Heterocyclic Sulfonamide Inhibitors of Beta Amyloid Production Containing an Azole

Abstract

Compounds useful for lowering beta amyloid levels are provided. The compounds have the structure of formula Ia: wherein, R 1 is lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, or SO 2 R 5 ; R 5 is phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, or substituted alkyl; R 2 is lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, or cycloalkyl; R 3 is hydrogen, lower alkyl, or substituted lower alkyl; R 4 is phenyl, substituted phenyl, heterocycle, substituted heterocycle, thiophene, or substituted thiophene; R 6 is hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, or substituted cycloalkyl; W, X and Y are independently CR 7 or N; and R 7 is hydrogen, halogen, lower alkyl, or substituted lower alkyl.

1 . A method of inhibiting beta amyloid production in a subject, said method comprising delivering a pharmaceutical composition comprising a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt, hydrate or prodrug thereof: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, and substituted heterocycle; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W, X and Y are independently selected from the group consisting of CR 7  and N; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl. 
 
   
   
       2 . The method according to  claim 1 , wherein said compound is:
 5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   4-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5yl]butyl}benzenesulfonamide;   4-Bromo-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}benzenesulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]ethyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Butyl-1H-pyrazol-5-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-(2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-[2-methyl-1-(1-phenyl-1H-pyrazol-5-yl)propyl]thiophene-2-sulfonamide;   5-Chloro-N-[1-(1-phenyl-1H-pyrazol-5-yl)ethyl]thiophene-2-sulfonamide;   5-Chloro-N-{2-methyl-1-[1-(4-methylphenyl)-1H-pyrazol-5-yl]propyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-methyl-1-[1-(3-methylphenyl)-1H-pyrazol-5-yl]propyl}thiophene-2-sulfonamide;   5-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]thiophene-2-sulfonamide;   5-Chloro-N-(2-ethyl-1-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-(2-ethyl-1-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,4-triazol-5-yl}butyl)thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-methylpropyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{2-methyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]propyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)ethyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]ethyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-imidazol-2-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-imidazol-2-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1H-imidazol-2-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-pyrrol-2-yl)-2-methylpropyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrrol-2-yl]-2-methylpropyl}thiophene-2-sulfonamide;   N-{1-[1-(Benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{(4-fluorophenyl)[1-(4-fluorophenyl)-1H-pyrazol-5-yl]methyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-phenylethyl}thiophene-2-sulfonamide;   4-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide;   4-Cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide;   4,5-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]thiophene-2-sulfonamide;   3,4-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide;   5-Bromo-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]thiophene-2-sulfonamide;   5-Chloro-N-{(1R)-1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   5-Chloro-N-{(1S)-1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   4-Cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylbenzenesulfonamide;   4-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylbenzenesulfonamide;   4,5-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylthiophene-2-sulfonamide;   5-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylthiophene-2-sulfonamide;   3,4-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylbenzenesulfonamide; or   5-Bromo-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylthiophene-2-sulfonamide.   
   
   
       3 . The method according to  claim 1 , wherein R 1  is substituted benzyl. 
   
   
       4 . The method according to  claim 1 , wherein R 1  is substituted phenyl. 
   
   
       5 . The method according to  claim 1 , wherein R 2  is lower alkyl. 
   
   
       6 . The method according to  claim 1 , wherein R 3  is hydrogen. 
   
   
       7 . The method according to  claim 1 , wherein R 4  is thiophene or substituted thiophene. 
   
   
       8 . The method according to  claim 7 , wherein R 4  is 5-chloro-2-thiophene. 
   
   
       9 . The method according to  claim 1 , wherein R 6  is H. 
   
   
       10 . A method of treating a disease selected from the group consisting of Alzheimer's Disease, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, mild cognitive impairment (MCI) and Down's syndrome, in a subject, said method comprising administering a compound of formula Ia to said subject in an amount sufficient to alleviate the symptoms or progress of said disease, wherein said compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, is selected from the group consisting of (a) and (b)
 (a) a compound of the structure:   
     
       
         
         
             
             
         
       
       wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, and substituted heterocycle; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W, X and Y are independently selected from the group consisting of CR 7  and N; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl; and 
 
       (b) a compound of the structure: 
     
     
       
         
         
             
             
         
       
       wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, and substituted heterocycle; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W, X and Y are independently selected from the group consisting of CR 7  and N; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl. 
 
     
   
   
       11 . The method according to  claim 10 , wherein said compound is:
 5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   4-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5yl]butyl}benzenesulfonamide;   4-Bromo-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}benzenesulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]ethyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Butyl-1H-pyrazol-5-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-(2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-hydroxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-[2-methyl-1-(1-phenyl-1H-pyrazol-5-yl)propyl]thiophene-2-sulfonamide;   5-Chloro-N-[1-(1-phenyl-1H-pyrazol-5-yl)ethyl]thiophene-2-sulfonamide;   5-Chloro-N-{2-methyl-1-[1-(4-methylphenyl)-1H-pyrazol-5-yl]propyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-methyl-1-[1-(3-methylphenyl)-1H-pyrazol-5-yl]propyl}thiophene-2-sulfonamide;   5-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]thiophene-2-sulfonamide;   5-Chloro-N-(2-ethyl-1-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-(2-ethyl-1-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,4-triazol-5-yl}butyl)thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-methylpropyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{2-methyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]propyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)ethyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]ethyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-imidazol-2-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-imidazol-2-yl]butyl}thiophene-2-sulfonamide;   5-Chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1H-imidazol-2-yl]butyl}thiophene-2-sulfonamide;   N-[1-(1-Benzyl-1H-pyrrol-2-yl)-2-methylpropyl]-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrrol-2-yl]-2-methylpropyl}thiophene-2-sulfonamide;   N-{1-[1-(Benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}-5-chlorothiophene-2-sulfonamide;   5-Chloro-N-{(4-fluorophenyl)[1-(4-fluorophenyl)-1H-pyrazol-5-yl]methyl}thiophene-2-sulfonamide;   5-Chloro-N-{1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-phenylethyl}thiophene-2-sulfonamide;   4-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide;   4-Cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide;   4,5-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]thiophene-2-sulfonamide;   3,4-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]benzenesulfonamide;   5-Bromo-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]thiophene-2-sulfonamide;   5-Chloro-N-{(1R)-1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   5-Chloro-N-{(1S)-1-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methylpropyl}thiophene-2-sulfonamide;   4-Cyano-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylbenzenesulfonamide;   4-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylbenzenesulfonamide;   4,5-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylthiophene-2-sulfonamide;   5-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylthiophene-2-sulfonamide;   3,4-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylbenzenesulfonamide; or   5-Bromo-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)butyl]-N-methylthiophene-2-sulfonamide.   
   
   
       12 . The method according to  claim 10 , wherein R 1  is substituted benzyl. 
   
   
       13 . The method according to  claim 10 , wherein R 1  is substituted phenyl. 
   
   
       14 . The method according to  claim 10 , wherein R 2  is lower alkyl. 
   
   
       15 . The method according to  claim 10 , wherein R 3  is hydrogen. 
   
   
       16 . The method according to  claim 10 , wherein R 4  is thiophene or substituted thiophene. 
   
   
       17 . The method according to  claim 10 , wherein R 4  is 5-chloro-2-thiophene. 
   
   
       18 . The method according to  claim 10 , wherein R 6  is H. 
   
   
       19 . A compound of formula (Ia), which is selected from the group consisting of (a), (b), (c), (d), and (e): 
     
       
         
         
             
             
         
       
       (a) a compound wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is phenyl or substituted phenyl; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W is N; 
 X and Y are CR 7 ; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl; 
 
       (b) a compound, wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is hydrogen; 
 R 4  is phenyl or substituted phenyl; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W is N; 
 X and Y are CR 7 ; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl; 
 
       (c) a compound, wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is phenyl or substituted phenyl; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W is N; 
 X is CR 7  and R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl; 
 Y is CR 7  and R 7  is halogen; 
 
       (d) a compound, wherein:
 R 1  is lower alkyl or substituted lower alkyl;
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is phenyl or substituted phenyl; 
 R 6  is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 W is N; 
 X and Y are CR 7 ; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl; and 
 
       (e) a compound, wherein:
 R 1  is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ; 
 R 5  is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl; 
 R 2  is selected from the group consisting of lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl; 
 R 3  is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl; 
 R 4  is phenyl or substituted phenyl; 
 R 6  is hydrogen; 
 W is N; 
 X and Y are CR 7 ; and 
 R 7  is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl.