Acylated amino acid amidyl pyrazoles and related compounds

Abstract

This invention is directed to acylated amino acid amidyl pyrazoles and related compounds of Formula I. The invention is also directed to a pharmaceutical formation comprising such compound or in a pharmaceutically acceptable salt form thereof. The invention is further directed to a method for inhibiting β-amyloid peptide release and/or synthesis, a method for inhibiting γ-secretase activity, and a method for treating neurological disorders associated with β-amyloid peptide production. The method comprises administering to a host a pharmaceutical formulation comprising an effective amount of a compound of Formula I. The compounds of Formula I are useful in the prevention and treatment of Alzheimer's disease.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt 
         wherein R is substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocyclic, alkoxy, 
       
       
         
           
           
               
               
           
         
         cycloalkoxy, aryloxy, heteroaryloxy, alkylamino, cycloaklylamino, arylamino, heteroarylamino; or R is
 wherein X′ and X″ are each independently hydrogen, hydroxy or fluoro, provided when one of X′ and X″ is fluoro, the other is not hydroxy; or 
 X′ and X″ together form an oxo group, 
 Z is selected from the group consisting of alkyl, nitrogen, oxygen, sulfur and a bond covalently linking R 1  to —CX′X″— 
 R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic; 
 R 2  is selected from the group consisting of hydrogen, C 1 -C 4  alkyl, —COOR 2a , and —COR 2a  wherein R 2a  is hydrogen, C 1-4  alkyl, cycloalkyl, or heterocycle; 
 R 3  is H, substituted or unsubstituted linear alkyl, branched alkyl, cycloalkyl, or phenyl; 
 R 5  is —Y—R 6 , wherein Y is substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl, or a bond; and 
 R 6  is substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocycle, heterocycloalkyl, aryloxide, heteroaryl N-oxide, or arylsulfide; 
 provided when Y is a bond, then either R 6  is cycloalkyl, or R 2  is alkylalkoxy or alkylthioalkoxy. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R═—CR 1 X′X″, X′ is H or OH, X″ is H, and R 1  is aryl or substituted aryl. 
     
     
         3 . The compound of  claim 1 , wherein R 3  is H or t-butyl. 
     
     
         4 . The compound of  claim 1 , wherein Y is substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclyl. 
     
     
         5 . The compound of  claim 1 , wherein Y is —CH 2 —CH 2 —; CH 3 —CH<; —CH(CH 3 )—; —C(CH 3 ) 2 CH 2 —; CH 3 —CH(phenyl)<; >CH(phenyl); or —CH═CH—. 
     
     
         6 . The compound of  claim 2 , wherein R 1  is 3,5-difluorophenyl. 
     
     
         7 . The compound of  claim 3 , wherein R 2  is methyl. 
     
     
         8 . The compound of  claim 1 , selected from the group consisting of: N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]-2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]propionamide, 2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-N-[5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]propionamide, 2-[2-(3,5-difluoro-phenyl)-2-hydroxy-acetylamino]-N-[5-(1-phenyl-cyclopropyl)-2H-pyrazol-3-yl]-propionamide, 2-[2-(3,5-difluoro-phenyl)-2-hydroxy-acetylamino]-N-[5-(1-phenyl-cyclopentyl)-2H-pyrazol-3-yl]-propionamide, 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-{5-[1-(4-fluoro-phenyl)-cyclopentyl]-2H-pyrazol-3-yl}-propionamide, 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-{5-[1-(4-chloro-phenyl)-cyclopentyl]-2H-pyrazol-3-yl}-propionamide, 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-[5-(1-phenyl-cyclohexyl)-2H-pyrazol-3-yl]-propionamide, 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-{5-[1-(2-fluoro-phenyl)-cyclopentyl]-2H-pyrazol-3-yl}-propionamide, 2-[2-(3,5-Difluoro-phenyl)-2-hydroxy-acetylamino]-N-[5-(4-phenyl-tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-propionamide, N-[2-tert-Butyl-5-(4-phenyl-tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-2-[2-(3,5-difluoro-phenyl)-2-hydroxy-acetylamino]-propionamide, N-(5-Cyclopentyl-2H-pyrazol-3-yl)-2-[2-(3,5-difluror-phenyl)2-2hydroxy-acetylamino]-propionamide, and N-[5-(1-Cyclopropyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]-2-[2′-(3,5-difluorophenyl)-2′-hydroxylacetylamino]-propionamide. 
     
     
         9 . A method for inhibiting β-amyloid peptide release or synthesis in a cell comprising administering to said cell a compound according to  claim 1 , in an amount effective in inhibiting the cellular release and/or synthesis of β-amyloid peptide. 
     
     
         10 . A method for inhibiting γ-secretase activity comprising administering to a host an effective amount of the compound according to  claim 1 . 
     
     
         11 . A method for treating or preventing a neurological disorder associated with β-amyloid peptide production comprising administering to a host a pharmaceutical formulation comprising a therapeutically effective amount of the compound according to  claim 1 . 
     
     
         12 . The method according to  claim 11 , wherein said neurological disorder is Alzheimer's disease.