Inhibitors of cyclin dependent kinases as anti-cancer agent

Abstract

The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia, psoriasis and the like.

1 . A compound of general formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       one of X 1  and X 2  is NR′O and the other of X 1  and X 2  is CR 9 ;  
       Z is NH, NHCO, NHSO 2 , NHCH 2 , CH 2 , CH 2 CH 2 , or CH═CH;  
       R 1 , R 2 , R 3  R 9  and R 10  are independently H, alkyl, aryl, aralkyl, heterocycle, halogeno, NO 2 , CN, OH, alkoxy, aryloxy, (R′″)nNH 2 , (R′″)nNH—R′, (R′″)nN—(R′)(R″), NH-aryl, N-(aryl) 2 , COOH, COO—R′, COO-aryl, CONH 2 , CONH—R′, CON—(R′)(R″), CONH-aryl, CON-(aryl) 2 , SO 3 H, SO 2 NH 2 , CF 3 , CO—R′, or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups may be further substituted with one or more groups selected from halogeno, NO 2 , CN, OH, O-methyl, NH 2 , COOH, CONH 2  and CF 3 ;  
       R 4 , R 5 , R 6 , R 7 , and R 8  are independently from each other H, substituted or unsubstituted lower alkyl, halogeno, NO 2 , CN, OH, substituted or unsubstituted alkoxy, NH 2 , NH—R′, N—(R′)(R″), COOH, COO—R′, CONH 2 , CONH—R′, CON—(R′)(R″), SO 3 H, SO 2 NH 2 , or CF 3 ;  
       wherein R 1  R″ and R′″ are each independently alkyl groups that may be the same or  
       different and n is 0 or 1;  
       with the proviso that when R 1  and R 2  are H, X 1  is NH, X 2  is CH, and R 3  is H, the phenyl group is not 
 unsubstituted,  
 4-ethyl,  
 3-methyl,  
 3-(1,1,2,2-tetrafluoroethoxy),  
 3,4,5-trimethoxy,  
 
       when the other groups R 4 -R 8  are H;  
       and pharmaceutically acceptable salts thereof.  
     
   
   
       2 . A compound according to  claim 1 , wherein; 
 X 1  and X 2  are CR 9  and NH respectively;    R 1 , R 2 , R 3  and R 9  are each independently selected from H, alkyl, aryl, aralkyl, heterocycle, halogeno, NO 2 , CN, OH, alkoxy, aryloxy, (R′″)nNH 2 , (R′″)nNH—R′, (R′″)nN—(R′)(R″), COOH, COO—R′, CONH 2 , CONH—R′, CON—(R′)(R″), SO 3 H, SO 2 NH 2 , CF 3 , and CO—R 1  wherein alkyl, aryl and aralkyl groups may be further substituted with one or more groups selected from halogeno, NO 2 , CN, OH, O-methyl, NH 2 , COOH, CONH 2  and CF 3 ;    Z is selected from NH, NHSO 2  and NHCH 2 ;    R 4 -R 8  are each independently selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N(R′)(R″), C 1-4  alkyl and substituted C 1-4  alkyl.    
   
   
       3 . A compound according to  claim 1 , wherein Z is NH and R 3  is H.  
   
   
       4 . A compound according to  claim 3 , wherein R 1 , R 2  and R 9  are each independently H, halogeno, CN, NO2, CO(NH2), (R′″)NH(R′)(R″) a C 1-4  alkyl group or a heterocyclic group.  
   
   
       5 . A compound according to  claim 4 , wherein when R 1  is halogeno, it is selected from chloro or bromo; when R 1  is alkylamino, it is diethylaminomethyl or dimethylaminomethyl; when R 1  is a heterocyclic group it is morpholin-4-ylmethyl or 4-methyl-piperazin-1-ylmethyl.  
   
   
       6 . A compound according to  claim 1 , wherein R 1  is H or CN, and R 2  and R 9  are both methyl.  
   
   
       7 . A compound according to  claim 6 , wherein R 1  is H.  
   
   
       8 . A compound according to  claim 7 , wherein R 1  is CN.  
   
   
       9 . A compound according to  claim 1 , wherein; 
 R 4 , R 5 , R 6 , R 7 , and R 8  are independently from each other H, unsubstituted lower alkyl, halogeno, NO 2 , CN, OH, N—(R′)(R″), or CF 3 ;    wherein R′ R″ and R′″ are each independently alkyl groups that may be the same or different and n is 0 or 1;    
   
   
       10 . A compound according to  claim 9 , wherein R 4  to R 8  are selected independently from H, F, NH 2 , NO 2 , OH, Cl, Br, I, CN, CH 2 OH, CF 3  and dimethylamino.  
   
   
       11 . A compound according to  claim 9  or  10 , wherein R 4  and R 8  are both hydrogen.  
   
   
       12 . A compound according to  claim 1 , wherein said compound is selected from 2-[N-(phenyl)]4-(2,4-dimethylpyrrol-3-yl)pyrimidineamines in which the phenyl group is 2-, 3-, 4-or 5-substituted by at least one of F, NH 2 , NO 2 , OH, Cl, Br, I, CN, CH 2 OH, CF 3  or OMe.  
   
   
       13 . A compound according to  claim 12 , wherein the phenyl group is mono-substituted by F, NH 2 , NO 2 , OH, Cl, Br, I, CH 2 OH, CN, CF 3  or OMe at any of the 2,3, 4 or 5-positions, or di-substituted by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro, 2,4-dichloro, 3,5-dichloro, 3,4-dichloro or 4-chloro-3-trifluoromethyl.  
   
   
       14 . A compound according to  claim 1 , wherein said compound is selected from 2-[N-(phenyl)]-4-(3,5-dimethyl-1H-pyrrole-2-carbonitrile)pyrimidineamines in which the phenyl group is 2-, 3- or 4-substituted by at least one of F, NH(CH 3 ) 2 , NO 2 , OH, Cl, Br, I or CF 3 .  
   
   
       15 . A compound according to  claim 14 , wherein the phenyl group is mono-substituted by F, NH(CH 3 ) 2 , NO 2 , OH, I or CF 3  at any of the 3 or 4-positions, or di-substituted by 4-methyl-3-nitro, 3-iodo-4-methyl, 4-chloro-3-methyl, 3-hydroxy-4-methyl, 4-fluoro-3-methyl or 4-methyl-3-fluoro.  
   
   
       16 . A compound according to  claim 1 , wherein said compound is selected from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidinamines wherein the phenyl group is mono-substituted by F, NH(CH 3 ) 2 , NO 2 , OH, I or CF 3  at the 4-position.  
   
   
       17 . A compound according to  claim 16 , wherein the phenyl group is substituted by a fluoro or NH(CH 3 ) 2  group.  
   
   
       18 . A compound according to  claim 1 , wherein said compound is selected from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-halogeno-1H-pyrrol-3-yl)-pyrimidinamines wherein the phenyl group is mono-substituted by F, NH(CH 3 ) 2 , NO 2 , OH, I or CF 3  at the 3 or 4-positions.  
   
   
       19 . A compound according to  claim 18 , wherein the phenyl group is substituted by a 4-fluoro or 3-nitro group, the halogeno group being chloro or bromo.  
   
   
       20 . A compound according to  claim 1 , selected from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-dialkylaminoalkyl-1H-pyrrol-3-yl)-pyrimidinamines wherein the phenyl group is mono-substituted by F, NH(CH 3 ) 2 , NO 2 , OH, I or CF 3  at the 4-position.  
   
   
       21 . A compound according to  claim 20 , wherein the phenyl group is substituted by fluoro, the dialkylaminoalkyl group preferably being diethylaminomethyl or dimethylaminomethyl.  
   
   
       22 . A compound according to  claim 1 , selected from 2-[N-(phenyl)]-4-(2,4-dimethyl-5-(heterocycle)-1H-pyrrol-3-yl)-pyrimidinamines wherein the phenyl group is preferably mono-substituted by F, NH(CH 3 ) 2 , NO 2 , OH, I or CF 3  at the 4-position.  
   
   
       23 . A compound according to  claim 22 , wherein the phenyl group is substituted by fluoro, the heterocycle group being 5-morpholin-4-ylmethyl or 4-methyl-piperazin-1-ylmethyl.  
   
   
       24 . A compound according to  claim 1  selected from: 
 [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yi]-(3-nitro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;    (3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    (4-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    (3 ,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;    3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;    (2,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    (2,4-Dichloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    (4-Chloro-3-trifluoromethyl-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yi)-pyrimidin-2-yl]-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl] -(4-trifluoromethyl-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-phenyl)-amine;    (3-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl] -amine;    N-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine;    (3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl)-amine;    3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3, 5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl] -3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(3-iodo-4-methyl-phenylamino)-pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin4-yi]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl] -3, 5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide;    [4-(3 ,5-Dimethyl-1H-pyrrol-2-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    (4-Fluoro-phenyl)-[4-( 1 ,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yi)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine;    [4-(5-Amino-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;    [4-(5-Chloro-2,4Adimethyl-1H-pyrrol-3-yl)-pyrirnidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amnine;    [4-(5-Dimethylaminomethyl-2,4-dimethyl 1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine; and    {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-I 1H-pyrrol-3-yl]-pyrimidin-2-yl}-(4-fluoro-phenyl)-amine.    
   
   
       25 . A compound according to  claim 24  selected from; 
 [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;    (3,4-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    (4-Chloro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    (3,5-Difluoro-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    4-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;    3-[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-ylamino]-phenol;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-amine;    (3-Chloro-4-iodo-phenyl)-[4-(2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl)-amine;    3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl] -3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide;    (4-Fluoro-phenyl)-[4-( 1 ,2,4-trimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-amine;    [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;    [4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl] -(4-fluoro-phenyl)-amine;    [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine, and    {4-[2,4-Dimethyl-5-(4-methyl-piperazin-1-ylmethyl)-1H-pyrrol-3-yl]-pyrimidin-2-yl }-(4-fluoro-phenyl)-amine.    
   
   
       26 . A compound according to  claim 25  selected from; 
 [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-trifluoromethyl-phenyl)-amine;    3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl] -3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yl] -3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Chloro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Dimethylamino-phenylamino)-pyrimidin-4-yl] -3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carboxylic acid amide;    [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl] -(4-fluoro-phenyl)-amine;    N-[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;    [4-(5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine, and    [4-(2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine.    
   
   
       27 . A compound according to  claim 26  selected from; 
 [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine;    [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-iodo-phenyl)-amine;    3,5-Dimethyl-4-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Hydroxy-phenylamino)-pyrimidin4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(4-Iodo-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    3,5-Dimethyl-4-[2-(4-methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-1H-pyrrole-2-carbonitrile;    4-[2-(3-Hydroxy-4-methyl-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-3-methyl-phenylamino)-pyrimidin-4-yl]-3,5-dimethyl-1H-pyrrole-2-carbonitrile;    4-[2-(4-Fluoro-phenylamino)-pyrimidin-4-yl]-3 ,5-dimethyl-1H-pyrrole-2-carboxylic acid amide;    [4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine;    [4-(5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine, and    [4-(5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine.    
   
   
       28 . A compound according to  claim 1 , wherein; 
 X 1  and X 2  are NH and CR 9  respectively;    R′, R 2 , R 3  and R 9  are each independently selected from H, alkyl, aryl, aralkyl, heterocycle, halogeno, NO 2 , CN, OH, alkoxy, aryloxy, (R′″)nNH 2 , (R′″)nNH—R′, (R′″)nN—(R′)(R″), COOH, COO—R′, CONH 2 , CONH—R′, CON—(R′)(R″), SO 3 H, SO 2 NH 2 , CF 3 , and CO—R 1  wherein alkyl, aryl and aralkyl groups may be further substituted with one or more groups selected from halogeno, NO 2 , CN, OH, O-methyl, NH 2 , COOH, CONH 2  and CF 3 ;    Z is selected from NH, NHSO 2  and NHCH 2 ;    R 4 , R 5  and R 8  are each independently selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N(R′)(R″), C 1-4  alkyl and substituted C 1-4  alkyl;    R6 is selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N(R′)(R″), methyl, propyl, butyl and substituted C 1-4  alkyl;    R7 is selected from H, halogeno, nitro, amino, aminoalkyl, hydroxy, carbamoyl, sulfamyl, N(R′)(R″ C 2-4  alkyl and substituted C 1-4  alkyl.    
   
   
       29 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient.  
   
   
       30 . Use of a compound of  claim 1  or a pharmaceutically acceptable salt thereof in the treatment of a proliferative disorder.  
   
   
       31 . Use according to  claim 30 , wherein the proliferative disorder is cancer or leukaemia.  
   
   
       32 . Use according to  claim 30  or  31 , wherein said compound is administered in an amount sufficient to inhibit at least one CDK enzyme.  
   
   
       33 . Use according to  claim 32 , wherein the CDK enzyme is CDK2 and/or CDK4.  
   
   
       34 . Use of a compound of formula  
     
       
         
         
             
             
         
       
       wherein:  
       one of X 1  and X 2  is NR 10  and the other of X 1  and X 2  is CR 9 ;  
       Z is NH, NHCO, NHSO 2 , NHCH 2 , CH 2 , CH 2 CH 2 , or CH═CH;  
       R 1 , R 2 , R 1  R 9  and R 10  are independently H, alkyl, aryl, aralkyl, heterocycle, halogeno, NO 2 , CN, OH, alkoxy, aryloxy, (R′″)nNH 2 , (R′″)nNH—R′, (R′″)nN—(R′)(R″), NH-aryl, N-(aryl) 2 , COOH, COO—R′, COO-aryl, CONH 2 , CONH—R′, CON—(R′)(R″), CONH-aryl, CON—(aryl) 2 , SO 3 H, SO 2 NH 2 , CF 3 , CO—R′, or CO-aryl, wherein alkyl, aryl, aralkyl and heterocycle groups may be further substituted with one or more groups selected from halogeno, NO 2 , CN, OH, O-methyl, NH 2 , COOH, CONH 2  and CF 3 ;  
       R 4 , R 5 , R 6 , R 7 , and R 8  are independently from each other H, substituted or unsubstituted lower alkyl, halogeno, NO 2 , CN, OH, substituted or unsubstituted alkoxy, NH 2 , NH—R′, N—(R′)(R″), COOH, COO—R′, CONH 2 , CONH—R′, CON—(R′)(R″), SO 3 H, SO 2 NH 2 , or CF 3 ;  
       wherein R 1  R″ and R′″ are each independently alkyl groups that may be the same or different and n is 0 or 1;  
       with the proviso that when R 1  and R 2  are H, X 1  is NH, X 2  is CH, and R 3  is H, the phenyl group is not 
 3-(1,1,2,2-tetrafluoroethoxy)b or  
 3,4,5-trimethoxy,  
 
       when the other groups R 4 —R 8  are H;  
       and pharmaceutically acceptable salts thereof;  
       in the manufacture of a medicament for use in the treatment of a proliferative disease.  
     
   
   
       35 . A method of treating a subject for a proliferative disorder, comprising administering to a subject a compound of  claim 1  or a pharmaceutically acceptable salt thereof, such that said proliferative disorder in said subject is treated.  
   
   
       36 . The method of  claim 35 , wherein the proliferative disorder is cancer or leukaemia.  
   
   
       37 . The method of  claim 35 , wherein said compound is administered in an amount sufficient to inhibit at least one CDK enzyme.  
   
   
       38 . The method of  37 , wherein the CDK enzyme is CDK2 and/or CDK4.