ANTI-HYPERCHOLESTEROLEMIC COMPOUNDS

1 . A compound of structural Formula Ia

and the pharmaceutically acceptable salts thereof, wherein

Ar 1 is selected from the group consisting of aryl and R 4 -substituted aryl;

R is selected from the group consisting of —OR 6 , —O(CO)R 6 , —O(CO)OR 8 , —O(CO)NR 6 R 7 , a sugar residue, a disugar residue, a trisugar residue and a tetrasugar residue;

R 1 is selected from the group consisting of —H, —C 1-6 alkyl and aryl;

R 4 is 1-5 substituents independently selected at each occurrence from the group consisting of: —OR 5 , —O(CO)R 5 , —O(CO)OR 8 , —O—C 1-5 alkyl-OR 5 , —O(CO)NR 5 R 6 , —NR 5 R 6 , —NR 5 (CO)R 6 , —NR 5 (CO)OR 8 , —NR 5 (CO)NR 6 R 7 , —NR 5 SO 2 R 8 , —COOR 5 , —CONR 5 R 6 , —COR 5 , —SO 2 NR 5 R 6 , —S(O) t R 8 , —O—C 1-10 alkyl-COOR 5 , —O—C 1-10 alkyl-CONR 5 R 6 and fluoro;

t is an integer selected from 0, 1 and 2;

R 5 , R 6 and R 7 are independently selected at each occurrence from the group consisting of —H, —C 1-6 alkyl, aryl and aryl-substituted —C 1-6 alkyl;

R 8 is selected from the group consisting of —C 1-6 alkyl, aryl and aryl-substituted —C 1-6 alkyl;

R 9 is selected from the group consisting of chloro, fluoro,

—C≡C—C 1-6 alkyl-NR 10 R 11 ,

—(CH 2 ) x CH═CH—C 1-6 alkyl-NR 10 R 11 ,

—C 1-8 alkyl-NR 10 R 11 ,

—C≡C—C 1-4 alkyl-CH—(CH 2 —NR 10 R 11 ) 2 ,

—(CH 2 ) x CH═CH—C 1-4 alkyl-CH—CH 2 —NR 10 R 11 ) 2 ,

—C 1-6 alkyl-CH—(CH 2 —NR 10 R 11 ) 2 ,

—C≡C—C 1-6 alkyl-R 11a ,

—(CH 2 ) x CH═CH—C 1-6 alkyl-R 11a ,

—C 1-8 alkyl-R 11a ,

—C≡C—C 1-6 alkyl,

—(CH 2 ) x CH═CH—C 1-6 alkyl,

—C 1-8 alkyl,

—C 2-15 alkynyl mono- or poly-substituted with —OH and optionally substituted with R 14 ,

—C 2-15 alkenyl mono- or poly-substituted with —H and optionally substituted with R 14 ,

—C 1-15 alkyl mono- or poly-substituted with —OH and optionally substituted with R 14 ,

and

x is an integer selected from 0, 1 and 2;

R 10 is independently selected at each occurrence from the group consisting of —H and —C 1-3 alkyl;

R 11 is independently selected at each occurrence from the group consisting of —H, —C 1-3 alkyl, —C(O)—C 1-3 alkyl, —C(O)—NR 10 R 10 , —SO 2 —C 1-3 alkyl and —SO 2 -phenyl;

R 11a is selected from the group consisting of —C(O)—NR 10 R 10 , —SO 2 —C 1-3 alkyl, and —SO 2 -phenyl;

R 12 is selected from the group consisting of —C 2-15 alkynyl mono- or poly-substituted with —OH and optionally substituted with R 14 , —C 2-15 alkenyl mono- or poly-substituted with —OH and optionally substituted with R 14 , —C 1-15 alkyl mono- or poly-substituted with —OH and optionally substituted with R 14 ;

R 13 is selected from the group consisting of —H and —OH; and

R 14 is a sugar residue optionally substituted with —COOH, —COOC 1-3 alkyl and —C 1-3 alkyl-OH;

provided that when R 9 is selected from the group consisting of —C≡C—(CH 2 ) 1-6 —NR 10 R 11 , —CH═CH—(CH 2 ) 1-6 —NR 10 R 11 and —(CH 2 ) 1-8 —NR 10 R 11 , then R 12 is not selected from the group consisting of —C 1-15 alkyl mono- or poly-substituted with —OH, —CH═CH—C 1-13 alkyl mono- or poly-substituted with —OH, —C≡C—C 1-13 alkyl mono- or poly-substituted with —OH, and

and excluding (3R,4S)-4-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(3-hydroxypropyl)phenyl]azetidin-2-one.

2 . The compound of claim 1 wherein Ar 1 is selected from the group consisting of aryl and R 4 -substituted aryl wherein R 4 is 1-2 substituents independently selected at each occurrence from the group consisting of: —OR 5 , —O(CO)R 5 , —O(CO)OR 8 , —O—C 1-5 alkyl-OR 5 , —O(CO)NR 5 R 6 , —NR 5 R 6 , —NR 5 (CO)R 6 , —NR 5 (CO)OR 8 , —NR 5 (CO)NR 6 R 7 , —NR 5 SO 2 R 8 , —COOR 5 , —CONR 5 R 6 , —COR 5 , —SO 2 NR 5 R 6 , —S(O) t R 8 , —O—C 1-10 alkyl-COOR 5 , —O—C 1-10 alkyl-CONR 5 R 6 and fluoro.

3 . The compound of claim 2 wherein R is —OR 6 and R 1 is —H.

4 . The compound of claim 1 having structural Formula Ib

and the pharmaceutically acceptable salts thereof.

5 . The compound of claim 4 selected from the group consisting of:

1) N-(5-[4-((2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-{4-[5-hydroxy-4-(hydroxymethyl)pentyl]phenyl}-4-oxoazetidin-1-yl)phenyl]-2-{[(methylsulfonyl)amino]methyl}pentyl)methanesulfonamide;

2) (3R,4S)-1,4-bis{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one;

3) (3R,4S)-4-(4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[5-hydroxy-4-(hydroxymethyl)pentyl]-phenyl}azetidin-2-one;

4) (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1,4-bis[4-(3-hydroxypropyl)phenyl]azetidin-2-one;

5) (3R,4S)-3-[(3S)−)-3-(4-fluorophenyl)-3-hydroxypropyl]-1,4-bis[4-(4-hydroxybutyl)phenyl]azetidin-2-one;

6) (3R,4S)-4-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-1-[4-(2,3-dihydroxypropyl)phenyl]-3-[(3S—)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one;

7) (3R,4S)-1-[4-(1,2-dihydroxyethyl)phenyl]-4-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one

8) (3R,4S)-4-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-propylphenyl)azetidin-2-one;

9) (3R,4S)-4-(4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-{4-[4-(methylsulfonyl)butyl]phenyl}azetidin-2-one;

10) (3R,4S)-4-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]1-{4-[6-(methylsulfonyl)hexyl]phenyl}azetidin-2-one;

11) methyl (2S,3S,4S,5R)-6-[4-{4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]propyl}phenyl)-4-oxoazetidin-2-yl]phenyl}-2-hydroxy-2-(hydroxymethyl)butoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; and

12) (2S,3S,4,S,5R)-6-[4-{4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-{3-[(methylsulfonyl)amino]propyl}phenyl)-4-oxoazetidin-2-yl]phenyl}-2-hydroxy-2-(hydroxymethyl)butoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

and the pharmaceutically acceptable salts thereof.

6 . A method of reducing plasma LDL-cholesterol levels comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

7 . The method of claim 6 further comprising administering a therapeutically effective amount of a cholesterol biosynthesis inhibitor to a patient in need of such treatment.

8 . A method of treating hypercholesterolemia comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

9 . A method of treating or reducing the risk for developing atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.

10 . A method of reducing the risk for having an atherosclerotic disease event comprising administering a prophylactically effective amount of a compound of claim 1 to a patient in at risk for such an event.

11 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

12 . The pharmaceutical composition of claim 11 further comprising a therapeutically effective amount of a cholesterol biosynthesis inhibitor.

13 . A compound selected from the group consisting of:

1) N-[4-(4-{(2S,3R)-2-{4-[3,4-dihydroxy-3-(hydroxymethyl)but-1-yn-1-yl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)but-3-yn-1-yl]methanesulfonamide;

2) N-[5-(4-{(2S,3R)-2-{4-[3,4-dihydroxy-3-(hydroxymethyl)but-1-yn-1-yl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)pent-4-yn-1-yl]methanesulfonamide;

3) N-[4-(4-{(2S,3R)-2-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)butyl]methanesulfonamide;

4) N-[5-(4-{(2S,3R)-2-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)pentyl]methanesulfonamide;

5) N-[6-(4-((2S,3R)-2-{4-[3,4-dihydroxy-3-(hydroxymethyl)butyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)hexyl]methanesulfonamide;

6) N-[4-(4-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-[4-(7-hydroxyheptyl)phenyl]-4-oxoazetidin-1-yl}phenyl)butyl]methanesulfonamide;

7) N-[4-(4-((2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-{4-[5-hydroxy-4-(hydroxymethyl)pent-1-yn-1-yl]phenyl}-4-oxoazetidin-1-yl)phenyl]but-3-yn-1-yl}methanesulfonamide;

8) N-[5-(4-((2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-{4-[5-hydroxy-4-(hydroxymethyl)pent-1-yn-1-yl]phenyl}-4-oxoazetidin-1-yl)phenyl]pent-4-yn-1-yl}methanesulfonamide;

9) N-{6-[4-((2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-{4-[5-hydroxy-4-(hydroxymethyl)pent-1-yn-1-yl]phenyl}-4-oxoazetidin-1-yl)phenyl]hex-5-yn-1-yl}methanesulfonamide;

10) N-{5-[4-((2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-{4-[5-hydroxy-4-(hydroxymethyl)pentyl]phenyl}-4-oxoazetidin-1-yl)phenyl]pentyl)methanesulfonamide;

11) N-{6-[4-((2,S, 3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-{4-[5-hydroxy-4-(hydroxymethyl)pentyl]phenyl)}-4-oxoazetidin-1-yl)phenyl]hexyl)methanesulfonamide;

12) N-[3-(4-{(2S,3R)-2-{4-[1,2-dihydroxy-1-(hydroxymethyl)ethyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]methanesulfonamide;

13) N-[3-(4-{(2S,3R)-2-{4-[4,5-dihydroxy-4-(hydroxymethyl)pentyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]methanesulfonamide;

14) N-[3-(4-{(2S,3R)-2-{4-[2,3-dihydroxy-2-(hydroxymethyl)propyl]phenyl}-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]methanesulfonamide;

15) N-[3-(4-{(2S,3R)-2-{4-[5,6-dihydroxy-5-(hydroxymethyl)hexyl]phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)propyl]methanesuslfonamide; and

16) N-{3-[4-((3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-oxo-4-{4-[1,2,5,6-tetrahydroxy-5-(hydroxymethyl)hexyl]phenyl}azetidin-1-yl)phenyl]propyl}methanesulfonamide;

and the pharmaceutically acceptable salts thereof.

14 . A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

15 . The pharmaceutical composition of claim 14 further comprising a therapeutically effective amount of a cholesterol biosynthesis inhibitor.

16 . A method of reducing plasma LDL-cholesterol levels comprising administering a therapeutically effective amount of a compound of claim 13 to a patient in need of such treatment.

17 . The method of claim 16 further comprising administering a therapeutically effective amount of a cholesterol biosynthesis inhibitor to a patient in need of such treatment.