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 selected from the group consisting of —O—, —NH—, —N(C 1 -C 5 alkyl)-, and —(CRR 6 )—;

Z is selected from the group consisting of —C(═O)—, —S(O) 2 —, and —C(═N—R 9 )—, wherein R 9 is selected from the group consisting of H, —CN, and C 1 -C 5 alkyl optionally substituted with 1-11 halogens;

Each R is 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;

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

R 1 and R 6 are each selected from the group consisting of H, —C 1 -C 5 alkyl, halogen, and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;

R 2 is selected from the group consisting of H, —C 1 -C 8 alkyl, halogen, A 1 , and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5 alkyl is optionally substituted with 1-11 halogens;

Wherein one of B and R 2 is A 1 ; and one of B, R 1 , R 2 , and R 6 is A 2 or —(C(R) 2 ) n A 2 ; so that the compound of Formula I comprises one group A 1 and one group A 2 ;

D is selected from the group consisting of:

(a) naphthyl;

(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;

(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group; and

(d) an 8-11-membered bicyclic heteroaromatic ring system comprising 2 fused rings and 1-5 heteroatoms independently selected from N, —S(O) x —, O, and —N(O)—, wherein the ring system optionally comprises 1-5 double bonds, so that each ring is independently saturated, partly unsaturated, or aromatic;

wherein ring D comprises at least two carbon atoms that are bonded to each other, wherein one of the two carbon atoms is bonded to the group A 3 and the other of the two carbon atoms is connected to the remainder of the structure of Formula I, so that A 3 and the remainder of the structure of formula I are ortho to each other on ring D;

A 3 is selected from the group consisting of:

(a) an aromatic ring selected from phenyl and naphthyl;

(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;

(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group; and

(d) an 8-11-membered bicyclic heteroaromatic ring system comprising 2 fused rings and 1-5 heteroatoms independently selected from N, —S(O) x —, O, and —N(O)—, wherein the ring system optionally comprises 1-5 double bonds, so that each ring is independently saturated, partly unsaturated, or aromatic;

wherein the point of attachment of A 3 to the ring D to which A 3 is attached is a carbon atom of ring A 3 ;

wherein A 3 is optionally substituted with 1-5 substituent groups independently selected from R b ;

A 2 is selected from the group consisting of:

(a) an aromatic ring selected from phenyl and naphthyl;

(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds;

(c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group;

(d) an 8-11-membered bicyclic heteroaromatic ring system comprising 2 fused rings and 1-5 heteroatoms independently selected from N, —S(O) x —, O, and —N(O)—, wherein the ring system optionally comprises 1-5 double bonds, so that each ring is independently saturated, partly unsaturated, or aromatic; and

(e) a —C 3 -C 8 cycloalkyl ring optionally having 1-3 double bonds;

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

wherein the point of attachment of A 2 to the structure of formula I to which A 2 is attached is a carbon atom of ring A 2 ;

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 , phenyl, naphthyl, 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 for compounds in which R a is a cyclic group selected from phenyl, naphthyl, —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds, and a heterocyclic ring, R a 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, —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 also 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 ;

Each R b 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, —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 , phenyl, naphthyl, 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 when R b is selected from the group consisting of a heterocyclic ring, —C 3 -C 8 cycloalkyl, naphthyl, —OC 3 -C 8 cycloalkyl, and —C(═O)C 3 -C 8 cycloalkyl, then the heterocyclic ring, naphthyl, and —C 3 -C 8 cycloalkyl groups of R b are optionally substituted with 1-5 substituent groups independently selected from halogen, —C 1 -C 3 alkyl, —C 2 -C 3 alkenyl, —NR 3 R 4 , —OC 1 -C 3 alkyl, —CO 2 H, —CN, and —CO 2 C 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl and —C 2 -C 3 alkenyl in all uses are optionally substituted with 1-7 halogens and optionally one group —OH;

when R b is selected from the group consisting of —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —C(═O)C 1 -C 6 alkyl, —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, then the alkyl, alkenyl, and alkynyl groups of R b are optionally substituted with 1-13 halogens and are 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, (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 ;

and when R b is phenyl, said phenyl is optionally substituted with 1-5 halogens and is optionally substituted with 1-3 substituents independently selected from —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —C 2 -C 4 alkynyl, —C 3 -C 6 cycloalkyl, —OC 1 -C 4 alkyl, —OC 2 -C 4 alkenyl, —OC 2 -C 4 alkynyl, —OC 3 -C 6 cycloalkyl, —C(═O)C 1 -C 4 alkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 4 alkyl, —NR 3 R 4 , —C(═O)NR 3 R 4 , —NR 3 C(═O)OC 1 -C 4 alkyl, —NR 3 C(═O)NR 3 R 4 , —S(O) x C 1 -C 4 alkyl, —S(O) y NR 3 R 4 , —NR 3 S(O) y NR 3 R 4 , —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 and optionally comprising 1-3 substituents independently selected from halogen, —CH 3 , —OCH 3 , —CF 3 , and —OCF 3 ; wherein when the substituents on phenyl when Rb is phenyl are selected from —C 1 -C 4 alkyl, —C 2 -C 4 alkenyl, —C 2 -C 4 alkynyl, —C 3 -C 6 cycloalkyl, —OC 1 -C 4 alkyl, —OC 2 -C 4 alkenyl, —OC 2 -C 4 alkynyl, —OC 3 -C 6 cycloalkyl, —C(═O)C 1 -C 4 alkyl, —CO 2 C 1 -C 4 alkyl, —NR 3 C(═O)OC 1 -C 4 alkyl, and —S(O) x C 1 -C 4 alkyl, then the alkyl, alkenyl, alkynyl, and cycloalkyl groups of said substituent groups optionally comprise 1-5 halogen substituents and also optionally comprise one substituent selected from —OH, —NR 3 R 4 , —OCH 3 optionally substituted with 1-3 F, and phenyl which is optionally substituted with 1-3 substituents independently selected from halogen, —CH 3 , —OCH 3 , —CF 3 , and —OCF 3 ;

n is 0 or 1;

p is an integer from 0-4;

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; and

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.

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

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

Y is —(CHR 1 )—;

X is —O—;

Z is —C(═O)—;

R is H;

n is 0;

p is an integer from 0-2; and

R 1 and R 5 are each independently selected from the group consisting of H and —C 1 -C 3 alkyl.

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

D is selected from the group consisting of naphthyl, pyridyl, quinolyl, indanyl, benzothienyl, tetrahydronaphthyl, isoxazolyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, N-oxido-pyridyl, 1,3-thiazolyl, 1,3-oxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl-5-oxide, benzothienyl-5-dioxide, dihydroindolyl; dihydroisoindolyl, dihydroisobenzofuranyl, and benzodioxolanyl;

A 3 is selected from the group consisting of phenyl, naphthyl, tetrahydronaphthyl, pyridyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, N-oxido-pyridyl, 1,3-thiazolyl, 1,3-oxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indanyl, benzothienyl, benzothienyl-5-oxide, benzothienyl-S-dioxide, dihydroindolyl; dihydroisoindolyl, dihydroisobenzofuranyl, and benzodioxolanyl; and

A 2 is selected from the group consisting of phenyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, benzodioxolyl, pyridyl, N-oxido-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl, and tetrahydropyranyl.

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

D is selected from the group consisting of naphthyl, pyridyl, quinolyl, indanyl, benzothienyl, tetrahydronaphthyl, isoxazolyl, 1,3-thiazolyl, pyrimidinyl, pyrazinyl, dihydroisoindolyl, dihydroisobenzofuranyl, and benzodioxolanyl;

A 3 is selected from the group consisting of phenyl, naphthyl, indanyl, and tetrahydronaphthyl; and

A 2 is phenyl.

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

R a and R b are each independently selected from the group consisting of —C 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, —OC 1 -C 3 alkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 4 alkyl, —OH, —NR 3 R 4 , halogen, —CN, —NO 2 , phenyl, 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 1-3 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 and R b are selected from the group consisting of —C 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —OC 1 -C 3 alkyl, and —CO 2 C 1 -C 4 alkyl, R a is optionally substituted with 1-7 halogens and is optionally substituted with one substituent group —OH;

wherein for compounds in which R a and R b are selected from the group consisting of phenyl and —C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, R a is optionally substituted with 1-5 halogens and is optionally substituted with 1-3 groups independently selected from —C 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, —OC 1 -C 3 alkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 4 alkyl, —OH, —NR 3 R 4 , halogen, —CN, and —NO 2 , wherein —C 1 -C 5 alkyl, —C 2 -C 5 alkenyl, —C 3 -C 6 cycloalkyl optionally having 1-2 double bonds, —OC 1 -C 3 alkyl, and —CO 2 C 1 -C 4 alkyl are optionally substituted with 1-5 halogens, and —C 1 -C 5 alkyl also is optionally substituted with one —OH; and

R 3 and R 4 are each independently selected from H and C 1 -C 3 alkyl.

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

Y is —(CHR 1 )—, wherein R 1 is selected from H and C 1 -C 2 alkyl;

R 5 is H;

X is —O—;

Z is —C(═O)—;

R is H;

n is 0;

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

B is A 1 and has the structure:

wherein D is selected from the group consisting of naphthyl, pyridyl, quinolyl, indanyl, benzothienyl, tetrahydronaphthyl, isoxazolyl, 1,3-thiazolyl, pyrimidinyl, pyrazinyl, dihydroisoindolyl, dihydroisobenzofuranyl, and benzodioxolanyl, wherein D is optionally substituted with 1-2 substituent groups independently selected from (a) halogen, (b) —C 1 -C 5 alkyl which is optionally substituted with 1-3 halogens, (c) —C 2 -C 3 alkenyl, (d) —C 3 -C 6 cycloalkyl, (e) —C 5 -C 6 cycloalkenyl, (f) —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens; (g) —SC 1 -C 3 alkyl, (h) —SO 2 C 1 -C 3 alkyl, (i) —C(═O)OCH 2 -Phenyl, (j) Phenyl optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 , (k) —NR 3 R 4 , where R 3 and R 4 are each independently selected from H and CH 3 , (l) —CN, and (m) —NO 2 ; and

A 3 is selected from the group consisting of phenyl, naphthyl, indanyl, and tetrahydronaphthyl, wherein A 3 is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —C 1 -C 5 alkyl which is optionally substituted with 1-3 halogens and optionally one group selected from —OH, —CO 2 H, and —CO 2 C 1 -C 3 alkyl, (c) —C 2 -C 3 alkenyl, (d) —C 3 -C 6 cycloalkyl which is optionally substituted with one group selected from [i] —CO 2 H, [ii] —OH, and [iii] —C 1 -C 5 alkyl which is optionally substituted with 1-3 halogens and optionally with 1 group selected from —OH, —CO 2 H, and —CO 2 CH 3 , (e) —C 5 -C 6 cycloalkenyl, (f) phenyl which is optionally substituted with 1-2 substituent groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , and optionally one group —CO 2 H or —CO 2 C 1 -C 3 alkyl, and (g) —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens.

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

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

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

wherein R is selected from the group consisting of:

wherein R is selected from the group consisting of:

wherein R is selected from the group consisting of:

wherein R is selected from the group consisting of:

wherein R is selected from the group consisting of:

11. 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.

12. 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.

13. 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.

14. 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.

15. The compound of claim 2 having formula Ia, or a pharmaceutically acceptable salt thereof, wherein:

Y is —(CHR 1 )—, wherein R 1 is selected from H and C 1 -C 2 alkyl;

R 5 is H;

X is —O—;

Z is —C(═O)—;

R is H;

n is 0;

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

A 1 has the structure:

wherein D is selected from the group consisting of naphthyl, pyridyl, quinolyl, indanyl, benzothienyl, tetrahydronaphthyl, isoxazolyl, 1,3-thiazolyl, pyrimidinyl, pyrazinyl, dihydroisoindolyl, dihydroisobenzofuranyl, and benzodioxolanyl, wherein D is optionally substituted with 1-2 substituent groups independently selected from (a) halogen, (b) —C 1 -C 5 alkyl which is optionally substituted with 1-3 halogens, (c) —C 2 -C 3 alkenyl, (d) —C 3 -C 6 cycloalkyl, (e) —C 5 -C 6 cycloalkenyl, (f) —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens; (g) —SC 1 -D 3 alkyl, (h) —SO 2 C 1 -C 3 alkyl, (i) —C(═O)OCH 2 Phenyl, (j) Phenyl optionally substituted with 1-3 substituents independently selected from halogen, CH 3 , CF 3 , —OCH 3 , and —OCF 3 , (k) —NR 3 R 4 , where R 3 and R 4 are each independently selected from H and CH 3 , (l) —CN, and (m) —NO 2 ; and

A 3 is selected from the group consisting of phenyl, naphthyl, indanyl, and tetrahydronaphthyl, wherein A 3 is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —C 1 -C 5 alkyl which is optionally substituted with 1-3 halogens and optionally one group selected from —OH, —CO 2 H, and —CO 2 C 1 -C 3 alkyl, (c) —C 2 -C 3 alkenyl, (d) —C 3 -C 6 cycloalkyl which is optionally substituted with one group selected from [i] —CO 2 H, [ii] —OH, and [iii] C 1 -C 5 alkyl which is optionally substituted with 1-3 halogens and optionally with 1 group selected from —OH, —CO 2 H, and —CO 2 CH 3 , (e) —C 5 -C 6 cycloalkenyl, (f) phenyl which is optionally substituted with 1-2 substituent groups independently selected from halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , and optionally one group —CO 2 H or —CO 2 C 1 -C 3 alkyl, and (g) —OC 1 -C 3 alkyl optionally substituted with 1-3 halogens.