WO2012041253A1

WO2012041253A1 - Compounds for increase of hdl-c level and uses thereof

Info

Publication number: WO2012041253A1
Application number: PCT/CN2011/080450
Authority: WO
Inventors: Xinshan Kang; Wei LONG; Yanping Wang; Yunyan Hu; Yinxiang Wang
Original assignee: Zhejiang Beta Pharma Inc.
Priority date: 2010-09-30
Filing date: 2011-09-30
Publication date: 2012-04-05

Abstract

Compounds for inhibiting cholesterol ester transport protein (CETP) activity and application thereof. These compounds include compounds of formula (I), and the pharmaceutically acceptable salts, solvates, non-covalent complexes,chelates, or prodrugs thereof, or the mixture of any form above mentioned. The application of these compounds in the preparation of medicine for preventing and/or treating atherosclerosis, increasing HDL-C and/or lowering LDL-C, in animals.

Description

THE DESCRIPTION

COMPOUNDS FOR INCREASE OF HDL-C LEVEL AND USES THEREOF

This application claims benefit of priority to Chinese priority patent application serial no. 201010297963.4 filed on September 30, 2010, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION

The invention relates to a compound for inhibition of cholesterol ester transport protein (CETP) activity, and their uses in increasing HDL-C levels in animals, especially in humans.

BACKGROUND OF THE INVENTION

Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and greater than one half million deaths are attributed to CHD each year. Further, this toll is expected to grow over the next quarter century as an epidemic in obesity and diabetes continues to grow.

It has long been recognized that in mammals, variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA Reductase inhibitors, especially the statins, in reducing coronary events is based on the reduction of circulating Lower Density Lipoprotein cholesterol (LDL-C), levels of which correlate directly with increased risk for atherosclerosis. More recently, epidemiologic studies have demonstrated an inverse relationship between High Density Lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that lower serum HDL-C levels are associated with an increased risk for CHD.

Metabolic control of lipoprotein levels is a complex and dynamic process involving many factors. One important metabolic control in man is the cholesteryl ester transfer protein (CETP), a plasma glycoprotein that catalyzes the movement of cholesteryl esters from HDL to the apoB containing lipoproteins, especially VLDL (see Hesler, C.B., et. al. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282). Under physiological conditions, the net reaction is a hetero exchange in which CETP carries triglyceride to HDL from the apoB lipoproteins and transports cholesterol ester from HDL to the apoB lipoproteins.

In humans, CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues. Intriguingly, many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al, (1998) Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3), 517-525). Numerous epidemiologic studies correlating the effects of natural variation in CETP activity with respect to coronary heart disease risk have been performed, including studies on a small number of known human null mutations (see Hirano, K.-L, Yamashita, S. and Matsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studies have clearly demonstrated an inverse correlation between plasma HDL-C concentration and CETP activity (see Inazu, A., et. al. (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin. Lipidol. 11(4), 389-396), leading to the hypothesis that pharmacologic inhibition of CETP lipid transfer activity may be beneficial to humans by increasing levels of HDL-C while lowering those of LDL.

Despite the significant therapeutic advance that statins such as simvastatin (ZOCOR®) represent, statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events. Currently, few pharmacologic therapies are available that favorably raise circulating levels of HDL-C. Certain statins and some fibrates offer modest HDL-C gains. Niacin, which provides the most effective therapy for raising HDL-C that has been clinically documented, suffers from patient compliance issues, due in part to side effects such as flushing. An agent that safely and effectively raises HDL cholesterol levels can answer a significant, but as yet unmet medical need by offering a means of pharmacologic therapy that can significantly improve circulating lipid profiles through a mechanism that is complementary to existing therapies.

New classes of chemical compounds that inhibit CETP are being investigated at several pharmaceutical companies or are in clinical trials. No CETP inhibitors are currently being marketed. Clinical trials of torcetrapib were terminated because of an increase in mortality in patients who were taking torcetrapib in an outcomes study. New compounds are needed so that one or more pharmaceutical compounds can be found that are safe and effective. The novel compounds described herein are very potent CETP inhibitors. The invention provides compounds for effectively inhibiting cholesterol ester transport protein (CETP) activity. The present invention also provides pharmaceutical compositions and metholds for safely and effectively increasing HDL cholesterol levels. DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to provide thiazolidinone derivatives for the inhibition of cholesterol ester transport protein (CETP) activity..

The thiazolidinone derivatives of the present invention are compounds of Formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a non-covalent complex thereof, a chelate thereof, a produg thereof, or mixtures of any of the foregoing,

Formula (I)

Wherein:

X is selected from the group consisting of an aryl containing k substituents Ai;

Ri is selected from the group consisting of an aryl containing m substituents A₂;

R₂ is selected from the group consisting of an aryl containing n substituents A₃, or a cycloalkyl containing n substituents A₃;

wherein k, m and n are each independently selected from any integer from 1 to 4 ;

Ai is selected from H, halogen, cyano, nitro, lower alkyl, substituted lower alkyl, lower alkyloxy, substituted lower alkyloxy, cycloalkyl, substituted cycloalkyl;

A₂ is selected from H, halogen, cyano, nitro, lower alkyl, substituted lower alkyl, lower alkyloxy, substituted lower alkyloxy, cycloalkyl, substituted cycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄ or -C(=0)R4; wherein, R₄ and R₅ are each independently selected from H, lower alkyl, substituted lower alkyl, lower alkyloxy, or substituted lower alkyloxy;

each A₃ is independently selected from H, lower alkyl, substituted lower alkyl, lower alkyloxy, substituted lower alkyloxy;

R₃ is selected from H, lower alkyl, substituted lower alkyl, lower alkyloxy or substituted lower alkyloxy, cycloalkyl or substituted cycloalkyl.

In some embodiments, X is selected from a C6-C20 aryl containg k substituents Ai. In some further embodiments, X is selected from a C6-C14 aryl containg k substituents Ai. In yet embodiments, X is selected from a C6-C10 aryl containing k substituents Ai.

In some embodiments, Ri is selected from a C6-C20 aryl containing m substituents A₂. In some further embodiments, Ri is selected from a C6-C14 aryl containing m substituents A₂. In yet embodiments, Ri is selected from a C6-C10 aryl containing m substituents A₂. In some embodiments, R₂ is selected from a C6-C20 aryl containing n substituents A₃, or a C3-C20 cycloalkyl containting n substituents A₃. In some further embodiments, R₂ is selected from a C6-C14 aryl containing n substituents A₃, or a C3-C10 cycloalkyl containing n substituents A₃. In yet embodiments, R₂ is selected from the group consisting of a C6-C10 aryl containing n substituents A₃, or a C3-C6 cycloalkyl containing n substituents A₃. In yet further embodiments, R₂ is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, phenanthryl, cyclopentyl, or cyclohexyl, optionally substituted with n substituents A₃.

In some embodiments, X is selected from a C6-C20 aryl containing k substituents Ai; Ri is selected from a C6-C20 aryl containing m substituents A₂; R₂ is selected from the group consisting of a C6-C20 aryl containing n substituents A₃, or a C3-C20 cycloalkyl containing n substituents A₃. In some further embodiments, X is selected from a C6-C14 aryl containing k substituents Ri is selected from a C6-C14 aryl containing m substituents A₂; R₂ is selected from the group consisting of a C6-C14 aryl containing n substituents A₃, or a C3-C10 cycloalkyl containing n substituents A₃. In yet embodiments, X is selected from a C6-C10 aryl containing k substituents Ai; Ri is selected from a C6-C10 aryl containing m substituents A₂; R₂ is selected from the group consisting of a C6-C10 aryl containing n substituents A₃, or a C3-C6 cycloalkyl containing n substituents A₃. In yet further embodiments, R₂ is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, phenanthryl, cyclopentyl, or cyclohexyl, optionally substituted with n substituents A₃.

In some embodiments, the thiazolidinone derivatives of the invention are compounds of Formula (la),

Formula (la)

wherein, k, m, n, and substituent(s) including A_ls A₂, A₃ and R3 are defined above.

In some embodiments, k is 1. In some further embodiments, A is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

In some embodiments, m=3. In some further embodiments, at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR4R5, -SR4, -S0₂R₄ or -C(=0)R₄.

In yet further embodiments, one of A₂ is selected from the group consisiting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄ or-C( =0) R₄, and the other two of A₂ are H; or two of A₂ are independently selected from the group consisiting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄ or -C(=0)R₄, and the other one of A₂ is H; or three of A₂ are independently selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄ or-C(=0)R₄.

In some embodiments, n is 2. In some further embodiments, at least one of A₃ is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

In yet further embodiments, one of A₃ is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl, and the other one of A₃ is H; or two of A₃ are independently selected from lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

In some embodiments, k is 1; m is 3; n is 2; Ai is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄ or -C(=0) R₄; at least one of A₃ is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

In some further embodiments, Ai is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C14 cycloalkyl, or C3-C14 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C14 cycloalkyl, C3-C14 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄ or -C(=0) R₄; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C14 cycloalkyl, or C3-C14 halocycloalkyl.

In yet further embodiments, Ai is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C10 cycloalkyl, or C3-C10 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄ or -C(=0) R₄; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C10 cycloalkyl, or C3-C10 halocycloalkyl.

In even further embodiments, Ai is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄ or -C(=0) R₄; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl.

In even more further embodiments, Ai is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; -NR4R5, -SR4, -SO2R4 or -C(=0) R₄; at least one of A₃ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens.

In even more further embodiments, Ai is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, -NR4R5, -SR4, -SO2R4 or -C(=0) R4; at least one of A₃ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃.

In some embodiments, k is 1; m is 3; n is 2; Ai is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄ or -C(=0) R₄; at least one of A₃ is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl; R₄ and R₅ are independently selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 haloalkyl or C1-C4 haloalkyloxy.

In some further embodiments, R₄ and R₅ are independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy, or sec-butoxy, optionally substituted with halogens.

In yet further embodiments, R₄ and R₅ are independently selected from -H, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, isopropoxy, n-butloxy, isobutloxy, t-butoxy, or sec-butoxy, optionally substituted by F, CI or Br.

In even further embodiments, R₄ and R₅ are independently selected from hydrogen or methyl.

In some embodiments, k is 1; m is 3; n is 2; Ai is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -NR4R5, -SR4, -S0₂R₄ or -C(=0) R4; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; R₄ and R₅ are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy or C1-C4 haloalkyloxy.

In some embodiments, k is 1; m is 3; n is 2; Ai is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; -NR4R5, -SR4, -S0₂R₄ or -C(=0) R₄; at least one of A₃ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; R₄ and R₅ are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, or sec-butoxy, optionally substituted by halogens.

In some further embodiments, at least one of A₂ is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, CF₃, -OCF₃, amino, dimethylamino, -SCH₃, sulfonyl or acetyl. In some embodiments, thiazolidinone derivatives of the invention are compounds of Formula (lb),

Formula (lb)

wherein:

R₃ is selected from the group consisting of -H, C 1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C 1-C4 haloalkyloxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl;

Re is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃;

R₇ and R₈ are independently selected from hydrogen, methyl, ethyl, propyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃, wherein at least one of R₇ and Rg is selected from methyl, ethyl, propyl, methoxy, cyclopropyl, -CF₃, or -OCF₃;

R₉, Rio and Rn are independently selected from hydrogen, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, sulfonyl or acetyl; wherein at least one of R₉, RiO and Ri l is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, sulfonyl or acetyl.

In some embodiments, R₃ is selected from: hydrogen; or methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, trifluromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted by F, CI or Br.

In some further embodiments, R₃ is selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, -CF₃ or -OCF₃.

In yet further embodiments, R₃ is methyl.

In some embodiments, R₃ is methyl, R₆ is selected from -F, -CI, -Br, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃.

In some embodiments, R₇ and Rg are independently selected from methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃.

In some embodiments, two of R₉, Rio and Rn are hydrogen. In some embodiments, at least two of R9, Rio and Rn are selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH_3i or sulfonyl.

In some embodiments, any one of R9, Rio and Rn is hydrogen.

In some embodiments, R9, Rio and Rn are independently selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, or sulfonyl.

In some embodiments, R₇ and Rg are independently selected from methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃; R₉, R₁₀ and Rn are independently selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, -SCH₃ or sulfonyl.

In some embodiments, R₃ is methyl; R^ is selected from -F, -CI, -Br, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃; R₇ and Rg are independently selected from methyl, methoxy, cyclopropyl, -CF₃ or -OCF₃; R₉, R₁₀ and Rn are independently selected from -F, -CI, -Br, cyano, nitro, methyl, isopropyl, methoxy, amino or sulfonyl.

In some embodiments, the thiazolidinone derivatives of the invention are compounds of Formula (Ic),

Formula (Ic)

wherein, R₃, 5, R₇, Rg, R9, Rio and R are defined above.

More specifically, the compounds of the current invention are most preferably selected from:

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl) biphenyl-2-yl)methyl)-4-methylthiazolidin-2-one;

(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluor omethyl)biphenyl-2-yl)methyl)-4-methylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl)methyl)-4-methylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-isopropyl-4-(trifluoromethyl)biphenyl-2-yl)methyl )-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-nitro-2'-methoxy-4-(trifluorometh

)methyl)-4-methylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-amino-2'-methoxy-4-(trifluoromethyl)biphenyl-2- yl)methyl)-4-methylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-methylthio-2'-methoxy-4-(trifiuoromethyl)bipheny

1- 2-yl)methyl)-4-methylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-methylsulfonyl-2'-methoxy-4-(trifluromethyl)biph enyl-2-yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-fluorobr^ -yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(triflulromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-cyclopropylbi^ nyl-2-yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-cyanobipheny -yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-methylbi^

2- yl)methyl)-4-methylthiazolidin-2-one;3-((4'-fluoro-4-(trifluoromethyl)b

-cyclohexylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -(5 -trifluoromethyl-2-(naphtha-2-yl)-phenylmethyl)-4- methylthiazolidin-2-one;

5-(naphth-2-yl)-3-((5'-isopropyl-2'-methoxy-4-(trifluromethyl)biphenyl-2-yl)methyl)-4 hylthiazolidin-2-one;

5 -(3 -methylphenyl)-3 -((5 '-isopropyl-4'-fluoro-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl) methyl)-4-methylthiazolidin-2-one; or

5-(3-methoxyphenyl)-3-((5'-isopropyl-4'-fluoro-2'-methoxy-4-(trifluromethyl)biph

)methyl)-4-methylthiazolidin-2-one.

In some embodiments, the compounds described herein inhibit cholesterol ester transport protein with IC50 values of 50 μΜ or less.

Also provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of at least one compound described herein, and at least one pharmaceutically acceptable excipient, adjuvant or carrier.

Further provided is the use of a composition described herein in manufacturing a medicament.

Also provided is the use of at least one compound described herein, or at least one pharmaceutical composition described herein, in manufacturing a medicament for the treatment and/or prevention of atherosclerosis, increasing HDL-C level and/or lowering LDL-C level in animals.

Further provided is the application of at least one compound described herein, or at least one pharmaceutical composition described herein, in the treatment and/or prevention of atherosclerosis, increasing HDL-C level and/or lowering LDL-C level in animals.

In some embodiments, animals described herein include humans and mammals.

In some further embodiments, animals are humans.

Also provided herein is a combination therapy comprising: (i) a compound described herein, or a pharmaceutical composition described herein, and (ii) at least one drug selected from the group consisting of HMG-CoA reductase inhibitors, other LDL-C lowering drugs, other HDL-C increasing drugs, antidiabetic drugs, anti-platelet drugs, antioxidants, vitamins, folic acid or related drugs.

The term "Alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-l-yl, and propan-2-yl, butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises from 1 to 20 carbon atoms. As used herein the term "lower alkyl" refers to an alkyl group comprising from 1 to 6 carbon atoms. Typical lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, s-butyl, pentyl, neopentyl or hexyl.

"Aryl" refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O, and S. In certain embodiments, an aryl group can comprise from 6 to 10 carbon atoms.

"Heteroaryl" refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and polycyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring. Particularly preferred heteroaryl groups are C3-C10 heteroaryl, include but are not limited to, pyrrolyl, furanyl, thienyl, pyridinyl, pyranyl, pyrazolyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, indolyl, benzofuranyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl and the like.

But, in any case, the heteroaryl and the aryl do not cross or include each other. Thereby, according to as defined above, if one or more full carbon aromatic ring fused with a heteroaryl is a heteroaryl, but not an aryl.

"Cycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In certain embodiments, the cycloalkyl group can be C3-10 cycloalkyl, such as, for example, C3-6 cycloalkyl.

"Heterocycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom and its associated hydrogen atoms, where appropriate. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, and Si. Where a specific level of saturation is intended, the nomenclature "heterocycloalkanyl" or "heterocycloalkenyl" is used. Typical heterocycloalkyl groups include, but are not limited to, groups derived from epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran and the like. Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo (=0) or oxide (-0-) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-l-thiomorpholinyl and 1,1-dioxo-l-thiomorpholinyl.

But, in any case, the heterocycloalkyl and the cycloalkyl do not cross or include each other.

Thereby, according to as defined above, if one or more full carbon hydrocarbon ring fused with a hererocycloalkyl to form a bi- or multi- or spiro-cyclic ring, is still defined as a hererocycloalkyl.

"Halogen" refers to fluorine (F), chlorine (CI), bromine (Br) or iodine (I) atoms.

"Halo" refers to a fluoro, chloro, bromo, or iodo group.

"Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, X, C3-C20 cycloalkyl, -OR₁₃, SR_i3, =0, =S, -C(O) R_i3, -C(S)Ri₃, =NR₁₃, -C(0)OR₁₃, -C(S)OR₁₃, -NR₁₃R₁₄, -C(0)NR₁₃R₁₄, cyano, nitro, -S(0)2R₁₃, -OS(02)OR₁₃, -OS(0)2Ri₃, -OP(0)(ORi₃)(ORi₄); wherein each X is independently a halogen (F, CI, Br or I), and Ri₃ and Ri₄ is independently selected from -H, lower alkyl, lower haloalkyl. In some embodiments, the substituent(s) is independently selected from the group consisting of -F, -CI, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, , -SCH₃, -SC2H5, formaldehyde group, -C(OCH₃), cyano, nitro, CF₃,-OCF₃, amino, dimethylamino, methyl thio, sulfonyl and acetyl. Particularly preferred substituent(s) is -F, -CI or -Br.

As used herein, the "compound " of the present invention includes the compounds of Formula (I), (la), (lb) and (Ic), and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms of the compounds include salts, solvates, non-covalent complexes, chelates, or produgs thereof, or the mixture of any form mentioned above.

As used herein, "pharmaceutically acceptable " refers to generally recognized for use in animals, and more particularly in humans.

"Therapeutically effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

"HMG-CoA reductase inhibitor", the inhibitor of hydroxymethylglutaryl coenzyme A reductase, is selected from, but is not limited to, statins such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin and derivatives thereof and the like.

"Other LDL-C-lowering agent", is selected from, but is not limited to, statins such as simvastatin,, pitavastatin and derivatives thereof and the like, non-statins such as cholesterol inhibitor such as ezetimibe, etc.

"Other HDL-C-increasing agent ", is selected from, but is not limited to, nicotinic acid, statins such as lovastatin, etc, torcetrapib, muraglitazar, tesaglitazar, naveglitazar, fibrates such as fenofibrate and, gemcitabine, bezafibrate etc.

"Antidiabetic reagent", is selected from, but is not limited to, antihyperglycemic agent such as TZD, biguanides, a-glycoside enzyme inhibitor etc. blood glucose-reducing agent such as sulfonylurea, benzoic acid derivatives, amino acid derivatives, GLP-1 analogues etc.

"Platelet inhibitor", is selected from, but is not limited to, aspirin, clopidogrel, ticlopidine, heparin, warfarin, dextran-10, dextran-40, ozagrel, ozagrel sodium, troxerutin, clofibrate, dazoxiben, beraprost, iloprost, epoprostenol, indobufen, cilostazol, dipyridamole, sulfinpyrazone etc.

"Antioxidant", is selected from, but is not limited to, biological flavones such as proanthocyanidins (OPCs), coenzyme Q10, zinc, selenium, germanium, copper, manganese, lipoic acid, β-carotene, lycopene, superoxide dismutase (SOD), catalase, seleniferous enzyme (GPX), a-fatty acid, half cystine, gluthione, N-Acetyl-L-cysteine (NAC).

"Vitamin" is selected from, but is not limited not, vitamin A, vitamin C, vitamin D, vitamin E and the like and derivatives thereof or the like.

CETP ASSAY

An in vitro continuous assay for determining IC50's of CETP inhibition was performed based on a modification of the method described by Epps et al. See Epps et Ai.(1995) Method for measuring the activities of cholesteryl ester transfer protein (lipid transfer protein), Chem. Phys. Lipids. 11, 51-63.

Particles used in the assay were created from the following sources: Synthetic donor HDL particles containing DOPC (Dioleoyl Phosphatidyl Choline), BODIPY@-CE (Molecular Probes C-3927), triolein (a triglyceride), and apoHDL were essentially created by probe sonication as described by Epps et al, but with the addition of a non-diffusable quencher molecule, dabcyl dicetylamide, in order to reduce background fluorescence. Dabcyl dicetylamide was made by heating dabcyl n-succinimide with dicetylamine in DMF at 95 ^°C overnight in the presence of diisopropylamine catalyst. Native lipoproteins from human blood were used as acceptor particles. Particles having a density less than 1.06 g/ml were collected by ultracentrifugation. These particles include VLDL, IDL, and LDL. Particle concentrations were expressed in terms of protein concentration as determined by BCA assay (Pierce, USA). Particles were stored at 40 ^°C until use.

An assay cocktail containing CETP, IX CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA), and half the final concentration of acceptor particles was prepared, and ΙΟΟμί of the assay cocktail was added to each well of a 96-well plate. Test compounds in DMSO were added in a volume of 3μί. The plate was mixed on a plate shaker and then incubated at 25 ^°C for 1 hour. A second assay cocktail containing donor particles, the remaining acceptor particles and IX CETP buffer was prepared. 47μί of the second assay cocktail was added to the reaction wells to start the assay. Assays were performed at 25 ^°C in a final volume of 150μί. Final concentrations of materials were: 5 ng/μΐ, donor particles, 30 ng/μΐ, acceptor particles (each expressed by protein content), IX CETP buffer, 0.8 nM recombinant human CETP (expressed in CHO cells and partially purified), and up to 2% DMSO when testing compounds. The assay was followed in a fluorescence plate reader set for a 45 minute kinetic run at 25 ^°C which read the samples every 45 sec at Ex = 480 nm, Em = 511 nm, with a cutoff filter at 495 nm, and 6 reads/well.

Data was evaluated by obtaining an initial rate, expressed in relative fluorescence units per second, for the pseudolinear portion of the curve, often 0-500 or 1000 sec. Comparison of the rates of samples with inhibitors to an uninhibited (DMSO only) positive control yielded a percent inhibition.

A plot of percent inhibition vs. log of inhibitor concentration was used to calculate IC50.

EXAMPLES

The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds of the invention.

The following examples are only used to describe some embodiments of the current invention to make the current invention more fully appreciated and understood by those skilled in the art, but should not limit the spirit and scope of the current invention in any way. The scope of the invention is defined by the appended claims. In the detailed description of the preferred embodiments of the current invention, those technologies or methods not stated expressly are those that are regular and apparent to those skilled in the art. Compounds of this invention have an IC50 value as measured using the assay described above of less than 50μΜ. Compounds preferably have an IC50 in the range of 5nM to 10μΜ, more preferably in the range of 5nM to ΙμΜ, even more preferably in the range of 5nM to 200nM, and still more preferably in the range of 5nM to ΙΟΟηΜ.

Example 1

Synthesis of 5-(3,5-bis(trifiuoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biph enyl-2-yl)methy l)-4-methylthiazolidin-2-

Step A: 50g 3, 5-bis-trifluoromethyl-benzaldehyde, 56.5g nitro ethane and 100 ml of anhydrous ethanol were added into a 500 mL 3-neck flask. Under nitrogen gas 86 ml 10% NaOH aqueous solution (m/v) was added at 0^°C . The reaction mixture was stirred for 1 hr, and then was added 650 mL 2% acetic acid aqueous solution (m/v) and stirred at room temperature for 1 hr. 1.2 L water and 1.2 L ethyl acetate were added. Aqueous phase and organic phase were separated, and the aqueous phase was further extracted by ethyl acetate (2x 1.2 L). The organic phases were combined and washed sequentially with 1 L saturated NaHC0₃ solution and 500 mL NaCl solution, then dried with Na₂SC"4 and filter. The filtrate went through vacuum distillation to give a colorless oil, a racemic product, 35g.

Step B: 2.6g triphenylphosphine and 35 mL tetrahydrofuran were added into 100 mL round-bottom flask at -10 ^°C . To the mixture 1.74g diethyl azodicarboxylate (DEAD) was added in. The reaction mixture was stirred at -10^°C for 8 hr to form cream-colored suspension.

To the reaction mixture, 0.61g l-(3,5-bis-trifluromethylphenyl)-2-nitro-l -hydroxy propane, 0.78g thioacetic acid and 7.5 ml tetrahydrofuran were added in at -10^°C , and stirred at room temperature for 20 hr.Then the reaction mixture was concentrated, dispersed with n-hexane, and filtered. The filtrate was washed by saturated NaCl solution, dried with anhydrous magnesium sulfate, and filtered. A crude product was then obtained by removing solvent under vacuum, and further purified by a Flash Chromatography to give 0.35g of product 1. Step C: 50 mg Raney nickel, 50 mg product 1, 0.75 mL 30% formic acid solution (v/v) and 10 mL methanol were mixed and stirred to form a suspension. At room temperature, 15 psi of hydrogen gas was introduced overnight till reaction completion verified by TLC. Catalyst was removed by filtering, and methanol was removed by vacuum distillation, then 28% of NH₄OH solution was added with pH value adjusted to 9-10, followed by diluting with 20 mL water. Solvent was removed by vaccum distillation to obtain a white solid product 2.

Step D:Under nitrogen gas, 39. lg product 2 and 100 mL dried dichloromethane were added into a 200 mL 3-neck flask, and then 106 mg N, N-diisopropyl ethylamine and 20.2 mg triphosgene were slowly added into the mixture. The reaction mixture was cooled to 0^°C in ice-bath, stirred for 1 hr, and then concentrated to about 5 ml. 50 mL water and 50 mL ethyl acetate were added. After separation, the water phase was further extracted by 250 ml ethyl acetate. The organic phases were combined and dried by anhydrous Na₂S0₄and distillated under vacuum to obtain a crude product. The crude product was further purfied by a flash chromatography to obtain 32.1 mg of product 3.

Step E: lOg (0.0405 mol) product 4, 11.05g(0.04455 mol) 2-methoxycarbonyl-4- trifiuromethylphenylboronic acid, 2.45g tetra-(triphenylphosphine) palladium, 16g anhydrous potassium carbonate and 100 ml tetrahydrofuran were added into a 250 mL 3-neck fiaskto form a suspension. The mixture was heated to reflux overnight, then cooled to room temperature, filtered, poured into 300 mL water, and was extracted by 3><300 mL ethyl acetate. The organic phase was washed by saturated NaCl solution, dried by anhydrous Na₂S0₄ and distilled under vacuum to obtain a yellow solid. Recrystallization in ethyl acetate gave 7.82g of product 5.

Step F: Under nitrogen gas, 5.0g. (0.0283 mol) product 5 was dissolved in 200 mL diethyl ether in a 500 mL 3-neck falsk. 2.16g (0.0566 mol) lithium aluminum hydride was added into the flask in batches, and heated to reflux for 10 hr till reaction completion shown by TLC. And then the reaction was quenched by slowly added into water, filtered and rotary evaporated, to obtain a crude product, The crude prouduct was further purified by silica gel column chromatography to obtain 7.76g of product 6.

Step G: 7.76g product 6 in methylene chloride was added into a 100 mL flask and sulfuric acid wad added in drops in ice-bath. After cooling down, the mixture was added hydrobromic acid (2.75g) in acetic acid solution in drops. The ice-bath was then removed. The reaction mixture was heated to reflux for 2 hr till reaction completion monitored by TLC. The reaction solution was extracted by methylene chloride three times, and combined, washed by water and dried. Rotary evaporation gave a product 7, 6.43g. Product 7 did not require further purification for the next step.

Step H: 6.43g prouduct 7 was dissolved in 80 mL DMF in a 250 mL flask, and 0.37g NaH( 70%) was added. 5.23g prouduct 3 in DMF(30 mL) solution was added in drops. The mixture was then heated to reflux at 80 ^°C and stirred for 5 hr till reaction completion monitored by TLC. The reaction mixture was further filtered, concentrated by rotary evaporation. Dichloromethane and water was used for extraction. The organic phase was washed by water, dried, and evaporated under vacuum to remove solvent, to give a crude product. The crude product was further purified by chromatography to obtain 6.22g white solid prouduct 8. LC-MS[M+H]-m/z is 655.

Example 2

Synthesis of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromet hyl)biphenyl-2-yl)methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 655. Example 3

Synthesis

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-isopropyl-2'-methoxy-4-(trifluoromethyl)biphi methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 637.

Example 4

Synthesis of 5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-isopropyl-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4- methylthiazolidin-2-one;

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 607.

Example 5

Synthesis of

5-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-nitro-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl)met hyl)-4-methylthiazolidin-2-one :

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 640.

Example 6

Synthesis of 5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-amino-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl)me thyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 610. Example 7

Synthesis of 5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-methylthio-2'-methoxy-4-(trifluoromethyl)biphenyl-2-y l)methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the

LC-MS[M+H]-m/z as 641.

Example 8

Synthesis

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-methylsulfonyl-2'-methoxy-4-(trifluromethyl)biphen 2-yl)methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS [M+H]-m/z as 673. Example 9

Synthesis of 5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-fluorobiph methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 605.

Example 10

Synthesis of 5-(3,5-bis(triflulromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-cyclopropylbiphenyl- 2-yl)methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 627.

Example 11

Synthesis

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-cyanobiphi methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 612.

Example 12

Synthesis of 5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-methylbiphenyl-2-yl) methyl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 601.

Example 13

Synthesis Of

3 -((4'-fluoro-4-(trifluoromethyl)biphenyl-2-yl)methyl)-5 -cyclohexylthiazolidin-2-one :

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 438.

Example 14

Synthesis of

5-(naphthyl-2-yl)-3-((5'-isopropyl-2'-methoxy-4-(trifluromethyl)biphenyl-2-yl)methyl)-4-methylt hiazolidin-2-one :

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 551.

Example 15

Synthesis of 5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -(5 -trifluoromethyl-2-(naphth-2-yl)-phenylmethy l)-4-methyl thiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 615.

Example 16

Synthesis of 5 -(3 -methylphenyl)-3 -((5 '-isopropyl-4'-fluoro-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl)meth yl)-4-methylthiazolidin-2-one:

Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 533.

Example 17

Synthesis of 5 -(3 -methoxyphenyl)-3 -((5 '-isopropyl-4'-fluoro-2'-methoxy-4-(trifluromethyl)biphenyl-2-yl)met hyl)-4-methylthiazolidin-2-one : Similar procedure to Example 1 was followed to arrive at the title compound, with the LC-MS[M+H]-m/z as 549.

Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the invention should not be limited to the description of the preferred versions described herein.

All features disclosed in the specification, including the abstract and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in the specification, including abstract and drawings, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Each reference cited in the present application is herein incorporated by reference in its entirety.

Claims

THE CLAIMS

1. A compound of Formula (I), and pharmaceutically acceptable salts, solvates, non-covalent complexes, chelates, or produgs of the compounds mentioned above, or the mixture of any form above mentioned,

Formula (I)

wherein,

Wherein, k, m and n are each independently selected from 1 , 2, 3, or 4;

Each Ai is independently selected from H, halogen, cyano, nitro, lower alkyl, substituted lower alkyl, lower alkyloxy, substituted lower alkyloxy, cycloalkyl, or substituted cycloalkyl;

Each A₂ is independently selected from H, halogen, cyano, nitro, lower alkyl, substituted lower alkyl, lower alkyloxy, substituted lower alkyloxy, cycloalkyl, substituted cycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄, or -C(=0)R₄; wherein, R₄ and R₅ are each independently selected from H, lower alkyl, substituted lower alkyl, lower alkyloxy, or substituted lower alkyloxy;

Each A₃ is independently selected from H, lower alkyl, substituted lower alkyl, lower alkyloxy, or substituted lower alkyloxy;

R₃ is selected from H, lower alkyl, substituted lower alkyl, lower alkyloxy or substituted lower alkyloxy, cycloalkyl, or substituted cycloalkyl.

2. The compound of claim 1 , wherein, X is selected from a C6-C20 aryl containg k substituents Ai.

3. The compound of claim 2, wherein, X is selected from a C6-C14 aryl containg k substituents Ai.

4. The compound of claim 3, wherein, X is selected from a C6-C10 aryl containing k substituents Ai.

5. The compound of claim 1 , wherein, Ri is selected from a C6-C20 aryl containing m substituents A₂.

6. The compound of claim 5, wherein, Ri is selected from a C6-C14 aryl containing m substituents A₂.

7. The compound of claim 6, wherein Ri is selected from a C6-C10 aryl containing m substituents A₂.

8. The compounds of claim 1, where R₂ is selected from a C6-C20 aryl containing n substituents A₃, or a C3-C20 cycloalkyl containting n substituents A₃.

9. The compound of claim 8, wherein R₂ is selected from a C6-C14 aryl containing n substituents A₃, or a C3-C10 cycloalkyl containing n substituents A₃.

10. The compound of claim 9, wherein R₂ is selected from the group consisting of a C6-C10 aryl containing n substituents A₃, or a C3-C6 cycloalkyl containing n substituents A₃.

11. The compound of claim 10, wherein R₂ is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, phenanthryl, cyclopentyl, or cyclohexyl, optionally substituted with n substituents A₃.

12. The compound of claim 1, wherein X is selected from a C6-C20 aryl containing k substituents Ai; Ri is selected from a C6-C20 aryl containing m substituents A₂; R₂ is selected from the group consisting of a C6-C20 aryl containing n substituents A₃, or a C3-C20 cycloalkyl containing n substituents A₃.

13. The compound of claim 12, wherein X is selected from a C6-C14 aryl containing k substituents Ai; Ri is selected from a C6-C14 aryl containing m substituents A₂; R₂ is selected from the group consisting of a C6-C14 aryl containing n substituents A₃, or a C3-C10 cycloalkyl containing n substituents A₃.

14. The compound of claim 13, wherein: X is selected from a C6-C10 aryl containing k substituents Ai; Ri is selected from a C6-C10 aryl containing m substituents A₂; R₂ is selected from the group consisting of a C6-C10 aryl containing n substituents A₃, or a C3-C6 cycloalkyl containing n substituents A₃.

15. The compound of claim 14, wherein R₂ is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, phenanthryl, cyclopentyl, or cyclohexyl, substituted with n substituents A₃.

16. The compound of of claim 1, wherein, the compound is as in Formula (la),

Formula (la).

17. The compound of claim 16, wherein, k is 1.

18. The compound of claim 17, wherein Ai is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

19. The compound of claim 16, wherein m=3.

20. The compound of claim 19, wherein at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄, or -C(=0) R₄.

21. The compound of claim 20, wherein, one of A₂ is selected from the group consisiting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄, or-C( =0) R₄, and the other two of A₂ are H.

22. The compound of claim 20, wherein, two of A₂ are independently selected from the group consisiting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -S0₂R₄,or -C(=0)R₄, and the other one of A₂ is H.

23. The compound of claim 20, three of A₂ are independently selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR4R5, -SR4, -S0₂R4, or -C(=0)R4.

24. The compound of claim 16, wherein, n is 2.

25. The compound of claim 24, wherein, at least one of A3 is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

26. The compound of claim 25, wherein, one of A₃ is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl, and the other one of A₃ is H.

27. The compoundof claim 25, wherein, two of A₃ are independently is selected from lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

28. The compound of claim 16, wherein, k is 1; m is 3; n is 2; Ai is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, C3-C20 halocycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄, or -C(=0)R₄; at least one of A₃ is selected from the group consisting of lower alkyl, lower haloalkyl, lower alkyloxy, lower haloalkyloxy, C3-C20 cycloalkyl, or C3-C20 halocycloalkyl.

29. The compound of claim 28, wherein, A₁ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C14 cycloalkyl, or C3-C14 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C14 cycloalkyl, C3-C14 halocycloalkyl, -NR4R5, -SR4, -S0₂R₄, or -C(=0)R4; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C14 cycloalkyl, or C3-C14 halocycloalkyl.

30. The compound of claim 29, wherein, Ai is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C10 cycloalkyl, or C3-C10 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C10 cycloalkyl, C3-C10 halocycloalkyl, -NR4R5, -SR4, -S0₂R₄, or -C(=0)R4; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, Cl-C4alkyloxy, Cl-C4haloalkyloxy, C3-C10cycloalkyl, or C3-C10halocycloalkyl.

31. The compound of claim 30, wherein, Ai is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -NR₄R₅, -SR₄, -SO₂R₄, or -C(=0)R4; at least one of A₃ is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl.

32. The compound of claim 31, wherein, A₁ is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens; -NR4R5, -SR4, -SO2R4, or at least one of A₃ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with halogens.

33. The compound of claim 32, wherein, A₁ is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃; at least one of A₂ is selected from the group consisting of halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, -NR₄R₅, -SR₄, -SO₂R₄, or -C(=0) R₄; at least one of A₃ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃.

34. The compound of claim 32, wherein, R₄ and R5 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, or sec-butoxy, optionally substituted by halogens.

35. The compound of claim 34, wherein, at least one of A₂ is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, CF₃, -OCF₃, amino, dimethylamino, -SCH₃, sulfonyl, or acetyl.

36. The compound of claim 31, wherein, R₄ and R₅ are independently selected from hydrogen, C 1 -C4 alkyl, C 1 -C4 haloalkyl, C 1 -C4 alkyloxy, or C 1 -C4 haloalkyloxy.

37. The compound of claim 28, wherein, R₄ and R5 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 haloalkyl, or C1-C4 haloalkyloxy, optionally substituted with halogens.

38. The compound of claim 37, wherein, R₄ and R₅ are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy, or sec-butoxy, optionally substituted with halogens.

39. The compound of claim 38 wherein, R₄ and R₅ are independently selected from -H, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, trifluromethoxy, ethoxy, propoxy, isopropoxy, n-butloxy, isobutloxy, t-butoxy, or sec-butoxy, optionally substituted by F, CI or Br.

40. The compound of claim 39, wherein, R₄ and R₅ are independently selected from hydrogen or methyl.

41. The compound of claim 16, wherein the compound is as in Formula (lb).

Formula (lb)

wherein,

R₃ is selected from the group consisting of -H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyloxy, C1-C4 haloalkyloxy, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl;

R6 is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃;

R₇ and Rg are independently selected from hydrogen, methyl, ethyl, propyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃, and at least one of R₇ and Rg is selected from methyl, ethyl, propyl, methoxy, cyclopropyl, -CF₃, or -OCF₃;

Rg, Rio and Rn are independently selected from hydrogen, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, sulfonyl, or acetyl; and at least one of Rg, Rio and Rn is selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, sulfonyl, or acetyl.

42. The compound of claim 41, wherein, R₃ is selected from: hydrogen; or methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, trifluromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted by F, CI or Br.

43. The compound of claim 42, wherein, R₃ is selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, -CF₃ or -OCF₃.

44. The compound of claim 43, wherein, R₃ is methyl.

45. The compound of claim 44, wherein, the compound is as in Formula (Ic).

Formula (Ic)

46. The compound of claim 41 , wherein, R₃ is methyl, R₆ is selected from -F, -CI, -Br, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃.

47. The compound of claim 41 , wherein, R₇ and Rs are independently selected from methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃.

48. The compound of claim 41 , wherein, two of R₉, Rio and Rn are hydrogen.

49. The compound of claim 41 , wherein, at least two of R₉, Rio and Rn are selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, or sulfonyl.

50. The compound of claim 41 , wherein, any one of R₉, Rio and Rn is hydrogen.

51. The compound of claim 41 , wherein, R₉, Rio and Rn are independently selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, dimethylamino, -SCH₃, or sulfonyl.

52. The compound of claim 41 , wherein, R₇ and Rs are independently selected from methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃; R₉, Rio and Rn are independently selected from halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, -OCF₃, amino, -SCH₃, or sulfonyl.

53. The compound of claim 41 , wherein, R₃ is methyl; 5 is selected from -F, -CI, -Br, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl, -CF₃, or -OCF₃; R₇ and Rg are independently selected from methyl, methoxy, cyclopropyl, -CF₃, or -OCF₃; R₉, Rio and Rn are independently selected from -F, -CI, -Br, cyano, nitro, methyl, isopropyl, methoxy, amino, or sulfonyl.

54. The compound of claim 1 , wherein the compound is selected from:

5-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-nitro-2'-methoxy-4-(trifluoromethyl)bi^

)methyl)-4-methylthiazolidin-2-one;

5 -(3 ,5 -bis(trifluoromethyl)phenyl)-3 -((5 '-methylthio-2'-methoxy-4-(trifluoromethyl)bipheny

1- 2-yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-fluorobiphe -yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(triflulromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-cyclopropylbiphe nyl-2-yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-cyanobiphenyl-2 -yl)methyl)-4-methylthiazolidin-2-one;

5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-methylbiph

2- yl)methyl)-4-methylthiazolidin-2-one;

3-((4'-fluoro-4-(trifluoromethyl)biphenyl-2-yl)methyl)-5-cyclohexylthiazolidin-2-one;

5 -(naphth-2-yl)-3 -((5 '-isopropyl-2'-methoxy-4-(trifluromethyl)bipheny l-2-yl)methyl)-4-met hylthiazolidin-2-one;

5 -(3 -methoxyphenyl)-3 -((5 '-isopropyl-4'-fluoro-2'-methoxy-4-(trifluromethyl)biphenyl-2-yl )methyl)-4-methylthiazolidin-2-one.

55. The compound according to any one of claims 1-54, wherein the compound inhibits cholesterol ester transport protein with IC50 values of 50 μΜ or less.

56. A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound according to any one of claims 1-55, and at least one pharmaceutically acceptable excipient, adjuvant or carrier.

57. Use of a composition according to claim 56 in manufacturing a medicament.

58. Use of at least one compound according to any one of claims 1-55, or at least one pharmaceutical composition according to claim 56, in manufacturing a medicament for the treatment and/or prevention of atherosclerosis, increasing HDL-C level and/or lowering LDL-C level in animals.

59. Use of at least one compound according to any one of claims 1-55, or at least one pharmaceutical composition according to claim 56, in the treatment and/or prevention of atherosclerosis, increasing HDL-C level and/or lowering LDL-C level in animals.

60. The use according to claims 58-59, wherein, the said animals include humans and mammals.

61. The use according to claim 60, wherein, the said animals are humans.

62. A combination therapy comprising: (i) a compound according to any one of claims 1-55, or a pharmaceutical composition according to claim 56, and (ii) at least one drug selected from the group consisting of HMG-CoA reductase inhibitors, other LDL-C lowering drugs, other HDL-C increasing drugs, antidiabetic drugs, anti-platelet drugs, antioxidants, vitamins, folic acid or related drugs.