AKT protein kinase inhibitors

Abstract

The present invention provides compounds, including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula: A-L-CR where CR is a cyclical core group, L is a linking group and A is as defined herein. Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

1 . A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound comprising Formula I:  
         A-L-CR  I  
       where: 
 CR is heteroaryl, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21 , —C(O)OR 21 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)R 24 , NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , —C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23 , —OR 21 , C 1 -C 4  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  alkynyl, C 2 -C 6  heteroalkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are further optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  heteroalkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, —SR 21 , —S(O)R 24 , —SO 2 R 24 , —C(O)R 21 , C(O)OR 21 , —C(O)NR 21 R 22 , —NR 21 R 22  and —OR 21 ;  
 L is selected from:  
                                       
 where R 12  is hydrogen, halogen, hydroxy, cyano, nitro, amino, azido, C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl, C 1 -C 5  heteroalkyl, C 2 -C 5  heteroalkenyl or C 2 -C 5  heteroalkynyl, wherein any of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, azido, C 1 -C 4  alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy;  
 A is  
                     
 W is N or CR 15 , provided that when L is a substituted or unsubstituted piperazinylene, W must be CR 15 ;  
 G is hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, nitro, azido, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21 , —C(O)OR 21 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)OR 24 , —NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 , —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23 , —OR 21 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl;  
 B 1 and B 2  are independently absent or C 1 -C 4  alkylene, C 1 -C 4  heteroalkylene, C 2 -C 4  alkenylene, C 2 -C 4  heteroalkenylene, C 2 -C 4  alkynylene, C 2 -C 4  heteroalkynylene, C 3 -C 6  cycloalkylene, and C 3 -C 6  heterocycloalkylene, wherein any of said alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene or heterocycloalkylene is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, NR 21 R 22  and OR 21 ;  
 R 21 , R 22  and R 23  independently are hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  heteroalkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;  
 R 24  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  heteroalkyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  heteroalkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;  
 or any two of R 21 , R 22 , R 23  or R 24  together with the atom(s) to which they are attached form a 4 to 10 membered carbocyclic, aryl, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, aryl, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;  
 R 13 and R 14  are independently hydrogen, hydroxyl, cyano, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  alkynyl, C 2 -C 6  heteroalkynyl, C 1 -C 6  cycloalkyl, C 1 -C 6  heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —C(O)R 21 , C(O)OR 21 , C(═NR 21 )NR 22 R 22 or —SO 2 R 24 ,wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, arylalkyl or heteroarylalkyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, nitro, azido, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21 , —C(O)OR 21 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)OR 24 , —NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , —C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 , —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23 , —OR 21 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl;  
 or R 13  and R 14  together with the atoms to which they are attached form a 4 to 10 membered carbocyclic, aryl, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, aryl, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, NR 21 R 22  and OR 21 ;  
 or R 13  and an atom of B 2  together with N form a 4 to 10 membered carbocyclic, aryl, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, aryl, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, NR 21 R 22  and OR 21 ;  
 R 15  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl or C 2 -C 4  heteroalkynyl, wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl or heteroalkynyl is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, NR 21 R 22  and OR 21 ;  
 or R 13  and R 15  together with atoms to which they are attached form a 3 to 10 membered carbocyclic, aryl, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, aryl, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, NR 21 R 22  and OR 21 ;  
 or, when W is CR 15 , R 15  and an atom of B 1  or B2 together with C, form a 3 to 10 membered carbocyclic, aryl, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, aryl, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, NR 21 R 22  and OR 21 .  
 
     
     
         2 . The compound of  claim 1 , where 
 CR is selected from:                          where X is N or CR 1 ;    Y is CR 2  or N, provided that when X is N, Y must be CR 2 ;    Z is CR 3 R 3a  or NR 2a , provided that when X is N, Z must be CR 3 ;    D 1 , D 2 , D 3  and D 4  are independently CR 4  or N, provided that no more than two of D 1 , D 2 , D 3  or D 4  are N;                          is an optional double bond;    D 5  is CR 5 R 5a , NR 2a , O or S, provided that when D 5  is O or S, D 8  must be C, D 7  must be CR 7  or N, and either (i) Q must be CR 6  or CR 6 R 6a  or (ii) D 7  must be CR 7  or CR 7 R 7a ;    Q is CR 6 , N or C═O, provided that either (w) when Q is N, one of D 5 , D 7 and D 8  must be C, or (x) when Q is C═O, D 5  must be CR 5  or N, D 7  must be CR 7  or N, and D 8  must be C;    D 7  is CR 7 , N, O or S, provided that when D 7 is O or S, D 8 must be C, D 5  must be CR 5  or N, and either (y) Q must be CR 6 , or (z) D 5  must be CR 5 ;    D 8  is C or N, provided that when D 8  is N, D 5  must be CR 5 R 5a  and Q must be CR 6  or CR 6 R 6a ;    either K or M is carbonyl, provided that both K and M are not carbonyl;    R 1 , R 5 , R 5a  and R 8  are independently hydrogen, halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino or ethoxy;    R 2  is hydrogen, halogen, hydroxyl, cyano, nitro, amino, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, C 1 -C 6  cycloalkyl, C 1 -C 6  heterocycloalkyl, C 1 -C 6  aryl, or C 1 -C 6  heteroaryl, wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are further optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino and ethoxy;    R 2a  is hydrogen, hydroxyl, cyano, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 6  heteroalkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, aryl or heteroaryl, wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino or ethoxy;    R 3  and R 3a  are independently hydrogen, halogen, hydroxyl, cyano, nitro, amino azido, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  alkynyl, C 2 -C 6  heteroalkynyl, C 1 -C 6  cycloalkyl, C 1 -C 6  heterocycloalkyl, aryl or heteroaryl, wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are further optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, OR 1 , NR 1 R 2 , and (C═O)R 2 ;    R 4 , R 6 , R 6a , R 7 , R 7a  and R 10  are independently hydrogen, hydroxyl, cyano, amino, nitro, azido, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21 , —C(O)OR 21 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)OR 24 , —NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , —C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 , —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23  or —OR 21 , wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, nitro, azido, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21 , —C(O)OR 221 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)OR 24 , —NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , —C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 , —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23 , —OR 21 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may optionally be further optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, nitro, azido, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 2 -C 4  alkenyl, C 2 -C 4  heteroalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, —NR 21 R 22 , and —OR 21 ;    or R 6  and R 7  together with the atoms to which they are attached form a 4 to 10 membered carbocyclic, aryl, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, aryl, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, OR 1 , NR 1 R 2 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; and    R 9  is hydrogen, halogen, hydroxyl, cyano, nitro, azido, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  heteroalkenyl, C 2 -C 6  alkynyl, C 2 -C 6  heteroalkynyl, C 1 -C 6  cycloalkyl, C 1 -C 6  heterocycloalkyl, aryl, heteroaryl, —NR 21 R 22 , —OR 21 , —NR 21 SO 2 R 2  and —NR 21 C(O)R 22 , wherein any of said alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are further optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, nitro, azido, OR 1 , NR 1 R 2 , and (C═O)R 2 .    
     
     
         3 . The compound of  claim 2 , where CR is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , where D 5  is NH.  
     
     
         5 . The compound of  claim 2 , where CR is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 2 , where L is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , where L is:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 2 , where A is:  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2 , where A is:  
       
         
           
           
               
               
           
         
         where G is hydrogen, alkyl, cycloalkyl, heterocycloaryl, aryl or heteroaryl, wherein any of said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, nitro, azido, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21  , —C(O)OR 21 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)OR 24 , —NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , —C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 , —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23 , —OR 21 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl.  
       
     
     
         10 . The compound of  claim 6 , where A is:  
       
         
           
           
               
               
           
         
         where G is hydrogen, alkyl, cycloalkyl, heterocycloaryl, aryl or heteroaryl, wherein any of said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, nitro, azido, —NR 21 SO 2 R 24 , —SO 2 NR 21 R 22 , —NR 21 S(O)R 4 , —S(O)R 4 , —S(O)NR 21 R 22 , —C(O)R 21 , —C(O)OR 21 , —OC(O)R 21 , —OC(O)OR 21 , —NR 21 C(O)R 24 , —NR 21 C(═NR 21 )NR 22 R 23 , —NR 21 C(O)R 22 , —C(O)NR 21 R 22 , —SR 21 , —S(O)R 24 , —SO 2 R 24 , —NR 21 R 22 , —NR 21 C(O)NR 22 R 23 , —NR 21 C(NCN)NR 22 R 23 , —OR 21 , C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl.  
       
     
     
         11 . The compound of  claim 6 , wherein A comprises:  
       
         
           
           
               
               
           
         
         where B 1  and B 2  are, independently, absent or C 1 -C 4  alkylene;  
         R 21a —R 21c  are independently H, halogen, CH 3 , CF 3 , CH 3 O, CN, NO 2 , NH 2 , Ph, OH, or OCH 2 Ph;  
         R 22a , R 22b , and R 24  are independently H, CH 3 , or halogen;  
         R23a is H; and  
         R23b is H, CH 3 , CH 2 NH 2 , CH 2 NHCH 2 , CH 2 CH 2 NH 2 , CH 2 CH 2 NHCH 2 , CH 2 CH 2 N(CH 2 ) 2 , —(C═O)CH 2 NH 2  or —(C═O)CH 2 CH 2 NH 2 ;  
         or R 23a  and R 23b  are joined to complete a 5 or 6 membered heterocyclic ring.  
       
     
     
         12 . The compound of  claim 7 , wherein A comprises:  
       
         
           
           
               
               
           
         
         where B 1  and B 2  are, independently, absent or C 1 -C 4  alkylene;  
         R 21a —R 21c  are independently H, halogen, CH 3 , CF 3 , CH 3 O, CN, NO 2 , NH 2 , Ph, OH, or OCH 2 Ph;  
         R 22a , R 22b , and R 24  are independently H, CH 3 , or halogen;  
         R 23a  is H; and  
         R 23b  is H, CH 3 , CH 2 NH 2 , CH 2 NHCH 2 , CH 2 CH 2 NH 2 , CH 2 CH 2 NHCH 2 , CH 2 CH 2 N(CH 2 ) 2 , —(C═O)CH 2 NH 2  or —(C═O)CH 2 CH 2 NH 2 ;  
         or R 23a  and R 23b  are joined to complete a 5 or 6 membered heterocyclic ring.  
       
     
     
         13 . The compound of  claim 6 , wherein A comprises:  
       
         
           
           
               
               
           
         
         wherein R 25  and R 26  are independently H or CH 3 ; and  
         R 27  is 1-naphthyl, 2-naphthyl, 3′-benzylthienyl, 2′-thienyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl, 4′-thiazolyl, or 3,3-diphenyl.  
       
     
     
         14 . The compound of  claim 7 , wherein A comprises:  
       
         
           
           
               
               
           
         
         wherein R 25  and R 26  are independently H or CH 3 ; and  
         R 27  is 1-naphthyl, 2-naphthyl, 3′-benzylthienyl, 2′-thienyl, 2′-pyridyl, 3′-pyridyl, 4′-pyridyl, 4′-thiazolyl, or 3,3-diphenyl.  
       
     
     
         15 . The compound of  claim 6 , where A is:  
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 7 , where A is:  
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 7 , where A is a D- or L-amino acid selected from the naturally occurring amino acids, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.  
     
     
         18 . The compound of  claim 17 , wherein the amino acid is alanine, phenylalanine, histidine, or tryptophan.  
     
     
         19 . The compound of  claim 1 , wherein the compound comprises:  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , wherein the compound comprises:  
       
         
           
           
               
               
           
         
         wherein R 28  is s H, halogen, CH 3 , CF 3 , CH 3 O, CN, NO 2 , NH 2 , Ph, OH, or OCH 2 Ph.  
       
     
     
         21 . The compound of  claim 1 , wherein the compound comprises:  
       
         
           
           
               
               
           
         
         wherein D 16  is O or N; and  
         R 29  is H, halogen, CH 3 , CF 3 , CH 3 O, CN, NO 2 , NH 2 , Ph, OH, or OCH 2 Ph.  
       
     
     
         22 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 1  to said mammal.  
     
     
         23 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 2  to said mammal.  
     
     
         24 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 3  to said mammal.  
     
     
         25 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 4  to said mammal.  
     
     
         26 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 5  to said mammal.  
     
     
         27 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 6  to said mammal.  
     
     
         28 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 7  to said mammal.  
     
     
         29 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 8  to said mammal.  
     
     
         30 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 9  to said mammal.  
     
     
         31 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 10  to said mammal.  
     
     
         32 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 11  to said mammal.  
     
     
         33 . A method of treating hyperproliferative diseases in a mammal comprising administering a therapeutically effective amount of the compound defined in  claim 12  to said mammal.  
     
     
         34 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         35 . A composition comprising a compound of  claim 2  and a pharmaceutically acceptable carrier.  
     
     
         36 . A composition comprising a compound of  claim 3  and a pharmaceutically acceptable carrier.  
     
     
         37 . A composition comprising a compound of  claim 4  and a pharmaceutically acceptable carrier.  
     
     
         38 . A composition comprising a compound of  claim 5  and a pharmaceutically acceptable carrier.  
     
     
         39 . A composition comprising a compound of  claim 7  and a pharmaceutically acceptable carrier.  
     
     
         40 . A composition comprising a compound of  claim 9  and a pharmaceutically acceptable carrier.  
     
     
         41 . A compound according to any one of claims  1 - 21  for use as a medicament.  
     
     
         42 . A compound according to any one of claims  1 - 21  for use as a medicament for the treatment of a hyperproliferative disorder.  
     
     
         43 . The use of a compound according to any one of claims  1 - 21  in the manufacture of a medicament for the treatment of a hyperproliferative disorder or an inflammatory condition.