5-anilinoimidazopyridines and methods of use

Abstract

The invention relates to a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of an imidazopyridine of formula I with anti-hyperproliferative activity.

1 . A method of treating an inflammatory disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound according to formula I: 
       
         
           
           
               
               
           
         
         and salts thereof, wherein: 
         Z 1  is CR 1  or N; 
         R 1  is H, C 1 -C 3  alkyl, halo, CF 3 , CHF 2 , CN, OR A  or NR A R A ; 
         R 1′  is H, C 1 -C 3  alkyl, halo, CF 3 , CHF 2 , CN, OR A , or NR A R A ; 
         wherein each R A  is independently H or C 1 -C 3  alkyl; 
         Z 2  is CR 2  or N; 
         Z 3  is CR 3  or N; provided that only one of Z 1 , Z 2  and Z 3  can be N at the same time; 
         R 2  and R 3  are independently selected from H, halo, CN, CF 3 , —OCF 3 , —NO 2 , —(CR 14 R 15 ) n C(═Y′)R 11 , —(CR 14 R 15 ) n C(═Y′)OR 11 , —(CR 14 R 15 ) n C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 11 R 12 , —(CR 14 R 15 ) n OR 11 , —(CR 14 R 15 ) n SR 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)R 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)OR 11 , —(CR 14 R 15 ) n NR 13 C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 12 SO 2 R 11 , —(CR 14 R 15 ) n OC(═Y′)R 11 , —(CR 14 R 15 ) n OC(═Y′)OR 11 , —(CR 14 R 15 ) n OC(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n OS(O) 2 (OR 11 ), —(CR 14 R 15 ) n OP(═Y′)(OR 11 )(OR 12 ), —(CR 14 R 15 ) n OP(OR 11 )(OR 12 ), —(CR 14 R 15 ) n S(O)R 11 , —(CR 14 R 15 ) n S(O) 2 R 11 , —(CR 14 R 15 ) n S(O) 2 NR 11 R 12 , —(CR 14 R 15 ) n S(O)(OR 11 ), —(CR 14 R 15 ) n S(O) 2 (OR 11 ), —(CR 14 R 15 ) n SC(═Y′)R 11 , —(CR 14 R 15 ) n SC(═Y′)OR 11 , —(CR 14 R 15 ) n SC(═Y′)NR 11 R 12 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; 
         R 4  is H, C 1 -C 6  alkyl or C 3 -C 4  carbocyclyl; 
         Y is W—C(O)— or W′; 
         W is 
       
       
         
           
           
               
               
           
         
         R 5  is H or C 1 -C 12  alkyl; 
         X 1  is selected from R 11′  and —OR 11′ ; when X 1  is R 11′ , X 1  is optionally taken together with R 5  and the nitrogen atom to which they are bound to form a 4-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n C(═Y′)OR 16 , —(CR 19 R 20 ) n C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n SR 16 , —(CR 19 R 20 ) n NR 16 C(═Y′)R 17 , —(CR 19 R 20 ) n NR 16 C(═Y′)OR 17 , —(CR 19 R 20 ) n NR 18 C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 17 SO 2 R 16 , —(CR 19 R 20 ) n OC(═Y′)R 16 , —(CR 19 R 20 ) n OC(═Y′)OR 16 , —(CR 19 R 20 ) n OC(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n OS(O) 2 (OR 16 ), —(CR 19 R 20 ) n OP(═Y′)(OR 16 )(OR 17 ), —(CR 19 R 20 ) n OP(OR 16 )(OR 17 ), —(CR 19 R 20 ) n S(O)R 16 , —(CR 19 R 20 ) n S(O) 2 R 16 , —(CR 19 R 20 ) n S(O) 2 NR 16 R 17 , —(CR 19 R 20 ) n S(O)(OR 16 ), —(CR 19 R 20 ) n S(O) 2 (OR 16 ), —(CR 19 R 20 ) n SC(═Y′)R 16 , —(CR 19 R 20 ) n SC(═Y′)OR 16 , —(CR 19 R 20 ) n SC(═Y′)NR 16 R 17 , and R 21 ; 
         each R 11′  is independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; 
         R 11 , R 12  and R 13  are independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, 
         or R 11  and R 12  together with the nitrogen to which they are attached form a 3-8, membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , C 1 -C 6  alkyl, —OH, —SH, —O(C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —SO 2 (C 1 -C 6  alkyl), —CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —NHC(O)(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)SO 2 (C 1 -C 6  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6  alkyl), —OC(O)N(C 1 -C 6  alkyl) 2 , —OC(O)O(C 1 -C 6  alkyl), —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)O(C 1 -C 6  alkyl), and —N(C 1 -C 6  alkyl)C(O)O(C 1 -C 6  alkyl); 
         R 14  and R 15  are independently selected from H, C 1 -C 12  alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; 
         W′ is 
       
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         each X 2  is independently O, S, or NR 9 ; 
         each R 7  is independently selected from H, halo, CN, CF 3 , —OCF 3 , —NO 2 , —(CR 14 R 15 ) n C(═Y′) R 11 , —(CR 14 R 15 ) n C(═Y′)OR 11 , —(CR 14 R 15 ) n C(═Y′) NR 11 R 12 , —(CR 14 R 15 ) n NR 11 R 12 , —(CR 14 R 15 ) n OR 11 , —(CR 14 R 15 ) n SR 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)R 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)OR 11 , —(CR 14 R 15 ) n NR 13 C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n NR 12 SO 2 R 11 , —(CR 14 R 15 ) n OC(═Y′)R 11 , —(CR 14 R 15 ) n OC(═Y′)OR 11 , —(CR 14 R 15 ) n OC(═Y′)NR 11 R 12 , —(CR 14 R 15 ) n OS(O) 2 (OR 11 ), —(CR 14 R 15 ) n OP(═Y′)(OR 11 )(OR 12 ), —(CR 14 R 15 ) n OP(OR 11 )(OR 12 ), —(CR 14 R 15 ) n S(O)R 11 , —(CR 14 R 15 ) n S(O) 2 R 11 , —(CR 14 R 15 ) n S(O) 2 NR 11 R 12 , —(CR 14 R 15 ) n S(O)(OR 11 ), —(CR 14 R 15 ) n S(O) 2 (OR 11 ), —(CR 14 R 15 ) n SC(═Y′)R 11 , —(CR 14 R 15 ) n SC(═Y′)OR 11 , —(CR 14 R 15 ) n SC(═Y′)NR 11 R 12 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; 
         each R 8  is independently selected from C 1 -C 12  alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; 
         R 9  is selected from H, —(CR 14 R 15 ) n C(═Y′)R 11 , —(CR 14 R 15 ) n C(═Y′)OR 11 , —(CR 14 R 15 ) n C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) q NR 11 R 12 , —(CR 14 R 15 ) q OR 11 , —(CR 14 R 15 ) q SR 11 , —(CR 14 R 15 ) q NR 12 C(═Y′)R 11 , —(CR 14 R 15 ) q NR 12 C(═Y′)OR 11 , —(CR 14 R 15 ) q NR 13 C(═Y′)NR 11 R 12 , —(CR 14 R 15 ) q NR 12 SO 2 R 11 , —(CR 14 R 15 ) q OC(═Y′) R 11 , —(CR 14 R 15 ) q OC(═Y′)OR 11 , —(CR 14 R 15 ) q OC(═Y′)NR 11 R 12 , —(CR 14 R 15 ) q OS(O) 2 (OR 11 ), —(CR 14 R 15 ) q OP(═Y′)OR 11 )(OR 12 ), —(CR 14 R 15 ) q OP(OR 11 )(OR 12 ), —(CR 14 R 15 ) n S(O)R 11 , —(CR 14 R 15 ) n S(O) 2 R 11 , —(CR 14 R 15 ) n S(O) 2 NR 11 R 12 , C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; 
         R 10  is H, C 1 -C 6  alkyl or C 3 -C 4  carbocyclyl; 
         X 4  is 
       
       
         
           
           
               
               
           
         
         R 6  is H, halo, C 1 -C 6  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heteroaryl, heterocyclyl, —OCF 3 , —NO 2 , —Si(C 1 -C 6  alkyl), —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , or —(CR 19 R 20 ) n —SR 16 ; 
         R 6′  is H, halo, C 1 -C 6  alkyl, carbocyclyl, CF 3 , —OCF 3 , —NO 2 , —Si(C 1 -C 6  alkyl), —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n —SR 16 , C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, heterocyclyl, aryl, or heteroaryl; 
         p is 0, 1, 2 or 3; 
         n is 0, 1, 2 or 3; 
         q is 2 or 3; 
         wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 7 , R 8 , R 9 , R 10 , R 11 , R 11′ , R 12 , R 13 , R 14 , R 15  and R A  is independently optionally substituted with one or more groups independently selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —Si(C 1 -C 6  alkyl), —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n C(═Y′)OR 16 , —(CR 19 R 20 ) n C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n SR 16 , —(CR 19 R 20 ) n NR 16 C(═Y′)R 17 , —(CR 19 R 20 ) n NR 16 C(═Y′)OR 17 , —(CR 19 R 20 ) n NR 18 C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 17 SO 2 R 16 , —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n OC(═Y′)OR 16 , —(CR 19 R 20 ) n OC(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n OS(O) 2 (OR 16 ), —(CR 19 R 20 ) n OP(═Y′)(OR 16 )(OR 17 ), —(CR 19 R 20 ) n OP(OR 16 )(OR 17 ), —(CR 19 R 20 ) n S(O)R 16 , —(CR 19 R 20 ) n S(O) 2 R 16 , —(CR 19 R 20 ) n S(O) 2 NR 16 R 17 , —(CR 19 R 20 ) n S(O)(OR 16 ), —(CR 19 R 20 ) n S(O) 2 (OR 16 ), —(CR 19 R 20 ) n SC(═Y′)R 16 , —(CR 19 R 20 ) n SC(═Y′)OR 16 , —(CR 19 R 20 ) n SC(═Y′)NR 16 R 17 , and R 21 ; 
         each R 16 , R 17  and R 18  is independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from halo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6  alkyl, —OH, —SH, —O(C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —SO 2 (C 1 -C 6  alkyl), CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —NHC(O)(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)SO 2 (C 1 -C 6  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6  alkyl), —OC(O)N(C 1 -C 6  alkyl) 2 , —OC(O)O(C 1 -C 6  alkyl), —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)O(C 1 -C 6  alkyl), and —N(C 1 -C 6  alkyl)C(O)O(C 1 -C 6  alkyl); 
         or R 16  and R 17  together with the nitrogen to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6  alkyl, —OH, —SH, —O(C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —SO 2 (C 1 -C 6  alkyl), —CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —NHC(O)(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)SO 2 (C 1 -C 6  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6  alkyl), —OC(O)N(C 1 -C 6  alkyl) 2 , —OC(O)O(C 1 -C 6  alkyl), —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)O(C 1 -C 6  alkyl), and —N(C 1 -C 6  alkyl)C(O)O(C 1 -C 6  alkyl); 
         R 19  and R 20  are independently selected from H, C 1 -C 12  alkyl, —(CH 2 ) n -aryl, —(CH 2 ) n -carbocyclyl, —(CH 2 ) n -heterocyclyl, and —(CH 2 ) n -heteroaryl; 
         R 21  is C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each member of R 21  is optionally substituted with one or more groups selected from halo, oxo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6  alkyl, —OH, —SH, —O(C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —SO 2 (C 1 -C 6  alkyl), —CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —NHC(O)(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)SO 2 (C 1 -C 6  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6  alkyl), —OC(O)N(C 1 -C 6  alkyl) 2 , —OC(O)O(C 1 -C 6  alkyl), —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)O(C 1 -C 6  alkyl), and —N(C 1 -C 6  alkyl)C(O)O(C 1 -C 6  alkyl); 
         each Y′ is independently O, NR 22 , or S; and 
         R 22  is H or C 1 -C 12  alkyl. 
       
     
     
         2 . The method of  claim 1  where the compound of formula I is selected from the group consisting of:
 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)-amide; 
 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide; 
 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-c]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide; 
 5-(4-bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)-amide; 
 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide; 
 5-(4-bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide; 
 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxy-ethoxy)-amide; 
 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide; 
 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide; 
 5-(2-fluoro-methanesulfanyl-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxy-ethoxy)-amide; 
 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (2-hydroxy-ethoxy)-amide; 
 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid ((S)-2-hydroxy-propoxy)-amide; 
 5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-hydroxy-ethoxy)-amide; 
 (R)—N-(2,3-dihydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide; 
 N-ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide; 
 N-(cyclopropylmethoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide; 
 5-(2-fluoro-4-iodophenylamino)-N-methylimidazo[1,5-a]pyrazine-6-carboxamide; 
 5-(4-bromo-2-fluorophenylamino)-N-(2-hydroxy-ethoxy)imidazo[1,5-a]pyrazine-6-carboxamide; 
 (S)-5-(4-bromo-2-fluorophenylamino)-N-(2-hydroxy-propoxy)imidazo[1,5-a]pyrazine-6-carboxamide; 
 (R)-5-(4-bromo-2-fluorophenylamino)-N-(2,3-dihydroxy-propoxy)imidazo[1,5-a]pyrazine-6-carboxamide; and, 
 5-(4-bromo-2-fluorophenylamino)-N-(cyclopropyl-methoxy)imidazo[1,5-a]pyrazine-6-carboxamide; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The method of  claim 1 , further comprising administering to said mammal an additional chemotherapeutic agent wherein said additional chemotherapeutic agent is administered sequentially or consecutively.