Chemical compounds 785

Abstract

DGAT-1 inhibitor compounds of formula (I), pharmaceutically-acceptable salts and pro-drugs thereof are described, together with pharmaceutical compositions, processes for making them and their use in treating, for example, obesity

1 . A compound of formula (I), or a pharmaceutically-acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 each r is independently 0 or 1 and 
 each X 1  is independently selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano; 
 each q is independently 0 or 1 and 
 each X 2  is independently selected from fluoro, chloro, bromo, amino, cyano, (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl and (1-2C)alkoxy; 
 Y 1  is selected from fluoro, chloro, bromo, cyano, (1-3C)alkyl and (1-2C)alkoxy; 
 n is 0, 1 or 2 and each Y 2  is independently selected from fluoro, chloro, bromo, cyano, hydroxy, (1-3C)alkyl and (1-2C)alkoxy; 
 p is 0, 1 or 2 and each Y 3  is independently (1-3C)alkyl or when p is 2 each Y 3  may also link to form a (3-5C)cycloalkyl ring; 
 Z is carboxy or a group Q selected from —CONHSO 2 Me or one of the following rings, 
 
       
         
           
           
               
               
           
         
       
       or Z is —CONRbRc
 wherein Rb and Rc are independently selected from hydrogen, (1-4C)alkyl and (1-4C)alkoxyethyl or Rb and Rc are linked so as to form a morpholine ring or a (4-6C)heterocyclic ring, and when Z is —CONRbRc the (1-4C)alkyl group and morpholine or (4-6C)heterocyclic rings that may be formed may be optionally substituted on an available carbon atom by carboxy or a group Q; 
 and wherein any carbon atom in a linear (1-3C)alkyl, (1-3C)alkyl or (1-2C)alkoxy containing group defined above may be optionally substituted by up to 3 fluoro atoms. 
 
     
     
         2 . A compound of formula (I), or a pharmaceutically-acceptable salt, thereof, as claimed in  claim 1 , wherein both r are 1 and each X 1  is linear (1-3C)alkyl. 
     
     
         3 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein Z is carboxy, —CONRbRc or a group 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein Z is carboxy. 
     
     
         5 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein Y 1  is chloro, fluororo or methyl. 
     
     
         6 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein Y 1  is chloro. 
     
     
         7 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein q is 0. 
     
     
         8 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein q is 1 and X 2  is chloro or fluoro. 
     
     
         9 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein p is 1 and Y 3  is methyl. 
     
     
         10 . A compound as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof, wherein p is 2 each Y 3  link to form a (3-5C)cycloalkyl ring; 
     
     
         11 . A pharmaceutical composition which comprises a compound of formula (I) as claimed in  claim 1 ), or a pharmaceutically-acceptable salt, thereof, in association with a pharmaceutically-acceptable excipient or carrier. 
     
     
         12 . (canceled) 
     
     
         13 . A method for producing an inhibition of DGAT1 activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) as claimed in  claim 1 , or a pharmaceutically-acceptable salt thereof. 
     
     
         14 . A method of treating diabetes mellitus and/or obesity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) as claimed in  claim 1 , or a pharmaceutically-acceptable salt, thereof. 
     
     
         15 . A process for preparing a compound of Formula (I) as defined in  claim 1  which process comprises
 (a) Suzuki coupling of a pyrazine derivative (IV), wherein X is a leaving group, with a substituted intermediate boron-containing compound of formula (II) wherein E is a boronic acid or derivative thereof: 
 
       
         
           
           
               
               
           
         
         (b) Suzuki coupling of a pyrazine ester (III), wherein P is a protecting group and X is a leaving group, with a substituted intermediate boron-containing compound of formula (II), wherein E is a boronic acid or derivative thereof, followed by removal of the protecting group and conversion to the corresponding primary carboxamide: 
       
       
         
           
           
               
               
           
         
         (c) Suzuki coupling of a phenyl derivative (V-B1), wherein X is a leaving group, with a substituted pyrazine intermediate boron-containing compound of formula (V) wherein E is a boronic acid or derivative thereof: 
       
       
         
           
           
               
               
           
         
         (d) Suzuki coupling of a pyrazine derivative (V-A1), wherein X is a leaving group, with a substituted phenyl intermediate boron-containing compound of formula (VI) wherein E is a boronic acid or derivative thereof: 
       
       
         
           
           
               
               
           
         
         (e) chiral compounds of the invention, wherein p=1, Y 3  is methyl and Z is carboxy, can be prepared by chiral reduction of an alpha methylene acid intermediate (VII) by catalytic hydrogentation to form a compound of formula (I): 
       
       
         
           
           
               
               
           
         
       
       and thereafter if necessary:
 i) converting a compound of Formula (I) into another compound of Formula (I); 
 ii) removing any protecting groups; 
 iii) forming a pharmaceutically acceptable salt.