Bridged bicyclic amino thiazine dioxide compounds as inhibitors of beta-secretase and methods of use thereof

Abstract

The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: wherein variables A 4 , A 5 , A 6 , A 8 , R 1 , R 2 , R 3 , R 7 and n of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formula II and sub-formula embodiments thereof, compounds of Formula III, intermediates and processes and methods useful for the preparation of compounds of Formulas I-III, and sub-Formulas thereof.

1 - 32 . (canceled) 
     
     
         33 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A pharmaceutical composition comprising the compound of  claim 33  and a pharmaceutically acceptable excipient. 
     
     
         35 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 33 . 
     
     
         36 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 33 . 
     
     
         37 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A pharmaceutical composition comprising the compound of  claim 37  and a pharmaceutically acceptable excipient. 
     
     
         39 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 37 . 
     
     
         40 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 37 . 
     
     
         41 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A pharmaceutical composition comprising the compound of  claim 41  and a pharmaceutically acceptable excipient. 
     
     
         43 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 41 . 
     
     
         44 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 41 . 
     
     
         45 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A pharmaceutical composition comprising the compound of  claim 45  and a pharmaceutically acceptable excipient. 
     
     
         47 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 45 . 
     
     
         48 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 45 . 
     
     
         49 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         50 . A pharmaceutical composition comprising the compound of  claim 49  and a pharmaceutically acceptable excipient. 
     
     
         51 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 49 . 
     
     
         52 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 49 . 
     
     
         53 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         54 . A pharmaceutical composition comprising the compound of  claim 53  and a pharmaceutically acceptable excipient. 
     
     
         55 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 53 . 
     
     
         56 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 53 . 
     
     
         57 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         58 . A pharmaceutical composition comprising the compound of  claim 57  and a pharmaceutically acceptable excipient. 
     
     
         59 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 57 . 
     
     
         60 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 57 . 
     
     
         61 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         62 . A pharmaceutical composition comprising the compound of  claim 61  and a pharmaceutically acceptable excipient. 
     
     
         63 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 61 . 
     
     
         64 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 61 . 
     
     
         65 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         66 . A pharmaceutical composition comprising the compound of  claim 65  and a pharmaceutically acceptable excipient. 
     
     
         67 . A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 65 . 
     
     
         68 . A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject a dose effective amount of the compound of  claim 65 .