Compounds for the prevention and treatment of cardiovascular diseases

Abstract

The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use for treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.

1 .- 30 . (canceled) 
     
     
         31 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         X is CR 11 ; 
         Y is CO; 
         R 11  is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl; 
         R 1  and R 3  are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen; 
         R 2  is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen; 
         R 6  and R 8  are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; 
         R 5  and R 9  are each hydrogen; 
         R 7  is selected from amide, alkyl, hydroxyl, and alkoxy; 
         R 10  is selected from hydrogen and methyl; 
         for W—(R 10 ) p , W is N and p is 1; 
         for W—(R 7 ) p , W is C and p is 1; 
         for W—(R 4 ) p , W is C, p is 1 and R 4  is H; 
         each other W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1; 
         Z 1  is a double bond, and Z 2  and Z 3  are each a single bond; 
         with the proviso that if R 1  is hydrogen, then R 3  is alkoxy; 
         with the proviso that if R 3  is hydrogen, then R 1  is selected from amino and alkoxy; 
         with the proviso that if R 7  is selected from alkyl, hydroxyl, and alkoxy, then at least one of R 6  and R 8  is independently selected from alkyl, alkoxy, amino, and halogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 .- 33 . (canceled) 
     
     
         34 . The compound according to  claim 31 , or a pharmaceutically acceptable salt thereof, wherein for W—(R 10 ) p , W is N and R 10  is hydrogen; and
 R 7  is selected from hydroxyl and alkoxy. 
 
     
     
         35 . The compound according to  claim 34 , wherein the compound of Formula II 3-(4-hydroxy-3,5-dimethyl phenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one or a pharmaceutically salt thereof. 
     
     
         36 . The compound according to  claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 6  and R 8  are each independently alkyl;
 R 2  is hydrogen; and   R 7  is selected from hydroxyl and alkoxy substituted with a hydroxyl.   
     
     
         37 . The compound according to  claim 36 , wherein the compound of Formula II is 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The compound according to  claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 7  is an alkoxy selected from the group represented by Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is O; 
 n is selected from 0, 1, 2, 3, 4 and 5; 
 B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, —C(O)O—, wherein each R h  is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and 
 R 20  is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. 
 
     
     
         39 . (canceled) 
     
     
         40 . The compound according to  claim 31 , wherein the compound of Formula II is selected from:
 3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         41 . A compound selected from:
 3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one;   4-Isoquinolin-3-yl-phenol;   4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate tetrahydrochloride;   4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate trihydrochloride;   4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol;   4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine;   or a pharmaceutically acceptable salt thereof.   
     
     
         42 . A pharmaceutical composition comprising a compound according to  claim 31 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         43 .- 44 . (canceled) 
     
     
         45 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         X is CH; 
         Y is CO; 
         R 1  and R 3  are each independently selected from alkoxy and hydrogen; 
         R 2  is selected from alkoxy, alkyl, and hydrogen; 
         R 6  and R 8  are each independently selected from alkyl, alkoxy, chloride, and hydrogen; 
         R 5  and R 9  are each hydrogen; 
         R 7  is selected from hydroxyl, alkoxy, and alkyl substituted with a heterocyclyl; 
         R 10  is hydrogen; or 
         two adjacent substituents selected from R 6 , R 7 , and R 8  are connected to form a heterocyclyl; 
         for W—(R 10 ) p , W is N and p is 1; 
         for W—(R 4 ) p , W is C, p is 1 and R 4  is H; 
         each other W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1; 
         Z 1  is a double bond, and Z 2  and Z 3  are each a single bond; 
         with the proviso that if R 2  is alkoxy or hydrogen, then least one of R 1  and R 3  is alkoxy; 
         with the proviso that if R 7  is selected from hydroxyl and alkoxy, then at least one of R 6  and R 8  are independently selected from alkyl, alkoxy, and chloride; 
         with the proviso that if for W—(R 7 ) p , W is N and p is 0, then at least one of R 6  and R 8  is selected from alkyl, alkoxy, and chloride; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . The compound according to  claim 45 , wherein the compound of Formula II is selected from:
 3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;   3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;   3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;   3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         47 . The compound according to claim  43 , or a pharmaceutically acceptable salt thereof, wherein R 7  is an alkoxy selected from the group represented by Formula III: 
       
         
           
           
               
               
           
         
         wherein:
 A is O; 
 n is selected from 0, 1, 2, 3, 4 and 5; 
 B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, and —C(O)O—, wherein each R h  is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and 
 R 20  is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. 
 
       
     
     
         48 . (canceled) 
     
     
         49 . A pharmaceutical composition comprising a compound according to  claim 45 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         50 .- 51 . (canceled) 
     
     
         52 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         X is CR 11 ; 
         Y is CO; 
         R 11  is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl; 
         R 1  and R 3  are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen; 
         R 2  is selected from —N—C(O)—R 18 , —N—SO 2 —R 18 , —CH 2 —C(R 18 ) 3 , —CH 2 —N(R 18 ) 2 , and —CH 2 —O—R 18 , wherein each R 18  is independently selected from alkoxy, alkyl, alkenyl, amide, amino, aryl, arylalkyl, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, and hydrogen; 
         R 6  and R 8  are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; 
         R 5  and R 9  are each hydrogen; 
         R 7  is selected from amino, amide, alkyl, hydroxyl, and alkoxy; 
         R 10  is selected from hydrogen and methyl; 
         for W—(R 10 ) p , W is N and p is 1; 
         for W—(R 7 ) p , W is C and p is 1; 
         for W—(R 4 ) p , W is C, p is 1 and R 4  is H; 
         each other W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1; 
         Z 1  is a double bond, and Z 2  and Z 3  are each a single bond; 
         with the proviso that if R 7  is selected from alkyl, hydroxyl, and alkoxy, then at least one of R 6  and R is independently selected from alkyl, alkoxy, amino, and halogen; 
         and pharmaceutically acceptable salts and hydrates thereof. 
       
     
     
         53 .- 54 . (canceled) 
     
     
         55 . The compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, wherein X is CH for W—(R 10 ) p , W is N and R 10  is hydrogen; and R 7  is selected from hydroxyl and alkoxy. 
     
     
         56 . The compound according to  claim 55 , wherein the compound of Formula II is selected from:
 3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one;   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl) isoquinolin-1(2H)-one; and   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         57 . The compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, wherein R 6  and R 8  are each independently alkyl; and R 7  is selected from hydroxyl and alkoxy. 
     
     
         58 . The compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, wherein R 7  is selected from an amino or an alkoxy selected from the group represented by Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is selected from O and N; 
 n is selected from 0, 1, 2, 3, 4 and 5; 
 B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, —C(O)O—, wherein each R h  is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and 
 R 20  is selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. 
 
     
     
         59 . The compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, wherein R 6  and R 8  are each independently alkyl. 
     
     
         60 . A pharmaceutical composition comprising a compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         61 .- 75 . (canceled)