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.

What is claimed is: 
     
       1. A compound having the formula: 
       
         
           
           
               
               
           
         
         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, 
         wherein R 1  is selected from the group consisting of C 3 -C 4  alkyl, C 3 -C 5  cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein each R 1  is optionally substituted with from 1-2 R a . 
       
     
     
       2. A compound of  claim 1 , 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, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein each R′ is optionally substituted with from 1-3 R a ;   R 2  is phenyl, which 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 1-2 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, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —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 and C 1 -C 4  alkyl 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, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —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 and C 1 -C 2  alkoxy.   
     
     
       3. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is H. 
     
     
       4. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of C 3 -C 4  alkyl, C 3 -C 5  cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein each R 1  is optionally substituted with from 1-2 R a . 
     
     
       5. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R 1  is optionally substituted with from 1-3 R a . 
     
     
       6. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of C 3 -C 4  alkyl, C 3 -C 5  cycloalkyl, and 4- to 6-membered heterocycloalkyl. 
     
     
       7. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 4- to 6-membered heterocycloalkyl, optionally substituted with from 1-2 R a  selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —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 and C 1 -C 4  alkyl. 
     
     
       8. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of cyclobutyl, isopropyl, isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and 1-methyl-3-pyrazolyl. 
     
     
       9. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is optionally substituted with from 1-2 R b . 
     
     
       10. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from the group consisting of phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl, 3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, and 3-(1,2,4-triazol-1-yl)phenyl. 
     
     
       11. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxyalkyl, and C 3 -C 4  cycloalkyl. 
     
     
       12. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and 2-methoxymethyl. 
     
     
       13. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is methyl. 
     
     
       14. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is isopropyl; R 2  is optionally substituted with 1-2 R b ; and R 3  is methyl. 
     
     
       15. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 4- to 6-membered heterocycloalkyl, optionally substituted with from 1-2 R a  selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —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 and C 1 -C 4  alkyl; R 2  is optionally substituted with 1-2 R b ; and R 3  is methyl. 
     
     
       16. A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R 1  is optionally substituted with from 1-3 R a ; R 2  is optionally substituted with from 1-2 R b ; and R 3  is methyl. 
     
     
       17. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
       18. A compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       19. A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       20. A compound having the structure 
       
         
           
           
               
               
           
         
        
       
     
     
       21. A pharmaceutically acceptable salt of a compound having the structure 
       
         
           
           
               
               
           
         
        
       
     
     
       22. A pharmaceutical composition comprising:
 the compound according to claim 20; and   a pharmaceutically acceptable excipient.   
     
     
       23. A pharmaceutical composition comprising:
 the pharmaceutically acceptable salt according to claim 21; and   a pharmaceutically acceptable excipient.