Antiproliferative pyrimidyl, fused pyrimidyl and pyrimidyl hydrazones

Abstract

The present invention is related to a novel series of pyrimidyl or fused pyrimidyl hydrazones. Compounds of Formula (I) wherein A is selected from the group consisting of Formulas (A1), (A2), (A3), (A4), (A5) are useful for the treatment and/or prevention of a proliferative disease.

1 . A compound according to Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         A is selected from the group consisting of A1, A2, A3, A4 and A5: 
       
       
         
           
           
               
               
           
         
         wherein each X is independently selected from the group consisting of CR 6 , N and NR 6 ; and each Y is independently selected from the group consisting of CR 6 , N, NR 6 , S and O; 
         L is either a bond or NR 6 ; 
         R 1 , R 6  and R 9  are independently either hydrogen or C 1 -C 6 -alkyl; 
         each R 2  is independently selected from the group consisting of hydrogen, halogen, cyano, thioamide, acyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxylamine, hydroxyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl; 
         n is an integer selected from 1, 2, 3, 4 or 5; 
         R 3  and R 7  are independently selected from the group consisting of hydrogen, halogen, cyano, thiourea, acylamine, carboxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine, hydroxyl, aryl and heteroaryl, wherein each of said C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine, hydroxyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl; 
         R 5  is selected from the group consisting of hydrogen, halogen, cyano, thiourea, amino, acylamine, carboxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine, hydroxyl, aryl and heteroaryl, wherein each of said C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine, hydroxyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl; 
         R 4  is selected from the group consisting of C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl bonded through a ring carbon, wherein each of said C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl bonded through a ring carbon is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, aminocarbonyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl; and 
         and geometrical isomers, enantiomers, diastereomers, tautomers, racemates or pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 each X is independently selected from the group consisting of CR 6 , N and NR 6 ;   each Y is independently selected from the group consisting of CR 6 , N, NR 6 , S and O;   L is either a bond or NR 6 ;   R 1  is either hydrogen or C 1 -C 6 -alkyl;   each R 2  is independently selected from the group consisting of hydrogen, halogen, cyano, thioamide, acyl, thiourea, acylamine, carboxy, C 1 -C 6 -alkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, hydroxylamine and hydroxyl;   n is an integer selected from 1, 2, or 3;   R 3  is selected from the group consisting of hydrogen, halogen, cyano, thiourea, acylamine, carboxy, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy;   R 4  is either aryl or an heteroaryl bonded through a ring carbon, wherein said aryl or heteroaryl bonded through a ring carbon is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl;   R 5  is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, sulfonylamine, thiourea, amino, acylamine, carboxy, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine and hydroxyl;   R 6  is either hydrogen or C 1 -C 6 -alkyl;   R 7  is selected from the group consisting of aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 8 -heterocycloalkyl, wherein each of said aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 8 -heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl; and   R 9  is either hydrogen or C 1 -C 6 -alkyl.   
     
     
         3 . The compound according to  claim 1 , wherein
 each X is CR 6 ;   each Y is independently selected from the group consisting of CR 6 ; N and NR 6 ;   L is NH;   R 1  is selected from the group consisting of hydrogen, methyl, and ethyl;   each R 2  is independently selected from the group consisting of hydrogen, methyl, ethyl, acyl, thioamide, chloro, methoxy, bromo and fluoro;   n is either 1 or 2;   R 3  is selected from the group consisting of hydrogen, methyl, ethyl, methoxy and ethoxy;   R 4  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R 5  is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, sulfonylamine, thiourea, amino, acylamine, carboxy, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine and hydroxyl; 
         R 6  is hydrogen; 
         R 7  is selected from the group consisting of aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 8 -heterocycloalkyl, wherein each of said aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 8 -heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl; and 
         R 9  is selected from the group consisting of hydrogen, methyl and ethyl. 
       
     
     
         4 . The compound according to  claim 1 , wherein
 each X is CR 6 ;   each Y is independently selected from the group consisting of CR 6 ; N and NR 6 ;   L is NH;   R 1  is selected from the group consisting of hydrogen, methyl, and ethyl;   each R 2  is independently selected from the group consisting of hydrogen, methyl, ethyl, acyl, thioamide, chloro, methoxy, bromo and fluoro;   n is either 1 or 2;   R 3  is selected from the group consisting of hydrogen, methyl, ethyl, methoxy and ethoxy;   R 4  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R 5  is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, sulfonylamine, thiourea, amino, acylamine, carboxy, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine and hydroxyl; 
         R 6  is hydrogen; 
         R 7  is selected from the group consisting of aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 8 -heterocycloalkyl, wherein each of said aryl, heteroaryl, C 3 -C 8 -cycloalkyl and C 3 -C 8 -heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, amine, cyano, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, sulfonylamine, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxyl, acylamine, hydroxy-C 1 -C 6 -alkyl, aryl and heteroaryl; and 
         R 9  is selected from the group consisting of hydrogen, methyl and ethyl. 
       
     
     
         5 . The compound according to  claim 1 , wherein said compound has Formula (II), 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , L, X and n are defined as in  claim 1 ; 
         and geometrical isomers, enantiomers, diastereomers, tautomers, racemates and pharmaceutically acceptable salts thereof. 
       
     
     
         6 . The compound according to  claim 1 , wherein said compound has Formula (III), 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 9 , L, X and n are defined as in  claim 1 ; 
         each R 8  is independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 -alkyl, sulfonylamine, thiourea, acylamine, carboxy, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, hydroxylamine and hydroxyl; and 
         m is an integer selected from 1, 2, 3 or 4; 
         and geometrical isomers, enantiomers, diastereomers, tautomers, racemates and pharmaceutically acceptable salts thereof. 
       
     
     
         7 . A pharmaceutical composition comprising at least one compound according to  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient thereof. 
     
     
         8 . A method of treating a mammal suffering from or susceptible to a proliferative disease comprising administering to the mammal an effective of amount of a compound according to  claim 1 . 
     
     
         9 . The method according to  claim 8 , wherein said proliferative disease is cancer. 
     
     
         10 . The method according to  claim 8 , wherein said compound is selected from the group consisting of:
 N-Methyl-N′-(1-m-tolyl-ethylidene)-N-(2-trifluoromethylquinazolin-4-yl)-hydrazine;   N-Methyl-N′-(1-p-tolyl-ethylidene)-N-(2-trifluoromethylquinazolin-4-yl)-hydrazine;   N-(1-p-Tolyl-ethylidene)-N′-(2-trifluoromethyl-quinazolin-4-yl)-hydrazine;   N-[1-(4-methoxy-phenyl)-ethylidene]-N′-(2-methyl-quinazolin-4-yl)-hydrazine;   N-(2-Methyl-quinazolin-4-yl)-N-(1-p-tolyl-ethylidene)-hydrazine;   N-(2-methyl-quinazolin-4-yl)-N′-(1-m-tolyl-ethylidene)-hydrazine;   N-Methyl-N-(2-methyl-quinazolin-4-yl)-N-(1-p-tolyl-ethylidene)-hydrazine;   Dimethyl-(4-{1-[(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]ethyl}-phenyl)amine;   [4-(1-{[6-(2-Methoxy-phenyl)-2-methyl-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-dimethylamine;   [4-(1-{[6-(3,5-dimethyl-isoxazol-4-yl)-2-methyl-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-dimethylamine;   Dimethyl-[4-(1-{[2-methyl-6-(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-amine;   [4-(1-{[6-(2-Isopropoxy-phenyl)-2-methyl-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-dimethylamine;   [4-(1-{[6-(2-Fluoro-phenyl)-2-methyl-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-dimethylamine;   [4-(1-{[6-(2-amino-phenyl)-2-methyl-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-dimethylamine;   (4-{1-[(2-Methoxy-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenyl)-dimethylamine;   [4-(1{[2-Ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]-dimethylamine;   [4-(1-{[6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-hydrazono}-ethyl)-phenyl]dimethyl amine;   Methyl-(4-{1-[(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenyl)-amine;   4-{1-[(2-Methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenyl)-thiourea;   N-(4-{1-[(2-Methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenyl)-acetamide;   2-Methyl-4-{N′-[1-(4-methylamino-phenyl)-ethylidene]-hydrazino}-6-phenyl-pyrimidin-5-ylamine;   N-(2-Methyl-6-phenyl-pyrimidin-4-yl)-N′-[1-p-tolyl-propylidene]-hydrazine;   N-[1-(4-Chloro-phenyl)ethylidene]-N′-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine;   N-[1-(4-Methoxy-phenyl)-ethylidene]-N′-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine;   N-[6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[2-Ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[6-(2-Fluoro-phenyl)-2-methyl-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[6-(3-Methoxy-phenyl)-2-methylpyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[6-(2-Methoxy-phenyl)-2-methylpyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[6-(4-Methoxy-phenyl)-2-methylpyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   2-(2-Methyl-6-{N′-[1-p-tolyl-ethylidene]-hydrazino}-pyrimidin-4-yl)-benzonitrile;   N-[6-(2-methyl-phenyl)-2-methyl-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[2-Methyl-6-(2-morpholin-4-yl-phenyl)-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[2-(2-Methyl-6-{N′-[1-p-tolyl-ethylidene]-hydrazino}-pyrimidin-4-yl)-phenyl]-acetamide;   [2-(2-Methyl-6-{N′-[1-p-tolyl-ethylidene]-hydrazino}-pyrimidin-4-yl)-phenyl]-methanol;   N-[6-(3,5-Dimethyl-isoxazol-4-yl)-2-methyl-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-(2-Methyl-6-pyridin-3-yl-pyrimidin-4-yl)-N′-[1-p-tolyl-ethylidene]-hydrazine;   2-(2-Methyl-6-{N′-[1-p-tolyl-ethylidene]-hydrazino}-pyrimidin-4-yl)-phenylamine;   N-Methyl-N-(2-methyl-6-phenyl-pyrimidin-4-yl)-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-[6-(2,6-Dimethoxy-phenyl)-2-methyl-pyrimidin-4-yl]-N′-[1-p-tolyl-ethylidene]-hydrazine;   N-(2-Methyl-6-phenyl-pyrimidin-4-yl)-N′-(1-p-tolyl-ethylidene)-hydrazine;   4-{1-[(2-Methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenylamine;   N-[1-(4-Ethyl-phenyl)-ethylidene]-N′-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine;   N-[1-(4-Bromo-phenyl)-ethylidene]-N′-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine;   N-[1-(4-Iodo-phenyl)-ethylidene]-N′-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine,   3-{1-[(2-Methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenylamine:   N-[1-(3,4-Dichloro-phenyl)-ethylidene]-N′-(2-methyl-6-phenyl-pyrimidin-4-yl)-hydrazine; and   4-{1-[(2-Methyl-6-phenyl-pyrimidin-4-yl)-hydrazono]-ethyl}-phenol.   
     
     
         11 . A method of inhibiting cancer cell proliferation comprising contacting a cancer cell with a compound according to  claim 1  in an amount effective to inhibit the proliferation of the cancer cell. 
     
     
         12 . A method of inhibiting angiogenesis comprising contacting an endothelial cell with a compound according to  claim 1  in an amount effective to inhibit angiogenesis of said endothelial cell. 
     
     
         13 . A process for the preparation of a compound according to according to  claim 1  comprising a condensation step: 
       
         
           
           
               
               
           
         
         wherein A, R 1 , R 2 , R 9 , X, L and n are as defined in  claim 1 .