CETP inhibitors

1. A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein

Y is selected from the group consisting of —C(═O)— and —(CRR 1 )—;

X is —O—;

Z is —C(═O)—;

R and R 1 are each independently selected from the group consisting of H, —C 1 -C 5 alkyl, and halogen, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;

R 5 is selected from the group consisting of H, —OH, —C 1 -C 5 alkyl, and halogen, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;

B and R 2 are each selected from the group consisting of A 1 and A 2 , wherein A 1 has the structure:

wherein one of the ═CH— groups of the phenyl ring of A 1 that are optionally unsubstituted may optionally be replaced by ═N—, so that A 1 comprises a pyridine ring;

Wherein one of B and R 2 is A 1 , and the other of B and R 2 is A 2 , so that the compound of Formula I comprises one group A 1 and one group A 2 ;

A 3 is —(CR 10 R 11 ) q NR 7 R 8 ;

A 2 is phenyl,

wherein A 2 is optionally substituted with 1-5 substituent groups independently selected from R a ;

Each R a is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8 cycloalkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —OH, —NR 3 R 4 , —C(═O)NR 3 R 4 , —NR 3 C(═O)OC 1 -C 6 alkyl, —NR 3 C(═O)NR 3 R 4 , —S(O) x C 1 -C 6 alkyl, —S(O) y NR 3 R 4 , —NR 3 S(O) y NR 3 R 4 , halogen, —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which R a is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, —C 1 -C 3 alkyl, and —OC 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens;

wherein for compounds in which R a is selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8 cycloalkyl, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —NR 3 C(═O)OC 1 -C 6 alkyl, and —S(O) x C 1 -C 6 alkyl, R a is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 substituent groups independently selected from (a) —OH, (b) —CN, (c) —NR 3 R 4 , (d) —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) —OC 1 -C 4 alkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from —OC 1 -C 2 alkyl and phenyl, (f) —OC 3 -C 8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) —CO 2 H, (h) —C(═O)CH 3 , (i) —CO 2 C 1 -C 4 alkyl which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ;

p is an integer from 0-4;

q is 0 or 1;

x is 0, 1, or 2;

y is 1 or 2;

R 3 and R 4 are each independently selected from H, —C 1 -C 5 alkyl, —C(═O)C 1 -C 5 alkyl and —S(O) y C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl in all instances is optionally substituted with 1-11 halogens;

R 7 and R 8 are each independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C(═O)C 1 -C 6 alkyl, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds, —C(═O)C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds, —C(═O)phenyl, —C(═O)NR 3 R 4 , —S(O) 2 C 1 -C 6 alkyl, and —S(O) 2 NR 3 R 4 ,

wherein —C 1 -C 6 alkyl in all instances is optionally substituted with 1-11 halogens and is optionally substituted with 1-2 substituents independently selected from —CO 2 H, —CO 2 C 1 -C 6 alkyl which is optionally substituted with 1-11 halogens, —NR 3 R 4 , —OH, —C(═O)H—, a 5-7 membered heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, —C 3 -C 8 cycloalkyl, and phenyl, wherein said —C 3 -C 8 cycloalkyl and phenyl groups are optionally substituted with (a) 1-5 substituents independently selected from (i) halogen, (ii) —C 1 -C 3 alkyl optionally substituted with 1-5 halogens, and (iii) —OC 1 -C 3 alkyl optionally substituted with 1-5 halogens, and (b) optionally 1-2 groups independently selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CO 2 C 1 -C 4 alkyl, —NR 3 R 4 , —CN, —NO 2 , —C(═O)NR 3 R 4 , —CH 2 C(═O)NR 3 R 4 , —S(O) 2 C 1 -C 3 alkyl, and —C 1 -C 5 alkyl optionally substituted with 1-2 groups independently selected from —NR 3 R 4 , —OH, —C(═O)H—, and a 5-7 membered heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, and optionally 1-5 halogens; wherein said 5-7 membered heterocycle in all uses as a substituent on —C 1 -C 6 alkyl is optionally substituted with 1-5 substituents independently selected from halogen, —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl, said —C 1 -C 3 alkyl and —OC 1 -C 3 alkyl being optionally substituted with 1-7 halogens;

wherein when R 7 or R 8 is —C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds, then said —C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds is optionally substituted with (a) 1-5 substituents independently selected from halogen, —C 1 -C 3 alkyl optionally substituted with 1-5 halogen, and —OC 1 -C 3 alkyl optionally substituted with 1-5 halogens, and (b) optionally also 1 group selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CO 2 C 1 -C 4 alkyl, —C(═O)NR 3 R 4 , —CH 2 C(═O)NR 3 R 4 , —CH 2 CH 2 C(═O)NR 3 R 4 , —CN, —NO 2 , and —S(O) 2 C 1 -C 3 alkyl;

and when R 7 or R 8 is —C(═O)phenyl or —C(═O)C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds, said phenyl or cycloalkyl which optionally comprises 1-2 double bonds is optionally substituted with (a) 1-5 substituents independently selected from halogen, —C 1 -C 3 alkyl optionally substituted with 1-5 halogens, and —OC 1 -C 3 alkyl optionally substituted with 1-5 halogens, and (b) optionally 1 group selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CO 2 C 1 -C 4 alkyl, —C(═O)NR 3 R 4 , —CH 2 C(═O)NR 3 R 4 , —CH 2 CH 2 C(═O)NR 3 R 4 , —CN, —NO 2 , and —S(O) 2 C 1 -C 3 alkyl;

wherein alternatively R 7 and R 8 are joined to form a monocyclic 5-7-membered heterocycle optionally having 1-2 heteroatoms independently selected from N, O and S(O) x in addition to the N to which R 7 and R 8 are connected or a bicyclic or tricyclic heterocycle having 5-16 atoms and optionally having 1-5 heteroatoms independently selected from N, O and S(O) x in addition to the N to which R 7 and R 8 are connected, said heterocycle being saturated, partly unsaturated or aromatic, said heterocycle being optionally substituted with (a) 1-5 substituent groups independently selected from halogen, —C 1 -C 3 alkyl optionally substituted with 1-5 halogens, and —OC 1 -C 3 alkyl optionally substituted with 1-5 halogens and optionally one —OH group, and (b) optionally 1 substituent selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, and —CH 2 CH 2 CO 2 C 1 -C 4 alkyl; and

R 10 and R 11 are each independently selected from the group consisting of H and —C 1 -C 5 alkyl, wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens.

2. The compound of claim 1 , which is selected from the group consisting of compounds having Formula Ia and Ib, or a pharmaceutically acceptable salt thereof:

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

Y is —(CRR 1 )—;

R, R 5 , and R 10 are H;

R 1 is selected from the group consisting of H and —C 1 -C 2 alkyl;

B is A 1 , and R 2 is A 2 ;

A 2 is phenyl which is optionally substituted with 1-3 substituent groups independently selected from R a ;

p is an integer from 0-2; and

Each R a is independently selected from the group consisting of —C 1 -C 3 alkyl optionally substituted with 1-3 halogens, —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens, —C 2 -C 4 alkenyl, halogen, —CN, —NO 2 , C 3 -C 6 cycloalkyl, and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which R a is attached is a carbon atom, wherein said heterocyclic ring and C 3 -C 6 cycloalkyl are optionally substituted with 1-3 substituent groups independently selected from halogen, —CH 3 , —OCH 3 , —CF 3 , and —OCF 3 .

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

One of R 7 and R 8 is optionally H, and R 7 and R 8 are each independently selected from the group consisting of —C 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C(═O)C 3 -C 6 cycloalkyl, —C(═O)phenyl, —C(═O)NR 3 R 4 , —S(O) 2 C 1 -C 3 alkyl, and —S(O) 2 NR 3 R 4 ,

wherein —C 1 -C 6 alkyl in all instances is optionally substituted with 1-3 F atoms and is optionally substituted with one substituent selected from —CO 2 H, —CO 2 C 1 -C 6 alkyl which is optionally substituted with 1-3 F atoms, —NR 3 R 4 , —OH, —C(═O)H—, a 5-6 membered heterocycle comprising 1-2 heteroatoms independently selected from N, O and S, —C 3 -C 6 cycloalkyl, and phenyl, wherein said —C 3 -C 6 cycloalkyl and phenyl groups are optionally substituted with (a) 1-2 substituents independently selected from (i) fluorine, (ii) —C 1 -C 3 alkyl optionally substituted with 1-3 F atoms, and (iii) —OC 1 -C 3 alkyl optionally substituted with 1-3 F atoms, and (b) optionally one group selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CO 2 C 1 -C 4 alkyl, —NR 3 R 4 , —CN, —NO 2 , —C(═O)NR 3 R 4 , —CH 2 C(═O)NR 3 R 4 , —S(O) 2 C 1 -C 3 alkyl, and —C 1 -C 5 alkyl optionally substituted with 1-2 groups independently selected from —NR 3 R 4 , —OH, —C(═O)H—, and a 5-6 membered heterocycle comprising 1-2 heteroatoms independently selected from N, O and S, and optionally 1-5 F atoms; wherein said 5-6 membered heterocycle in all uses as a substituent on —C 1 -C 6 alkyl is optionally substituted with 1-3 substituents independently selected from F, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ,

wherein when R 7 or R 8 is —C 3 -C 6 cycloalkyl, said cycloalkyl is optionally substituted with (a) 1-5 substituents independently selected from F, —CH 3 , and —CF 3 ; and (b) optionally 1 group selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CO 2 C 1 -C 4 alkyl, —C(═O)NR 3 R 4 , —CH 2 C(═O)NR 3 R 4 , —CH 2 CH 2 C(═O)NR 3 R 4 , —CN, —NO 2 , and —S(O) 2 C 1 -C 3 alkyl;

and when R 7 or R 8 is —C(═O)phenyl or —C(═O)C 3 -C 6 cycloalkyl, said phenyl or cycloalkyl is optionally substituted with (a) 1-2 substituents independently selected from F, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ; and (b) optionally 1 group selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, —CH 2 CH 2 CO 2 C 1 -C 4 alkyl, —C(═O)NR 3 R 4 , —CH 2 C(═O)NR 3 R 4 , —CH 2 CH 2 C(═O)NR 3 R 4 , —CN, —NO 2 , and —S(O) 2 C 1 -C 3 alkyl;

wherein alternatively R 7 and R 8 are joined to form a monocyclic 5-7-membered heterocycle optionally having 1-2 heteroatoms independently selected from N, O and S(O) x in addition to the N to which R 7 and R 8 are connected or a bicyclic heterocycle having 6-12 atoms and optionally having 1-2 heteroatoms independently selected from N, O and S(O) x in addition to the N to which R 7 and R 8 are connected, said heterocycle being optionally substituted with (a) 1-3 substituent groups independently selected from F, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ; and (b) optionally 1 substituent selected from —CO 2 H, —CO 2 C 1 -C 4 alkyl, —CH 2 CO 2 H, —CH 2 CO 2 C 1 -C 4 alkyl, —CH 2 CH 2 CO 2 H, and —CH 2 CH 2 CO 2 C 1 -C 4 alkyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently selected from H and C 1 -C 3 alkyl;

A 2 is phenyl which is optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 3 alkyl optionally substituted with 1-3 halogens, and —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens;

p is an integer from 0-2; and

Each R a is selected from the group consisting of halogen, C 1 -C 3 alkyl optionally substituted with 1-3 halogens, —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens, C 2 -C 4 alkenyl, and C 3 -C 6 cycloalkyl.

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

7. The compound of claim 1 , which is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

8. The compound of claim 1 , which is selected from the following compounds, or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , and R 3 for each compound are defined as follows:

EXAM-

PLE

R 1

R 2

R 3

75

CF 3

H

76

CF 3

H

77

CF 3

CH 3

78

OCF 3

H

79

OCF 3

H

80

OCF 3

H

81

OCF 3

H

82

OCF 3

H

83

CF3

H

84

CF3

H

wherein R 1 is selected from the group consisting of:

wherein R 1 is selected from the group consisting of:

9. 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.

10. A method of raising HDL-C 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.

11. A method of lowering LDL-C 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.

12. 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.