Kinase inhibitors

Abstract

The invention relates to inhibitors of kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating disease or disease symptoms. The invention also provides for methods of making kinase inhibitor compounds, methods of inhibiting kinase activity, and methods for treating disease or disease symptoms.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein, 
 Each R 1  and R 2  is independently R 3 ; R 8 ; NHR 3 ; NHR 5 ; NHR 6 ; NR 5  R 5 ; NR 5 R 6 ; SR 5 ; SR 6 ; OR 5 ; OR 6 ; C(O)R 3 ; heterocyclyl optionally substituted with 1-4 independent R 4  on each ring; or C1-C10 alkyl substituted with 1-4 independent R 4 ;  
 Each R 3  is independently aryl; phenyl optionally substituted with 1-4 independent R 4 ; or heteroaryl optionally substituted with 1-4 independent R 4  on each ring;  
 Each m is independently 0, 1, 2 or 3;  
 Each n is independently 1 or 2;  
 Each X is O or S;  
 Each R 4  is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 ; halo; haloalkyl; CF 3 ; SR 5 ; OR 5 ; OC(O)R 5 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; S(O) n R 5;  S(O) n NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O) n NR 5 R 5 ; NR 5 S(O) n R 5 ; NR 5 S(O) n R 8 ; NR 5 C(O)C(O)NR 5 R 5 ; NR 5 C(O)C(O)NR 5 R 6 ; C1-C10 alkyl substituted with 1-3 independent aryl, R 7  or R 8 ; or C2-C10 alkenyl substituted with 1-3 independent aryl, R 7  or R 8 ;  
 Each R 5  is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 9 ; haloalkyl; C1-C10 alkyl substituted with 1-3 independent aryl, R 7  or R 9  groups; C3-C10 cycloalkyl substituted with 1-3 independent aryl, R 7  or R 9  groups; or C2-C10 alkenyl substituted with 1-3 independent aryl, R 7  or R 9 ;  
 Each R is independently C(O)R 5 , COOR 5 , C(O)NR 5 R 5 , or S(O) n R 5 ;  
 Each R 7  is independently halo, CF 3 , SR 10 , OR 1 , OC(O)R 10 , NR 10 R 10 , NR 10 R 1 , NR 11 R 11 , COOR 10 , NO 2 , CN, C(O)R 10 , OC(O)NR 10 R 10 , C(O)NR 10 R 10 , N(R 10 )C(O)R 10 , N(R 10 ) (COOR 10 ), S(O) n NR 10 R 10;    
 Each R 8  is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 9 ; halo; sulfuir; oxygen; CF 3 ; SR 5 ; OR 5 ; OC(O)R 5 ; NR 5 R 5 ; NR 5 R 6 ; NR 6 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)NR 5 R 5 ; S(O) n NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)R 9 ; NR 5 S(O) n NR 5 R 5 ; NR 5 S(O)NR 9 ; C1 C10 alkyl substituted with 1-3 independent R 7 , R 9  or aryl; or C2-C10 alkenyl substituted with 1-3 independent R 7 , R 9  or aryl;  
 Each R 9  is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF 3 ; SR 10 ; OR 10 ; NRtR 10 ; NR 10 R 11 ; NR 1 , R 11 ; COOR 10 ; NO 2 ; CN; S(O)NR 11 ; S(O) n NR 10 R 10 ; C(O)R 10 ; or C(O)NR 10 R 10 ;  
 Each R 10  is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF 3 , OR 12 , SR 12 , NR 12 R 12 , COOR 12 , NO 2 , CN, C(O)R 12 , C(O)NR 12 R 12 , NR 12 C(O)R 12 , N(R 12 )(COOR 12 ), S(O) n R 12 R 12 , or OC(O)R 12 ; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF 3 , OR 12 , SR 12 , NR 12 R 12 , COOR 12 , NO 2 , CN, C(O)R 12 , C(O)NR 12 R 12 , NR 12 C(O)R 12 , N(R 12 )(COOR 12 ), S(O) n NR 12 R 12 , or OC(O)R 12 ;  
 Each R 11  is independently C(O)R 10 , COOR 10 , C(O)NR 10 R 10  or S(O) n R 10 ;  
 Each R 12  is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl substituted with 1-3 independent C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF 3 , OR 13 , SR 13 , NR 13 R 13 , COOR 13 , NO 2 , CN, C(O)R 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , or OC(O)R 13 ; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF 3 , OR 13 , SR 13 , NR 13 R 13 , COOR 13 , NO 2 , CN, C(O)R 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , or OC(O)R 13 ;  
 Each R 13  is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF 3 , OR 14 , SR 14 , NR 14 R 14 , COOR 14 , NO 2 , CN; or phenyl optionally substituted with halo, CF 3 , OR 14 , SR 14 , NR 14 R 14 , COOR 14 , NO 2 , CN;  
 Each R 14  is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;  
 Each R 15  is independently H; CF 3 ; CN; COOR 5 ; or C1-C10 alkyl substituted with 1-3 independent OR 5 , SR 5 , or NR 5 R 5 ;  
 Each R is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 ; halo; haloalkyl; CF 3 ; COOR 5 ; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; S(O) n R 5 : S(O) n NR 5 R 4 ; C1-C10 alkyl substituted with 1-3 independent aryl, R 7  or R 8 ; or C2-C10 alkenyl substituted with 1-3 independent aryl, R 7  or R 8 ;  
 Each R 17  is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 17 ; halo; haloalkyl; CF 3 ; SR 5 ; OR 18 ; OC(O)R 5 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; S(O) n R 5 ; S(O) n NR 5 R 5 ; NR 5 C(O)NR 5 R 5 ; NR 5 C(O)C(O)R 5 ; NR 5  C(O)R 5 ; NR 5  (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O) n NR 5 R 5 ; NR 5 S(O) n R 5 ; NR 5 S(O) n R 8 ; NR 5 C(O)C(O)NR 5 R 5 ; NR 5 C(O)C(O)NR 5 R 6 ; C1-C10 alkyl substituted with 1-3 independent aryl, R 7  or R 8 ; or C1-C10 alkenyl substituted with 1-3 independent aryl, R 7  or R 8 ;  
 Each R 18  is independently aryl; R 8 ; C1-C10 alkyl substituted with 1-3 independent aryl, CF 3 , OC(O)R 10 , NHR 19 , NR 10 R 11 , NR 11 R 11 , COOR 10 , NO 2 , CN, C(O)R 10 , OC(O)NR 10 R 10 , C(O)NR 10 R 10 , N(R 10 )C(O)R 10 , N(R 10  (COOR 10 ), S(O) n NR 10 R 10 , or R 8 ; or C2-C10 alkenyl substituted with 1-3 independent aryl, CF 3 , OC(O)R 10 , NHR 19 , NR 10 R 11 , NR 11 R 11 , COOR 10 , NO 2 , CN, C(O)R 10 , OC(O)NR 10 R 10 , C(O)NR 10 R 10 , N(R 10 )C(O)R 10 , N(R 10 )(COOR 10 ), S(O) n NR 10 OR 10 , or R 8 ;  
 Each R 19  is independently C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 9 ; haloalkyl;  
 Each R 20  is independently NR 5 R 16 ; OR 5 ; SR 5 ; or halo;  
 Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;  
 Each aryl is independently a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R 9 ; halo; haloalkyl; CF 3 ; OR 10 ; SR 10 ; NR 10 R 11 ; NR 10 R 11 ; COOR 10 ; NO 2 ; CN; C(O)R 10 ; C(O)C(O)R 10 ; C(O)NR 10 R 10 ; N(R 10 )C(O)NR 10  R 10 ; N(R 10 )C(O)R; N(R 10 )S(O)R 10 ; N(R 10 )(COOR 10 ); NR 10 C(O)C(O)R 10 ; NR 10 C(O)R 9 ; NR 10 S(O) n NR 10 R 10 ; NR 10 S(O) n R 9 ; NR 12 C(O)C(O)NR 12 R 2 ; S(O) n   10 ; S(O) n NR 10 R 10 ; OC(O)R 10 ; C1-C10 alkyl substituted with 1-3 independent R 9 , halo, CF 3 , OR 10 , SR 10 , OC(O)R 10 , NR 11 R 11 , NR 10 R 10 , NR 10 R 11 , COOR 10 , NO 2 , CN, C(O)R 10 , OC(O)NR 10 R 10 , C(O)NR 10 R 10 , N(R 10 )C(O)R 10 , N(R 10 ) (COOR 10 ), S(O) n NR 10 R 10 ; R 10 ; or C2-C10 alkenyl substituted with 1-3 independent R 9 , halo, CF 3 , OR 10 , SR 10 , OC(O)R 10 , NR 11 R 11 , NR 10 R 10 , NR 10 R 11 , COOR 10 , NO 2 , CN, C(O)R 10 , OC(O)NR 10 R 10 , C(O)NR 10 R 10 , N(R 10 )C(O)R 10 , N(R 10 ) (COOR 10 ), S(O) n NR 10 R 10 ;  
 Each heterocyclyl is independently a 5-8 membered nonaromatic monocyclic, 8-12 membered nonaromatic bicyclic, or 11-14 membered nonaromatic tricyclic, ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S;  
 Each heteroaryl is independently a 5-8 membered aromatic monocyclic, 8-12 membered aromatic bicyclic, or 11-14 membered aromatic tricyclic ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S.  
 
     
     
         2 . The compound of  claim 1 , wherein: 
 Each R 1  is independently NHR 3 ; and    Each R 2  is independently NHR 3.      
     
     
         3 . The compound of  claim 1 , wherein: 
 Each R 1  is independently NHR 3 ; and    Each R 2  is independently one of the formulae:                          wherein m is 1 or 2, said 1 or 2 R 4  not being H, and wherein each R 17  is independently C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 ; haloalkyl; CF 3 ; SR 5 ; OR 18 ; OC(O)R 5 ; NR 5 R 5 ; NR 5 R 6 ; COOR 5 ; NO 2 ; CN; C(O)R 5 ; C(O)C(O)R 5 ; C(O)NR 5 R 5 ; S(O) n R 5 S(O) n NR 5 R 5 ; NR 5 C(O)NR 5 ; NR 5 C(O)C(O)R 5 ; NR 5 C(O)R 5 ; NR 5 (COOR 5 ); NR 5 C(O)R 8 ; NR 5 S(O) n NR 5 R 5 ; NR 5 S(O) n R 5 ; NR 5 S(O) n R 8 ; NR 5 C(O)C(O)NR 5 R 5 ; NR 5 C(O)C(O)NR 5 R 6 ; C1-C10 alkyl substituted with 1-3 independent aryl, R 7  or R 8 ; or C1-C10 alkenyl substituted with 1-3 independent aryl, R 7  or R 8      
     
     
         4 . The compound of  claim 1 , wherein: 
 Each R 1  is independently NHR 3 ; wherein the R 3  group in R 1  is heteroaryl substituted with 1-4 independent R 4 , wherein at least one R 4  is not H, on each ring; and    Each R 2  is independently one of the formulae:                          
     
     
         5 . The compound of  claim 1 , wherein: 
 Each R 1  is independently NHR 3 ; wherein the R 3  group in R 1  is pyrazolyl, triazolyl, imidazolyl, pyrrolyl, indolyl, or indazolyl, each substituted with 1-4 independent R 4  on each ring, wherein at least one of said R 4  is not H; and    Each R 2  is independently one of the formulae:                          
     
     
         6 . The compound of  claim 1 , wherein: 
 Each R 1  is independently R 3  and    Each R 2  is independently NHR 3 .    
     
     
         7 . The compound of  claim 1 , wherein: 
 Each R 1  is independently heterocyclyl substituted with 1-4 independent R 4  on each ring; and    Each R 2  is independently NHR 3 ;    wherein each R 1  may not be l-alkyl-1,2,3,4-tetrahydroisoquinolin-2-yl (wherein alkyl is defined as methyl, ethyl or propyl).    
     
     
         8 . The compound of  claim 1 , wherein: 
 Each R 1  is independently heterocyclyl substituted with 1-4 independent R 4  on each ring; and    Each R 2  is independently one of the formulae:                          wherein each R 1  may not be 1-alkyl-1,2,3,4-tetrahydroisoquinolin −2 -yl (wherein alkyl is defined as methyl, ethyl or propyl).    
     
     
         9 . The compound of  claim 1 , wherein: 
 Each R 1  is independently heterocyclyl substituted with 1-4 independent R 4  on each ring, wherein said heterocyclyl comprises at least one nitrogen heteroatom and said heterocyclyl is attached at said nitrogen heteroatom;    Each R 2  is independently NHR 3 ;    wherein each R 1  may not be 1-alkyl-1,2,3,4-tetrahydroisoquinolin-2-yl (wherein alkyl is defined as methyl, ethyl or propyl).    
     
     
         10 . The compound of  claim 1 , wherein: 
 Each R 1  is independently pyrrolyl substituted with 1-4 independent R 4  on each ring, wherein at least one of said R 4  is not H; and    Each R 2  is independently NHR 3 .    
     
     
         11 . The compound of  claim 1 , wherein: 
 Each R 1  is independently pyrazolyl substituted with 1-4 independent R 4  on each ring, wherein at least one of said R 4  is not H; and    Each R 2  is independently NHR 3 .    
     
     
         12 . The compound of  claim 1 , wherein: 
 Each R 1  is independently benzimidazolyl substituted with 1-4 independent R 4  on each ring, wherein at least one of said R 4  is not H; and    Each R 2  is independently NHR 3 .    
     
     
         13 . The compound of  claim 1 , wherein: 
 Each R 1  is independently heteroaryl substituted with 1-4 independent R 4  on each ring, wherein said heteroaryl comprises at least one nitrogen heteroatom and said heteroaryl is attached at said nitrogen heteroatom, and said heteroaryl is not unsubstituted pyrrolyl; and    Each R 2  is independently NHR 3 .    
     
     
         14 . The compound of  claim 1 , wherein: 
 Each R 1  is independently heteroaryl substituted with 1-4-independent R 4  on each ring, wherein said heteroaryl comprises at least one nitrogen heteroatom and said heteroaryl is attached at said nitrogen heteroatom, and said heteroaryl is not unsubstituted pyrrolyl; and    Each R 2  is independently one of the formulae:                          
     
     
         15 . The compound of  claim 1 , wherein: 
 Each R 2  is independently NHR 3; and    Each R 1  is independently of the formula:                          
     
     
         16 . The compound of  claim 1 , wherein: 
 Each R 2  is independently NHR 3 ; and    Each R 1  is independently of the formula:                          
     
     
         17 . The compound of  claim 1 , wherein: 
 Each R 2  is independently NHR 3; and    Each R 1  is independently of the formula:                          
     
     
         18 . The compound of  claim 1 , wherein: 
 Each R 2  is independently NHR 3 ; and    Each R 1  is independently of the formula:                          
     
     
         19 . A composition comprising a compound according to any of claims  1 - 18  and a pharmaceutically acceptable carrier.  
     
     
         20 . The composition according to  claim 19 , further comprising an additional therapeutic agent.  
     
     
         21 . A method of treating a kinase mediated disease or disease symptoms in a mammal comprising administration to said mammal of a compound of  claim 1 .  
     
     
         22 . The method of  claim 21 , wherein the mammal is a human.  
     
     
         23 . A method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a compound of  claim 1 .  
     
     
         24 . The method of  claim 23 , wherein said mammal is a human.  
     
     
         25 . A method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound of  claim 1 .  
     
     
         26 . The method of  claim 25 , wherein said mammal is a human.  
     
     
         27 . A method of making a pharmaceutically useful composition comprising combining a compound of  claim 1  with one or more pharmaceutically acceptable carriers.  
     
     
         28 . The method of  claim 27 , further comprising combining an additional therapeutic agent.  
     
     
         29 . A method of making a compound of  claim 1  comprising reacting a pyrimidine of any of the formulae:  
       
         
           
           
               
               
           
         
       
       with one or more appropriate nucleophilic agent(s), wherein the groups in said formula are as defined in  claim 1.