Compounds, pharmaceutical compositions, and methods for inhibiting cyclin-dependent kinases

Abstract

Pharmaceutical compositions containing effective amounts of CDK-inhibiting diaminothiazole compounds of the following formula (where R 1 and R 2 are as defined in the specification) or their salts, or prodrugs or active metabolites of such compounds or salts, are useful for treating disorders and diseases such as cancer: In preferred embodiments, R 1 and R 2 are independently unsubstituted or substituted carbocyclic or heterocyclic aryl ring structures. Compounds where R 2 is ortho-substituted aryl are especially potent inhibitors of CDKs such as CDK4.

What is claimed is:  
     
         1 . A compound of the Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a substituted or unsubstituted group selected from: C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; C 1-6 -alkoxyl; C 1-6 -alcohol; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; carbonyl; ether; (C 1-6 -alkyl)-carbonyl; (C 1-6 -alkyl)-aryl; (C 1-6 -alkyl)-cycloalkyl; (C 1-6 -alkyl)-(C 1-6 -alkoxyl); aryl-(C 1-6 -alkoxyl); thioether; thiol; and sulfonyl; wherein when R 1  is substituted, each substituent independently is a halogen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; or carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; and  
 R 2  is a carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure having a substituent at the position adjacent to the point of attachment, which ring structure is optionally further substituted, where each substituent of R 2  independently is a halogen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; or carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl;  
 or a pharmaceutically acceptable salt of a compound of the Formula I, or a prodrug or pharmaceutically active metabolite of a compound of the Formula I or pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound, pharmaceutically acceptable salt, prodrug, or pharmaceutically active metabolite thereof according to  claim 1 , wherein: when R 1  is substituted, each substituent independently is a halogen, haloalkyl, C 1-6 -alkyl, C 1-6 -alkenyl, C 1-6 -alkynyl, hydroxyl, oxygen, C 1-6 -alkoxyl, amino, nitro, thiol, thioether, imine, cyano, amido, phosphonato, phosphine, carboxyl, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, or ester; and each substituent of R 2  independently is a halogen, haloalkyl, C 1-6 -alkyl, C 1-6 -alkenyl, C 1-6 -alkynyl, hydroxyl, C 1-6 -alkoxyl, amino, nitro, thiol, thioether, imine, cyano, amido, phosphonato, phosphine, carboxyl, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, or ester.  
     
     
         3 . A compound, pharmaceutically acceptable salt, prodrug, or active metabolite according to  claim 1 , wherein R 1  is a substituted phenyl group.  
     
     
         4 . A compound, pharmaceutically acceptable salt, prodrug, or active metabolite according to  claim 1 , wherein R 1  is phenyl substituted with an alkylamine or pyridine group.  
     
     
         5 . A compound, pharmaceutically acceptable salt, prodrug, or active metabolite according to  claim 1 , wherein R 1  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A compound, pharmaceutically acceptable salt, prodrug, or active metabolite according to  claim 1 , wherein R 1  is phenyl substituted by optionally substituted carbonyl or sulfonamide.  
     
     
         7 . A compound, pharmaceutically acceptable salt, prodrug, or active metabolite according to  claim 1 , wherein R 1  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       where R 3  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, aryl, aryloxy, and amine.  
     
     
         8 . A compound, pharmaceutically acceptable salt, prodrug or active metabolite according to  claim 1 , wherein R 2  is ortho-substituted phenyl or thienyl.  
     
     
         9 . A compound, pharmaceutically acceptable salt, prodrug or active metabolite according to  claim 9 , wherein R 2  is o-halophenyl or o-dihalophenyl.  
     
     
         10 . A compound, pharmaceutically acceptable salt, prodrug or active metabolite according to  claim 10 , wherein R 2  is o-difluorophenyl.  
     
     
         11 . A compound according to  claim 1  selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or active metabolite of said compound.  
     
     
         12 . A compound according to  claim 1  selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or active metabolite of said compound.  
     
     
         13 . A compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or active metabolite of said compound.  
     
     
         14 . A pharmaceutical composition comprising: 
 (a) an amount of a cell-cycle control agent effective to inhibit CDK4 or a CDK4/cyclin complex, said cell-cycle control agent being selected from the group consisting of: 
 (i) a compound of the Formula I:  
                     
  wherein: 
 R 1  is a substituted or unsubstituted group selected from: C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; C 1-6 -alkoxyl; C 1-6 -alcohol; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; carbonyl; ether; (C 1-6 -alkyl)-carbonyl; (C 1-6 -alkyl)-aryl; (C 1-6 -alkyl)-cycloalkyl; (C 1-6 -alkyl)-(C 1-6 -alkoxyl); aryl-(C 1-6 -alkoxyl); thioether; thiol; and sulfonyl; wherein when R 1  is substituted, each substituent independently is a halogen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; or carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; and  
 R 2  is a carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure having a substituent at the position adjacent to the point of attachment, which ring structure is optionally further substituted, where each substituent of R 2  independently is a halogen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; or carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl;  
 
 (ii) a pharmaceutically acceptable salt of a compound of the Formula I; and  
 (iii) a prodrug or pharmaceutically active metabolite of a compound of the Formula I or a pharmaceutically acceptable salt thereof; and  
   (b) a pharmaceutically acceptable carrier.    
     
     
         15 . A method of treating a disease or disorder mediated by inhibition of CDK4 or a CDK4/cyclin complex, comprising administering to a subject in need of such treatment a cell-cycle control agent selected from the group consisting of: 
 compounds of the Formula I:                           wherein: 
 R 1  is a substituted or unsubstituted group selected from: C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; C 1-6 -alkoxyl; C 1-6 -alcohol; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; carbonyl; ether; (C 1-6 -alkyl)-carbonyl; (C 1-6 -alkyl)-aryl; (C 1-6 -alkyl)-cycloalkyl; (C 1-6 -alkyl)-(C 1-6 -alkoxyl); aryl-(C 1-6 -alkoxyl); thioether; thiol; and sulfonyl; wherein when R 1  is substituted, each substituent independently is a halogen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; oxygen; C 1-6 -alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester; and  
 R 2  is a carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure having a substituent at the position adjacent the point of attachment, which ring structure is optionally further substituted, where each substituent of R 2  independently is a halogen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester;  
   pharmaceutically acceptable salts of compounds of the Formula I; and    prodrugs and pharmaceutically active metabolites of compounds of the Formula I and their pharmaceutically acceptable salts.    
     
     
         16 . A compound of the Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from:  
                     
 R 2  is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure; where each optional substituent for R 2  is independently a halogen; oxygen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester;  
 or a pharmaceutically acceptable salt of a compound of the Formula I, or a prodrug or pharmaceutically active metabolite of a compound of the Formula I or pharmaceutically acceptable salt thereof.  
 
     
     
         17 . A pharmaceutical composition comprising: 
 (a) an effective amount for inhibiting a CDK or a CDK/cyclin complex of a cell-cycle control agent selected from: 
 (i) compounds of the Formula I:  
                     
  wherein: 
 R 1  is selected from:  
                     
 R 2  is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure; where each optional substituent for R 2  is independently a halogen; oxygen; haloalkyl; C 1-6 -alkyl; C 1-6 -alkenyl; C 1-6 -alkynyl; hydroxyl; C 1-6 -alkoxyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester;  
 
 (ii) pharmaceutically acceptable salts of compounds of the Formula I; and  
 (iii) prodrugs and pharmaceutically active metabolites of compounds of the Formula I or pharmaceutically acceptable salts thereof; and  
   (b) a pharmaceutically acceptable carrier.