5-cyano-2-aminopyrimidine derivatives

Abstract

Pyrimidines of formula (1) are described wherein Ar is an optionally substituted aromatic or heteroaromatic group; R 1 is a hydrogen atom or a straight or branched chain alkyl group; R 2 is a —X 1 —R 3 group where X 1 is a direct bond or a linker atom or group, and R 3 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof. The compounds are selective KDR Kinase and/or FGFr Kinase inhibitors and are of use in the prophylaxis and treatment of disease states associated with angiogenesis.

1 . A compound of formula (1):  
       
         
           
           
               
               
           
         
       
       wherein Ar is an optionally substituted aromatic or heteroaromatic group; 
 R 1  is a hydrogen atom or a straight or branched chain alkyl group;  
 R 2  is a —X 1 —R 3  group where X 1  is a direct bond or a linker atom or group, and R 3  is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;  
 and the salts, solvates, hydrates and N-oxides thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is a hydrogen atom.  
     
     
         3 . A compound according to  claim 1  wherein R 2  is a group —X 1 R 3  in which X 1  is a direct bond.  
     
     
         4 . A compound according to  claim 3  in which R 3  is an optionally substituted aromatic or heteroaromatic group, said heteroaromatic group containing one or two ring oxygen, sulphur and/or nitrogen atoms.  
     
     
         5 . A compound according to  claim 4  wherein R 3  is a phenyl, thienyl, thiazolyl, indolyl or pyridyl group optionally substituted by one, two or three —R 4b  or -Alk(R 4b ) m  substituents in which R 4b  is a halogen atom, or an amino (—NH 2 ), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO 2 H), esterified carboxyl, thiol (—SH), substituted thiol, —COR 5  [where R 5  is a -Alk(R 4 ) m , aryl or heteroaryl group], —CSR 5 , —SO 3 H, —SO 2 R 5 , —SO 2 NH 2 , —SO 2 NHR 5 , —SO 2 N[R 5 ] 2 , —CONH 2 , —CSNH 2 , —CONHR 5 , —CSNHR 5 , —CON[R 5 ] 2 , —CSN[R 5 ] 2 , —NHSO 2 H, —NHSO 2 R 5 , —N[SO 2 R 5 ] 2 , —NHSO 2 NH 2 , —NHSO 2 NHR 5 , —NHSO 2 N[R 5 ] 2 , —NHCOR 5 , —NHCONH 2 , —NHCONHR 5 , —NHCON[R 5 ] 2 , —NHCSR 5 , —NHC(O)OR 5 , or optionally substituted cycloaliphatic, hetero-cycloaliphatic, aryl or heteroaryl group; Alk is a straight or branched C 1-6  alkylene, C 2-6  alkenylene or C 2-6  alkynylene chain, optionally interrupted by one, two or three —O— or —S— atoms or groups selected from —S(O)—, —S(O) 2 — or —N(R 6 ) [where R 6  is a hydrogen atom or a straight or branched chain C alkyl group]; and m is zero or an integer 1, 2 or 3.  
     
     
         6 . A compound according to  claim 1  wherein Ar is a phenyl, pyridyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl or benzoxazolyl group each substituted by one, two or three —R 4  or -Alk(R 4 ) m  substituents in which R 4  is a halogen atom, or an amino (—NH 2 ), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO 2 H), esterified carboxyl, thiol (—SH), substituted thiol, —COR 5  [where R 5  is a -Alk(R 4 ) m , aryl or heteroaryl group], —CSR 5  —SO 3 H, —SO 2 R 5 , —SO 2 NH 2 , —SO 2 NHR 5 , SO 2 N[R 5 ] 2 , —CONH 2 , —CSNH 2 , —CONHR 5 , —CSNHR 5 , —CON[R 5 ] 2 , —CSN[R 5 ] 2 , —NHSO 2 H, —NHSO 2 R 5 , —N[SO 2 R 5 ] 2 , —NHSO 2 NH 2 , —NHSO 2 NHR 5 , —NHSO 2 N[R 5 ] 2 , —NHCOR 5 , —NHCONH 2 , —NHCONHR 5 , —NHCON[R 5 ] 2 , —NHCSR 5 , —NHC(O)OR 5 , or optionally substituted cycloaliphatic, hetero-cycloaliphatic, aryl or heteroaryl group; Alk is a straight or branched C 1-6  alkylene, C 2-6  alkenylene or C 2-6  alkynylene chain, optionally interrupted by one, two or three —O— or —S— atoms or groups selected from —S(O)—, —S(O) 2 — or —N(R 6 )— [where R 6  is a hydrogen atom or a straight or branched chain C 1-6  alkyl group]; and m is zero or an integer 1, 2 or 3.  
     
     
         7 . A compound according to  claim 6  wherein Ar is a phenyl group substituted by one, two or three —R 4  or -Alk(R 4 ) m  substituents.  
     
     
         8 . A compound according to any one of  claim 5  to  claim 7  wherein at least one of —R 4 , -Alk(R 4 ) m , R 4b  or -Alk(R 4b ) m  is a —X 1a (Alk a ) p NR 7a R 7b ) (where X 1a  is a direct bond or a linker atom or group, Alk a  is as defined for Alk, p is zero or an integer 1 and R 7a  and R 7b  which may be the same or different is each a hydrogen atom or a straight or branched C 1-6 alkyl group), —X 1a (Alk a ) p NHet 1  (where —NHet 1  is an optionally substituted C 3-7 cyclicamino group optionally containing one or more —O— or —S— atoms or —N(R 6 ) [where R 6  is a hydrogen atom or a straight or branched chain C 1-6 alkyl group]) or —X 1a (Alk a ) p Ar 2  group (where Ar 2  is a nitrogen containing heteroaromatic group).  
     
     
         9 . A compound which is: 
 5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;    5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylphenyl)pyrimidine-2-amine;    5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;    5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;    5-Cyano-4-[2-(3(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol-5-yl)pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;    5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylpyrimidine-2-amine;    5-Cyano-4-phenyl-N-4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl)pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4(1,2,3-triazol-1-yl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N[{4-2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine;    N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide;    4-[3-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-12-(2-methyl-imidazol-1-yl)ethyl]phenyl}pyrimidine-2-amino;    5-Cyano-4-[4-(imiadzol-1-yl)methyl]phenyl-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amino;    and the salts, solvates, hydrates and N-oxides thereof.    
     
     
         10 . A compound which is: 
 4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine;    5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4(1-dimethylamino-1-methyl ethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]phenyl}pydimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;    5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine;    5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl)pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrimidine-2-amine;    and the salts, solvates, hydrates and N-oxides thereof.    
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  together with one or more pharmaceutically acceptable carriers, excipients or diluents