Patent Publication Number: US-2010120725-A1

Title: Substituted Phenylsulfonamide Inhibitors of Beta Amyloid Production

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. patent application Ser. No. 11/528,011, filed Sep. 27, 2006, which is a divisional of U.S. patent application Ser. No. 10/457,641, filed Jun. 9, 2003, now U.S. Pat. No. 7,166,622, issued Jan. 23, 2007, which claims the benefit of the priority of U.S. Patent Application No. 60/387,690, filed Jun. 11, 2002, now expired. These priority applications are herein incorporated by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     Alzheimer&#39;s disease (AD) is the most common form of dementia (loss of memory) in the elderly. The main pathological lesions of AD found in the brain consist of extracellular deposits of beta amyloid protein in the form of plaques and angiopathy and intracellular neurofibrillary tangles of aggregated hyperphosphorylated tau protein. 
     Recent evidence has revealed that elevated beta amyloid levels in the brain not only precede tau pathology but also correlate with cognitive decline. Further suggesting a causative role for beta amyloid in AD, recent studies have shown that aggregated beta amyloid is toxic to neurons in cell culture and has a detrimental effect on memory. This suggests that reducing beta amyloid levels is a viable therapeutic strategy for the treatment of AD. 
     Beta amyloid protein is composed mainly of 39 to 42 amino acid peptides and is produced from a larger precursor protein called amyloid precursor protein (APP) by the sequential action of the proteases beta and gamma secretase. Although rare, cases of early onset AD have been attributed to genetic mutations in APP that lead to an overproduction of either total beta amyloid protein or its more aggregation-prone 42 amino acid isoform. Furthermore, people with Down&#39;s syndrome possess an extra chromosome that contains the gene that encodes APP and thus have elevated beta amyloid levels and invariably develop AD later in life. 
     There continues to be a need for compositions useful in inhibiting beta amyloid production and in the prevention and treatment of Alzheimer&#39;s disease. 
     SUMMARY OF THE INVENTION 
     This invention relates to small molecular compounds which inhibit beta amyloid production and have utility in the treatment of Alzheimer&#39;s disease. 
     In one aspect, a method of lowering beta amyloid levels is provided which includes delivering to a patient a phenylsulfonamide compound and monitoring the beta amyloid levels in the patient. 
     In another aspect, a method of lowering beta amyloid levels is provided which includes delivering to a patient a compound of formula I: 
     
       
         
         
             
             
         
       
     
     In a further aspect, a method of preventing or treating Alzheimer&#39;s disease is provided which includes delivering to a patient, a compound of formula I: 
     
       
         
         
             
             
         
       
     
     In yet another aspect, a compound of formula Ia is provided, wherein formula Ia is: 
     
       
         
         
             
             
         
       
     
     In a further aspect, a compound of formula Ib is provided, wherein formula Ib is: 
     
       
         
         
             
             
         
       
     
     Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides methods of monitoring beta amyloid production in patients at risk for, or suffering from, AD and other diseases resulting from elevated levels of beta amyloid protein in the brain. 
     The present invention also provides methods of lowering beta amyloid levels which includes delivering to a patient a pharmaceutically acceptable amount of a compound of the invention and monitoring the levels of beta-amyloid in the patient. 
     By the term “patient” as used herein is meant to describe a mammal which has been diagnosed as having or is at risk of having one or more of the conditions for which modulation of beta amyloid levels is desirable. Preferably, the patient is a human, domestic animal, including canines and felines, or livestock and more preferably is a human. Thus, the compounds are useful for treatment and/or prevention of a number of human and veterinary conditions. 
     By the twin “lowering beta amyloid levels” as used herein is meant to describe decreasing or inhibiting beta amyloid production in a patient. A variety of conditions can be treated by lowering beta amyloid production in a patient and include Alzheimer&#39;s disease, dementia, Down&#39;s syndrome, and mild cognitive impairment, among others. 
     As used herein, the term “prevention” encompasses precluding the onset of symptoms in a patient who has been identified with or is at risk for a condition resulting from elevated levels of beta amyloid protein in the brain. The patient may not have been diagnosed with the same or have not yet presented any symptoms thereof. 
     I. Compositions of the Invention 
     In one embodiment, the present invention provides compounds of formula I: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O; 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H and halogen; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; or 
     R 1  and R 2 ; R 2  and R 3 ; R 4  and R 5 ; or R 3  and R 4  are fused to form a carbon-based, naphthalene ring with the benzene ring; 
     R 6  is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 7  is selected from the group consisting of H, lower alkyl, and cycloalkyl; 
     R 8  is selected from the group consisting of lower alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -3-indole, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; or 
     R 7  and R 8  are fused to form a saturated carbon-based ring; 
     T is 
     
       
         
         
             
             
         
       
     
     R 9  and R 10  are H; or 
     R 9  is H and R 10  is selected from the group consisting of lower alkyl, CF 3 , lower alkenyl, methyl-substituted alkenyl, lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH 2 CH 2 -1,3-dioxolane; or 
     R 9  and R 10  are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl; 
     wherein:
         (i) when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  is N═N and R 1  is O; R 2  is bound to R 1  to form a heterocyclic ring;   (v) when R 4  is N═N and R 5  is O; R 4  is bound to R 5  to form a heterocyclic ring; and   (vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is halogen unless R 1  and R 2 ; R 2  and R 3 ; R 4  and R 5 ; or R 3  and R 4  are fused to form a carbon-based, naphthalene ring with the benzene ring;
 
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
       

     In another embodiment, the compound is of formula Ia: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O; 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H and halogen; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; 
     R 6  is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 8  is selected from the group consisting of n-propyl, iso-propyl, iso-butyl, n-butyl, t-butyl, substituted butyl, optionally substituted hexyl, optionally substituted heptyl, cycloalkyl, CH 2  cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, CH(OH)-4-SCH 3 -phenyl, and (CH 2 ) 2 —S-lower alkyl; 
     T is 
     
       
         
         
             
             
         
       
     
     R 9  and R 10  are H; or 
     R 9  is H and R 10  is selected from the group consisting of lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF 3 , cycloalkyl, substituted phenyl, 1-naphthyl, and CH 2 CH 2 -1,3-dioxolane; or 
     R 9  and R 10  are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl; 
     wherein:
         when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  is N═N and R 1  is O; R 2  is bound to R 1  to form a heterocyclic ring;   (v) when R 4  is N═N and R 5  is O; R 4  is bound to R 5  to form a heterocyclic ring; and   (vi) one or more of R 1  to R 5  is a halogen;
 
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
       

     In a further embodiment, the compound is of formula I: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O; 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H and halogen; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; or 
     R 1  and R 2  or R 4  and R 5  are fused to form a carbon-based, unsaturated ring; 
     R 6  is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 7  is selected from the group consisting of H, lower alkyl, and cycloalkyl; 
     R 8  is selected from the group consisting of benzyl and substituted benzyl; 
     T is 
     
       
         
         
             
             
         
       
     
     R 9  and R 10  are H; or 
     R 9  is H and R 10  is selected from the group consisting of lower alkyl, lower alkenyl, methyl-substituted alkenyl, CF 3 , lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH 2 CH 2 -1,3-dioxolane; or 
     R 9  and R 10  are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl; 
     wherein:
         (i) when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  is N═N and R 1  is O; R 2  is bound to R 1  to faun a heterocyclic ring;   (v) when R 4  is N═N and R 5  is O; R 4  is bound to R 5  to form a heterocyclic ring; and   (vi) one or more of R 1  to R 5  is a halogen;
 
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
       

     In yet another embodiment, the compound is of formula Ib: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O; 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H, bromine, fluorine, and iodine; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; 
     R 6  is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 7  is selected from the group consisting of H, lower alkyl, and cycloalkyl; 
     T is 
     
       
         
         
             
             
         
       
     
     R 9  and R 10  are H; or 
     R 9  is H and R 10  is selected from the group consisting of lower alkyl, lower alkenyl, methyl-substituted alkenyl, CF 3 , lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH 2 CH 2 -1,3-dioxolane; or 
     R 9  and R 10  are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl; 
     wherein:
         (i) when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  or R 4  is N═N; R 1  or R 5  is 0 and R 2  or R 4  is bound to R 1  or R 5  to form a heterocyclic ring; and   (v) one or more of R 1  to R 5  is a halogen; or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.       

     In a further embodiment, the compound is of formula I: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O, 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H and halogen; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; 
     R 6  is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 7  is selected from the group consisting of lower alkyl and cycloalkyl; 
     R 8  is selected from the group consisting of cycloalkyl, phenyl, substituted phenyl, CH 2  cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; 
     T is 
     
       
         
         
             
             
         
       
     
     R 9  and R 10  are H; or 
     R 9  is H and R 10  is selected from the group consisting of lower alkyl, lower alkenyl, methyl-substituted alkenyl, lower alkynyl, CF 3 , cycloalkyl, substituted phenyl, 1-naphthyl, and CH 2 CH 2 -1,3-dioxolane; or 
     R 9  and R 10  are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl; 
     wherein:
         (i) when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  is N═N and R 1  is O; R 2  is bound to R 1  to form a heterocyclic ring; and   (v) when R 4  is N═N and R 5  is O; R 4  is bound to R 5  to form a heterocyclic ring; and   (vi) one or more of R 1  to R 5  is a halogen;
 
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
       

     In yet a further embodiment, the compound is of formula I: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O; 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H and halogen; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; or 
     R 1  and R 2 ; R 2  and R 3 ; R 4  and R 5 ; or R 3  and R 4  are fused to form a carbon-based, naphthalene ring with the benzene ring; 
     R 6  is selected from the group consisting of H, lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 7  is selected from the group consisting of H, lower alkyl, and cycloalkyl; 
     R 8  is selected from the group consisting of cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl, CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl; or 
     R 7  and R 8  are fused to form a saturated carbon-based ring; 
     T is 
     
       
         
         
             
             
         
       
     
     wherein:
         (i) when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  is N═N and R 1  is O; R 2  is bound to R 1  to form a heterocyclic ring;   (v) when R 4  is N═N and R 5  is O; R 4  is bound to R 5  to form a heterocyclic ring;   (vi) when each of R 1 , R 2 , R 4 , R 5 , and R 6  is H, R 3  is halogen, and R 7  is H, then R 8  is C 5  to C 8  alkyl or R 7  and R 8  are fused to form a saturated carbon-based ring;   (vii) when each of R 3 , R 4 , R 5 , R 6 , and R 7  is H and R 1  and R 2  are fused to form a carbon-based naphthalene ring, then R 8  is selected from the group consisting of lower alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH(lower alkyl)-2-furan, CH(lower alkyl)-4-methoxyphenyl; CH(lower alkyl) phenyl, and CH(OH)-4-SCH 3 -phenyl;   (viii) when each of R 1 , R 2 , R 4 , R 5 , and R 6  is H and R 3  is halogen, then R 7  and R 8  are not both CH 3 ; and   (ix) at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is halogen unless R 1  and R 2 ; R 2  and R 3 ; R 4  and R 5 ; or R 3  and R 4  are fused to form a carbon-based, naphthalene ring with the benzene ring;
 
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
       

     In another embodiment, the compound is of formula I: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 1  is selected from the group consisting of H, halogen, and O; 
     R 2  is selected from the group consisting of H, halogen, and N═N; 
     R 3  is selected from the group consisting of H and halogen; 
     R 4  is selected from the group consisting of H, halogen, amino, and N═N; 
     R 5  is selected from the group consisting of H, halogen, methoxy, methyl, and O; or 
     R 1  and R 2 ; R 2  and R 3 ; R 4  and R 5 ; or R 3  and R 4  are fused to form a carbon-based, naphthalene ring with the benzene ring; 
     R 6  is selected from the group consisting of lower alkyl, lower alkenyl, 3-phenyl-2-propyn-1-yl, benzyl, substituted benzyl, CH 2  cycloalkyl, CH 2 -2-furan, (CH 2 ) 2 SCH 3 , and (CH 2 ) 2 NHBOC; 
     R 7  and R 8  are fused to form a saturated carbon-based ring; 
     T is 
     
       
         
         
             
             
         
       
     
     R 9  and R 10  are H; or 
     R 9  is H and R 10  is selected from the group consisting of lower alkyl, lower alkenyl, methyl-substituted alkenyl, CF 3 , lower alkynyl, cycloalkyl, substituted phenyl, 1-naphthyl, and CH 2 CH 2 -1,3-dioxolane; or 
     R 9  and R 10  are independently selected from the group consisting of lower alkyl, lower alkenyl, phenyl, 4-substituted-phenyl, and 1-naphthyl; 
     wherein:
         (i) when R 5  is a methoxy; R 2  is halogen and R 1 , R 3 , and R 4  are H;   (ii) when R 5  is a methyl; R 1  is halogen and R 2 , R 3 , and R 4  are H;   (iii) when R 4  is an amino; R 3  is halogen and R 1 , R 2 , and R 5  are H;   (iv) when R 2  is N═N and R 1  is O; R 2  is bound to R 1  to form a heterocyclic ring;   (v) when R 4  is N═N and R 5  is O; R 4  is bound to R 5  to form a heterocyclic ring; and   (vi) at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is halogen unless R 1  and R 2 ; R 2  and R 3 ; R 4  and R 5 ; or R 3  and R 4  are fused to form a carbon-based, naphthalene ring with the benzene ring;
 
or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof.
       

     In yet a further embodiment, the compound is selected from the group consisting of 2-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 3-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 3-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-1,2,3-benzoxadiazole-7-sulfonamide, 2-chloro-4-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 5-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-methoxybenzenesulfonamide, 2-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-6-methylbenzenesulfonamide, 3,5-dichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 2,4-difluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 2-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]naphthalene-1-sulfonamide, N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]naphthalene-2-sulfonamide, 3-amino-4-chloro-N-[(1S,25)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, N-[(1S)-1-benzyl-2-hydroxyethyl]-4-bromo benzenesulfonamide, 4-bromo-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide, 4-bromo-N-[(1R)-2-hydroxy-1-(4-hydroxyphenypethyl]benzenesulfonamide, 4-bromo-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide, 4-bromo-N-[(1S)-2-hydroxy-1-(1H-indol-2-ylmethyl)ethyl]benzenesulfonamide, 4-bromo-2,5-difluoro-N-[(1S,2S)-1-(hydroxymethyl-2-methylbutyl]benzenesulfonamide, 2,5-dibromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzene sulfonamide, 3,4-dibromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzene sulfonamide, 2,3-dichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 3,4-dichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzene sulfonamide, 2,4,5-trichloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-2,5-difluoro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide, 3,4-dichloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide, 2,4,6-trichloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide, 3,4-dibromo-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide, 3,4-dichloro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide, 2,4,5-trichloro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide, 2,4,6-trichloro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide, 4-bromo-N-[(1R,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-N-[(1S)-1-(hydroxymethyl)-1,2-dimethylpropyl]benzenesulfonamide, 4-bromo-N-[1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S)-1-(hydroxymethyl)-1,2-dimethylpropyl]benzenesulfonamide, 4-chloro-N-[1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, N-allyl-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, N-([1,1′-biphenyl]-4-ylmethyl)-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, tert-butyl 2-{[(4-chlorophenyl) sulfonyl][(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]amino}ethylcarbamate, 4-chloro-N-(4-chlorobenzyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-(cyclobutylmethyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-(2-furylmethyl)-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-N42-(methylthio)ethyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-N-(3-phenylprop-2-ynyl)benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)propyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-methyloctyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide, 4-chloro-N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-2-ethyl-1-(hydroxymethyl)-4-methylpentyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylpentyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)pentyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-4-methyl-2-propylpentyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)pentyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-propyloctyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-phenylpentyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylheptyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)-heptyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-pentyloctyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-4-methyl-2-phenylpentyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-phenyloctyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)butyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)-4-methyl pentyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)octyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2,3-dimethylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-isopropyloctyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)propyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-methyloctyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-2-ethyl-1-(hydroxymethyl)-4-methylpentyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)butyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-2-ethyl-1-(hydroxymethypoctyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylpentyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl) pentyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-4-methyl-2-propylpentyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-1-(hydroxymethyl)-2-propyloctyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylheptyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl) heptyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-phenylbutyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)propyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)butyl]benzenesulfonamide, 4-bromo-N-[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)-4-methylpentyl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-isopropyl-4-methylpentyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)octyl]benzenesulfonamide, 4-chloro-N-[(1S,2R)-2-ethyl-1-(hydroxymethypoctyl]benzenesulfonamide, 4-chloro-N-methyl-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-benzenesulfonamide, 4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide, 4-bromo-N-[1-(hydroxymethyl)cyclopentyl]benzenesulfonamide, 4-chloro-N-[(1S)-2-cyclohexyl-1-(hydroxymethypethyl]benzenesulfonamide, N-{(1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl}-4-chlorobenzenesulfonamide, 4-chloro-N-[(1R)-1-(hydroxymethyl)-1-methylpropl]benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-benzenesulfonamide, 4-bromo-N-[1-(hydroxymethyl)pentyl]benzenesulfonamide, 4-bromo-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide, 4-bromo-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide, 4-bromo-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide, 4-chloro-N-[1-(hydroxymethy)cyclopentyl]benzenesulfonamide, 4-bromo-N-[1-(hydroxymethyl)butyl]benzenesulfonamide, 3-chloro-N-[1-(hydroxymethyl)butyl]benzenesulfonamide, 3-chloro-N-[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]benzenesulfonamide, 3-chloro-N-[(1R)-1-(hydroxymethyl)-3-(methylthio)propyl]benzenesulfonamide, 3-chloro-N-[(1S)-1-(hydroxymethyl)propyl]benzenesulfonamide, 2-fluoro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide, 2-fluoro-N-[1-(hydroxymethyl)pentyl]benzenesulfonamide, 2-fluoro-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide, 2-fluoro-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide, 2-fluoro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide, 2-fluoro-N-[1-(hydroxymethyl)cyclopentyl]benzenesulfonamide, N-[(1S)-2-cyclohexyl-1-(hydroxymethypethyl]-2-fluorobenzenesulfonamide, 2-fluoro-N-{(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-[4-(methylthio)phenyl]ethyl}benzenesulfonamide, 2-fluoro-N-[(1S)-1-(hydroxyl-methylethyl]benzenesulfonamide, N-[(1S)-1-benzyl-2-hydroxyethyl]-2-fluorobenzenesulfonamide, 2-fluoro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide, 4-bromo-N-[1-(hydroxymethyl)cyclohexyl]benzenesulfonamide, 4-bromo-N-[2-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide, 4-bromo-N-[1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide, 4-chloro-N-[1-(hydroxymethyl)cyclohexyl]benzenesulfonamide, 4-chloro-N-[1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide, 4-chloro-N-(1-cyclobutyl-2-hydroxy-1-phenylethyl)benzenesulfonamide, 4-fluoro-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-fluoro-N-{(1S,2S)-1-[hydroxy-(2-methylphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-fluoro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-fluoro-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, N-{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S,2S)-1-[hydroxy(1-naphthyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-bromo-N-{(1S,3E)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-pentynyl}benzenesulfonamide, 4-bromo-N-((1S,2S)-1-{hydroxy-[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-formyl-2-methylbutyl]benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(2-methylphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-pentynyl}benzenesulfonamide, 4-chloro-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(1-naphthyl)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, 3-chloro-N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 3-chloro-N-((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2-methylbutyl)benzenesulfonamide, N-{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 2-fluoro-N-{(1S,2S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, 2-fluoro-N-{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-2-fluorobenzenesulfonamide, 4-bromo-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-bromo-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-bromo benzenesulfonamide, 4-bromo-N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, N-{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-4-bromobenzenesulfonamide, 4-bromo-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-bromo-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, 4-bromo-N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}benzenesulfonamide, 4-bromo-N-((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-chloro-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]benzenesulfonamide, 4-chloro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-4-chlorobenzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 4-chloro-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-chloro benzenesulfonamide, 4-chloro-N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-chloro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-chloro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-chloro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methyl propyl]-5-hexenyl}-4-chlorobenzenesulfonamide, 4-chloro-N-((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-fluoro-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl]benzenesulfonamide, 4-fluoro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-2-isopropyl-3-methyl-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-fluoro benzenesulfonamide, N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 4-fluoro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 4-fluoro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-4-fluorobenzenesulfonamide, N-{(1S,2S)-1-[bis[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide, 4-fluoro-N-((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl)benzenesulfonamide, 3-chloro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, N-{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-3-chlorobenzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide, 3-chloro-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-3-chloro benzenesulfonamide, 3-chloro-N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide, N-{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-3-chloro benzenesulfonamide, 3-chloro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 3-chloro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 3-chloro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-3-chlorobenzenesulfonamide, 2-fluoro-N-{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl}benzenesulfonamide, 2-fluoro-N-{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl}benzenesulfonamide, N-{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-2-fluorobenzenesulfonamide, N-{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-2-fluorobenzenesulfonamide, N-{(1S,2S)-1-[bis(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluorobenzenesulfonamide, N-{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluoro benzenesulfonamide, 2-fluoro-N-{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide, 2-fluoro-N-((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide, 2-fluoro-N-{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide, N-{1(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-2-fluorobenzenesulfonamide, 4-chloro-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide, 4-chloro-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide, 4-chloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide, 4-bromo-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide, 4-iodo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide, and 4-chloro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide; or a pharmaceutically acceptable salt, hydrate, metabolite, or prodrug thereof. 
     In another embodiment, the compound is 4-chloro-N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]benzenesulfonamide or a pharmaceutically acceptable salt, metabolite, hydrate, or prodrug thereof 
     The compounds of the invention can contain one or more asymmetric carbon atoms and some of the compounds can contain one or more asymmetric (chiral) centers and can thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, when the compounds can contain one or more chiral centers, preferably at least one of the chiral centers is of S-stereochemistry. Most preferably, the carbon atom to which N, T, R 7  and R 8  are attached is of S-stereochemistry. Thus, the invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure stereoisomers; as well as other mixtures of the R and S stereoisomers, and pharmaceutically acceptable salts, hydrates, metabolites, and prodrugs thereof. 
     The term “alkyl” is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having about one to about ten carbon atoms, preferably one to eight carbon atoms and, most preferably, one to six carbon atoms. The term “lower alkyl” is used herein to refer to straight- and branched-chain saturated aliphatic hydrocarbon groups having about one to about six carbon atoms. The term “alkenyl” is used herein to refer to straight- and branched-chain alkyl groups having at least one carbon-carbon double bond and about two to about eight carbon atoms, preferably two to six carbon atoms. The term “alkynyl” is used herein to refer to straight- and branched-chain alkyl groups having at least one carbon-carbon triple bond and about two to about eight carbon atoms, preferably two to six carbon atoms. 
     The terms “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as just described having from one to three substituents selected from the group consisting of halogen, CN, OH, NO 2 , amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio, which groups can be optionally substituted. These substituents can be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety. 
     The team “aryl” is used herein to refer to a carbocyclic aromatic system, which can be a single ring, or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl. 
     The term “substituted aryl” refers to aryl as just defined having one or more substituents including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. Preferably, a substituted aryl group is substituted with one to about four substituents. 
     The term “heterocyclic” is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or wholly unsaturated. The heterocyclic ring has in its backbone carbon atoms and one or more heteroatoms including N, O, and S atoms. Preferably, the heterocyclic ring has about 1 to about 4 heteroatoms in the backbone of the ring. When the heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of the above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring can be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. 
     A variety of heterocyclic groups are known in the art and include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations thereof. Oxygen-containing rings include, but are not limited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings. Nitrogen-containing rings include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfur-containing rings include, without limitation, thienyl and dithiolyl rings. Mixed heteroatom containing rings include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and diazepinyl rings. Fused heteroatom-containing rings include, but are not limited to, benzofuranyl, benzo[b]thienyl or benzo[c]thienyl, indolyl, benazazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl, benzodiazonyl, naphthyridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl, xanthenyl, acridinyl, and purinyl rings. 
     As used herein, an N-substituted piperidinyl group can be defined as a substituted heterocyclic group. Among particularly desirable substituents are N-alkyl-, N-aryl-, N-acyl-, and N-sulfonyl piperidinyl groups. One particularly suitable N-acyl-piperidinyl group is N-t-butyloxycarbonyl (BOC)-piperidine. However, other suitable substituents can be readily identified by one of skill in the art. 
     The term “substituted heterocyclic” is used herein to describe a heterocyclic group having one or more substituents including halogen, CN, OH, NO 2 , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. Preferably, a substituted heterocyclic group has 1 to about 4 substituents. 
     The term “alkoxy” is used herein to refer to the O(alkyl) group, where the point of attachment is through the oxygen-atom and the alkyl group is optionally substituted. The term “aryloxy” is used herein to refer to the O(aryl) group, where the point of attachment is through the oxygen-atom and the aryl group is optionally substituted. 
     The term “alkylcarbonyl” is used herein to refer to the CO(alkyl) group, where the point of attachment is through the carbon-atom of the carbonyl moiety and the alkyl group is optionally substituted. 
     The term “alkylcarboxy” is used herein to refer to the COO(alkyl) group, where the point of attachment is through the carbon-atom of the carboxy group and the alkyl group is optionally substituted. 
     The term “aminoalkyl” is used herein to refer to secondary and tertiary amines where the point of attachment is through the nitrogen-atom and the alkyl groups are optionally substituted. Preferably, the alkyl groups contain one to eight carbon atoms and can be either same or different. 
     The term “halogen” refers to Cl, Br, F, or I. 
     The term “ring” structure, e.g., when R 3  and R 4  can form a ring structure, includes a monocyclic structure, a bridged cyclo structure, and fused cyclo structures, unless the type of ring structure is otherwise specified. 
     The compounds of the present invention encompass tautomeric forms of the structures provided herein characterized by the bioactivity of the exemplary compounds and drawn structures. Further, the compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids, bases, alkali metals and alkaline earth metals. 
     Physiologically acceptable acids include those derived from inorganic and organic acids. A number of inorganic acids are known in the art and include hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoric acids, among others. Similarly, a variety of organic acids are known in the art and include, without limitation, lactic, formic, acetic, fumaric, citric, propionic, oxalic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, tartaric, malonic, mallic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic, and galacturonic acids, among others. 
     Physiologically acceptable bases include those derived from inorganic and organic bases. A number of inorganic bases are known in the art and include aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc hydroxide compounds, among others. A number of organic bases are known in the art and include, without limitation, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine, among others. 
     Physiologically acceptable alkali salts and alkaline earth metal salts can include, without limitation, sodium, potassium, calcium and magnesium salts in the form of esters, hydroxides, and carbamates. Other conventional “pro-drug” forms can also be utilized which, when delivered in such form, convert to the active moiety in vivo. 
     These salts, as well as other compounds of the invention can be in the form of esters, carbamates and other conventional “pro-drug” forms, which, when administered in such form, convert to the active moiety in vivo. In a currently preferred embodiment, the prodrugs are esters. See, e.g., B. Testa and J. Caldwell, “Prodrugs Revisited: The “Ad Hoc” Approach as a Complement to Ligand Design“, Medicinal Research Reviews, 16(3):233-241, ed., John Wiley &amp; Sons (1996). 
     The compounds discussed herein also encompass “metabolites” which are unique products formed by processing the compounds of formula I, Ia, or Ib by the cell or patient. Preferably, metabolites are formed in vivo. 
     The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art. The compounds of the present invention can be prepared using the methods described below, together with synthetic methods known in the synthetic organic arts or variations of these methods by one skilled in the art. See, generally, Comprehensive Organic Synthesis, “Selectivity, Strategy &amp; Efficiency in Modern Organic Chemistry”, ed., I. Fleming, Pergamon Press, New York (1991); Comprehensive Organic Chemistry, “The Synthesis and Reactions of Organic Compounds”, ed. J. F. Stoddard, Pergamon Press, New York (1979). Preferred methods include, but are not limited to, those outlined below. 
     In certain embodiments, it may be desirable to utilize chirally pure α-amino acids, 1,2-aminoalcohols, N-sulfonyl α-amino acids, and N-sulfonyl 1,2-aminoalcohols in the reactions described herein for the production of the phenylsulfonamides of the invention. A number of methods for producing these compounds are known in the art. Among desirable methodologies are those described in U.S. Patent Application No. 60/339,264, filed Dec. 11, 2001, and later filed as U.S. patent application Ser. No. 10/304,322 and International Patent Application PCT/US02/38119, both filed Nov. 26, 2002, “Process for the Synthesis of Chirally Pure α-Amino-Alcohols”; U.S. patent application Ser. No. 10/014,304, filed Dec. 11, 2001, entitled “Heterocyclic Sulfonamide Inhibitors of Beta Amyloid Production”, published as US-2002-0183361-A on Dec. 5, 2002; and U.S. patent application Ser. No. 10/166,896, filed Jun. 11, 2002 and later published Jan. 16, 2003 as US-2003-0013892-A1, entitled “Production of Chirally Pure α-Amino Acids and N-Sulfonyl α-Amino Acids”. 
     A first method of preparation for the compounds of the invention consists of reaction of a 1,2-aminoalcohol II with the appropriate sulfonyl halide in the presence of a base such as triethylamine (TEA) and in a suitable solvent to afford compounds of formula III. For compounds where R 9  and R 10  are hydrogen, oxidation of the N-sulfonyl primary alcohol with pyridinium chlorochromate (PCC) or under Swern conditions then affords the corresponding aldehyde IV which can be reacted with Grignard reagents to afford the secondary alcohols V as a mixture of diastereomers which can be separated by high performance liquid chromatography (HPLC) or other suitable methods (Scheme 1). 
     
       
         
         
             
             
         
       
     
     A second method of preparation involves reaction of an α-amino acid or ester IX with the appropriate sulfonyl halide in the presence of a base such as triethylamine and in a suitable solvent to afford compounds of formula X (Scheme 2). The intermediate N-sulfonyl acid X (Rx=H) can be converted to the corresponding primary alcohol VIII (R 9 ═R 10 ═H) utilizing standard methodology such as LiAlH 4  (LAH), B 2 H 6  or cyanuric chloride/NaBH 4 . The intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can also be reduced to the corresponding primary alcohol VIII utilizing standard methodology such as LiAlH 4 . Alternatively, the intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can be converted to the aldehyde IV with diisobutyl aluminumhydride (DiBAL). Finally, the intermediate N-sulfonyl ester X (Rx=alkyl, Bn) can be reacted with 2 equivalents of Grignard reagent to afford the tertiary alcohols III with R 9 ═R 10 . Alternatively, for tertiary alcohols III with R 9  not equal to R 10 , the corresponding Weinreb amide (see Scheme 7) of the N-sulfonyl acid can be prepared and subsequently reacted with R 9 MgX and R 10 MgX. 
     
       
         
         
             
             
         
       
     
     In a variation of the second method to prepare the primary alcohols, an α-amino acid or ester (or N-protected derivative thereof) VI is first converted to the corresponding primary 1,2-aminoalcohol VII (using the methodology outlined in the previous paragraph), which is subsequently, after deprotection (if necessary), reacted with the appropriate sulfonyl halide (Scheme 3) to afford compounds of formula VIII. 
     
       
         
         
             
             
         
       
     
     For the preparation of compounds derived from unnatural α-amino acids containing beta branching in the amino acid side chain, a method of preparation based on the work of Hruby (Tet. Lett. 38: 5135-5138 (1997)), incorporated by reference, is outlined in Scheme 4. This route entails formation of the α,β-unsaturated amide XII of the Evans chiral auxiliary from an α,β-unsaturated acid XI, followed by conjugate addition of an organocuprate, trapping of the resulting enolate anion XIII with N-bromosuccinimide (NBS), displacement of the bromide XIV with azide anion to afford XV, followed by reduction to the 1,2-aminoalcohol and subsequent sulfonylation to afford the target compound XVI. 
     
       
         
         
             
             
         
       
     
     For the preparation of N-alkylated sulfonamides XVII (R 6  can be alkyl, substituted alkyl, allyl, substituted allyl, benzyl, or substituted benzyl), the sulfonamide ester X can be N-alkylated by either treatment with a suitable base such as sodium hydride followed by the alkylating agent R 6 X or by employing Mitsunobu conditions (R 6 OH/DEAD, TPP). LiBH 4  reduction of the N-alkylated sulfonamide ester affords the N-alkylated sulfonamide in the primary alcohol series XVII (Scheme 5). These primary alcohols XVII can be converted to N-alkylated analogs of the secondary alcohols V or aldehyde IV series by chemistry that has been outlined above. Alternatively, the N-alkylated sulfonamide esters, or their corresponding Weinreb amides, can be treated with Grignard reagents to afford the N-alkylated analogs of the tertiary alcohols III (where R 9  and R 10  are non-hydrogen). 
     
       
         
         
             
             
         
       
     
     An alternate preparation of sulfonamides derived from unnatural 1,2-aminoalcohols utilizes the Bucherer modification of the Strecker α-amino acid synthesis (Scheme 6). In this route, an aldehyde XVIII is reacted with cyanide anion and ammonium carbonate to afford the hydantoin XIX, which is hydrolyzed to the α-amino acid XX. This compound is then reduced to XXI and sulfonylated to afford the desired compounds of formula XXII. 
     
       
         
         
             
             
         
       
     
     As previously noted (Scheme 1), the preparation of sulfonamides derived from 1,2-aminoalcohols in the secondary alcohol series V results in the formation of a diastereomeric mixture. An alternate method of preparation of these compounds that results in the production of a pure diastereomer is outlined in Scheme 7 for compounds derived from L-isoleucine. This method, which utilizes chemistry previously employed by Roux (Tetrahedron 50: 5345-5360 (1994)), consists of addition of Grignard reagents to the Weinreb amide XXIII (derived from the requisite α-amino acid) followed by stereospecific reduction of the ketone XXIV to afford a single diastereomeric N-protected 1,2-aminoalcohol XXV. Deprotection of this compound followed by reaction with sulfonyl chlorides affords the pure diastereomeric sulfonamide secondary alcohols of formula XXVI. 
     
       
         
         
             
             
         
       
     
     Where catalysts or solvents are included in a reaction step of this invention, it is expected that other catalysts or solvents known in the art, but not mentioned herein, can be used. Those skilled in the art will readily be able to determine suitable catalysts, solvents and reaction conditions for each reaction step included in the invention. 
     The invention includes certain types of reactions, such as enolate trapping, hydrolysis, and reduction reactions that are generally known in the art, but previously had not been applied in the novel manner of the present invention. Variations in the specific methods of accomplishing individual steps of the invention can be apparent to those in the art. Although all of these possible variations cannot be set forth herein, such variations are contemplated to be within the scope of the present invention. 
     II. Formulations of the Invention 
     The compounds described herein can be formulated in any form suitable for the desired route of delivery using a pharmaceutically effective amount of one or more of the compounds of the invention. For example, the compositions of the invention can be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, sublingual, intracranial, epidural, intratracheal, intranasal, vaginal, rectal, or by sustained release. Preferably, delivery is oral. 
     A pharmaceutically effective amount of a compound used according to the present invention can vary depending on the specific compound, mode of delivery, severity of the condition being treated, and any other active ingredients used in the formulation or the selected regimen The dosing regimen can be adjusted to provide the optimal therapeutic response. Several divided doses can be delivered daily or a single daily dose can be delivered. The dose can however be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. 
     As described herein, a pharmaceutically useful amount of a compound of the invention is that amount of a compound which alleviates the symptoms of the disease, e.g., AD, or which prevents the onset of symptoms, or the onset of more severe symptoms. Generally, an individual dose (i.e., per unit, e.g., tablet) of a compound of the invention can be in the range from about 1 μg/kg to about 10 g/kg, more preferably 10 mg/kg to about 5 g/kg, and most preferably about 1 mg/kg to about 200 mg/kg. Desirably, these amounts are provided on a daily basis. However, the dosage to be used in the treatment or prevention of a specific cognitive deficit or other condition can be subjectively determined by the attending physician. The variables involved include the specific cognitive deficit and the size, age and response pattern of the patient. 
     The compounds of the invention can be combined with one or more pharmaceutically acceptable carriers or excipients including, without limitation, solid and liquid carriers which are compatible with the compounds of the present invention. Such carriers can include adjuvants, syrups, elixirs, diluents, binders, lubricants, surfactants, granulating agents, disintegrating agents, emollients, solubilizers, suspending agents, fillers, glidants, compression aids, encapsulating materials, emulsifiers, buffers, preservatives, thickening agents, colors, viscosity regulators, stabilizers, osmo-regulators, and combinations thereof. Optionally, one or more of the compounds of the invention can be mixed with other active agents. 
     Adjuvants can include, without limitation, flavoring agents, sweeteners, coloring agents, preservatives, and supplemental antioxidants, which can include vitamin E, ascorbic acid, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). 
     Elixers and syrups can be prepared from acceptable sweeteners such as sugar, saccharine or a biological sweetener, a flavoring agent, and/or solvent. In one embodiment, a syrup can contain about 10 to about 50% of a sugar carrier. In another embodiment, the elixir can contain about 20 to about 50% of an ethanol carrier. 
     Diluents can include materials in which the compound can be dispersed, dissolved, or incorporated. Preferably, the diluents include water, lower monovalent alcohols, monohydric alcohols, polyhydric alcohols, and low molecular weight glycols and polyols, including propylene glycol, diethylene glycol, polyethylene glycol, polypropylene glycol, glycerol, butylene glycol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, sorbitol esters, butanediol, ethyl oleate, isopropyl myristate, ether propanol, ethoxylated ethers, propoxylated ethers, oils such as corn, peanut, fractionated coconut, arachis, sesame oils, dimethylsulfoxide (DMSO), dimethylformamide (DMF), waxes, preferably low-melting waxes, dextrin, and combinations thereof. Preferably, the diluent is water. 
     Binders can include, without limitation, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidine, gelatin, gum arabic, polyethylene glycol, starch, sugars such as sucrose, kaolin, cellulose kaolin, and lactose, among others. 
     Lubricants can include magnesium stearate, light anhydrous silicic acid, talc and sodium lauryl sulfate, among others. 
     Granulating agents can include, without limitation, silicon dioxide, microcrystalline cellulose, starch, calcium carbonate, pectin, crospovidone, and polyplasdone, among others. 
     Disintegrating agents can include starch, carboxymethylcellulose, hydroxypropylstarch, substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, and calcium citrate, among others 
     Emollients can include, without limitation, stearyl alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum jelly, palmitic acid, oleic acid, and myristyl myristate. 
     Alternatively, the use of sustained delivery devices can be desirable, in order to avoid the necessity for the patient to take medications on a daily basis. The term “sustained delivery” is used herein to refer to delaying the release of an active agent, i.e., a compound of the invention, until after placement in a delivery environment, followed by a sustained release of the agent at a later time. A number of sustained delivery devices are known in the art and include hydrogels (U.S. Pat. Nos. 5,266,325; 4,959,217; 5,292,515), osmotic pumps (U.S. Pat. Nos. 4,295,987 and 5,273,752 and European Patent No. 314,206, among others); hydrophobic membrane materials, such as ethylenemethacrylate (EMA) and ethylenevinylacetate (EVA); bioresorbable polymer systems (International Patent Publication No. WO 98/44964 and U.S. Pat. Nos. 5,756,127 and 5,854,388); and other bioresorbable implant devices composed of, for example, polyesters, polyanhydrides, or lactic acid/glycolic acid copolymers (U.S. Pat. No. 5,817,343). For use in such sustained delivery devices, the compounds of the invention can be formulated as described herein. 
     III. Formulation Delivery 
     The present invention provides methods of providing the compounds of the invention to a patient. The compounds can be delivered by a route such as oral, dermal, transdermal, intrabronchial, intranasal, intravenous, intramuscular, subcutaneous, parenteral, intraperitoneal, sublingual, intracranial, epidural, intratracheal, intranasal, vaginal, rectal, or by sustained release. Preferably, delivery is oral. 
     In one embodiment, the compositions are delivered orally in solid or liquid form by powder, tablet, capsule, microcapsules, dispersible powder, granule, suspension, syrup, elixir, and aerosol. 
     Desirably, when the compound is delivered orally, it is sub-divided in a dose containing appropriate quantities of the active ingredient. The unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Preferably, the powders and tablets contain up to 99% of the active ingredient. 
     In another embodiment, the compounds are delivered intravenously, intramuscularly, subcutaneously, parenterally and intraperitoneally in the form of sterile injectable solutions, suspensions, dispersions, and powders which are fluid to the extent that easy syringe ability exits. Such injectable compositions are sterile, stable under conditions of manufacture and storage, and free of the contaminating action of microorganisms such as bacteria and fungi. 
     Injectable formations can be prepared by combining the compound with a liquid. The liquid can be selected from among water, glycerol, ethanol, propylene glycol and polyethylene glycol, oils, and mixtures thereof, and more preferably the liquid carrier is water. In one embodiment, the oil is vegetable oil. Optionally, the liquid carrier contains about a suspending agent. 
     In a further embodiment, the compounds are delivered rectally or vaginally in the form of a conventional suppository. 
     In yet another embodiment, the compositions are delivered intranasally or intrabronchially in the form of an aerosol. 
     In a further embodiment, the compositions are delivered transdermally or by sustained release through the use of a transdermal patch containing the composition and an optional carrier that is inert to the compound, is nontoxic to the skin, and allows for delivery of the compound for systemic absorption into the blood stream. Such a carrier can be a cream, ointment, paste, gel, or occlusive device. The creams and ointments can be viscous liquid or semisolid emulsions. Pastes can include absorptive powders dispersed in petroleum or hydrophilic petroleum. Further, a variety of occlusive devices can be utilized to release the active reagents into the blood stream and include semi-permeable membranes covering a reservoir contain the active reagents, or a matrix containing the reactive reagents. 
     IV. Methods of Use 
     The compounds of the present invention have utility for the prevention and treatment of disorders involving beta amyloid production, including cerebrovascular diseases, and the prevention and treatment of AD by virtue of their ability to reduce beta amyloid production. 
     In preliminary studies using protease specific assays, the compounds of the invention have been shown to exhibit specific inhibition with respect to protease activity. Thus, the compounds of the present invention are useful for treatment and prevention of a variety of conditions in which modulation of beta amyloid levels provides a therapeutic benefit. Such conditions include, e.g., amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Alzheimer&#39;s disease (AD), hereditary cerebral hemorrhage with amyloidosis of the Dutch type, inclusion body myositis, Down&#39;s syndrome and mild cognitive impairment, among others. 
     The compounds of the present invention have also been shown to inhibit beta amyloid production. In one embodiment, a subject or patient can be monitored for circulating levels of the compounds and/or beta-amyloid levels, from time to time following administration of a compound of the invention, or during the course of treatment. A variety of assays can be utilized for this purpose, including those described below. Additionally, cellular, cell-free and in vivo screening methods, as well as radioimmunoassays and enzyme-linked immunosorbent assay (ELISA) to detect inhibitors of beta amyloid production are known in the art (See, e.g., P. D. Mehta, et al., Techniques in Diagnostic Pathology, vol. 2, eds., Bullock et al, Academic Press, Boston, pages 99-112 (1991), International Patent Publication No. WO 98/22493, European Patent No. 0 652 009, and U.S. Pat. Nos. 5,703,129 and 5,593,846). 
     The compounds can further be utilized in generating reagents useful in diagnosis of conditions associated with abnormal levels of beta amyloid. For example, the compounds of Formula I can be used to generate antibodies which would be useful in a variety of diagnostic assays. Methods for generating monoclonal, polyclonal, recombinant, and synthetic antibodies or fragments thereof, are well known to those of skill in the art. See, e.g., E. Mark and Padlin, “Humanization of Monoclonal Antibodies”, Chapter 4, The Handbook of Experimental Pharmacology, Vol. 113, The 
     Pharmacology of Monoclonal Antibodies, Springer-Verlag (June, 1994); Kohler and Milstein and the many known modifications thereof; International Patent Application No. PCT/GB85/00392; British Patent Application Publication No. GB2188638A; Amit et al., Science, 233:747-753 (1986); Queen et al., Proc. Nat&#39;l. Acad. Sci. USA, 86:10029-10033 (1989); International Patent Publication No. WO 90/07861; and Riechmann et al., Nature, 332:323-327 (1988); Huse et al, Science, 246:1275-1281 (1988). Alternatively, the compounds of Formula I can themselves be used in such diagnostic assays. Regardless of the reagent selected (e.g., antibody or compound of Formula I), suitable diagnostic formats including, e.g., radioimmunoassays and enzyme-linked immunosorbent assays (ELISAs), are well known to those of skill in the art and are not a limitation on this embodiment of the invention. 
     The following examples are provided to illustrate the production and activity of representative compounds of the invention and to illustrate their performance in a screening assay. One skilled in the art will appreciate that although specific reagents and conditions are outlined in the following examples, these reagents and conditions are not a limitation on the present invention. 
     EXAMPLES 
     Example 1 
     2-Bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of (S) isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was added triethylamine (46 μL, 0.24 mmol) and 2-bromobenzenesulfonyl chloride (51 mg, 0.2 mmol). The solution was stirred for 8 to 16 hours, then concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC using the following conditions: 
     Column: Phenomenex C18 Luna® 21.6 mm×60 mm column, 5μ 
     Solvent A: Water (0.02% TFA buffer) 
     Solvent B: Acetonitrile (0.02% TFA buffer) 
     Solvent Gradient: Time 0: 10% B; 2.5 min: 10% B; 14 min: 90% B. 
     Flow Rate: 22.5 mL/min 
     The product peak was collected based on UV absorption and concentrated to give Example 1 (37.7 mg). 
     The following compounds (Table 1; Examples 1-13) were prepared using 2-bromobenzenesulfonyl chloride, 3-bromobenzenesulfonyl chloride, 3-chlorobenzenesulfonyl chloride, 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole, 2-chloro-4-fluorobenzenesulfonyl chloride, 5-chloro-2-methoxy-benzenesulfonyl chloride, 2-chloro-6-methylbenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 2,4-difluoro benzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 2-fluorobenzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, and 2-naphthalenesulfonyl chloride and following the procedure outlined in Example 1. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 LCMS Data 1   
               
            
           
           
               
               
               
            
               
                   
                 Ex- 
                 Molecular ion 
               
               
                 RSO 2 Cl 
                 ample 
                 and retention time 
               
               
                   
               
            
           
           
               
               
               
            
               
                 2-bromobenzenesulfonyl chloride 
                 1 
                 (338.0 M + H); 2.850 min 
               
               
                 3-bromobenzenesulfonyl chloride 
                 2 
                 (338.0 M + H); 3.014 min 
               
               
                 3-chlorobenzenesulfonyl chloride 
                 3 
                 (292.1 M + H); 2.949 min 
               
               
                 4-chloro-7-chlorosulfonyl-2, 
                 4 
                 (334.1 M + H); 3.073 min 
               
               
                 1,3-benzoxadiazole 
               
               
                 2-chloro-4-fluorobenzenesulfonyl 
                 5 
                 (311.1 M + H); 2.910 min 
               
               
                 chloride 
               
               
                 5-chloro-2-methoxy- 
                 6 
                 (322.1 M + H); 3.018 min 
               
               
                 benzenesulfonyl chloride 
               
               
                 2-chloro-6- 
                 7 
                 (306.1 M + H); 3.017 min 
               
               
                 methylbenzenesulfonyl chloride 
               
               
                 3,5-dichlorobenzenesulfonyl 
                 8 
                 (326.0 M + H); 3.320 min 
               
               
                 chloride 
               
               
                 2,4-difluorobenzenesulfonyl 
                 9 
                 (294.1 M + H); 2.740 min 
               
               
                 chloride 
               
               
                 4-fluorobenzenesulfonyl 
                 10 
                 (277.1 M + H); 2.691 min 
               
               
                 chloride 
               
               
                 2-fluorobenzenesulfonyl chloride 
                 11 
                 (276.1 M + H); 2.608 min 
               
               
                 1-naphthalenesulfonyl chloride 
                 12 
                 (308.1 M + H); 3.087 min 
               
               
                 2-naphthalenesulfonyl chloride 
                 13 
                 (308.1 M + H); 3.103 min 
               
               
                   
               
               
                   1 LCMS conditions: Hewlett Packard 1100 MSD; YMC ODS-AM ® 2.0 mm × 50 mm 5 μ column at 23° C.; 3 μL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.3 min: 95% A; 4.7 min: 10% A; 4.9 min: 95% A. Flow rate 1.5 mL/min; Detection: 254 nm DAD; API-ES Scanning Mode Positive 150-700; Fragmentor 70 mV. 
               
            
           
         
       
     
     Example 14 
     3-Amino-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     A. Preparation of 3-Nitro-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     To a solution of S-isoleucinol (3.0 g, 25.6 mmol), triethylamine (2.85 g, 28.2 mmol) and methylene chloride (30 mL) at 0° C., was added a solution of 4-chloro-3-nitro-benzenesulfonyl chloride (6.55 g, 25.6 mmol) in CH 2 Cl 2  (30 mL). After 15 minutes, the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into a saturated sodium bicarbonate solution (125 mL). The organic phase was separated and washed sequentially with 1N HCl solution (100 mL), distilled water and brine, dried over MgSO 4  and evaporated to give a crude solid that was recrystallized from ethyl acetate-hexane (5.52 g, 64%). MS (+ESI) 354 ([M+NH 4 ] + ). Anal. Calc&#39;d for C 12 H 17 ClN 2 O 5 S: C, 42.80; H, 5.09; N, 8.32; Found: C, 42.82; H, 5.05; N, 8.23. 
     B. Preparation of 3-Amino-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     A standard hydrogenation bottle was charged with 3-nitro-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide (0.50 g, 1.48 mmol), 10% palladium on carbon (0.05 g), methanol (25 mL) and hydrogen gas. It was shaken on a Parr hydrogenation apparatus for 50 minutes. The reaction mixture was filtered and the solvent evaporated to produce a crude oil that was flash chromatographed (eluant: ethyl acetate-hexane, 3-2) to afford the product as a solid, mp 89-92° C. (0.12 g, 26%). MS (+APCI) 307.03 ([M+H] + ). Anal. Calc&#39;d for C 12 H 19 ClN 2 O 3 S: C, 46.98; H, 6.24; N, 9.13; Found: C, 47.44; H, 6.32; N, 8.88. 
     Example 15  
     N-[(1S)-1-benzyl-2-hydroxyethyl]-4-bromobenzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of (S)-(−) 2-amino-3-phenyl-1-propanol (37 mg, 0.25 mmol) in THF (3 mL) was added triethylamine (58 uL, 0 3 mmol) and 4-bromobenzenesulfonyl chloride (63 mg, 0.25 mmol). The solution was stirred for 8 to 16 hours, then concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC using the conditions described in Example 1 to give Example 15 (9.8 mg). This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 R 1 R 2 NH 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 (S)-(−) 2-amino-3-phenyl-1-propanol 
                 Example 15; (372.0 
               
               
                   
                   
                 M + H); 3.110 min 
               
               
                   
                   
               
            
           
         
       
     
     Example 16 
     4-Bromo-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of 4-bromobenzenesulfonyl chloride (102 mg, 0.4 mmol) in THF (1 mL) was added L-cyclohexylglycine (77.4 mg, 0 4 mmol) in 1 N sodium hydroxide (1 mL) The reaction was shaken at 25° C. for 16 hours, then concentrated. 
     The residue was dissolved in THF (1 mL) and lithium aluminum hydride (1 M solution in THF, 0.8 mmol, 0.8 mL) was added and the reaction shaken for 2 hours. Water (240 μL), 15% sodium hydroxide (240 μL) and water (960 μL) were added with shaking between each addition. The reaction mixture was filtered and the filtrate concentrated and purified as described for Example 1 to give Example 16 (1.9 mg). This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     The following compounds (Examples 16-19, Table 3) were prepared using 4-bromobenzensulfonyl chloride with L-cyclohexylglycine, D-4-hydroxyphenylglycine, D-methionine, and L-tryptophan and following the procedure outlined in Example 16. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Retention time 
               
               
                 Amino Acid 
                 Example 
                 Molecular Ion 
                 (min) 
               
               
                   
               
               
                 L-cyclohexylglycine 
                 16 
                 (364.0 M + H) 
                 3.216 
               
               
                 D-4-hydroxy phenylglycine 
                 17 
                 (374.0 M + H) 
                 2.371 
               
               
                 D-methionine 
                 18 
                 (355.0 M + H) 
                 2.692 
               
               
                 L-tryptophan 
                 19 
                 (411.0 M + H) 
                 3.004 
               
               
                   
               
            
           
         
       
     
     Example 20 
     4-Bromo-2,5-difluoro-N-[(1S,2S)-1-(hydroxymethyl)-2methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of (S)-isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was added triethylamine (46 μL, 0.24 mmol) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (58 mg, 0.2 mmol). The solution was stirred for 8 to 16 hours. The solvent was removed and the residue purified as described for Example 1 to give Example 20 (4.7 mg). 
     The following compounds (Table 4) were prepared using (S)-(+)-isoleucinol, (S)-(+)-2-amino-3-methyl-1-butanol, and (S)-tert-leucinol with 4-bromo-2,5-difluoro benzenesulfonyl chloride, 2,5-dibromobenzenesulfonyl chloride, 3,4-dibromo benzenesulfonyl chloride, 2,3-dichlorobenzenesulfonyl chloride, 3,4-dichloro benzenesulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, and 2,4,6-trichloro benzenesulfonyl chloride and following the procedure outlined in Example 20. 
     This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 Aminoalcohol 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 (S)-(+)-2-amino-3- 
                   
               
               
                 RSO 2 Cl 
                 (S)-(+)-isoleucinol 
                 methyl-1-butanol 
                 (S)-tert-leucinol 
               
               
                   
               
               
                 4-bromo-2,5-difluorobenzenesulfonyl 
                 Ex. 20 
                 Ex. 26 
                   
               
               
                 chloride 
                 (374.0 M + H); 
                 (358.0 M + H); 
               
               
                   
                 3.663 min 
                 3.006 min 
               
               
                 2,5-dibromobenzenesulfonyl chloride 
                 Ex. 21 
               
               
                   
                 (417.9 M + H); 
               
               
                   
                 3.340 min 
               
               
                 3,4-dibromobenzenesulfonyl chloride 
                 Ex. 22 
                   
                 Ex. 29 
               
               
                   
                 (415.9 M + H); 
                   
                 (415.9 M + H); 
               
               
                   
                 3.387 min 
                   
                 3.357 min 
               
               
                 2,3-dichlorobenzenesulfonyl chloride 
                 Ex. 23 
               
               
                   
                 (328.0 M + H); 
               
               
                   
                 3.152 min 
               
               
                 3,4-dichlorobenzenesulfonyl chloride 
                 Ex. 24 
                 Ex. 27 
                 Ex. 30 
               
               
                   
                 (328.0 M + H); 
                 (312.0 M + H); 
                 (326.0 M + H); 
               
               
                   
                 3.314 min 
                 3.105 min 
                 3.041 min 
               
               
                 2,4,5-trichlorobenzenesulfonyl 
                 Ex. 25 
                   
                 Ex. 31 
               
               
                 chloride 
                 (362.0 M + H); 
                   
                 (362.0 M + H); 
               
               
                   
                 3.533 min 
                   
                 3.505 min 
               
               
                 2,4,6-trichlorobenzenesulfonyl 
                   
                 Ex. 28 
                 Ex. 32 
               
               
                 chloride 
                   
                 (348.0 M + H); 
                 (362.0 M + H); 
               
               
                   
                   
                 3.210 min 
                 3.404 min 
               
               
                   
               
            
           
         
       
     
     Example 33 
     4-Bromo-N-[(1R,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of D-isoleucine (32.8 mg, 0.25 mmol) in THF (2 mL) was added lithium aluminum hydride (1 M solution in THF) (0.8 mL, 0.8 mmol) and the solution was heated at 60° C. for 4 hours. The solution was then stirred at 25° C. for 8 to 16 hours. The reaction was quenched by addition of water (45 uL), 15% aqueous sodium hydroxide (45 μL) and water (105 μL) with vigorous stirring between each addition. The mixture was then filtered and concentrated. 
     To the residue in THF (3 mL) was added triethylamine (69 μL, 0.50 mmol) and 4-bromobenzenesulfonyl chloride (63.9 mg, 0.25 mmol). The solution was stirred for 8 to 16 hours, then concentrated and the residue purified as described for Example 1 to give 50.8 mg. 
     The following compounds (Examples 33-39, Table 5) were prepared using 4-bromobenzenesulfonyl chloride, and 4-chlorobenzenesulfonyl chloride, with D-isoleucine, L-α-methyl-valine, β-methyl-DL-phenylalanine, and L-allo-isoleucine and following the procedure outlined in Example 33. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 RSO 2 Cl 
               
            
           
           
               
               
               
            
               
                   
                 4-bromobenzenesulfonyl 
                 4-chlorobenzenesulfonyl 
               
               
                 Amino Acid 
                 chloride 
                 chloride 
               
               
                   
               
               
                 D-isoleucine 
                 Ex. 33 
                   
               
               
                   
                 (336.0 M + H); 2.858 min 
               
               
                 L-α-methyl- 
                 Ex. 34 
                 Ex. 37 
               
               
                 valine 
                 (338.0 M + H); 2.872 min 
                 (292.0 M + H); 2.806 min 
               
               
                 β-methyl-DL- 
                 Ex. 35 
                 Ex. 38 
               
               
                 phenylalanine 
                 (386.0 M + H); 3.089 min 
                 (342.0 M + H); 3.035 min 
               
               
                 L-allo- 
                 Ex. 36 
                 Ex. 39 
               
               
                 isoleucine 
                 (336.0 M + H); 2.828 min 
                 (292.0 M + H); 2.763 min 
               
               
                   
               
            
           
         
       
     
     Example 40  
     N-Allyl-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of L-isoleucine methyl ester hydrochloride (1.82 g, 10 mmol) and 4-chlorobenzenesulfonyl chloride (2.11 g, 10 mmol) in CH 2 Cl 2  was added triethylamine (4.18 mL, 30 mmol). The mixture was stirred at 25° C. for 16 hours, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel using 10% ethyl acetate in hexane to give N-4-chlorobenzenesulfonyl L-isoleucine methyl ester 3.53 g. 
     To a solution of N-4-chlorobenzenesulfonyl L-isoleucine methyl ester (80 mg, 0.25 mmol) in a mixture of DCM (1.5 mL) and THF (1.5 mL) was added allyl alcohol (17 μL, 0.25 mmol), triphenylphosphine (66 mg, 0.25 mmol) and diethylazodicarboxylate (39 μL, 0.25 mmol). The reaction was shaken at 25° C. for 24 hours. 
     Lithium borohydride (11 mg, 0.5 mmol) was added to this reaction solution and the reaction was shaken at 45° C. for 24 hours then quenched by addition of water (2 mL) and extracted into ethyl acetate (3.5 mL). The organic phase was evaporated and the residue purified as described for Example 1 to give 11.6 mg. 
     The following compounds (Examples 40-48, Table 6) were prepared using allyl alcohol, 4-biphenylmethanol, t-butyl N-(2-hydroxyethyl)-carbamate, p-chlorobenzyl alcohol, cyclobutanemethanol, 3,4-dimethoxybenzyl alcohol, furfuryl alcohol, 2-(methylthio)ethanol, and 3-phenyl-2-propyn-1-ol and following the procedure outlined in Example 40. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 (LCMS Data 1 ) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Retention 
               
               
                 R 1 OH 
                 Example 
                 Molecular Ion 
                 Time 
               
               
                   
               
               
                 allyl alcohol 
                 40 
                 332.24 M + H 
                 3.57 min 
               
               
                 4-biphenylmethanol 
                 41 
                 458.0 M + H 
                 4.225 min  
               
               
                 t-butyl N-(2-hydroxyethyl)- 
                 42 
                 435.33 M + H 
                 3.68 min 
               
               
                 carbamate 
               
               
                 p-chlorobenzyl alcohol 
                 43 
                 416.14 M + H 
                 3.97 min 
               
               
                 cyclobutanemethanol 
                 44 
                 360.31 M + H 
                 3.97 min 
               
               
                 3,4-dimethoxybenzyl alcohol 
                 45 
                 442.1 M + H 
                 3.333 min  
               
               
                 furfuryl alcohol 
                 46 
                 372.1 M + H 
                 3.403 min  
               
               
                 2-(methylthio)ethanol 
                 47 
                 366.27 M + H 
                 3.69 min 
               
               
                 3-phenyl-2-propyn-1-ol 
                 48 
                 406.33 M + H 
                 4.05 min 
               
               
                   
               
            
           
         
       
     
     Example 49 
     4-Chloro-N-[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)propyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     Part 1: 
     A solution of 2-pentenoic acid (4.05 mL, 40 mmol) in THF (100 mL) was cooled to −78° C. Triethylamine (5.85 mL, 42 mmol) and trimethylacetyl chloride (pivaloyl chloride) (5.17 mL, 42 mmol) were added via syringe in that order. The dry ice bath was replaced with an ice bath and the reaction stirred at 0° C. for 1 hour, then the reaction was recooled to −78° C. In a separate flask 4-(R)-4-benzyl-2-oxazolidinone (7.0 g, 40 mmol) was dissolved in THF (100 mL) and cooled to −78° C., then n-butyl lithium (1.6 M, 25 mL) was added via syringe. The mixture was stirred for 20 minutes then the above reaction mixture was added by removing the septum and pouring quickly from one flask to the other (Note* attempts to transfer reaction mixture via cannula failed due to the suspended triethylammonium chloride in the mixture). 
     The resulting mixture was stirred at −78° C. for 30 minutes then allowed to warm to 25° C. for 1 to 2 hours before quenching with saturated aqueous NH 4 Cl solution (100 mL). Volatiles were removed on the rotary evaporator and the aqueous slurry was diluted with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phase was dried over MgSO 4 , filtered and concentrated. The product may crystallize out of solution and be of high purity. If purification is required, the crude product can be purified by flash chromatography using 20-30% ethyl acetate in hexane. 
     Part 2: 
     To a copper (I) bromide-dimethyl sulfide complex (246 mg, 1.2 mmol) in THF/DMS (2:1, 15 mL), cooled to −40° C., was added 4-methoxyphenyl magnesium bromide (4.8 mL 0.5 M solution in THF, 2.4 mmol). The solution was allowed to stir for 10 minutes while warming to −15° C. The mixture was recooled to −40° C. and the product from Part 1 (245 mg, 1 mmol) in THF (6 mL) was added. The solution was stirred at 25° C. for 8 to 16 hours. The solution was cooled to −78° C. and N-bromosuccinimide (356 mg, 2 mmol) in THF (2 mL) was added. The solution was allowed to warm to 0° C. and shaken at 0° C. for 3 hours. The reaction was quenched with a 1:1 solution of saturated ammonium carbonate and 0.5 N potassium bisulfate (5 mL). The organic phase was decanted off and concentrated. 
     Part 3: 
     To the product from Part 2 dissolved in acetonitrile (5 mL) was added tetramethylguanidine azide (0.6 mL, 4 mmol). The solution was stirred for 72 to 120 hours. The solution was concentrated to dryness, redissolved in CH 2 Cl 2  and 1 N HCl (2 mL) was added. The layers were separated and the organic layer was filtered through a pad of silica gel, washed with CH 2 Cl 2  (5 mL) and concentrated. 
     Part 4: 
     To the product from Part 3 (131 mg, 1 mmol) in THF (5 mL) at 0° C. was added lithium aluminum hydride (1 M solution in THF) (2 mL, 2 mmol) and the solution stirred at 25° C. for 4 hours. The reaction was quenched by addition of water (114 μL), 15% aqueous sodium hydroxide (114 μL), and water (266 μL) with vigorous stirring between each addition. The mixture was then filtered and concentrated. 
     Part 5: 
     To the solution from Part 4 (0.5 mmol) in THF (2 mL) was added triethylamine (83.7 μL, 0.6 mmol) and 4-chlorobenzenesulfonyl chloride (130.8 mg, 0.5 mmol). The solution was stirred for 8 to 16 hours, then concentrated. The solvent was removed and the residue purified as described for Example 1 to give 50.8 mg. 
     The following compounds (Examples 49-70, Table 7) were prepared using 4-chlorobenzenesulfonyl chloride with crotonic acid, 2-pentenoic acid, 2-hexenoic acid, 2-octenoic acid, cinnamic acid, furylacrylic acid, and 4-methyl-2-pentenoic acid and methyl, ethyl, isobutyl, 4-methoxyphenyl, hexyl and phenyl magnesium bromide and following the procedure outlined in Example 49. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 R′MgX 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 4-methoxy- 
                   
                   
               
               
                 R 
                 methyl 
                 Ethyl 
                 isobutyl 
                 phenyl 
                 n-hexyl 
                 phenyl 
               
               
                   
               
               
                 Methyl 
                   
                   
                   
                 Ex. 49 
                 Ex. 50 
                 Ex. 51 
               
               
                   
                   
                   
                   
                 (370.0 
                 (348.1 
                 (340.0 
               
               
                   
                   
                   
                   
                 M + H); 
                 M + H); 
                 M + H); 
               
               
                   
                   
                   
                   
                 3.168 min 
                 4.017 min 
                 3.244 min 
               
               
                 Ethyl 
                   
                 Ex. 52 
                 Ex. 53 
               
               
                   
                   
                 (306.0 
                 (334.0 
               
               
                   
                   
                 M + H); 
                 M + H); 
               
               
                   
                   
                 3.189 min 
                 3.648 min 
               
               
                 n-propyl 
                 Ex. 54 
                 Ex. 55 
                 Ex. 56 
                 Ex. 57 
                 Ex. 58 
                 Ex. 59 
               
               
                   
                 (306.0 
                 (320.0 
                 (348.1 
                 (398.1 
                 (376.1 
                 (368.1 
               
               
                   
                 M + H); 
                 M + H); 
                 M + H); 
                 M + H); 
                 M + H); 
                 M + H); 
               
               
                   
                 3.215 min 
                 3.372 min 
                 3.891 min 
                 3.635 min 
                 4.415 min 
                 3.706 min 
               
               
                 n-pentyl 
                 Ex. 60 
                 Ex. 61 
                   
                   
                 Ex. 62 
               
               
                   
                 (334.1 
                 (348.1 
                   
                   
                 (404.2 
               
               
                   
                 M + H); 
                 M + H); 
                   
                   
                 M + H); 
               
               
                   
                 3.746 min 
                 3.949 min 
                   
                   
                 4.834 min 
               
               
                 Phenyl 
                 Ex. 63 
                   
                 Ex. 64 
                   
                 Ex. 65 
               
               
                   
                 (340.0 
                   
                 (382.1 
                   
                 (410.1 
               
               
                   
                 M + H); 
                   
                 M + H); 
                   
                 M + H); 
               
               
                   
                 3.259 min 
                   
                 3.876 min 
                   
                 4.366 min 
               
               
                 2-furyl 
                   
                 Ex. 66 
                 Ex. 67 
                   
                 Ex. 68 
               
               
                   
                   
                 (344.0 
                 (372.1 
                   
                 (400.1 
               
               
                   
                   
                 M + H); 
                 M + H); 
                   
                 M + H); 
               
               
                   
                   
                 3.225 min 
                 3.649 min 
                   
                 4.152 min 
               
               
                 i-propyl 
                 Ex. 69 
                   
                   
                   
                 Ex. 70 
               
               
                   
                 (306.0 
                   
                   
                   
                 (376.1 
               
               
                   
                 M + H); 
                   
                   
                   
                 M + H); 
               
               
                   
                 3.199 min 
                   
                   
                   
                 4.414 min 
               
               
                   
               
            
           
         
       
     
     The following compounds (Examples 71-87, Table 8) were prepared using 4-bromobenzenesulfonyl chloride with crotonic acid, 2-pentenoic acid, 2-hexenoic acid, 2-octenoic acid, cinnamic acid, b-(3-pyridyl)-acrylic acid, furylacrylic acid, and 4-methyl-2-pentenoic acid and methyl, ethyl, isobutyl, 4-methoxyphenyl, and hexyl magnesium bromide and following the procedure outlined in Example 49. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 R′ 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 4-methoxy- 
                   
               
               
                 R 
                 Methyl 
                 ethyl 
                 Isobutyl 
                 phenyl 
                 n-hexyl 
               
               
                   
               
               
                 Methyl 
                   
                   
                   
                 Ex. 71 
                 Ex. 72 
               
               
                   
                   
                   
                   
                 (414.0 M + H); 
                 (394.0 M + H); 
               
               
                   
                   
                   
                   
                 3.230 min 
                 4.071 min 
               
               
                 Ethyl 
                   
                   
                 Ex. 73 
                 Ex. 74 
                 Ex. 75 
               
               
                   
                   
                   
                 (380.0 M + H); 
                 (430.0 M + H); 
                 (406.1 M + H); 
               
               
                   
                   
                   
                 3.710 min 
                 3.460 min 
                 4.256 min 
               
               
                 n-propyl 
                 Ex. 76 
                 Ex. 77 
                 Ex. 78 
                   
                 Ex. 79 
               
               
                   
                 (352.0 M + H); 
                 (364.0 
                 (394.0 M + H); 
                   
                 (422.1 M + H); 
               
               
                   
                 3.291 min 
                 M + H); 
                 3.949 min 
                   
                 4.466 min 
               
               
                   
                   
                 3.422 min 
               
               
                 n-pentyl 
                 Ex. 80 
                 Ex. 81 
               
               
                   
                 (380.0 M + H); 
                 (392.1 
               
               
                   
                 3.797 min 
                 M + H); 
               
               
                   
                   
                 4.007 min 
               
               
                 Phenyl 
                 Ex. 82 
                 Ex. 83 
               
               
                   
                 (386.0 M + H); 
                 (398.0 M + H); 
               
               
                   
                 3.328 min 
                 3.546 min 
               
               
                 2-furyl 
                 Ex. 84 
                 Ex. 85 
                 Ex. 86 
               
               
                   
                 (376.0 M + H); 
                 (388.0 M + H); 
                 (418.0 M + H); 
               
               
                   
                 3.057 min 
                 3.305 min 
                 3.712 min 
               
               
                 i-propyl 
                   
                   
                 Ex. 87 
               
               
                   
                   
                   
                 (394.0 M + H); 
               
               
                   
                   
                   
                 3.948 min 
               
               
                   
               
            
           
         
       
     
     Example 88 
     4-Chloro-N-[(1S,2S)-2-ethyl-1-(hydroxymethyl)octyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     Following the procedure outlined in Example 49 (Part 1 and 2), 2-pentenoic acid was coupled with 4-(R)-4-benzyl-2-oxazolidinone to give (R)-3-(2′-pentenyl)-4-benzyl-2-oxazolidinone. Addition of hexyl magnesium bromide was followed by trapping by N-bromosuccinimide. After workup, flash chromatography over silica gel using 5% ether in hexane, gave approximately a 2:1 mixture of (1R-2R):(1R-2S)-3-(2′-bromo-3′ethylnonanyl)-4-benzyl-2-oxazolidinone. Each isomer was converted to the corresponding sulfonylated amino alcohol following the procedure in Example 49, (Steps 3-5). 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 (LCMS Data 1 : Molecular ion and retention time) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Retention 
               
               
                   
                 Isomer 
                 Example 
                 Molecular Ion 
                 Time (min) 
               
               
                   
                   
               
               
                   
                 1S-2S 
                 88 
                 363 M + H 
                 4.24 min 
               
               
                   
                 1S-2R 
                 89 
                 363 M + H 
                 4.24 min 
               
               
                   
                   
               
            
           
         
       
     
     Example 90 
     4-Chloro-N-methyl-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of 4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide (0.10 g, 0.343 mmol) dissolved in DMF (2.0 mL) was added potassium carbonate (47 mg, 0.343 mmol). After 30 minutes, the reaction mixture was cooled to 0° C. and iodomethane (50 μL, 0.686 mmol) was added. After 2 hours, the ice bath was removed and the reaction mixture was stirred at 25° C. for 24 hours. The insolubles were then filtered off and the DMF solution was diluted with EtOAc (50 mL) and washed sequentially with 10% citric acid (50 mL) and saturated brine (50 mL), dried over MgSO 4  and evaporated to a clear oil which was washed with Et 2 O and then purified by flash chromatography (eluant: 95-5 CHCl 3 /iPrOH) to afford the desired product as a clear oil (71 mg, 68%). Mass Spectrum (+APCI): 306 ([M+H] + ). Anal: Calc&#39;d for C 13 H 20 ClNO 3 S: C, 51.06; H, 6.59; N, 4.58. Found: C, 51.15; H, 6.73; N, 4.36. 
     Example 91 
     4-Chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of (S)-isoleucinol (17.6 mg, 0.15 mmol) in CH 3 CN (600 μL) was added Et 3 N (300 μL, 1M in CH 3 CN) and 4-chlorobenzenesulfonyl chloride (21.07 mg, 0.1 mmol) as a solution in CH 3 CN (400 μL). The vial was capped and shaken for 8 to 12 hours at 40° C. The solvent was removed, and the oil was dissolved in EtOAc (1 mL). The resulting solution was washed with 1M HCl (2×1 mL). The solvent was removed in vacuo, and the residue dissolved in 1.6 mL DMSO (0.03 M). 
     The following compounds (Examples 91-119, Table 10) were prepared using 4-chloro, 4-bromo, 3-chloro, and 3-fluorobenzenesulfonyl chloride with (S)-isoleucinol, L-leucinol, DL-2-amino-1-hexanol, (1S,2R)-(+)-phenyl-propanolamine, (S)-(+)-2-phenylglycinol, (R)-(−)-leucinol, 1-amino-1-cyclopentanemethanol, DL-2-amino-1-pentanol, (S)-2-amino-3-cyclohexyl-1-propanol, H-tyrosinol(bzl), (R)-(+)-methioninol, (S)-(+)-2-amino-1-butanol, (1S,2S)-(+)-thiomicamine, L-alaninol, L-phenylalaninol, L-valinol, and (R)-(+)-2-amino-2-methyl-1-butanol following the procedure outlined in Example 91. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 (LCMS Data 2 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 X-Ph 
               
            
           
           
               
               
               
               
               
            
               
                 Aminoalcohol 
                 4-chloro-Ph 
                 4-bromo-Ph 
                 3-chloro-Ph 
                 3-fluoro-Ph 
               
               
                   
               
               
                 (S)-isoleucinol 
                 Ex. 91 
                 Ex. 98 
                   
                   
               
               
                   
                 290.54 (M − H) 
                 334.48 (M − H) 
               
               
                   
                 0.96 min 
                 1.00 min 
               
               
                 L-leucinol 
                 Ex. 92 
                   
                   
                 Ex. 109 
               
               
                   
                 290.53 (M − H) 
                   
                   
                 274.57 (M − H) 
               
               
                   
                 0.96 min 
                   
                   
                 0.87 min 
               
               
                 DL-2-amino-1-hexanol 
                   
                 Ex. 99 
                   
                 Ex. 110 
               
               
                   
                   
                 334.49 (M − H) 
                   
                 274.55 (M − H) 
               
               
                   
                   
                 1.02 min 
                   
                 0.86 min 
               
               
                 (1S,2R)-(+)-phenyl- 
                 Ex. 93 
                 Ex. 100 
                   
                 Ex. 111 
               
               
                 propanolamine 
                 324.54 (M − H) 
                 368.44 (M − H) 
                   
                 308.55 (M − H) 
               
               
                   
                 1.05 min 
                 1.09 min 
                   
                 0.96 min 
               
               
                 (S)-(+)-2- 
                   
                 Ex. 101 
                   
                 Ex. 112 
               
               
                 phenylglycinol 
                   
                 354.44 (M − H) 
                   
                 294.53 (M − H) 
               
               
                   
                   
                 0.96 min 
                   
                 0.81 min 
               
               
                 (R)-(−)-leucinol 
                   
                 Ex. 102 
                   
                 Ex. 113 
               
               
                   
                   
                 334.48 (M − H) 
                   
                 274.48 (M − H) 
               
               
                   
                   
                 1.00 min 
                   
                 0.89 min 
               
               
                 1-amino-1- 
                 Ex. 94 
                 Ex. 103 
                   
                 Ex. 114 
               
               
                 cyclopentane methanol 
                 332.47 (M − H) 
                 288.52 (M − H) 
                   
                 272.55 (M − H) 
               
               
                   
                 0.95 min 
                 0.91 min 
                   
                 0.78 min 
               
               
                 DL-2-amino-1- 
                   
                 Ex. 104 
                 Ex. 105 
               
               
                 pentanol 
                   
                 320.47 (M − H) 
                 276.49 (M − H) 
               
               
                   
                   
                 0.93 min 
                 0.89 min 
               
               
                 (S)-2-amino-3- 
                 Ex. 95 
                   
                 Ex. 106 
                 Ex. 115 
               
               
                 cyclohexyl-1-propanol 
                 330.57 (M − H) 
                   
                 330.57 (M − H) 
                 314.59 (M − H) 
               
               
                   
                 1.16 min 
                   
                 1.16 min 
                 1.07 min 
               
               
                 H-tyrosinol (bzl) 
                 Ex. 96 
               
               
                   
                 430.54 (M − H) 
               
               
                   
                 1.22 min 
               
               
                 (R)-(+)-methioninol 
                   
                   
                 Ex. 107 
               
               
                   
                   
                   
                 308.50 (M − H) 
               
               
                   
                   
                   
                 0.85 min 
               
               
                 (S)-(+)-2-amino-1- 
                   
                   
                 Ex. 108 
               
               
                 butanol 
                   
                   
                 262.49 (M − H) 
               
               
                   
                   
                   
                 0.80 min 
               
               
                 (1S,2S)-(+)- 
                   
                   
                   
                 Ex. 116 
               
               
                 thiomicamine 
                   
                   
                   
                 370.51 (M − H) 
               
               
                   
                   
                   
                   
                 0.85 min 
               
               
                 L-alaninol 
                   
                   
                   
                 Ex. 117 
               
               
                   
                   
                   
                   
                 232.47 (M − H) 
               
               
                   
                   
                   
                   
                 0.52 min 
               
               
                 L-phenyl alaninol 
                   
                   
                   
                 Ex. 118 
               
               
                   
                   
                   
                   
                 308.56 (M − H) 
               
               
                   
                   
                   
                   
                 0.89 min 
               
               
                 L-valinol 
                   
                   
                   
                 Ex. 119 
               
               
                   
                   
                   
                   
                 260.51 (M − H) 
               
               
                   
                   
                   
                   
                 0.74 min 
               
               
                 (R)-(+)-2-amino-2- 
                 Ex. 97 
               
               
                 methyl-1-butanol 
                 275.91 (M − H) 
               
               
                   
                 0.49 min 
               
               
                   
               
               
                   2 LCMS conditions: ZMD (Waters) or Platform ™ (Micromass) or LCZ (Micromass); Zorbax ® SB-C8 column; solvent: AcCN + H 2 O containing 0.1% TFA or 0.1% FA; gradient: 2.5 min 15% AcCN-95% AcCN; flow rate: 3 mL/min; detection: ELSD detection (SEDEX ™ 55 instrument); UV253 detection (Schimadzu). 
               
            
           
         
       
     
     Example 120 
     4-Bromo-N-[1-(hydroxymethyl)-cyclohexyl]-benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     Part 1: 
     To a suspension of 1-amino-1-cyclohexane carboxylic acid (5 g, 35 mmol) and THF (100 mL) was added borane dimethyl sulfide (50 mL, 2M in THF) at 0° C. The cold bath was allowed to expire and the reaction was stirred at 25° C. for 24 hours. NaOH (3M, 100 mL) was added and the mixture was stirred for 4 hours. The reaction mixture was saturated with K 2 CO 3  and extracted with Et 2 O (2×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over MgSO 4  and evaporated to give 4.35 g (96%) of the desired amino alcohol. 
     Part 2:  
     The amino alcohol was sulfonylated as in example 91. 
     The following compounds (Examples 120-125, Table 11) were prepared using the following amino acids: 1-amino-1-cyclohexane carboxylic acid, 2-amino-2-norbornane carboxylic acid, d, 1-1-aminoindane-1-carboxylic acid, and d-1-2-cyclobutyl-2-phenylglycine with 4-bromo and 4-chlorobenzenesulfonyl chloride following the procedure outlined for example 120. This procedure is outlined in the following Scheme 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 (LCMS Data 2 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 X-Ph 
               
            
           
           
               
               
               
            
               
                 Amino Acid 
                 4-bromo-Ph 
                 4-chloro-Ph 
               
               
                   
               
               
                 1-amino-1-cyclohexane 
                 Example 120 
                 Example 123 
               
               
                 carboxylic acid 
                 348.07 (M − H) 
                 302.18 (M − H) 
               
               
                   
                 1.02 min 
                 1.00 min 
               
               
                 2-amino-2-norbornane carboxylic 
                 Example 121 
               
               
                 acid 
                 360.05 (M − H) 
               
               
                   
                 1.07 min 
               
               
                 d,l-1-aminoindane-1-carboxylic 
                 Example 122 
                 Example 124 
               
               
                 acid 
                 381.96 (M − H) 
                 336.17 (M − H) 
               
               
                   
                 1.06 min 
                 1.04 min 
               
               
                 d,l-2-cyclobutyl-2-phenylglycine 
                   
                 Example 125 
               
               
                   
                   
                 364.21 (M − H) 
               
               
                   
                   
                 1.22 min 
               
               
                   
               
            
           
         
       
     
     Example 165A 
     4-Chloro-N-[(1S,2S)-1-formyl-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of 4-chlorobenzenesulfonyl chloride (1.93 g, 9.1 mmol) in CH 3 CN (25 mL) and (S)-isoleucinol (1.07 g, 9.1 mmol) was added Et 3 N (1.91 mL, 13.7 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The solvent was removed and the oil was dissolved in CH 2 Cl 2  (20 mL). The solution was washed with water (2×20 mL) and dried over Na 2 SO 4 . The solvent was removed to give N-4-chloro benzenesulfonyl isoleucinol, which was carried on without further purification. 
     To a stirred solution of N-4-chlorobenzenesulfonyl isoleucinol (˜9.1 mmol) in CH 2 Cl 2  (100 mL) was added a mixture of pyridinium chlorochromate (5.88 g, 27.3 mmol) and silica gel (˜6 g). The resulting slurry was stirred at 25° C. until the alcohol was consumed by TLC analysis. The reaction mixture was diluted with Et 2 O (250 mL) and filtered through wet silica gel (eluant: 20% EtOAc/hex). Following removal of solvent, the residue was subjected to a Biotage™ column eluting with 10→20% EtOAc/hex to give 1.94 g (74%, two steps) of the aldehyde (LCMS=288.14 (M−H), rt=1.07 min) 
     Example 165 
     4-Chloro-N-[(1S,2S)-1-(hydroxyethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of the aldehyde from Example 165A (23.1 mg, 80 mmol) in THF (400 μL) was added methyl magnesium bromide (400 uL, 1.0 M in THF, 5 eq). The vial was capped and agitated at 50° C. for 12 hours. The reaction was quenched with saturated aqueous NH 4 Cl (1.5 mL) and EtOAc (1 mL). The organic layer was transferred into a tared vial and the aqueous layer was extracted with EtOAc (1 mL). The combined organics were concentrated (Savant, medium heat) and the resulting mixture of diastereomers was dissolved in DMSO such that the final concentration was 30 mM. 
     The following compounds (Examples 126-210, Table 12) were prepared using N-4-fluoro, 4-bromo, 4-chloro, 3-chloro and 2-fluorophenylsulfonyl isoleucinal with methylmagnesium bromide, cyclopentylmagnesium bromide, hexylmagnesium bromide, pentylmagnesium bromide, butylmagnesium bromide, isopropylmagnesium bromide, o-tolylmagnesium bromide, tert-butylmagnesium bromide, isobutylmagnesium bromide, vinylmagnesium bromide, allylmagnesium bromide, ethylmagnesium bromide, 4-fluorophenylmagnesium bromide, 4-chlorophenylmagnesium bromide, 2-methyl-1-propenylmagnesium bromide, isopropenylmagnesium bromide, 4-anisylmagnesium bromide, 1-methyl-1-propenylmagnesium bromide, 2-[2-(1,3-dioxanyl)]ethylmagnesium bromide, 3-butenylmagnesium bromide, 1-propynylmagnesium bromide, 4-thioanisolemagnesium bromide, 4-N,N-dimethylanilinemagnesium bromide, and 1-naphthylmagnesium bromide following the procedures outlined in examples 165A and 165. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 (LCMS Data 2 : Molecular ion and retention time(s)) 
               
            
           
           
               
               
            
               
                   
                 X-Ph 
               
            
           
           
               
               
               
               
               
               
            
               
                 RMgX 
                 4-fluoro-Ph 
                 4-bromo-Ph 
                 4-chloro-Ph 
                 3-chloro-Ph 
                 2-fluoro-Ph 
               
               
                   
               
               
                 Methyl 
                 Ex. 126 
                 Ex. 145 
                 Ex. 165 
                 Ex. 185 
                   
               
               
                 magnesium 
                 288.18 (M − H) 
                 350.05 (M − H) 
                 304.10 (M − H) 
                 304.15 (M − H) 
               
               
                 bromide 
                 1.01 min 
                 1.12 min 
                 1.04 min, 1.10 min 
                 1.05 min, 1.12 min 
               
               
                 Cyclopentyl 
                 Ex. 127 
                 Ex. 146 
                 Ex. 166 
                 Ex. 186 
                 Ex. 202 
               
               
                 magnesium 
                 242.21 (M − H) 
                 404.05 (M − H) 
                 358.18 (M − H) 
                 358.18 (M − H) 
                 342.22 (M − H) 
               
               
                 bromide 
                 1.30 min 
                 1.40 min 
                 1.37 min 
                 1.39 min 
                 1.29 min 
               
               
                 Hexyl 
                 Ex. 128 
                   
                 Ex. 167 
                 Ex. 187 
                 Ex. 203 
               
               
                 magnesium 
                 358.24 (M − H), 
                   
                 374.21 (M − H) 
                 374.22 (M − H) 
                 358.24 (M − H) 
               
               
                 bromide 
                 1.40 min, 1.44 min 
                   
                 1.48 min, 1.52 min 
                 1.48 min, 1.53 min 
                 1.41 min, 1.46 min 
               
               
                 Pentyl 
                 Ex. 129 
                 Ex. 147 
                 Ex. 168 
                 Ex. 188 
                 Ex. 204 
               
               
                 magnesium 
                 344.23 (M − H) 
                 406.10 (M − H) 
                 360.19 (M − H) 
                 360.20 (M − H) 
                 344.22 (M − H) 
               
               
                 bromide 
                 1.32 min, 1.36 min 
                 1.40 min, 1.46 min 
                 1.40 min, 1.45 min 
                 1.40 min, 1.46 min 
                 1.32 min, 1.36 min 
               
               
                 Butyl 
                 Ex. 130 
                 Ex. 148 
                 Ex. 169 
                 Ex. 189 
                 Ex. 205 
               
               
                 magnesium 
                 330.21 (M − H) 
                 392.07 (M − H) 
                 346.18 (M − H) 
                 346.17 (M − H) 
                 330.23 (M − H) 
               
               
                 bromide 
                 1.24 min, 1.28 min 
                 1.34 min, 1.39 min 
                 1.33 min, 1.37 min 
                 1.33 min, 1.38 min 
                 1.25 min, 1.30 min 
               
               
                 Isopropyl 
                   
                   
                 Ex. 170 
                 Ex. 190 
               
               
                 magnesium 
                   
                   
                 332.17 (M − H) 
                 332.18 (M − H) 
               
               
                 bromide 
                   
                   
                 1.25 min, 1.30 min 
                 1.26 min, 1.31 min 
               
               
                 o-tolyl 
                 Ex. 131 
                   
                 Ex. 171 
               
               
                 magnesium 
                 364.19 (M − H) 
                   
                 380.17 (M − H) 
               
               
                 bromide 
                 1.28 min 
                   
                 1.36 min 
               
               
                 tert-butyl 
                 Ex. 132 
                 Ex. 149 
                 Ex. 172 
                 Ex. 191 
               
               
                 magnesium 
                 330.21 (M − H) 
                 392.08 (M − H) 
                 346.17 (M − H) 
                 346.18 (M − H) 
               
               
                 bromide 
                 1.31 min 
                 1.42 min 
                 1.40 min 
                 1.40 min 
               
               
                 Isobutyl 
                   
                 Ex. 150 
                 Ex. 173 
                 Ex. 192 
               
               
                 magnesium 
                   
                 392.06 (M − H) 
                 346.17 (M − H) 
                 346.18 (M − H) 
               
               
                 bromide 
                   
                 1.33 min, 1.37 min 
                 1.31 min, 1.36 min 
                 1.32 min, 1.37 min 
               
               
                 Vinyl 
                 Ex. 133 
                 Ex. 151 
                 Ex. 174 
                 Ex. 193 
                 Ex. 206 
               
               
                 magnesium 
                 300.18 (M − H) 
                 362.07 (M − H) 
                 316.14 (M − H) 
                 316.16 (M − H) 
                 300.18 (M − H) 
               
               
                 bromide 
                 1.04 min, 1.08 min 
                 1.16 min, 1.20 min 
                 1.13 min, 1.17 min 
                 1.13 min, 1.18 min 
                 1.03 min, 1.08 min 
               
               
                 Allyl 
                 Ex. 134 
                 Ex. 152 
                 Ex. 175 
                 Ex. 194 
               
               
                 magnesium 
                 314.19 (M − H) 
                 376.05 (M − H) 
                 330.14 (M − H) 
                 330.17 (M − H) 
               
               
                 bromide 
                 1.12 min, 1.16 min 
                 1.22 min, 1.26 min 
                 1.21 min, 1.25 min 
                 1.20 min, 1.25 min 
               
               
                 Ethyl 
                 Ex. 135 
                 Ex. 153 
                 Ex. 176 
                 Ex. 195 
               
               
                 magnesium 
                 302.19 (M − H) 
                 364.09 (M − H) 
                 318.16 (M − H) 
                 318.16 (M − H) 
               
               
                 bromide 
                 1.06 min, 1.11 min 
                 1.18 min, 1.23 min 
                 1.16 min, 1.21 min 
                 1.16 min, 1.21 min 
               
               
                 4-fluorophenylmagnesium 
                   
                 Ex. 154 
                   
                   
                 Ex. 207 
               
               
                 bromide 
                   
                 429.99 (M − H) 
                   
                   
                 368.17 (M − H) 
               
               
                   
                   
                 1.28 min, 1.33 min 
                   
                   
                 1.18 min, 1.23 min 
               
               
                 4-chlorophenylmagnesium 
                 Ex. 136 
                 Ex. 155 
                 Ex. 177 
                 Ex. 196 
                 Ex. 208 
               
               
                 bromide 
                 384.14 (M − H) 
                 446.01 (M − H) 
                 402.03 (M − H) 
                 402.06 (M − H) 
                 384.14 (M − H) 
               
               
                   
                 1.26 min, 1.30 min 
                 1.35 min, 1.40 min 
                 1.33 min, 1.35 min 
                 1.33 min, 1.38 min 
                 1.25 min, 1.30 min 
               
               
                 2-methyl-1- 
                 Ex. 137 
                 Ex. 156 
                   
                 Ex. 197 
               
               
                 propenylmagnesium 
                 238.18 (M − H) 
                 390.04 (M − H) 
                   
                 344.19 (M − H) 
               
               
                 bromide 
                 1.16 min, 1.21 min 
                 1.25 min, 1.31 min 
                   
                 1.24 min, 1.30 min 
               
               
                 Isopropenyl 
                 Ex. 138 
                 Ex. 157 
               
               
                 magnesium 
                 314.19 (M − H) 
                 376.06 (M − H) 
               
               
                 bromide 
                 1.14 min, 1.17 min 
                 1.24 min, 1.28 min 
               
               
                 4-anisylmagnesium 
                 Ex. 139 
                 Ex. 158 
                 Ex. 178 
                 Ex. 198 
                 Ex. 209 
               
               
                 bromide 
                 380.20 (M − H) 
                 442.01 (M − H) 
                 396.16 (M − H) 
                 396.19 (M − H) 
                 380.20 (M − H) 
               
               
                   
                 1.15 min, 1.21 min 
                 1.24 min, 1.30 min 
                 1.23 min, 1.29 min 
                 1.22 min, 1.28 min 
                 1.14 min, 1.19 min 
               
               
                 1-methyl-1- 
                   
                 Ex. 159 
               
               
                 propenylmagnesium 
                   
                 390.03 (M − H) 
               
               
                 bromide 
                   
                 1.26 min, 1.35 min 
               
               
                 2-[2-(1,3- 
                 Ex. 140 
                 Ex. 160 
                 Ex. 179 
                 Ex. 199 
                 Ex. 210 
               
               
                 dioxanyl)]ethyl 
                 388.22 (M − H) 
                 450.07 (M − H) 
                 404.18 (M − H) 
                 404.19 (M − H) 
                 388.21 (M − H) 
               
               
                 magnesium 
                 0.99 min, 1.04 min 
                 1.09 min, 1.15 min 
                 1.08 min, 1.13 min 
                 1.13 min 
                 0.98 min, 1.03 min 
               
               
                 bromide 
               
               
                 3-butenylmagnesium 
                 Ex. 141 
                 Ex. 161 
                 Ex. 180 
                 Ex. 200 
               
               
                 bromide 
                 328.21 (M − H) 
                 390.06 (M − H) 
                 344.16 (M − H) 
                 344.16 (M − H) 
               
               
                   
                 1.19 min, 1.23 min 
                 1.29 min, 1.33 min 
                 1.27 min, 1.31 min 
                 1.27 min, 1.31 min 
               
               
                 1-propynylmagnesium 
                   
                 Ex. 162 
                 Ex. 181 
               
               
                 bromide 
                   
                 374.01 (M − H) 
                 328.15 (M − H) 
               
               
                   
                   
                 1.19 min 
                 1.18 min 
               
               
                 4-thio anisole 
                 Ex. 142 
                 Ex. 163 
                 Ex. 182 
                 Ex. 201 
               
               
                 magnesium 
                 396.17 (M − H) 
                 458.01 (M − H) 
                 412.14 (M − H) 
                 412.15 (M − H) 
               
               
                 bromide 
                 1.25 min, 1.29 min 
                 1.33 min, 1.38 min 
                 1.32 min, 1.37 min 
                 1.32 min, 1.37 min 
               
               
                 4-N,N- 
                 Ex. 143 
                 Ex. 164 
                 Ex. 183 
               
               
                 dimethylanilinemagnesium 
                 393.24 (M − H) 
                 455.07 (M − H) 
                 409.22 (M − H) 
               
               
                 bromide 
                 0.77 min, 0.81 min 
                 0.95 min 
                 0.92 min 
               
               
                 1-naphthylmagnesium 
                 Ex. 144 
                   
                 Ex. 184 
               
               
                 bromide 
                 400.21 (M − H) 
                   
                 416.18 (M − H) 
               
               
                   
                 1.35 min 
                   
                 1.41 min 
               
               
                   
               
            
           
         
       
     
     Example 211 
     4-Bromo-N-[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-ethylbutyl]benzenesulfonamide 
     Part 1:  
     
       
         
         
             
             
         
       
     
     To a solution of 4-bromobenzenesulfonyl chloride (1.278 g, 5 mmol) in CH 3 CN (20 mL) was added (L)-isoleucine methyl ester hydrochloride (908.5 mg, 5 mmol) as a solution in CH 3 CN (10 mL) and Et 3 N (1 mL, 7.2 mmol). The reaction mixture was heated at 50° C. with shaking for 3 days. The solvent was removed and the oil was dissolved in EtOAc (10 mL). The solution was washed with water (5 mL), sat. NH 4 OH (5 mL), brine (5 mL), and dried over MgSO 4 . The solvent was removed to give 1.62 g (89%) of the desired sulfonamide ester. 
     To a solution of the sulfonamide ester (45.5 mg, 0.125 mmol) in THF (500 μL) was added methyl magnesium bromide (333 μL, 3.0 M in THF, 8 eq). The vial was capped and agitated at 50° C. for 12 hours. The reaction was quenched with saturated NH 4 Cl (1.5 mL) and EtOAc (1 mL). The organic layer was transferred into a tared vial and the aqueous layer was extracted with EtOAc (1 mL). The combined organic extract was concentrated (Savant, medium heat) and the product was dissolved in DMSO such that the final concentration was 30 mM. 
     The following compounds (Examples 211-271, Table 13) were prepared using (from part 2) N-4-bromo, 4-chloro, 4-fluoro, 3-chloro and 2-fluorobenzenesulfonyl isoleucine methyl ester with methylmagnesium bromide, hexylmagnesium bromide, pentylmagnesium bromide, butylmagnesium bromide, isopropylmagnesium bromide, isobutylmagnesium bromide, allylmagnesium bromide, ethylmagnesium bromide, 4-fluorophenylmagnesium bromide, 4-chlorophenylmagnesium bromide, 2-methyl-1-propenylmagnesium bromide, isopropenylmagnesium bromide, 4-anisylmagnesium bromide, 1-methyl-1-propenylmagnesium bromide, 3-butenylmagnesium bromide, 1-propynylmagnesium bromide, 4-N,N-dimethylanilinemagnesium bromide, and 1-naphthylmagnesium bromide following the procedure outlined in example 211. This procedure is outlined in the following Scheme. 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 (LCMS Data 2 : Molecular ion and retention time) 
               
            
           
           
               
               
            
               
                   
                 X-Ph 
               
            
           
           
               
               
               
               
               
               
            
               
                 RMgX 
                 4-bromo-Ph 
                 4-chloro-Ph 
                 4-fluoro-Ph 
                 3-chloro-Ph 
                 2-fluoro-Ph 
               
               
                   
               
               
                 Methyl 
                 Ex. 211 
                 Ex. 223 
                 Ex. 235 
                   
                   
               
               
                 magnesium 
                 364.51 (M − H) 
                 318.61 (M − H) 
                 302.64 (M − H) 
               
               
                 bromide 
                 1.117 min 
                 1.15 min 
                 1.06 min 
               
               
                 Hexyl 
                   
                 Ex. 224 
                 Ex. 236 
                 Ex. 249 
                 Ex. 261 
               
               
                 magnesium 
                   
                 458.78 (M − H) 
                 442.78 (M − H) 
                 458.75 (M − H) 
                 442.78 (M − H) 
               
               
                 bromide 
                   
                 1.87 min 
                 1.80 min 
                 1.87 min 
                 1.81 min 
               
               
                 Pentyl 
                 Ex. 212 
                   
                 Ex. 237 
                 Ex. 250 
                 Ex. 262 
               
               
                 magnesium 
                 476.49 (M − H) 
                   
                 414.82 (M − H) 
                 430.76 (M − H) 
                 414.74 (M − H) 
               
               
                 bromide 
                 1.76 min 
                   
                 1.70 min 
                 1.76 min 
                 1.70 min 
               
               
                 Butyl 
                 Ex. 213 
                 Ex. 225 
                 Ex. 238 
                 Ex. 251 
               
               
                 magnesium 
                 448.59 (M − H) 
                 402.72 (M − H) 
                 386.73 (M − H) 
                 402.68 (M − H) 
               
               
                 bromide 
                 1.65 min 
                 1.63 min 
                 1.58 min 
                 1.65 min 
               
               
                 Isobutyl 
                 Ex. 214 
                 Ex. 226 
                 Ex. 240 
                 Ex. 252 
               
               
                 magnesium 
                 448.58 (M − H) 
                 402.70 (M − H) 
                 386.73 (M − H) 
                 402.74 (M − H) 
               
               
                 bromide 
                 1.65 min 
                 1.63 min 
                 1.58 min 
                 1.65 min 
               
               
                 Phenyl 
                 Ex. 215 
                 Ex. 227 
                   
                 Ex. 253 
                 Ex. 263 
               
               
                 magnesium 
                 488.51 (M − H) 
                 442.65 (M − H) 
                   
                 442.64 (M − H) 
                 426.67 (M − H) 
               
               
                 bromide 
                 1.50 min 
                 1.48 min 
                   
                 1.50 min 
                 1.43 min 
               
               
                 Allyl 
                 Ex. 216 
                 Ex. 228 
                 Ex. 241 
                 Ex. 254 
                 Ex. 264 
               
               
                 magnesium 
                 416.53 (M − H) 
                 370.65 (M − H) 
                 354.69 (M − H) 
                 370.64 (M − H) 
                 354.67 (M − H) 
               
               
                 bromide 
                 1.43 min 
                 1.41 min 
                 1.34 min 
                 1.43 min 
                 1.35 min 
               
               
                 Ethyl 
                 Ex. 217 
                 Ex. 229 
                 Ex. 242 
                 Ex. 255 
                 Ex. 265 
               
               
                 magnesium 
                 392.55 (M − H) 
                 346.67 (M − H) 
                 330.67 (M − H) 
                 346.66 (M − H) 
                 330.74 (M − H) 
               
               
                 bromide 
                 1.37 min 
                 1.35 min 
                 1.28 min 
                 1.37 min 
                 1.28 min 
               
               
                 4-fluorophenylmagnesium 
                   
                   
                   
                   
                 Ex. 266 
               
               
                 bromide 
                   
                   
                   
                   
                 462.64 (M − H) 
               
               
                   
                   
                   
                   
                   
                 1.45 min 
               
               
                 4-chlorophenylmagnesium 
                 Ex. 218 
                   
                   
                 Ex. 256 
                 Ex. 267 
               
               
                 bromide 
                 556.39 (M − H) 
                   
                   
                 511.96 (M − H) 
                 494.57 (M − H) 
               
               
                   
                 1.61 min 
                   
                   
                 1.66 min 
                 1.56 min 
               
               
                 isopropenyl 
                 Ex. 219 
                 Ex. 230 
                 Ex. 243 
                 Ex. 257 
                 Ex. 268 
               
               
                 magnesium 
                 416.51 (M − H) 
                 370.64 (M − H) 
                 354.69 (M − H) 
                 370.66 (M − H) 
                 354.68 (M − H) 
               
               
                 bromide 
                 1.50 min 
                 1.48 min 
                 1.43 min 
                 1.48 min 
                 1.43 min 
               
               
                 4-anisylmagnesium 
                   
                 Ex. 231 
                 Ex. 244 
                 Ex. 258 
                 Ex. 269 
               
               
                 bromide 
                   
                 502.64 (M − H) 
                 486.67 (M − H) 
                 502.62 (M − H) 
                 486.71 (M − H) 
               
               
                   
                   
                 1.43 min 
                 1.38 min 
                 1.43 min 
                 1.37 min 
               
               
                 1-methyl-1- 
                 Ex. 220 
                 Ex. 232 
                 Ex. 245 
                 Ex. 259 
                 Ex. 270 
               
               
                 propenylmagnesium 
                 444.59 (M − H) 
                 398.69 (M − H) 
                 382.73 (M − H) 
                 398.65 (M − H) 
                 382.50 (M − H) 
               
               
                 bromide 
                 1.63 min 
                 1.61 min 
                 1.54 min 
                 1.61 min 
                 1.56 min 
               
               
                 3-butenylmagnesium 
                 Ex. 221 
                 Ex. 233 
                 Ex. 246 
                 Ex. 260 
                 Ex. 271 
               
               
                 bromide 
                 444.60 (M − H) 
                 398.66 (M − H) 
                 382.71 (M − H) 
                 518.68 (M − H) 
                 382.70 (M − H) 
               
               
                   
                 1.54 min 
                 1.52 min 
                 1.46 min 
                 1.21 min 
                 1.46 min 
               
               
                 4-N,N- 
                   
                   
                 Ex. 247 
               
               
                 dimethylanilinemagnesium 
                   
                   
                 512.73 (M − H) 
               
               
                 bromide 
                   
                   
                 0.97 min 
               
               
                 1-naphthylmagnesium 
                 Ex. 222 
                 Ex. 234 
                 Ex. 248 
               
               
                 bromide 
                 558.46 (M − H) 
                 542.56 (M − H) 
                 526.69 (M − H) 
               
               
                   
                 1.65 min 
                 1.63 min 
                 1.58 min 
               
               
                   
               
            
           
         
       
     
     Example 272 
     4-Chloro-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     A. Preparation of (αS)-α-[[(4-chlorophenyl)sulfonyl]aminoicyclohexaneacetic acid              
     To a solution of S-cyclohexylglycine (1.00 g, 5.16 mmol) in H 2 O (10 mL) and THF (11 mL) was added 4-chlorobenzenesulfonyl chloride (1.53 g, 7.23 mmol) followed by 2.5N NaOH (8.26 mL) at 25° C. with stirring. After 24 hours, the reaction was quenched by addition of 6 N HCl until pH=2. The reaction mixture was then extracted with EtOAc (2×50 mL). The combined organic extracts were washed with saturated brine (2×50 mL), dried over MgSO 4 , and evaporated to afford a white solid. This white solid was taken up in Et 2 O, filtered and evaporated to afford an amorphous white solid which after washing with hexane afforded 0.90 g (52%) of product, mp 120-128° C. Mass Spectrum (+ESI): 354 ([M+Na] + ). Anal: Calc&#39;d for C 14 H 18 ClNO 4 S: C, 50.68; H, 5.47; N, 4.22. Found: C, 50.59; H, 5.46; N, 4.19. 
     B. Preparation of 4-Chloro-N-[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide 
     To a solution of LAH (1.0 M in THF, 1.5 mL, 1.5 mmol) was added dropwise at 0° C. a solution of (αS)-α-[[(4-chlorophenyesulfonyl]amino]cyclohexaneacetic acid (0.50 g, 1.507 mmol) in THF (8.0 mL). After the addition was complete, the reaction mixture was allowed to warm to 25° C. After 24 hours, the reaction was quenched by sequential addition of H 2 O (60 μL), 15% NaOH (60 μL) and H 2 O (180 μL). The precipitate was filtered and washed with THF. The combined THF solution was evaporated to a clear oil which afforded a white solid after washing with hexane. This white solid was purified by flash chromatography (eluant: 1-1 hexane/ethyl acetate), washed with hexane and pumped on to afford 0.179 g (37%) of the desired product as a white solid, mp 115-118° C. Mass Spectrum (+APCI): 318 ([M+H] + ). Anal: Calc&#39;d for C 14 H 20 ClNO 3 S: C, 52.91; H, 6.34; N, 4.41. Found: C, 52.16; H, 6.25; N, 4.40. 
     Example 273 
     4-Chloro-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of S-2-phenyl-glycinol (0.50 g, 3.645 mmol) and Et 3 N (0.561 mL, 4.01 mmol) in CH 2 Cl 2  (7.5 mL) was added dropwise at 0° C. a solution of 4-chloro benzenesulfonyl chloride (0.769 g, 3.645 mmol) in CH 2 Cl 2  (7.5 mL). After the addition was complete, the reaction mixture was allowed to warm to 25° C. After 24 hours, the reaction was diluted with CH 2 Cl 2  (20 mL) and washed sequentially with saturated sodium bicarbonate (30 mL), 1N HCl (30 mL), H 2 O (30 mL) and saturated brine (30 mL), dried over MgSO 4  and evaporated to a white solid which was washed with hexane twice. This white solid was purified by flash chromatography (eluant: 1-1 hexane/ethyl acetate), washed with hexane and pumped on to afford 0.347 g (29%) of the desired product as a white solid, mp 127-128° C. Mass Spectrum (+APCI): 329 ([M+NH 4 ] + ). Anal: Calc&#39;d for C 14 H 14 ClNO 3 S: C, 53.93; H, 4.53; N, 4.49. Found: C, 53.96; H, 4.49; N, 4.39. 
     Example 274 
     4-Chloro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of S-valinol (0.52 g, 5.0 mmol), triethylamine (0.55 g, 5 5 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-chlorobenzenesulfonyl chloride (1.06 g, 5.0 mmol) in CH 2 Cl 2  (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (20 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (20 mL), distilled water and brine, dried over MgSO 4  and evaporated to give a colorless oil that crystallized upon standing, mp 83-85° C. (1.30 g, 94%). MS (+ESI) 278.1 ([M+H] + ); 257.2; 237.1. Anal. Calc&#39;d for C 11 H 16 ClNO 3 S: C, 47.56; H, 5.81; N, 5.04. Found: C, 47.78; H, 5.81; N, 4.99. 
     Example 275 
     4-Bromo-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of S-valinol (0.52 g, 5.0 mmol), triethylamine (0.55 g, 5.5 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-bromobenzenesulfonyl chloride (1.28 g, 5.0 mmol) in CH 2 Cl 2  (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (20 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (20 mL), distilled water and brine, dried over MgSO 4  and evaporated to give a colorless oil that crystallized upon standing under vacuum, mp 89-94° C. (1.49 g, 93%). MS (+APCI) 324.03 ([M+H] + ). Anal. Calc&#39;d for C 11 H 16 BrNO 3 S: C, 41.00; H, 5.00; N, 4.35; Found: C, 41.09; H, 4.85; N, 4.28. 
     Example 276 
     4-Iodo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of S-isoleucinol (0.50 g, 4.26 mmol), triethylamine (0.47 g, 4.68 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-iodo benzenesulfonyl chloride (1.29 g, 4.26 mmol) in CH 2 Cl 2  (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (22 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (25 mL), distilled water and brine, dried over MgSO 4  and evaporated to give a crude solid that was recrystallized from ethyl acetate-hexane, mp 118-120° C. (1.07 g, 66%). MS (+APCI) 383.96 ([M+H] + ); 283.81; 191.95. Anal. Calc&#39;d for C 12 H 18 INO 3 S: C, 37.61; H, 4.73; N, 3.65; Found: C, 37.55; H, 4.61; N, 3.61. 
     Example 277 
     4-Chloro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
     To a solution of S-tert-leucinol (0.20 g, 1.70 mmol), triethylamine (0.19 g, 1.87 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-chloro benzenesulfonyl chloride (0.36 g, 1.70 mmol) in CH 2 Cl 2  (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (20 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (20 mL), distilled water and brine, dried over MgSO 4  and evaporated to give the desired product as a white solid, mp 128-130° C. (0.46 g, 94%). Ms (+APCI) 292.06 ([M+H] + ). Anal. Calc&#39;d for C 12 H 18 ClNO 3 S: C, 49.39; H, 6.22; N, 4.80; Found: C, 49.40; H, 6.17; N, 4.79. 
     
       
         
           
               
               
             
               
                 TABLE 14 
               
               
                   
               
               
                 Ex # 
                 Compound 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 1 
                 2-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 2 
                 3-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 3 
                 3-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 4 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-1,2,3-benzoxadiazole-7-sulfonamide 
               
               
                 5 
                 2-chloro-4-fluoro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 6 
                 5-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-methoxy benzenesulfonamide 
               
               
                 7 
                 2-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-6-methyl benzenesulfonamide 
               
               
                 8 
                 3,5-dichloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 9 
                 2,4-difluoro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 10 
                 4-fluoro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 11 
                 2-fluoro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 12 
                 N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]naphthalene-1-sulfonamide 
               
               
                 13 
                 N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]naphthalene-2-sulfonamide 
               
               
                 14 
                 3-amino-4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 15 
                 N—[(1S)-1-benzyl-2-hydroxyethyl]-4-bromobenzenesulfonamide 
               
               
                 16 
                 4-bromo-N—[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide 
               
               
                 17 
                 4-bromo-N—[(1R)-2-hydroxy-1-(4-hydroxyphenyl)ethyl]benzenesulfonamide 
               
               
                 18 
                 4-bromo-N—[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide 
               
               
                 19 
                 4-bromo-N—[(1S)-2-hydroxy-1-(1H-indol-2-ylmethyl)ethyl]benzenesulfonamide 
               
               
                 20 
                 4-bromo-2,5-difluoro-N—[(1S,2S)-1-(hydroxymethyl-2-methylbutyl] benzenesulfonamide 
               
               
                 21 
                 2,5-dibromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 22 
                 3,4-dibromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 23 
                 2,3-dichloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 24 
                 3,4-dichloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 25 
                 2,4,5-trichloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 26 
                 4-bromo-2,5-difluoro-N—[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
               
               
                 27 
                 3,4-dichloro-N—[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
               
               
                 28 
                 2,4,6-trichloro-N—[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
               
               
                 29 
                 3,4-dibromo-N—[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl] benzenesulfonamide 
               
               
                 30 
                 3,4-dichloro-N—[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl] benzenesulfonamide 
               
               
                 31 
                 2,4,5-trichloro-N—[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl] benzenesulfonamide 
               
               
                 32 
                 2,4,6-trichloro-N—[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl] benzenesulfonamide 
               
               
                 33 
                 4-bromo-N—[(1R,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 34 
                 4-bromo-N—[(1S)-1-(hydroxymethyl)-1,2-dimethylpropyl]benzenesulfonamide 
               
               
                 35 
                 4-bromo-N—[1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide 
               
               
                 36 
                 4-bromo-N—[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 37 
                 4-chloro-N—[(1S)-1-(hydroxymethyl)-1,2-dimethylpropyl]benzenesulfonamide 
               
               
                 38 
                 4-chloro-N—[1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide 
               
               
                 39 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 40 
                 N-allyl-4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 41 
                 N-([1,1′-biphenyl]-4-ylmethyl)-4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2- 
               
               
                   
                 methylbutyl]benzenesulfonamide 
               
               
                 42 
                 tert-butyl 2-{[(4-chlorophenyl)sulfonyl][(1S,2S)-1-(hydroxymethyl)-2- 
               
               
                   
                 methylbutyl]amino}ethylcarbamate 
               
               
                 43 
                 4-chloro-N-(4-chlorobenzyl)-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 44 
                 4-chloro-N-(cyclobutylmethyl)-N—[(1S,2S)-1-(hydroxymethyl)-2- 
               
               
                   
                 methylbutyl]benzenesulfonamide 
               
               
                 45 
                 4-chloro-N-(3,4-dimethoxybenzyl)-N—[(1S,2S)-1-(hydroxymethyl)-2- 
               
               
                   
                 methylbutyl]benzenesulfonamide 
               
               
                 46 
                 4-chloro-N-(2-furylmethyl)-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 47 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-N-[2-(methylthio)ethyl] 
               
               
                   
                 benzenesulfonamide 
               
               
                 48 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-N-(3-phenylprop-2- 
               
               
                   
                 ynyl)benzenesulfonamide 
               
               
                 49 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)propyl] benzenesulfonamide 
               
               
                 50 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-methyloctyl]benzenesulfonamide 
               
               
                 51 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide 
               
               
                 52 
                 4-chloro-N—[(1S)-2-ethyl-1-(hydroxymethyl)butyl]benzenesulfonamide 
               
               
                 53 
                 4-chloro-N—[(1S,2R)-2-ethyl-1-(hydroxymethyl)-4-methylpentyl] benzenesulfonamide 
               
               
                 54 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylpentyl]benzenesulfonamide 
               
               
                 55 
                 4-chloro-N—[(1S,2S)-2-ethyl-1-(hydroxymethyl)pentyl]benzenesulfonamide 
               
               
                 56 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-4-methyl-2-propylpentyl] benzenesulfonamide 
               
               
                 57 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)pentyl] benzenesulfonamide 
               
               
                 58 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-propyloctyl]benzenesulfonamide 
               
               
                 59 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-phenylpentyl]benzenesulfonamide 
               
               
                 60 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylheptyl]benzenesulfonamide 
               
               
                 61 
                 4-chloro-N—[(1S,2S)-2-ethyl-1-(hydroxymethyl)heptyl]benzenesulfonamide 
               
               
                 62 
                 4-chloro-N—[(1S,2R)-1-(hydroxymethyl)-2-pentyloctyl]benzenesulfonamide 
               
               
                 63 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide 
               
               
                 64 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-4-methyl-2-phenylpentyl] benzenesulfonamide 
               
               
                 65 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-phenyloctyl]benzenesulfonamide 
               
               
                 66 
                 4-chloro-N—[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)butyl]benzenesulfonamide 
               
               
                 67 
                 4-chloro-N—[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)-4-methylpentyl] benzenesulfonamide 
               
               
                 68 
                 4-chloro-N—[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)octyl]benzenesulfonamide 
               
               
                 69 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2,3-dimethylbutyl]benzenesulfonamide 
               
               
                 70 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-isopropyloctyl]benzenesulfonamide 
               
               
                 71 
                 4-bromo-N—[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)propyl]benzenesulfonamide 
               
               
                 72 
                 4-bromo-N—[(1S,2R)-1-(hydroxymethyl)-2-methyloctyl]benzenesulfonamide 
               
               
                 73 
                 4-bromo-N—[(1S,2R)-2-ethyl-1-(hydroxymethyl)-4-methylpentyl] benzenesulfonamide 
               
               
                 74 
                 4-bromo-N—[(1S,2R)-1-(hydroxymethyl)-2-(4-methoxyphenyl)butyl] benzenesulfonamide 
               
               
                 75 
                 4-bromo-N—[(1S,2R)-2-ethyl-1-(hydroxymethyl)octyl]benzenesulfonamide 
               
               
                 76 
                 4-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylpentyl]benzenesulfonamide 
               
               
                 77 
                 4-bromo-N—[(1S,2S)-2-ethyl-1-(hydroxymethyl)pentyl]benzenesulfonamide 
               
               
                 78 
                 4-bromo-N—[(1S,2R)-1-(hydroxymethyl)-4-methyl-2-propylpentyl] benzenesulfonamide 
               
               
                 79 
                 4-bromo-N—[(1S,2R)-1-(hydroxymethyl)-2-propyloctyl]benzenesulfonamide 
               
               
                 80 
                 4-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylheptyl]benzenesulfonamide 
               
               
                 81 
                 4-bromo-N—[(1S,2S)-2-ethyl-1-(hydroxymethyl)heptyl]benzenesulfonamide 
               
               
                 82 
                 4-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-phenylpropyl]benzenesulfonamide 
               
               
                 83 
                 4-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-phenylbutyl]benzenesulfonamide 
               
               
                 84 
                 4-bromo-N—[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)propyl]benzenesulfonamide 
               
               
                 85 
                 4-bromo-N—[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)butyl]benzenesulfonamide 
               
               
                 86 
                 4-bromo-N—[(1S,2R)-2-(2-furyl)-1-(hydroxymethyl)-4-methylpentyl] benzenesulfonamide 
               
               
                 87 
                 4-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-isopropyl-4-methylpentyl] benzenesulfonamide 
               
               
                 88 
                 4-chloro-N—[(1S,2S)-2-ethyl-1-(hydroxymethyl)octyl]benzenesulfonamide 
               
               
                 89 
                 4-chloro-N—[(1S,2R)-2-ethyl-1-(hydroxymethyl)octyl]benzenesulfonamide 
               
               
                 90 
                 4-chloro-N-methyl-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 91 
                 4-chloro-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-benzenesulfonamide 
               
               
                 92 
                 4-chloro-N—[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide 
               
               
                 93 
                 4-chloro-N—[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide 
               
               
                 94 
                 4-bromo-N—[1-(hydroxymethyl)cyclopentyl]benzenesulfonamide 
               
               
                 95 
                 4-chloro-N—[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]benzenesulfonamide 
               
               
                 96 
                 N—{(1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl}-4-chlorobenzenesulfonamide 
               
               
                 97 
                 4-chloro-N—[(1R)-1-(hydroxymethyl)-1-methylpropyl]benzenesulfonamide 
               
               
                 98 
                 4-bromo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-benzenesulfonamide 
               
               
                 99 
                 4-bromo-N—[1-(hydroxymethyl)pentyl]benzenesulfonamide 
               
               
                 100 
                 4-bromo-N—[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide 
               
               
                 101 
                 4-bromo-N—[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide 
               
               
                 102 
                 4-bromo-N—[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide 
               
               
                 103 
                 4-chloro-N-[1-(hydroxymethyl)cyclopentyl]benzenesulfonamide 
               
               
                 104 
                 4-bromo-N-[1-(hydroxymethyl)butyl]benzenesulfonamide 
               
               
                 105 
                 3-chloro-N-[1-(hydroxymethyl)butyl]benzenesulfonamide 
               
               
                 106 
                 3-chloro-N—[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]benzenesulfonamide 
               
               
                 107 
                 3-chloro-N—[(1R)-1-(hydroxymethyl)-3-(methylthio)propyl]benzenesulfonamide 
               
               
                 108 
                 3-chloro-N—[(1S)-1-(hydroxymethyl)propyl]benzenesulfonamide 
               
               
                 109 
                 2-fluoro-N—[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide 
               
               
                 110 
                 2-fluoro-N-[1-(hydroxymethyl)pentyl]benzenesulfonamide 
               
               
                 111 
                 2-fluoro-N—[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide 
               
               
                 112 
                 2-fluoro-N—[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide 
               
               
                 113 
                 2-fluoro-N—[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide 
               
               
                 114 
                 2-fluoro-N-[1-(hydroxymethyl)cyclopentyl]benzenesulfonamide 
               
               
                 115 
                 N—[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]-2-fluorobenzenesulfonamide 
               
               
                 116 
                 2-fluoro-N—{(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-[4-(methylthio)phenyl]ethyl}benzenesulfonamide 
               
               
                 117 
                 2-fluoro-N—[(1S)-1-(hydroxyl-methylethyl]benzenesulfonamide 
               
               
                 118 
                 N—[(1S)-1-benzyl-2-hydroxyethyl]-2-fluorobenzenesulfonamide 
               
               
                 119 
                 2-fluoro-N—[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
               
               
                 120 
                 4-bromo-N-[1-(hydroxymethyl)cyclohexyl]benzenesulfonamide 
               
               
                 121 
                 4-bromo-N-[2-(hydroxymethyl)bicyclo[2.2.1.]hept-2-yl]benzenesulfonamide 
               
               
                 122 
                 4-bromo-N-[1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide 
               
               
                 123 
                 4-chloro-N-[1-(hydroxymethyl)cyclohexyl]benzenesulfonamide 
               
               
                 124 
                 4-chloro-N-[1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide 
               
               
                 125 
                 4-chloro-N-(1-cyclobutyl-2-hydroxy-1-phenylethyl)benzenesulfonamide 
               
               
                 126 
                 4-fluoro-N—[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 127 
                 N—{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}-4-fluoro benzenesulfonamide 
               
               
                 128 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl}benzenesulfonamide 
               
               
                 129 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl}benzenesulfonamide 
               
               
                 130 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide 
               
               
                 131 
                 4-fluoro-N—{(1S,2S)-1-[hydroxy(2-methylphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 132 
                 4-fluoro-N—{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 133 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl} benzenesulfonamide 
               
               
                 134 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl} benzenesulfonamide 
               
               
                 135 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide 
               
               
                 136 
                 N—{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-4-fluorobenzenesulfonamide 
               
               
                 137 
                 4-fluoro-N—{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl}benzenesulfonamide 
               
               
                 138 
                 4-fluoro-N—{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl}benzenesulfonamide 
               
               
                 139 
                 4-fluoro-N—{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 140 
                 N—{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-4- 
               
               
                   
                 fluorobenzenesulfonamide 
               
               
                 141 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl} benzenesulfonamide 
               
               
                 142 
                 4-fluoro-N—((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 143 
                 N—{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}-4- 
               
               
                   
                 fluorobenzenesulfonamide 
               
               
                 144 
                 4-fluoro-N—{(1S,2S)-1-[hydroxy(1-naphthyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 145 
                 4-bromo-N—[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 146 
                 4-bromo-N—{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 147 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl} benzenesulfonamide 
               
               
                 148 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide 
               
               
                 149 
                 4-bromo-N—{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 150 
                 4-bromo-N—{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl} benzenesulfonamide 
               
               
                 151 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl} benzenesulfonamide 
               
               
                 152 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl} benzenesulfonamide 
               
               
                 153 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}benzenesulfonamide 
               
               
                 154 
                 4-bromo-N—{(1S,2S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 155 
                 4-bromo-N—{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 156 
                 4-bromo-N—{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl} benzenesulfonamide 
               
               
                 157 
                 4-bromo-N—{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-butenyl} benzenesulfonamide 
               
               
                 158 
                 4-bromo-N—{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 159 
                 4-bromo-N—{(1S,3E)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl} 
               
               
                   
                 benzenesulfonamide 
               
               
                 160 
                 4-bromo-N—{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} 
               
               
                   
                 benzenesulfonamide 
               
               
                 161 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl} benzenesulfonamide 
               
               
                 162 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-pentynyl} benzenesulfonamide 
               
               
                 163 
                 4-bromo-N—((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 164 
                 4-bromo-N—{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2- 
               
               
                   
                 methylbutyl}benzenesulfonamide 
               
               
                 165A 
                 4-chloro-N—[(1S,2S)-1-formyl-2-methylbutyl]benzenesulfonamide 
               
               
                 165 
                 4-chloro-N—[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 166 
                 4-chloro-N—{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide 
               
               
                 167 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 168 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl} benzenesulfonamide 
               
               
                 169 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl} benzenesulfonamide 
               
               
                 170 
                 4-chloro-N—{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 171 
                 4-chloro-N—{(1S,2S)-1-[hydroxy(2-methylphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 172 
                 4-chloro-N—{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 173 
                 4-chloro-N—{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl} benzenesulfonamide 
               
               
                 174 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl} benzenesulfonamide 
               
               
                 175 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl} benzenesulfonamide 
               
               
                 176 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 177 
                 4-chloro-N—{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}benzenesulfonamide 
               
               
                 178 
                 4-chloro-N—{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl}benzenesulfonamide 
               
               
                 179 
                 4-chloro-N—{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1- 
               
               
                   
                 methylpropyl]butyl}benzenesulfonamide 
               
               
                 180 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl} benzenesulfonamide 
               
               
                 181 
                 4-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-pentynyl} benzenesulfonamide 
               
               
                 182 
                 4-chloro-N—((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 183 
                 4-chloro-N—{(1S,2S)-1-[[4-(dimethylamino)phenyl](hydroxy)methyl]-2- 
               
               
                   
                 methylbutyl}benzenesulfonamide 
               
               
                 184 
                 4-chloro-N—{(1S,2S)-1-[hydroxy(1-naphthyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 185 
                 3-chloro-N—[(1S,2S)-1-(1-hydroxyethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 186 
                 3-chloro-N—{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 187 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 188 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl} benzenesulfonamide 
               
               
                 189 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl} benzenesulfonamide 
               
               
                 190 
                 3-chloro-N—{(1S)-2-hydroxy-3-methyl-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 191 
                 3-chloro-N—{(1S)-2-hydroxy-3,3-dimethyl-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 192 
                 3-chloro-N—{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]pentyl} benzenesulfonamide 
               
               
                 193 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl} benzenesulfonamide 
               
               
                 194 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl} benzenesulfonamide 
               
               
                 195 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 196 
                 3-chloro-N—{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 197 
                 3-chloro-N—{(1S)-2-hydroxy-4-methyl-1-[(1S)-1-methylpropyl]-3-pentenyl} benzenesulfonamide 
               
               
                 198 
                 3-chloro-N—{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 199 
                 3-chloro-N—{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} 
               
               
                   
                 benzenesulfonamide 
               
               
                 200 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl} benzenesulfonamide 
               
               
                 201 
                 3-chloro-N—((1S,2S)-1-{hydroxy[4-(methylsulfanyl)phenyl]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 202 
                 N—{(1S,2S)-1-[cyclopentyl(hydroxy)methyl]-2-methylbutyl}-2-fluoro benzenesulfonamide 
               
               
                 203 
                 2-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 204 
                 2-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]heptyl} benzenesulfonamide 
               
               
                 205 
                 2-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl} benzenesulfonamide 
               
               
                 206 
                 2-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-3-butenyl} benzenesulfonamide 
               
               
                 207 
                 2-fluoro-N—{(1S,2S)-1-[(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 208 
                 N—{(1S,2S)-1-[(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluoro benzenesulfonamide 
               
               
                 209 
                 2-fluoro-N—{(1S,2S)-1-[hydroxy(4-methoxyphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 210 
                 N—{(1S)-4-(1,3-dioxan-2-yl)-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-2- 
               
               
                   
                 fluorobenzenesulfonamide 
               
               
                 211 
                 4-bromo-N—[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 212 
                 4-bromo-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl} benzenesulfonamide 
               
               
                 213 
                 4-bromo-N—{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}benzenesulfonamide 
               
               
                 214 
                 4-bromo-N—{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide 
               
               
                 215 
                 4-bromo-N—{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 216 
                 N—{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-bromo benzenesulfonamide 
               
               
                 217 
                 4-bromo-N—{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 218 
                 N—{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-4- 
               
               
                   
                 bromobenzenesulfonamide 
               
               
                 219 
                 4-bromo-N—{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3- 
               
               
                   
                 butenyl}benzenesulfonamide 
               
               
                 220 
                 4-bromo-N—{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1- 
               
               
                   
                 methylpropyl]-3-pentenyl}benzenesulfonamide 
               
               
                 221 
                 4-bromo-N—{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5- 
               
               
                   
                 hexenyl}benzenesulfonamide 
               
               
                 222 
                 4-bromo-N—((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl) benzenesulfonamide 
               
               
                 223 
                 4-chloro-N—[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 224 
                 4-chloro-N—{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 225 
                 N—{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-4-chloro benzenesulfonamide 
               
               
                 226 
                 4-chloro-N—{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide 
               
               
                 227 
                 4-chloro-N—{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 228 
                 N—{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-chloro benzenesulfonamide 
               
               
                 229 
                 4-chloro-N—{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 230 
                 4-chloro-N—{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3- 
               
               
                   
                 butenyl}benzenesulfonamide 
               
               
                 231 
                 4-chloro-N—((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 232 
                 4-chloro-N—{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1- 
               
               
                   
                 methylpropyl]-3-pentenyl}benzenesulfonamide 
               
               
                 233 
                 N—{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-4- 
               
               
                   
                 chlorobenzenesulfonamide 
               
               
                 234 
                 4-chloro-N—((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl) benzenesulfonamide 
               
               
                 235 
                 4-fluoro-N—[(1S,2S)-1-(1-hydroxy-1-methylethyl)-2-methylbutyl] benzenesulfonamide 
               
               
                 236 
                 4-fluoro-N—{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 237 
                 4-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl} benzenesulfonamide 
               
               
                 238 
                 N—{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-4-fluoro benzenesulfonamide 
               
               
                 239 
                 4-fluoro-N—{(1S)-2-hydroxy-2-isopropyl-3-methyl-1-[(1S)-1- 
               
               
                   
                 methylpropyl]butyl}benzenesulfonamide 
               
               
                 240 
                 4-fluoro-N—{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1-methylpropyl]pentyl}benzenesulfonamide 
               
               
                 241 
                 N—{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-4-fluoro benzenesulfonamide 
               
               
                 242 
                 N—{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-4-fluoro benzenesulfonamide 
               
               
                 243 
                 4-fluoro-N—{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3- 
               
               
                   
                 butenyl}benzenesulfonamide 
               
               
                 244 
                 4-fluoro-N—((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 245 
                 4-fluoro-N—{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1- 
               
               
                   
                 methylpropyl]-3-pentenyl}benzenesulfonamide 
               
               
                 246 
                 N—{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-4- 
               
               
                   
                 fluorobenzenesulfonamide 
               
               
                 247 
                 N—{(1S,2S)-1-[bis[4-(dimethylamino)phenyl](hydroxy)methyl]-2-methylbutyl}-4- 
               
               
                   
                 fluorobenzenesulfonamide 
               
               
                 248 
                 4-fluoro-N—((1S,2S)-1-{hydroxy[di(1-naphthyl)]methyl}-2-methylbutyl) benzenesulfonamide 
               
               
                 249 
                 3-chloro-N—{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 250 
                 3-chloro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl} benzenesulfonamide 
               
               
                 251 
                 N—{(1S)-2-butyl-2-hydroxy-1-[(1S)-1-methylpropyl]hexyl}-3-chloro benzenesulfonamide 
               
               
                 252 
                 3-chloro-N—{(1S)-2-hydroxy-2-isobutyl-4-methyl-1-[(1S)-1- 
               
               
                   
                 methylpropyl]pentyl}benzenesulfonamide 
               
               
                 253 
                 3-chloro-N—{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 254 
                 N—{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-3-chloro benzenesulfonamide 
               
               
                 255 
                 3-chloro-N—{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl} benzenesulfonamide 
               
               
                 256 
                 N—{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-3- 
               
               
                   
                 chlorobenzenesulfonamide 
               
               
                 257 
                 3-chloro-N—{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3- 
               
               
                   
                 butenyl}benzenesulfonamide 
               
               
                 258 
                 3-chloro-N—((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2- 
               
               
                   
                 methylbutyl)benzenesulfonamide 
               
               
                 259 
                 3-chloro-N—{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1- 
               
               
                   
                 methylpropyl]-3-pentenyl}benzenesulfonamide 
               
               
                 260 
                 N—{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-3- 
               
               
                   
                 chlorobenzenesulfonamide 
               
               
                 261 
                 2-fluoro-N—{(1S)-2-hexyl-2-hydroxy-1-[(1S)-1-methylpropyl]octyl} benzenesulfonamide 
               
               
                 262 
                 2-fluoro-N—{(1S)-2-hydroxy-1-[(1S)-1-methylpropyl]-2-pentylheptyl} benzenesulfonamide 
               
               
                 263 
                 2-fluoro-N—{(1S,2S)-1-[hydroxy(diphenyl)methyl]-2-methylbutyl} benzenesulfonamide 
               
               
                 264 
                 N—{(1S)-2-allyl-2-hydroxy-1-[(1S)-1-methylpropyl]-4-pentenyl}-2-fluoro benzenesulfonamide 
               
               
                 265 
                 N—{(1S)-2-ethyl-2-hydroxy-1-[(1S)-1-methylpropyl]butyl}-2-fluoro benzenesulfonamide 
               
               
                 266 
                 N—{(1S,2S)-1-[bis(4-fluorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluoro 
               
               
                   
                 benzenesulfonamide 
               
               
                 267 
                 N—{(1S,2S)-1-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methylbutyl}-2-fluoro 
               
               
                   
                 benzenesulfonamide 
               
               
                 268 
                 2-fluoro-N—{(1S)-2-hydroxy-2-isopropenyl-3-methyl-1-[(1S)-1-methylpropyl]-3- 
               
               
                   
                 butenyl}benzenesulfonamide 
               
               
                 269 
                 2-fluoro-N—((1S,2S)-1-{hydroxy[bis(4-methoxyphenyl)]methyl}-2-methylbutyl)benzenesulfonamide 
               
               
                 270 
                 2-fluoro-N—{(1S,3E)-2-hydroxy-3-methyl-2-[(1E)-1-methyl-1-propenyl]-1-[(1S)-1- 
               
               
                   
                 methylpropyl]-3-pentenyl}benzenesulfonamide 
               
               
                 271 
                 N—{(1S)-2-(3-butenyl)-2-hydroxy-1-[(1S)-1-methylpropyl]-5-hexenyl}-2- 
               
               
                   
                 fluorobenzenesulfonamide 
               
               
                 272 
                 4-chloro-N—[(1S)-1-cyclohexyl-2-hydroxyethyl]benzenesulfonamide 
               
               
                 273 
                 4-chloro-N—[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide 
               
               
                 274 
                 4-chloro-N—[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
               
               
                 275 
                 4-bromo-N—[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide 
               
               
                 276 
                 4-iodo-N—[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide 
               
               
                 277 
                 4-chloro-N—[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide 
               
               
                   
               
            
           
         
       
     
     Example 278 
     Repressor Release Assay (RRA) 
     The beta amyloid inhibitory activity of the compounds of the present invention was determined using the Repressor Release Assay (RRA). See, Table 17. A compound was considered active in RRA if it leads to at least a 1.5 fold increase in luciferase activity at 10 μg/mL and was non-toxic. 
     A. Cell Culture 
     CHO-K1 cells were cultured in whole DMEM media (DMEM—High Glucose with 10% fetal bovine serum, 1% Non-essential Amino Acids, and 1% Penicillin-Streptomycin) at 37° C. with 5% CO 2 . Two million cells were plated into 10-cm dishes 24 hrs prior to transfection. 
     Transient transfections were completed as recommended by Gibco BRL using their Lipofectamine Plus system. First, 6 μg of pRSVO-luc and 6 μg of APP-lacI construct DNA were added to 460 μL, Opti-Mem transfection media and incubated with 30 μL. Plus reagent for 15 minutes. Then, a lipid mixture of 40 μL Lipoferthmine reagent and 460 μL Opti-Mem transfection media was incubated with the DNA-Plus reagent mixture for 15 minutes. During the DNA-lipid incubation, the CHO-K1 cells were washed once and covered in 5.0 mL DMEM media without Penicillin-Streptomycin. The DNA-lipid preparation was then layered onto these cells and incubated at 37° C. overnight. 
     One and one half million transfected cells per well (100 μL total volume) were plated into sterile, opaque Packard 96-well Culture-Plates in clear DMEM whole media (DMEM—without phenol red) and incubated at 37° C. with 5% CO 2  for 3-5 hours. 
     B. Compound Dilution 
     Compounds were diluted using two different protocols; one protocol was used for compounds supplied neat (weighed powder in vial) and the other protocol was used for compounds supplied in solution (20 mM in DMSO in 96-well plates). For both protocols, 25 mM Hepes and 25 mM Hepes/1% DMSO were prepared fresh to be used as diluent. The Hepes/DMSO was used as the diluent control on all experimental plates. 
     The following table depicts the steps for compound dilution (please note that the last step was the addition of compound to cells/media in tissue culture plate). 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 15 
               
               
                   
                   
               
               
                   
                 Concentration 
                 Dilution 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Stock Solution 
                  10 mg/mL 
                 x mg compound (vial) 
               
               
                   
                   
                   
                 diluted with 100% DMSO 
               
               
                   
                 Dilution 1 
                  1 mg/mL 
                 20 μL stock solution 
               
               
                   
                   
                   
                 180 μL 25 mM Hepes 
               
               
                   
                 Dilution 2 
                 200 μg/mL 
                 60 μL Dilution 1 
               
               
                   
                   
                   
                 240 μL 25 mM Hepes 
               
               
                   
                 Dilution 3 
                  20 μg/mL 
                 11.3 μL Dilution 2 
               
               
                   
                 (in Cell Plate) 
                   
                 (in 100 μL cells/well) 
               
               
                   
                   
               
            
           
         
       
     
     Because some compounds were present in 96-well format at 20 mM, the following represents the protocol for their dilution (note that an average molecular weight of these compounds was used to calculate these dilutions and as above, the last step was the addition of compound to cells/media in tissue culture plate). 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 16 
               
               
                   
                   
               
               
                   
                 Concentration 
                 Dilution 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Stock Solution 
                 — 
                 20 mM Solution 
               
               
                   
                 (original conc.) 
               
               
                   
                 Dilution 1 
                 ~200 μg/mL 
                 6 μL stock solution 
               
               
                   
                   
                   
                 194 μL 25 mM Hepes 
               
               
                   
                 Dilution 2 (in 
                  ~20 μg/mL 
                 11.3 μL Dilution 2 
               
               
                   
                 Cell Plate) 
                   
                 (in 100 μL cells/well) 
               
               
                   
                   
               
            
           
         
       
     
     Once the compounds were diluted, they were applied in duplicate on cells in tissue culture plates (prepared above). Cells were incubated with compound at 37° C. with 5% CO 2  for an additional 36-48 hours. 
     C. Assay Measurement 
     Luciferase assays (LucLite reagent, Packard) were performed and were read on a Packard TopCount instrument. Media was removed from each 96-well plate and replaced with 100 μL PBS per well (with Mg 2+  and Ca 2+ ). An equal volume (100 μL) of the LucLite lysis/substrate buffer was added to each well and the plates were sealed and mixed in the dark on a rotary shaker for 15-30 minutes at room temperature. 
     Luciferase readings were then taken on the TopCount instrument. Measurements were expressed as relative light units (RLU) and are calculated and analyzed in MS Excel as follows: 
     D. Analysis of Data 
     “Fold Increase” refers to the amount of luciferase activity (measured in relative light units) over diluent control. “SEM” refers to the standard error of the mean for fold increase. “Activity”: A compound is considered active if it results in at least a 1.5 fold increase in luciferase activity at 10 μM/mL. 1=non-toxic, 0=toxic in Table 17. “Toxicity” is determined by loss of signal (≦0.75 fold increase). 
     E. Standard Beta Amyloid Inhibitor 
     The reference gamma secretase inhibitor DAPT (LY374973, AN37124: Dovey, H. F. et al,  J. Neurochem.  76: 173-181 (2001)) was prepared as outlined in International Patent Publication No. WO 98/22494 and tested in RRA and exhibited a 6.0-28.1 fold increase in luciferase activity at 10 μg/mL. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Repressor Release Assay 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 APPI 
                 APPI % of 
                 (%) 
               
               
                 Example 
                 Conc (μg/ml) 
                 Fold Increase 
                 Example #98 
                 APPI Toxicity 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 20 
                 1.6 
                 27.2 
                 1 
               
               
                 2 
                 20 
                 2.8 
                 48.1 
                 1 
               
               
                 3 
                 20 
                 3.6 
                 62.9 
                 1 
               
               
                 4 
                 20 
                 1.5 
                 26.5 
                 1 
               
               
                 5 
                 20 
                 2.5 
                 43.2 
                 1 
               
               
                 6 
                 20 
                 1.7 
                 30.2 
                 1 
               
               
                 7 
                 20 
                 1.6 
                 27.1 
                 1 
               
               
                 8 
                 20 
                 2 
                 35.3 
                 1 
               
               
                 9 
                 10 
                 2.2 
                 63.5 
                 1 
               
               
                   
                 20 
                 1.8 
                 30.5 
                 1 
               
               
                 10 
                 20 
                 2.4 
                 62.5 
                 1 
               
               
                   
                 20 
                 3.6 
                 63.2 
                 1 
               
               
                 10 
                 20 
                 3.3 
                 113.6 
                 1 
               
               
                 11 
                 20 
                 2.3 
                 63.2 
                 1 
               
               
                 12 
                 20 
                 2.9 
                 54 
                 1 
               
               
                 13 
                 20 
                 1.8 
                 33.5 
                 1 
               
               
                 14 
                 20 
                 1.9 
                 67 
                 1 
               
               
                 15 
                 20 
                 1.5 
                 26.5 
                 1 
               
               
                 16 
                 20 
                 2.7 
                 68.5 
                 1 
               
               
                 17 
                 20 
                 2.2 
                 56.4 
                 1 
               
               
                 18 
                 20 
                 1.9 
                 48.6 
                 1 
               
               
                   
                 20 
                 1.7 
                 41.8 
                 1 
               
               
                 19 
                 20 
                 1.6 
                 40.5 
                 1 
               
               
                 20 
                 20 
                 3.3 
                 78.2 
                 1 
               
               
                 21 
                 20 
                 1.6 
                 37.2 
                 1 
               
               
                 22 
                 20 
                 1.7 
                 39.5 
                 1 
               
               
                 23 
                 10 
                 3.6 
                 116.23 
                 1 
               
               
                   
                 20 
                 8.3 
                 197.5 
                 1 
               
               
                   
                 3 
                 1.67 
                 54.13 
                 1 
               
               
                 24 
                 20 
                 1.6 
                 38.6 
                 1 
               
               
                 25 
                 20 
                 1.8 
                 44.1 
                 1 
               
               
                 26 
                 20 
                 2.4 
                 58 
                 1 
               
               
                 27 
                 20 
                 2.2 
                 53.6 
                 1 
               
               
                 28 
                 20 
                 1.5 
                 34.8 
                 1 
               
               
                 29 
                 20 
                 2.1 
                 49.5 
                 1 
               
               
                 30 
                 20 
                 2.1 
                 50.5 
                 1 
               
               
                 31 
                 20 
                 2.8 
                 66.7 
                 1 
               
               
                 32 
                 20 
                 2.2 
                 51.6 
                 1 
               
               
                 33 
                 20 
                 3.9 
                 112 
                 1 
               
               
                 34 
                 20 
                 4.2 
                 122.5 
                 1 
               
               
                 35 
                 20 
                 2.4 
                 68.1 
                 1 
               
               
                 36 
                 10 
                 3.33 
                 107.5 
                 1 
               
               
                   
                 20 
                 6.4 
                 186.2 
                 1 
               
               
                   
                 20 
                 4.5 
                 107 
                 1 
               
               
                   
                 1 
                 1.6 
                 51.68 
                 1 
               
               
                   
                 3 
                 2.05 
                 66.34 
                 1 
               
               
                 37 
                 20 
                 4.7 
                 136.5 
                 1 
               
               
                 38 
                 20 
                 3.3 
                 94.8 
                 1 
               
               
                 39 
                 10 
                 2.47 
                 79.99 
                 1 
               
               
                   
                 20 
                 5.5 
                 158.9 
                 1 
               
               
                   
                 3 
                 1.56 
                 50.53 
                 1 
               
               
                 40 
                 20 
                 3.4 
                 126.2 
                 1 
               
               
                 41 
                 20 
                 4.9 
                 182.1 
                 1 
               
               
                 42 
                 20 
                 1.9 
                 71.7 
                 1 
               
               
                 43 
                 20 
                 5.1 
                 190 
                 1 
               
               
                 44 
                 20 
                 2.6 
                 95.7 
                 1 
               
               
                 45 
                 20 
                 1.5 
                 55.9 
                 1 
               
               
                 46 
                 20 
                 1.8 
                 67.4 
                 1 
               
               
                 47 
                 20 
                 2.4 
                 88.9 
                 1 
               
               
                 48 
                 20 
                 3.1 
                 116.6 
                 1 
               
               
                 49 
                 20 
                 2.5 
                 59.1 
                 1 
               
               
                 50 
                 20 
                 2.5 
                 59.3 
                 1 
               
               
                 51 
                 20 
                 1.6 
                 37.6 
                 1 
               
               
                 52 
                 20 
                 6.2 
                 145.7 
                 1 
               
               
                   
                 20 
                 8.6 
                 43.8 
                 1 
               
               
                 53 
                 20 
                 5.2 
                 121.9 
                 1 
               
               
                 54 
                 20 
                 5 
                 117 
                 1 
               
               
                 55 
                 20 
                 5.6 
                 131.5 
                 1 
               
               
                 56 
                 20 
                 3.6 
                 85.4 
                 1 
               
               
                 57 
                 20 
                 1.7 
                 39.1 
                 1 
               
               
                 58 
                 20 
                 2.6 
                 61.2 
                 1 
               
               
                 59 
                 20 
                 3.2 
                 76.3 
                 1 
               
               
                 60 
                 20 
                 4.6 
                 109.3 
                 1 
               
               
                 61 
                 20 
                 6.5 
                 152.3 
                 1 
               
               
                 62 
                 20 
                 1.8 
                 42.2 
                 1 
               
               
                 63 
                 20 
                 2 
                 47.9 
                 1 
               
               
                 64 
                 20 
                 1.7 
                 39.3 
                 1 
               
               
                 65 
                 20 
                 1.9 
                 44.6 
                 1 
               
               
                 66 
                 20 
                 5.5 
                 129.1 
                 1 
               
               
                 67 
                 20 
                 3.9 
                 91.5 
                 1 
               
               
                 68 
                 20 
                 2 
                 47.5 
                 1 
               
               
                 69 
                 20 
                 3.1 
                 73 
                 1 
               
               
                 70 
                 20 
                 2 
                 48 
                 1 
               
               
                 71 
                 20 
                 1.9 
                 43.9 
                 1 
               
               
                 72 
                 20 
                 3.2 
                 76.4 
                 1 
               
               
                 73 
                 20 
                 5.4 
                 127.1 
                 1 
               
               
                 74 
                 20 
                 2.5 
                 57.7 
                 1 
               
               
                 75 
                 20 
                 4.8 
                 112.3 
                 1 
               
               
                 76 
                 20 
                 5.8 
                 135.2 
                 1 
               
               
                 77 
                 20 
                 5.9 
                 139.8 
                 1 
               
               
                 78 
                 20 
                 4.4 
                 102.4 
                 1 
               
               
                 79 
                 20 
                 1.5 
                 34.1 
                 1 
               
               
                 80 
                 20 
                 3.9 
                 91.1 
                 1 
               
               
                 81 
                 20 
                 5 
                 118 
                 1 
               
               
                 82 
                 20 
                 2.6 
                 66 
                 1 
               
               
                 83 
                 20 
                 3.4 
                 86.8 
                 1 
               
               
                 84 
                 20 
                 3.4 
                 86.6 
                 1 
               
               
                 85 
                 20 
                 3.4 
                 87.3 
                 1 
               
               
                 86 
                 20 
                 1.6 
                 41.4 
                 1 
               
               
                 87 
                 20 
                 8.8 
                 223.8 
                 1 
               
               
                 88 
                 20 
                 6.4 
                 27.9 
                 1 
               
               
                 89 
                 20 
                 22.4 
                 97.9 
                 1 
               
               
                 90 
                 20 
                 1.6 
                 54.4 
                 1 
               
               
                 91 
                 10 
                 2.38 
                 92.18 
                 1 
               
               
                   
                 3 
                 1.71 
                 66.26 
                 1 
               
               
                   
                 20 
                 5 
                 116.7 
                 1 
               
               
                   
                 20 
                 3.1 
                 81 
                 1 
               
               
                   
                 20 
                 4.4 
                 154.8 
                 1 
               
               
                   
                 20 
                 3.8 
                 105 
                 1 
               
               
                   
                 20 
                 2 
                 46.8 
                 1 
               
               
                 92 
                 20 
                 1.7 
                 43.2 
                 1 
               
               
                 93 
                 20 
                 1.5 
                 39.2 
                 1 
               
               
                 94 
                 20 
                 2.5 
                 69.2 
                 1 
               
               
                   
                 20 
                 1.7 
                 38 
                 1 
               
               
                 95 
                 20 
                 1.6 
                 36.3 
                 1 
               
               
                 96 
                 20 
                 1.5 
                 44.7 
                 1 
               
               
                 97 
                 20 
                 1.5 
                 47.3 
                 1 
               
               
                 98 
                 10 
                 2.58 
                 100 
                 1 
               
               
                   
                 10 
                 2.91 
                 112.76 
                 1 
               
               
                   
                 10 
                 3.09 
                 100 
                 1 
               
               
                   
                 10 
                 3.26 
                 100 
                 1 
               
               
                   
                 10 
                 2.56 
                 100 
                 1 
               
               
                   
                 10 
                 2.7 
                 100 
                 1 
               
               
                   
                 10 
                 2.62 
                 100 
                 1 
               
               
                   
                 10 
                 2.5 
                 100 
                 1 
               
               
                   
                 10 
                 2.17 
                 100 
                 1 
               
               
                   
                 10 
                 2.92 
                 100 
                 1 
               
               
                   
                 10 
                 2.11 
                 100 
                 1 
               
               
                   
                 10 
                 2.36 
                 100 
                 1 
               
               
                   
                 10 
                 2.06 
                 100 
                 1 
               
               
                   
                 10 
                 2.25 
                 100 
                 1 
               
               
                   
                 10 
                 2.75 
                 100 
                 1 
               
               
                   
                 10 
                 2.52 
                 100 
                 1 
               
               
                   
                 10 
                 5.5 
                 100 
                 1 
               
               
                   
                 10 
                 3.2 
                 100 
                 1 
               
               
                   
                 10 
                 4.3 
                 100 
                 1 
               
               
                   
                 10 
                 3.5 
                 100 
                 1 
               
               
                   
                 10 
                 3.8 
                 100 
                 1 
               
               
                   
                 20 
                 3.7 
                 100 
                 1 
               
               
                   
                 10 
                 3.3 
                 100 
                 1 
               
               
                   
                 10 
                 2.69 
                 100 
                 1 
               
               
                   
                 20 
                 5.6 
                 100 
                 1 
               
               
                   
                 20 
                 5.5 
                 100 
                 1 
               
               
                   
                 20 
                 5.8 
                 100 
                 1 
               
               
                   
                 20 
                 4.4 
                 100 
                 1 
               
               
                   
                 20 
                 3.2 
                 100 
                 1 
               
               
                   
                 20 
                 2.7 
                 100 
                 1 
               
               
                   
                 20 
                 3.3 
                 100 
                 1 
               
               
                   
                 20 
                 3.3 
                 100 
                 1 
               
               
                   
                 20 
                 3.6 
                 100 
                 1 
               
               
                   
                 20 
                 4.4 
                 100 
                 1 
               
               
                   
                 20 
                 3.9 
                 100 
                 1 
               
               
                   
                 20 
                 3.7 
                 100 
                 1 
               
               
                   
                 20 
                 4.2 
                 100 
                 1 
               
               
                   
                 20 
                 7 
                 100 
                 1 
               
               
                   
                 20 
                 19.5 
                 100 
                 1 
               
               
                   
                 20 
                 4.2 
                 100 
                 1 
               
               
                   
                 20 
                 5.5 
                 100 
                 1 
               
               
                   
                 20 
                 4 
                 100 
                 1 
               
               
                   
                 20 
                 3.2 
                 100 
                 1 
               
               
                   
                 20 
                 4.4 
                 100 
                 1 
               
               
                   
                 20 
                 3.5 
                 100 
                 1 
               
               
                   
                 20 
                 4.5 
                 100 
                 1 
               
               
                   
                 20 
                 5.7 
                 100 
                 1 
               
               
                   
                 20 
                 5.4 
                 100 
                 1 
               
               
                   
                 20 
                 3.4 
                 100 
                 1 
               
               
                   
                 20 
                 2.9 
                 100 
                 1 
               
               
                   
                 20 
                 3.3 
                 100 
                 1 
               
               
                   
                 20 
                 3.3 
                 100 
                 1 
               
               
                   
                 20 
                 3.2 
                 100 
                 1 
               
               
                   
                 20 
                 3.5 
                 100 
                 1 
               
               
                   
                 20 
                 4.3 
                 100 
                 1 
               
               
                   
                 20 
                 4.3 
                 100 
                 1 
               
               
                   
                 20 
                 6.8 
                 158.9 
                 1 
               
               
                   
                 20 
                 3.9 
                 100 
                 1 
               
               
                   
                 20 
                 4.2 
                 100 
                 1 
               
               
                   
                 20 
                 2.7 
                 100 
                 1 
               
               
                   
                 10 
                 2.53 
                 100 
                 1 
               
               
                   
                 20 
                 3 
                 76.7 
                 1 
               
               
                   
                 10 
                 2.9 
                 100 
                 1 
               
               
                   
                 10 
                 2.78 
                 100 
                 1 
               
               
                   
                 10 
                 2.47 
                 95.68 
                 1 
               
               
                   
                 3 
                 1.79 
                 69.39 
                 1 
               
               
                   
                 20 
                 1.8 
                 32.5 
                 1 
               
               
                 99 
                 20 
                 1.7 
                 42.9 
                 1 
               
               
                 100 
                 20 
                 1.6 
                 41 
                 1 
               
               
                 101 
                 20 
                 1.6 
                 42 
                 1 
               
               
                 102 
                 20 
                 1.5 
                 39.6 
                 1 
               
               
                 103 
                 20 
                 2.6 
                 70.8 
                 1 
               
               
                   
                 20 
                 1.5 
                 34.9 
                 1 
               
               
                 104 
                 20 
                 1.5 
                 31.2 
                 1 
               
               
                 105 
                 10 
                 1.54 
                 47.3 
                 1 
               
               
                 106 
                 20 
                 1.6 
                 32.8 
                 1 
               
               
                 107 
                 1 
                 2.35 
                 91.1 
                 1 
               
               
                 108 
                 3 
                 1.66 
                 59.78 
                 1 
               
               
                 109 
                 20 
                 1.9 
                 52.6 
                 1 
               
               
                 110 
                 20 
                 1.7 
                 46.5 
                 1 
               
               
                 111 
                 20 
                 1.7 
                 47.8 
                 1 
               
               
                 112 
                 20 
                 1.8 
                 50.3 
                 1 
               
               
                 113 
                 20 
                 1.6 
                 43.9 
                 1 
               
               
                 114 
                 20 
                 1.5 
                 30.9 
                 1 
               
               
                 115 
                 20 
                 1.8 
                 37.3 
                 1 
               
               
                 116 
                 20 
                 1.6 
                 44.8 
                 1 
               
               
                 117 
                 20 
                 1.5 
                 31 
                 1 
               
               
                 118 
                 20 
                 1.6 
                 33.6 
                 1 
               
               
                 119 
                 20 
                 1.5 
                 46.5 
                 1 
               
               
                 120 
                 20 
                 5 
                 135.2 
                 1 
               
               
                 121 
                 20 
                 1.7 
                 45.1 
                 1 
               
               
                 122 
                 20 
                 1.5 
                 42.1 
                 1 
               
               
                 123 
                 20 
                 4.4 
                 121 
                 1 
               
               
                   
                 20 
                 3.5 
                 97.4 
                 1 
               
               
                 124 
                 20 
                 2 
                 55.1 
                 1 
               
               
                 125 
                 20 
                 1.8 
                 49.2 
                 1 
               
               
                 126 
                 10 
                 1.52 
                 59.52 
                 1 
               
               
                   
                 3 
                 1.54 
                 56.2 
                 1 
               
               
                 127 
                 10 
                 2.97 
                 116.04 
                 1 
               
               
                 128 
                 10 
                 10.76 
                 420.7 
                 1 
               
               
                   
                 10 
                 2.13 
                 77.43 
                 1 
               
               
                 129 
                 10 
                 7.12 
                 278.35 
                 1 
               
               
                   
                 10 
                 1.62 
                 59.13 
                 1 
               
               
                 130 
                 10 
                 2.4 
                 93.87 
                 1 
               
               
                 131 
                 10 
                 1.65 
                 64.57 
                 1 
               
               
                 132 
                 10 
                 1.54 
                 60.21 
                 1 
               
               
                 133 
                 10 
                 1.79 
                 79.67 
                 1 
               
               
                 134 
                 10 
                 3 
                 133.7 
                 1 
               
               
                   
                 10 
                 2.6 
                 47 
                 1 
               
               
                   
                 3 
                 1.5 
                 27.5 
                 1 
               
               
                 135 
                 10 
                 1.91 
                 84.91 
                 1 
               
               
                   
                 10 
                 2 
                 37 
                 1 
               
               
                 136 
                 10 
                 3.04 
                 135.09 
                 1 
               
               
                 137 
                 10 
                 1.61 
                 71.59 
                 1 
               
               
                 138 
                 10 
                 1.57 
                 69.78 
                 1 
               
               
                 139 
                 10 
                 2.12 
                 94.48 
                 1 
               
               
                 140 
                 10 
                 1.52 
                 67.81 
                 1 
               
               
                 141 
                 10 
                 1.79 
                 76.02 
                 1 
               
               
                 142 
                 10 
                 2.71 
                 114.62 
                 1 
               
               
                 143 
                 10 
                 5.72 
                 242.28 
                 1 
               
               
                 144 
                 10 
                 1.69 
                 71.37 
                 1 
               
               
                 145 
                 10 
                 3.9 
                 152.49 
                 1 
               
               
                   
                 10 
                 2.57 
                 102.15 
                 1 
               
               
                 146 
                 10 
                 4.26 
                 166.6 
                 1 
               
               
                   
                 3 
                 1.53 
                 60.66 
                 1 
               
               
                   
                 10 
                 2.33 
                 92.64 
                 1 
               
               
                 147 
                 10 
                 1.94 
                 75.86 
                 1 
               
               
                 148 
                 10 
                 1.88 
                 73.4 
                 1 
               
               
                 149 
                 10 
                 4.29 
                 167.71 
                 1 
               
               
                   
                 10 
                 2.02 
                 80.24 
                 1 
               
               
                 150 
                 10 
                 3.39 
                 132.65 
                 1 
               
               
                   
                 10 
                 1.59 
                 63.18 
                 1 
               
               
                 151 
                 10 
                 2.9 
                 129.13 
                 1 
               
               
                 152 
                 10 
                 6.64 
                 295.59 
                 1 
               
               
                   
                 10 
                 3.7 
                 67.7 
                 1 
               
               
                   
                 3 
                 1.6 
                 29.7 
                 1 
               
               
                 153 
                 10 
                 4.77 
                 212.3 
                 1 
               
               
                   
                 3 
                 2 
                 36.2 
                 1 
               
               
                   
                 10 
                 2.9 
                 53.4 
                 1 
               
               
                 154 
                 10 
                 1.68 
                 74.73 
                 1 
               
               
                 155 
                 10 
                 4.37 
                 194.25 
                 1 
               
               
                 156 
                 10 
                 2.01 
                 89.37 
                 1 
               
               
                   
                 10 
                 1.64 
                 106.77 
                 1 
               
               
                   
                 3 
                 1.52 
                 98.84 
                 1 
               
               
                 157 
                 10 
                 1.96 
                 87.36 
                 1 
               
               
                 158 
                 10 
                 2.28 
                 101.49 
                 1 
               
               
                 159 
                 10 
                 2.11 
                 94.03 
                 1 
               
               
                 160 
                 10 
                 1.66 
                 73.83 
                 1 
               
               
                 161 
                 10 
                 1.69 
                 71.57 
                 1 
               
               
                 162 
                 10 
                 1.63 
                 68.85 
                 1 
               
               
                 163 
                 10 
                 1.64 
                 69.41 
                 1 
               
               
                 164 
                 10 
                 3.53 
                 149.31 
                 1 
               
               
                 165 
                 10 
                 2.05 
                 70.81 
                 1 
               
               
                   
                 10 
                 1.6 
                 63.92 
                 1 
               
               
                 166 
                 10 
                 5.49 
                 189.28 
                 1 
               
               
                   
                 10 
                 2.05 
                 82.01 
                 1 
               
               
                 167 
                 10 
                 9.66 
                 332.83 
                 1 
               
               
                 168 
                 10 
                 8.32 
                 286.71 
                 1 
               
               
                   
                 10 
                 2.2 
                 87.86 
                 1 
               
               
                 169 
                 10 
                 2.85 
                 98.28 
                 1 
               
               
                   
                 10 
                 2.01 
                 80.19 
                 1 
               
               
                 170 
                 10 
                 1.92 
                 66.13 
                 1 
               
               
                 171 
                 10 
                 1.54 
                 53.17 
                 1 
               
               
                 172 
                 10 
                 2.51 
                 86.45 
                 1 
               
               
                   
                 10 
                 1.59 
                 63.78 
                 1 
               
               
                 173 
                 10 
                 2.56 
                 88.08 
                 1 
               
               
                 174 
                 10 
                 2.1 
                 102.08 
                 1 
               
               
                 175 
                 10 
                 4.24 
                 205.87 
                 1 
               
               
                   
                 10 
                 2.01 
                 124.61 
                 1 
               
               
                 176 
                 10 
                 2.63 
                 127.84 
                 1 
               
               
                   
                 10 
                 1.87 
                 116.42 
                 1 
               
               
                 177 
                 10 
                 1.95 
                 94.93 
                 1 
               
               
                 178 
                 10 
                 1.68 
                 81.88 
                 1 
               
               
                 179 
                 10 
                 1.63 
                 79.4 
                 1 
               
               
                 180 
                 10 
                 1.69 
                 80.17 
                 1 
               
               
                 181 
                 10 
                 1.76 
                 83.43 
                 1 
               
               
                 182 
                 10 
                 2.58 
                 122.24 
                 1 
               
               
                 183 
                 10 
                 4.49 
                 212.53 
                 1 
               
               
                 184 
                 10 
                 1.7 
                 80.39 
                 1 
               
               
                 185 
                 10 
                 1.51 
                 51.91 
                 1 
               
               
                 186 
                 10 
                 3.86 
                 133.06 
                 1 
               
               
                 187 
                 10 
                 9.02 
                 310.99 
                 1 
               
               
                 188 
                 10 
                 3.54 
                 122.17 
                 1 
               
               
                 189 
                 10 
                 1.51 
                 52.11 
                 1 
               
               
                 190 
                 10 
                 1.76 
                 60.57 
                 1 
               
               
                 191 
                 10 
                 2.42 
                 83.48 
                 1 
               
               
                 192 
                 10 
                 2.21 
                 76.01 
                 1 
               
               
                 193 
                 10 
                 1.78 
                 86.66 
                 1 
               
               
                 194 
                 10 
                 3.42 
                 166.42 
                 1 
               
               
                   
                 10 
                 1.97 
                 122.18 
                 1 
               
               
                 195 
                 10 
                 2.16 
                 104.89 
                 1 
               
               
                 196 
                 10 
                 1.78 
                 86.69 
                 1 
               
               
                 197 
                 10 
                 1.54 
                 74.67 
                 1 
               
               
                 198 
                 10 
                 1.54 
                 74.68 
                 1 
               
               
                 199 
                 10 
                 1.61 
                 78.5 
                 1 
               
               
                 200 
                 10 
                 1.85 
                 87.52 
                 1 
               
               
                 201 
                 10 
                 2.45 
                 116.18 
                 1 
               
               
                 202 
                 10 
                 1.62 
                 55.79 
                 1 
               
               
                 203 
                 10 
                 3.47 
                 119.61 
                 1 
               
               
                 204 
                 10 
                 3.73 
                 128.72 
                 1 
               
               
                 205 
                 10 
                 1.72 
                 59.11 
                 1 
               
               
                 206 
                 10 
                 1.9 
                 92.42 
                 1 
               
               
                 207 
                 10 
                 1.81 
                 87.79 
                 1 
               
               
                 208 
                 10 
                 2.01 
                 97.83 
                 1 
               
               
                 209 
                 10 
                 1.81 
                 88.04 
                 1 
               
               
                 210 
                 10 
                 1.68 
                 81.7 
                 1 
               
               
                 211 
                 10 
                 2.09 
                 71.66 
                 1 
               
               
                 212 
                 10 
                 4.85 
                 166.42 
                 1 
               
               
                   
                 10 
                 2.4 
                 70.1 
                 1 
               
               
                 213 
                 10 
                 3.03 
                 103.82 
                 1 
               
               
                   
                 10 
                 1.6 
                 46.4 
                 1 
               
               
                 214 
                 10 
                 4.93 
                 169.16 
                 1 
               
               
                   
                 10 
                 1.8 
                 53.2 
                 1 
               
               
                 215 
                 10 
                 1.65 
                 75.81 
                 1 
               
               
                 216 
                 10 
                 1.58 
                 72.76 
                 1 
               
               
                 217 
                 10 
                 1.68 
                 77.38 
                 1 
               
               
                 218 
                 10 
                 1.55 
                 71.25 
                 1 
               
               
                 219 
                 10 
                 1.8 
                 82.73 
                 1 
               
               
                   
                 20 
                 2.8 
                 75.9 
                 1 
               
               
                 220 
                 10 
                 3.29 
                 151.23 
                 1 
               
               
                 221 
                 10 
                 5.73 
                 263.29 
                 1 
               
               
                 222 
                 10 
                 1.59 
                 54.46 
                 1 
               
               
                 223 
                 10 
                 2.33 
                 79.87 
                 1 
               
               
                 224 
                 10 
                 2.22 
                 76.16 
                 1 
               
               
                 225 
                 10 
                 6.82 
                 234.08 
                 1 
               
               
                 226 
                 10 
                 4.6 
                 157.69 
                 1 
               
               
                 227 
                 10 
                 1.65 
                 75.91 
                 1 
               
               
                 228 
                 10 
                 1.56 
                 71.57 
                 1 
               
               
                 229 
                 10 
                 1.52 
                 69.7 
                 1 
               
               
                 230 
                 10 
                 1.75 
                 80.53 
                 1 
               
               
                   
                 20 
                 1.9 
                 51 
                 1 
               
               
                 231 
                 10 
                 2.49 
                 114.39 
                 1 
               
               
                 232 
                 10 
                 1.94 
                 89.04 
                 1 
               
               
                   
                 20 
                 4.2 
                 115 
                 1 
               
               
                 233 
                 10 
                 6.67 
                 306.66 
                 1 
               
               
                 234 
                 10 
                 2.9 
                 99.47 
                 1 
               
               
                   
                 10 
                 1.6 
                 49.5 
                 1 
               
               
                 235 
                 10 
                 1.88 
                 64.32 
                 1 
               
               
                 236 
                 10 
                 6.55 
                 224.57 
                 1 
               
               
                   
                 10 
                 3.2 
                 101.3 
                 1 
               
               
                 237 
                 10 
                 6.05 
                 207.45 
                 1 
               
               
                   
                 10 
                 3.8 
                 119.8 
                 1 
               
               
                 238 
                 10 
                 4.5 
                 154.18 
                 1 
               
               
                 239 
                 10 
                 1.54 
                 52.99 
                 1 
               
               
                 240 
                 10 
                 3.82 
                 131.15 
                 1 
               
               
                 241 
                 10 
                 1.58 
                 72.82 
                 1 
               
               
                 242 
                 10 
                 1.6 
                 73.53 
                 1 
               
               
                 243 
                 10 
                 1.7 
                 78.07 
                 1 
               
               
                 244 
                 10 
                 1.51 
                 69.29 
                 1 
               
               
                 245 
                 10 
                 2.05 
                 94.29 
                 1 
               
               
                   
                 20 
                 3.5 
                 95.1 
                 1 
               
               
                 246 
                 10 
                 2.42 
                 111.39 
                 1 
               
               
                   
                 20 
                 1.9 
                 50.9 
                 1 
               
               
                 247 
                 10 
                 1.54 
                 57.33 
                 1 
               
               
                 248 
                 10 
                 3.53 
                 121.19 
                 1 
               
               
                   
                 10 
                 1.5 
                 46.6 
                 1 
               
               
                 249 
                 10 
                 1.9 
                 58.4 
                 1 
               
               
                 250 
                 10 
                 2.4 
                 72.2 
                 1 
               
               
                 251 
                 10 
                 3.4 
                 103.5 
                 1 
               
               
                 252 
                 10 
                 1.8 
                 53.8 
                 1 
               
               
                 253 
                 10 
                 1.61 
                 59.95 
                 1 
               
               
                 254 
                 10 
                 1.93 
                 71.92 
                 1 
               
               
                 255 
                 10 
                 2.03 
                 75.56 
                 1 
               
               
                 256 
                 10 
                 1.5 
                 55.91 
                 1 
               
               
                 257 
                 10 
                 2.54 
                 94.5 
                 1 
               
               
                   
                 20 
                 2.5 
                 68.8 
                 1 
               
               
                 258 
                 10 
                 1.72 
                 63.9 
                 1 
               
               
                 259 
                 10 
                 2.19 
                 81.37 
                 1 
               
               
                   
                 1 
                 1.7 
                 31.1 
                 1 
               
               
                   
                 0.3 
                 1.7 
                 31.1 
                 1 
               
               
                   
                 3 
                 1.7 
                 31.5 
                 1 
               
               
                   
                 10 
                 1.6 
                 49.1 
                 1 
               
               
                   
                 20 
                 4.4 
                 119.7 
                 1 
               
               
                   
                 10 
                 1.7 
                 31.6 
                 1 
               
               
                 260 
                 10 
                 6.23 
                 231.76 
                 1 
               
               
                   
                 3 
                 1.5 
                 26.7 
                 1 
               
               
                 261 
                 10 
                 3.5 
                 104.4 
                 1 
               
               
                 262 
                 10 
                 2.2 
                 63.8 
                 1 
               
               
                 263 
                 10 
                 1.57 
                 58.4 
                 1 
               
               
                 264 
                 10 
                 2 
                 74.18 
                 1 
               
               
                 265 
                 10 
                 1.78 
                 66.02 
                 1 
               
               
                 266 
                 10 
                 1.57 
                 58.25 
                 1 
               
               
                 267 
                 10 
                 1.59 
                 58.97 
                 1 
               
               
                 268 
                 10 
                 1.75 
                 65.06 
                 1 
               
               
                 269 
                 10 
                 1.58 
                 58.74 
                 1 
               
               
                 270 
                 10 
                 1.86 
                 69.21 
                 1 
               
               
                 271 
                 10 
                 1.82 
                 67.61 
                 1 
               
               
                   
                 20 
                 2.4 
                 43.2 
                 1 
               
               
                 272 
                 20 
                 2.3 
                 81.3 
                 1 
               
               
                 273 
                 20 
                 1.5 
                 38.7 
                 1 
               
               
                 274 
                 20 
                 2.1 
                 44.8 
                 1 
               
               
                 275 
                 20 
                 2 
                 41.9 
                 1 
               
               
                 276 
                 20 
                 2 
                 46.3 
                 1 
               
               
                   
                 20 
                 2.1 
                 73.4 
                 1 
               
               
                 277 
                 20 
                 1.5 
                 53.4 
                 1 
               
               
                   
               
            
           
         
       
     
     All publications cited in this specification are incorporated herein by reference. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.