Azacycloalkane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase

Abstract

Azacycloalkane derivatives of structural formula I are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; and liver steatosis.

1 - 23 . (canceled) 
   
   
       24 . A compound of structural formula I: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
       each m is independently an integer from 0 to 4; 
       each n is independently an integer from 0 to 2; 
       each s is independently an integer from 1 to 3; 
       each t is independently an integer from 1 to 3; 
       q is 0 or 1; 
       r is 0 or 1; 
       Z is O, S, or NR 4 ; 
       X—Y is N—CR a R b , CR 14 —O, CR 14 —S(O) 0-2 , or CR 13 —CR a R b ; 
       W is heteroaryl selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       Ar is phenyl, naphthyl, or heteroaryl optionally substituted with one to five R 3  substituents; 
       R a  and R b  are each independently hydrogen or C 1-3  alkyl, wherein alkyl is optionally substituted with one to three substituents independently selected from fluorine and hydroxy; 
       R 1  is heteroaryl selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       wherein R c  is —(CH 2 ) m CO 2 H, —(CH 2 ) m CO 2 C 1-3  alkyl, —(CH 2 ) m -Z-(CH 2 ) p CO 2 H, or —(CH 2 ) m -Z-(CH 2 ) p CO 2 C 1-3  alkyl, wherein each (CH 2 ) methylene group is optionally substituted with one or two substituents selected from the group consisting of C 1-4  alkyl, fluorine, oxo, and hydroxy; and wherein said R 1  heteroaryl ring is optionally substituted with one substituent independently selected from the group consisting of cyano, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfonyl, and trifluoromethyl; 
       each R 2  is independently selected from the group consisting of:
 hydrogen, 
 halogen, 
 hydroxy, 
 cyano, 
 amino, 
 nitro, 
 C 1-4  alkyl, optionally substituted with one to five fluorines, 
 C 1-4  alkoxy, optionally substituted with one to five fluorines, 
 C 1-4  alkylthio, optionally substituted with one to five fluorines, 
 C 1-4  alkylsulfonyl, 
 carboxy, 
 C 1-4  alkyloxycarbonyl, and 
 C 1-4  alkylcarbonyl; 
 
       each R 3  is independently selected from the group consisting of:
 C 1-6  alkyl, 
 C 2-6  alkenyl, 
 (CH 2 ) n -phenyl, 
 (CH 2 ) n -naphthyl, 
 (CH 2 ) n -heteroaryl, 
 (CH 2 ) n -heterocyclyl, 
 (CH 2 ) n C 3-7  cycloalkyl, 
 halogen, 
 nitro, 
 (CH 2 ) n OR 4 , 
 (CH 2 ) n N(R 4 ) 2 , 
 (CH 12 ) n C≡N, 
 (CH 2 ) n CO 2 R 4 , 
 (CH 2 ) n NR 4 SO 2 R 4    
 (CH 2 ) n SO 2 N(R 4 ) 2 , 
 (CH 2 ) n S(O) 0-2 R 4 , 
 (CH 2 ) n NR 4 C(O)N(R 4 ) 2 , 
 (CH 2 ) n C(O)N(R 4 ) 2 , 
 (CH 2 ) n NR 4 C(O)R 4 , 
 (CH 2 ) n NR 4 CO 2 R 4 , 
 (CH 2 ) n C(O)R 4 , 
 O(CH 2 ) n C(O)N(R 4 ) 2 , 
 (CH 2 ) s -Z-(CH 2 ) t -phenyl 
 (CH 2 ) s -Z-(CH 2 ) t -naphthyl, 
 (CH 2 ) s -Z-(CH 2 ) t -heteroaryl, 
 (CH 2 ) s -Z-(CH 2 ) t -heterocyclyl, 
 (CH 2 ) s -Z-(CH 2 ) t —C 3-7  cycloalkyl, 
 (CH 2 ) s -Z-(CH 2 ) t —OR 4 , 
 (CH 2 ) s -Z-(CH 2 ) t —N(R 4 ) 2 , 
 (CH 2 ) s -Z-(CH 2 ) t —NR 4 SO 2 R 4 , 
 (CH 2 ) s -Z-(CH 2 ) t —C≡N, 
 (CH 2 ) s -Z-(CH 2 ) t —CO 2 R 4 , 
 (CH 2 ) s -Z-(CH 2 ) t —SO 2 N(R 4 ) 2 , 
 (CH 2 ) s -Z-(CH 2 ) t —S(O) 0-2 R 4 , 
 (CH 2 ) s -Z-(CH 2 ) t —NR 4 C(O)N(R 4 ) 2 , 
 (CH 2 ) s -Z-(CH 2 ) t —C(O)N(R 4 ) 2 , 
 (CH 2 ) s -Z-(CH 2 ) t —NR 4 C(O)R 4 , 
 (CH 2 ) s -Z-(CH 2 ) t —NR 4 CO 2 R 4 , 
 (CH 2 ) s -Z-(CH 2 ) t —C(O)R 4 , 
 CF 3 , 
 CH 2 CF 3 , 
 OCF 3 , and 
 OCH 2 CF 3 ; 
 
       in which phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4  alkyl, trifluoromethyl, and C 1-4  alkoxy; and wherein any methylene (CH 12 ) carbon atom in R 3  is optionally substituted with one to two groups independently selected from fluorine, hydroxy, and C 1-4  alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; 
       each R 4  is independently selected from the group consisting of
 hydrogen, 
 C 1-6  alkyl, 
 (CH 2 ) n -phenyl, 
 (CH 2 ) n -heteroaryl, 
 (CH 2 ) n -naphthyl, and 
 (CH 2 ) n C 3-7  cycloalkyl; 
 
       wherein alkyl, phenyl, heteroaryl, and cycloalkyl are optionally substituted with one to three groups independently selected from halogen, trifluoromethyl, C 1-4  alkyl, and C 1-4  alkoxy; or 
       two R 4  groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, NH, and NC 1-4  alkyl; 
       R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are each independently hydrogen, fluorine, or C 1-3  alkyl, wherein alkyl is optionally substituted with one to three substituents independently selected from fluorine and hydroxy; 
       R 13  is hydrogen, C 1-3  alkyl, fluorine, or hydroxy; and 
       each R 14  is hydrogen or C 1-3  alkyl. 
     
   
   
       25 . The compound of  claim 24  wherein m is 1 or 2. 
   
   
       26 . The compound of  claim 24  wherein q and r are both 1. 
   
   
       27 . The compound of  claim 24  wherein X—Y is CH—O. 
   
   
       28 . The compound of  claim 27  wherein Ar is phenyl substituted with one to three R 3  substituents. 
   
   
       29 . The compound of  claim 24  wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are each hydrogen. 
   
   
       30 . The compound of  claim 24  wherein each R 2  is hydrogen. 
   
   
       31 . The compound of  claim 24  wherein R 1  is heteroaryl selected from the group consisting of 
     
       
         
         
             
             
         
       
       wherein R c  is —CH 2 CO 2 H or —CH 2 CO 2 C 1-3  alkyl. 
     
   
   
       32 . The compound of  claim 31  wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       33 . The compound of  claim 24  wherein q and r are both 1; X—Y is CH—O; W is heteroaryl selected from the group consisting of: 
     
       
         
         
             
             
         
       
       and R 1  is heteroaryl selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       wherein R c  is —CH 2 CO 2 H or —CH 2 CO 2 C 1-3  alkyl. 
     
   
   
       34 . The compound of  claim 33  wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are each hydrogen. 
   
   
       35 . A compound which is selected from the group consisting 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       36 . A pharmaceutical composition comprising a compound in accordance with  claim 24  in combination with a pharmaceutically acceptable carrier. 
   
   
       37 . A method for treating Type 2 diabetes in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 24 . 
   
   
       38 . A method for treating obesity in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 24 .