Pyrimidinedione compounds

Abstract

Provided are novel pyrimidine dione compounds and pharmaceutically acceptable salts thereof, that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds and pharmaceutically acceptable salts thereof, are described, as well as methods for treating HCM and other forms of heart disease.

1 - 22 . (canceled) 
     
     
         23 . A process for preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is a member selected from the group consisting of C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl-C 1 -C 4  alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C 1 -C 4  alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C 1 -C 4  alkyl, wherein each R 1  is optionally substituted with from 1-3 R a ; 
 R 2  is a member selected from the group consisting of phenyl, phenyl-C 1 -C 4  alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C 1 -C 4  alkyl, wherein each R 2  is optionally substituted with from 1-5 R b ; 
 R 3  is a member selected from the group consisting of C 1 -C 4  alkyl, C 3 -C 4  cycloalkyl, and 4- to 7-membered heterocycloalkyl wherein each R 3  is optionally substituted with from 1-3 R c ; 
 R 4  is H; 
 X is a member selected from the group consisting of H and F; 
 each R a  is independently selected from the group consisting of halo, CN, hydroxyl, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, phenyl, phenyl-C 1 -C 4  alkyl, phenyl-C 1 -C 4  alkoxy, phenoxy, —COR a1 , —CO 2 R a1 , —SO 2 R a1 , —SO 2 NR a1 R a2 , and —CONR a1 R a2 , wherein each R a1  and R a2  is independently selected from the group consisting of H, C 1 -C 4  alkyl, and phenyl or optionally R a1  and R a2  when attached to a nitrogen atom are combined to form a 4- to 6-membered ring; 
 each R b  is independently selected from the group consisting of halo, CN, hydroxyl, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, phenoxy, phenyl-C 1 -C 4  alkoxy, methylenedioxy, difluoromethylenedioxy, —COR b1 , —CO 2 R b1 , —SO 2 R b1 , —SO 2 NR b1 R b2 , CONR b1 R b2 , NR b1 R b2 , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted with oxo, wherein each R b1  and R b2  is independently selected from the group consisting of H and C 1 -C 4  alkyl or optionally R b1  and R b2  when attached to a nitrogen atom are combined to form a 4- to 6-membered ring; and 
 each R c  is independently selected from the group consisting of halo, hydroxyl and C 1 -C 2  alkoxy; 
 the process comprising: 
 reacting a compound of formula vi with a compound of formula vii to form the compound of Formula (I) 
 
       
         
           
           
               
               
           
         
         wherein Lg is a leaving group. 
       
     
     
         24 . The process of  claim 23 , wherein Lg is a halogen. 
     
     
         25 . The process of  claim 23 , further comprising derivatizing a compound of formula v with a leaving group to form the compound of formula vi 
       
         
           
           
               
               
           
         
       
     
     
         26 . The process of  claim 24 , further comprising derivatizing a compound of formula v with a leaving group to form the compound of formula vi 
       
         
           
           
               
               
           
         
       
     
     
         27 . The process of  claim 25 , further comprising reacting a compound of formula iii with a compound of formula iv in a condensation reaction to form the compound of formula v 
       
         
           
           
               
               
           
         
       
     
     
         28 . The process of  claim 26 , further comprising reacting a compound of formula iii with a compound of formula iv in a condensation reaction to form the compound of formula v 
       
         
           
           
               
               
           
         
       
     
     
         29 . The process of  claim 23 , further comprising preparing the compound of formula vii by reacting a compound of formula ix with a compound of formula x to form a compound of formula xii, reacting the compound of formula xii with a compound of formula xiii to form a compound of formula xiv, and converting the compound of formula xiv to the compound of formula vii 
       
         
           
           
               
               
           
         
       
     
     
         30 . The process of  claim 28 , further comprising preparing the compound of formula vii by reacting a compound of formula ix with a compound of formula x to form a compound of formula xii, reacting the compound of formula xii with a compound of formula xiii to form a compound of formula xiv, and converting the compound of formula xiv to the compound of formula vii 
       
         
           
           
               
               
           
         
       
     
     
         31 . The process of  claim 23 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 . The process of  claim 30 , wherein the compound of Formula (I) is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . A process of preparing a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the process comprising: 
         reacting a compound of formula: 
       
       
         
           
           
               
               
           
         
         with a compound of formula: 
       
       
         
           
           
               
               
           
         
         to produce the compound of formula: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The process of  claim 33 , further comprising reacting a compound of formula: 
       
         
           
           
               
               
           
         
         with POCl 3  to produce the compound of formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         35 . The process of  claim 34 , further comprising reacting a compound of formula: 
       
         
           
           
               
               
           
         
         with dimethyl malonate to produce the compound of formula: