Therapeutic thiazolidinone compounds

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

Wherein each R is independently H or —C 1 -C 3 alkyl;

R 1 is H or —C 1 -C 3 alkyl, wherein —C 1 -C 3 alkyl is optionally substituted with 1-5 halogens;

A and B are each A 1 or A 2 , wherein one of A and B is A 1 and the other of A and B is A 2 ,

A 1 has the structure:

wherein D is selected from the group consisting of:

(a) phenyl, and

(b) HET(1);

wherein ring D comprises at least two carbon atoms that are bonded to each other, wherein one of the two carbon atoms that are bonded to each other in ring D is connected to the group A 3 and the other of the two carbon atoms that are bonded to each other in ring D 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;

wherein HET(1) is a monocyclic 5-8-membered heterocyclic or heteroaromatic ring having 1-4 heteroatom groups independently selected from N, NH, S, O, —S(O)—, —S(O) 2 —, —C(═O)—, and —N(O)—, wherein HET(1) optionally comprises 1-4 double bonds;

A 3 is

(a) phenyl, or

(b) HET(1), wherein

A 3 is optionally substituted with 1-5 substituent groups independently selected from R a and optionally one or two groups X;

provided that when B is A 1 ; and D and A 3 are both phenyl, then A 2 is HET(1), or A 3 is substituted with one group X, wherein X is phenyl or HET(1);

A 2 is

(a) phenyl,

(b) HET(1), or

(c) —C 3 -C 8 cycloalkyl optionally having 1-3 double bonds;

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, —OC 1 -C 6 alkyl, —OC 2 -C 6 alkenyl, —OC 2 -C 6 alkynyl, —C(═O)C 1 -C 6 alkyl, —C(═O)H, —OH, —NR 6 R 7 , —C(═O)NR 6 R 7 , —NR 6 C(═O)OC 1 -C 6 alkyl, —NR 6 C(═O)NR 6 R 7 , —S(O) x C 1 -C 6 alkyl, —S(O) y NR 6 R 7 , —NR 6 S(O) y NR 6 R 7 , —NR 6 S(O) y C 1 -C 6 alkyl, halogen; —CN, —NO 2 , or a 3-7-membered heterocycle having heteroatoms which are independently N, S or O, and optionally one group —C(═O)—, wherein the heterocycle optionally has 1-3 double bonds and is optionally substituted with 1-3 substituent groups which are independently halogen, CH 3 , CF 3 , —OCH 3 , or —OCF 3 ;

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, —C(═O)C 1 -C 6 alkyl, —NR 6 C(═O)OC 1 -C 6 alkyl, —S(O) x C 1 -C 6 alkyl, and —NR 6 S(O) y C 1 -C 6 alkyl, R a is optionally substituted with 1-11 halogens;

X is (a) C 3 -C 8 cycloalkyl which optionally comprises 1-2 double bonds and which is optionally substituted with 1-2 groups D1 and optionally with 1-5 substituent groups which are independently halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —CN, or —OH, wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-11 halogens and optionally 1-2 groups —OH; (b) C 1 -C 5 alkyl which is optionally substituted with 1-2 groups D1 and optionally with 1-2-OH and 1-11 halogens; (c) phenyl which is optionally substituted with 1-2 groups D1 and optionally with 1-5 substituent groups which are halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —CN, or —OH, wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-11 halogens and optionally 1-2 groups —OH; (d) HET(1) which is optionally substituted with 1-2 groups D1 and optionally with 1-5 substituent groups which are halogen, C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —CN, or —OH, wherein C 1 -C 5 alkyl and —OC 1 -C 5 alkyl are optionally substituted with 1-11 halogens and optionally with 1-2 groups —OH; or (e) D1;

D 1 is —CO 2 R 8 , —C(O)NR 6 R 7 , SO 2 NR 6 R 7 , or HET(1);

R 6 and R 7 are each independently H or —C 1-5 alkyl;

R 8 is H or —C 1-5 alkyl optionally substituted with 1-7 halogens;

p is an integer from 0-4;

x is 0, 1, or 2; and

y is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is A 1 and A is A 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is A 2 and A is A 1 .

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

Each R is H or CH 3 ; and

p is an integer from 0-2.

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

R is H.

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

D and A 3 are each independently phenyl, pyridyl, isoxazolyl, thienyl, imidazolyl, furyl, pyrrolyl, pyrazolyl, N-oxido-pyridyl, 1,3-thiazolyl, 1,3-oxazolyl, 1,2,4-triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrahydropyranyl, or tetrahydrofuryl; and

A 2 is phenyl, thienyl, imidazolyl, furyl, 1,3-thiazolyl, 1,3-oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyridyl, N-oxido-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, or tetrahydrofuryl.

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

R is H;

R 1 is CH 3 ;

B is A 1 , wherein A 1 has the structure of formula II:

wherein Y 1 , Y 2 , and Y 3 are each N or —CH—, wherein —CH— is optionally substituted with R a2 in place of H;

R a1 is (a) a 3-7-membered heterocycle having 1-2 heteroatoms which are independently N, S or O, and optionally one group —C(═O)— wherein the heterocycle optionally has 1-3 double bonds and is optionally substituted with 1-3 substituent groups which are independently halogen, CH 3 , CF 3 , —OCH 3 , or —OCF 3 ; (b) —NR 6 R 7 ; (c) —N(C 1 -C 3 alkyl)(SO 2 C 1 -C 3 alkyl); (d) C 1 -C 3 alkyl optionally substituted with 1-7 halogens; (e) —OC 1 -C 3 alkyl optionally substituted with 1-7 halogens; and (f) —SC 1 -C 3 alkyl optionally substituted with 1-7 halogens;

Each R a2 is optionally halogen, CH 3 , CF 3 , —OCH 3 , or —OCF 3 ;

A is A 2 , wherein A 2 is phenyl or pyridyl optionally substituted with 1-3 groups which are independently halogen, CH 3 , CF 3 , —OCH 3 , —OCF 3 , or —CN;

A 3 is phenyl or pyridyl, which is optionally substituted with one group X and with 1-4 substituent groups which are independently halogen, C 1 -C 3 alkyl optionally substituted with 1-7 halogens, or —OC 1 -C 3 alkyl optionally substituted with 1-7 halogens;

X is (a) C 3 -C 7 cycloalkyl optionally substituted with one group D1, and cycloalkyl is optionally substituted with 1-3 substituent groups which are independently halogen, —OH, C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-5 halogens and optionally with 1-2 groups —OH; (b) C 1 -C 3 alkyl-D1 in which alkyl is optionally substituted with 1-7 halogens and optionally with 1-2-OH; (c) phenyl optionally substituted with one group D1, wherein phenyl is optionally substituted with 1-3 substituent groups which are halogen, —OH, C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl in which C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens and optionally with 1-2 OH; (d) pyridyl which is optionally substituted with one group D1, wherein pyridyl is optionally substituted with 1-3 substituent groups which are halogen, —OH, C 1 -C 3 alkyl, or —OC 1 -C 3 alkyl, wherein C 1 -C 3 alkyl and —OC 1 -C 3 alkyl are optionally substituted with 1-7 halogens and optionally with 1-2 groups —OH; or (e) D1;

D 1 is —CO 2 R 8 ;

R 6 and R 7 are each independently H or —C 1-5 alkyl;

R 8 is H or —C 1-5 alkyl optionally substituted with 1-7 halogens; and

d is 0, 1 or 2.

8. The compound of claim 1 having formula I or a pharmaceutically acceptable salt thereof, wherein

R is H;

R 1 is CH 3 ;

B is A 1 , wherein A 1 has the structure of formula II:

Y 1 , Y 2 , and Y 3 are each —CH— or —N—;

A is A 2 wherein A 2 is phenyl or pyridyl optionally substituted with 1-3 groups independently selected from F, —CN, CH 3 , CF 3 , —OCH 3 , —OCF 3 ;

R a1 is —CF 3 ;

A 3 is

wherein Z is —CH— or —N—;

X is 4-cyclohexyl-D 1 , 4-phenyl-D 1 optionally substituted with 1-2-CH 3 groups, —CH 2 CH 2 D 1 , cyclopentyl optionally substituted with 1-2-OH groups, HET(1), or isopropyl, wherein D 1 is —CO 2 R 8 ;

R 8 is H or —CH 3 ;

R b is —OCH 3 or halogen;

d is 0; and

e is an integer from 0-3.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

y 1 and Y 3 are —CH—;

y 2 is —CH— or —N—;

A 2 is phenyl which is substituted with 2 groups CF 3 .

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. 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.

13. 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.

14. 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.

15. 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.

16. 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;

(xvii) ileal bile acid transporters; and

(xviii) niacin receptor agonists.