Fatty acid synthase inhibitors

Abstract

This invention relates to triazolones and triazolones for the modulation, notably the inhibition of the activity or function of fatty acid synthase (FAS). Suitably, the present invention relates to the use of triazolones in the treatment of cancer.

1 . A compound selected from the group consisting of:
 (S)-3-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-4-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-3-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-3-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-4-(2-fluoro-4-(3-fluoroquinolin-7-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(2-fluoro-4-(3-fluoroquinolin-7-yl)phenyl)-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)-1-methyl-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-1-methyl-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-3-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-1-methyl-1H-1,2,4-triazol-5(4H)-one; and   (S)-4-(2-fluoro-4-(3-fluoroquinolin-7-yl)phenyl)-1-methyl-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         2 . A compound of  claim 1  which is: (S)-4-(2-fluoro-4-(3-methylquinolin-7-yl)phenyl)-1-methyl-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one, having the Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A compound of  claim 1  which is: (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-1-methyl-3-((1-propionylpyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one having the Formula (II) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound of  claim 1  which is: (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-3-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-1-methyl-1H-1,2,4-triazol-5(4H)-one having the Formula (III) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound of  claim 1  which is: (S)-4-(4-(3-chloroquinolin-7-yl)-2-fluorophenyl)-3-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)methyl)-1H-1,2,4-triazol-5(4H)-one having the Formula (IV) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . A compound of  claim 1  wherein said compound has an IC50 for FAS inhibition of <20 nM versus human FAS. 
     
     
         7 . A compound according to  claim 1  with a low or moderate in vivo clearance. 
     
     
         8 . A compound according to  claim 1  with a clearance of less than or equal to 39 mL/min/kg when administered intravenously to a rat. 
     
     
         9 . A compound according to  claim 1  with a clearance of less than 30 mL/min/kg when administered intravenously to a mouse. 
     
     
         10 . A compound according to  claim 1  capable of achieving a DNAUC greater than about 101 ng·h/mL/mg/kg wherein administered orally to a rodent. 
     
     
         11 . A pharmaceutical composition comprising a compound pharmaceutically acceptable salt thereof according to  claim 1 . 
     
     
         12 . A method of treating cancer in a human in need thereof comprising administering to said human a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method of treating cancer in a human in need thereof comprising administering to said human a pharmaceutical composition according to  claim 11 . 
     
     
         14 . The method of  claim 12  wherein the cancer is selected from the group consisting of: gastric, brain (gliomas), glioblastomas, leukemias, lymphomas, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, renal, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, bladder, stomach, and giant cell tumor of bone and thyroid. 
     
     
         15 . A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of
 a) a compound of  claim 1  or a pharmaceutically acceptable salt thereof; and   b) at least one anti-neoplastic agent.   
     
     
         16 . A method of treating cancer in a human in need thereof comprising administering a compound of Formula (I), Formula (II), Formula (III) and/or Formula IV or pharmaceutically acceptable salt thereof orally to said human at a dose of about 0.001 to about 100 mg/kg/day.