Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases

Abstract

The invention concerns compounds of Formula (I): wherein L 1 , R 1 , R 2 , R 3 , R 4 and X are as defined in the description. The present invention also relates to processes for the preparation of such compounds, pharmaceutical compositions containing them and their use in the treatment of disease, for example cancer.

1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         Wherein: 
         X represents —CH 2 —, —NR 8 —, —O— or —S(O) n —; 
         R 1  represents CH 1-6 alkyl, C 2-6 alkoxy, CH 1-6 alkoxyCH 1-6 alkyl, hydroxyCH 1-6 alkyl, hydroxyC 1-6 alkoxy or hydroxyC 1-6 alkoxyC 1-6 alkyl; 
         R 2  represents hydrogen, C 1-6 alkyl or phenyl wherein said phenyl is optionally substituted with 1, 2 or 3 substituents selected from R 6 ; 
         R 3  represents C 1-6 alkyl, C 1-6 alkoxy or —S—C 1-6 alkyl; 
         R 4  represents hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy; 
         L 1  represents a direct bond, —(CR 9 R 10 ) m —, —CH═CH—(CR 9 R 10 ) q —, —C≡C—(CR 9 R 10 ) q —, —O—(CR 9 R 10 ) q —, —C(O)—O—(CR 9 R 10 ) q — or —O—(CH 2 ) q —NR 8 -(CH 2 ) q —; 
         R 5  represents methyl, hydroxy, —NR 11 R 12 , C 3-6 cycloalkyl, phenyl or a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms independently selected from O, N or S wherein said phenyl and heterocyclic rings are optionally substituted with 1, 2 or 3 substituents selected from R 7 ; 
         R 6  represents C 1-6 alkyl, fluoroC 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, cyano, —S(O) n —CH 1-6 alkyl or —CH 2 —C(O)—O—CH 1-6 alkyl; 
         R 7  represents C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, hydroxy, hydroxyC 1-6 alkyl or —(CH 2 ) q —NR 11 R 12 ; 
         R 8  represents hydrogen or C 1-6 alkyl; 
         R 9  and R 10 , identically or differently on each occurrence, represents hydrogen or methyl; 
         R 11  and R 12  independently represent hydrogen, C 1-4 alkyl or C 1-4 alkoxyC 2-4 alkyl; 
         m represents 1, 2, 3, 4, 5 or 6; 
         n represents 0, 1 or 2; and 
         q represents 0, 1, 2, 3, 4, 5 or 6; 
         with the proviso that the compound of Formula (I) is other than: 
         [3-(2-amino-4-methyl-6-pentylamino-pyrimidin-5-ylmethyl)]-benzoic acid ethyl ester; 
         methyl 4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-3-methoxybenzoate; 
         or 
         methyl 4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-3-fluorobenzoate. 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X represents —CH 2 —. 
     
     
         3 . A compound according to  claim 1  or  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1  represents C 1-6 alkyl. 
     
     
         4 . A compound according to any one of  claims 1  to  3 , or a pharmaceutically acceptable salt thereof, wherein R 2  represents hydrogen. 
     
     
         5 . A compound according to any one of  claims 1  to  3 , or a pharmaceutically acceptable salt thereof, wherein R 2  represents phenyl wherein said phenyl is optionally substituted with 1, 2 or 3 substituents selected from R 6 . 
     
     
         6 . A compound according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, wherein R 3  represents methyl. 
     
     
         7 . A compound according to any one of  claims 1  to  6 , or a pharmaceutically acceptable salt thereof, wherein R 4  represents C 1-6 alkoxy. 
     
     
         8 . A compound according to any one of  claims 1  to  6 , or a pharmaceutically acceptable salt thereof, wherein R 4  represents hydrogen. 
     
     
         9 . A compound according to any one of  claims 1  to  8 , or a pharmaceutically acceptable salt thereof, wherein R 4  is bonded at the ortho position of the phenyl ring relative to linkage —X—. 
     
     
         10 . A compound according to any one of  claims 1  to  9 , or a pharmaceutically acceptable salt thereof, wherein q represents 1, 2 or 3. 
     
     
         11 . A compound according to any one of  claims 1  to  10 , or a pharmaceutically acceptable salt thereof, wherein q represents 2 or 3. 
     
     
         12 . A compound according to any one of  claims 1  to  11 , or a pharmaceutically acceptable salt thereof, wherein L 1  represents —(CR 9 R 10 ) m —, —CH═CH—(CR 9 R 10 ) q — or —C≡C—(CR 9 R 10 ) q l —   
     
     
         13 . A compound according to any one of  claims 1  to  11 , or a pharmaceutically acceptable salt thereof, wherein L 1  represents —O—(CR 9 R 10 ) q —. 
     
     
         14 . A compound according to any one of  claims 1  to  13 , or a pharmaceutically acceptable salt thereof, wherein L 1  is bonded at the para position of the phenyl ring relative to linkage —X—. 
     
     
         15 . A compound according to any one of  claims 1  to  13 , or a pharmaceutically acceptable salt thereof, wherein L 1  is bonded at the meta position of the phenyl ring relative to linkage —X—. 
     
     
         16 . A compound according to any one of  claims 1  to  8  or  10  to  13 , or a pharmaceutically acceptable salt thereof, wherein L 1  is bonded at the ortho position of the phenyl ring relative to linkage —X—. 
     
     
         17 . A compound according to any one of  claims 1  to  16 , or a pharmaceutically acceptable salt thereof, wherein R 5  represents NR 11 R 12  or a monocyclic 4, 5, 6 or 7 membered heterocyclic ring which comprises 1, 2 or 3 heteroatoms independently selected from O, N or S wherein said heterocyclic ring is optionally substituted with 1, 2 or 3 substituents selected from R 7 . 
     
     
         18 . A compound according to any one of  claims 1  to  17 , or a pharmaceutically acceptable salt thereof, wherein R 5  represents NR 11 R 12  and R 11  and R 12  both represent methyl. 
     
     
         19 . A pharmaceutical composition which comprises a compound according to any one of  claims 1  to  18 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. 
     
     
         20 . A compound according to any one of  claims 1  to  18 , or a pharmaceutically acceptable salt thereof, for use as a medicament. 
     
     
         21 . A compound according to any one of  claims 1  to  18 , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. 
     
     
         22 . Use of a compound according to any one of  claims 1  to  18 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer. 
     
     
         23 . A method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of  claims 1  to  18 .