Compounds, compositions and methods

Abstract

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of KSP are disclosed.

1 . (canceled)  
     
     
         2 . A compound selected from those represented by Formula II:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1 , R 2 , R 3  and R 4  are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halogen, hydroxyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, optionally substituted aryl and optionally substituted heteroaryl;  
         R 5  and R 5′  are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; or R 5  and R 5′  taken together form an optionally substituted 3- to 7-membered carbocyclic ring;  
         R 6  is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;  
         R 7 , R 7′ , R 8 , R 8′ , R 9  and R 9′  are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;  
         X and Y are each independently chosen from C(R 10 )(R 11 ), N(R 12 ), O and S, wherein R 10  and R 11  are each independently chosen from H, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl; and  
         R 12  is H, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted heteroaralkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heteroaryloxycarbonyl, optionally substituted aralkyloxycarbonyl, or optionally substituted heteroaralkyloxycarbonyl;  
         T and U are independently a covalent bond, —C(O)—, or optionally substituted alkylene;  
         A, B, D and E are independently N, C, CH, O, S or absent, provided that. 
 no more than one of A, B, D or E is absent;  
 no more than two of A, B, D and E are —N═, and  
 A, B, D or E can be O or S only when one of A, B, D or E is absent; and  
 
         provided that R 1 , R 2 , R 3  or R 4  is absent where A, B, D or E, respectively, is —N═, O, S or absent;  
         and pharmaceutically acceptable salts thereof.  
       
     
     
         3 . A compound according to  claim 2  wherein A, B, D and E are independently chosen from —C═ and —N═.  
     
     
         4 . A compound according to  claim 2  or  3  wherein T is optionally substituted C 1 -C 4  alkylene or is a covalent bond.  
     
     
         5 . A compound according to  claim 2 , wherein U is optionally substituted C 1 -C 4  alkylene or is a covalent bond.  
     
     
         6 . A compound according to  claim 2  wherein R 1 , R 2 , R 3  and R 4  are each independently selected from H, halogen, cyano, optionally substituted C 1 -C 4  alkyl; C 1 -C 4  haloalkyl, optionally substituted C 1 -C 4  alkoxy, and C 1 -C 4  haloalkoxy.  
     
     
         7 . A compound according to  claim 2  wherein R 1 , R 2 , R 3  and R 4  are each independently selected from H and halogen.  
     
     
         8 . A compound according to  claim 2  wherein R 1 , R 2  and R 4  are each H and R 3  is halogen.  
     
     
         9 . A compound according to  claim 2  wherein R 5  and R 5′  are each independently selected from H and C 1 -C 4  alkyl.  
     
     
         10 . A compound according to  claim 2  wherein R 5′ , is H and R 5  is C 1 -C 4  alkyl.  
     
     
         11 . A compound according to  claim 9  wherein R 5′  is H and R 5  is H, ethyl, cyclopropyl or iso-propyl.  
     
     
         12 . A compound according to  claim 2  wherein R 6  is C 1 -C 8  alkyl, aryl-C 1 -C 4  alkyl- or heteroaryl-C 1 -C 4  alkyl-.  
     
     
         13 . A compound according to  claim 2  wherein R 6  is phenyl-C 1 -C 4  alkyl-.  
     
     
         14 . A compound according to  claim 2 , wherein R 6  is benzyl.  
     
     
         15 . A compound according to  claim 2  wherein R 7 , R 7′ , R 8 , R 8′ , R 9  and R 9′  are each independently selected from H and C 1 -C 4  alkyl.  
     
     
         16 . A compound according to  claim 2  wherein R 9  and R 9′  are each H and R 7  and R 7′  or R 8  and R 8′  are each independently H or C 1 -C 4  alkyl.  
     
     
         17 . A compound according to  claim 2  wherein R 7 , R 7′ , R 8 , R 8′ , R 9 , and R 9′  are each H; or R 7 , R 7′ , R 9 , and R 9′  are each H and R 8  and R 8′  are each H or C 1 -C 4  alkyl, or R 8 , R 8′ , R 9 , and R 9′  are each H and R 7  and R 7′  are each H or C 1 -C 4  alkyl.  
     
     
         18 . A compound according to  claim 2  wherein each of said C 1 -C 4  alkyl is methyl.  
     
     
         19 . A compound according to  claim 2  wherein one of X or Y is C(R 10 )(R 11 ), wherein R 10  and R 11  are each independently selected from H or C 1 -C 4  alkyl, and the other of X or Y is N(R 12 ), where R 12  is H, C 1 -C 4  alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, C 1 -C 6  alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted heteroaralkylcarbonyl, C 1 -C 6  alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heteroaryloxycarbonyl, optionally substituted aralkyloxycarbonyl, optionally substituted heteroaralkyloxycarbonyl, where the optionally substituted aryl or heteroaryl groups or moieties are unsubstituted or substituted with one or more substituents selected from C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, amino, C 1 -C 4  alkylamino, di-C 1 -C 4  alkylamino, carboxy, C 1 -C 4  alkylcarbonyloxy, C 1 -C 4  alkoxycarbonyl, carboxamido, C 1 -C 4  alkylcarboxamido, aminocarbonyl, C 1 -C 4  alkylaminocarbonyl, di-C 1 -C 4  alkylaminocarbonyl, cyano, C 1 -C 4  alkylcarbonyl, halogen, hydroxyl, mercapto and nitro.  
     
     
         20 . A compound according to  claim 2  wherein X is C(R 10 )(R 11 ), wherein R 10  and R 11  are each H or C 1 -C 4  alkyl, and Y is N(R 12 ), where R 12  is H, C 1 -C 4  alkyl, aralkyl, heteroaralkyl, C 1 -C 6 , alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl.  
     
     
         21 . A compound according to  claim 2  wherein X is CH 2 , and Y is N(R 12 ), where R 12  is H, methyl, benzyl or acetyl (—C(O)methyl).  
     
     
         22 . A compound according to  claim 2  wherein R 5  and R 5′  are each attached to a stereogenic center having an R-configuration.  
     
     
         23 . (canceled)  
     
     
         24 . A compound selected from: 
 3-Benzyl-7-chloro-2-[2-methyl-1-(7-oxo-[1,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one;    3-Benzyl-7-chloro-2-[2-methyl-1-(4-methyl-7-oxo-[1,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one3-benzyl-7-chloro-2-[(R)-2-methyl-1-(7-oxo-[1,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one; 2-[1-(Acetyl-7-oxo-[1,4]diazepan-1-yl)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one; 3-Benzyl-7-chloro-2-[1-(3,3-dimethyl-7-oxo-[1,4]diazepan-1-yl)-2-methyl-propyl]-3H-quinazolin-4-one;    3-Benzyl-2-[1-(4-benzyl-7-oxo-[1,4]diazepan-1-yl)-2-methyl-propyl]-7-chloro-3H-quinazolin-4-one;    3-Benzyl-7-chloro-2-[1-(7-oxo-[1,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one; and    3-Benzyl-7-chloro-2-[1-(6,6-dimethyl-7-oxo-[1,4]diazepan-1-yl)-2-methyl-propyl]-3H-quinazolin-4-one;    or a pharmaceutically acceptable salt thereof.    
     
     
         25 . (canceled)  
     
     
         26 . (canceled)  
     
     
         27 . A composition comprising a pharmaceutically acceptable excipient and a compound according to  claim 2 .  
     
     
         28 . A composition according to  claim 27 , wherein said composition further comprises a taxane, a vinca alkaloid, or a topoisomerase I inhibitor.  
     
     
         29 . A method of modulating KSP kinesin activity which comprises contacting said kinesin with an effective amount of the compound according to  claim 2 .  
     
     
         30 . A method of inhibiting KSP which comprises contacting said kinesin with an effective amount of the compound according to  claim 2 .  
     
     
         31 . A method for the treatment of a disease of proliferating cells comprising administering to a subject in need thereof the compound according to  claim 2 .  
     
     
         32 . (canceled)  
     
     
         33 . A method according to  claim 31  wherein said disease is cancer.  
     
     
         34 . (canceled)