Thiopyrimidine and isothiazolopyrimidine Kinase Inhibitors

Abstract

Compounds having the formula are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     or a therapeutically acceptable salt thereof, wherein 
 X is selected from the group consisting of —N— and —CR 3 —;  
 Z 1  is selected from the group consisting of —N— and —CR 4 —;  
 z 2  is selected from the group consisting of —N— and —CR 5 —;  
 Z 3  is selected from the group consisting of —N— and —CR 6 —;  
 Z 4  is selected from the group consisting of —N— and —CR 7 —;  
 R 1  is selected from the group consisting of hydrogen and NH 2 ;  
 R 2  is selected from the group consisting of alkoxy, cyano, hydroxy, nitro, —NR a R b , and -LR 8 ;  
 R 3  is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, arylalkyl, carboxyalkyl, halo, haloalkyl, heteroarylalkyl, (heterocyclyl)alkyl, hydroxyalkyl, (NR a R b )alkyl, and (NR a R b )C(O)alkyl;  
 R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of hydrogen, alkoxy, alkyl, NR a R b , halo, and hydroxy;  
 R 8  is selected from the group consisting of alkoxyalkyl, alkyl, aryl, arylalkenyl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and (heterocyclyl)alkyl;  
 L is selected from the group consisting of —O—, —(CH 2 ) n C(O)(CH 2 ) p —, —C∉C—(CH 2 ) n O—, —C(O)NR 9 —, —NR 9 C(O)—, —NR 9 —, —(CH 2 ) n NR 9 C(O)NR 10 (CH 2 ) p —, —NR 9 C(S)NR 10 —, —NR 9 C(═NCN)NR 10 —, —NR 9 C(═NCN)O—, —OC(═NCN)NR 9 —, —NR 9 SO 2 —, and —SO 2 NR 9 —, wherein each group is drawn with its right side attached to R 8 , and wherein R 9  and R 10  are independently selected from the group consisting of hydrogen, and alkyl;  
 m, n, and p are independently 0-2;  
 provided that at least one of Z 1 , Z 2 , Z 3 , and Z 4  is other than —N—.  
 
   
   
       2 . The compound of  claim 1  wherein 
 Z 1  is —CR 4 —;    Z 3  is —CR 6 —; and    Z 4  is —CR 7 —.    
   
   
       3 . The compound of  claim 2  wherein 
 Z 2  is —CR 5 —;    R 1  is hydrogen;    R 2  is -LR 8 ; and    m is 0.    
   
   
       4 . The compound of  claim 3  wherein X is —N—.  
   
   
       5 . The compound of  claim 3  wherein X is —CR 3 —.  
   
   
       6 . The compound of  claim 5  wherein L is selected from the group consisting of —(CH 2 ) n C(O)(CH 2 ) p —, —C∉C—(CH 2 ) n O—, —C(O)NR 9 —, —NR 9 C(O)—, —NR 9 —, —NR 9 C(S)NR 10 —, —NR 9 C(═NCN)NR 10 —, —NR 9 C(═NCN)O, and NR 9 SO 2 —.  
   
   
       7 . The compound of  claim 5  wherein L is —(CH 2 ) n NR 9 C(O)NR 10 (CH 2 ) p —.  
   
   
       8 . The compound of  claim 7  wherein n and p are 0.  
   
   
       9 . The compound of  claim 8  wherein R 8  is aryl.  
   
   
       10 . The compound of  claim 9  wherein R 3  is selected from the group consisting of alkenyl, alkoxyalkyl, arylalkyl, halo, heteroarylalkyl, heterocyclylalkyl, hydroxyalkyl, and (NR a R b )alkyl.  
   
   
       11 . The compound of  claim 9  wherein R 3  is (NR a R b )C(O)alkyl.  
   
   
       12 . The compound of  claim 9  wherein R 3  is hydrogen.  
   
   
       13 . The compound of  claim 9  wherein R 3  is alkyl.  
   
   
       14 . The compound of  claim 13  wherein the alkyl is selected from the group consisting of ethyl, isopropyl, and propyl.  
   
   
       15 . The compound of  claim 13  wherein the alkyl is methyl.  
   
   
       16 . A compound which is 
 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.    
   
   
       17 . A compound which is 
 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-methylphenyl)urea.    
   
   
       18 . A compound which is 
 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-N′-(3-chlorophenyl)urea.    
   
   
       19 . A compound which is 
 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea.    
   
   
       20 . A compound which is 
 N-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea.    
   
   
       21 . A pharmaceutical composition comprising a compound of  claim 1  or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.  
   
   
       22 . A method for inhibiting a protein kinase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.  
   
   
       23 . A method for inhibiting KDR in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.  
   
   
       24 . A method for inhibiting Tie-2 in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.  
   
   
       25 . A method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of  claim 1 , or a therapeutically acceptable salt thereof.