Methods and compositions utilizing quinazolinones

Abstract

Quinazolinones of formulae (a, b, c and d) are disclosed. They are useful for treating cellular proliferative diseases and disorders associated with KSP kinesin activity.

We claim:  
     
         1 . A method of treating cellular proliferative diseases comprising administering a compound chosen from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;  
 R 3  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R 15 O— and R 15 —NH—;  
 R 3′  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 15 —NH—;  
 R 3″  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;  
 R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;  
 R 15  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A method of treating a disorder associated with KSP kinesin activity comprising administering a compound chosen from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;  
 R 3  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R 15 O— and R 15 —NH—;  
 R 3 ′ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R 15 —NH—;  
 R 3 ″ is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;  
 R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;  
 R 15  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A method of inhibiting KSP kinesin comprising contacting KSP kinesin with a compound chosen from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;  
 R 3  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R 15 O— and R 15 —NH—;  
 R 3 ′ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R 15 —NH—;  
 R 3 ″ is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;  
 R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;  
 R 15  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         4 . A method according to  claim 1 ,  2  or  3  wherein: 
 R 1  is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl and substituted alkylheteroaryl;  
 R 2  is chosen from hydrogen, alkyl and substituted alkyl;  
 R 2 ′ is hydrogen;  
 R 3  is chosen from alkyl, substituted alkyl, alkylaryl, heteroaryl, aryl, substituted aryl, substituted hereroaryl, substituted oxaalkylaryl R 15 O— and R 15 —NH—;  
 R 4  is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted aryl, and R 16 -alkylene-;  
 R 5  is hydrogen;  
 R 6 , R 7  and R 8  are independently chosen from hydrogen, halogen, methyl, cyano and trifluoromethyl;  
 R 15  is chosen from alkyl, aryl and substituted aryl;  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino and N-heterocyclyl.  
 
     
     
         5 . A method according to  claim 1 ,  2  or  3  wherein: R 2  is chosen from hydrogen, alkyl and substituted alkyl; R 2 ′ is hydrogen; and the stereogenic center to which R 2  and R 2 ′ are attached is of the R configuration.  
     
     
         6 . A method according to  claim 1 ,  2  or  3  comprising administering a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A method according to  claim 6  wherein R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, alkylaryl and substituted alkylaryl.  
     
     
         8 . A method according to  claim 7  wherein R 1  is chosen from hydrogen, ethyl, propyl, methoxyethyl, naphthyl, phenyl, bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and (ethoxycarbonyl)ethyl.  
     
     
         9 . A method according to  claim 6  wherein R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl; R 2 ′ is hydrogen; and the stereogenic center to which R 2  and R 2 ′ are attached is of the R configuration.  
     
     
         10 . A method according to  claim 9  wherein R 2  is chosen from hydrogen, methyl, ethyl, propyl, methylthioethyl, aminobutyl, (CBZ)aminobutyl, cyclohexylmethyl, benzyloxymethyl, methylsulfinylethyl, methylsulfinylmethyl, hydroxymethyl, benzyl and indolylmethyl.  
     
     
         11 . A method according to  claim 6  wherein R 3  is chosen from C 1 -C 13  alkyl; substituted lower alkyl; aryl, substituted aryl, alkylaryl, alkylheteroaryl, oxaalkylaryl, oxaalkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, substituted oxaalkylaryl, and substituted oxaalkylheteroarlyl.  
     
     
         12 . A method according to  claim 11  wherein R 3  is chosen from ethyl, propyl, chloropropyl, butoxy, heptyl butyl, octyl, tridecanyl, (ethoxycarbonyl)ethyl, dimethylaminoethyl, dimethylaminomethyl, phenyl, naphthyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl)phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, chloronaphthyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, phenoxymethyl, dimethoxyphenyl, phenylvinyl, nitrochlorophenyl, nitrophenyl, dinitrophenyl, bis(trifluoromethyl)phenyl, benzyloxymethyl, benzyl, furanyl, benzofuranyl, pyridinyl, indolyl, methylpyridinyl, quinolinyl, picolinyl, pyrazolyl, and imidazolyl.  
     
     
         13 . A method according to  claim 6  wherein R 3  is R 15 —NH— and R 15  is chosen from lower alkyl; cyclohexyl; phenyl; and phenyl substituted with halo, lower alkyl, loweralkoxy, or lower alkylthio.  
     
     
         14 . A method according to  claim 13  wherein R 15  is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and methylthiophenyl.  
     
     
         15 . A method according to  claim 6  wherein R 4  is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R 16 -alkylene-, wherein R 16  is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.  
     
     
         16 . A method according to  claim 15  wherein R 4  is chosen from methyl, ethyl, propyl, butyl, cyclohexyl, carboxyethyl, carboxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylaminopropyl, aminopropyl, methylaminopropyl, 2,2-dimethyl-3-(dimethylamino)propyl, 1-cyclohexyl-4-(diethylamino)butyl, aminoethyl, aminobutyl, aminopentyl, aminohexyl, aminoethoxyethyl, isopropylaminopropyl, diisopropylaminoethyl, 1-methyl-4-(diethylamino)butyl, (t-Boc)aminopropyl, hydroxyphenyl, benzyl, methoxyphenyl, methylmethoxyphenyl, dimethylphenyl, tolyl, ethylphenyl, (oxopyrrolidinyl)propyl, (methoxycarbonyl)ethyl, benzylpiperidinyl, pyridinylethyl, pyridinylmethyl, morpholinylethyl, morpholinylpropyl, piperidinyl, azetidinylmethyl, azetidinylpropyl, pyrrolidinylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinylethyl, imidazolylpropyl, imidazolylethyl, (ethylpyrrolidinyl)methyl, (methylpyrrolidinyl)ethyl, (methylpiperidinyl)propyl, (methylpiperazinyl)propyl, furanylmethyl and indolylethyl.  
     
     
         17 . A method according to  claim 6  wherein 
 R 1  is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;  
 R 2  is chosen from hydrogen, alkyl, substituted lower alkyl and benzyl;  
 R 2 ′ is hydrogen;  
 R 3  is chosen from substituted phenyl and naphthyl;  
 R 4  is chosen from substituted alkyl and R 16 -alkylene-;  
 R 5  is hydrogen or halo  
 R 6  is hydrogen, methyl or halo;  
 R 7  is hydrogen, halo, lower alkyl, substituted lower alkyl, lower alkoxy or cyano;  
 R 8  is hydrogen or halo; and  
 R 16  is chosen from di(lower alkylamino), (lower alkyl)amino, amino, N-heterocyclyl and substituted N-heterocyclyl.  
 
     
     
         18 . A method according to  claim 1 ,  2  or  3  wherein 
 R 1  is benzyl or halobenzyl;  
 R 2  is chosen from ethyl and propyl;  
 R 2 ′ is hydrogen;  
 R 3  is substituted phenyl;  
 R 3′  is substituted phenyl;  
 R 3″  is substituted phenyl;  
 R 4  is —(CH 2 ) m OH or —(CH 2 ) p —R 16  wherein m is 2 or 3 and p is 1-3;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is halo;  
 R 8  is hydrogen; and  
 R 16  is chosen from amino, propylamino, and azetidinyl.  
 
     
     
         19 . A method according to  claim 18  wherein the stereogenic center to which R 2  and R 2′  are attached is of the R configuration.  
     
     
         20 . A method according to  claim 1 ,  2  or  3  comprising administering a compound of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         21 . A method according to  claim 20  wherein: 
 R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;  
 R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl and R 2 ′ is hydrogen;  
 R 3′  is chosen from C 1 -C 13  alkyl; phenyl; naphthyl; phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl; biphenylyl, benzyl and heteroaryl; and  
 R 4  is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R 16 -alkylene, wherein 
 R 16  is amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.  
 
 
     
     
         22 . A method according to  claim 20  wherein 
 R 1  is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;  
 R 2  is hydrogen or lower alkyl;  
 R 2 ′ is hydrogen;  
 R 3′  is chosen from substituted phenyl and naphthyl;  
 R 4  is R 16 -alkylene-, hydroxy lower alkyl or carboxy lower alkyl;  
 R 6  and R 7  are chosen from hydrogen and halo;  
 R 5  and R 8  are hydrogen;  
 R 16  is chosen from di(lower alkylamino), (lower alkyl)amino, amino, piperidinyl, azetidinyl pyrrolidinyl and morpholinyl.  
 
     
     
         23 . A method according to  claim 1 ,  2  or  3  comprising administering a compound of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof  
     
     
         24 . A method according to  claim 23  wherein: 
 R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;  
 R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl and R 2 ′ is hydrogen; and  
 R 4  is chosen from lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R 16 -alkylene, wherein R 16  is di(lower alkyl)amino, alkylamino, amino, lower alkoxy, or N-heterocyclyl.  
 
     
     
         25 . A method according to  claim 23  wherein 
 R 1  is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;  
 R 2  is hydrogen or lower alkyl;  
 R 2 ′ is hydrogen;  
 R 4  is R 16 -alkylene-;  
 R 6  and R 7  are chosen from hydrogen and halo;  
 R 5  and R 8  are hydrogen; and  
 R 16  is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidinyl, piperidinyl, imidazolyl and morpholinyl.  
 
     
     
         26 . A method according to  claim 1 ,  2  or  3  comprising administering a compound of formula:  
       
         
           
           
               
               
           
         
       
     
     
         27 . A method according to  claim 26  wherein: 
 R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;  
 R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl and R 2 ′ is hydrogen;  
 R 3″  is chosen from C 1 -C 13  alkyl; substituted lower alkyl; phenyl; naphthyl; phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl; biphenylyl; benzyl and heterocyclyl; and  
 R 4  is chosen from lower alkyl, substituted lower alkyl; cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; substituted benzyl; heterocyclyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R 16 -alkylene, wherein 
 R 16  is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.  
 
 
     
     
         28 . A method according to  claim 27  wherein 
 R 1  is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;  
 R 2  is hydrogen or lower alkyl;  
 R 2 ′ is hydrogen;  
 R 3″  is chosen from substituted phenyl, heterocyclyl and naphthyl;  
 R 4  is chosen from subtituted benzyl, heterocyclyl substituted lower alkyl and R 16 -alkylene-;  
 R 6  and R 7  are chosen from hydrogen and halo;  
 R 5  and R 8  are hydrogen;  
 R 16  is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidinyl, azetidinyl piperidinyl, imidazolyl and morpholinyl.  
 
     
     
         29 . A method according to  claim 28  wherein 
 R 1  is benzyl;  
 R 2  is ethyl;  
 R 2 ′ is hydrogen;  
 R 3″  is chosen from halophenyl, polyhalophenyl, tolyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, bis(trifluoromethyl)phenyl, carboxyphenyl, t-butylphenyl, methoxycarbonylphenyl, piperidinyl and naphthyl;  
 R 4  is chosen from substituted benzyl, piperidinyl, hydroxy (lower alkyl) and R 16 -alkylene-;  
 R 6  and R 7  are chosen from hydrogen and halo;  
 R 5  and R 8  are hydrogen;  
 R 16  is chosen from dimethylamino, amino, pyrrolidinyl and piperidinyl.  
 
     
     
         30 . A method according to  claim 1  or  2  wherein said disease or disorder is chosen from the group consisting of cancer, hyperplasia, restenosis, and cardiac hypertrophy.  
     
     
         31 . A compound chosen from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is chosen from hydrogen, alkyl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted alkylaryl, and substituted alkylheteroaryl;  
 R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;  
 R 3  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R 15 O— and R 15 —NH—;  
 R 3″  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;  
 R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;  
 R 15  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl,  
 or a pharmaceutically acceptable salt thereof,  
 with the proviso that when R 3  is R 15 —NH—, both of R 2  and R 4  must be other than hydrogen.  
 
     
     
         32 . A compound chosen from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;  
 R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;  
 R 3 ′ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R 15 —NH—;  
 R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;  
 R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;  
 R 15  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         33 . A compound or salt according to  claim 31  or  32  wherein: 
 R 1  is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl and substituted alkylaryl;  
 R 2  is chosen from hydrogen, alkyl and substituted alkyl; R 2 ′ is hydrogen; and the stereogenic center to which R 2  and R 2 ′ are attached is of the R configuration.  
 R 3  is chosen from alkyl, aryl, alkylaryl, heteroaryl, substituted aryl, substituted alkyl, substituted heteroaryl, oxaalkylaryl, substituted oxaalkylaryl, R 15 O— and R 15 —NH—;  
 R 4  is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted aryl, and R 16 -alkylene-;  
 R 5  is hydrogen;  
 R 6 , R 7  and R 8  are independently chosen from hydrogen, halogen, methyl and trifluoromethyl;  
 R 15  is chosen from alkyl, aryl and substituted aryl; and  
 R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino and N-heterocyclyl.  
 
     
     
         34 . A compound according to  claim 31  of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         35 . A compound or salt according to  claim 34  wherein R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, alkylaryl or substituted alkylaryl.  
     
     
         36 . A compound or salt according to  claim 35  wherein R 1  is chosen from hydrogen, ethyl, propyl, methoxyethyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and (ethoxycarbonyl)ethyl.  
     
     
         37 . A compound or salt according to  claim 34  wherein R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl; R 2 ′ is hydrogen; and the stereogenic center to which R 2  and R 2 ′ are attached is of the R configuration.  
     
     
         38 . A compound or salt according to  claim 37  wherein R 2  is chosen from ethyl, i-propyl, c-propyl or t-butyl.  
     
     
         39 . A compound or salt according to  claim 34  or  37  wherein R 3  is chosen from aryl, substituted aryl, alkylaryl, alkylheteroaryl, oxaalkylaryl, oxaalkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, substituted oxaalkylaryl or substituted oxaalkylheteroaryl.  
     
     
         40 . A compound or salt according to  claim 39  wherein R 3  is chosen from phenyl, substituted phenyl, benzyl, substituted benzyl, phenylvinyl, substituted phenylvinyl, phenoxy lower alkyl and substituted phenoxy lower alkyl, furanyl, benzofuranyl, pyridinyl, indolyl, methylpyridinyl, quinolinyl, picolinyl, pyrazolyl, and imidazolyl.  
     
     
         41 . A compound or salt according to  claim 40  wherein R 3  is chosen from halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl)phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, methylphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, dimethoxyphenyl, phenylvinyl, nitrochlorophenyl, nitrophenyl, dinitrophenyl, bis(trifluoromethyl)phenyl.  
     
     
         42 . A compound or salt according to  claim 37  wherein R 3  is R 15 —NH— where R 15  is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and methylthiophenyl.  
     
     
         43 . A compound or salt according to  claim 34 ,  37  or  39  wherein R 4  is chosen from lower alkyl, substituted lower alkyl, and R 16 -alkylene-, wherein R 16  is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.  
     
     
         44 . A compound or salt according to  claim 34 ,  37  or  39  wherein R 5 , R 6 , R 7  and R 8  are chosen from hydrogen, halo, lower alkyl, substituted lower alkyl, lower alkoxy and cyano.  
     
     
         45 . A compound or salt according to  claim 44  wherein R 5 , R 6  and R 8  are hydrogen.  
     
     
         46 . A compound or salt according to  claim 45  wherein R 7  is halo.  
     
     
         47 . A compound or salt according to  claim 34  wherein: 
 R 1  is chosen from alkylaryl or substituted alkylaryl;  
 R 2  is lower alkyl; R 2 ′ is hydrogen; and the stereogenic center to which R 2  and R 2 ′ are attached is of the R configuration;  
 R 3  is substituted aryl;  
 R 4  is substituted alkyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is halo or cyano; and  
 R 8  is hydrogen.  
 
     
     
         48 . The compound or salt according to  claim 47  wherein: 
 R 1  is benzyl or substituted benzyl;  
 R 2  is i-propyl;  
 R 3  is methyl- and/or halo-substituted phenyl;  
 R 4  is 3-amino-n-propyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is chloro or cyano; and  
 R 8  is hydrogen.  
 
     
     
         49 . The compound or salt according to  claim 47  wherein: 
 R 1  is benzyl;  
 R 2  is i-propyl;  
 R 3  is p-fluorophenyl;  
 R 4  is 3-amino-n-propyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is fluoro; and  
 R 8  is hydrogen.  
 
     
     
         50 . The compound or salt according to  claim 47  wherein: 
 R 1  is benzyl;  
 R 2  is i-propyl;  
 R 3  is p-fluorophenyl;  
 R 4  is 3-amino-n-propyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is chloro; and  
 R 8  is hydrogen.  
 
     
     
         51 . The compound or salt according to  claim 47  wherein: 
 R 1  is benzyl;  
 R 2  is i-propyl;  
 R 3  is 3-fluoro-4-methylphenyl;  
 R 4  is 3-amino-n-propyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is chloro; and  
 R 8  is hydrogen.  
 
     
     
         52 . The compound or salt according to  claim 47  wherein: 
 R 1  is benzyl;  
 R 2  is i-propyl;  
 R 3  is p-methylphenyl;  
 R 4  is 3-amino-n-propyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is chloro; and  
 R 8  is hydrogen.  
 
     
     
         53 . The compound or salt according to  claim 47  wherein: 
 R 1  is benzyl;  
 R 2  is i-propyl;  
 R 3  is p-methylphenyl;  
 R 4  is 3-amino-n-propyl;  
 R 5  is hydrogen;  
 R 6  is hydrogen;  
 R 7  is cyano; and  
 R 8  is hydrogen.  
 
     
     
         54 . A compound according to  claim 32  of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         55 . A compound according to  claim 54  wherein: 
 R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;  
 R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl and R 2 ′ is hydrogen;  
 R 3 ′ is chosen from C 1 -C 13  alkyl; phenyl; naphthyl; phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl; biphenylyl, benzyl and heteroaryl; and  
 R 4  is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R 16 -alkylene, wherein 
 R 16  is amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.  
 
 
     
     
         56 . A compound according to  claim 55  wherein: 
 R 1  is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;  
 R 2  is hydrogen or lower alkyl;  
 R 2 ′ is hydrogen;  
 R 3  is chosen from substituted phenyl and naphthyl;  
 R 4  is R 16 -alkylene-, hydroxy(lower alkyl) or carboxy (lower alkyl);  
 R 7  is hydrogen, fluoro, chloro or methyl;  
 R 5 , R 6  and R 8  are hydrogen;  
 R 16  is chosen from di(lower alkyl)amino, (lower alkyl)amino, amino, pyrrolidinyl and piperidinyl.  
 
     
     
         57 . A compound according to  claim 32  of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         58 . A compound or salt according to  claim 57  wherein: 
 R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;  
 R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl and R 2 ′ is hydrogen; and  
 R 4  is chosen from lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R 16 -alkylene, wherein R 16  is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.  
 
     
     
         59 . A compound or salt according to  claim 58  wherein: 
 R 1  is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;  
 R 2  is hydrogen or lower alkyl;  
 R 2 ′ is hydrogen;  
 R 4  is R 16 -alkylene-;  
 R 7  is hydrogen, fluoro, chloro or methyl;  
 R 5 , R 6  and R 8  are hydrogen;  
 R 16  is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidinyl, piperidinyl, imidazolyl and morpholinyl.  
 
     
     
         60 . A compound according to  claim 31  of formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         61 . A compound or salt according to  claim 60  wherein: 
 R 1  is chosen from hydrogen, lower alkyl, substituted lower alkyl, alkylaryl or substituted alkylaryl;  
 R 2  is chosen from hydrogen, lower alkyl and substituted lower alkyl; R 2 ′ is hydrogen; and the stereogenic center to which R 2  and R 2 ′ are attached is of the R configuration;  
 R 3″  is chosen from aryl, substituted aryl, alkylaryl, alkylheteroaryl, oxaalkylaryl, oxaalkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, substituted oxaalkylaryl or substituted oxaalkylheteroaryl; and  
 R 4  is chosen from lower alkyl, substituted lower alkyl, and R 16 -alkylene, wherein 
 R 16  is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.  
 
 
     
     
         62 . A compound according to  claim 31  wherein said compound is of a formula as defined in FIG. 3.  
     
     
         63 . A method of screening for KSP kinesin modulators comprising: 
 (a) combining a kinesin, a candidate bioactive agent and a compound chosen from the group consisting of:                          wherein:    R 1  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;    R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;    R 3  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R 15 O— and R 15 —NH—;    R 3′  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R 15 —NH—;    R 3″  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;    R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;    R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;    R 15  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and    R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl; and    (b) determining the effect of said candidate bioactive agent on the activity of said kinesin.    
     
     
         64 . A method of screening for compounds that bind to KSP kinesin comprising: 
 (a) combining a kinesin, a candidate bioactive agent and a labeled compound chosen from the group consisting of:                          wherein:    R 1  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;    R 2  and R 2 ′ are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R 2  and R 2 ′ taken together form a 3- to 7-membered ring;    R 3  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, oxaalkylheteroaryl, substituted oxaalkylheteroaryl, R 15 O— and R 15 —NH—;    R 3 ′ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R 15 —NH—;    R 3″  is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;    R 4  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;    R 5 , R 6 , R 7  and R 8  are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;    R 15  is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and    R 16  is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl; and    (b) determining the binding of said candidate bioactive agent to said kinesin.