Methods of use of diazacarbazoles for treating cancer

Abstract

Methods of use of compounds of formula (I) for treating cancer: wherein X, Y, X, R 3 , R 5 and R 6 are as defined herein.

1 . 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 a compound of formula (I), or a salt thereof: 
       
         
           
           
               
               
           
         
         X is CR 2  or N; 
         Y is CR 4  or N; 
         Z is CR 8  or N; provided that no more than one of X, Y and Z is N at the same time; 
         R 2  is H, halo, CN, CF 3 , —OCF 3 , OH, —NO 2 , C 1 -C 5  alkyl, —O(C 1 -C 5  alkyl), —S(C 1 -C 5  alkyl), or N(R 22 ) 2 ; 
         R 3  is H, halo, CN, —O—R 9 , —N(R 22 )—R 9 , —S(O) p —R 9 , or R 9 ; 
         p is 0, 1 or 2; 
         R 4  is H, halo, CN, CF 3 , —OCF 3 , OH, —NO 2 , —(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 S(O) p R 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 )—NR 12 C(═Y′)NR 11 R 12 , —(CR 14 R 15 )—NR 12 SO 2 R 11 , —(CR 14 R 15 ) n C(═Y′)R 11 , —(CR 14 R 15 ) n OC(═Y′)NR 11 R 12 , —(CR 14 R 15 )—S(O) 2 NR 11 R 12 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 13  groups; 
         each n is independently 0-5; 
         R 5  is H, halo, CN, CF 3 , —OCF 3 , OH, —NO 2 , —(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 12 C(═Y′)R 11 , —(CR 14 R 15 ) n NR 11 R 12 , —(CR 14 R 15 ) n OR 11 , —(CR 14 R 15 ) n S(O) p R 11 , —(CR 14 R 15 ) n NR 12 C(═Y′)OR 11 , (CR 14 R 15 ) n NR 12 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′)NR 11 R 12 ; —(CR 14 R 15 )—S(O) 2 NR 11 R 12 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl wherein the said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 13  groups; 
         R 6  is CN, —CF 3 , —OCF 3 , halo, —C(═Y′)NR 11 R 12 ; —OR 11 , —OC(═Y′) R   11 , —NR 11 R 12 ; NR 12 C(═Y′)R 11 , —NR 12 C(═Y′)NR 11 R 12 ; NR 12 S(O) q R 11 ; —SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —OC(═Y′)NR 11 R 12 , S(O) 2 NR 11 R 12 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R 13  groups; 
         R 8  is H, halo, CN, NO 2 , N(R 22 ) 2 , OH, O(C 1 -C 3  alkyl), or C 1 -C 3  alkyl, wherein each said alkyl is optionally substituted with one to three fluoro groups; 
         each R 9  is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each member of R 9  is independently substituted with one to three R 10  groups; 
         each R 10  is independently H, CN, —CF 3 , —OCF 3 , —NO 2 , halo, R 11 , —OR 11 , —NR 12 C(═Y═)R 11 , —NR 12 C(═NR 12 )R 11 , —NR 12 S(O) q R 11 , —SR 11 , —NR 11 R 12 , oxo, —C(═Y′)OR 11 , —C(═Y′)NR 11 R 12 , —S(O) q R 11 , NR 12 C(Y′)OR 11 , —NR 12 C(═Y′)NR 11 R 12 ; —OC(═Y′)R 11 , —OC(═Y′)NR 11 R 12 , or —S(O) 2 NR 11 R 12 ; 
         each q independently is 1 or 2; 
         R 11  and R 12  are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 13  groups, wherein two geminal R 13  groups are optionally taken together with the atom to which they are attached to form a 3-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R 18  groups; 
         R 11  and R 12  are optionally taken together with the attached N atom to form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R 13  groups; 
         each R 13  is independently halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —(CR 14 R 15 ) n C(═Y′)R 16 , —(CR 14 R 15 ) n C(═Y′)OR 16 , —(CR 14 R 15 ) n C(═Y′)NR 16 R 17 , —(CR 14 R 15 ) n NR 16 R 17 , —(CR 14 R 15 ) n OR 16 , —(CR 14 R 15 ) n SR 16 , —(CR 14 R 15 ) n NR 16 C(═Y)R 17 , —(CR 14 R 15 ) n NR 16 C(═Y′)OR 17 , —(CR 14 R 15 ) n NR 17 C(═Y′)NR 16 R 17 , —(CR 14 R 15 ) n NR 17 SO 2 R 16 , —(CR 14 R 15 ) n OC(═Y′)R 16 , —(CR 14 R 15 ) n C(═Y)NR 16 R 17 , —(CR 14 R 15 ) n S(O)R 16 , —(CR 14 R 15 )—S(O) 2 R 16 , —(CR 14 R 15 ) n S(O) 2 NR 16 R 17 , or R 16 ; 
         R 14  and R 15  are independently selected from H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 18  groups; 
         R 16  and R 17  are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 18  groups; 
         R 16  and R 17  are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R 18  groups; 
         each R 18  is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —(CR 19 R 20 ) n C(═Y′)R 23 , —(CR 19 R 20 ) n  C(═Y′)OR 23 , —(CR 19 R 20 ) n  C(═Y′)NR 23 R 24 , —(CR 19 R 20 ) n NR 23 R 24 , —(CR 19 R 20 ) n OR 23 , —(CR 19 R 20 ) n —SR 23 , —(CR 19 R 20 ) n NR 24 C(═Y ‘)R 23 , —(CR 19 R 20 ) n NR 24 C(═Y’)OR 23 , —(CR 19 R 20 ) n NR 22 C(═Y′)NR 23 R 24 , —(CR 19 R 20 ) n NR 24 SO 2 R 23 , —(CR 19 R 20 ) n OC(═Y′)R 23 , —(CR 19 R 20 ) n  OC(═Y′)NR 23 R 24 , —(CR 19 R 20 ) n S(O)R 23 , —(CR 19 R 20 ) n S(O) 2 R 23 , or —(CR 19 R 20 ) n S(O) 2 NR 23 R 24 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R 21  groups; 
         R 19  and R 20  are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 25  groups; 
         R 23  and R 24  are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R 21  groups; 
         R 23  and R 24  are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R 21  groups; 
         each R 21  is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —C(═Y)R 25 , —C(═Y′)OR 25 , —C(═Y′)NR 25 R 26 , —NR 25 R 26 , —OR 25 , —SR 25 , —NR 26 C(═Y′)R 25 , —NR 26 C(═Y′)OR 25 , —NR 22 C(═Y′)NR 25 R 26 , NR 26 SO 2 R 25 , —OC(═Y′)R 25 , —OC(═Y′)NR 25 R 26 , —S(O)R 25 , —S(O) 2 R 25 , or —S(O) 2 NR 25 R 26 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R 25  groups; 
         each R 25  and R 26  is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to four groups selected from halo, —CN, —OCF 3 , —CF 3 , —NO 2 , —C 1 -C 6  alkyl, —OH, oxo, —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 , —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 25  and R 26  are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four groups selected from halo, —CN, —OCF 3 , CF 3 , —NO 2 , —C 1 -C 6  alkyl, —OH, oxo, —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 , —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); 
         Y′ is independently O, NR 22 , or S; and 
         each R 22  is independently H or C 1 -C 5  alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein X is CR 2 . 
     
     
         3 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 2  is H. 
     
     
         4 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein Y is CR 4 . 
     
     
         5 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 4  is H. 
     
     
         6 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein Z is CR 8 . 
     
     
         7 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 8  is H. 
     
     
         8 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 3  is Br. 
     
     
         9 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 3  is H. 
     
     
         10 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 3  is R 9 . 
     
     
         11 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 9  is C 1 -C 6  alkyl, C 2 -C 3  alkynyl, C 6  aryl, or 5-6 membered monocyclic or 8-10-membered bicyclic heteroaryl having 1 to 2 ring atoms selected from N, O and S; and wherein each member of R 9  is independently substituted with one to two R 10  groups. 
     
     
         12 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 9  is isopropyl, propynyl, phenyl, pyrazolyl, furanyl, thienyl, pyridyl, imidazolyl, pyrimidinyl, benzothienyl, thiazolyl, tetrahydrothienopyridinyl, tetrahydrothiazolopyridinyl, isothiazolyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, triazolyl, dihydrobenzodioxinyl, dihydroindolyl, oxazolyl, or tetrahydrobenzothienyl, wherein each member of R 9  is independently substituted with one to two R 10  groups. 
     
     
         13 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 10  is halo, R 11 , —OR 11 , CN, —CF 3 , —OCF 3 , NR 12 C(═O)R 11 , —NR 12 S(O) q R 11 , —SR 11 , —NR 11 R 12 , —C(═O)NR 11 R 12 , oxo, —S(O) q R 11 , —S(O) 2 NR 11 R 12 , or —C(═O)OR 11 , wherein R 11  and R 12  are optionally taken together with the attached N atom to form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R 13  groups. 
     
     
         14 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 10  is R 11 . 
     
     
         15 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 11  is C 1 -C 6  alkyl, or 4-6 membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2 heteroatoms selected from N and O, wherein said alkyl and heterocyclyl are optionally substituted with one to four R 13  groups, wherein two geminal R 13  groups are optionally taken together with the atom to which they are attached to form a six-membered ring having 0-2 heteroatom selected from O, S, and N, said ring being optionally substituted with one to four R 18  groups. 
     
     
         16 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 11  is C 1 -C 6  alkyl, wherein alkyl is optionally substituted with one to two R 13  groups and wherein each R 13  is independently halo, CN, CF 3 , —OCF 3 , oxo, —(CR 14 R 15 ) n C(O)OR 16 , —(CR 14 R 15 ) n C(O)NR 16 R 17 , —(CR 14 R 15 ) n NR 16 R 17 , —(CR 14 R 15 ) n OR 16 , —(CR 14 R 15 ) n NR 16 C(O)R 17 , —(CR 14 R 15 ) n S(O) 2 NR 16 R 17 , or R 16 . 
     
     
         17 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 11  is 4-6 membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2 heteroatoms selected from N and O, wherein said alkyl and heterocyclyl are optionally substituted with one to two R 13  groups and wherein each R 13  is independently halo, CN, CF 3 , —OCF 3 , oxo, (CR 14 R 15 ) n C(O)OR 16 , —(CR 14 R 15 ) n C(O)NR 16 R 17 , —(CR 14 R 15 ) n NR 16 R 17 , —(CR 14 R 15 ) n OR 16 , —(CR 14 R 15 ) n NR 16 C(O)R 17 , —(CR 14 R 15 ) n S(O) 2 NR 16 R 17 , or R 16 . 
     
     
         18 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 10  is —OR 11 . 
     
     
         19 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 11  is H, C 1 -C 4  alkyl, or 4-6 membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or heterocyclyl is optionally substituted with one to two R 13  groups, wherein each R 13  is independently halo, CN, CF 3 , —OCF 3 , oxo, —(CR 14 R 15 )—C(O)OR 16 , (CR 14 R 15 ) n C(O)NR 16 R 17 , —(CR 14 R 15 ) n NR 16 R 17 , —(CR 14 R 15 ) n OR 16 , —(CR 14 R 15 ) n NR 16 C(O)R 17 , —(CR 14 R 15 ) n S(O) 2 NR 16 R 17 or R 16 . 
     
     
         20 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 5  is H. 
     
     
         21 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 5  is —(CR 14 R 15 ) n C(O)NR 11 R 12 , (CR 14 R 15 ) n NR 12 C(O)R 11 , —(CR14R 15 ) n NR 11 R 12 , —(CR 14 R 15 ) n OR 11 , C 1 -C 6  alkyl, or 4-6 membered monocyclic or 7-10 membered bicyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or heterocyclyl is optionally substituted with one to two R 13  groups; wherein R 14  and R 15  are H; n is 0-2; each R 11  is independently H, C 1 -C 4  alkyl, or 5-6 membered monocyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkyl or heterocyclyl is optionally substituted with one to two R 13  groups; and R 13  is OH, O(C 1 -C 3  alkyl), or C 1 -C 3  alkyl. 
     
     
         22 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 6  is CN, halo, —C(O)NR 11 R 12 , —OR 11 , —NR 11 R 12 , —NR 12 C(O)R 11 , C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl, 5-6 membered heterocyclyl having 1 to 2 heteroatoms, C 6  aryl, or 5-6 membered heteroaryl having 1 to 2 heteroatoms; wherein said alkyl is substituted with one to two R 13  groups except H; and said cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one to two R 13  groups; wherein heteroatoms are selected from N, O and S; wherein each R 12  is H or C 1 -C 3  alkyl and each R 11  is independently H or C 1 -C 3  alkyl optionally substituted by one to two R 13  groups. 
     
     
         23 . The method of  claim 1 , wherein the compounds of formula (I) are those wherein R 6  is CN. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the compounds of formula (I) are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . The method of any one of  claims 1  to  25  and  33  to  44  wherein the hyperproliferative disorder is cancer in a mammal. 
     
     
         31 . The method of  claim 30 , wherein cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma, myelomas leukemia and acute myelogenous leukemia (AML). 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         36 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         37 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         39 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         40 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         41 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . The method of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         45 . The method of  claim 1 , comprising administering a second therapeutic agent selected from the group consisting of: Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkyl sulfonates comprising busulfan, improsulfan and piposulfan; aziridines comprising benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines comprising altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins comprising bullatacin and bullatacinone; bryostatin; callystatin; CC-1065 comprising its adozelesin, carzelesin and bizelesin synthetic analogs; cryptophycins comprising cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin comprising the synthetic analogs, KW-2189 and CB1-TM1; eleutherobin; pancratistatin; a sarcodictyin; spongistatin; folic acid analogs comprising denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs comprising fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs comprising ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens comprising calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals comprising aminoglutethimide, mitotane, and trilostane; folic acid replenisher comprising frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; lentinan; lonidainine; maytansinoids comprising maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes comprising T-2 toxin, verracurin A, roridin A and anguidine); urethan; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); chloranmbucil; 6-thioguanine; mercaptopurine; ifosfamide; mitoxantrone; novantrone; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; difluoromethylornithine (DMFO); anti-hormonal agents that act to regulate or inhibit hormone action on tumors comprising anti-estrogens and selective estrogen receptor modulators (SERMs), comprising tamoxifen comprising NOLVADEX®; tamoxifen citrate, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, comprising 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); anti-androgens comprising flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; troxacitabine comprising 1,3-dioxolane nucleoside cytosine analogs; protein kinase inhibitors; lipid kinase inhibitors; antisense oligonucleotides, comprising those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, comprising PKC-alpha, Ralf and H-Ras; ribozymes comprising VEGF expression inhibitors comprising ANGIOZYME® and HER2 expression inhibitors; vaccines comprising gene therapy vaccines, comprising ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitor comprising LURTOTECAN®; ABARELIX® rmRH; anti-angiogenic agents comprising bevacizumab (AVASTIN®, Genentech); inhibitors of MEK, comprising MAP kinase kinase, comprising XL518 (Exelixis, Inc.) and AZD6244 (Astrazeneca); inhibitors of Raf, comprising XL281 (Exelixis, Inc.), PLX4032 (Plexxikon), and ISIS5132 (Isis Pharmaceuticals); inhibitors of mTor comprising rapamycin, AP23573 (Ariad Pharmaceuticals), temsirolimus (Wyeth Pharmaceuticals) and RAD001 (Novartis); inhibitors of PI3K (phosphoinositide-3 kinase), comprising SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.), and GDC-0941 (Genentech); inhibitors of cMet, comprising PHA665752 (Pfizer), XL-880 (Exelixis, Inc.), ARQ-197 (ArQule), and CE-355621; DNA damaging agent comprising thiotepa and CYTOXAN® cyclosphosphamide; alkylating agents comprising cis-platin; carboplatin; cyclophosphamide; nitrogen mustards comprising chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; busulphan; nitrosoureas comprising carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine and temozolomide; antimetabolites comprising antifolates comprising fluoropyrimidines like 5-fluorouracil (5-FU) and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and GEMZAR® (gemcitabine); antitumour antibiotics comprising enediyne antibiotics comprising calicheamicin comprising calicheamicin gamma1I and calicheamicin omegaI1; anthracyclines comprising adriamycin; dynemicin, comprising dynemicin A; bisphosphonates, comprising clodronate; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins comprising mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimitotic agents comprising vinca alkaloids like vincristine, vinblastine, vindesine and NAVELBINE® (vinorelbine) and taxoids like taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel, and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); topoisomerase inhibitors comprising RFS 2000, epipodophyllotoxins like etoposide and teniposide, amsacrine, a camptothecin comprising the synthetic analog topotecan, and irinotecan and SN-38 and cytodifferentiating agents comprising retinoids comprising all-trans retinoic acid, 13-cis retinoic acid and fenretinide; an agent that modulates the apoptotic response comprising inhibitors of IAP (inhibitor of apoptosis proteins) comprising AEG40826 (Aegera Therapeutics); and inhibitors of bcl-2 comprising GX15-070 (Gemin X Biotechnologies), CND0103 (Apogossypol; Coronado Biosciences), HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate), AT101 (Ascenta Therapeutics), ABT-737 and ABT-263 (Abbott); and pharmaceutically acceptable salts thereof. 
     
     
         46 . The method of  claim 45 , wherein the second therapeutic agent is selected from the group consisting of Gemcitabine, Irinotecan, SN-38, arabinoside (“Ara-C”) and a topoisomerase inhibitor 1 or 2. 
     
     
         47 . A method of treating cancer selected from the group consisting of breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma, myelomas, leukemia and acute myelogenous leukemia (AML) in a mammal comprising administering to said mammal a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof and a second chemotherapeutic agent selected from the group consisting of Gemcitabine, Irinotecan, SN-38, arabinoside (“Ara-C”) and a topoisomerase inhibitor 1 or 2.