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 . 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-C1-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. 
       
     
     
         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 1  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 method of treating hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method of treating a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled)