Compounds and compositions as protein kinase inhibitors

Abstract

The invention relates to compounds of formula (I) wherein the substituents X 1 , R 1 , R 2 , R 3 and R 4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease.

1 . A process for the preparation of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein the following fragment is referred to as the “left hand ring” 
       
       
         
           
           
               
               
           
         
         
           the left hand ring 
         
         wherein 
         X 1  is oxygen, 
         X is C—R 5 , R 5  is H, R 2  is H, and Y and Z are both N, whereby the left hand ring has the structure of Fragment (B): 
       
       
         
           
           
               
               
           
         
         wherein R 1  is of the formula R z —NR a — wherein R a  is hydrogen; 
         and R z  is 
       
       
         
           
           
               
               
           
         
         a group of the formula
 where: 
 ring A represents a 6-membered carbocyclic or heterocyclic ring; 
 m is 0, 1 or 2; 
 the or each R b  is independently selected from -L 2 -NR c R d ; -L 2 -RING where RING is a mono- or bi-cyclic ring optionally substituted as defined below; halogen; hydroxy; protected hydroxyl; amino; amidino; guanidino; hydroxyguanidino; formamidino; isothioureido; ureido; mercapto; acyl having 4 in-chain atoms; acyloxy having 4 in-chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; or nitro; and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens and/or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionally substituted on at least one heteroatom by one or, where possible, more C 1 -C 7  aliphatic groups, 
 wherein L 2  is a direct bond; a linkage selected from —O—; —S—; —C(O)—; —OC(O)—; —NR a C(O)—; —C(O)—NR a —; —OC(O)—NR a —; cyclopropyl and —NR a —; or is a linear or branched alkyl group having 1, 2, 3 or 4 carbon atoms optionally interrupted and/or terminated at a single end or at both ends by a said linkage; 
 and wherein R c  and R d  are each independently selected from hydrogen, and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens, by an optionally substituted 5- or 6-membered heterocyclic or carbocyclic ring, and/or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are in turn optionally substituted on at least one heteroatom by one or more C 1 -C 7  aliphatic groups, 
 or R c  and R d  together with their adjoining nitrogen form a 5- or 6-membered ring optionally substituted as described below, 
 said optionally substituted rings independently of each other being substituted by 0, 1, 2, 3, 4 or 5 substituents selected from halogen; hydroxy; protected hydroxy; amino; amidino; guanidino; hydroxyguanidino; formamidino; isothioureido; ureido; mercapto; acyl having 4 in-chain atoms; acyloxy having 4 in-chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; C 1 -C 7  aliphatic optionally substituted by one or more halogens and/or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 in-chain atoms, acyloxy having 4 in-chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the aforesaid hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally being substituted on at least one heteroatom by one or, where possible, more C 1 -C 7  aliphatic groups; 
 
         R 3  is H, a straight chain or branched C 1 -C 4  alkyl or a straight chain or branched C 1 -C 4  alkyl substituted by a 5- or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring; 
         or pharmaceutically acceptable salts, hydrates, solvates, esters, N-oxides, protected derivatives, individual stereoisomers and mixture of stereoisomers thereof; 
         said process comprising,
 a) reacting 4,6-Dichloropyrimidine, 
 
       
       
         
           
           
               
               
           
         
         
           
             with a compound of formula R 3 NH 2  to provide a compound of formula: 
           
         
       
       
         
           
           
               
               
           
         
         
           b) reacting said compound of formula: 
         
       
       
         
           
           
               
               
           
         
         
           
             with a compound of formula R z NH 2  to provide a compound of formula: 
           
         
       
       
         
           
           
               
               
           
         
         
           and then, 
           b) reacting said compound of formula: 
         
       
       
         
           
           
               
               
           
         
         
           
             with 2,6-dichloro-3,5-dimethoxyphenylisocyanate. 
           
         
       
     
     
         2 . The process according to  claim 1 , wherein said 2,6-dichloro-3,5-dimethoxyphenylisocyanate is obtained by reacting 2,6-dichloro-3,5-dimethoxyaniline with phosgene (COCl 2 ). 
     
     
         3 . The process according to  claim 1 , wherein the left hand ring has a structure corresponding to Fragment (D1), (D2), (E1) or (E2): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The process according to  claim 3 , wherein the phenyl ring of said Fragments has 1, 2, 3 or 4 further substituents, selected from halogen, methyl, methoxy and trifluoromethyl. 
     
     
         5 . The process according to  claim 1  wherein RING is a saturated heterocycle which contains an in-ring nitrogen. 
     
     
         6 . The process according to  claim 1  in which the compound of formula (I) contains a moiety NR c R d  and wherein R c  and R d  are the same or different and selected from straight chain or branched alkyl having 1, 2, 3 or 4 carbon atoms. 
     
     
         7 . The process according to  claim 1  in which the compound of formula (I) contains a moiety NR c R d  and wherein R c  and R d  together with the adjoining nitrogen form a 5- or 6-membered heterocyclic ring, optionally substituted as by 0, 1, 2, 3, 4 or 5 substituents selected from straight chain or branched C 1 , C 2 , C 3  or C 4  alkyl, halogen and C 1 , C 2 , C 3  or C 4  alkoxy, wherein alkyl and the alkyl part of alkoxy are unsubstituted or substituted by halogen. 
     
     
         8 . The process according to  claim 7  wherein L 2 NR c R d  is selected from -Pip, -Morph, —OCH 2 Pip, —OCH 2 -Morph, —OCH 2 CH 2 Pip, —OCH 2 CH 2 -Morph, —OCH 2 CH 2 CH 2 Pip, —OCH 2 CH 2 CH 2 -Morph, —CH 2 Pip, —CH 2 -Morph, —CH 2 CH 2 Pip, —CH 2 CH 2 -Morph, —CH 2 CH 2 CH 2 Pip, —CH 2 CH 2 CH 2 -Morph, —C(O)Pip and —C(O)Morph, where “Pip” stands for piperazine and “Morph” for morpholine, piperazine optionally being N-substituted by straight chain or branched C 1 , C 2 , C 3  or C 4  alkyl. 
     
     
         9 . The process according to  claim 3  wherein the left hand ring has the structure of the following Fragment (F): 
       
         
           
           
               
               
           
         
       
     
     
         10 . The process according to  claim 1 , wherein the compound according to formula (I) is selected from:
 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamino}-pyrimidin-4-yl)-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(3-dimethylamino-propyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-ethyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(2,6-dimethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-1-{6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(3-dimethylaminomethyl-phenylamino)-pyrimidin-4-yl]-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-ethyl-{6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamino]-pyrimidin-4-yl}-methyl-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-(6-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-pyrimidin-4-yl)-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-dimethylaminomethyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-phenylamino)-pyrimidin-4-yl]-1-methyl-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[3-(4-isopropyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea;   1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[3-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea;   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-{6-[3-(1-methyl-piperidin-4-yloxy)-phenylamino]-pyrimidin-4-yl}-urea; and   3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-[6-(3-diethylaminomethyl-phenylamino)-pyrimidin-4-yl]-1-methyl-urea.   
     
     
         11 . The process according to  claim 10 , wherein the compound according to formula (I) is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea. 
     
     
         12 . The process according to  claim 10 , wherein the compound according to formula (I) is 1-(2,6-Dichloro-3,5-dimethoxy-phenyl)-3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea. 
     
     
         13 . The process according to  claim 1 , wherein the compound according to formula: 
       
         
           
           
               
               
           
         
         is N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine. 
       
     
     
         14 . The compound 2,6-dichloro-3,5-dimethoxyaniline. 
     
     
         15 . The compound 2,6-dichloro-3,5-dimethoxyphenylisocyanate. 
     
     
         16 . The compound N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine.