3-(5-chloro-2-oxobenzo[d]oxazol-3(2h)-yl) propanoic acid derivatives as kmo inhibitors

Abstract

A compound of formula (I) or a salt thereof are provided: wherein R 1 , X and R 3 are defined in the specification, useful in the treatment of disorders mediated by KMO such as acute pancreatitis, chronic kidney disease, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure.

1 . (canceled) 
     
     
         2 . A compound of formula (I) or a salt thereof 
       
         
           
           
               
               
           
         
         wherein: 
         X is a bond and R 1  is —H, -halo or —CN; or 
         X is —CH 2 — and R 1  is —H or —C 1-3 alkyl; or 
         X is —O— and R 1  is —C 1-4 alkyl, —(CH 2 ) m CF 3 , —CHR 2 CH 2 OMe, —(CH 2 ) n C 3-4 cycloalkyl, —(CH 2 ) n oxetane, -benzyl or —CHR 2 heteroaryl; wherein heteroaryl may be additionally substituted by halo, methyl, ethyl or O; 
         m=1 or 2; 
         n=0 or 1; 
         R 2 =—H, -methyl or -ethyl; and 
         R 3 ═H or -methyl, 
         provided that the compound of formula (I) or a salt thereof is not 3-(5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid or 3-(5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)-2-methylpropanoic acid. 
       
     
     
         3 . A compound of formula (I) as defined in  claim 2  wherein X is —CH 2 — and R 1  is —H or —C 1-3 alkyl. 
     
     
         4 . A compound of formula (I) as defined in  claim 2  wherein X is —CH 2 — and R 1  is —H. 
     
     
         5 . A compound of formula (I) as defined in  claim 2  wherein X is —O— and R 1  is —C 1-4 alkyl, —(CH 2 ) m CF 3 , —CHR 2 CH 2 OMe, —(CH 2 ) n C 3-4 cycloalkyl, —(CH 2 ) n oxetane, -benzyl or —CHR 2 heteroaryl; wherein heteroaryl may be additionally substituted by methyl or O. 
     
     
         6 . A compound of formula (I) as defined in  claim 2 , wherein X is —O— and R1 is —CHR2heteroaryl. 
     
     
         7 . A compound of formula (I) or a salt thereof which is a compound selected from the group consisting of:
 3-(5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   (S)-3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5,6-dichloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-methoxy-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-cyano-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(6-bromo-5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-ethoxy-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-ethyl-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-isobutoxy-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-(cyclopropylmethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-(cyclobutylmethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(6-(benzyloxy)-5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-(2-methoxyethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-2-oxo-6-propoxybenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-2-oxo-6-(3,3,3-trifluoropropoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-2-oxo-6-(pyridin-2-ylmethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-isopropoxy-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-cyclobutoxy-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-cyclopropoxy-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-2-oxo-6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-(oxetan-3-yloxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-isobutyl-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-(oxetan-3-ylmethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((1-methoxypropan-2-yl)oxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-((6-methyl pyridin-3-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-((2-methyl pyridin-4-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   2-(((3-(2-carboxyethyl)-5-chloro-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)oxy)methyl)pyridine 1-oxide;   3-(5-chloro-6((1-methyl-1H-imidazol-2-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-((2-methyl pyridin-3-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-2-oxo-6-(pyrimidin-2-ylmethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((2-methyloxazol-5-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((5-methyloxazol-2-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(6-((1H-imidazol-2-yl)methoxy)-5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid; and   3-(5-chloro-2-oxo-6-(pyridazin-3-ylmethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6-(1-(2-methyloxazol-5-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid (racemic);   (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((5-fluoropyridin-2-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((5-chloropyridin-2-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((5-methylpyridin-2-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-6-(1-(6-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)propoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-6-(1-(4-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-2-oxo-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   (S)-3-(5-chloro-2-oxo-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid;   3-(5-chloro-6((6-methylpyridazin-3-yl)methoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid;   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)-2-methylpropanoic acid;   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)-2-methylpropanoic acid;   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)-2-methylpropanoic acid;   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)-2-methylpropanoic acid;   3-(5-chloro-2-oxo-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoic acid (single unknown enantiomer);   (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid; and   (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A compound of formula (I) which is 3-(5-chloro-6-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid of formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . A compound of formula (I) or a pharmaceutically acceptable salt thereof which is the 2-amino-2-(hydroxymethyl)-1,3-propanediol salt of 3-(5-chloro-6-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid of formula 
       
         
           
           
               
               
           
         
       
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A method of treatment of conditions or disorders mediated by KMO which comprises administering to a host in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 1  or  claim 7 . 
     
     
         16 . A method of treatment of acute pancreatitis, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy, or acute renal failure which comprises administering to a host in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 1  or  claim 7 . 
     
     
         17 . A pharmaceutical composition comprising a) a compound as defined in  claim 1  or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients. 
     
     
         18 . A pharmaceutical composition according to  claim 17  comprising 3-(5-chloro-6-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method of treating acute pancreatitis, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure in a host, the method comprising administering to the host a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 1  or  claim 7  and one or more pharmaceutically acceptable excipients.