Neprilysin inhibitors

Abstract

In one aspect, the invention relates to compounds having the formula X: where R a , R b , R 2 , R 7 , and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds described herein are prodrugs of compounds having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

1 . A compound of formula X: 
       
         
           
           
               
               
           
         
       
       where,
 (i) R a  is F; R b  is Cl; X is 
 
       
         
           
           
               
               
           
         
       
       R is H or —CH 3 ; and
 R 2  is H and R 7  is selected from —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )—COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)—O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, benzyl, 
 
       
         
           
           
               
               
           
         
       
       or R 2  is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , and R 7  is H; or R 2  is —C(O)CH 2 NH 2  and R 7  is —CH 2 CH 3 ; or
 (ii) R a  is H; R b  is Cl; X is 
 
       
         
           
           
               
               
           
         
       
       and
 R 2  is H, R 3  is —OH, and R 7  is selected from —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 2 OCH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and —CH 2 OC(O)—CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 ; or R 2  is selected from —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, and —P(O)(OR e ) 2 , R 3  is —OH, and R 7  is H; or R 2  is H, R 3  is selected from —OCHR c OC(O)—C 1-4 alkyl, —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , —OCH 2 OC(O)—CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 , and 
 
       
         
           
           
               
               
           
         
       
       and R 7  is H;
 where each R c  is independently H or —C 1-3 alkyl; each R d  is independently H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl; and each R e  is independently H, —C 1-6 alkyl, or phenyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , of the formula IV: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , where R is —CH 3 , R 2  is H, and R 7  is selected from —CH 2 CF 2 CF 3 , —(CH 2 ) 2 OCH 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH(CH 3 )OC(O)O-cyclohexyl, —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 , 
       
         
           
           
               
               
           
         
       
       or R is —CH 3 ; R 2  is selected from —C(O)CH 2 CH 3 , —C(O)CH 2 NH 2 , —C(O)CH(CH 3 )NH 2 , —C(O)CH[CH(CH 3 ) 2 ]NH 2 , and —C(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 ; and R 7  is H; or R is —CH 3 , R 2  is —C(O)CH 2 NH 2 , and R 7  is —CH 2 CH 3 . 
     
     
         12 - 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , of the formula VIII: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16 , where R 2  is H, R 3  is —OH, and R 7  is selected from —CH 2 OC(O)CH 3 , —CH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , and —CH 2 OC(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 ; or R 2  is selected from —C(O)CH 2 CH 3 , —C(O)CH 2 CH(CH 3 ) 2 , —C(O)CH[CH(CH 3 ) 2 ]NH 2 , and —C(O)CH[CH(CH 3 ) 2 ]—NHC(O)OCH 3 , R 3  is —OH, and R 7  is H; or R 2  is H, R 3  is selected from —OCH 2 OC(O)CH 3 , —OCH 2 OC(O)(CH 2 ) 2 CH 3 , —OCH 2 OC(O)OCH 2 CH 3 , —OCH 2 OC(O)OCH(CH 3 ) 2 , —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]NH 2 , —OCH 2 OC(O)CH[CH(CH 3 ) 2 ]NHC(O)OCH 3 , and 
       
         
           
           
               
               
           
         
       
       and R 7  is H. 
     
     
         18 - 24 . (canceled)