Compounds for the prevention and treatment of cardiovascular disease

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein

Y is carbon;

W is nitrogen;

R a 6 is selected from fluoride, hydrogen, C 1 -C 3 alkoxy, cyclopropyloxy, SO 2 R 3 , SOR 3 , and SR 3 , wherein if Y is nitrogen then Ra 6 is absent;

R a 7 is selected from hydrogen, fluoride, SO 2 R 3 , SOR 3 , and SR 3 ;

R a 8 is selected from hydrogen, C 1 -C 3 alkoxy, cyclopropyloxy, chloride, and bromide;

AR is

n is selected from 1, 2, or 3;

D is selected from O, NH, NR 1 , S, or C;

R b 3 and R b 5 are independently selected from hydrogen and C 1 -C 3 alkyl;

R c 3 and R c 5 are independently selected from hydrogen, C 1 -C 3 alkyl, and cyclopropyl;

R c 4 is selected from F, Cl, Br, I, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, NHC(O)R 4 , NHSO 2 R 4 , C(O)OR 4 , and

R 1 , R′ 1 , R 2 and R′ 2 are independently selected from hydrogen, fluoride, C 1 -C 3 alkyl, and cyclopropyl, wherein R 1 and R 2 and/or R′ 1 and R′ 2 may be connected to form a 3-6 membered ring;

R 3 is selected from C 1 -C 3 alkyl and cyclopropyl; and

R 4 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, and aryl, provided that if R a 7 or R a 6 is fluoride, then R c 4 is not bromide.

2. The compound according to claim 1 , wherein R c 4 is selected from F, Cl, Br, I, CF 3 , C 1 -C 6 alkyl, cyclohexyl, —NHC(O)R 4 , —NHSO 2 R 4 , —C(O)OR 4 , and

wherein

R 4 is selected from hydrogen, C 1 -C 4 alkyl, and aryl; and

R 1 and R 2 are independently selected from hydrogen and C 1 -C 3 alkyl.

3. A compound of Formula II:

or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof wherein:

W is carbon or nitrogen;

AR is

T is carbon or nitrogen;

R a 6 , R a 7 , and R a 8 are independently selected from hydrogen and fluoride;

R b 4 is selected from hydrogen, Cl, Br, F, CF 3 , C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 4 alkoxy, C 3 -C 5 cycloalkoxy, methoxy, -Oaryl, phenyl, CH 2 OH, —CH 2 morpholino, morpholino, piperidinyl, —CH 2 piperazino, —CH 2 (N-methylpiperazino), —NR 1 R 2 , and —CH 2 NR 1 R 2 ;

R b 5 is selected from hydrogen, Cl, Br, F, aryl, and —NR 1 R 2 , wherein R b 4 and R b 5 may be connected to form a ring;

R c 4 is selected from Cl, Br, C 2 -C 5 alkyl, C 3 -C 5 cycloalkyl, —SR 1 , —NHSO 2 R 1 , —NR 1 R 2 ; and

R 1 and R 2 are independently selected from C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl wherein R 1 and R 2 may be connected to form a 3-6-membered ring, provided that

if R b 4 is fluoride, phenyl, methoxy, CH 2 OH, —CH 2 morpholino, morpholino, —CH 2 piperazino, or —CH 2 (N-methylpiperazino) then R c 4 is not chloride;

if R a 7 or R a 6 is fluoride, then R c 4 is not bromide;

if R b 5 is fluoride then R c 4 is not chloride;

if R c 4 is chloride or bromide, then at least one of R b 2 , R b 4 , or R b 5 is not hydrogen;

if T is N, then R c 4 is not halogen; and

if AR is

 then R c 4 is not sec-butyl.

4. The compound according to claim 3 , wherein R a 5 , R a 7 , and R a 8 are each hydrogen.

5. The compound according to claim 3 , wherein R b 4 and R b 5 together to which the atoms they are bound form a phenyl ring.

6. A compound of Formula III:

or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof wherein:

W is nitrogen;

AR is selected from:

T, U, and V are independently selected from carbon and nitrogen;

R 1 is selected from hydrogen, C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl, and —SO 2 R 3 ;

R 2 is selected from hydrogen, C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl, and CH 2 OH;

R 3 is selected from hydrogen, C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl, and optionally substituted aryl;

R 4 is selected from hydrogen, C 1 -C 5 alkyl, and C 3 -C 5 cycloalkyl;

R 5 is selected from hydrogen, C 1 -C 5 alkyl, and C 3 -C 5 cycloalkyl;

R a 5 , R a 6 , R a 7 , and R a 8 are independently selected from hydrogen and fluoride;

R b 2 and R b 3 are independently selected from hydrogen, F, Cl, Br, C 1 -C 3 alkyl, cyclopropyl, and C 1 -C 3 alkoxy; and

R c 4 is selected from C 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, F, Cl, Br, I, OCF 3 , and —NR 4 R 5 , provided that

if R 1 is methyl, then R c 4 is not sec-butyl; and

if R 2 is CH 2 OH, then R c 4 is not Cl.

7. The compound according to claim 6 , wherein T is nitrogen and U and V are both carbon.

8. The compound according to claim 6 , wherein T is carbon and U and V are both carbon.

9. The compound according to claim 6 , wherein T is carbon, U is carbon, and V is nitrogen.

10. A compound selected from the group consisting of:

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)phenyl)quinazolin-4(3H)-one;

3-(4-fluorophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-iodophenyl)quinazolin-4(3H)-one;

3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-6-fluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one,

3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-7-fluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-(methylsulfonyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-(methylsulfonyl)quinazolin-4(3H)-one;

3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;

3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one,

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-isopropylphenyl)quinazolin-4(3H)-one;

3-(4-bromophenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;

3-(4-bromophenyl)-8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3-(4-morpholinophenyl)quinazolin-4(3H)-one;

3-(4-tert-butylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)isobutyramide;

Methyl 4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)benzoate;

3-(4-cyclohexylphenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)formamide;

3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)methanesulfonamide;

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)p

N-(4-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)propane-2-sulfonamide;

3-(4-(dimethylamino)phenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(4-(2-hydroxyethoxy)-3-methylphenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(quinolin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(5-fluoropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-methoxypyridin-3-yl)quinazolin-4(3H)-one;

2-(6-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one;

2-(6-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(pyrimidin-5-yl)quinazolin-4(3H)-one,

3-(4-sec-butylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(6-phenoxypyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-fluoropyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-phenoxypyridin-3-yl)quinazolin-4(3H)-one,

3-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-phenylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(5-phenylpyridin-3-yl)quinazolin-4(3H)-one;

2-(5-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one;

2-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(5-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(5-phenylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(5-(diethylamino)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-cyclopentylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3-yl)quinazolin-4(3H)-one;

2-(6-methylpyridin-3-yl)-3-(4-(methylthio)phenyl)quinazolin-4(3H)-one;

3-(4-isopropylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

N-(4-(2-(6-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl)phenyl)methanesulfonamide;

3-(4-sec-butylphenyl)-2-(6-(morpholinomethyl)pyridin-3-yl)quinazolin-4(3H)-one;

3-(4-cyclopropylphenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

3-(4-(dimethylamino)phenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;

2-(6-chloropyridin-3-yl)-3-(4-cyclopropylphenyl)quinazolin-4(3H)-one; and

3-(4-sec-butylphenyl)-2-(6-morpholinopyridin-3-yl)quinazolin-4(3H)-one,

3-(4-sec-butylphenyl)-2-(1H-indazol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-6-yl)quinazolin-4(3H)-one;

2-(1H-indol-5-yl)-3-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one;

2-(1H-indol-5-yl)-3-(4-isopropylphenyl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-(4-methoxyphenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-(4-fluorophenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4(3H)-one;

3-(4-(dimethylamino)phenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(2-(hydroxymethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1-methyl-1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-cyclopentylphenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-6-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-7-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(1H-indol-6-yl)quinazolin-4(3H)-one;

3-(4-sec-butylphenyl)-2-(1H-indol-7-yl)quinazolin-4(3H)-one;

3-(4-chlorophenyl)-2-(1H-indol-4-yl)quinazolin-4(3H)-one; and

3-(4-sec-butylphenyl)-2-(1H-indol-4-yl)quinazolin-4(3H)-one,

and pharmaceutically acceptable salts and hydrates thereof.

11. A pharmaceutical composition comprising a compound according to claim 1 , 3 , 6 , or 10 and a pharmaceutically acceptable carrier.

12. A method of increasing the expression of ApoA-I in a subject, comprising administering a therapeutically effective amount of a compound according to claim 1 , 3 , 6 , or 10 .

13. The method of claim 12 , wherein increasing the expression of ApoA-I in the subject treats a cardiovascular disease or a cholesterol-, or lipid-related disorder or reduces the risk of acquiring a cardiovascular disease or cholesterol-, or lipid-related disorder.

14. The method of claim 13 , wherein the method comprises regression of arteriosclerosis lesions or reduction of the risk of acquiring arteriosclerosis lesions.

15. The method of claim 13 , wherein the method comprises decreasing blood cholesterol levels.

16. The method of claim 12 , wherein the subject has a genetic or non-genetic predisposition to a cardiovascular disease or cholesterol- or lipid related disorder.