WO2013157792A1

WO2013157792A1 - Bicyclic heteroaryl derivative and pharmaceutical composition comprising same

Info

Publication number: WO2013157792A1
Application number: PCT/KR2013/003149
Authority: WO
Inventors: Seung Hyun Jung; Ji Sook Kim; Dong Jin Hong; Young Hee Jung; Wook Jang
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2012-04-17
Filing date: 2013-04-15
Publication date: 2013-10-24
Also published as: KR20130117678A

Abstract

Bicyclic heteroaryl derivatives of Formula 1, and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof can selectively and effectively inhibit DGAT1, and thus can be useful as medicines for effectively treating dangerous diseases such as obesity, type 2 diabetes, abnormal lipidemia, metabolic syndrome (syndrome X) and the like, which are caused by DGAT1, with no adverse side effects.

Description

DESCRIPTION

BICYCLIC HETEROARYL DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING SAME FIELD OF THE INVENTION

The present invention relates to novel bicyclic heteroaryl derivatives inhibiting diacylglycerol O-acyltransferase type 1 (DGAT1), and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof, and a pharmaceutical composition comprising same as an effective ingredient.

BACKGROUND OF THE INVENTION

Triglyceride (triacylglycerol) is a major energy storage medium of eukaryotes. Triglyceride is primarily synthesized in the small intestine, the liver and lipocytes in mammals, and mainly functions to absorb dietary fat, wrap synthetic fatty acids in the living body and store fatty acids in adipose tissues (see Subauste et al., Current Drug Targets - Immune, Endocrine & Metabolic Disorders (2003) 3, pp.263-270).

Diacylglycerol O-acyltransferase (DGAT), also known as diglyceride acyltranferase, is a major enzyme for triglyceride synthesis, and accelerates the final rate-deterrnining step in the synthesis of triacylglycerol from 1,2-diacylglycerol (DAG) and long-chain aliphatic acyl-CoA, which are substrates. Therefore, DGAT plays important roles in the metabolism of diacylglycerol, in the production of triglyceride, and in the homeostasis of energy storage (see Mayorek et al., European Journal of Biochemistry (1989) 182, pp. 395-400).

DGAT exists in two subtypes of DGAT 1 and DGAT2 (see Cases et al., Proceedings of the National Academy of Science, USA (1998) 95, pp. 13018-13023; Lardizabal et al., Journal of Biological Chemistry (2001) 276, pp. 38862-38869; and Cases et al., Journal of Biological Chemistry (2001) 276, pp. 38870-38876). The two enzymes are not homologous although they use the same substrate, and the degree of expression thereof is relatively different with respect to each tissue although they are widely expressed in various tissues.

Meanwhile, it was reported that when DGAT knock-out mice were prepared by using genes coding mouse DGATl, these mice did not express an active DGAT enzyme, but continuously synthesized triglyceride {see Smith et al., Nature Genetics (2000), 25, pp. 87-90). This result supports the fact that a different catalyst mechanism, such as DGAT2, contributes to the synthesis of triglyceride {see Lehner et al., Progress in Lipid Research (1996) 35, pp.169-210).

A disorder or imbalance in metabolism of triglyceride, such as the absorption and synthesis of triglyceride, may cause various dangerous diseases. Examples of such dangerous diseases may include obesity, insulin resistance syndrome, 2-type diabetes, abnormal lipidernia, metabolic syndrome (syndrome X), coronary artery diseases and the like {see Kahn et al., Nature Genetics (2000) 25, pp. 6-7; Yanovski, New England Journal of Medicine (2002) 346, pp. 591- 602; Lewis et al., Endocrine Reviews (2002) 23, p. 201; Brazil, Nature Reviews Drug Discovery (2002) 1 , p. 408; Malloy et al., Advances in Internal Medicine (2001 ) 47, p. Il l; Subauste et al., Endocrine & Metabolic Disorders (2003) 3, pp. 263-270; and Yoo et al., Annals of Medicine (2004) 6, pp. 252-261). Therefore, compounds capable of inhibiting or decreasing the activity of a DGAT enzyme, thereby reducing the synthesis of triglyceride from diacylglycerol, are useful as therapeutic agents for treating dangerous diseases accompanying abnormal metabolism of triglyceride.

Examples of DGAT inhibitors known in the art include dibenzoxazepinone {see Ramharack et al., EP 1219716; and Burrows et al., 26* National Medicinal Chemistry Symposium (1998) poster C-22); substituted amino-pyrimidino-oxazines {see WO 2004/047755); chalcones, such as Xanthohumol {see Tabata et al., Phytochemistry (1997) 46, pp. 683-687; and Casaschi et al., Journal of Nutrition (2004) 134, pp. 1340-1346); substituted benzyl-phosphonates {see Kurogj et al., Journal of Medicinal Chemistry (1996) 39, pp. 1433-1437; Goto et al., Chemistry and Pharmaceutical Bulletin (1996) 44, pp. 547-551; Ikeda et al., Thirteenth International Symposium on Atherosclerosis (2003), abstract 2P-0401; and JP 2004-067635]; arylalkyl acid derivatives {see WO 2004/100881 and US 2004/0224997); furan and thiophene derivatives {see WO 2004/022551); pyrrolo[l,2 yridazine derivatives {see WO 2005/103907); and substituted sulfoneamides {see WO 2005/044250). Further, examples of other DGAT inhibitors known in the art include 2-bromo-palmitic acid {see Colman et al., Biochimica et Biophysica Acta (1992) 1125, pp. 203-209), 2-bromo-octanoic acid (Mayorek et al., Journal of Biological Chemistry (1985) 260, pp. 6528-6532), roselipins {see Noriko et al., Journal of Antibiotics (1999) 52, pp. 815- 826), amidepsin {see Tomoda et al., Journal of Antibiotics (1995) 48, pp. 942-947), isochromophilones and prenylflavonoids {see Chung et al., Planta Medica (2004) 70, pp. 258- 260), polyacetylenes {see Lee et al., Planta Medica (2004) 70, pp. 197-200), cochlioquinones {see Lee et al., Journal of Antibiotics (2003) 56, pp. 967-969), tanshinones {see Ko et al., Archives of Pliarmaceutical Research (2002) 25, pp. 446^448), gemfibrozils {see Zhu et al., Atherosclerosis (2002) 164, pp. 221-228), and substituted quinolones {see Ko et al., Planta Medica (2002) 68, pp. 1131-1133). Further, there are examples of DGAT activity adjusters {see US 2004/0185559).

However, it has been still required in the relevant art to develop more effective and selective DGAT1 inhibitors for treating metabolic disorders such as obesity, type 2 diabetes, metabolic syndromes and the like, and having an IC₅₀ value of less than 1 uM. SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide a novel compound for selectively and effectively inhibiting DGAT1, and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof, and a pharmaceutical composition comprising same.

In order to accomplish the above object, an aspect of the present invention provides a compound selected from the group consisting of a bicyclic heteroaryl compound of Formula 1 below, and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof:

Formula 1

wherein X is -0-, -S-, -NH-, or -N(C_Malkyl)-;

C3.8cycloalkyl, carboxyC_3-8cycloalkyl, C alkoxycarbonylCs-scycloalkyl, C_6-i₄aryl, 5- to 13- memebered heteroaryl or 3- to 13-membered heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl may each independently be substituted with one or more substituents selected from the group consisting of halogen,

and Q-isalkoxy;

A is

H ; R¹ is H, C^aUcyl, C_3-8cycloalkyl, C_6-i₄aryl, 5- to 13-membered heteroaryl or 3- to 13- membered heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, Ci^alkyl, haloCi-₆alkyl, ^alkoxy, Q-scycloalkyl, Ci^alkylamino, di- Ci-ealkylamino, Ci.₆alkylcarbonylamino, Ce-waryl, haloC₆-i₄aryl, 5- to 13-membered heteroaryl, 5- to 13-membered heteroaryl containing

and 3- to 13-membered heterocycloalkyl;

R² is =0, =S, =NH or =N-C_M alkyl;

B is C_6-14arylene or 5- to 13-membered heteroarylene which is unsubstituted or substituted with halogen; and

R^x, R^y, R^m and R* are each independently H, C_halky! or haloQ-ealkyl,

wherein each of the heteroaryl, heterocycloalkyl and heteroarylene independently contains at least one heteroatom selected from the group consisting of N, O and S.

Further, another aspect of the present invention provides a pharmaceutical composition for inhibiting DGATl, comprising said compound selected from the group consisting of the bicyclic heteroaryl compound of Formula 1 above, and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof as an effective ingredient.

DETAILED DESCRIPTION OF THE INVENTION Hereinafter, the present invention will be described in detail.

The term "halogen" or "halo" used herein refers to fluoro, chloro, bromo or iodo.

Further, the term "alkyl" refers to a linear or branched, saturated hydrocarbon radical chain of Q to C₆. Specific examples of alkyl may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, rc-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, and the like.

Further, the term "alkoxy" refers to a -OR_a group, wherein R_a is the above-defined alkyl. Specific examples of alkoxy may include, but are not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, t-butoxy, and the like.

Further, the term "heteroaryl" refers to a monocyclic, bicyclic or more cyclic aromatic group containing at least one heteroatom selected from the group consisting of O, N and S, unless specified otherwise. Specific examples of monocyclic heteroaryl may include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups thereof. Specific examples of bicyclic heteroaryl may include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, and similar groups thereof.

Further, the term "heterocycloalkyl" refers to a cycloalkyl group∞ntaining at least one heteroatom selected from the group consisting of O, N and S in the cycloalkyl ring thereof, unless specified otherwise.

According to an embodiment of the present invention, there is provided a bicyclic heteroaryl compound of Formula 1 below:

Formula 1

wherein X is -0-, -S-, -NH-, or -N(C_Malkyl)-;

Y is carboxy,

hydroxyCi-ealkyl, carboxyC_3-8cycloalkyl, carboxyC_]-6alkylamido or . ₆alkylsulfonyl; p1 R² R1 O R1 H _r1

A is H H , H , O or H ; R¹ is

C_3-8cycloalkyl, 3- to 13-membered heterocycloalkyl, C₆-i₄aryl or 5- to

13-membered heteroaryl, wherein the aryl, heteroaryl and heterocycloalkyl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, C^alkyl, haloC_]-3alkyl, C_1-3alkoxy, Ci_-3alkylamino, di-C).₃alkylamino, C\. 3alkylcarbonylamino, Ce-waryl, haloC₆-ioaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl containing haloCi-₃alkyl and 5- to 10-membered heterocycloalkyl;

R² is =0, =S, =NH or =N-C_Malkyl;

B is C6-i₄arylene or 5- to 13-membered heteroarylene which is unsubstituted or substituted with halogen; and R^x, R^y, R^m and R are each independently H, C^alkyl or haloC^alkyl,

According to another embodiment of the present invention, there is provided a bicyclic heteroaryl compound of Formula 1 above:

wherein X is -0-, -S-, - H-, or -N(C_Malkyl)-;

Y is carboxy, carboxyCi_-3alkyl, Ci-₃alkoxycarbonylCi_-3alkyl, armnocarboxyC^alkyl or carooxyCi_₃alkylamido;

₀1 R² i O R1 H _DI

N N

A is H H , " H - , O or " H ;

R¹ is

or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, Ci_-3alkyl, haloCi_-3alkyl,

Ci-₃alkylarnino, di-Q. ₃alkylamino,

phenyl, halophenyl and

R² is =0, =S or=NH;

B is C6-ioarylene or 5- to 10-membered heteroarylene; and

R^x, R^y, R²³ and R* are each independently H or C_1-3alkyl,

According to still another embodiment of the present invention, there is provided a bicyclic heteroaryl compound of Formula 1 above:

wherein X is -S-;

Y is carboxy or carboxyCi_-2 alkyl;

R^l is Q-ioaryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, methyl, trifluoromethyl, acetamido, phenyl, chlorophenyl, difluorophenyl and trifluoromethylpyridinyl;

R² is =0;

B is phenylene; and

wherein the heteroaryl contains at least one heteroatom selected from the group consisting of N, O and S.

Specific examples of the bicyclic heteraryl compound of Formula 1 above according to the present invention are as follows, wherein pharmaceutically acceptable salts, isomers, hydrates and solvates thereof can also be used:

1 ) 2-(4-(4-(4-(3-cWorberizamido)phenyl)tMeno[3,2-^pyriniidin-7- yl)cyclohexyl)acetic acid;

2) 2-(4-(4-(4-(2-naphtharmdo)phenyl)t

acid;

3) 2-(4-(4-(4-(2-phenyl-5-(ttifluoromethy

(¾pyrirnidin-7-yl)cyclohexyl)acetic acid;

4) 2-(4-(4-(4-(5-cMoro-2-rri1robenzarnid^^

yl)cyclohexyl)acetic acid;

5) 2-(4-(4-(4-(2-aniino-5-chlorobenzarn ^

yl)cyclohexyl)acetic acid;

6) 2-(4-(4-(4-(2-acetamido-5-cWorobenzar^

yl)cyclohexyl)acetic acid;

7) 2-(4-(4-(4-(6-(trifluoromemyl)ni »tinamido)phenyl)1rri

yl)cyclohexyl)acetic acid;

8) 4-(4-(4-(3-cMorobenzaniido)phenyl)tlti

yl)cyclohexanecarboxylic acid;

9) 3-(4-(4-(4-(3-cWorobenzamido)phenyl)tlri^

yl)cyclohexyl)propanoic acid;

10) 2-(4-(4-(4-((3,4Kiime lphmyl)c^

yl)cyclohexyl)acetic acid;

11) 2-(4-(4-(4-((7-phenylthieno[3,2-¾pyrirrddin-4-yl)amm

^pyrirnidin-7-yl)cyclohexyl)acetic acid; 12) 2-(4-(4-(4-((6-phenyltMeno[3,2^

^pyrirnidin-7-yl)cyclohexyl)acetic acid;

13) 2-(4-(4-(4 (7-(3-cMorophenyl)thieno[3,2^

yl)arnino)phenyl)tMeno[3,2- ]pyrirnidin-7-yl^

14) 2-(4-(4 4-((7-(3,4 iifluoroph^^

yl)arnino)phenyl)trueno[3,2-<¾yrim acid;

15) 2-(4 4 4-((7-(6-(trifluorome l)pyridin-3-yl)thieno[3 ,2-^pyrimidin-4- yl)amino)phenyl)tMeno[3,2-<¾pvrimidin-7-yl)cycloh^

16) 2-(4-(4-(4-(thieno[3,2-^pyrirmdin-4-ylamino)phe^

yl)cyclohexyl)acetic acid;

17) 2-(4-(4-(4-((lH-benzo[^irnidazol-2-yl)arnino)phenyl)to

yl)cyclohexyl)acetic acid;

18) 2-(4-(4-(4-(3-(3-cWorophmyl)ureido)ph^

yl)cyclohexyl)acetic acid;

19) cis 2-(4-(4-(4-(3-(3-cMorophenyl)ureido)phenyl)lM

yl)cyclohexyl)acetic acid;

20) trans 2-(4-(4-(4-(3-(3-cMorophenyl)ureido)phenyl)to

yl)cyclohexyl)acetic acid;

21) 2-(4-(4-(4-(3-(2-fluoro-5-(trifluorophenyl)phenyl)ureido)phenyl)tW ^pyrirnidin-7-yl)cyclohexyl)acetic acid;

22) cis 2-(4-(4-(4-(3-(2-fluoro-5-(trifluorophenyl)phenyl)ureido)phenyl)tiiieno[3 ,2- <f]pyrimidin-7-yl)cyclohexyl)acetic acid;

23) trans 2-(4-(4~(4-(3-(2-fluoro-5-(trifluorophe^^

c ]pyrirnidin-7-yl)cyclohexyl)acetic acid;

24) 2-(4 4-(4-(3-(4-cWoropyridin-2-yl)u^^

yl)cyclohexyl)acetic acid; and

25) 2-(4-(4-(4-(3-(4-bromopyrkiin-3^

yl)cyclohexyl)acetic acid.

The category of the compounds according to the present invention includes not only the bicyclic heteroaryl compounds of Formula 1 above, but also pharmaceutically acceptable salts, isomers, hydrates and solvates thereof. Such pharmaceutically acceptable salts may be used without limitation as long as they are pharmaceutically acceptable salts of inorganic acids or organic acids. Examples of the pharmaceutically acceptable salts may include: salts of inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, and the like; salts of organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, malic acid, tartaric acid, gluconic acid, lactic acid, fumaric acid, lactobionic acid, salicylic acid, phthalic acid, embonic acid, aspartic acid, glutamic acid, acetylsalicylic acid (asprin) and the like; salts of amino acids, such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline and the like; salts of sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like; salts of alkali metals, such as sodium, potassium and the like; and salts of ammonium ions.

Further, salts of organic bases, such as tris(hydroxymemyl)met ylamine, dicyclohexylamine and the like, may be used.

Such pharmaceutically acceptable salts of the bicyclic heteroaryl compounds of

Formula 1 may be prepared by conventional methods known in the art. For example, the pharmaceutically acceptable salts thereof may be prepared by dissolving the bicyclic heteroaryl compounds of Formula 1 in a water-miscible solvent such as methanol, ethanol, actecone and 1,4-dioxane, adding a free acid or a free base to the mixed solution, and then crystallizing the resulting solution.

The bicyclic heteroaryl compounds of Formula 1, and the pharmaceutically acceptable salts, isomers, hydrates and solvates thereof can selectively and effectively inhibit DGAT 1, and thus can be effective in the prevention or treatment of the diseases or conditions caused by DGAT1.

Therefore, the present invention provides a pharmaceutical composition for inhibiting

DGAT1, comprising a compound selected from the group consisting of the bicyclic heteroaryl compounds of Formula 1, and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof as an effective ingredient.

The pharmaceutical composition of the present invention can be used for the prevention or treatment of the diseases or conditions caused by DGAT 1.

In addition, the present invention provides a use of the inventive compound for the manufacture of a medicament for preventing or treating the diseases or conditions caused by DGATl.

Further, the present invention provides a method for preventing or treating the diseases or conditions caused by DGATl, which comprises administering the inventive compound to a mammal in need thereof.

Examples of the diseases or conditions caused by DGATl may include, but are not limited to, metabolic disorders, e.g., obesity, diabetes, neurogenic anorexia, adephagja, dyscrasia, syndrome X, insulin resistance syndrome, hypoglycemia, hyperglycemia, hyperuricacidemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, combined dyslipidemia, hypertriglyceridemia, pancreatitis, and nonalcoholic fatty liver disease; cardiovascular disorders, e.g., arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, acute heart failure, blood- congestive heart failure, coronary artery disease, myocardosis, cardiac infarction, angina, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aortic disease, restenosis and angiostenosis; neoplastic diseases, e.g., solid tumors (such as, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, uterine cervical cancer, uterine cancer, testicular cancer, and ovarian cancer), skin cancer, melanoma, lymphoma, and endothelioma; and dermatological conditions, e.g., pimple, etc.

More preferably, examples of the diseases or conditions caused by DGATl may be selected from the group consisting of obesity, hyperlipidemia, hypertriglyceridemia, insulin resistance syndrome, hyperglycemia, diabetes, nonalcoholic fatty liver diseases, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, stroke, ischemic reperfusion injury, myocardosis, cardiac infarction, and coronary artery diseases.

The pharmaceutical composition of the present invention includes a faro-, thieno- or pyrrolo-[3,2-(¾pyrirnidine derivative of Formula 1 above and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof as an effective ingredient. The pharmaceutical composition may be formed into a formulation for oral administration, e.g., a pill, a tablet, a capsule, a troche, a liquid form, a suspension and the like, or a formulation for parenteral administration by the addition of a pharmaceutically acceptable carrier, additive, diluting agent, etc.

A solid formulation for oral administration may be formed by mixing at least one furo-

, thieno- or pyirolo-[3,2-<¾pyrimidine derivative with at least one vehicle, e.g., starch, calcium carbonate, sucrose, lactose, gelatin and the like. Further, a lubricant, e.g., magnesium stearate, talc and the like, may be used in the formation of the solid formulation, in addition to the vehicle.

A suspension agent, a liquid medicine, an emulsion, syrups and the like may be used in the formation of a liquid formulation for oral administration. Further, various kinds of vehicles, e.g., a wetting agent, a sweetening agent, a flavoring agent, a preservative and the like may also be used in the preparation of the liquid formulation, in addition to a simple diluting agent, e.g., water, liquid paraffin and the like.

A formulation for parenteral administration includes a sterilized aqueous solution, a nonaqueous solvent, a suspension solvent, an emulsion, a freezing and drying agent, a suppository and the like. Propylene glycol, polyethylene glycol, a plant oil such as olive oil and the like, or an injectable ester such as ethyl oleate and the like may be used as a nonaqueous solvent or suspension solvent. Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, gelatin and the like may be used as a base material of the suppository.

The dosage of the pharmaceutical composition according to the present invention in humans may be changed depending on the age, weight and sex of a patient, the dosage form of the composition, the health state of a patient and the degree of the disease. The dosage of the pharmaceutical compostion may be 20 to 200 mg/day, and preferably, 50 to 100 mg/day based on an adult patient having a weight of 70 kg. The pharmaceutical composition may be administered to a human once a day or several times at regular intervals per day. Hereinafter, a method of preparing the compound of Formula 1 above will be described in detail.

According to an embodiment of the present invention, the compound of Formula 1 above may be prepared by using a compound of Formula 2 below or a compound of Formula 3 below as an intermediate:

Formula 2

Formula 3

wherein R^x, R^y, R²³, R* X and Y are the same as those defined in the above Formula

1.

A method of preparing the compound of Formula 1 above is represented by Reaction Schemes 1 and 2 below.

In Reaction Scheme 1, step (A-l) shows a reaction of preparing a compound of Formula 2 as an intermediate, and steps (B-1), (B-2) and (B-3) show a method of preparing a compound of Formula 1 (a compound of Formula la, lb or lc) by using the compound of Formula 2.

In Reaction Scheme 2, step (A-2) shows a reaction of preparing a compound of Formula 3 as an intermediate, and steps (C) shows a method of preparing a compound of Formula 1 (a compound of Formula Id) by using the compound of Formula 3.

Reaction Scheme 1

Reaction Scheme 2

1d

In Reaction Scheme 1 or 2, R , R^y, R²³, R* R¹, R², X and Y are the same as those defined in the above Formula 1.

In Reaction Scheme 1, first, in order to prepare a compound of Formula 4 as a starting material, Suzuki coupling reaction of 7-bromo and 4-chloro-substitued pyrrolo-, furo- or trueno[3,2- ]pyrimidine (a compound of Formula 6) with i-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenylcarbamate is performed to obtain 4-chloride-substituted arylpyrrolo-, arylfuro- or arylthieno[3,2-<fJpyrirnidine (a compound of Formula 4).

Thereafter, as shown in step (A-l) of Reaction Scheme 1, Suzuki coupling reaction of the compound of Formula 4 with a cyclohexenylborolane compound of Formula 5 is performed, and then hydrogenation and deprotection reactions are sequentially conducted to obtain a compound of Formula 2. In this case, the compound of Formula 5 can be prepared by using the method disclosed in WO 2009/016462.

Next, as shown in step (B-l) of Reaction Scheme 1, the compound of Formula 2 is reacted with carbonyl chloride or carboxylic acid to prepare a compound of Formula 1 a.

Further, as shown in step (B-2) of Reaction Scheme 1, a compound of Formula lb can be prepared by reacting the compound of Formula 2 with an isocyanate or thioisocyanate compound, or by subjecting a compound obtained from the reaction of the compound of Formula 2 with phenylchloroformate or phenylthiochloroformate to substitution reaction with an aniline or an aminoheteroaryl compound.

Further, as shown in step (B-3) of Reaction Scheme 1, the compound of Formula 2 is reacted with heteroaryl chloride to prepare a compound of Formula lc. Alternatively, the compound of Formula 2 is made into the thioisocyanate, and then subjected to cyclization reaction with an aryldiamine compound to prepare a compound of Formula 1 c.

In a differently way, as shown in step (A-2) of Reaction Scheme 2, in order to obtain a compound of Formula 3 as another intermediate, Suzuki coupling reaction of a compound of Formula 6 with 4-(methoxycarbonyl)phenylboronic acid (a compound of Formula 7) is carried out followed by a hydrolysis reaction, thereby obtaining 4-chloride-substituted arylpyrrolo-, arylfuro- or aryltWeno[3,2-<^pyrimidine (a compound of Formula 3).

Next, as shown in step (C) of Reaction Scheme 2, a compound obtained by reacting the compound of Formula 3 with aniline or an aminoheteroaryl compound is Suzuki-coupling- reacted with a cyclohexenylborolane compound of Formula 5, and then hydrogenated to obtain a compound of Formula Id.

Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are set forth to illustrate the present invention, and the scope of the present inventon is not limited thereto. Preparation Example 1: i-Buryl ^(7-bromothieno[3,2-^pyrimidin-4- yl)phenylcarbamate (compound of Formula 4)

13 g of 7-bromo-4-chlorotWeno[3,2-i¾pyrirnidine (CY C37043, KindChem

Corporation), 20 g of i-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate, 3.16 g of teti^s(triphenylphosphine)palladium and 8.28 g of sodium carbonate were added to 100 mL of a mixed solvent of 1,4-dioxane/water (4:1), and then stirred at 80 °C for 18 hours under an argon gas atmosphere. After the reaction, the reaction solution was extracted with 300 mL of ethyl acetate and 300 mL of water, dried using anhydrous magnesium sulfate, and then concentrated. Subsequently, 30 mL of methanol was added to the reaction solution, the reaction solution was stirred to produce crystals, and then filtered to obtain 12.5 g of the yellow title compound.

In this case, the starting material, t-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenylcarbamate, had been prepared by the protection reaction of 4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)aniline (T 1951 , TCI Corporation) with a t-butoxycarbonyl group.

H NMR(300MHz, DMSO- ¾) δ 9.80(s, 1H), 9.31(s, 1H), 8.7(s, 1H), 8.12(d, 2H), 7.73(d, 2H), 1.50(s, 9H). Preparation Examples of compound of Formula 1

Example 1: 2-(4-(4-(4-(3-CWorobenzimido)phenyl)thieno[3,2-< |pvrim^ yl)cyclohexyl)acetic acid

Step 1 : Methyl 2-(4-( -(4-((t-butoxycarbonyl)amino)phe^^

yl)cycloh -3-en-l- l)acetate

0.56 g of t-butyl 4-(7-bromot ieno[3,2-^pyrimidin-4-yl)phenylcarbamate prepared in Preparation Example 1, 0.5 g of 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3- en-l-yl)acetate prepared in the method disclosed in WO 2009/016462, and 94.9 mg of tetralds(triphenylphosphine)palladium were added to a mixed solvent of 2.06 mL of a 2 N aqueous sodium carbonate solution and 8.2 mL of 1,4-dioxane, and then stirred at 100 °C for 12 hours under an argon gas atmosphere. After the reaction, the reaction solution was extracted with 300 mL of ethyl acetate and 300 mL of water to obtain an organic layer. The organic layer was dried using anhydrous magnesium sulfate, filtered and then concentrated. Subsequently, methanol was added to the reaction solution, stirred to produce crystals, and then filtered to obtain 315 mg of the yellow title compound.

Ή NMR(300MHz, CDC1₃) δ 9.29(s, 1H), 8.17(d, J=8.7Hz, 2H), 7.43(s, 1H), 7.59(d, J=8.7Hz, 2H), 7.16(bs, 1H), 6.69(s, 1H), 3.71(s, 3H), 2.64 ~ 2.38(m, 3H), 2.26~2.02(m, 6H), 1.56(s, 9H).

Step 2: Methyl 2-i4-i4-(^"4-((Y-butoxycaroonvD

vDcvclohexyDacetate

50 mL of ethanol and 20 niL of 1 ,4-dioxane were added to 315 mg of methyl 2-(4-(4- (4-(^butoxycarbonyl)amino)phenyl)t^

prepared in step 1. 158 mg of 20% charcoal-shaped palladium hydroxide was added thereto and then the resulting suspension was hydrogenated at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through a Celite, and then the filtrate was concentrated to obtain 190 mg of the title compound. This compound was used in the following step without further purification.

^JH NMR(300MHz, CDC1₃) δ 9.26(s, 1H), 8.17(d, J=8.5Hz, 2H), 7.68~7.62(m, 1H), 7.59(d, J=8.2Hz, 2H), 6.71(s, 1H), 3.69(s, 3H), 3.32~3.17(m, 1H), 2.48~2.46(m, 2H), 2.31~1.80(m, 7H), 1.55(s, 9H), 1.28~1.22(m, 2H).

Step 3: Methyl 2-(4-(4-(4-aminophenyl)tMenor3,2-^pyrimidin-7- vDcyclohexyDacetate

280 mg of methyl 2-(4-(4-(4-(^butoxycarbonyl)amino)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetate prepared in step 2 was added to 5 mL of dichloromethane. 0.6 mL of trifluoroacetic acid was added thereto, followed by stirring at room temperarture for 12 hours. Subsequently, a large amount of a solvent was removed from the mixed solution by reduced-pressure distillation, and then dichloromethane and a saturated aqueous sodium bicarbonate solution were added thereto, and then sufficiently stirred, followed by extracting an organic layer. The extracted organic layer was dried using anhydrous magnesium sulfate, and then concentrated to obtain 190 mg of the title compound.

Ή NMR(300MHz, CDC1₃) δ 9.22(s, 1H), 8.09(d, J=8.2Hz, 2H), 7.69~7.58(m, 1H), 6.82(d, J=8.2Hz, 2H), 4.05(bs, 2H), 3.69(s, 3H), 3.33~3.19(m, 1H), 2.48~2.30(m, 1H), 2.28~2.16(m, 3H), 2.04~1.81(m, 5H), 1.63~1.53(m, 2H).

Step 4: Methyl 2-(4-(4-(4-(3-cMorobergamido)phenyl)fa yl)cyclohex l)acetate

148 mg of methyl 2-(4-(4-(4-arninophenyl)thieno[3,2-^pyrimidin-7- yl)cyclohexyl)acetate prepared in step 3 was dissolved in 3 mL of dichloromethane. After the reaction temperature was lowered to 0 ~ 5 °C, 31 mg of pyridine was added thereto, and then stirred for 10 minutes. After 69.7 mg of 3-chlorobenzoyl chloride was slowly added dropwise to the mixed solution, the reaction temperature was increased to room temperature, followed by stirring for 2 hours. After the reaction, 20 mL of dichloromethane and 20 mL of a saturated aqueous sodium bicarbonate solution were added to the reaction solution with sufficiently stirring to extract an organic layer. The extracted organic layer was dried using anhydrous magnesium sulfate and then filtered under reduced pressure. The filtrate was concentrated, and then separated by column chromatography (ethyl acetate: rc-hexane = 1 :3) to obtain 67 mg of the title compound.

'H MR(300MHZ, CDCI₃) δ 9.29(s, 1H), 8.28~8.25(m, 2H), 7.96~7.78(m, 5H), 7.58~7.45(m, 3H), 3.70(s, 3H), 3.33~3.23(m, 1H), 2.31~2.18(m, 3H), 1.95~1.85(m, 3H), 1.60~1.53(m, 3H), 1.33~1.18(m, 2H).

Step 5: 2-(4-(4-(4-(3-CMorobenzamido)phenyl)tM

67 mg of the methyl 2-(4-(4-(4-(3-cUorobenzamido)phenyl)tMeno[3,2-^pyrimidin-7- yl)cyclohexyl)acetate prepared in step 4 was added to a mixed solvent of tetrahydrofuran/methanol/water (1 :1:1) and then stirred, and then 51.5 mg of sodium hydroxide was added thereto and then further stirred. After the reaction, the pH of the reaction solution was lowered to 3 ~ 4 by using a 1 N aqueous hydrogen chloride solution. The obtained solid was filtered, and washed with water to obtain 42.3 mg of the title compound.

Ή NMR(300MHz, DMSO-</₆) S 10.7(s, 1H), 9.27(s, 1H), 8.42~7.95(m, 7H), 7.74~7.52(m, 2H), 3.35~3.22(m, 1H), 2.17~1.95(m, 2H), 1.83~1.62(m, 7H), 1.21~1.08(m, 2H). Example 2: 2-(4-(4-(4-(2-Naphmamido)phenyl)t eno[3,2-^pyrirnidin-7- yl)cyclohexyl)acetic acid

The title compound was prepared in the same manner as in steps 4 to 5 of Example 1 , except that 2-naphthoyl chloride was used instead of 3-chlorobenzoyl chloride in step 4 of Example 1.

'H NMR(300MHZ, DMSO-t/₆) δ 10.78(s, IH), 9.26(s, IH), 8.63(s, IH), 8.27~8.07(m, 8H), 7.66~7.64(m, 2H), 3.16-3.1 l(m, IH), 2.39~2.36(m, IH), 2.26~2.06(m, 2H), 1.84~1.37(m, 6H), 1.21~1.05(m, 2H).

Example 3: 2-(4-(4-(4-(2-Phenyl-5-(triQuoro

carboxamido)phenyl)t-ueno[3,2^pyrimidm-7-yl)cyclohexyl)aceti^

59 mg of methyl 2-(4-(4-(4-aminophenyl)tMeno[3,2-^pyrimidin-7- yl)cyclohexyl)acetate prepared in step 3 of Example 1 and 40 mg of 2-phenyl-5- (trifluoromethyl)oxazole-4-carboxylic acid prepared by the method disclosed in WO 2007/060140 were dissolved in tetrahydrofuran, and then 17.2 mg of triethylamine was added to the mixd solution. After the reaction temperature was lowered to 0 ~ 5 °C, 0.17 mL of a 1.0 M toluene solution containing isopropylchloroformate was added to the mixed solution. After, the mixed solution was stirred for 30 minutes, the reaction temperature was increased to room temperature, followed by stirring overnight. After the reaction, the reaction solution was extracted with 20 mL of ethyl acetate and 20 mL of water to separate an organic layer. The separated organic layer was dried by using anhydrous magnesium sulfate, and then filtered to obtain a filtrate. The filtrate was concentrated by reduced-pressure distillation, and then separated and refined by Prep. TLC (ethyl acetate: n-hexane = 3: 1) to obtain 25 mg of methyl 2- (4-(4-(4-(2-phenyl-5-(m^uoromeftyl)oxazote yl)cyclohexyl)acetate. 13 mg of the title compound was obtained from the above compound by the same manner as in step 5 of Example 1.

'H NMR(300MHZ, DMSO-< ₆) S 12.10(bs, 1H), 10.94(s, 1H), 9.28(s, 1H), 8.29-8.1 l(m, 6H), 7.71~7.64(m, 3H), 3.25~2.98(m, 1H), 2.40~2.38(m, 1H), 2.18~2.05(m, 2H), 1.84-1.57(m, 4H), 1.27-1.16(m, 4H).

Example 4: 2-(4-(4-(4-(5-Chioro-2-nitrobenzamido)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetic acid

0.1 g of methyl 2-(4-(4-(4-aminophenyl)tWeno[3,2-(i]pyrirnidin-7- yl)cyclohexyl)acetate prepared in step 3 of Example 3 was dissolved in 1 mL of dimethylfoimamide, and then 53 mg of 5-chloro-2-nitrobenzoic acid, 0.2 g of HATU, 7 mg of HOBt and 13 mg of N,N-diisopropylamine were added thereto, followed by stirring at 50 °C overnight. After the reaction, the reaction solution was extracted with 10 mL of ethyl acetate and 10 mL of water. The separated organic layer was dried by using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and then separated by Prep. TLC (ethyl acetate: rc-hexane = 1:1) to obtain methyl 2-(4-(4-(4-(5-chloro-2- nitrobenzamido)phenyl)thieno[3,2-(f]pyrimidin-7-yl)cyclohexy^ Then, this compound was dissolved in a mixed solvent of tetrahydrofuran: methanol: water (1:1:1), and then 10 mg of sodium hydroxide was added dropwise thereto so as to hydrolyze the resulting mixed solution. After the reaction, the pH of the reaction solution was lowered to 3 ~ 4 to obtain a solid. Then, the resulting solid was filtered, and then washed with water to obtain 70 mg of the title compound.

Ή NMR(300MHz, MeOD): δ 9.14(s, 1H), 8.55~8.20(m, 3H), 7.99~7.75(m, 5H), 2.59~2.51(m, 2H), 2.28-2.16(m, 1H), 1.67~1.28(m, 9H).

Example 5: 2-(4-(4-(4-(2-Ammo-5-chlorobenzamido)phenyl)thieno[3,2- ^pyrimidin-7-yI)cyclohexyl)acetic acid

50 mg of 2-(4-(4-(4-(5-cMoro-2-nitrobenzamido)ph^

yl)cyclohexyl)acetic acid prepared in Example 4 was dissolved in 5 mL of methanol, and 5 mg of Raney nickel was added thereto, followed by stirring at room temperature during the night under a hydrogen atmosphere. After the reaction, the reaction solution was filtered through a Celite, and then the filtrate was concentrated to obtain a residue. Then, the residue was separated by Prep. TLC (dichloromethane: methanol = 8: 1) to obtain 7 mg of the title compound.

Ή NMR(300MHz, DMSO-<&): δ 10.47(s, IH), 9.24(s, IH), 8.40~8.31(m, 2H), 8.00(m, IH), 7.74(m, 2H), 7.27~7.26(m, IH), 6.87~6.78(m, IH), 6.5(bs, 2H), 2.37~2.35(m, IH), 2.12~2.07(m, 2H), 1.83~1.59(m, 7H), 1.20~1.09(m, 2H).

Example 6: 2-( -(4-(4-(2-Acetamido-5-cMorobenzamido)phenyl)thi( ^pyrimidin-7-yl)cyclohexyl)acetic acid

4 mg of the title compound was obtained in the same manner as in Example 4, except that 2-acetamido-5-chlorobenzoic acid prepared by the method disclosed in WO 2003/007959 was used instead of 5-chloro-nitrobenzoic acid.

Ή NMR(300MHz, CDC1₃): δ 9.34(s, IH), 8.42(d, J=8.3Hz, 2H), 8.25(s, IH), 7.75~7.67(m, 3H), 7.49(d, J=8.3Hz, 2H), 3.38(m, IH), 2.49~2.30(m, IH), 2.30(s, 3H), 1.97~1.84(m, 6H), 1.31~1.25(m, IH).

Example 7: 2-(4-(4-(4-(6-(Trffluoromemyl)mcotmamido)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetic acid

12 mg of the title compound was obtained in the same manner as in Example 4, except that 6-(mfluoromethyl)nicx)tinic acid was used instead of 5-chloro-nitrobenzoic acid.

'H NMR(300MHz, DMSO-i/₆): δ 11.01(s, 1H), 9.34~9.31(m, 2H), 8.67~8.64(m, 1H),

8.33~8.09(m, 5H), 3.52~3.45(m, 1H), 2.44~2.31(m, 1H), 2.24~2.10(m, 1H), 1.89~1.62(m, 7H), 1.27~1.22(m, 2H).

Example 8: 4-(4-(4-(3-Chlorobenzamido)phenyl)thieno[3,2-^pyrimidin-7- yl)cyclohexanecarboxy!ic acid

Step 1 : Methyl 4-hydroxycyclohexanecarboxylate

OMe

HO- .

O

4.32 g of methyl 4-cyclohexanecarboxylic acid was dissolved in 20 mL of methanol, 7.08 g of thionyl chloride was added dropwise thereto, and then the reaction mixture was stirred at 70 °C overnight. After the reaction, a solvent was removed from the reaction mixture by reduced-pressure distillation to obtain 4.7 g of the title compound.

Ή MR(300MHz, DMSO- ₆) δ 4.33(br, 1H), 3.68~3.36(m, 1H), 3.57(s, 3H), 2.37~2.31(m, 1H), 1.82~1.74(m, 2H), 1.53~1.45(m, 6H). tep 2: Methyl 4-oxocyclohexanecarboxylate

0.75 g of sodium acetate, 9.92 g of pyridine chlorochromate and 2.4 g of Celite were added to 50 mL of dichloromethane. 4.7 g of the methyl 4-hydroxycyclohexanecarboxylate prepared in step 1 was dissolved in 15 mL of dichloromethane, and then added dropwise to the above mixture at room temperature for 20 minutes, followed by stirring at room temperatrure for 7 hours. After the reaction, the residual solid was removed by filtration, and the organic layer was washed with 100 mL of water. The organic layer was dried by using anhydrous magnesium sulfate, concentrated and then separated by column chromatography (ethyl acetate: n-hexane = 1 :3) to obtain 1.9 g of the title compound.

Ή NMR(300MHz, CDC1₃) δ 3.73(s, 3H), 2.79~2.78(m, 1H), 2.50~2.37(m, 4H), 2.22-2.21 (m, 2H), 2.05~2.02(m, 2H).

Step 3: Methyl 4-(4A5,5-tetramethyl-L3,2-dioxaborolan-2-yl)cyclohex-3-ene- carboxyla

0.6 g of methyl 4-oxocyclohexanecarboxylate prepared in step 2 was dissolved in 23 mL of dichloromethane, 0.91 g of 2,6-di-t-butyl-4-methylpyridine was added thereto, and then 1.14 g of trifluoromethane sulfonate was added dropwise to the mixed solution for 30 minutes. The mixed solution was stirred at room temperature for 7 hours. After the end of the reaction was confirmed, the reaction solution was distilled under reduced pressure. Subsequently, 30 mL of diethyl ether was added to the reaction solution, residual solid was removed by filteration, and the reaction solution was concentrated to obtain methyl 4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-carboxylate without additional purification process. 94 mg of PdCl₂(dppf)CH₂Cl₂, 880 mg of bis(pinacolato)diboron and 1.13 g of potassium acetate were added to methyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene- carboxylate so obtained, and then the mixure was dissolved in 15 mL of dimethylsulfoxide. The mixed solution was stirred at 50 °C for 2 hours under an argon gas atmosphere. After the reaction, the reaction solution was cooled, and then extracted with 50 mL of ethyl acetate and 50 mL of water. This reaction solution was dried by using anhydrous magnesium sulfate, concentrated and then separated by column chromatography (dichloromethane: «-hexane = 1 :9) to obtain 597 mg of the title compound.

Ή NMR(300MHz, CDC1₃) δ 6.54(s, 1H), 3.68(s, 3H), 2.35~2.32(m, 4H), 2.24~2.03(m, 3H), 1.25(s, 12H).

Step 4_L 4-(4-(4-(3-CMorbenzarrudo)phenyl)tMeno[3,2- /]pyrimi yDcvclohexanecarboxylic acid

30 mg of the title compound was obtained by Prep. TLC (ethyl acetate: «-hexane = 1 :1) in the same manner as in steps 1 to 5 of Example 1, except that methyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-carboxylate prepared in step 3 of Example 4 was used instead of methyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate prepared in step 1 of Example 1.

Ή NMR(300MHz, DMSO-c¾) δ 10.78(s, 1H), 9.24(s, 1H), 8.22~7.84(m, 6H), 7.70~7.56(m, 2H), 3.38~3.34(m, 1H), 2.15~2.12(m, 2H), 1.90~1.84(m, 3H), 1.76~1.69(m, 4H).

Example 9: 3-(4-(4-(4-(3-Chlorobenzamido)phenyl)thie^

yl)cyclohexyl)propanoic acid

Ste 1 : Methyl l,4-dioxaspiro[4.5 decane-8-carboxylate

1.3 g of methyl 4-oxocyclohexanecarboxylate prepared in step 2 of Example 8, 0.64 g of ethylene glycol and 0.14 g of /?-toluenesulfonic acid were added to 40 mL of toluene, and then the mixed solution was refluxed and stirred overnight while removing water by using a Dean- Stark trap. After the reaction, toluene was removed by reduced-pressure distillation, and then the reaction solution was extracted with 50 mL of diethyl ether and 50 mL of water. Then, the reaction solution was dried by using anhydrous magnesium sulfate, and the reaction mixture was distilled (138 ~ 145 °C, 15 mn Hg) to obtain 0.42 g of the title compound as oil.

Ή NMR(300MHz, CDC1₃) S 3.95(s, 4H), 3.67(s, 3H), 2.36~2.32(m, 1H), 1.94~1.91(m, 2H), 1.83~1.75(m, 4H), 1.61-1.55(m, 2H).

Ste 2: l,4-Dioxaspiro[4.51decan-8-yl methanol

0.42 g of methyl l,4-dioxaspiro[4.5]decane-8-carboxylate prepared in step 1 was in 10 mL of tetrahydrofuran, 4.2 mL of a 1.0 M lithium aluminum hydride tetrahydrofuran solution was added thereto, and the mixed solution was refluxed and stirred. The reaction temperature was lowered to room temperature, and a saturated aqueous sodium bicarbonate solution was added to the mixed solution to finish the reaction. After the reaction, the reaction solution was filtered through a Celite, and then the filtrate was distilled under reduced pressure. 20 mL of dichloromethane was added, and then the reaction solution was washed with 20 mL of a saturated aqueous sodium bicarbonate solution, dried by using anhydrous sodium sulfate, filtered and then distilled under reduced pressure to obtain 0.35 g of the title compound.

Ή NMR(300MHz, CDC1₃) δ 3.96(s, 4H), 3.48(d, J=6.4Hz, 2H), 1.86~1.77(m, 4H), 1.63-1.49(m, 3H), 1.32-1.25(m, 2H).

Step 3: l^-Dioxaspiro[4.51decane-8-carbaldehvde

#

0.32 g of oxalyl chloride was added to 9 mL of dichloromethane under a nitrogen atmosphere. After the temperature was lowered to -60 °C, 0.41 g of dimethyl sulfoxide was dissolved in 9 mL of dichloromethane, slowly added dropwise to the above mixture and then stirred for 15 minutes. 0.35 g of 1 ,4-dioxaspiro[4.5]decan-8-yl methanol prepared in step 2 was dissolved in 9 mL of dichloromethane, added dropwise for 20 minutes and then stirred for 15 minutes. 0.68 g of triethylamine added thereto, and the reaction mixture was heated to room temperature. After the reaction, the reaction mixture was washed with 20 mL of water three times, dried by using anhydrous magnesium sulfate, and then filtered under reduced pressure. The reaction mixture was concentrated, and then separated by column chromatography (ethyl acetate: rc-hexane = 1 :3) to obtain 245 mg of the title compound.

Ή NMR(300MHz, CDC1₃) δ 9.69(s, 1H), 3.96(s, 4H), 2.27~2.25(m, 1H), 2.05-1.50(m, 8H).

Step 4: Ethyl 3-(l,4-dioxaspiro[4.51decan-8-yl)acrylate OEt

245 mg of the l,4-dioxaspiro[4.5]decane-8-carbaldehyde was dissolved in 13 mL of toluene, 263 mg of DBU was added to the solution, and the reaction mixture was heated to 80 °C for 5 hours under an argon atmosphere. Subsequently, 0.75 g of ethyl (triphenylphosphoranylidene)acetate was added to the reaction mixture, and then stirred at 100 °C overnight. The reaction solution was cooled, and then washed with 10 mL of 5% KHSO₄, 10 mL of a saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic layer was dried by using anhydrous sodium sulfate, and then concentrated. The residue was separated by column chromatography (ethyl acetate: n-hexane = 1 :5) to obtain 197 mg of the title compound.

'H NMR(300MHz, CDCl₃) < 6.92(dd, J=15.8Hz, 6.4Hz, 1H), 5.81(dd, J=15.8, 1.4Hz, 1H), 4.21~4.09(m, 2H), 3.95(s, 4H), 3.06~3.04(m, 1H), 2.30~2.26(m, 2H), 1.80~1.52(m, 6H), 1.28~1.23(m, 3H). -dioxaspiro[4.5]decan-8-yl)propanoate

197 mg of ethyl 3-(l,4-dioxaspiro[4.5]decan-8-yl)acrylate prepared in step 4 was dissolved in 15 mL of ethanol, and 40 mg of 5% charcoal-shaped palladium were added thereto, and then the resulting suspension was hydrogenated at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to obtain 178 mg of the title compound. This compound was used in the following step without further purification.

Ή NMR(300MHz, CDClj) δ 4.18-4.1 l(m, 2H), 3.94(s, 4H), 2.39~2.29(m, 2H),

1.75~1.52(m, 11H), 1.29~1.23(m, 3H). . xocvclohexyl)propanoate

178 mg of the ethyl 3-(l,4-dioxaspiro[4.5]decan-8-yl)propanoate prepared in step 5 was dissolved in 10 mL of tetrahydrofuran. The reaction temperature was lowered to 0 ~ 5 °C, and then 6 mL of a 2 N aqueous hydrogen chloride solution was slowly dropwise to the above mixture and stirred at 10 °C or lower for 3 hours. After the reaction, the reaction solution was extracted with 20 mL of ethyl acetate and 20 mL of water, dried by using anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to obtain 130 mg of the title compound. Ή NMR(300MHz, CDC1₃) δ 4.17~4.10(m, 2H), 2.39~2.29(m, 2H), 2.18-2.15(m, 4H), 1.72~1.50(m, 7H), 1.28~1.20(m, 3H).

Step 7: Ethyl 3-(4-f4 ,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cvclohex-3-en-l- vDpropanoate

98 mg of the title compound was prepared in the same manner as in step 3 of Example 8, excep that 0.13 g of ethyl 3-(4-oxocyclohexyl)propanoate prepared in step 6 of Example 9 was used instead of methyl 4-oxocyclohexanecarboxylate prepared in step 3 of Example 8.

^JH NMR(300MHz, CDC1₃) δ 6.53(s, IH), 4.15~4.08(m, 2H), 2.36~2.31(m, 2H), 2.25~2.16(m, 2H), 1.72~1.50(m, 7H), 1.26~1.23(s, 15H).

Step 8: 3-(4-(4-(4-i3-CMorobenzarrado)phenyl)fa^

vDcyclohex ropanoic acid

42 mg of the title compound was prepared in the same manner as in step 3 of Example 8, excep that 0.13 g of ethyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)propanoate prepared in step 7 of Example 9 was used instead of t-butyl 4-(7-bromothieno[3,2- <^pyrimidin-4-yl)phenylcarbamate prepared in step 1 of Example 1.

Ή NMR(300MHz, DMSO- ₆) δ 12.05(bs, IH), 10.67(s, IH), 9.25(s, IH), 8.24-8.16(m, 3H), 8.06~8.04(m, 2H), 7.96~7.93(m, IH), 7.71~7.57(m, 2H), 3.27~3.10(m, IH), 2.28~2.23(m, 2H), 2.07-1.48(m, 9H), 1.13-1.09(m, 2H).

Example 10: 2-(4-(4-(4-((3,4-Dimethylphenyl)carbamoyl)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetic acid

1.14 g of 7-bromo-4-cWorotWeno[3,2-(¾pyrirnidine, 0.82 g of (4- (methoxycarbonyl)phenyl)boronic acid, and 0.316 g of tetrakis(triphenylphosphine)palladium were added to a mixed solvent of 7 mL of a 2 N aqueous sodium carbonate solution and 30 mL of 1 ,4-dioxane, and then stirred at 80 °C for 16 hours under an argon gas atmosphere. After the reaction, the reaction solution was extracted with 30 mL of ethyl acetate and 30 mL of water. The organic layer was dried by using anhydrous magnesium sulfate, filtered and then concentrated to obtain the title compound. This compound was used in the following step without further purification.

^!H NMR(300MHz, DMSO- ) S 9.42(s, 1H), 8.82(s, 1H), 8.38~8.18(m, 4H), 3.89(s,

3H). no[3,2-t ]pyrimidin-4-yl)benzoic acid

25 mL of 1,4-dioxane, 15 mL of water and 103 mg of lithium hydroxide were added to 0.5 mg of methyl 4-(7-bromotMeno[3,2-^pyrimidin-4-yl)benzoate prepared in step 1, and then the mixed solution was stirred at room temperature overnight. After the reaction, the reaction solution was acidified with a 1 N aqueous hydrogen chloride solution, followed by stirring at 0 °C for 1.5 hours. Then the reaction product was filtered, and the solid compound so obtained was dissolved in a mixed solvent of methanol and dichloromethane and then concentrated. The concentrated solid compound was crystallized by using a mixed solvent of dichloromethane and ether, and then filtered to obtain 0.351 g of the title compound.

Ή NMR(300MHz, DMSO-i¾) δ 13.40(bs, 1H), 9.42(s, 1H), 8.82(s, 1H) 8.38-8.18(m, 4H). 2- yrirmdm-4-v^

0.109 g of 4-(7-bromothieno[3,2-i¾pyrimidin-4-yl)benzoic acid prepared in step 2, 43 mg of 3,4-dimethyl aniline, 68 mg of EDC hydrochloride, 48 mg of HOBt, 0.123 mL of N,N- diisopropylethylamine and 5 mL of dimethylformamide were put into a 20 mL vial, and stirred at room temperature for 18 hours. After the reaction, 5 mL of water was added to the reaction mixture, and then stirred at room temperature for 1 hour. Then, the obtained solid was filtered, and dried in vacuum to obtain 110 mg of the title compound.

Ή NMR(300MHz, CDC1₃) δ 9.46(s, 1H), 8.30(d, J=8.2Hz, 2H), 8.10~8.08(m, 3H), 7.79(s, 1H), 7.47(s, 1H), 7.39(d, J=7.6Hz, 1H), 7.15(d, J=7.9Hz, 1H), 2.30(s, 3H), 2.27(s, 3H).

Step 4: Methyl 2-(4-f4-(4-((3,4-dimethylphenyl)carbamoyl)phenyl)thienor3,2- <^pyrirnidin-7- yl)cvclohex-3 -en- 1 -vDacetate

53 mg of 4-(7-bromothieno[3,2-i/]pyiimidin-4-yl)-N-(3,4-dimethylpheny¾^ prepared in step 3, 41 mg of methyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex- 3-en-l-yl)acetate prepared by the method disclosed in WO2009/016462, 8.3 mg of tetrakis(mphenylphosphine)palladium, 0.18 mL of a 2 N aqueous sodium carbonate solution and 30 mL of 1,4-dioxane were put into an 8 mL vial, and then stirred at 100 °C for 15 hours under an argon gas atmosphere. After the reaction, the reaction solution was extracted with 30 mL of ethyl acetate and 30 mL of water. The organic layer was dried by using anhydrous magnesium sulfate, filtered and then concentrated to obtain 81 mg of the title compound.

^]H NMR(300MHz, DMSC s) δ 10.32(s, IH) 9.37(s, IH), 8.37(s, IH), 8.28(d, J=8.46Hz, 2H), 8.19(d, J=8.25Hz, 2H), 7.63~7.52(m, 2H), 7.28(s, IH), 7.12(d, J=8.1Hz, IH), 3.64(s, 3H), 2.39(d, J=6.72Hz, 3H), 2.23(s, 3H), 2.21(s, 3H), 2.08(s, IH), 1.18~1.15(m, 5H).

Step 5: Methyl 2-(4-(4-(4-((3 -dimethylphenvncarbamoyl phenvnthieno ,2- ( lpyrirriidin^-yl^'lcvclohexyDacetate

80 mg of methyl 2-(4-(4-(4-((3,4-dimethylphenyl)carbamoyl)phenyl)thieno[3,2- i¾pyrirnidin-7-yl)cyclohex-3-en-l-yl)acetate prepared in step 4 was dissolved in a mixed solvent of 5 mL of methanol and 5 mL of ethyl acetate, and 40 mg of 5% charcoal-shaped palladium were added thereto, and then the resulting suspension was hydrogenated at room temperature during the night under a hydrogen atmosphere. The reaction mixture was filtered through a Celite, and then the filtrate was concentrated and then separated by Prep. TLC (ethyl acetate: n- hexane = 1 : 1 ) to obtain 17 mg of the title compound.

'H MR(300MHz, DMSO-C/₆) δ 10.31(s, IH), 9.34(s, IH), 8.33~8.17(m, 5H), 7.59(s, IH), 7.52(d, J=8.28, IH), 7.12(d, J=7.83Hz, IH), 3.57(s, 3H), 2.41(d, J=4.77Hz, 2H), 2.23(s, 3H), 2.20(s, 3H), 2.08(s, IH), 1.85- .83(m, 3H), 1.70-1.67(m, 2H), 1.62-1.60(m, 2H), 1.23(s, 2H).

Step 6: 2-(4-(4-(4-((3,4-Dimethylphenyl)caroamoy^

yl)cyclohexyl)acetic acid

16 mg of methyl 2-(4-(4-(4-((3,4-dimethylphenyl)carbamoyl)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetate prepared in step 5 was added to 1 mL of a mixed solvent of tetrahydrofuran/methanol/water (1:1:1) and then stirred. 51.5 mg of sodium hydroxide was added thereto, followed by stirring. After the reaction, the pH of the reaction solution was lowered to 5 ~ 6 by using a 1 N aqueous hydrogen chloride solution to obtain a solid. The obtained solid was filtered, and washed with water to obtain 12 mg of the title compound.

'H NMR(300MHz, DMSO-J₆) δ 10.30(s, IH), 9.34(s, IH), 8.32~8.17(m, 5H), 7.59(s, IH), 7.53(d, J=8.34, IH), 7.12(d, J=8.46Hz, IH), 2.39(d, J=7.47Hz, 2H), 2.23(s, 3H), 2.21(s, 3H), 2.08(s, IH), 1.85~1.83(m, 3H), 1.70~1.67(m, 2H), 1.62~1.60(m, 2H), 1.23(s, 2H).

Example 11: 2-(4-(4-(4-((7-PhenyltWeno[3 < |pyrimidin-4- yl)amino)phenyl)thieno[3,2^pyrimidin-7-yl)cycIohexyl)a

Step L Methyl 2-i4-f4-(4-((7-bromotMenor3,2-^pyrM yl)amino)phenyl)thimo[3 - 1 yrimidin-7-yl)c clohexyl)aceta

70 mg of methyl 2-(4-(4-(4-arninophenyl)tWeno[3,2-<fJpyrirnidin-7- yl)cyclohexyl)acetate prepared in step 3 of Example 1 and 46 mg of 7-bromo-4- cWorotWmo[3,2-<¾pyrimidine were dissolved in 1 mL of 2-propanol, and then stirred at 100 °C overnight. After the reaction, the reaction solution was cooled to room temperature to form a sohd. The formed solid was filtered under reduced pressure to 18 mg of the title compound.

Ή NMR(300MHz, DMSO- ₆) δ 10.24(s, IH), 9.24(s, IH), 8.76(s, IH), 8.48(s, IH) 8.25(m, 2H), 8.14(m, 2H), 3.59(s, 3H), 3.20(m, IH), 2.28~2.18(m, 2H), 2.03(m, IH), 1.83~1.56(m, 7H), 1.15(m, IH).

Step 2: 2-(4-f4-i4-ii7-Phenyltluenor3,2- ]pyriiri

|pyrirnidin-7-yl)cvclohexyl)acetic acid

18 mg of methyl 2-(4-(4-(4-((7-bromolWeno[3,2-^pyrimidin-4- yl)amino)phenyl)tMeno[3,2-^pyrirnidin-7-yl)cyclohe prepared in step 1, 3.6 mg of phenylboronic acid, and 2 mg of te1ralds(triphenylphosphine)palladium were added to a mixed solvent of 0.04 mL of a 2 N aqueous sodium carbonate solution and 0.16 mL of 1 ,4-dioxane, and then stirred at 100 °C for 12 hours under an argon gas atmosphere. After the reaction, the reaction solution was separated by Prep. TLC (ethyl acetate: rc-hexane = 1:1) to obtain 12 mg of methyl 2-(4-(4-(4-((7-phenyllMeno[3,2-i^pyiirrudin-4-yl)anm

7-yl)cyclohexyl)acetate. This compound was added to a mixed solvent of tetrahydrofuran: methanol: water (1:1:1), stirred and then hydrolyzed by 5 mg of sodium hydroxide. After the reaction, the pH of the reaction product was lowered to 3 ~ 4 by using a 1 N aqueous hydrogen chloride solution to obtain a solid. The obtained solid was filtered, and washed with water to obtain 3 mg of the title compound.

Ή NMR(300MHz, CDC13): δ 9.29(s, 1H), 8.92(s, 1H), 8.30(d, J=8.7Hz, 2H), 8.00~7.92(m, 4H), 7.87(s, 1H), 7.54~7.37(m, 4H), 3.34-3.03(m, 1H), 2.49(m, 1H),

2.29~2.17(m, 1H), 1.83~1.62(m, 7H), 1.21~1.08(m, 2H).

Example 12: 2-( -(^(4-((6-PhenyltMeno[3 ^pvrimidin-4- yl)ammo)phenyl)thieno[3,2^pyrM

4 mg of the title compound was prepared in the same manner as in steps 1 and 2 of Example 11, except that 6-bromo-4-cMorotWeno[3,2-c/]pyrimidine was used instead of the 7- bromo-4-cUorolWeno[3,2-i ]pyrirnidine of step 1 of Example 11.

Ή NMR(300MHz, DMSO-</₆): δ 10.1 l(s, 1H), 9.26(s, 1H), 8.71(s, 1H), 8.25(d, J=9.7Hz, 2H), 8.18(d, J=8.8Hz, 2H), 7.97(s, 1H), 7.92(d, J=6.9Hz, 2H), 7.59~7.50(m, 3H), 3.12~3.01(m, 1H), 2.38~2.36(m, 2H), 2.18~2.16(m, 2H), 1.98~1.58(m, 7H). Example 13: 2-( -(4-( -((7-(3-CWorophenyl)t eno[3,2w/lpyrimidin-4- yl)ammo)phenyl)thieno[3,2 /Jpyrimidm-7-yl)cydohexyl)acetic ad^

4 mg of the title compound was prepared in the same manner as in steps 1 and 2 of Example 11, except that 3-chlorophenylboronic acid pinacol ester was used instead of the phenylboronic acid of step 2 of Example 11.

^!H NMR(300MHz, DMSO-<&): δ 10.17(s, IH), 9.27(s, IH), 8.83(s, IH), 8.69(s, IH), 8.29~8.18(m, 5H), 8.09~8.06(m, IH), 7.57~7.46(m, 2H), 2.39~2.37(m, 2H), 2.27~2.17(m, 2H), 1.86~1.58(m, 6H), 1.21~1.05(m, 2H).

Example 14: 2-(4-(4-(4-((7-(3,4-Dffluorophenyl)tMeno[3,2-i |pyrimidto^ yl)animo)phenyl)thieno[3,2-^pyrimidm-7-yl)cydohexyl)acetic ad^

7 mg of the title compound was prepared in the same manner as in steps 1 and 2 of Example 11, except that 3,4-difluorophenylboronic acid pinacol ester was used instead of the phenylboronic acid of step 2 of Example 11.

Ή NMR(300MHz, DMSO- ₆): δ 10.20(s, IH), 9.25(s, IH), 8.81(s, IH), 8.66(s, IH), 8.31~8.16(m, 5H), 7.98~7.97(m, IH), 7.61~7.51(m, IH), 3.39~2.36(m, IH), 2.17~2.05(m, IH), 1.84~1.57(m, 8H), 1.21~1.05(m, 2H).

Example 15: 2 4-(4-(4-((7-(6-(Trifluoromemyl)pyridm-3-yl)thieno[3,2- </Jpyrimi -4-yl)animo)phenyI)m^

12 mg of the title compound was prepared in the same manner as in steps 1 and 2 of Example 11, except that 2-trifluoromethylpyridine-5-boronic acid pinacol ester was used instead of the phenylboronic acid of step 2 of Example 11. 'Η NMR(300MHz, DMSO-i¾): S 10.12(s, 1H), 9.41(s, 1H), 9.24(s, 1H), 8.86~8.81(m, 2H), 8.29~8.05(m, 5H), 8.04(d, J=7.9Hz, 1H), 2.32~2.26(m, 2H), 2.13~2.04(m, 2H), 1.84~1.63(m, 6H), 1.21~1.07(m, 2H).

Example 16: 2-(4-(4-(4-(TMeno[3,2-< |pyriniidm-4-yl)ammo)phenyl)tWeno[3,^ ^pvrimidin-7-yl)cycIohexyI)acetic acid

10 mg of the title compound was prepared by hydrolysis in the same manner as in steps 1 and 2 of Example 11, except that 4-cMorothieno[3,2-c¾pyrirnidine was used instead of the 7-bromo-4-cUorothieno[3,2-<i]pyrimidine of step 1 of Example 11.

Ή NMR(300MHz, DMSO-<4): δ 10.85(s, 1H), 9.28(s, 1H), 8.87(s, 1H), 8.46~8.44(m, 1H), 8.29~8.26(m, 1H), 8.11~8.09(m, 2H), 7.58~7.56(m, 1H), 3.26~3.24(m, 1H), 2.30~2.28(m, 2H), 2.18~2.16(m, 1H), 1.86~1.59(m, 8H).

Example 17: 2-(4-(4-(4-((lH-benzo[^iinidazol-2-yl)ainmo)phenyl)tMeno[3,2-

Step 1 : Methyl 2-(^,4-(4-(4-isotMenocvanatophenyl)1hienor3 -< 1pyrimidin-7- vDcyclohexyDacetate

200 mg of methyl 2-(^(4-(4-aminophmyl)tMeno[3,2-^pyrirnidin-7- yl)cyclohexyl)acetate prepared in step 3 of Example 1 was dissolved in 2 mL of anhydrous dichloromethane under a nitrogen atmosphere, and then cooled to 5 °C or lower. 107.5 mg of Ι, -lhienorarbonyldiirnidazole was added thereto, and the mixed solution was stirred at 5°C or lower for 18 hours and then further stirred at room temperature. After the reaction, an organic layer is concentrated, and then separated by Prep. TLC to obtain 180 mg of the title compound.

^!H NMR(300MHz, CDC1₃) δ 9.30(s, 1H), 8.23(d, 2H), 7.71~7.65(m, 1H), 7.43(d, 2H), 3.70(s, 3H), 3.36~3.18(m, 1H), 2.27(d, 1H), 2.40~2.10(m, 2H), 2.03~1.71(m, 4H), 1.69~1.47(m, 2H), 1.48-1.19(m, 2H).

Step 2: Methyl 2-(4-(4-r4-(^'(lH-benzor_li1imid-izol-2-yl)ammo phenyl)tnienor3 - ^pyrirnid -7-yl)cyclohexyl)acetate

90 mg of methyl 2-(4-(4-(4-isotWenocyanatophenyl)mieno[3,2-(¾pyrimidin-7- yl)cyclohexyl)acetate prepared in step 1 was dissolved in dichloromethane, 24.1 mg of 1,2- phenylenediamine was added thereto, and then the resulting mixture was stirred at room temperature for 5 days. The mixed solution was concentrated by removing an organic solvent, and then separated by Prep. TLC to obtain an intermediate. The obtained intermediate and EDC hydrochloride were dissolved in dichloromethane, and then stirred at room temperature for 18 hours. After the reaction, the reaction solution was extracted with water to obtain an organic layer. The organic layer was dried by using anhydrous magnesium sulfate, filtered, concentrated, and then separated by Prep. TLC to obtain the title compound.

Ή NMR(300MHz, CDC1₃) δ 9.26(s, 1H), 8.19(d, 2H), 7.68~7.56(m, 3H), 7.46- 7.34(m, 2H), 7.20-7.09(m, 2H), 3.70(s, 3H), 3.36-3.18(m, 2H), 2.27(d, 2H), 2.40-2.10(m, 4H), 2.03~1.71(m, 8H), 1.69-1.47(m, 4H), 1.48-1.19(m, 4H).

Step 3: 2-r4-(4-(4-(qH-benzor limidazol-2-vnan ino)phenyl)thienor3,2-

(i1pyrirnidin-7-yl)cvclohexyl)acetic acid

The methyl 2-(4-(4-(4-((lH-benzo[i/]imidazol-2-yl)animo)phenyl)thieno[3,2- ^pyrirnidin-7-yl)cyclohexyl)acetate prepared in step 2 was added to 2 mL of a mixed solvent of tetrahydrofuran/methanol/water (1:1:1) and stirred, and then 15 mg of sodium hydroxide was added thereto and then further stirred. After the reaction, the pH of the reaction solution was lowered to 5 ~ 6 by using a 1 N aqueous hydrogen chloride solution to obtain a solid. The obtained solid was filtered, and washed with water to obtain 40.1 mg of the title compound.

Ή NMR(300MHz, DMSO-c ₆) δ 11.3(bs, IH), 9.30(s, IH), 8.31(d, 2H), 8.22(s, IH), 7.81(d, 2H), 7.55~7.41(m, 2H), 7.32~7.20(m, 2H), 3.25~3.01(m, IH), 2.40(d, IH), 2.24-1.99(m, 2H), 1.93-1.47 (m, 7H), 1.32-1.10 (m, IH).

Example 18: 2-(4-(4-(4-(3-(3-Chlorophenyl)ureido)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetic acid

Step 1: Methyl 2-( -(4-(4-(3-(3-cMorophmylurrido)phenvD^

vDcvclohex acetate

3.1 mg of methyl 2-(4-(4-(4-aminophenyl)tMeno[3,2-^pyrimidin-7- yl)cyclohexyl)acetate prepared in step 3 of Example 1 was dissolved in 60 mL of anhydrous tetrahydrofuran, and then 1.37 g of 3-chlorophenyl isocyanate was added thereto. The resulting mixture was stirred at room temperarture for 18 hours. After the reaction, the reaction solution was concentrated by distilling an excess of a solvent under reduced pressure, crystallized by adding diethyl ether, and then filtered to obtain 4.06 g of the light yellow title compound.

^]H NMR(300MHz, DMSO-J₆) δ 9.23(s, IH), 9.18(s, IH), 9.04(s, IH), 8.26-8.16(m, 3H), 7.75-7.72(m, 3H), 7.36~7.29(m, 2H), 7.07~7.03(m, IH), 3.61(s, 3H), 3.30~3.02(m, IH), 2.28(d, IH), 2.27~2.14(m, IH), 2.21~2.01(m, IH), 1.89~1.49(m, 7H), 1.30-1. l l(m, IH).

Step 2: 2-(4-(4-i4-(3-G-CMorophenylureido ^

vDcvclohexyDacetic acid

100 mg of methyl 2-(4-(4-(4-(3-(3-chlorophenylureido)phenyl)thieno[3,2- d]pyrimidin-7-yl)cyclohexyl)acetate prepared in step 1 was added to 2 mL of a mixed solvent of tetrahydrofuran/methanol/water (1 :1:1) and then stirred. , In addition, 30 mg of sodium hydroxide was added thereto and then further stirred. After the reaction, the pH of the reaction solution was lowered to 5 ~ 6 by using a 1 N aqueous hydrogen chloride solution to obtain a solid. The obtained solid was filtered, and washed with water to obtain 85 mg of the title compound.

1H NMR(300MHz, DMSO-</₆) δ 12.1(s, IH), 9.44(s, IH), 9.30(s, IH), 9.23(s, IH), 8.31~8.16(m, 3H), 7.77~7.74(m, 3H), 7.34~7.29(m, 2H), 7.06~7.03(m, IH), 3.34~3.03(m, IH), 2.38(d, lH), 2.18(d, lH), 2.10~2.01(m, IH), 1.91~1.47(m, 7H), 1.30-1.10(m, IH).

Example 19: Sodium cis 2-(4-(4-(4-(3-(3-chIorophenyI)ureido)phenyl)thieno[3,2- ^pyrimidin-7-yl)cyclohexyl)acetate

filtrate

Step 1 : cis Methyl 2-(4-(4-f4-i3-(^"3-chlorophenylureido)phenyl)thienor3,2- (i1pyrimid -7-yl)cyclohexyl acetate

150 mg of methyl 2-(4-(4-(4-(3-(3-chlorophenylureido)phenyl)thieno[3,2-

^pyrimidin-7-yl)cyclohexyl)acetate prepared in step 1 of Example 18 was dissolved 2 mL of ethyl acetate, stirred at 70 °C for 12 hours, and then cooled to room temperature to form a solid. The formed solid was filtered, and then the filtrate was distilled under reduced pressure to 76 mg of the yellow title compound.

¾ MR(300MHz, DMSO- ₆): δ 9.23(s, IH), 9.19(s, IH), 9.05(s, IH), 8.26(s, IH), 8.18(d, 2H), 7.75~7.72(m, 3H), 7.36~7.29(m, 2H), 7.07~7.03(m, IH), 3.61(s, 3H), 3.31~3.18(m, IH), 2.52(d, 2H), 2.28~2.14(m, IH), 1.89~1.49(m, 8H).

Step 2: cis 2-(4-(4-(4-(3-(3-CMorophenylurddo)phenyl)tMeno[3,2- 1pyrimidin-7-

The title compound was prepared by using cis methyl 2-(4-(4-(4-(3-(3- cMorophenylureido)phenyl)thieno[3,2-<f]^ prepared in step 1 in the same manner as in step 2 of Example 18.

Ή NMR(300MHz, DMSO-i¼): δ 12.08(s, IH), 9.23(s, IH), 9.20(s, IH), 9.06(s, IH), 8.25(s, IH), 8.17(d, 2H), 7.79~7.69(m, 3H), 7.38~7.26(m, 2H), 7.07~7.01(m, IH), 3.30~3.14(m, IH), 2.38(d, 2H), 2.25~2.10(m, IH), 1.9( .50(m, 8H).

Step 3: Sodium cis 2-(4-(4-(4-(3-(3-chlorophenyl)ureido)phenyl)thieno 3,2- f|pyrimidin-7-yl)cvclohexyl)acetate

1.97 g of cis 2-(^(4-(4-(3-(3-cMorophenylurddo)phen^

yl)cyclohexyl)acetic acid prepared in step 2 was diluted with 20 mL of methanol, 3.78 n L of a 1 N aqueous sodium hydroxide solution was added thereto. The resulting mixture was stirred at room temperature for 2 hours. The mixed solution was distilled under reduced pressure to remove a solvent therefrom, thus obtaining 2.09 g of the yellow title compound.

Ή NMR(300MHz, DMSO- ₆): δ 9.15(s, IH), 8.18(s, IH), 8.08(s, 2H), 7.86(t, IH), 7.79(d, 2H), 7.43(d, IH), 7.17(1, IH), 6.79(d, IH), 3.98~3.31(bs, 3H), 3.29~3.15(m, IH), 2.34~2.12(m, 3H), 1.95~1.57(m, 8H).

Example 20: trans 2-(4-(4-(4-(3-(3-Chlorophenyl)ureido)phenyl)thieno[3,2- ^pyrimidin-7- l)cyclohexyl)acetic acid

Step 1: trans Methyl 2-f4-(4-(4-(3-(3-chlorophenylureido)phenyl)thieno[3,2- ^pyrimid -7-yl)cvclohexyl)acetate

The solid obtained in step of Example 19 was filtered to obtain 72 mg of the yellow title compound.

'H NMR(300MHZ, DMSO-< ): δ 9.23(s, IH), 9.20(s, IH), 9.06(s, IH), 8.19~8.16(m, 3H), 7.75~7.72(m, 3H), 7.36-7.3 l(m, 2H), 7.07~7.03(m, IH), 3.63(s, 3H), 3.20~3.05(m, IH), 2.28(d, 2H), 2.13-2.01 (m, 2H), 1.90-1.72(m, 3H), 1.68~1.50(m, 2H), 1.29-1.1 l(m, 2H).

Step 2: trans 2-(4-(4-(4-(3-(3-CMorophenylureido)phenyl)tMeno[3,2- 1pyrimidin-7- vDcyclohexyDacetic acid

The title compound was prepared by using trans methyl 2-(4-(4-(4-(3-(3- chlorophenylureido)phenyl)tnieno[3,2-c ]pyiimidin-7-yl)cycloh^ prepared in step 1 in the same manner as in step 2 of Example 18.

Ή NMR(300MHz, DMSO- ₆): δ 12.06(s, IH), 9.23(s, 2H), 9.10(s, IH), 8.19~8.16(m, 3H), 7.75~7.72(m, 3H), 7.36~7.31(m, 2H), 7.07~7.03(m, IH), 3.20~3.05(m, IH), 2.18(d, 2H), 2.13-2.01 (m, 2H), 1.92-1.79(m, 3H), 1.70-1.50(m, 2H), 1.30-1.1 l(m, 2H).

Example 21: 2-(4-(4-(4-(3-(2-Fluoro-5- (trifluoro henyl)phenyl)ureido)phenyl)thieno[3,2-^pyrimi

17 mg of the title compound was prepared in the same manner as in steps 1 and 2 of Example 18, except that 2-fluoro-5-trifluorophenyl isocyanate was used instead of 3- chlorophenyl isocyanate of step 1 of Example 18.

Ή NMR(300MHz, DMSO-rf₆) δ 12.05(bs, IH), 9.56(s, IH), 9.23(s, IH), 9.04(s, IH), 8.64(d, IH), 8.31-8.18(m, 3H), 7.75(d, 2H), 7.52(t, IH), 7.42-7.44(m, IH), 3.1 l(m, IH), 2.39(d, lH), 2.18(d, 2H), 2.09-2.05(m, IH), 1.86-1.82(m, 2H), 1.61-1.57(m, IH), 1.22-1.14(m, 4H). Example 22: Sodium cis 2-(4-(4-(4-(3-(2-Fluoro-5-

(trifluoro henyl)phenyl)ureido)phenyl)m^

1N NaOH

MeOH, rt

SStteepp 11:: c ciiss MMeetthhyyll 22--((44--((44--((44--aammmmoopphheennyyll))tthhiieennoo[[33 --<< 11Ppyyririmmiiddiinn--77-- yl)cyclohexyl)acetate

The fitrate of methyl 2-(4-(4-(4-(^butoxycarbonyl)amino)phenyl)thieno[3,2- i¾pyriinidin-7-yl)cyclohexyl)acetate was collected and concentrated, and then separated by column chromatography to obtain cis methyl 2-(4-(4-(4-((t- butoxycaroonyl)amino)phenyl)tMeno[3,2^ Thereafter, 3.13 g of the title compound was prepared by using this compound in the same manner as in step 3 of Example 1.

^!H NMR(300MHz, CDC1₃) δ 9.21 (s, 1H), 8.09(d, 2H), 7.64(s, 1H), 6.83(d, 2H), 4.04(bs, 2H), 3.69(s, 3H), 3.41-3.26(m, 1H), 2.46(d, 2H), 2.40~2.26(m, 1H), 2.06~1.51(m, 8H). Ste£ 2j _cis Methyl 2-(4-(4-(4-(3-(2-fluoro-5-

(trifluorophenyl)phenyl)ureido)phe

300 mg of cis methyl 2-(4-(4-(4-aminophenyl)tWeno[3,2-^pyrimidin-7- yl)cyclohexyl)acetate prepared in step 1 was dissolved in 5 mL of anhydrous tetrahydrofuran, and then 169.4 mg of 2-fluoro-5-trifluorophenyl isocyanate was added thereto. The resulting mixture was stirred at room temperarture for 18 hours. After the reaction, the reaction solution was concentrated by distilling an excess of a solvent under reduced pressure, crystallized by adding diethyl ether, and then filtered to obtain 314.7 mg of the light yellow title compound.

lK NMR(300MHz, DMSO-<&) δ 9.55(bs, 1H), 9.23(s, 1H), 9.03(bs, 1H), 8.63(d, 1H), 8.26(s, 1H), 8.20(d, 2H), 7.75(d, 2H), 7.58-7.39(m, 2H), 3.61(s, 3H), 3.31-3.20(m, 1H), 2.50(d, 2H), 2.25~2.10(m, 1H), 1.91-1.51(m, 8H).

Step 3j Sodium cis 2-(4-(4-(4-(3-f2-fluoro-5-

(trifluorophenyl)phenyl)ureido)phenyl)u^

310 mg of cis methyl 2-(4-(4-(4-(3-(2-fluoro-5-

(trifluorophenyl)phenyl)ureido)ph^ prepared in step 2 was added to 3 mL of a mixed solvent of tetr^ydrofuran/methanol/water (1 :1 :1) and then stirred. 100 mg of sodium hydroxide was added thereto and then further stirred. After the reaction, the pH of the reaction solution was lowered to 5 ~ 6 by using a 1 N aqueous hydrogen chloride solution to obtain a solid. The obtained solid was filterd, and washed with water to obtain 299 mg of yellow cis 2-(4-(4-(4-(3-(2-fluoro-5- (trifluorophenyl)phenyl)ureido)phenyl) Subsequently, 299 mg of cis 2-(4-(4-(4-(3-(2-fluoro-5- (trifluorophenyl)phenyl)ureido)phenyl)thieno[3 ,2-i^pyrimidin-7-yl)cyclohexyl)acetic acid so obtained was diluted with 3 mL of methanol, and 0.47 mL of a 1 N aqueous sodium hydroxide solution was added thereto. The resulting mixture was stirred at room temperature for 1 hour and concentrated. The mixed solution was crystallized using diethyl ether to form crystals, and the crystals are filtered to obtain 227 mg of the light yellow title compound.

Ή NMR(300MHz, DMSO-< ): δ 11.7(bs, 2H), 9.20(s, 1H), 8.43 (d, 1H), 8.21- 8.08(m, 3H), 7.87(d, 2H), 7.50-7.31(m, 2H), 3.29-3.21(m, 1H), 2.20 (bs, 3H), 1.96~1.57(m, 8H). Example 23: trans 2-(4-(4-(4-(3-(2-Fhioro-5-

(trifluorophenyl)phenyI)ureido)phenyI)m^

115 mg of methyl 2-(4-(4-(4-(3-(2-fluoro-5-

(mfluorophenyl)phenyl)ureido)phe^ was added to 5 mL of ethyl acetate, heated and refluxed to be dissolved. Then, the reaction temperature was slowly lowered to 40 °C to form a solid, and the formed solid was filtered to obtain trans methyl 2-(4-(4-(4-(3-(2-fluoro-5-(trifluorophenyl)phenyl)ureido)phenyl)thieno[3,2- i ]pyrirnidin-7-yl)cyclohexyl)acetate. Subsequently, 23.4 mg of the title compound was prepared by using the obtained compound in the same manner as in step 2 of Example 18.

'H NMRPOOMHZ, DMSO- ₆) δ 12.03(bs, 1H), 9.64(s, 1H), 9.24(s, 1H), 9.10(s, 1H),

8.64(d, 1H), 8.21-8.1 l(m, 3H), 7.76(d, 2H), 7.55-7.43(m, 2H), 3.22-3.02(m, 1H), 2.28-1.99(m, 4H), 1.97-1.69(m, 3H), 1.68-1.49(m, 2H), 1.31-1.09(m, 2H).

Example 24: 2-(4-(4-(4-(3-(4-CMoropyridine-2-yl)ureido)phenyl)thieno[2 < |pyrimidin- - l c l h x l ti a id

mg of methyl 2-(4-(4-(4-arriinophenyl)tMeno[3,2-^pyrimidin- yl)cyclohexyl)acetate prepared in step 3 of Example 1 and 33.3 mg of 4- nitrophenylchloroformate were added to 3 mL of 1,4-dioxane, and then reflexed and stirred for 3 hours. After the reaction temperature was lowered to room temperature, 22.7 mg of N,N- diisopropylethylamine and 24.9 mg of 4-cWoropyridine-2-amine were added to the mixed solution, followed by stirring under reflux overnight. After the reaction, the first reaction solution was extracted with 10 mL of ethyl acetate and 10 mL of water. The organic layer was dried by using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and then separated by Prep. TLC (dichlormethane: methanol = 8:1) to obtain methyl 2-(4-(4-(4- (3-(5-cMoropyridin-3-yl)ureido)pheny Then, this compound was dissolved in a mixed solvent of tetrahydrofuran: methanol: water (1:1:1), and then 11 mg of sodium hydroxide was added thereto and then further stirred. After the reaction, the pH of the reaction solution was lowered to 3 ~ 4 to obtain a solid. Then, the obtained solid was filtered, and then washed with water to obtain 32 mg of the title compound.

Ή NMR(300MHz, DMSO- ₆) δ 12.05(bs, 1H), 10.33(s, 1H), 9.85(s, 1H), 9.22(s, 1H), 8.28~8.17(m, 4H), 7.79~7.76(m, 3H), 7.18~7.16(m, 1H), 3.33~3.09(m, 1H), 2.38~2.36(m, 1H), 2.25~2.07(m, 3H), 1.83-1.59(m, 6H), 1.21-1.07(m, 1H).

Example 25: 2-( -(4-(4-(3-(5-Bromopyridin-3-yl)ureido)phenyl)thieno[3,2- ^pvrimidin-7-yl)cyclohexyl)acetic acid

20 mg of the title compound was prepared in the same manner as in Example 24, except that 5-bromopyridine-3-amine was used instead of 4-cWoropyridine-2-amine of Example 24.

'H NMR(300MHZ, DMSO-i/₆) δ 12.10(bs, 1H), 9.44(s, 1H), 9.31(s, 1H), 9.23(s, 1H), 8.88(s, 1H), 8.57(s, 2H), 8.26(s, 1H), 8.04~8.01(m, 2H), 7.76~7.74(m, 2H), 3.24~3.26(m, 1H), 2.39~2.37(m, lH), 2.27~2.04(m, 2H), 1.84~1.57(m, 7H), 1.22-1.18(m, 1H).

The compounds prepared in Examples 1 to 25 were evaluated as follows. Test Example: Measurment of DGAT1 inhibition concentration (ICsn)

The medicinal effects of DGAT1 inhibitors in vitro were evaluated by using a human recombinant DGAT1 enzyme expressed in insect cells (SF9 cells). SF9 cells were homogenized by washing them with DPBS (Dulbecco's phosphate-buffered saline) and then suspending cell pellets with a tris buffer (250 mM sucrose; 10 mM Tris-HCl (pH 7.4); proteinase inhibitor). The resulting product was centrifugally separated at 10,000 x g for 30 minutes to remove the cell debris remaining in the lower layer thereof, and was centrifugally separated at 100,000 x g for 60 minutes to obtain a microsomal membrane. Further, membrane fractions were resuspended by the tris buffer, and then stored at -80 °C.

The activity of DGAT1 was measured with reference to the method disclosed in the article, Journal of Medicinal Chemistry (2009) 52, 1558-1568. Specifically, 0.0001 ~ 10 μΜ (final cone.) of the test compounds were cultured at room temperature (25 °C) for 15 minutes with a 10 μΜ (final cone.) of SF9 microsomal protein solution and 100 mM (final cone.) of MgCl₂ solution, and were then further cultured at room temperature (25 °C) for 30 minutes after the addition of 100 μΜ (final cone, in 12.5% EtOH) of 1 ,2-dioleyl-sn-glycerol and 30 μΜ (final cone.) of ¹⁴C-oleyl coenzyme A. The reaction was completed by the addition of 300 μΐ, of a mixed solution of 2-propanol/heptane (7:1), and radioactive triglyceride was separated from an organic solvent layer by using 200 piL of heptane and 200 L of a 0.1 M carbonate buffer (pH 9.5). The amount of triglyceride was measured by liquid scintillography (Perkin Elmer) after mixing with an organic solvent and an equivalent amount of scintillation solvent (MicroScint™- O). The effects of inhibiting DGAT1 were calculated by percentage in comparison with a control material. The IC50 values of the compounds prepared in Examples 1 to 25 for inhibiting DGAT1 activity in SF9 cells are given in Table 1 below.

[Table 1]

As given in Table 1 above, it is found that the compounds of Formula 1 of the present invention have excellent activity of inhibiting DGAT1.

While the invention has been described with repect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

What is claimed is:

1. A compound selected from the group consisting of a tricyclic heteroaryl compound of Formula 1 below, and pharmaceutically acceptable salts, isomers, hydrates and solvates thereof:

Formula 1

wherein X is -0-, -S-, -NH-, or -N(C_Malkyl)-;

Y is carboxy, C_1-6alkyl,

Ci-ealkylamido,

C₃-₈cycloalkyl, carboxyC₃^cycloalkyl, Ci^alkoxycarbonylCs^cycloalkyl, Q-^aryl, 5- to 13- memebered heteroaryl or 3- to 13-membered heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl may each independently be substituted with one or more substituents selected from the group consisting of halogen,

di-Ci-galkylarnino and Ci-ealkoxy,

R¹ is H, Ci-ealkyl, C₃-₈cycloalkyl, C^ai l, 5- to 13-membered heteroaryl or 3- to 13- membered heterocycloalkyl, wherein the aryl, heteroaryl and heterocycloalkyl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino,

C₃.₈cycloalkyl, di- Ci-₆alkylamino, Ci-ealkylcarbonylamino, C -i₄aryl, haloC_6-i₄aryl, 5- to 13-membered heteroaryl, 5- to 13-membered heteroaryl containing

and 3- to 13-membered heterocycloalkyl;

R² is =0, =S, =NH or =N-C_M alkyl;

B is C₆-i₄arylene or 5- to 13-membered heteroarylene which is unsubstituted or substituted with halogen; and

R^x, R^y, R⁷³ and R* are each independently H, C^alkyl or haloCi^alkyl,

2. The compound of claim 1 ,

wherein X is -0-, -S-, -NH-, or -N(C_Malkyl)-;

Y is carboxy,

aminocarboxyCi^alkyl, hydroxyCi^alkyl, carboxyC_3-8cycloalkyl, carboxyCi-ealkylamido or C\. alkylsulfonyl;

₀1 R² _R1 O R1 H _R1

A is H H , H , O or H ;

R¹ is Ci^alkyl, C_3-8cycloalkyl, 3- to 13-membered heterocycloalkyl, Q^aryl or 5- to 13-membered heteroaryl, wherein the aryl, heteroaryl and heterocycloalkyl may each independently be substituted with one or more substituents selected f om the group consisting of halogen, nitro, amino, Ci_-3alkyl, haloC_1-3alkyl, Ci-₃alkoxy, Ci_-3alkylamino, di-C_1-3alkylamino, Q. ₃alkylcaroonylamino, Cg-ioaryl, haloC_6-ioaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl containing haloCi_-3alkyl and 5- to 10-membered heterocycloalkyl;

R² is =0, =S, =NH or =N-C i₄alkyl;

B is Q-_Marylene or 5- to 13-membered heteroarylene which is unsubstituted or substituted with halogen; and

R^x, R^y, R²³ and R* are each independently H, C_1-6alkyl or

3. The compound of claim 1 ,

wherein X is -0-, -S-, - Ή-, or -N(Ci-₄alkyl)-;

Y is carboxy, carboxyCi.₃alkyl, Ci.₃alkoxycarbonylCi_-3alkyl, arninocarboxyCi^alkyl or carboxyCi^alkylamido;

D1 R² R1 O R1 H R1

A is H H , H , O or H _;

R¹ is C^ioaryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, Ci_-3alkyl, haloCi_-3alkyl, Ci.₃alkoxy, Ci_-3alkylamino, di-Q. ₃alkylamino,

phenyl, halophenyl and haloC_1-3alkylpyridinyl;

R² is =0, =S or=NH;

B is Ce-ioarylene or 5- to 10-membered heteroarylene; and

R^x, R^y, R²³ and R* are each independently H or C_1-3alkyl,

4. The compound of claim 1 ,

wherein X is -S-;

Y is carboxy or carboxyCi_-2 alkyl;

R¹ is Q-ioaryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl may each independently be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, methyl, trifluoromethyl, acetamido, phenyl, chlorophenyl, difluorophenyl and trifluoromethylpyridinyl;

R² is =0;

B is phenylene; and

R^x, R^y, R^za and R* are H,

wherein the heteroaryl contains at least one heteroatom selected from the group consisting of N, O and S .

5. The compound of claim 1, wherein the bicyclic heteroaryl compound of Formula 1 is selected from the group consisting of:

1) 2-(4-(4-(4-(3-cMorbenzamido)phenyl)tMeno[3,2-<i]pyrird yl)cyclohexyl)acetic acid;

2) 2-(4-(4-(4-(2-naphmamido)phenyl)trdeno[3,2- ]pyrimidin- acid;

3) 2-(4-(4-(4-(2-phmyl-5-(trifluoromethyl)oxazole-4-carboxamido)phenyl)thieno[3,2- ^pyrirnidin-7-yl)cyclohexyl)acetic acid;

4) 2-(4-(4-(4-(5-cMoro-2-iiifrobeiizamido^ yl)cyclohexyl)acetic acid;

5) 2-(4-(4-(4-(2-amino-5-cMorobenzan^

yl)cyclohexyl)acetic acid;

6) 2-(4-(4-(4-(2-acetamido-5-cMorober£

yl)cyclohexyl)acetic acid;

7) 2-(4-(4-(4-(6-(trifluoromethyl)iii∞^

yl)cyclohexyl)acetic acid;

8) 4-(4-(4-(3-cMorobertzamido)phenyl)tto

yl)cyclohexanecarboxylic acid;

9) 3-(4-(4-(4-(3-cMorobertzamido)phenyl)^

yl)cyclohexyl)propanoic acid;

10) 2-(4-(4-(4-((3,4-dime1hylphenyl)caft

yl)cyclohexyl)acetic acid;

11) 2-(4-(4-(4-((7-phenylthieno[3,2-(¾pyrimidin-4-yl)amm

<i]pyriniidin-7-yl)cyclohexyl)acetic acid;

12) 2-(4-(4-(4-((6-phenyltWeno[3,2-^pyrimidin-4-yl)amino)phe^

<¾pyrimidin-7-yl)cyclohexyl)acetic acid;

13) 2-(4-(4 4-((7-(3-cWorophenyl)tWeno[3,2-i/]pyrimidin-4- yl)arnino)phenyl)tWeno[3,2-<i]pyrir^

14) 2 4 4 4-((7-(3,4-difluorophenyl)lMeno[3,2-<i]pyrimidin-4- yl)arnino)phenyl)lWeno[3,2- ]pyri^

15) 2-(4-(4-(4-((7-(6-(trifluorome l)p^

yl)amino)phenyl)tMeno[3,2-^pyrimidin-7-yl)cyclohexyl)ace^

16) 2-(4-(4-(4-(thieno[3,2-<¾pyrimidin-4-ylamino)phenyl)^

yl)cyclohexyl)acetic acid;

17) 2-(4-(4-(4-((lH-benzo[cf]imidazol-2-yl)amino)phenyl)1bie^

yl)cyclohexyl)acetic acid;

18) 2-(4-(4-(4-(3-(3-cMorophenyl)ureM^^

yl)cyclohexyl)acetic acid;

19) cis 2-(4-(4-(4-(3-(3-cMorophenyl)ureido)pheny

yl)cyclohexyl)acetic acid;

20) trans 2-(4-(4-(4-(3-(3-cMorophenyl)ureido)pheny^^ yl)cyclohexyl)acetic acid;

21 ) 2-(4-(4-(4-(3-(2-fluoro-5-(trifluorop ,2- <i]pyrimidin-7-yl)cyclohexyl)acetic acid;

22) cis 2-(4-(4-(4-(3-(2-fluoro-5-(trifluorop

(fJpyrirnidin-7-yl)cyclohexyl)acetic acid;

23) trans 2-(4-(4-(4-(3-(2-fluoro-5-(trifluorophenyl)phenyl)urddo)phenyl)thieno[3,2- ^pyrirrudin-7-yl)cyclohexyl)acetic acid;

24) 2-(4-(4-(4-(3-(4-cMoropyridin-2-yl)ureido^

yl)cyclohexyl)acetic acid; and

25) 2-(4-(4-(4-(3-(4-bromopyridm-3-yl)ura

yl)cyclohexyl)acetic acid.

6. A pharmaceutical composition comprising the compound of claim 1 as an effective ingredient for inhibiting diacylglycerol O-acyltransferase type 1 (DGAT1).

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is used for the prevention or treatment of the diseases or conditions caused by DGAT1.

8. The pharmaceutical composition of claim 7, wherein the diseases or conditions caused by DGAT1 is selected from the group consisting of obesity, hyperlipidemia, hypertriglyceridemia, insulin resistance syndrome, hyperglycemia, diabetes, nonalcoholic fatty liver diseases, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, stroke, ischemic reperfusion injury, myocardosis, cardiac infarction and coronary artery diseases.

9. A use of the compound of claim 1 for the manufacture of a medicament for preventing or treating the diseases or conditions caused by DGAT1.

10. A method for preventing or treating the diseases or conditions caused by DG AT 1 , which comprises administering the compound of claim 1 to a mammal in need thereof.