New azacyclic compounds

Abstract

The invention provides novel compounds having the general formula (I) wherein R 1 , R 2 and n are as described herein, compositions including the compounds and methods of using the compounds. The compounds are useful as inhibitors of hormone sensitive lipase (HSL) for the treatment of diabetes, metabolic syndrome and obesity.

1 . A compound according to formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl and 2-oxo-1,2-dihydro-pyridinyl, and is optionally substituted with one to three substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl and hydroxyhaloalkyl; 
         R 2  is selected from the group consisting of: imidazolyl, pyrazolyl, triazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl and 2-oxo-1,2-dihydro-pyridinyl, and is optionally substituted with one to three substituents independently selected from the group consisting of: alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxyhaloalkyl and benzyloxy; and 
         n is zero, 1, 2 or 3; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  is selected from the group consisting of:
 phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl or 2-oxo-1,2-dihydro-pyridinyl, and is optionally substituted with one to three substituents independently selected from the group consisting of: alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl and hydroxyhaloalkyl.   
     
     
         3 . A compound according to  claim 1 , wherein R 1  is phenyl substituted with one to three haloalkoxy groups. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  is trifluoromethoxyphenyl or 2,2,2-trifluoro-1-methyl-ethoxyphenyl. 
     
     
         5 . A compound according to  claim 1 , wherein R 2  is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, pyrimidyl, pyridazinyl or 2-oxo-1,2-dihydro-pyridinyl, and is optionally substituted with one to three substituents independently selected from the group consisting of: alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxyhaloalkyl and benzyloxy. 
     
     
         6 . A compound according to  claim 1 , wherein R 2  is selected from the group consisting of: phenyl, pyridinyl and 2-oxo-1,2-dihydro-pyridinyl,
 and is optionally substituted with one to three substituents independently selected from the group consisting of: alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy and benzyloxy.   
     
     
         7 . A compound according to  claim 1 , wherein R 2  is pyridinyl or 2-oxo-1,2-dihydro-pyridinyl,
 and is optionally substituted with one to three substituents independently selected from alkyl and hydroxy.   
     
     
         8 . A compound according to  claim 1 , wherein R 2  is selected from the group consisting of:
 2-hydroxypyridinyl, 1-methyl-2-oxo-1,2-dihydro-pyridinyl and 2-oxo-1-propyl-1,2-dihydro-pyridinyl.   
     
     
         9 . A compound according to  claim 1 , wherein n is zero. 
     
     
         10 . A compound according to  claim 1 , selected from the group consisting of:
 8-(2-Fluoro-4-trifluoromethyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Fluoro-5-trifluoromethyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Fluoro-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(3-Trifluoromethoxy-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Chloro-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2,6-Difluoro-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Methoxy-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Methoxy-5-methyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Methoxy-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-fluoro-5-methylpyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-1-one;   8-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-1-one;   8-(2-Oxo-1-propyl-1,2-dihydro-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Hydroxy-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Hydroxy-5-methyl-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Hydroxy-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(6-Benzyloxy-pyridin-2-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(6-Hydroxy-pyridin-2-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(1-Methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-[4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;   and pharmaceutically acceptable salts thereof.   
     
     
         11 . A compound according to  claim 1 , selected from the group consisting of:
 8-(2-Oxo-1-propyl-1,2-dihydro-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one;   8-(2-Hydroxy-phenyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one; and   8-(1-Methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-[4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;   and pharmaceutically acceptable salts thereof.   
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 1  and a therapeutically inert carrier.