Substituted benzopiperazines as CETP inhibitors

1. A compound of formula Ia, or a pharmaceutically acceptable salt thereof:

wherein R 1 is CF 3 or CH 3 ;

R 2 is phenyl; naphthyl; a 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from N and —(NR 8 )—, or phenyl to which is fused a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, S, and —(NR 8 )—, wherein R 2 is optionally substituted with 1-2 substituent groups independently selected from C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —NR 8 R 9 , —C(═O)NR 8 R 9 , —C(═O)OC 1 -C 3 alkyl, —S(O) 2 C 1 -C 3 alkyl, Cl, F, —CN, and phenyl, wherein phenyl is optionally substituted with 1-3 substituents independently selected from CF 3 , CH 3 , —OCF 3 , —OCH 3 , and halogen, wherein C 1 -C 3 alkyl in all instances is optionally substituted with one —OH and optionally 1-5 F;

R 6 and R 5 are each independently H, CF 3 , CH 3 or halogen;

R 7 and R 10 are H;

R 8 and R 9 are each independently H or C 1 -C 2 alkyl;

R 3 is phenyl, naphthyl, a 6-membered heteroaromatic ring having 1-2 heteroatoms independently selected from N and —(NR 8 )—, thienyl, C 5 -C 6 cycloalkyl optionally having one double bond, or a 6-membered saturated heterocycle having 1-2 heteroatoms independently selected from O, S, N, and NR 8 , wherein R 3 is optionally substituted with C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, F, Cl, and a 6-membered saturated heterocycle having 1-2 heteroatoms independently selected from O, S, N, and NR 8 , wherein C 1 -C 3 alkyl and OC 1 -C 3 alkyl are optionally substituted with 1-5 F, and the 6-membered saturated heterocycle having 1-2 heteroatoms independently selected from O, S, N, and NR 8 is optionally substituted with 1-3 substituents independently selected from CF 3 , CH 3 , —OCF 3 , —OCH 3 , Br, Cl, and F;

R 4 is H or C 1 -C 2 alkyl;

or alternatively, R 3 is phenyl and R 4 has the formula (—CH 2 —) y , wherein y is an integer from 2-4 and (—CH 2 —) y optionally comprises one double bond, wherein R 4 is connected to the phenyl group R 3 at the position ortho to the carbon atom which is connected to the carbon atom to which R 3 , R 4 , and R 7 are connected, thereby yielding a 4-7 membered cycloalkyl or cycloalkenyl ring fused to the phenyl group R 3 , wherein the phenyl ring R 3 and the fused cycloalkyl or cycloalkenyl ring together are optionally substituted with 1-4 groups independently selected from CF 3 , CH 3 , —OCF 3 , —OCH 3 , and halogen; and

x is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is CF 3 ; and

R 2 is phenyl, naphthyl, pyrazolyl, pyridinyl, pyrimidinyl, or 2,3-dihydrobenzodioxinyl, wherein R 2 is optionally substituted with 1-2 substituents independently selected from CH 3 , —OCH 3 , CF 3 , —OCF 3 , —OC 2 H 5 , —OCF 2 H, —OCF 2 CF 2 H, —C(CH 3 ) 2 OH, —C(═O)NHCH 3 , —C(═O)OCH 3 , —SO 2 CH 3 , —N(CH 3 ) 2 , F, Cl, —CN, and phenyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is phenyl, pyridinyl, thienyl, cyclohexyl, cyclohexenyl, or tetrahydropyranyl optionally substituted with 1-2 substituent groups independently selected from CH 3 , —OCH 3 , CF 3 , —OCF 2 H, —OCF 3 , C 2 H 5 , —OC 2 H 5 , —OCH(CH 3 ) 2 , —OCF 2 CF 2 H, F, Cl, and morpholinyl;

R 4 is H or CH 3 ;

or alternatively, when R 3 is phenyl, R 4 optionally is (—CH 2 —) 3 or —HC═CH—, wherein R 4 is attached to the phenyl group R 3 at the position that is ortho to the carbon atom that is attached to the carbon atom to which R 3 , R 4 , and R 7 are attached, thereby yielding a tetrahydronaphthalenyl or indenyl ring connected to the N of the benzopiperazine;

R 5 is H or F; and

R 6 , R 7 and R 10 are H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula Ib:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula Ic:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula Id:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula Ie:

8. The compound of claim 1 , having the structure below:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , having the structure below:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , having the structure below:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, having the structure below:

12. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:

(i) 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors;

(ii) bile acid sequestrants;

(iii) niacin and related compounds;

(iv) peroxisome proliferator-activated receptor α agonists;

(v) cholesterol absorption inhibitors;

(vi) acyl CoA:cholesterol acyltransferase inhibitors;

(vii) phenolic anti-oxidants;

(viii) microsomal triglyceride transfer protein/apolipoprotein B secretion inhibitors;

(ix) anti-oxidant vitamins;

(x) thyromimetics;

(xi) low density lipoprotein receptor inducers;

(xii) platelet aggregation inhibitors;

(xiii) vitamin B12;

(xiv) folic acid or a pharmaceutically acceptable salt or ester thereof;

(xv) farnesoid X and liver X ligands;

(xvi) agents that enhance ATP-binding cassette, sub-family A, member 1 gene expression; and

(xvii) ileal bile acid transporters.

14. A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.

15. A method of raising high-density lipoprotein cholesterol in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.

16. A method of lowering low-density lipoprotein cholesterol in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.

17. A method of treating dyslipidemia in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 to said patient, or a pharmaceutically acceptable salt thereof.