4.5-disubstituted-2-aminopyrimidines

Abstract

Pyrimidines of formla (1) are described: wherein R 1 is a —XR 6 group; R 2 and R 3 which may be the same or different is each a hydrogen or halogen atom or a group selected from an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, —OH, —OR 10 [where R 10 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group] —SH, —NO 2 , —CN, —SR 10 , —COR 10 , S(O)R 10 , —SO 2 R 8 , —SO 2 N(R 8 )(R 9 ), —CO 2 R 8 , —CON(R 8 )(R 9 ), —CSN(R 8 )(R 9 ), —NH 2 or substituted amino group; R 4 is a X 1 R 11 group where X 1 is a covalent bond or a —C(R 12 )(R 13 )— [where each of R 12 and R 13 is a hydrogen or halogen atom or a hydroxyl, alkyl or haloalkyl group] or —C(O)— group and R 11 is an optionally substituted phenyl, thienyl, thiazolyl or indolyl group; R 5 is a halogen atom or an alkynyl 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 R 1  is a —XR 6  group [where X is a covalent bond, —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —S(O)—, —S(O 2 )—, —CH 2 —, -or N(R 7 )— [where R 7  is a hydrogen atom or a straight or branched alkyl group] and R 6  is a hydrogen or halogen atom or an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, or a —NO 2 , —CN, —SO 2 N(R 8 )(R 9 ) [where R 8  and R 9 , which may be the same or different is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group], —CON(R 8 )(R 9 ), —CSN(R 8 )(R 9 ), —NH 2  or substituted amino group;  
         R 2  and R 3  which may be the same or different is each a hydrogen or halogen atom or a group selected from an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, —OH, —OR 10  [where R 10  is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group] —SH, —NO 2 , —CN, —SR 10 , —COR 10 , S(O)R 1 °, —SO 2 R 8 , —SO 2 N(R 8 )(R 9 ), —CO 2 R 8 , —CON(R 8 )(R 9 ), —CSN(R 8 )(R 9 ), —NH 2  or substituted amino group;  
         R 4  is a X 1 R 11  group where X 1  is a covalent bond or a —C(R 12 )(R 13 )— [where each of R 12  and R 13  is a hydrogen or halogen atom or a hydroxyl, alkyl or haloalkyl group] or —C(O)— group and R 11  is an optionally substituted phenyl, thienyl, thiazolyl or indolyl group;  
         R 5  is a halogen atom or an alkynyl group;  
         and the salts, solvates, hydrates and N-oxides thereof.  
       
     
     
         2 . A compound according to  claim 1  wherein R 5  is a bromine or chlorine atom.  
     
     
         3 . A compound according to  claim 1  wherein R 4  is a X 1  R 11  group in which X 1  is a covalent bond.  
     
     
         4 . A compound according to any one of  claim 1  wherein R 4  is a X 1  R 11  group and R 11  is a phenyl or substituted phenyl group containing one, two, or three R 17  substituents in which each R 17  substituent is an atom or group R 18  or -Alk(R 18 ) m , where R 18  is a halogen atom, or an amino (—NH 2 ), —NHR 1  9 [where R 19  is an -Alk(R 18 ) m  heterocycloaliphatic, -Alk-heterocycloaliphatic, aryl or heteroaryl group], —N(R 19 ) 2  [where each R 19  group is the same or different], nitro, cyano, hydroxyl (—OH), —OR 19 , formyl, carboxyl (—CO 2 H), esterified carboxyl, thiol (—SH), —SR 19 , —COR 19 , —CSR 19 , —SO 3 H, —SO 2 R 19 , —SO 2 NH 2 , —SO 2 NHR 19 , SO 2 N[R 19 ] 2 , —CONH 2 , —CSNH 2 , —CONHR 1  9, —CSNHR 19 , —CON(R 19 ] 2 , —CSN[R 19 ] 2 , —N(R 14 )SO 2 H [where R 14  is a hydrogen atom or a C 1-6 alkyl group], —N(R 14 )SO 2 R 19 , —N[SO 2 R 19 ] 2 , —N(R 14 ) SO 2  NH 2 , —N(R 14 )SO 2 NHR 19 , —N(R 14 )SO 2 N[R 1  9]2, —N(R 14 ) C O R 19 , —N(R 14 ) CON H 2 , —N(R 14 )CONHR 19 , —N(R 14 )CON[R 19 ] 2 , —N(R 14 )CSR 19 , —N(R 14 )CSNH 2 , —N(R 14 )CSNHR 19 , —N(R 14 )CSN(R 19 ] 2 , —N(R 14 )C(O)OR 1  9, or an optionally substituted cycloaliphatic, heterocycloaliphatic, 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 S(O)—, —S(O) 2 — or —N(R 14 )— groups; and m is zero or an integer 1, 2 or 3.  
     
     
         5 . A compound according to any one of  claim 1  wherein one or both of R 2  and R 3  is a hydrogen atom.  
     
     
         6 . A compound according to  claim 5  wherein R 2  and R 3  is each a hydrogen atom.  
     
     
         7 . A compound according to any one of  claim 1  wherein R 1  is a group -(Alk 2 ) p NH 2  (where Alk 2  is a straight or branched C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene chain, optionally substituted by one, two or three —O— or —S— atoms or —S(O)—, —S(O) 2 — or —N(R 14 )— group [where R 14  is a hydrogen atom or a C 1-6 alkyl group] and p is zero or an integer 1), -(Alk 2 ) p NR 15 R 16  [where R 15  is an optionally substituted C 1- 6alkyl, C 2-6 alkenyl or C 2-6 alkynyl group optionally interrupted by an —O— or —S— atom or a —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 14 )—, —CON(R 14 )—, —OC(O)N(R 14 )—, —CSN(R 14 )—, —N(R 14 )CO—, —N(R 14 )C(O)O—, —N(R 14 )CS—, —SON(R 14 ), —SO 2 N(R 14 ), —N(R 14 )SO 2 —, —N(R 14 )CON(R 14 )—, —N(R 14 )CSN(R 14 )—, —N(R 14 )SON(R 14 )— or —N(R 14 )SO 2 N(R 14 ) group and R 16  is a hydrogen atom or a group as just defined for R 15 ], (-Alk 2 ) p NHet 2  (where —NHet 2  is an optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group), -(Alk 2 ) p OH or -(Alk 2 )pAr (where Ar is a ntrogen-containing heteroaromatic group).  
     
     
         8 . A compound according to  claim 7  wherein R 1  is a group -Alk 2 NH 2 , -Alk 2 NR 15 R 16 , -(Alk 2 ) p NHet 2  (where —NHet 2  is an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group), -Alk 2 OH or -Alk 2 Ar (where Ar is an optionally substituted imidazolyl or benzimidazolyl group).  
     
     
         9 . A compound of formula (I a):  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4  and R 5  is each as defined in  claim 1 .  
     
     
         10 . A compound which is: 
 4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-hydroxyethyl) phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[3-(2-hydroxyethyl) phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(1-imidazolyl) phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(imidazol-1-yl)ethyl)phenyl]pyrimidine-2-amine;    4-(4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-methylimidazol-1-yl)ethyl)phenyl]pyrimidine-2-amine; 4-[4-(11-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-isopropylimidazol-1-yl)ethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-thiomorpholino)ethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(tertbutylamino) ethyl)phenyl]pyrimidine-2-amine;    4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl]pyrimridine-2-amine;    4-[4(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl]pyrimidine-2-amine;    4-[4(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(3,5-dimethylpiperazin-1-yl)ethyl)phenyl]pyrimidine-2-amine;    4-[4(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-(pyrid-2-yl) piperazin-1-yl)ethyl)phenyl]pyrimidine-2-amine;    4-[4(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(pyrrolidin-1-yl)ethyl)phenyl]pyrimidine-2-amine;    4-[4(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(piperidin-1-yl)ethyl) phenyl]pyrimidine-2-amine;    (R)-4-[4-(i-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(3-dimethylaminopyrrolidin-1-yl)ethyl)phenyl]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.