KR20180009693A - Oxazolidinone derivative compounds as a CETP inhibitor - Google Patents

Abstract

Provided are an oxazolidinone derivative compound represented by chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by chemical formula I inhibits cholesteryl ester transfer protein (CETP), bringing an increase in amounts of high-density lipoprotein (HDL)-cholesterol while reducing low-density lipoprotein (LDL)-cholesterol level. Accordingly, the pharmaceutical composition containing the same can be used to prevent or treat disorders or diseases caused by inhibition of CETP or mediation by CETP.

Description

Oxazolidinone derivative compounds as CETP inhibitors < RTI ID = 0.0 >

The present invention relates to an oxazolidione derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; A pharmaceutical composition comprising these as an active ingredient; A therapeutic method using them; And their use for the manufacture of medicaments.

Atherosclerosis and associated coronary artery disease (CAD) are one of the major causes of death in modern industrialized societies. Coronary Heart Disease (CHD) is the most common cause of death in the United States, although attempts to change secondary risk factors such as smoking, obesity, and lack of exercise are continuing and dyslipidemia can be treated with dietary modification and drug therapy Cardiovascular disease accounts for 44% of all deaths, and 53% of these deaths are known to be associated with atherosclerotic coronary heart disease.

The risk of developing such coronary heart disease is known to be closely related to certain plasma lipid levels. Although elevated LDL-cholesterol may be the most well-known form of dyslipidemia, this is not the only significant lipid-related contributor to coronary heart disease (CHD). Low HDL-cholesterol is also a known risk factor for coronary heart disease. High levels of LDL-cholesterol and triglyceride are positively correlated with risk of developing cardiovascular disease, while high levels of HDL-cholesterol are negatively correlated with this.

Controlling the lipoprotein level metabolism is a complex and dynamic process involving many factors. One of the key factors controlling the lipoprotein level metabolism in the human body is cholesteryl ester transfer protein, a plasma glycoprotein that catalyzes the transfer of cholesteryl esters from HDL-cholesterol to lipoproteins, especially to apoB containing VLDL transfer protein (hereinafter referred to as "CETP"). The overall reaction involving CETP is the heterotransformation in which CETP carries the triglyceride from apoB lipoprotein to HDL-cholesterol and transports the cholesterol ester from HDL-cholesterol to apoB lipoprotein. CETP is a protein involved in cholesterol reverse transport (cholesterol is transported from the end of the liver to the liver), and if it inhibits it effectively increases HDL-cholesterol to prevent cardiovascular disease, then developing a compound that can inhibit it very important.

In connection with the risk of coronary heart disease, a number of epidemiological studies have been conducted that relate to the effects of natural deformation in CETP activity. These studies have clearly demonstrated an inverse relationship between plasma HDL-cholesterol concentration and CETP activity, and the pharmacological inhibition of CETP lipid transport activity by increasing levels of HDL-cholesterol, while lowering LDL-cholesterol levels, The hypothesis was that it could work favorably.

However, at present, pharmacologic therapies in a manner that advantageously raises the circulating level of HDL-cholesterol are rarely useful. While certain statins and some fibrates offer moderate HDL-cholesterol gains, statins only help to achieve a reduction in risk of about one-third of the risk of atherosclerosis treatment and prevention, leading to atherosclerotic disease It can not be prevented. Clinically reported niacin, which provides the most effective treatment for elevating HDL-cholesterol, has the problem of side effects such as partial flushing.

On the other hand, a new class of compounds that inhibit CETP is under study or in clinical trials in some pharmaceutical companies, and there are currently no CETP inhibitors available to the market. The CETP inhibitors developed so far include structurally similar Torcetrapib (WO 02/088085), Anacetrapib (WO 2006/014357), Evacetrapib, And DEZ001 (TA-8995), and the other is a benzenethiol derivative Dalcetrapib (International Patent Publication No. WO 98/35937) .

However, Pfizer's Torcetrapib was stopped in Phase 3 due to increased blood pressure and mortality, and this side effect was due to increased levels of the hormone levels of aldosterone and corticosterone associated with elevated blood pressure Studies have shown that increased blood pressure and increased wall thickness can lead to inflammation-induced mortality (Forrest et al., British Journal of Pharmacology, 2008, 1-9).

Another CETP inhibitor, Roche's Dalcetrapib, has also been discontinued in Phase III clinical trials, although side effects such as Tocetraplast have not been reported, but are known to lack effective side effects (Alyse S Goldberg et al, Drug Design Development and Theraphy, 2012, 6, 251-259).

Recently, Merck's Anacetrapib found that patients who took anacetrapib in the clinical trials of DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) increased HDL-cholesterol by 138% and LDL - A 40% reduction in cholesterol was reported (Philip Barter et al, The New England Journal of Medicine, 2010, 363, 2406-2415). Based on these results, Merck is conducting clinical trials on the improvement of cardiovascular disease in patients taking anacetrapib for about 30,000 people (ClinicalTrials.gov, NCT01252953).

In addition, Lilly's Evacetrapib started clinical trials for 10,000 patients in recent years, showing that HDL-cholesterol is increased in a dose-dependent manner in clinical 2 and there are no side effects such as elevated blood pressure (Clinical Trials .gov, NCT01687998), and the program (ACCELERATE) was concluded in October 2015 because it was judged to be ineffective in large-scale clinical trials of Phase III clinical trials.

Meanwhile, DEZ001, which has been transferred from Dezima to Amgen, has completed Phase II clinical trials (TULIP) in September 2015.

The CETP inhibitor to be newly developed strives to have advantages over the CETP inhibitors or CETP inhibitors developed so far, and these advantages include, for example, efficacy, off-target effects ), Bioavailability, and food effect (food effect).

International Patent Publication No. WO 02/088085 (published Nov. 11, 2002) International Publication No. WO 2006/014357 (published on Mar. 2, 2006) WO 98/35937 (published Aug. 20, 1998) US Patent Application Publication No. US 2010/0331309 (disclosed on December 30, 2010)

It is an object of the present invention to provide a novel oxazolididinone compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition comprising a novel oxazolidinone derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, A pharmaceutical composition for the treatment or prevention of < RTI ID = 0.0 > A method of treating the disorder or disease using the oxazolidinone derivative compound or the like; And an oxazolidinone derivative compound for the preparation of a medicament for the treatment of the above-mentioned disorder or disease.

However, the problems to be solved by the present invention are not limited to the above-mentioned problems, and other problems not mentioned can be clearly understood by those skilled in the art from the following description.

A first aspect of the present invention provides an oxazolidinone derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

(I)

In this formula,

R ¹ is -halo or -CF ₃ ;

R ² is H, - (C ₁ -C ₄ alkyl) or - (CH ₂ ) _m -aryl, wherein one or more of the hydrogens of the aryl may be substituted with halo or -O- (C ₁ -C ₄ alkyl) And wherein at least one hydrogen of the -O- (C ₁ -C ₄ alkyl) may be substituted with halo;

R ³ is H, halo, - (C ₁ -C _{4 alkyl), -CF 3, -C (=} O) - (C 1 -C 4 alkyl), -C (= O) - (C 2 -C 4 Alkenyl), -O- (C ₁ -C ₄ alkyl), or -O- (C ₃ -C ₇ cycloalkyl), wherein -C (═O) - (C ₁ -C ₄ alkyl) (= O) - (C ₂ -C ₄ alkenyl) may be substituted with halo;

R < ⁴ > is H or halo;

L is - (C? C) - or nothing;

또는 -SiR⁸R⁹R¹⁰ 이고,X is H, - (C ₁ -C ₄ alkyl), - (C ₁ -C ₄ alkyl) - (C ₃ -C ₇ cycloalkyl), - (C ₃ -C ₇ cycloalkyl)

And or -SiR ⁸ R ⁹ R ^10,

R ⁵ is H or -O (C ₁ -C ₄ alkyl)

R ⁶ is H, - (C ₁ -C ₄ alkyl), -CF ₃ or halo,

R ⁷ is H, -OH or -Y- (CH ₂ ) _n -Z,

R ⁸ , R ⁹ and R ¹⁰ are each independently - (C ₁ -C ₄ alkyl) or aryl,

Y is -O- or -S-,

Z is - (C ₃ -C ₇ cycloalkyl), -C = N, -C ( = O) -R A, -C (= S) -R B, -P (= O) (OH) -R C _{, -S (= O) 2 -R} D, -NHC (= O) NHS (= O) 2 -R E, aryl, heteroaryl,

또는

이고 {여기서, -(C₃-C₇ 시클로알킬)의 하나 이상의 수소는 -(C=O)-OH 또는 -(C=O)-O(C₁-C₄ 알킬)로 치환될 수 있고, 아릴 또는 헤테로아릴의 하나 이상의 수소는 -OH, -O(C=O)-(C₁-C₄ 알킬) 또는 할로로 치환될 수 있음};

or

Wherein at least one hydrogen of - (C ₃ -C ₇ cycloalkyl) may be replaced by - (C═O) -OH or - (C═O) -O (C ₁ -C ₄ alkyl) aryl or heteroaryl of at least one hydrogen is -OH, -O (C = O) - it may be substituted with (C ₁ -C ₄ alkyl) or halo};

R ^A to R ^E are each independently - (C ₁ -C ₄ alkyl), -OH, -O (C ₁ -C ₄ alkyl), or -NR ^F R ^G ;

R ^F and R ^G are each independently H, - (C ₁ -C ₄ alkyl) or -C (= O) - (C ₁ -C ₄ alkyl);

V ¹ to V ⁴ are each independently -CH ₂ -, -NH-, -O- or -S-;

W is -O- or -S-;

m is an integer from 0 to 2;

n is an integer of 0 to 6;

A second aspect of the invention provides a compound according to the first aspect of the invention and embodiments thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; And at least one pharmaceutically acceptable carrier.

A third aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the first aspect of the present invention and embodiments thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, For the treatment or prophylaxis of a disorder or disease responsive to the treatment of a disease.

A fourth aspect of the invention is directed to a method of inhibiting CETP-mediated or CETP-mediated disorders, using a compound according to the first aspect of the disclosure and embodiments thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, Or a method for treating a disease.

A fifth aspect of the invention is directed to a compound according to the first aspect of the present invention and its embodiments, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder or disease mediated by CETP or responsive to the inhibition of CETP To provide the use of these pharmaceutically acceptable salts.

The novel oxazolididinone compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention exhibits a small side effect and an effective effect of inhibiting CETP.

The novel oxazolididinone compound, its optical isomer, or a pharmaceutically acceptable salt thereof according to the present invention is useful as a therapeutic or prophylactic agent for a disorder or disease mediated by CETP or reacting with an inhibitor of CETP Can be used.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. It should be understood, however, that the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In the drawings, the same reference numbers are used throughout the specification to refer to the same or like parts.

Throughout this specification, when an element is referred to as "including " an element, it is understood that the element may include other elements as well, without departing from the other elements unless specifically stated otherwise.

The terms "about "," substantially ", etc. used to the extent that they are used throughout the specification are intended to be taken to mean the approximation of the manufacturing and material tolerances inherent in the stated sense, Accurate or absolute numbers are used to help prevent unauthorized exploitation by unauthorized intruders of the referenced disclosure.

The word " step (or step) "or" step "used to the extent that it is used throughout the specification does not mean" step for.

Throughout this specification, the term "combination (s) thereof " included in the expression of the machine form means a mixture or combination of one or more elements selected from the group consisting of the constituents described in the expression of the form of a marker, Quot; means at least one selected from the group consisting of the above-mentioned elements.

Throughout this specification, the description of "A and / or B" means "A or B, or A and B".

Throughout this specification, "halo" or "halo group" may be, but is not limited to, F, Cl, Br, or I.

For the purposes of the present specification, "alkyl" or "alkyl group" may be a linear or branched, saturated or unsaturated alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, , Hexyl, heptyl, octyl, nonyl, decyl, or isomers thereof, but is not limited thereto.

Throughout this specification, the term "aryl" or "aryl group", alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring, such as phenyl, substituted phenyl, as well as a fused group, For example, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl, indanyl, and the like. For example, the "aryl" or "aryl group" includes one or more rings having 6 or more atoms, up to 5 rings containing up to 22 atoms may be present, Double bonds between suitable heteroatoms can alternately (resonate) exist. Said "aryl" or "aryl group" is optionally substituted with one or more substituents selected from halogen, such as F, Br, Cl or I, alkyl such as methyl, ethyl, propyl, alkoxy such as methoxy or ethoxy, (O) m (O = 1, 2) or a thiol, but is not limited thereto, such as, for example, methyl, ethyl, propyl, isopropyl, And may be substituted with one or more groups which are not limited. For example, the "aryl" or "aryl group" may be, but is not limited to, phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above.

Throughout this specification, "alkoxy" or "alkoxy group" may include, but is not limited to, an "alkyl group" as defined above and an alkoxy group bonded to an oxygen atom.

For the purposes of the present specification, "alkylene-dioxy group" may mean that an alkylene group is located between two oxygen atoms, and the above-mentioned "alkylene group" may be an alkylene group having 1 to 10 carbon atoms, But are not limited to, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, or isomers thereof.

Throughout the specification, the term "amine group ", alone or as part of another group, refers to -NH ₂ , wherein the" amine group "may also be substituted with one or two substituents which may be the same or different, Aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, carbonyl or ≪ / RTI > carboxyl.

Hereinafter, embodiments and examples of the present invention will be described in detail with reference to the accompanying drawings. However, the present invention is not limited to these embodiments and examples and drawings.

Oxazolidinone  A derivative compound

A first aspect of the present invention provides an oxazolidinone derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

(I)

In this formula,

R ¹ is -halo or -CF ₃ ;

R ² is H, - (C ₁ -C ₄ alkyl) or - (CH ₂ ) _m -aryl, wherein one or more of the hydrogens of the aryl may be substituted with halo or -O- (C ₁ -C ₄ alkyl) And wherein at least one hydrogen of the -O- (C ₁ -C ₄ alkyl) may be substituted with halo;

R ³ is H, halo, - (C ₁ -C _{4 alkyl), -CF 3, -C (=} O) - (C 1 -C 4 alkyl), -C (= O) - (C 2 -C 4 Alkenyl), -O- (C ₁ -C ₄ alkyl), or -O- (C ₃ -C ₇ cycloalkyl), wherein -C (═O) - (C ₁ -C ₄ alkyl) (= O) - (C ₂ -C ₄ alkenyl) may be substituted with halo;

R < ⁴ > is H or halo;

L is - (C? C) - or nothing;

또는 -SiR⁸R⁹R¹⁰ 이고,X is H, - (C ₁ -C ₄ alkyl), - (C ₁ -C ₄ alkyl) - (C ₃ -C ₇ cycloalkyl), - (C ₃ -C ₇ cycloalkyl)

And or -SiR ⁸ R ⁹ R ^10,

R ⁵ is H or -O (C ₁ -C ₄ alkyl)

R ⁶ is H, - (C ₁ -C ₄ alkyl), -CF ₃ or halo,

R ⁷ is H, -OH or -Y- (CH ₂ ) _n -Z,

R ⁸ , R ⁹ and R ¹⁰ are each independently - (C ₁ -C ₄ alkyl) or aryl,

Y is -O- or -S-,

Z is - (C ₃ -C ₇ cycloalkyl), -C = N, -C ( = O) -R A, -C (= S) -R B, -P (= O) (OH) -R C _{, -S (= O) 2 -R} D, -NHC (= O) NHS (= O) 2 -R E, aryl, heteroaryl,

또는

이고 {여기서, -(C₃-C₇ 시클로알킬)의 하나 이상의 수소는 -(C=O)-OH 또는 -(C=O)-O(C₁-C₄ 알킬)로 치환될 수 있고, 아릴 또는 헤테로아릴의 하나 이상의 수소는 -OH, -O(C=O)-(C₁-C₄ 알킬) 또는 할로로 치환될 수 있음};

or

Wherein at least one hydrogen of - (C ₃ -C ₇ cycloalkyl) may be replaced by - (C═O) -OH or - (C═O) -O (C ₁ -C ₄ alkyl) aryl or heteroaryl of at least one hydrogen is -OH, -O (C = O) - it may be substituted with (C ₁ -C ₄ alkyl) or halo};

R ^A to R ^E are each independently - (C ₁ -C ₄ alkyl), -OH, -O (C ₁ -C ₄ alkyl), or -NR ^F R ^G ;

R ^F and R ^G are each independently H, - (C ₁ -C ₄ alkyl) or -C (= O) - (C ₁ -C ₄ alkyl);

V ¹ to V ⁴ are each independently -CH ₂ -, -NH-, -O- or -S-;

W is -O- or -S-;

m is an integer from 0 to 2;

n is an integer of 0 to 6;

In one embodiment of the present invention, the oxazolididinone compound represented by the above formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the first aspect of the present invention is an oxazolidione derivative represented by the following formula A derivative thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

(Ia)

In this formula,

R ¹ is -halo or -CF ₃ ;

R ² is H or - (C ₁ -C ₄ alkyl);

R ³ is H, halo, - (C ₁ -C ₄ alkyl), -C (═O) - (C ₁ -C ₄ alkyl), -C (═O) - (C ₂ -C ₄ alkenyl) -CF ₃ and wherein one or more hydrogens of -C (= O) - (C ₁ -C ₄ alkyl) or -C (= O) - (C ₂ -C ₄ alkenyl) may be substituted with halo };

R ⁶ is H, - (C ₁ -C ₄ alkyl), -CF ₃ or halo;

R ⁷ is H, -OH or -Y- (CH ₂ ) _n -Z;

Y is -O- or -S-;

Z is - (C ₃ -C ₇ cycloalkyl), -C = N, -C ( = O) -R A, -C (= S) -R B, -P (= O) (OH) -R C _{, -S (= O) 2 -R} D, -NHC (= O) NHS (= O) 2 -R E, aryl, heteroaryl,

또는

이고 {여기서, -(C₃-C₇ 시클로알킬)의 하나 이상의 수소는 -(C=O)-OH 또는 -(C=O)-O(C₁-C₄ 알킬)로 치환될 수 있고, 아릴 또는 헤테로아릴의 하나 이상의 수소는 -OH, -O(C=O)-(C₁-C₄ 알킬) 또는 할로로 치환될 수 있음};

or

Wherein at least one hydrogen of - (C ₃ -C ₇ cycloalkyl) may be replaced by - (C═O) -OH or - (C═O) -O (C ₁ -C ₄ alkyl) aryl or heteroaryl of at least one hydrogen is -OH, -O (C = O) - it may be substituted with (C ₁ -C ₄ alkyl) or halo};

R ^A to R ^E are each independently - (C ₁ -C ₄ alkyl), -OH, -O (C ₁ -C ₄ alkyl), or -NR ^F R ^G ;

R ^F and R ^G are each independently H, - (C ₁ -C ₄ alkyl) or -C (= O) - (C ₁ -C ₄ alkyl);

V ¹ to V ⁴ are each independently -CH ₂ -, -NH-, -O- or -S-;

W is -O- or -S-;

n is an integer of 0 to 6;

Further, in one embodiment of the present invention, the oxazolididinone compound represented by the above formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the first aspect of the present invention is represented by the formula An isomer thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

(Ib)

In this formula,

또는 -SiR⁸R⁹R¹⁰ 이고,X is H, - (C ₁ -C ₄ alkyl), - (C ₁ -C ₄ alkyl) - (C ₃ -C ₇ cycloalkyl), - (C ₃ -C ₇ cycloalkyl)

And or -SiR ⁸ R ⁹ R ^10,

R ⁵ is -OCH ₃ ;

R ⁶ is H or halo;

R ⁷ is H or -O- (CH ₂ ) _n - (C = O) -R ^A ;

R ⁸ , R ⁹ and R ¹⁰ are each independently - (C ₁ -C ₄ alkyl) or aryl,

R ^A is -OH or -O (C ₁ -C ₄ alkyl); n is an integer of 1 to 5;

Further, in one embodiment of the present invention, the oxazolididinone compound represented by the above formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the first aspect of the present invention is represented by the following formula An isomer thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

(Ic)

In this formula,

R ³ is -O- (C ₁ -C ₄ alkyl) or -O- (C ₃ -C ₇ cycloalkyl)

R < ⁴ > is halo,

R ⁸ and R ⁹ are each independently H, halo or -O- (C ₁ -C ₄ alkyl), wherein one or more hydrogens of -O- (C ₁ -C ₄ alkyl) },

and m is an integer of 0 to 2.

In one embodiment of the present invention, the compound represented by Formula (Ia) is selected from the group consisting of compounds represented by the following Table 1, an oxazolidione derivative compound, an optical isomer thereof, But it is not limited thereto.

[Table 1]

In one embodiment of the present invention, the compound represented by formula (Ib) may be an oxazolidione derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds represented by the following formulas , But is not limited thereto.

[Table 2]

In one embodiment of the present invention, the compound represented by the formula (Ic) is an oxazolididinone compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds represented by the following formulas: But are not limited to:

[Table 3]

Herein, the pharmaceutically acceptable salt means a salt commonly used in the medical industry, and examples thereof include inorganic ion salts such as calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodine An inorganic acid salt prepared from an acid, perchloric acid and sulfuric acid or the like, an acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, , Organic acid salts prepared from glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acid salts prepared from naphthalenesulfonic acid and the like, amino acid salts prepared with glycine, arginine, lysine and the like, and amino acid salts such as trimethylamine, triethylamine, ammonia, pyridine, Picoline, and the like. However, the types of salts as defined in the present invention are not limited by these listed salts.

The compounds of formula (I) may contain one or more asymmetric carbons and thus may exist as racemates, racemic mixtures, single enantiomers, diastereomer mixtures and individual diastereomers. Such isomers may be separated by conventional techniques, for example by resolution of the compounds of formula I by column chromatography or HPLC. Alternatively, stereoisomers of each of the compounds of formula (I) may be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequence.

Oxazolidinone  Pharmaceutical composition comprising a derivative compound, a therapeutic method using the same, or a use thereof

A second aspect of the invention provides a compound according to the first aspect of the invention and embodiments thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; And at least one pharmaceutically acceptable carrier.

In the second aspect of the present invention, a detailed description of parts overlapping with those described in the first aspect of the present application is omitted, but the description of the first aspect of the present application is omitted from the second aspect of the present invention The same can be applied.

For example, the carrier may be those conventionally used, and examples thereof include sugars, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, Hydrogen, calcium, hydrogen, or a mixture thereof, but the present invention is not limited thereto.

For example, the composition may include, but is not limited to, binders, disintegrants, lubricants, pH adjusting agents, antioxidants, and the like.

For example, the binder may be selected from the group consisting of starch, microcrystalline cellulose, highly disperse silica, mannitol, di-mannitol, sucrose, lactose, polyethylene glycols, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymers , Hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof may be used, but the present invention is not limited thereto.

For example, the disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clays such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropylcellulose or carboxymethylcellulose; Alginates such as sodium alginate and alginic acid; Crosslinked celluloses such as croscarmellose sodium; Guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Sodium bicarbonate, citric acid and the like, or a mixture thereof may be used, but the present invention is not limited thereto.

For example, the lubricant may be selected from the group consisting of talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monooleate, , Glyceryl palmitostearate, colloidal silicon dioxide, or a mixture thereof, may be used, but the present invention is not limited thereto.

For example, the pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ethoxide, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, There may be used, but not limited to, a basic agent such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, and calcium triphosphate.

For example, the antioxidant may be selected from the group consisting of dibutylhydroxytoluene, butylated hydroxyanisole, tocopheryl acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyruvate and the like. The dissolution aid may be, but not limited to, polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, docusate sodium, poloxamer, and the like.

The compounds according to the first aspect of the invention and their embodiments exhibit the action of inhibiting CETP activity, elevating high density lipoprotein (HDL-cholesterol) and lowering low density lipoprotein (LDL-cholesterol) The compositions of the second aspect of the invention, wherein the composition comprises a compound according to the first aspect of < RTI ID = 0.0 > and / or < / RTI > embodiments thereof, can be used as a therapeutic or prophylactic agent for a disorder or disease that is mediated by CETP or responds to inhibition of CETP , But may not be limited thereto.

A third aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the first aspect of the present invention and embodiments thereof, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, For the treatment or prophylaxis of a disorder or disease responsive to the treatment of a disease.

In the third aspect of the present invention, a detailed description of parts overlapping with those described in the first and second aspects of the present application is omitted. However, the description of the first and second aspects of the present application is not limited to the description 3, the same description can be applied even if the description is omitted.

In one embodiment herein, the disorder or disease is selected from the group consisting of hyperlipidemia, atherosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetal lipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, Coronary heart disease, coronary artery disease, coronary vascular disease, angina pectoris, ischemia, cardiac ischemia, thrombosis, cardiac infarction, myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, coronary heart disease, But are not limited to, restenosis after angioplasty, hypertension, congestive heart failure, diabetes, diabetic vascular complications, obesity, endotoxemia, and combinations thereof.

One embodiment of the subject matter may relate to, but is not limited to, a method of inhibiting CETP activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect of the invention and embodiments thereof . For example, the subject may include, but is not limited to, humans, monkeys, cows, horses, dogs, cats, rabbits, mice,

An embodiment of the present invention relates to the use of a compound according to the first aspect of the present application and embodiments thereof for the manufacture of a medicament for the treatment of a disorder or disease mediated by CETP or responsive to inhibition of CETP in a subject But may not be limited thereto.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following Examples are given for the purpose of helping understanding of the present invention, but the present invention is not limited to the following Examples.

[ Manufacturing example ] Preparation of intermediate compounds

Manufacturing example  1: Preparation of compound of formula 1-3

Step 1: Preparation of compound of formula 1-2

(23.5 mmol, 6 g) and carbon tetrabromide (30.6 mmol, 10.4 g) were dissolved in dichloromethane at room temperature, to which was added dichloro (2-bromo-5- (trifluoromethyl) After adding triphenylphosphine (30.6 mmol, 8 g) dissolved in methane, the reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 100: 0 to 90: 10) to obtain a transparent liquid compound (1-2).

Step 2: Preparation of compound of formula 1-3

To a solution of (4S, 5R) -5- (3,5-bis (trifluoromethoxy) phenyl) -thiophene in 10 ml of THF was added NaH (60% oil dispersion; 17.2 mmol, 0.413 g) Methyl) phenyl) -4-methyloxazolidin-2-one (11.5 mmol, 3.60 g) was slowly added at room temperature and stirred for 30 minutes. Then, 1-bromo-2- (bromomethyl) -4- (trifluoromethyl) benzene (Formula 1-2) (13.8 mmol, 4.38 g) dissolved in THF (20 ml) was slowly added, Was stirred for 14 hours. The reaction mixture was then quenched with a saturated aqueous solution of NH ₄ Cl (30 ml) and extracted three times with EtOAc (60 ml). Thereafter, the organic layer was dried over anhydrous MgSO ₄ and then separated and purified by MPLC (hexane / ethyl acetate; 90:10 → 80:20) to obtain a viscous oil compound (Formula 1-3).

Manufacturing example  2: Preparation of the compound of formula (2-4)

Step 1: Preparation of compound of formula (2-2)

(45.5 mmol, 5.04 g) and acetyl chloride (46.1 mmol, 3.62 g) were dissolved in dichloromethane at 0 ° C, and pyridine (89 mg, mmol, 7.01 g) was carefully added dropwise for 3 minutes, the temperature was slowly raised to room temperature, and the mixture was stirred for 12 hours. After the reaction was completed, the reaction mixture was extracted with water (50 ml) and dichloromethane (300 ml), and the organic layer was washed twice with 1 M aqueous HCl (30 ml), dried over anhydrous MgSO ₄ , An orange solid compound (compound of formula 2-2) was obtained.

Step 2: Preparation of compound of formula 2-3

(2.34 mmol, 1.30 g) and 2-fluoro-4-methoxyphenylacetate (23.2 mmol, 8.87 g) dissolved in acetonitrile (100 ml) 72.3 mmol, 12.9 g) was added and the reaction mixture was heated to reflux for 14 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the mixture was extracted with a saturated aqueous solution of ethyl acetate (150 ml) and NaHCO ₃ (50 ml). The organic layer was then dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The product was isolated and purified by MPLC (hexane / ethyl acetate; 10: 90 - > 15: 85) to obtain an orange solid compound (compound of formula 2-3).

Step 3: Preparation of compound of formula 2-4

A solution of 5-bromo-2-chloro-4-methoxyphenol (18.2 mmol, 4.3 g), potassium acetate (72.6 mmol, 7.12 g) and B ₂ Pin ₂ (23.6 mmol, ml) and stirred under nitrogen for 30 minutes. Pd (dppf) Cl ₂ -CH ₂ Cl ₂ (1.8 mmol, 1.48 g) was added, the temperature was raised to 80 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was dried under reduced pressure. After that, the organic layer was washed successively with 50 ml of 0.5 M HCl and 50 ml of a saturated aqueous solution of NaHCO ₃ , and dried over anhydrous MgSO ₄ , And then the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 100: 0 - > 80: 20) to obtain a white solid compound (2-4).

[ Example ] Oxazolidinone  Preparation of derivative compounds

Example  1-1: Ia -1 < / RTI >

(Trifluoromethyl) benzyl) -4- (4-fluorophenyl) -5- (3,5-bis (trifluoromethyl) 2-one (Formula 1-3; 1.23 mmol, 0.675 g) and 2-fluoro-4-methoxy-5- (4,4,5,5-tetramethyl (2-4) (1.23 mmol, 0.380 g) was dissolved in THF (8 ml) and then potassium carbonate (2 ml) dissolved in water 3.68 mmol, 0.509 g). The two phase reaction mixture was degassed by nitrogen for 10 minutes. Pd (dtbpf) Cl ₂ (0.184 mmol, 0.120 g) was added to the reaction mixture, and the reaction mixture was stirred at 60 ° C for 12 hours Lt; / RTI > After the reaction was completed, the organic layer was extracted three times with ethyl acetate (20 ml) and washed with water (10 ml) and aqueous NaCl solution (10 ml). After drying over anhydrous MgSO ₄ , the solvent was removed under reduced pressure. The reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 95: 5 - > 80:20) to give white solid compound (Ia-1).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.83-7.58 (m, 5H), 7.38-7.62 (m, 1H), 7.00 (dd, J = 8.4 Hz, 12.6 Hz, 1H), 6.82 (dd, J = 5.2 Hz, 11.4 Hz, 1H ), 5.46 (dd, J = 7.9 Hz, 80.2 Hz, 1H), 4.96 (dd, J = 15.8 Hz, 126.1 Hz, 1H), 3.96 (dd, J = 16.0 Hz, 83.5 Hz, 1H) 3.67 (d, J = 7.5 Hz, 3H), 3.65-3.61 (m, 1H), 2.32 (d, J = 2.9 Hz, 3H), 0.46 (dd, J = 6.3 Hz, 61.0 Hz, 3H ).

LCMS: [M + H ^& lt ^{; +} & gt ^; ] 654.

Example  1-2: Ia -2 < / RTI >

(4S, 5R) -5- (3,5-bis (trifluoromethyl) phenyl) -4-methyl-2-oxooxazolidin-3-yl (Ia-1) (0.918 mmol, 0.600 g) in tetrahydrofuran (1 ml) was added dropwise to a solution of 4- (4-fluoro- Was dissolved in MeOH / water (8 ml: 2 ml), potassium carbonate (4.59 mmol, 0.634 g) was added and the reaction mixture was stirred at room temperature for 30 minutes. After termination of the reaction, The reaction mixture was diluted with ethyl acetate (10 ml) and acidified by gradually adding 1 M HCl aqueous solution until the water layer reached pH 7. The aqueous layer was extracted twice more with ethyl acetate (10 ml), and the organic layer was washed with anhydrous MgSO ₄ , And the solvent was dried under reduced pressure to obtain a yellow solid compound (formula (Ia-2)).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.85 (s, 1H), 7.69-7.58 (m, 4H), 7.34-7.32 (m, 1H), 6.81 (dd, J = 9.6 Hz, 24.0 Hz, 1H ), 5.51 (dd, J = 7.9 Hz, 74.0 Hz, 1H), 5.24 (d, J = 42.0 Hz, 1H), 4.91-4.84 (m, 1H), 3.90-3.77 , 3H), 0.49 (dd, J = 6.3 Hz, 42.0 Hz, 3H).

LCMS: [M + H ^& lt ^{; +} & gt ^; ] 612.

Example  1-3: Ia -3 < / RTI >

(4S, 5R) -5- (3,5-bis (trifluoromethyl) phenyl) -3 - ((4'-fluoro-5'- (Formula Ia-2; 0.090 mmol, 55 mg) was added to a solution of 4- (trifluoromethyl) - [1,1'- biphenyl] , Potassium carbonate (0.540 mmol, 75 mg) and sodium iodide (0.360 mmol, 54 mg) were dissolved in acetone (1 ml), and ethyl bromoacetate (0.360 mmol, 0.060 g) After the reaction was completed, the solvent was removed under reduced pressure, diluted with ethyl acetate (5 ml), and washed with water (2 ml). The organic layer was washed with anhydrous MgSO 4 ₄ ≪ / RTI > and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC (hexane / ethyl acetate; 95: 5 - > 80:20) to give white solid compound (Ia-3).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.85-7.71 (m, 3H), 7.65-7.58 (m, 2H), 7.36-7.30 (m, 1H), 6.89-6.77 (m, 2H), 5.53 ( (dd, J = 8.1 Hz, 50.7 Hz, 1H), 4.93 (dd, J = 15.7 Hz, 64.6 Hz, 1H), 4.74-4.61 (m, 2H), 4.26-4.09 J = 15.8 Hz, 70.1 Hz, 1H), 3.76 (d, J = 13.8 Hz, 3H), 1.27-1.22 (m, 4H), 0.48 (dd, J = 6.4 Hz, 51.2 Hz, 3H).

LCMS: [M + H ^& lt ^{; +} & gt ^; ] 699.

Example  1-4: Ia -4 < / RTI >

(4S, 5R) -5- (3,5-bis (trifluoromethyl) phenyl) -4-methyl-2-oxooxazolii prepared in Example 1-3 (Trifluoromethyl) - [1,1'-biphenyl] -3-yl) oxy) acetate (Ia- 3, 0.067 mmol, 47 mg) in THF / water (0.6 ml: 0.3 ml) was added lithium hydroxide monohydrate (0.134 mmol, 5.6 mg). The reaction mixture was then stirred at 55 < 0 > C for 3 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (5 ml) and acidified by carefully adding 1 M HCl until the water layer was pH 3. The organic layer was then dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 80:20 - > 50:50) to obtain a white solid compound (Ia-4).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.85 (s, 1H), 7.72-7.58 (m, 4H), 7.35-7.32 (m, 1H), 6.90-6.79 (m, 2H), 5.56-5.50 ( m, 1H), 4.83 (d , J = 16.0 Hz, 1H), 4.73-4.63 (m, 2H), 3.98 (dd, J = 16.0 Hz, 53.0 Hz, 1H), 3.93-3.74 (m, 4H), 0.49 (dd, J = 6.5 Hz, 39.0 Hz, 3H).

LCMS: [M + H ^& lt ^{; +} & gt ^; ] 670.

Example  1-5 to 1-55: Ia -5 to Ia -55 < / RTI >

The compounds of Examples 1-5 to 1-55 were prepared by using the same method as that described in Examples 1-1 to 1-4, but with different substituents as shown in Table 4 below.

[Table 4]

Example  2-1: Ib -1 < / RTI >

(Trifluoromethyl) benzyl) -4- (4-fluorophenyl) -5- (3,5-bis (trifluoromethyl) (0.068 mmol, 13 mg), triphenylphosphine (PPh ₃ ; 0.034 mmol, 9 mg), and a solution of methyl iodide Tinylprimethylsilane (1.02 mmol, 0.100 g) was dissolved in triethylamine / THF (3 ml: 0.3 ml) and stirred for 5 minutes under nitrogen. Then, Pd (PPh ₃ ) ₂ Cl ₂ (0.068 mmol, 0.048 g) was added thereto, followed by stirring at 50 ° C for 12 hours. After termination of the reaction, the reaction mixture was filtered through celite and the solvent was dried under reduced pressure. Then, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 95: 5 - > 90: 10) to obtain a light brown solid compound (formula (Ib-1)).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.89 (s, 1H), 7.78 (s, 2H), 7.66-7.61 (m, 2H), 7.56-7.54 (m, 1H), 5.70 (d, J = 8.1Hz, 1H), 4.97 (d , J = 15.5Hz, 1H), 4.48 (d, J = 15.4Hz, 1H), 4.02-3.95 (m, 1H), 0.80 (d, J = 6.6 Hz, 3H) , 0.26 (s, 9H).

LCMS: [M + H ^& lt ^{; +} & gt ^; ] 568.

Example  2-2 to 2-21: Ib -2 to Ib -21 < / RTI >

The compounds of Examples 2-2 to 2-21 were prepared by using the same method as described in Example 2-1 but with different substituents as shown in Table 5 below.

[Table 5]

It will be understood by those of ordinary skill in the art that the foregoing description of the embodiments is for illustrative purposes and that those skilled in the art can easily modify the invention without departing from the spirit or essential characteristics thereof. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.

The scope of the present invention is defined by the appended claims rather than the detailed description, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be interpreted as being included in the scope of the present invention .

Claims (10)

An oxazolidinone derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(I)

In this formula,
R ¹ is -halo or -CF ₃ ,
R ² is H, - (C ₁ -C ₄ alkyl) or - (CH ₂ ) _m -aryl, wherein one or more of the hydrogens of the aryl may be substituted with halo or -O- (C ₁ -C ₄ alkyl) And wherein at least one hydrogen of the -O- (C ₁ -C ₄ alkyl) may be substituted with halo}
R ³ is H, halo, - (C ₁ -C _{4 alkyl), -CF 3, -C (=} O) - (C 1 -C 4 alkyl), -C (= O) - (C 2 -C 4 Alkenyl), -O- (C ₁ -C ₄ alkyl), or -O- (C ₃ -C ₇ cycloalkyl), wherein -C (═O) - (C ₁ -C ₄ alkyl) (= O) - (C ₂ -C ₄ alkenyl) may be substituted with halo}
R < ⁴ > is H or halo,
L is - (C? C) - or nothing,
X is H, - (C ₁ -C ₄ alkyl), - (C ₁ -C ₄ alkyl) - (C ₃ -C ₇ cycloalkyl), - (C ₃ -C ₇ cycloalkyl)

And or -SiR ⁸ R ⁹ R ^10,
R ⁵ is H or -O (C ₁ -C ₄ alkyl)
R ⁶ is H, - (C ₁ -C ₄ alkyl), -CF ₃ or halo,
R ⁷ is H, -0H or -Y- (CH ₂ ) _n -Z,
R ⁸ , R ⁹ and R ¹⁰ are each independently - (C ₁ -C ₄ alkyl) or aryl,
Y is -O- or -S-,
Z is - (C ₃ -C ₇ cycloalkyl), -C = N, -C ( = O) -R A, -C (= S) -R B, -P (= O) (OH) -R C _{, -S (= O) 2 -R} D, -NHC (= O) NHS (= O) 2 -R E, aryl, heteroaryl,

or

Wherein at least one hydrogen of - (C ₃ -C ₇ cycloalkyl) may be replaced by - (C═O) -OH or - (C═O) -O (C ₁ -C ₄ alkyl) may be substituted with (C ₁ -C ₄ alkyl)} or halo-aryl or heteroaryl group at least one hydrogen of the -OH, -O (C = O)
R ^A to R ^E are each independently - (C ₁ -C ₄ alkyl), -OH, -O (C ₁ -C ₄ alkyl), or -NR ^F R ^G ,
R ^F and R ^G are each independently H, - (C ₁ -C ₄ alkyl) or -C (═O) - (C ₁ -C ₄ alkyl)
V ¹ to V ⁴ are each independently -CH ₂ -, -NH-, -O- or -S-,
W is -O- or -S-,
m is an integer of 0 to 2,
n is an integer of 0 to 6; The oxazolidinone derivative compound according to claim 1, which is represented by the following formula (Ia), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(Ia)

In this formula,
R ¹ is -halo or -CF ₃ ,
R ² is H or - (C ₁ -C ₄ alkyl)
R ³ is H, halo, - (C ₁ -C ₄ alkyl), -C (═O) - (C ₁ -C ₄ alkyl), -C (═O) - (C ₂ -C ₄ alkenyl) -CF ₃ and wherein one or more hydrogens of -C (= O) - (C ₁ -C ₄ alkyl) or -C (= O) - (C ₂ -C ₄ alkenyl) may be substituted with halo },
R ⁶ is H, - (C ₁ -C ₄ alkyl), -CF ₃ or halo,
R ⁷ is H, -OH or -Y- (CH ₂ ) _n -Z,
Y is -O- or -S-,
Z is - (C ₃ -C ₇ cycloalkyl), -C = N, -C ( = O) -R A, -C (= S) -R B, -P (= O) (OH) -R C _{, -S (= O) 2 -R} D, -NHC (= O) NHS (= O) 2 -R E, aryl, heteroaryl,

or

Wherein at least one hydrogen of - (C ₃ -C ₇ cycloalkyl) may be replaced by - (C═O) -OH or - (C═O) -O (C ₁ -C ₄ alkyl) may be substituted with (C ₁ -C ₄ alkyl)} or halo-aryl or heteroaryl group at least one hydrogen of the -OH, -O (C = O)
R ^A to R ^E are each independently - (C ₁ -C ₄ alkyl), -OH, -O (C ₁ -C ₄ alkyl), or -NR ^F R ^G ,
R ^F and R ^G are each independently H, - (C ₁ -C ₄ alkyl) or -C (═O) - (C ₁ -C ₄ alkyl)
V ¹ to V ⁴ are each independently -CH ₂ -, -NH-, -O- or -S-,
W is -O- or -S-,
n is an integer of 0 to 6; The oxazolidinone derivative compound according to claim 1, which is represented by the following formula (Ib), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(Ib)

In this formula,
X is H, - (C ₁ -C ₄ alkyl), - (C ₁ -C ₄ alkyl) - (C ₃ -C ₇ cycloalkyl), - (C ₃ -C ₇ cycloalkyl)

And or -SiR ⁸ R ⁹ R ^10,
R ⁵ is -OCH ₃ ,
R ⁶ is H or halo,
R ⁷ is H or -O- (CH ₂ ) _n - (C = O) -R ^A ,
R ⁸ , R ⁹ and R ¹⁰ are each independently - (C ₁ -C ₄ alkyl) or aryl,
R ^A is -OH or -O (C ₁ -C ₄ alkyl)
n is an integer of 1 to 5; The oxazolidinone derivative compound according to claim 1, which is represented by the following formula (Ic), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(Ic)

In this formula,
R ³ is -O- (C ₁ -C ₄ alkyl) or -O- (C ₃ -C ₇ cycloalkyl)
R < ⁴ > is halo,
R ⁸ and R ⁹ are each independently H, halo or -O- (C ₁ -C ₄ alkyl), wherein one or more hydrogens of -O- (C ₁ -C ₄ alkyl) },
m is an integer of 0 to 2; The oxazolidinone derivative compound according to claim 2, wherein the compound represented by formula (Ia) is selected from the group consisting of compounds represented by the following formulas, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

4. The oxazolidinone derivative compound according to claim 3, wherein the compound represented by the formula (Ib) is selected from the group consisting of compounds represented by the following formulas, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

The oxazolidinone derivative compound according to claim 4, wherein the compound represented by the formula (Ic) is selected from the group consisting of compounds represented by the following formulas, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

8. A composition comprising a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 7. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, as a pharmaceutical composition for the treatment or prevention of disorders or diseases which are mediated by CETP or which respond to inhibition of CETP ≪ / RTI > or a pharmaceutically acceptable salt thereof. 10. The method of claim 9, wherein the disorder or disease is selected from the group consisting of hyperlipidemia, atherosclerosis, atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetal lipoproteinemia, hypolipidemia proteinuria, hypercholesterolemia, hypertriglyceridemia Coronary heart disease, coronary artery disease, coronary vascular disease, angina pectoris, ischemia, cardiac ischemia, thrombosis, cardiac infarction, myocardial infarction, stroke, peripheral vascular disease, reperfusion injury, angioplasty Hypertension, congestive heart failure, diabetes, diabetic vascular complications, obesity, endotoxemia, and combinations thereof.