Ghrelin o-acyltransferase inhibitors

Abstract

This invention relates to novel compounds according to Formula (I) which are inhibitors of ghrelin O-acyltransferase (GOAT), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of metabolic disorders (e.g. Prader-Willi syndrome, metabolic syndrome, insulin resistance, impaired glucose tolerance, prediabetes, diabetes mellitus (e.g., type II diabetes mellitus), dysglycemia (e.g., hyperglycemia), obesity (e.g., obesity caused by Prader-Willi syndrome), increased adiposity, poor glycemic control, hyperphagia, impaired satiety, dyslipidemia (e.g., atherogenic dyslipidemia), hepatic steatosis (e.g., non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis))), psychiatric disorders (e.g., eating disorders (e.g., bulimia nervosa, binge eating disorder, night-time eating syndrome), substance related disorders (e.g., addiction disorders (e.g., alcohol, smoking, overeating, or use of illicit drugs))), as well as disorders related to or complications of metabolic or psychiatric disorders (e.g., cardiovascular diseases (e.g., diabetic heart disease (e.g., diabetic cardiomyopathy), heart failure, or hypertension), ischemia (e.g., myocardial ischemia, cerebral ischemia, ischemic stroke), or BMI-related cancers (e.g., pancreatic cancer, gallbladder cancer, esophageal cancer, colorectal cancer, breast cancer etc.).

1 - 30 . (canceled) 
     
     
         31 . A method of preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, or —C(═O)NH 2 ; 
 X is CH 2  or O; 
 R 2  is halogen; and 
 R 3  is hydrogen or halogen; 
 
         comprising hydrolyzing a compound of Formula (IV): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  is hydrogen, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, or —C(═O)NH 2 ; 
 X is CH 2  or O; 
 R 2  is halogen; 
 R 3  is hydrogen or halogen; and 
 R 4  is (C 1 -C 4 )alkyl; 
 
         in the presence of water and a base. 
       
     
     
         32 . The method of  claim 31 , wherein the compound of Formula (I) is of the Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The method of  claim 31 , wherein the compound of Formula (I) is of the Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The method of  claim 31 , wherein the base is a hydroxide base. 
     
     
         35 . The method of  claim 34 , wherein the hydroxide base is lithium hydroxide. 
     
     
         36 . The method of  claim 34 , wherein the hydroxide base is sodium hydroxide. 
     
     
         37 . The method of  claim 31 , further comprising a solvent. 
     
     
         38 . The method of  claim 37 , wherein the solvent comprises an alcohol. 
     
     
         39 . The method of  claim 38 , wherein the solvent further comprises water. 
     
     
         40 . The method of  claim 38 , wherein the alcohol is methanol. 
     
     
         41 . The method of  claim 31 , wherein the compound of Formula (IV) is of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         42 . The method of  claim 31 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . A method of preparing a compound of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  is hydrogen, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, or —C(═O)NH 2 ; 
 X is CH 2  or O; 
 R 2  is halogen; 
 R 3  is hydrogen or halogen; and 
 R 4  is (C 1 -C 4 )alkyl; 
 
         comprising contacting a first compound of the formula: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         R 1  is hydrogen, halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, or —C(═O)NH 2 ; 
         X is CH 2  or O; and 
         R 5  is —OH, or —Cl; 
         with a second compound of the formula: 
       
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         44 . The method of  claim 43 , wherein the first compound is of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         45 . The method of  claim 43 , wherein the first compound is of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         46 . The method of  claim 43 , wherein the first compound is of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         47 . The method of  claim 43 , wherein the second compound is of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         48 . The method of  claim 43 , further comprising contacting the compounds in the presence of a base. 
     
     
         49 . The method of  claim 48 , wherein the base is potassium carbonate. 
     
     
         50 . The method of  claim 43 , further comprising contacting the compounds in the presence of a phosphine.