -N=N-; -O-; -C(=O)-; -C(=S)-; -O-C(=O)-; -C(=O)-O-;

-O-C(=O)-Cι_₆alkyl-; -C(=O)-O-Cι-₆alkyl-; -O-Cι.₆alkyl-C(=O)-;

-C(=O)-Cι_₆alkyl-O-; -O-C(=O)-NR¹-; -NR¹-C(=O)-O-; -O-C(=O)-C(=O)-;

-C(=O)-NR¹-, -NR^C^O)-; -C(=S)-NR¹-, -NR^C^S)-; -NR¹-C(=O)-NR¹-; -NR¹-C(=S)-NR¹-; -NR¹-S(=O)-NR¹-; -NR¹-S(-O)₂-NR¹-; -Cι.₆alkyl-C(-O)-NR¹-;

-O-Cι.₆alkyl-C(=O)-NR¹-; -Cι.₆alkyl-O-C(=O)-NR¹-; -Cι.₆alkyl-; -O-Cι.₆alkyl-;

-Cι-₆alkyl-O-; -d-ealkyl-NR¹-; -C₂_₆alkenyl-; -C₂.₆alkynyl-; -O-C₂_₆alkenyl-;

-C₂.₆alkenyl-O-; -NR¹-C₂.₆alkenyl-; -C₂.₆alkenyl-NR¹-; -NR^d-ealkenyl-NR¹-; -NR¹-C₂.₆alkenyl-C₃_₇cycloalkyl-; -O-C₂.₆alkynyl-; -C₂.₆alkynyl-O-; -NR¹-C₂.₆alkynyl-; -d-ealkynyl-NR¹-; -NR¹-C₂.₆alkynyl-C₃.₇cycloalkyl-; -O-Cι.₆alkyl-O-; -O-C₂.₆alkenyl-O-; -O-C₂-₆alkynyl-O-; -CHOH-; -S-; -S(=O)-; -S(=O)₂-; -S(=O)-NR¹-; -S^O^-NR¹-; -NR'-Sf^O)-; -NR^S^O):_.-; -S-Cι.₆alkyl-; -Cι.₆alkyl-S-; -S-C₂.₆alkenyl-;

-C₂-6alkenyl-S-; -S-C₂.₆alkynyl-; -C₂_₆alkynyl-S-; -O-Cι.₆alkyl-S(=O)₂- or a direct bond; Z is a direct bond, Ci-6alkanediyl, C2-6alkenediyl, C2-6alkynediyl; -O-; -O-Cι_₆alkyl-;

-S-; -C(=O)-; -C(=O)-O-; -O-C(=O)-; -C(=S)-; -S(=O)-; -S(=O)₂-; -NR¹-; -NR^Ci-ealkyl-; -NR¹-C(=O)-; -O-C(=O)-NR¹-; -NR^t Tj-O-; -NR^Cf^S)-;

-S(=O)-NR¹-; -S(=O)₂-NR¹-; -NR¹-S(=O)-; -NR¹-S(=O)₂-; -NR¹-(C=O)-NR¹-;

-NR¹-C(=S)-NR¹-; - R^SH^-NR¹-; -NR¹-S(=O)₂-NR¹-; R² is hydrogen, Ci-ioalkyl, C₂-ι₀alkenyl, C₂-ι₀alkynyl, R²⁰, each of said groups representing R may optionally be substituted where possible with one or more substituents each independently being selected from =S; =O; R¹⁵; hydroxy; halo; nitro; cyano; R¹⁵-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-;

R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(0)₂-; R N;

R⁵R°N-Cι-₆alkyl; R⁵R⁶N-C₃_₇cycloalkyl; R⁵R°N-Cι-₆alkyloxy; R⁵R°N-C(=O)-;

R⁵R°N-C(=S)-; R^sR°N-C(=O)-NH-; R⁵R⁶N-C(=S)-NH-; R⁵R°N-S(=O)„-; R⁵R°N-S(=O) _n-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-;

R¹⁵-S(=O)_n-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-;

R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yj-; H-Y₂-NR¹⁹-Y ; R³ is hydrogen; hydroxy; halo; Cι-₆alkyl; Cι_₆alkyl substituted with cyano, hydroxy or

-C(=O)R⁷; C₂_₆alkenyl; C₂-₆alkenyl substituted with one or more halogen atoms or cyano; C₂.₆alkynyl; C₂.₆alkynyl substituted with one or more halogen atoms or cyano; Cι. alkyloxy; Ci-βalkylthio; Cι_₆alkyloxycarbonyl; Ci-βalkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(Cι-₆alkyl)amino; polyhaloCi-_δalkyl; polyhaloCι-₆alkyloxy; polyhalod-ealkylfhio; R²¹; R²¹-C_walkyl; R²¹-O-; R²¹-S-;

R²¹-C(=O)-; R²¹-S( ))_P-; R⁷-S(=O)_p-; R⁷-S(=O)_p-NH-; R²¹-S(=O)_p-NH-; R⁷-C(=O)-; -NHC(=O)H; -C(=O)NHNH₂; R⁷-C(=O)-NH-; R²¹-C(=O)-NH-;

R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵-S(=O)₂-; R⁵R°N; R⁵R°NC₃-₇cycloalkyl; R⁵R°NCι.₆alkyloxy; R⁵R°N-C(=O)-; R⁵R°N-C(=S)-; R⁵R°N-C(=O)-NH-; R⁵R°N-C(=S)-NH-; R⁵R°N-S(=O)_n-; R⁵R⁶N-S(=O)„-NH-; R¹⁵-C(=S)-; R¹⁵-C(=O)-NH-; R¹⁵-O-C(=O)-NH-; R¹⁵-S(=O) „-NH-; R¹⁵-O-S(=O)_n-NH-; R¹⁵-C(=S)-NH-; R¹⁵-O-C(=S)-NH-; R¹⁷R¹⁸N-Yι_a-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Y_!-; R¹⁵-Y₂-NR¹⁹-Yι-;

R^D and R° each independently are hydrogen, R^s, -Yι-NR^y-Y₂-NR l^ιO^υRrj ll , -Y NR -Yi-R⁸,

-Yι-NR⁹R¹⁰, or R⁵ and R 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;

R⁷is Cι.₆alkyl, Cι_₆alkyloxy, amino, mono- or di(Cι.₆alkyl)amino or polyhaloCι_₆alkyl; R⁸ is Cι_₆alkyl; 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; Cι_₆alkyl 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 R¹¹ may together be Cι_₆alkanediyl 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-O-; SH; R¹⁵-S-; formyl; carboxyl; R¹⁵-C(=O)-; R¹⁵-O-C(=O)-; R¹⁵-C(=O)-O-; R¹⁵-O-C(=O)-O-; -SO₃H; R¹⁵-S(=O)-; R¹⁵~S(=O)₂-; R¹⁵R¹⁶N-S(=O)-; R¹⁵R¹⁶N-S(=O)₂-; R¹⁷R¹⁸N-Yι-; R¹⁷R¹⁸N-Y₂-NR¹⁶-Yι-; R¹⁵-Y₂-NR¹⁹-Yi-; H-Y₂-NR¹⁹-Yι-; oxo, or any two of R¹², R¹³ and R¹⁴ may together be Cι_₆alkanediyl or C₂.₆alkenediyl 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 -O-(CH₂)_r-O- 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 Cι.₆alkyl, 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; Cι-₆alkyl 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 Cι-₆alkanediyl 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 Cι.₆alkanediyl 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;

91

• 91 • • representing R may optionally be substituted with one or more substituents selected from R¹², R¹³ and R¹⁴; Yi_a is -Y₃-S(X))-Y₄-; -Y₃-S(=O)₂-Y₄-, -Y₃-C(=O)-Y₄-, -Y₃-C(=S)-Y₄-, -Y₃-O-Y₄-, Yi or Y₂ each independently are a direct bond, -Y₃-S(=O)-Y₄-; -Y₃-S(=O)₂-Y -,

-Y₃-C(=O)-O-Y₄-; Y₃ or Y₄ each independently are a direct bond, Cι_₆alkanediyl, C₂_₆alkenediyl or

C₂.₆alkynediyl; 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, Cl-6alkyloxy, cyano, nitro, polyhaloCι.₆alkyl and polyhaloCi-_δalkyloxy;

9 provided that -X-R and/or R is other than hydrogen.

12. The use of a compound as defined in any one of claims 1 to 9 for the manufacture of a medicament for the prevention or the treatment of diseases mediated through GSK3.

13. The use of a compound as defined in any one of claims 1 to 9 or 12 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.

14. The use of a compound as claimed in claim 13 for the prevention or the treatment of Alzheimer's disease, diabetes, cancer, inflammatory diseases or bipolar disorder.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 9.

16. A process for preparing a pharmaceutical composition as claimed in claim 15 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1 to 9 is intimately mixed with a pharmaceutically acceptable carrier.

17. 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

with Wi representing a suitable leaving group, and s, Z, R¹, R², R³, R⁴, X and ring A as defined in claim 1; b) by reacting an intermediate of formula (II) with an intermediate of formula (III) in the presence of a suitable solvent, a suitable catalyst, a suitable ligand and a suitable base

with Wi representing a suitable leaving group, and s, Z, R¹, R², R³, R⁴, X and ring A as defined in claim 1 ; c) reacting an intermediate of formula (IV) with an intermediate of formula (V) in the able base,

with W₂ representing a suitable leaving group, and s, Z, R¹, R², R³, R⁴, X and ring A 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

with W₃ representing a suitable leaving group, and s, Z, R¹, R , R³, R , X and ring A as defined in claim 1 ; e) reacting an intermediate of formula (VIII) with an intermediate of formula (IX) in

with W₄ representing a suitable leaving group, and s, R¹, R², R³, R⁴, X and ring A as defined in claim 1 ; f) reacting an intermediate of formula (VI) with an intermediate of formula (X) in the presence of a suitable catalyst, a suitable base and a suitable solvent

(l-b) with W₃ representing a suitable leaving group, and s, R¹, R², R³, R⁴, X and ring A as defined in claim 1 ; g) reacting an intermediate of formula (XI) with sodium azide in the presence of a suitable salt and a suitable solvent

with s, R¹, R², R³, X and ring A as defined in claim 1 ; h) reacting an intermediate of formula (XX) with an intermediate of formula (XXI) in the presence of a suitable solvent and a suitable base

(XX) ⁽x ^{i) (}i-^d) with s, R¹, R², R³, R⁴ and X as defined in claim 1 ;

and, if desired, converting compounds of formula (I) into each other following art- known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment 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; and, if desired, preparing stereochemically isomeric forms, quaternary amines or N-oxide forms thereof.