Heterocyclic Sulfonamide Inhibitors of Beta Amyloid Production

Abstract

Compounds of Formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T, W, X, Y and Z are as defined herein are provided, together with pharmaceutically acceptable salt, hydrates and/or prodrugs thereof. Methods of using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's disease and Down's syndrome are described.

1 . A method of inhibiting beta amyloid production in a subject, said method comprising delivering a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are hydrogen; 
 R 3  is hydrogen; 
 R 4  is alkyl; 
 R 5  is benzyl or substituted benzyl; 
 R 6  is halogen; 
 T is: 
 
       
         
           
           
               
               
           
         
         W is C; 
         Y and Z are CR 10 ; 
         R 10  is hydrogen; 
         X is S; 
         provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry. 
       
     
     
         2 . The method according to  claim 1 , wherein said compound is delivered orally or by injection. 
     
     
         3 . The method according to  claim 1 , wherein R 6  is chlorine or bromine. 
     
     
         4 . The method according to  claim 1 , wherein R 6  is chlorine. 
     
     
         5 . The method according to  claim 1 , wherein R 4  is lower alkyl of S-stereochemistry. 
     
     
         6 . The method according to  claim 1 , wherein R 5  is benzyl comprising one to five substituents selected from the group consisting of halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio, wherein said substituents are on the benzene ring of the benzyl. 
     
     
         7 . The method according to  claim 6 , wherein R 5  is benzyl comprising one to five substituents selected from the group consisting of halogen and alkyl. 
     
     
         8 . The method according to  claim 7 , wherein R 5  is benzyl comprising one halogen substituent. 
     
     
         9 . The method according to  claim 6 , wherein R 5  is benzyl comprising two halogen substituents. 
     
     
         10 . The method according to  claim 6 , wherein R 5  is benzyl comprising one alkyl substituent. 
     
     
         11 . The method according to  claim 1 , wherein R 5  is benzyl. 
     
     
         12 . The method according to  claim 1 , wherein said pharmaceutically acceptable salt is selected from the group consisting of salts of acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, salts of bases, and mixtures thereof. 
     
     
         13 . The method according to  claim 1 , wherein said compound is 5-chloro-N-(3-chlorobenzyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide. 
     
     
         14 . 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, and Down's syndrome, in a subject, said method comprising administering a compound of formula (I) said subject in an amount sufficient to alleviate the symptoms or progress of said disease, wherein said compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are hydrogen; 
 R 3  is hydrogen; 
 R 4  is alkyl; 
 R 5  is benzyl or substituted benzyl; 
 R 6  is halogen; 
 T is: 
 
       
         
           
           
               
               
           
         
         W is C; 
         Y and Z are CR 10 ; 
         R 10  is hydrogen; 
         X is S; 
         provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry. 
       
     
     
         15 . The method according to  claim 14 , wherein said compound is 5-chloro-N-(3-chlorobenzyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide. 
     
     
         16 . A method of inhibiting beta amyloid production in a subject, said method comprising delivering a compound selected from the group consisting of:
 3-bromo-5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   4-bromo-5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   2,5-dichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-3-sulfonamide;   4,5-dichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide;   5-bromo-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide;   4,5-dibromo-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]thiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)-2-phenylpropyl]thiophene-2-sulfonamide;   5-bromo-N-[1-(hydroxymethyl)-2-phenylpropyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide 1,1-dioxide;   5-chloro-N-[1-(hydroxymethyl)-2,3-dimethylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)-2-methylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[2-ethyl-1-(hydroxymethyl]hexyl]thiophene-2-sulfonamide;   5-chloro-N-[2-hydroxy-1-(2,4,6-trimethylcyclohex-3-en-1-yl)ethyl]thiophene-2-sulfonamide;   5-chloro-N-(1-cyclohex-3-en-1-yl-2-hydroxyethyl)thiophene-2-sulfonamide;   5-chloro-N-(1-cyclopentyl-2-hydroxyethyl)thiophene-2-sulfonamide;   5-bromo-N-[(1S)-1-(hydroxymethyl)-1,2-dimethylpropyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S)-1-(hydroxymethyl)-1,2-dimethylpropyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2,4-dimethylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)propyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-methyloctyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-2-ethyl-1-(hydroxymethyl)-4-methyl pentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)butyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)pentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-4-methyl-2-propylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)pentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-propyloctyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-phenylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylheptyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S)-2-propyl-1-(hydroxymethyl)pentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)heptyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-isobutylheptyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)heptyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-pentyloctyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-phenylheptyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-phenylpropyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-4-methyl-2-phenylpentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)propyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)-4-methyl pentyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)octyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-isopropyloctyl]thiophene-2-sulfonamide;   N-[(1S,2S)-2-[1,1′-biphenyl]-4-yl-1-(hydroxymethyl)propyl]-5-chlorothiophene-2-sulfonamide;   N-[(1S,2S)-2-[1,1′-biphenyl]-4-yl-1-(hydroxymethyl)butyl]-5-chlorothiophene-2-sulfonamide;   N-[(1S,2S)-2-[1,1′-biphenyl]-4-yl-1-(hydroxymethyl)-4-methylpentyl]-5-chlorothiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2,4-dimethylpentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-methyloctyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-2-ethyl-1-(hydroxymethyl)-4-methylpentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)pentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-4-methyl-2-propylpentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)heptyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-isobutylheptyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)heptyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-pentyloctyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-phenylpropyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-phenylbutyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-4-methyl-2-phenylpentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-4-methyl-2-pyridin-3-ylpentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)propyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)-4-methylpentyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)octyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)-3-methylbutyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-isopropyl-4-methylpentyl]thiophene-2-sulfonamide;   N-[(1S,2S)-2-[1,1′-biphenyl]-4-yl-1-(hydroxymethyl)butyl]-5-bromothiophene-2-sulfonamide;   5-chloro-N-[(1S,2R)-2-ethyl-1-(hydroxymethyl)octyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)octyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2R)-2-ethyl-1-(hydroxymethyl)octyl]thiophene-2-sulfonamide;   5-bromo-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)octyl]thiophene-2-sulfonamide;   5-chloro-N-[(1S)-1-(hydroxymethyl)-2-(methylamino)butyl]-2-thiophenesulfonamide;   5-chloro-N-[(1S)-2-(ethylamino)-2-(hydroxymethyl)propyl]-2-thiophenesulfonamide;   5-chloro-N-[(1S)-2-[(2-hydroxyethyl)amino]-1-(hydroxymethyl)propyl]-2-thiophenesulfonamide;   5-chloro-N-[(1S)-2-[(2-hydroxyethyl)amino]-1-(hydroxymethyl)butyl]-2-thiophenesulfonamide;   5-chloro-N-[(1S)-2-[(2-hydroxyethyl)amino]-1-(hydroxymethyl)heptyl]-2-thiophenesulfonamide;   N-[(1S)-2-(benzylamino)-1-(hydroxymethyl)propyl]-5-chloro-2-thiophenesulfonamide;   N-[(1S)-2-(benzylamino)-1-(hydroxymethyl)butyl]-5-chloro-2-thiophenesulfonamide;   5-chloro-N-[(1S)-2-(cyclopentylamino)-1-(hydroxymethyl)propyl]-2-thiophenesulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-N-(2-phenoxyethyl)thiophene-2-sulfonamide;   5-chloro-N-(3-chlorobenzyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-phenylethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-1-(hydroxymethyl)-3-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)pentyl]thiophene-2-sulfonamide;   5-chloro-N-(2-hydroxy-1,1-dimethylethyl)thiophene-2-sulfonamide;   N-[1,1-bis(hydroxymethyl)propyl]-5-chlorothiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)cyclopentyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]thiophene-2-sulfonamide;   N—[(S)-1-benzyl-2-hydroxyethyl]-5-chlorothiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-1-(hydroxymethyl)-2,2-dimethylpropyl]thiophene-2-sulfonamide;   5-chloro-N—[(R,R)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-1-(hydroxymethyl)propyl]thiophene-2-sulfonamide;   N—[R-2-(benzylthio)-1-(hydroxymethyl)ethyl]-5-chlorothiophene-2-sulfonamide;   N—[(R,S)-2-(benzyloxy)-1-(hydroxymethyl)propyl]-5-chlorothiophene-2-sulfonamide;   5-chloro-N—[(R,R)-2-hydroxy-1-(hydroxymethyl)propyl]thiophene-2-sulfonamide;   5-bromo-N—[(S)-2-hydroxy-1-phenylethyl]thiophene-2-sulfonamide;   5-bromo-N—[(S)-1-(hydroxymethyl)-3-methylbutyl]thiophene-2-sulfonamide;   5-bromo-N-[1-(hydroxymethyl)pentyl]thiophene-2-sulfonamide;   5-bromo-N-(2-hydroxy-1,1-dimethylethyl)thiophene-2-sulfonamide;   N-[1,1-bis(hydroxymethyl)propyl]-5-bromothiophene-2-sulfonamide;   5-bromo-N-[1-(hydroxymethyl)cyclopentyl]thiophene-2-sulfonamide;   5-bromo-N—[(S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]thiophene-2-sulfonamide;   5-bromo-N—[(S)-1-(hydroxymethyl)-3-(methylthio)propyl]thiophene-2-sulfonamide;   5-bromo-N-[1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   5-bromo-N—[(S)-1-(hydroxymethyl)-2,2-dimethylpropyl]thiophene-2-sulfonamide;   N—[R-2-(benzylthio)-1-(hydroxymethyl)ethyl]-5-bromothiophene-2-sulfonamide;   5-bromo-N—(R-2-hydroxy-1-{[(3-methylbenzyl)thio]methyl}ethyl)thiophene-2-sulfonamide;   N—{(S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl}-5-bromothiophene-2-sulfonamide;   5-bromo-N—[(R,R)-2-hydroxy-1-(hydroxymethyl)propyl]thiophene-2-sulfonamide;   5-chloro-N—[(S,S)-1-formyl-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N—[(S,S)-1-(1-hydroxyethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]octyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]heptyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]hexyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-3-methyl-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-3,3-dimethyl-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-4-methyl-1-[(S)-1-methylpropyl]pentyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]but-3-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]pent-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-4-methyl-1-[(S)-1-methylpropyl]pent-3-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-3-methyl-1-[(S)-1-methylpropyl]but-3-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,E)-2-hydroxy-3-methyl-1-[(S)-1-methylpropyl]pent-3-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]hex-5-enyl}thiophene-2-sulfonamide;   5-chloro-N—((S,S)-1-{hydroxy[4-(methylthio)phenyl]methyl}-2-methylbutypthiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   N—{(S,S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]octyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]heptyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]hexyl}thiophene-2-sulfonamide;   N—{(S,S)-1-[hydroxy(2-methylphenyl)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-3,3-dimethyl-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]but-3-enyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methyl propyl]pent-4-enyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   N—{(S,S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   N—{(S)-4-(1 ,3-dioxan-2-yl)-2-hydroxy-1-[(S)-1-methyl propyl]butyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]hex-5-enyl}thiophene-2-sulfonamide;   N—{(S)-2-hydroxy-1-[(S)-1-methylpropyl]pent-3-ynyl}thiophene-2-sulfonamide;   N—((S,S)-1-{hydroxy[4-(methylthio)phenyl]methyl}-2-methylbutyl)thiophene-2-sulfonamide;   N—{(S,S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[(S)-cyclohex-2-en-1-yl(hydroxy)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S,E)-2-hydroxy-1-[(S)-1-methyl propyl]hex-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,R,E)-2-hydroxy-1-[(S)-1-methylpropyl]hex-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,R,E)-2-hydroxy-1-[(S)-1-methylpropypept-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-2-hydroxy-4-methyl-1-[(S)-1-methylpropyl]pent-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,R)-2-hydroxy-4-methyl-1-[(S)-1-methylpropyl]pent-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,E)-2-hydroxy-1-[(S)-1-methylpropyl]-5-phenylpent-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—[(S,S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-1-[(S)-1-methyl propyl]-2-pentylheptyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}thiophene-2-sulfonamide;   N—{(S)-2-allyl-2-hydroxy-1-[(S)-1-methyl propyl]pent-4-enyl}-5-chlorothiophene-2-sulfonamide;   5-chloro-N—{(S)-2-ethyl-2-hydroxy-1-[(S)-1-methylpropyl]butyl}thiophene-2-sulfonamide;   N—{(S,S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-5-chlorothiophene-2-sulfonamide;   5-chloro-N—{(S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(S)-1-methylpropyl]but-3-enyl}thiophene-2-sulfonamide;   5-chloro-N—((S,S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutypthiophene-2-sulfonamide;   5-chloro-N—{(S,E)-2-hydroxy-3-methyl-2-[(E)-1-methylprop-1-enyl]-1-[(S)-1-methylpropyl]pent-3-enyl}thiophene-2-sulfonamide;   N—{(S)-2-but-3-enyl-2-hydroxy-1-[(S)-1-methyl propyl]hex-5-enyl}-5-chlorothiophene-2-sulfonamide;   5-chloro-N—((S,S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)thiophene-2-sulfonamide;   5-bromo-N—{(S)-2-ethyl-2-hydroxy-1-[(S)-1-methyl propyl]butyl}thiophene-2-sulfonamide;   5-bromo-N—{(S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(S)-1-methyl propyl]but-3-enyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,E)-2-hydroxy-3-methyl-2-[(E)-1-methylprop-1-enyl]-1-[(S)-1-methylpropyl]pent-3-enyl}thiophene-2-sulfonamide;   5-bromo-N—{(S)-2-but-3-enyl-2-hydroxy-1-[(S)-1-methylpropyl]hex-5-enyl}thiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)cyclohexyl]thiophene-2-sulfonamide;   5-chloro-N-[2-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]thiophene-2-sulfonamide;   5-chloro-N-[1-(hydroxymethyl)-2,3-dihydro-H-inden-1-yl]thiophene-2-sulfonamide;   5-chloro-N-[2-(hydroxymethyl)-2,3-dihydro-H-inden-2-yl]thiophene-2-sulfonamide;   5-bromo-N-[1-(hydroxymethyl)cyclohexyl]thiophene-2-sulfonamide;   5-bromo-N-[2-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]thiophene-2-sulfonamide;   5-bromo-N-[2-(hydroxymethyl)-2,3-dihydro-H-inden-2-yl]thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[(S)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[R-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-2-hydroxy-1-[(S)-1-methylpropyl]pentyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,R)-2-hydroxy-1-[(S)-1-methylpropyl]pentyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-2-hydroxy-1-[(S)-1-methylpropyl]pent-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—{(S,R)-2-hydroxy-1-[(S)-1-methylpropyl]pent-4-enyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,S)-1-[(S)-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,S)-1-[R-1-hydroxyethyl]-2-methylbutyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,S)-2-hydroxy-1-[(S)-1-methylpropyl]pentyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,R)-2-hydroxy-1-[(S)-1-methylpropyl]pentyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,S)-2-hydroxy-1-[(S)-1-methylpropyl]pent-4-enyl}thiophene-2-sulfonamide;   5-bromo-N—{(S,R)-2-hydroxy-1-[(S)-1-methyl propyl]pent-4-enyl}thiophene-2-sulfonamide;   5-chloro-N—[(S,S)-2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)butyl]thiophene-2-sulfonamide;   5-chloro-N-[1-(1-hydroxybut-3-enyl)cyclohexyl]thiophene-2-sulfonamide;   5-chloro-N-[1-(1-hydroxy-3-methyl but-3-enyl)cyclohexyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-methoxycyclohexyl)ethyl]thiophene-2-sulfonamide;   5-Chloro-N—[(S)-2-hydroxy-1-(4-hydroxycyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-propoxycyclohexyl)ethyl]thiophene-2-sulfonamide;   N—{(S)-1-[4-(allyloxy)cyclohexyl]-2-hydroxyethyl}-5-chlorothiophene-2-sulfonamide;   N—{(S)-1-[4-(benzyloxy)cyclohexyl]-2-hydroxyethyl}-5-chlorothiophene-2-sulfonamide;   N-[1-acetyl-4-(hydroxymethyl)piperidin-4-yl]-5-chlorothiophene-2-sulfonamide;   5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-furansulfonamide;   N-[(1S)-2-butyl-1-(hydroxymethyl)hexyl]-5-chloro-2-thiophenesulfonamide;   N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-furansulfonamide;   N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-5-iodo-2-thiophenesulfonamide;   5-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-thiophenesulfonamide;   4-[1-(5-chloro-thiophene-2-sulfonylamino)-2-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester;   N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-benzylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-methylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-ethylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-npropylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-allylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-(3-pyridyl)methylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-morpholinocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-(4-pyridyl)methylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-(2-pyridyl)methylaminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-(4-(carboethoxymethyl)aminocyclohexyl)ethyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-ethyl-1-formylbutyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-ethyl-1-(1-hydroxyethyl)butyl]thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-ethyl-1-(1-hydroxy-1-methylethyl)butyl]thiophene-2-sulfonamide;   5-chloro-N-(2-hydroxy-1-tetrahydro-H-thiopyran-4-ylethyl)thiophene-2-sulfonamide;   5-chloro-N—[(S)-2-hydroxy-1-piperidin-4-ylethyl]thiophene-2-sulfonamide;   N—[(S)-2-ethyl-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide;   N—[(S)-2-ethyl-1-(hydroxymethyl)butyl]-5-fluorothiophene-2-sulfonamide;   5-chloro-N—[(S)-1-(2,3-dihydro-H-inden-2-yl)-2-hydroxyethyl]thiophene-2-sulfonamide;   5-chloro-N—{(S,S)-1-[(Z)-(hydroxyimino)methyl]-2-methylbutyl}thiophene-2-sulfonamide; and   5-chloro-N—{(S,S)-1-[(E)-(hydroxyimino)methyl]-2-methylbutyl}thiophene-2-sulfonamide.