Inhibitors of akt activity

Abstract

The instant invention provides for substituted naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.

1 - 16 . (canceled) 
     
     
         17 . A compound according to Formula C-1: 
       
         
           
           
               
               
           
         
       
       wherein:
 a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is 0, 1 or 2; 
 the dashed line represents an optional double bond; 
 R 2  is independently selected from: (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, CO 2 H, halo, OH and NH 2 ; 
 Ring Y is (C 4 -C 7 )cycloalkyl; 
 R 1  is selected from: H, oxo, (C═O) a O b (C 1 -C 10 )alkyl, (C═O) a O b -aryl, (C═O) a O b (C 2 -C 10 )alkenyl, (C═O) a O b (C 2 -C 10 )alkynyl, CO 2 H, halo, OH, O b (C 1 -C 6 )perfluoroalkyl, (C═O) a NR 7 R 8 , CN, (C═O) a O b (C 3 -C 8 )cycloalkyl, S(O) m NR 7 R 8 , SH, S(O) m —(C 1 -C 10 )alkyl and (C═O) a O b -heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ; 
 R 6  is: (C═O) a O b C 1 -C 10  alkyl, (C═O) a O b aryl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, (C═O) a O b  heterocyclyl, CO 2 H, halo, CN, OH, O b C 1 -C 6  perfluoroalkyl, O a (C═O) b NR 7 R 8 , oxo, CHO, (═O)R 7 R 8 , S(O) m NR 7 R 8 , SH, S(O) m —(C 1 -C 10 )alkyl or (C═O) a O b C 3 -C 8  cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 6a ; 
 R 6a  is selected from: (C═O) a O b (C 1 -C 10 )alkyl, O a (C 1 -C 3 )perfluoroalkyl, (C 0 -C 6 )alkylene-S(O) m R a , SH, oxo, OH, halo, CN, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 0 -C 6 )alkylene-aryl, (C 0 -C 6 )alkylene-heterocyclyl, (C 0 -C 6 )alkylene-N(R b ) 2 , C(O)R a , (C 0 -C 6 )alkylene-CO 2 R a , C(O)H, and (C 0 -C 6 )alkylene-CO 2 H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O a (C═O) b (C 1 -C 6 )alkyl, oxo, and N(R b ) 2 ; 
 R 7  and R 8  are independently selected from: H, (C═O) a O b (C 1 -C 10 )alkyl, (C═O) a O b (C 3 -C 8 )cycloalkyl, (C═O) a O b -aryl, (C═O) a O b -heterocyclyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, SH, SO 2 R a , and (C═O) a NR b   2 , said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6a , or R 7  and R 8  can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6a ; 
 R a  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and 
 R b  is independently: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O) a O b (C 1 -C 6 )alkyl, or S(O) m R a ; 
 
       or a tautomer; 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         18 . A compound according to  claim 17 , wherein:
 R 1  is selected from: oxo, (C═O) a O b (C 1 -C 10 )alkyl, (C═O) a O b -aryl, (C═O) a O b (C 2 -C 10 )alkenyl, (C═O) a O b (C 2 -C 10 )alkynyl, CO 2 H, halo, OH, O b (C 1 -C 6 )perfluoroalkyl, (C═O) a NR 7 R 8 , CN, (C═O) a O b (C 3 -C 8 )cycloalkyl, S(O) 2 NR 7 R 8 , SH, S(O) 2 —(C 1 -C 10 )alkyl and (C═O) a O b -heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with R 6a ;   
       or a tautomer; 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         19 . A compound according to  claim 17 , wherein:
 R 1  is selected from: oxo, (C═O) a O b (C 1 -C 10 )alkyl, CO 2 H, halo, OH, CN, (C 1 -C 6 )alkoxy, S(O) 2 NR 7 R 8 , SH, S(O) 2 —(C 1 -C 10 )alkyl, O(C═O)(C 1 -C 6 )alkyl and N(R b ) 2 , said alkyl is optionally substituted with R 6a ;   
       or a tautomer; 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         20 . A compound according to  claim 17 , wherein:
 R 1  is selected from: oxo, NH 2 , OH, SH, O a (C 1 -C 6 )alkyl, said alkyl is optionally substituted with R 6a ;   
       or a tautomer; 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         21 . A compound according to Formula C: 
       
         
           
           
               
               
           
         
       
       wherein:
 p is 0, 1 or 2; 
 Ring Y is cyclobutyl; 
 R 1  is selected from: H, heterocyclyl, (C 3 -C 6 )cycloalkyl, OH, (C 1 -C 6 )alkyl, NH(C 1 -C 6 )alkyl, NH-heterocyclyl, NH-cycloalkyl, said heterocyclyl, cycloalkyl and alkyl is optionally substituted with: halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-NH 2 , OH, O(C 1 -C 6 )alkyl; and 
 R 2  is H or F; 
 
       or a tautomer; 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         22 . A compound according to  claim 17  which is selected from: 
       1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-[4-(9-phenyl-3-pyrimidin-2-yl-[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-[4-(9-phenyl-3-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-[4-(9-phenyl-3-pyrazolo[1,5-a]pyrimidin-3-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-[4-(3-imidazo[2,1-b][1,3]thiazol-6-yl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-{4-[9-phenyl-3-(1H-1,2,3-triazol-4-yl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol; 
       1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-{4-[3-(difluoromethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       {8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}methanol; 
       1-{4-[3-(methoxymethyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}ethanol; 
       2-{8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}propan-2-ol; 
       1-[4-(3-cyclopropyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-[4-(3-cyclohexyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine; 
       1-{4-[9-phenyl-3-(tetrahydro-2H-pyran-2-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[3-(4-methylmorpholin-2-yl)-9-phenyl-[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[3-(2-methyltetrahydro-2H-pyran-2-yl)-9-phenyl-[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[9-phenyl-3-(tetrahydro-2H-pyran-3-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[9-phenyl-3-(tetrahydro-2H-pyran-4-yl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-(4-fluorophenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[3-methyl-9-(4-fluorophenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-{4-[3-(ethylamino)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine; 
       1-[2-({8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}amino)ethyl]-1-methylpiperidine; 
       8-[4-(1-aminocyclobutyl)phenyl]-N-cyclohexyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine; 
       8-[4-(1-aminocyclobutyl)phenyl]-N-(tert-butyl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine; 
       N′-{8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-yl}-N,N-dimethylpropane-1,3-diamine; 
       1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclopentanamine; 
       1-{4-[3-methyl-9-(4-fluorophenyl) [1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclopentanamine; 
       1-{4-[3-(1-Methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclohexanamine; 
       1-{4-[3-Methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclohexanamine; and 
       8-[4-(1-aminocyclohexyl)phenyl]-N-ethyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine; 
       or a tautomer; 
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         23 . A compound which is: 
       
         
           
           
               
               
           
         
       
       8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol; 
       or a tautomer; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A compound which is: 
       
         
           
           
               
               
           
         
       
       8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of  claim 17 . 
     
     
         26 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutic effective amount of a compound of  claim 17 .