Cyclic amine substituted heterocyclic CETP inhibitors

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein A 3 is represented by Formula II;

wherein Y 1 and Y 2 are each N;

R 1 is H, CF 3 , or C 1-3 alkyl;

Each R a is independently C 1-3 alkyl optionally substituted with 1-6 halogens; —OC 1-3 alkyl optionally substituted with 1-6 halogens; halogen; —CN; or C 3-4 cycloalkyl optionally substituted with 1-3 halogens;

R c is (a) a 4-7 membered monocyclic heterocycle having one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the monocyclic heterocycle optionally has 1-3 double bonds, one carbonyl, and 1-3 additional heteroatom groups which are each independently N, O, S, S(O), or S(O) 2 ; or (b) a 5-8 membered bicyclic heterocycle having one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the bicyclic heterocycle optionally has 1-3 double bonds, one carbonyl, and 1-3 additional heteroatom groups which are each independently N, O, S, S(O), or S(O) 2 , wherein R c as defined in (a) or (b) is optionally substituted with 1-3 substituent groups which are independently halogen, —OH, —CN, C 1-3 alkyl, or —OC 1-3 alkyl, wherein C 1-3 alkyl and —OC 1-3 alkyl are optionally substituted with 1-6 halogens;

Each R c1 is independently C 1-3 alkyl, —OC 1-3 alkyl, or halogen, wherein alkyl in either case is optionally substituted with 1-6 halogens;

R b is H, C 1-4 alkyl, —OC 1-4 alkyl, —OC 3-6 cycloalkyl, halogen, —CN, —NO 2 , or —OH, wherein C 1-4 alkyl and —OC 1-4 alkyl are optionally substituted with 1-6 halogens, and —OC 3-6 cycloalkyl is optionally substituted with 1-3 halogens;

Each R b1 is independently C 1-3 alkyl, —OC 1-3 alkyl, or halogen, wherein C 1-3 alkyl and —OC 1-3 alkyl are optionally substituted with 1-6 halogens;

X is:

(a) (i) halogen, (ii) —C 1-4 alkyl, (iii) —C 3-6 cycloalkyl-Y, or C 1-3 alkyl-Y, wherein Y is —CN, —OH, or —OCH 3 , (iv) —C 3-6 cycloalkyl, or (v) -phenyl which is optionally substituted with 1-3 groups which are independently halogen, —CN, —OH, —C 1-4 alkyl, —OC 1-4 alkyl, or —C(═O)C 1-2 alkyl, and optionally one group —C 1-4 alkyl-OH, wherein alkyl in all uses is optionally substituted with 1-6 halogens, and cycloalkyl in all uses is optionally substituted with 1-3 groups which are independently halogen or —C 1-3 alkyl which are optionally substituted with 1-6 halogens;

(b) D 1 , wherein D 1 is —CO 2 H, —CO 2 C 1-4 alkyl, or —C(═O)NR 2 R 3 ;

(c) —C 1-3 alkyl-D 1 , wherein —C 1-3 alkyl is optionally substituted with 1-6 halogens;

(d) —C 3-6 cycloalkyl-D 1 , wherein cycloalkyl is optionally substituted with 1-2 groups which are independently —C 1-3 alkyl or halogen, wherein —C 1-3 alkyl is optionally substituted with 1-6 halogens;

(e) —C 3-6 cycloalkyl-CH 2 -D 1 , wherein cycloalkyl is optionally substituted with 1-2 groups which are independently —C 1-3 alkyl or halogen, wherein —C 1-3 alkyl is optionally substituted with 1-6 halogens;

(f) -phenyl-D 2 , wherein D 2 is D 1 , HET, or —C(═O)NH—HET, wherein phenyl is optionally substituted with 1-3 substituents which are independently halogen, —CN, —OH, —C 1-3 alkyl optionally substituted with 1-6 halogens, or —OC 1-3 alkyl optionally substituted with 1-6 halogens;

(g) -HET-D 1 , wherein HET is a 5-6-membered heteroaromatic ring having 1-4 heteroatom groups which are each independently N, O, S, S(O), S(O) 2 , or C(═O), wherein HET is optionally substituted with 1-3 groups which are independently halogen, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 ; or

(h) —(C 1-2 alkyl) 0-2 -HET, wherein HET is optionally substituted with 1-3 groups which are independently halogen, —OH, —NH 2 , —C 1-4 alkyl optionally substituted with 1-6 halogens, or —OC 1-3 alkyl optionally substituted with 1-6 halogens, and optionally one group which is —C 1-3 alkyl-CN or —CH 2 C(═O) NR 2 R 3 ;

R 2 and R 3 are each independently H or —C 1-3 alkyl, or R 2 and R 3 are optionally joined to form a bridging group having 3-5 carbons, thereby yielding a 4-6 membered cyclic amide group;

d is an integer from 0-2;

e is an integer from 0-3; and

f is an integer from 0-2.

2. The compound of claim 1 , wherein

R 1 is H or C 1-3 alkyl;

Each R a is independently CF 3 , —OCF 3 , CH 3 , —OCH 3 , halogen, —CN, or cyclopropyl which is optionally substituted with 1-3 halogens;

R c is (a) a 4-6 membered monocyclic amine having one N which is bonded to the heteroaromatic ring to which R c is connected, wherein the monocyclic amine optionally has one O in the ring and optionally 1-2 double bonds, wherein R c is optionally substituted with 1-2 groups which are each independently halogen, —OH, CH 3 , —OCH 3 , CF 3 , or —OCF 3 ;

Each R c1 is independently CH 3 , CF 3 , —OCH 3 , —OCF 3 or halogen;

R b is H, C 1-4 alkyl, —OC 1-4 alkyl, —OC 3-6 cycloalkyl, or halogen, wherein C 1-4 alkyl and —OC 1-4 alkyl are optionally substituted with 1-6 halogens, and —OC 3-6 cycloalkyl is optionally substituted with 1-3 halogens;

Each R b1 is independently halogen, CF 3 , or CH 3 ;

d is 0 or 1;

e is an integer from 1-3; and

f is 0 or 1,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein

R 1 is CH 3 ;

Each R a is independently F, —CF 3 , or —OCF 3 ;

R c is (1) a 4-5 membered saturated monocyclic amine having one N which is bonded to the heteroaromatic ring to which R c is connected and which is optionally substituted with 1-2 groups which are independently F, CH 3 , or —OH, (2) morpholino in which the N of the morpholino group is connected to the heteroaromatic ring to which R c is connected, or (3) imidazolyl in which the N of the imidazolyl group is connected to the heteroaromatic ring to which R c is connected;

Each R c1 is independently —CH 3 or Br;

R b is C 1-4 alkyl or —OC 1-4 alkyl, wherein C 1-4 alkyl and —OC 1-4 alkyl are optionally substituted with 1-6 halogens; and

R b1 is F,

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 wherein

R b is —C 1-4 alkyl or —OC 1-2 alkyl, wherein —C 1-4 alkyl and —OC 1-2 alkyl are optionally substituted with 1-6 halogens;

d is 0;

e is an integer from 1-3; and

f is 0,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein

e is an integer from 1-2,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein

X is:

(a) (i) halogen; (ii) —C 1-4 alkyl which is optionally substituted with 1-6 halogens; (iii) C 1-3 alkyl-Y, wherein C 1-3 alkyl is optionally substituted with 1-6 halogens and Y is —CN, —OH, or —OCH 3 ; or (iv) —C 3-6 cycloalkyl optionally substituted with 1-3 groups independently selected from halogen and —CH 3 ;

(b) D 1 , wherein D 1 is —CO 2 H, —CO 2 C 1-4 alkyl, or —C(═O)NR 2 R 3 ;

(c) —C 1-3 alkyl-D 1 , wherein alkyl is optionally substituted with 1-6 halogens;

(d) —C 3-6 cycloalkyl-D 1 , wherein cycloalkyl is optionally substituted with 1-2 groups which are independently —CH 3 , CF 3 , or halogen;

(e) —C 3-6 cycloalkyl-CH 2 -D 1 , wherein cycloalkyl is optionally substituted with 1-2 groups which are independently —CH 3 , CF 3 , or halogen;

(f) -phenyl-D 2 , wherein D 2 is D 1 , 1,3,4-oxadiazol-2(3H)-one, tetrazole, or —C(═O)NH-tetrazole, wherein phenyl is optionally substituted with 1-3 substituents which are independently halogen, —CH 3 , —CF 3 , —OCH 3 , or —OCF 3 ; or

(g) HET, wherein HET is a 5-membered heteroaromatic ring having 1-3 heteroatoms groups which are each independently N, O, or S and is optionally substituted with 1-3 groups which are independently halogen, —C 1-3 alkyl optionally substituted with 1-6 halogens, or —OC 1-3 alkyl optionally substituted with 1-6 halogens, and is optionally substituted with one group which is —C 1-3 alkyl-CN or —CH 2 C(═O) NR 2 R 3 ;

and R 2 and R 3 are independently H or —CH 3 ,

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein

X is:

(a) (i) Cl; (ii) —C 1-4 alkyl which is optionally substituted with 1-6 halogens; (iii) C 1-3 alkyl-Y, wherein C 1-3 alkyl is optionally substituted with 1-6 halogens and Y is —OH;

or (iv) —C 3-6 cycloalkyl;

(b) —C 1-3 alkyl-D 1 , wherein D 1 is —CO 2 H, —CO 2 C 1-4 alkyl, or —C(═O)NR 2 R 3 ;

(c) -phenyl-D 2 , wherein D 2 is D 1 , 1,3,4-oxadiazol-2(3H)-one, tetrazole, or —C(═O)NH-tetrazole, wherein phenyl is optionally substituted with 1-3 substituents which are independently halogen, —CH 3 , or —CF 3 ; or

(g) HET, wherein HET is a 5-membered heteroaromatic ring having 1-3 heteroatoms which are each independently N, O, or S and is optionally substituted with 1-3 groups which are each independently halogen, —C 1-3 alkyl optionally substituted with 1-6 halogens, or —OC 1-3 alkyl optionally substituted with 1-6 halogens, and is optionally substituted with one group which is —C 1-3 alkyl-CN or —CH 2 C(═O) NR 2 R 3 ;

wherein R 2 and R 3 are independently H or —CH 3 ,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 , wherein HET is oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, thiophene, furan, pyrrole, triazole, tetrazole, or thiadiazole,

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein HET is isoxazole, thiazole, or pyrazole, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure below:

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

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure below:

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

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

15. A method of lowering LDL-C in a patient in need of treatment comprising the administration to said patient of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

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

17. 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) HMG-CoA reductase inhibitors;

(ii) bile acid sequestrants;

(iii) niacin and related compounds;

(iv) PPARα agonists;

(v) cholesterol absorption inhibitors;

(vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors;

(vii) phenolic anti-oxidants;

(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors;

(ix) anti-oxidant vitamins;

(x) thyromimetics;

(xi) LDL (low density lipoprotein) receptor inducers;

(xii) platelet aggregation inhibitors;

(xiii) vitamin B12 (also known as cyanocobalamin);

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

(xv) FXR and LXR ligands;

(xvi) agents that enhance ABCA1 gene expression; and

(xvii) ileal bile acid transporters.