KR100968705B1 - 2-phenylpyrimidine derivatives and processes for the preparation thereof - Google Patents

Abstract

The present invention provides novel 2-phenylpyrimidine derivatives or pharmaceutically acceptable salts thereof, methods for their preparation, and compositions comprising them. 2-phenylpyrimidine derivatives of the present invention or pharmaceutically acceptable salts thereof have excellent effect on peroxysomal proliferator-activated receptors (PPARs) alpha and gamma and have very good hypoglycemic effect and bioavailability upon oral administration. Has

Phenylpyrimidine, Peroxysome Proliferator-Activated Receptor, Diabetes, PPAR

Description

Novel 2-phenylpyrimidine derivatives and preparation methods thereof {2-PHENYLPYRIMIDINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF}

Peroxisome proliferator-activated receptors (PPARs receptors) are nuclear receptors belonging to the steroid / retinoid receptor family that are activated by ligand binding and regulate the expression of target genes. Regulates a number of intracellular responses involved in the storage and catabolism of fat and carbohydrates [Kota, BP et al . , Pharm. Res. (2004) 1-10. Receptors activated by mammalian peroxysomal proliferators are isolated from three species, PPAR-alpha, gamma, and delta (or beta), which are distinguished in their tissue distribution, ligand preference, and biological function. [Willson T. et al., J Med Chem (2000) 43, 527-550.

PPAR-alpha is activated to 1) decrease triglyceride biosynthesis by increasing the catabolism of fatty acids, 2) increase LPL expression directly in the target organ, and 3) decrease the expression of apolipoprotein C-III, an LDL inhibitor, It lowers triglyceride levels in blood and decreases low density lipoprotein (LDL) levels in serum. In addition, PPAR-alpha ligands increase serum high density lipoprotein (HDL) concentrations by increasing the synthesis of apolipoproteins AI, A-II in the liver [Francis G. et al . , Curr . Opin . Pharmacol . (2003) 3, 186-191.

PPAR-gamma is an intranuclear receptor that is involved in the expression of genes that respond to insulin. It has been shown to reduce blood triglycerides by improving insulin resistance and antidiabetic effect of reducing glycated hemoglobin (HbA1c) and fasting blood glucose. Saltiel A. et al.Curr Opin Endocrinol Diabetes (1995) 2, 341-347; Chaiken R. et al.,Diabetologia (1995) 38, 1307-1312.

Selective Ligands in PPAR-Delta Serum HDL and LDL-cholesterol-lowering effects have been reported in monkeys [Oliver, WR et al . , Proc . Natl . Acad . Sci, USA (2001) 276, 5306-5311], the exact physiology is not yet known.

Recently, there has been an attempt to develop a single drug to treat insulin resistance and fat metabolism simultaneously by acting on two or more types of PPARs. For example, benzylamide derivatives having thiazolidine-2,4-dione (TZD) groups or phenoxazine derivatives having phenylpropanoic acid groups as compounds which simultaneously act on PPAR-alpha and PPAR-gamma. [WO 99/019313] and phenylsulfonate derivatives, [WO 99/062872], and phenyloxazole derivatives having a benzyl glycine group [WO 2001/021602] [Henke BR J. Med . Chem . (2004) 47, 4118-4127. In addition, compounds that act simultaneously on PPAR-delta and gamma or Edward P., Drug Discov . Today (2002) 7 (19), 1022], there are compounds that act both on PPAR-alpha, PPAR-gamma and PPAR-delta [Danial, DS, Annual Rep . Med . Chem, (2003) 38, 71-80.

The present invention provides a novel 2-phenylpyrimidine derivative and its pharmaceutically acceptable salts which have excellent effect on peroxysomal proliferator-activated receptors (PPARs) alpha and gamma and have a very good hypoglycemic effect upon oral administration. to provide.

According to one aspect of the invention, a 2-phenylpyrimidine derivative or a pharmaceutically acceptable salt thereof is provided.

In addition, according to another aspect of the present invention, there is provided a method for preparing a 2-phenylpyrimidine derivative or a pharmaceutically acceptable salt thereof.

In addition, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a 2-phenylpyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

According to one aspect of the invention, there is provided a compound of formula 1 or a pharmaceutically acceptable salt thereof:

Where

Q is -O- or-(CH ₂ ) m-, where m is an integer from 1 to 3,

n is an integer from 1 to 5,

R is hydrogen or C ₁ -C ₅ alkyl,

R ₁ and R ₂ are independently of each other hydrogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or phenoxy,

R ₃ is hydrogen, C ₁ -C ₅ alkoxy or halogen,

R ₄ and R ₅ independently of one another are hydrogen, halogen, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, trifluoromethyl or phenyl.

In a compound of Formula 1, or a pharmaceutically acceptable salt thereof, Q is -O- or -CH _2- , n is an integer from 1 to 3. R is hydrogen or C ₁ -C ₃ alkyl, R ₁ and R ₂ are independently of each other hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or phenoxy, R ₃ is hydrogen, C ₁ -C Or a pharmaceutically acceptable derivative thereof wherein ₃ alkoxy or halogen, R ₄ and R ₅ are independently of each other hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl or phenyl Possible salts are preferred.

The compounds of the present invention may be in the form of pharmaceutically acceptable non-toxic salts. The non-toxic salts may be in the form of conventional acid addition salts used in the pharmaceutical art, for example, salts generated from non-toxic inorganic or organic acids. Such conventional non-toxic salts include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propanoic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid , Salts derived from sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanedisulfonic acid, ethanedisulfonic acid, oxalic acid, or trifluoroacetic acid. It may also be in the form of salts produced from non-toxic inorganic or organic salts. Such conventional non-toxic salts include sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, calcium carbonate, potassium t-butoxide, sodium ethanol, triethylamine, ammonia, guanidine, ethylenediamine, ethanolamine, di Salts derived from ethanolamine, triethanolamine, pepperazine, morpholine, dicyclohexylamine.

Non-toxic salts of the compounds according to the invention can be prepared by conventional methods from compounds of the invention containing basic amines and carboxylic acid residues. In general, salts may be prepared by reacting an organic acid / base or inorganic acid / base with a stoichiometric amount or excess of the desired salt-forming inorganic acid, inorganic salt, organic acid or inorganic salt in a suitable solvent or various combinations of solvents.

The present invention also encompasses a process for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, according to Scheme 1 below:

In Scheme 1, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Q are the same as defined above, Y is hydroxy, methanesulfonyl, benzenesulfonyl, toluenesulfonyl or halogen Indicates.

Specifically, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be prepared by a process comprising the step of reacting a compound of Formula 2 with a compound of Formula 3.

In the process of Scheme 1, the reaction may be carried out a direct nucleophilic substitution of the compound of Formula 2 with the compound of Formula 3, or after the activation of the compound of Formula 2 or the compound of Formula 3 may be carried out a coupling reaction. Methods of activating the compound of formula (2) or phenol include catalytic amounts of sodium iodide (NaI), lithium iodide (NaI), potassium iodide (KI), iodine (I ₂ ), triphenylphosphine (Ph) ₃ P) can be preferably carried out.

In addition, the reaction can be preferably carried out both under the presence of a base or in the absence of a base, and usable bases include sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate, potassium bicarbonate, sodium hydride, cesium carbonate, Potassium t-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. In addition, as a reaction solvent, a polar organic solvent such as dichloromethane, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide may be used, and the reaction temperature is preferably -20 ° C to 150 ° C.

In the process of Scheme 1, the compound of formula 3 can be purchased commercially and known methods (Sauerberg et al . , J. Med . Chem . 2002, 45, 789-804; Ebdrup et al. , J. Med . Chem. 2003, 46 1306-1317). In addition, the compound of formula 2 may be prepared according to the following scheme 2:

R ₃ , R ₄ , R ₅ , and Y in Scheme 2 are the same as defined above, X represents halogen, Z represents halogen, boronic acid or trifluoromethanesulfonyl.

Specifically, the compound of Formula 2 may be prepared by a manufacturing method comprising the step of reacting the compound of Formula 4 with the compound of Formula 5.

In the process of Scheme 2, the compounds of formulas 4 and 5 can be purchased commercially and known methods (Robichaud et al . , J. Med . Chem . 2003, 46 , 3709-3727; T. Ishiyama et al . , Tetrahedron 2001, 57 9813-9816). In addition, the reaction may be preferably performed under a palladium catalyst, and usable catalysts include palladium diacetate (Pd (OAc) ₂ ) and tris (dibenzylideneacetone) dipalladium, Pd ₂ (dba) ₂ ]. When the reaction is carried out under a palladium catalyst, the reaction may be carried out by adding a ligand and a base in addition to the palladium catalyst, and usable ligands include (S) -2,2-bis (diphenylphosphino) -1,1- Binaphthyl (BINAP), 1,1'-bis (diphenylphosphino) ferrocene (dppf), or (tri-O-toryl) phosphine (P (O-Tol) ₃ ); Furnace includes inorganic bases such as cesium carbonate (Cs ₂ CO ₃ ), sodium t-butoxide (t-BuONa) or potassium t-butoxide (t-BuOK). In addition, as the reaction solvent, non-polar organic solvents such as benzene and toluene or polar organic solvents such as dioxane and tetrahydrofuran may be used, and the reaction temperature may be performed at 50 ° C to 150 ° C, and 80 ° C to 110 ° C. More preferred.

The present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 as defined above or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Compounds of formula (1) or pharmaceutically acceptable salts thereof include diabetes, as well as dyslipidemia, hyperlipidemia, obesity, hypertension, and arteriosclerosis of the arteries. It can be used for the prevention and treatment of metabolic diseases such as blood clotting disorders or cardiovascular diseases and other diseases including bulimia nervosa.

Compositions of the present invention may include excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, tonicity agents, and the like which are well known and can be used, and may be sweetening and / or flavoring agents. It may include.

The composition of the present invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. That is, the composition according to the present invention may be administered in the form of a tablet or capsule, or as an aqueous solvent or suspension. In the case of oral tablets, carriers commonly used include lactose and corn starch, and lubricants such as magnesium stearate can usually be added. Useful diluents for capsule form may include lactose and dry corn powder. If an aqueous suspension is required for oral use, it may include emulsifiers and suspensions. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared, and may include a buffer that can suitably adjust the pH of the solution, and for intravenous administration will include isotonic agents. Can be. In addition, the composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.

The compound of the present invention may be administered to an patient in an effective amount of about 0.1 μg to 1,000 mg per day. The dose may of course vary with the age, weight, sensitivity, or symptoms of the patient.

Hereinafter, the present invention will be described in more detail with reference to examples. However, this does not limit the scope of the present invention.

Example  1-2 Ethoxy -3- [4- (4-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid ethyl ester

Step 1) 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2yl) benzyl alcohol

4-bromobenzyl alcohol (1.0 g, 5.3 mmol), bis (pinacolato) diboron (1.5 g, 5.8 mmol) and potassium acetate (KOAc; 1.6 g, 15.9 mmol) were dried over anhydrous dimethylformamide (DMF; After dissolving in 10 ml), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 130 mg, 0.2 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 5 hours, the reaction mixture was cooled to room temperature, added to water (20 ml) to terminate the reaction, and the aqueous layer was extracted with ethyl acetate (30 ml × 2). The extracted organic layer was washed with saturated brine (10 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (741 mg).

Rf = 0.29 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.81 (d, 2H), 7.37 (d, 2H), 4.72 (s, 2H), 1.35 (s, 12H)

Step 2) 4- (pyrimidin-2-yl) benzyl alcohol

4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol (200 mg, 0.8 mmol) prepared in step 1), 2-chloro Pyrimidine (117 mg, 1.0 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf)); 21 mg, 0.02 mmol) was dissolved in dimethylformamide (DMF; 1 ml) and 2N-sodium carbonate aqueous solution (Na ₂ CO ₃ ; 1.1 ml, 2.2 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (20 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (59 mg).

Rf = 0.27 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.44 (d, 2H), 7.50 (d, 2H), 7.20 (t, 1H), 4.79 (s, 2H)

Step 3) Preparation of 2-ethoxy-3- [4- (4-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester

4- (pyrimidin-2-yl) benzyl alcohol (50 mg, 0.27 mmol), triphenyl phosphine (PPh ₃ ; 106 mg, 0.40 mmol) prepared in step 2), 2-ethoxy-3- ( 4-hydroxyphenyl) propanoic acid ethyl ester (77 mg, 0.32 mmol) was dissolved in anhydrous tetrahydrofuran (THF; 2 ml), cooled to 0 ° C., and then diisopropyl azodicarboxylate (DIAD; 0.106 ml, 0.54 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (56 mg).

Rf = 0.29 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.46 (d, 2H), 7.55 (d, 2H), 7.16-7.21 (m, 3H), 6.91 (d, 2H), 5.13 (s, 2H), 4.16 (q, 2H), 3.96 (t, 1H), 3.60 (m, 1H), 3.36 (m, 1H), 2.95 (d, 2H), 1.22 (t, 3H), 1.17 ( t, 3H)

Example  2. 2- Ethoxy -3- [4- (4-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid

2-ethoxy-3- [4- (4-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester (50 mg) prepared in Example 1 was dissolved in tetrahydrofuran (THF; 1 ml). Then 1N aqueous lithium hydroxide solution (LiOH; 1 ml, 1 mmol) was added dropwise and stirred overnight at room temperature. Tetrahydrofuran in the reaction mixture was removed under reduced pressure and diluted with water (5 ml). The aqueous layer was washed with diethyl ether (5 ml × 2) and then acidified with 1N aqueous hydrochloric acid. The aqueous layer was saturated with salt and extracted with acetonitrile (10 ml x 2). The extracted organic layer was dehydrated with magnesium sulfate (MgSO ₄ ) and filtered to give the title compound (8 mg).

Rf = 0.12 (MC: MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.87 (d, 2H), 8.39 (d, 2H), 7.58 (d, 2H), 7.41 (t, 1H), 7.15 (dd, 2H), 6.93 ( d, 2H), 5.15 (s, 2H), 3.99-4.05 (m, 1H), 3.57-3.59 (m, 1H), 3.34- 3.36 (m, 1H), 2.89-2.97 (m, 2H), 1.11 ( t, 3H)

Example  3. 2- Ethoxy -3- [4- (3-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid ethyl ester

Step 1) 3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol

3-bromobenzyl alcohol (1.5 g, 8.0 mmol), bis (pinacolato) diboron (2.4 g, 9.6 mmol) and potassium acetate (KOAc; 2.4 g, 24.0 mmol) were dissolved in anhydrous dimethylformamide (DMF; After dissolving in 15 ml), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 196 mg, 0.2 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 5 hours, the reaction mixture was cooled to room temperature, added to water (30 ml) to terminate the reaction, and the aqueous layer was extracted with ethyl acetate (45 ml × 2). The extracted organic layer was washed with saturated brine (20 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.7 g).

Rf = 0.28 (n-Hex: EtOAc = 3: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.80 (s, 1H), 7.74 (d, 1H), 7.49 (d, 1H), 7.38 (t, 1H), 4.70 (s, 2H), 1.35 (s , 12H)

Step 2) 3- (pyrimidin-2-yl) benzyl alcohol

3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol (160 mg, 0.7 mmol) prepared in step 1), 2-chloro Pyrimidine (93 mg, 0.8 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 17 mg, 0.02 mmol) were converted to dimethylformamide (DMF; 1 After dissolving in ml), 2N aqueous sodium carbonate solution (Na ₂ CO ₃ ; 850 μl, 1.7 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (20 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (51 mg).

Rf = 0.15 (n-Hex: EtOAc = 1: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.82 (d, 2H), 8.44 (s, 1H), 8.38 (d, 1H), 7.50-7.54 (m, 2H), 7.21 (t, 1H), 4.81 (s, 2H)

Step 3) Preparation of 2-ethoxy-3- [4- (3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester

3- (pyrimidin-2-yl) benzyl alcohol (50 mg, 0.27 mmol) prepared in step 2), triphenyl phosphine (PPh ₃ ; 106 mg, 0.40 mmol), 2-ethoxy-3- ( 4-hydroxyphenyl) propanoic acid ethyl ester (77 mg, 0.32 mmol) was dissolved in anhydrous tetrahydrofuran (THF; 2 ml), cooled to 0 ° C. and then diisopropyl azodicarboxylate (DIAD; 0.11 ml, 0.54 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (42 mg).

Rf = 0.30 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.82 (d, 2H), 8.51 (s, 1H), 8.41 (d, 1H), 7.58 (d, 1H), 7.52 (t, 1H), 7.21 (t , 1H), 7.16 (d, 2H), 6.93 (d, 2H), 5.14 (s, 2H), 4.16 (q, 2H), 3.97 (t, 1H), 3.58-3.60 (m, 1H), 3.33- 3.37 (m, 1H), 2.96 (d, 2H), 1.21 (t, 3H), 1.17 (t, 3H)

Example  4. 2- Ethoxy -3- [4- (3-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid

Using the 2-ethoxy-3- [4- (3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester (38 mg) prepared in Example 3, according to the same method as in Example 2 The title compound (4 mg) was obtained.

Rf = 0.10 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.88 (d, 2H), 8.46 (s, 1H), 8.31 (d, 1H), 7.58 (d, 1H), 7.52 (t, 1H), 7.41 ( t, 1H), 7.13 (d, 1H), 7.11 (d, 1H), 6.92 (d, 2H), 5.12 (s, 2H), 4.02-4.04 (m, 1H), 3.54-3.56 (m, 1H) , 3.33-3.35 (m, 1H), 2.87-2.92 (m, 2H), 1.10 (t, 3H)

Example  5. 2- Ethoxy -3-4- [3- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid  Ethyl ester

Step 1) 3- (5-ethyl-pyrimidin-2-yl) benzyl alcohol

3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol (500 mg, 2.1 mmol) prepared in step 1) of Example 3; Using 2-chloro-5-ethylpyrimidine (306 μl, 2.5 mmol), the title compound (206 mg) was obtained following the same method as step 2) of Example 3.

Rf = 0.21 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.66 (s, 2H), 8.40 (s, 1H), 8.33 (t, 1H), 7.49 (d, 2H), 4.80 (s, 2H), 2.69 (q , 2H), 1.32 (t, 3H)

Step 2) Preparation of 2-ethoxy-3-4- [3- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Using the 3- (5-ethyl-pyrimidin-2-yl) benzyl alcohol (206 mg, 1.0 mmol) prepared in step 2) above, the title compound (186 mg) was obtained.

Rf = 0.31 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.66 (s, 2H), 8.47 (s, 1H), 8.37 (d, 1H), 7.55 (d, 1H), 7.50 (t, 1H), 7.16 (d , 2H), 6.92 (d, 2H), 5.14 (s, 2H), 4.14 (q, 2H), 3.97 (t, 1H), 3.59 (m, 1H), 3.36 (m, 1H), 2.95 (d, 2H), 2.69 (q, 2H), 1.32 (t, 3H), 1.23 (t, 3H), 1.18 (t, 3H)

Example  6. 2- Ethoxy -3-4- [3- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

Example 2 was prepared using 2-ethoxy-3-4- [3- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (179 mg) prepared in Example 5. The title compound (98 mg) was obtained following the same method.

Rf = 0.42 (CH ₂ Cl ₂ : MeOH = 10: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.69 (s, 2H), 8.44 (s, 1H), 8.29 (d, 1H), 7.54 (d, 1H), 7.48 (t, 1H), 7.20 ( d, 2H), 6.92 (d, 2H), 5.12 (s, 2H), 3.85 (m, 1H), 3.59 (m, 1H), 3.26 (m, 1H), 2.95-2.99 (m, 1H), 2.82 -2.84 (m, 1H), 2.69 (q, 2H), 1.28 (t, 3H), 1.09 (t, 3H)

Example  7. 2- Ethoxy -3-4- [3- (4- Trifluoromethyl Pyrimidin-2-yl) Benzyloxy ] Pe Nylpropanoic acid ethyl ester

Step 1) 3- (4-Trifluoromethyl-pyrimidin-2-yl) benzyl alcohol

3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol (400 mg, 1.7 mmol) prepared in step 1) of Example 3; Using 2-chloro-4- (trifluoromethyl) pyrimidine (304 μl, 2.5 mmol), the title compound (330 mg) was obtained following the same method as step 2) of Example 3.

Rf = 0.29 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.04 (d, 1H), 8.50 (s, 1H), 8.44 (d, 1H), 7.51-7.57 (m, 3H), 4.81 (d, 2H), 1.91 (t, 1H)

Step 2) Preparation of 2-ethoxy-3-4- [3- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Using the 3- (4-trifluoromethyl-pyrimidin-2-yl) benzyl alcohol (200 mg, 0.8 mmol) prepared in step 2), according to the same method as in step 3) of Example 3, Compound (167 mg) was obtained.

Rf = 0.34 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.06 (d, 1H), 8.57 (s, 1H), 8.48 (d, 1H), 7.63 (d, 1H), 7.52-7.56 (m, 2H), 7.18 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 4.16 (q, 2H), 3.97 (t, 1H), 3.58-3.62 (m, 1H), 3.33-3.37 (m, 1H ), 2.96 (d, 2H), 1.23 (t, 3H), 1.17 (t, 3H)

Example  8. 2- Ethoxy -3-4- [3- (4- Trifluoromethyl Pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

It was carried out using 2-ethoxy-3-4- [3- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (160 mg) prepared in Example 7. According to the same method as in Example 2, the title compound (93 mg) was obtained.

Rf = 0.33 (CH ₂ Cl ₂ : MeOH = 10: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.04 (d, 1H), 8.50 (s, 1H), 8.38 (d, 1H), 7.64 (d, 1H), 7.56 (d, 1H), 7.46 ( t, 1H), 7.15 (d, 2H), 6.90 (d, 2H), 5.06 (s, 2H), 3.98 (dd, 1H), 3.56-3.60 (m, 1H), 3.30-3.34 (m, 1H) , 2.97 (dd, 1H), 2.85 (dd, 1H), 1.10 (t, 3H)

Example  9. 2- Ethoxy -3-4- [3- (4- Methoxy Pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid  Ethyl ester

Step 1) 3- (4-methoxy-pyrimidin-2-yl) benzyl alcohol

3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol (500 mg, 1.2 mmol) prepared in step 1) of Example 3; The title compound (177 mg) was obtained following the same method as step 2) of Example 3, except that 2-chloro-4-methoxypyrimidine (364 mg, 2.5 mmol) was used.

Rf = 0.23 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.51 (d, 1H), 8.43 (s, 1H), 8.38 (d, 1H), 7.49-7.53 (m, 2H), 6.65 (d, 1H), 4.80 (d, 2H), 4.10 (s, 3H), 1.82 (m, 1H)

Step 2) Preparation of 2-ethoxy-3-4- [3- (4-methoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Using the 3- (4-methoxy-pyrimidin-2-yl) benzyl alcohol (177 mg, 0.8 mmol) prepared in step 2), the title compound ( 145 mg) was obtained.

Rf = 0.32 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.49-8.51 (m, 2H), 8.41 (d, 1H), 7.56 (d, 1H), 7.50 (t, 1H), 7.16 (d, 2H), 6.92 (d, 2H), 6.64 (d, 1H), 5.13 (s, 2H), 4.14 (q, 2H), 4.09 (s, 3H), 3.97 (t, 1H), 3.60 (m, 1H), 3.35- 3.38 (m, 1H), 2.96 (d, 2H), 1.23 (t, 3H), 1.17 (t, 3H)

Example  10. 2- Ethoxy -3-4- [3- (4- Methoxy Pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

Example 2 using 2-ethoxy-3-4- [3- (4-methoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (138 mg) prepared in Example 9 According to the same method as the title compound (53 mg) was obtained.

Rf = 0.31 (CH ₂ Cl ₂ : MeOH = 10: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.49 (d, 1H), 8.46 (s, 1H), 8.34 (d, 1H), 7.57 (d, 1H), 7.49 (t, 1H), 7.19 ( d, 2H), 6.93 (d, 2H), 6.75 (d, 1H), 5.14 (s, 2H), 4.08 (s, 3H), 3.86-3.88 (m, 1H), 3.58-3.62 (m, 1H) , 3.27-3.29 (m, 1H), 2.96-2.97 (m, 1H), 2.81-2.85 (m, 1H), 1.08 (t, 3H)

Example  11. 2-Ethoxy-3-4- [3- (4,6-dimethoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Step 1) 3- (4,6-dimethoxy-pyrimidin-2-yl) benzyl alcohol

3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl alcohol (500 mg, 2.1 mmol) prepared in step 1) of Example 3, 2-chloro-4,6-dimethoxypyrimidine (440 mg, 2.5 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 51 mg, 0.06 mmol) was dissolved in dimethylformamide (DMF; 3 ml) and 2N aqueous sodium carbonate solution (Na ₂ CO ₃ ; 1.6 ml, 3.2 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 3 hours, cooled to room temperature and water (20 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (30 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (263 mg).

Rf = 0.26 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.44 (s, 1H), 8.40 (d, 1H), 7.47-7.49 (m, 2H), 5.98 (s, 1H), 4.80 (s, 2H), 4.06 (s, 6H)

Step 2) 2-Ethoxy-3-4- [3- (4,6-dimethoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

3- (4,6-dimethoxy-pyrimidin-2-yl) benzyl alcohol (263 mg, 1.1 mmol) prepared in step 1) was dissolved in dichloromethane (5 ml) and cooled to 0 ° C. Triethylamine (Et ₃ N; 0.2 ml, 1.6 mmol) and methanesulfonyl chloride (0.1 ml, 1.3 mmol) were added dropwise, and the reaction mixture was stirred at 0 ° C. for about 1 hour. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (15 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue obtained was dissolved in acetonitrile (2 ml) and then 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (69 mg, 0.27 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 166 mg, 0.51 mmol) was added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (147 mg).

Rf = 0.38 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.49 (s, 1H), 8.41 (d, 1H), 7.55 (d, 1H), 7.47 (t, 1H), 7.16 (d, 2H), 6.92 (d , 2H), 5.97 (s, 1H), 5.13 (s, 2H), 4.15 (q, 2H), 4.04 (s, 6H), 3.97 (t, 1H), 3.58-3.62 (m, 1H), 3.33- 3.37 (m, 1H), 2.96 (d, 2H), 1.21 (t, 3H), 1.16 (t, 3H)

Example  12. 2- Ethoxy -3-4- [3- (4,6- Dimethoxy Pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [3- (4,6-dimethoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (147 mg) prepared in Example 11, The title compound (123 mg) was obtained in the same manner as in Example 2.

Rf = 0.28 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.49 (s, 1H), 8.37 (d, 1H), 7.56 (d, 1H), 7.47 (t, 1H), 7.17 (d, 2H), 6.94 ( d, 2H), 6.04 (s, 1H), 5.15 (s, 2H), 4.03 (s, 6H), 3.98-4.01 (m, 1H), 3.56-3.59 (m, 1H), 3.33-3.36 (m, 1H), 2.96-2.97 (m, 1H), 2.87-2.89 (m, 1H), 1.11 (t, 3H)

Example  13. 2- Ethoxy -3-4- [3- (4- Cyano Pyrimidin-2-yl) Benzyloxy ] Phenylpropane Acid ethyl ester

Step 1) 3- (4-cyano-pyrimidin-2-yl) benzyl alcohol

3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2yl) benzyl alcohol (500 mg, 2.1 mmol) prepared in step 1) of Example 3, and 2 Using -chloro-pyrimidine-4-carbonitrile (352 mg, 2.5 mmol), the title compound (112 mg) was obtained following the same method as step 2) of Example 3.

Rf = 0.22 (n-Hex: EtOAc = 3: 2, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.02 (d, 1H), 8.48 (s, 1H), 8.40 (d, 1H), 8.08 (d, 2H), 7.58 (d, 1H), 4.82 (s , 2H)

Step 2) Preparation of 2-ethoxy-3-4- [3- (4-cyano-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Using the 3- (4-cyano-pyrimidin-2-yl) benzyl alcohol (112 mg, 0.5 mmol) prepared in step 1), the title compound ( 17 mg) was obtained.

Rf = 0.28 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.01 (d, 1H), 8.54 (s, 1H), 8.43 (d, 1H), 7.64 (d, 1H), 7.54 (t, 1H), 7.50 (d , 1H), 7.18 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 4.15 (q, 2H), 3.97 (t, 1H), 3.60 (t, 1H), 3.36 (t, 1H), 2.96 (d, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  14. 2- Ethoxy -3-4- [3- (4- Cyano Pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

Example 2 using 2-ethoxy-3-4- [3- (4-cyano-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (12 mg) prepared in Example 13 The title compound (4 mg) was obtained following the same method as the above.

Rf = 0.28 (CH ₂ Cl ₂ : MeOH = 10: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.07 (d, 1H), 8.65 (s, 1H), 8.51 (d, 1H), 7.94 (d, 1H), 7.63 (d, 1H), 7.54 ( t, 1H), 7.20 (d, 2H), 6.93 (d, 2H), 5.18 (s, 2H), 3.82 (m, 1H), 3.59 (td, 1H), 3.26 (td, 1H), 2.93-2.96 (m, 1H), 2.78-2.83 (m, 1H), 1.08 (t, 3H)

Example  15. 2- Ethoxy -3- [4- (4- Fluoro -3-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid ethyl ester

Step 1) [4-Fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol

3-bromo-4-fluorobenzyl alcohol (2.2 g, 11.0 mmol), bis (pinacolato) diboron (3.3 g, 13.1 mmol) and potassium acetate (KOAc; 3.2 g, 32.7 mmol) After dissolving in formamide (DMF; 7 ml) [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.3 g, 0.3 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 3 hours, the reaction mixture was cooled to room temperature and added to water (10 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate (20 ml x 2). The extracted organic layer was washed with saturated brine (10 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.8 g).

Rf = 0.48 (n-Hex: EtOAc = 7: 3, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.72 (dd, 1H), 7.47-7.43 (m, 1H), 7.03 (t, 1H), 4.66 (s, 2H), 1.36 (s, 12H)

Step 2) (4-fluoro-3-pyrimidin-2-ylphenyl) methyl alcohol

[4-Fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) above (500 mg) , 2.0 mmol), 2-chloropyrimidine (275 mg, 2.4 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 48 mg, 0.06 mmol) After dissolving in dimethylformamide (DMF; 3 ml), an aqueous 2N-sodium carbonate solution (Na ₂ CO ₃ ; 2.4 ml, 5.0 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 3 hours, cooled to room temperature and water (15 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (20 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (388 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.88 (d, 2H), 8.05 (d, 1H), 7.49-7.46 (m, 1H), 7.26 (t, 1H), 7.20 (dd, 1H), 4.74 (s, 2H), 1.93 (bs, 1H)

Step 3) 2-Ethoxy-3- [4- (4-fluoro-3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester

(4-fluoro-3-pyrimidin-2-ylphenyl) methyl alcohol (388 mg, 1.9 mmol) prepared in step 2) was dissolved in dichloromethane (5 ml) and cooled to 0 ° C., and then Ethylamine (Et ₃ N; 0.4 ml, 2.8 mmol) and methanesulfonyl chloride (0.2 ml, 2.3 mmol) were added dropwise one after another, and the reaction mixture was stirred at 0 ° C. for about 1 hour. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (15 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The obtained residue was dissolved in acetonitrile (5 ml), and then 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (362 mg, 1.5 mmol) was cesium carbonate (Cs ₂ CO ₃ ; 928 mg, 2.8 mmol) was added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (15 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (20 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (185 mg).

Rf = 0.35 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.90 (d, 2H), 8.06 (dd, 1H), 7.61 (m, 1H), 7.46 (t, 1H), 7.27 (dd, 1H), 7.17 (d , 2H), 6.93 (d, 2H), 5.11 (s, 2H), 3.99 (dd, 1H), 3.58 (m, 1H), 3.33 (m, 1H), 2.98 (dd, 1H), 2.86 (dd, 1H), 1.11 (t, 3H)

Example  16. 2- Ethoxy -3- [4- (4- Fluoro -3-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid

Example 2 using 2-ethoxy-3- [4- (4-fluoro-3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester (180 mg) prepared in Example 15 The title compound (156 mg) was obtained according to the same method as.

Rf = 0.41 (CH ₂ Cl ₂ : MeOH = 10: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.90 (d, 2H), 8.06 (dd, 1H), 7.61 (m, 1H), 7.46 (t, 1H), 7.27 (dd, 1H), 7.17 ( d, 2H), 6.93 (d, 2H), 5.11 (s, 2H), 3.99 (dd, 1H), 3.58 (m, 1H), 3.33 (m, 1H), 2.98 (dd, 1H), 2.86 (dd , 1H), 1.11 (t, 3H)

Example  17. 2- Ethoxy -3-4- [4- Fluoro -5- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Pe Nylpropanoic acid ethyl ester

Step 1) [3- (5-ethyl-pyrimidin-2-yl) -4-fluorophenyl) methyl alcohol

[4-Fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 15 (250 mg, 0.99 mmol) and 2-chloro-5-ethylpyrimidine (144 μl, 1.19 mmol) gave the title compound (81 mg) in the same manner as in Step 2) of Example 15.

Rf = 0.07 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.72 (s, 2H), 8.01 (d, 1H), 7.44-7.48 (m, 1H), 7.20 (t, 1H), 4.74 (s, 2H), 2.72 (q, 2H), 1.34 (t, 3H)

Step 2) 2-Ethoxy-3-4- [4-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Example 3) of Example 15, using [3- (5-ethyl-pyrimidin-2-yl) -4-fluorophenyl) methyl alcohol (81 mg, 0.35 mmol) prepared in step 1). The same method gave the title compound (57 mg).

Rf = 0.20 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.72 (s, 2H), 8.10 (d, 1H), 7.51-7.52 (m, 1H), 7.18-7.23 (m, 1H), 7.16 (d, 2H) , 6.89 (d, 2H), 5.07 (s, 2H), 4.16 (q, 2H), 3.97 (t, 1H), 3.58-3.60 (m, 1H), 3.35-3.37 (m, 1H), 2.95 (d , 2H), 2.70 (q, 2H), 1.33 (t, 3H), 1.21 (t, 3H), 1.16 (t, 3H)

Example  18. 2- Ethoxy -3-4- [4- Fluoro -5- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [4-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (57 mg) prepared in Example 17 , The title compound (46 mg) was obtained in the same manner as in Example 2.

Rf = 0.13 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.78 (s, 2H), 8.03 (d, 1H), 7.58-7.59 (m, 1H), 7.25 (t, 1H), 7.17 (d, 2H), 6.92 (d, 2H), 5.11 (s, 2H), 3.97-3.99 (m, 1H), 3.56-3.58 (m, 1H), 3.30-3.33 (m, 1H), 2.97 (dd, 1H), 2.87 ( dd, 1H), 2.76 (q, 2H), 1.33 (t, 3H), 1.24 (t, 3H), 1.11 (t, 3H)

Example  19. 2- Ethoxy -3-4- [4- Fluoro -5- (4- Trifluoromethyl -Pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Step 1) [3- (4-Trifluoromethyl-pyrimidin-2-yl) -4-fluorophenyl) methyl alcohol

[4-Fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 15 (250 mg, 0.99 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (143 μl, 1.19 mmol) were used for the title compound (159 mg) in the same manner as in Example 2 step 2). ) Was obtained.

Rf = 0.17 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.13 (d, 1H), 8.14 (dd, 1H), 7.59 (d, 1H), 7.51-7.53 (m, 1H), 7.20-7.25 (m, 1H) , 4.77 (s, 2 H)

Step 2) 2-Ethoxy-3-4- [4-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Example 15 step, using [3- (4-trifluoromethyl-pyrimidin-2-yl) -4-fluorophenyl) methyl alcohol (159 mg, 0.58 mmol) prepared in step 1) above The title compound (131 mg) was obtained in the same manner as 3).

Rf = 0.33 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.12 (d, 1H), 8.21 (d, 1H), 7.57-7.59 (m, 2H), 7.22-7.24 (m, 1H), 7.17 (d, 2H) , 6.90 (d, 2H), 5.09 (s, 2H), 4.16 (q, 2H), 3.97 (t, 1H), 3.58-3.62 (m, 1H), 3.33-3.37 (m, 1H), 2.95 (d , 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  20. 2- Ethoxy -3-4- [4- Fluoro -5- (4- Trifluoromethyl -Pyrimidin-2-yl) benzyloxy] phenylpropanoic acid

2-Ethoxy-3-4- [4-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester prepared in Example 19 (128 mg) Using, the title compound (116 mg) was obtained in the same manner as in Example 2.

Rf = 0.13 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.18 (d, 1H), 8.20 (d, 1H), 7.81 (d, 1H), 7.64-7.65 (m, 1H), 7.28 (t, 1H), 7.18 (d, 2H), 6.93 (d, 2H), 5.13 (s, 2H), 3.97-4.00 (m, 1H), 3.56-3.59 (m, 1H), 3.30-3.35 (m, 1H), 2.97 ( dd, 1H), 2.87 (dd, 1H), 1.11 (t, 3H)

Example  21.2- Ethoxy -3- [4- (2- Fluoro -5-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid ethyl ester

Step 1) [2-Fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol

5-bromo-2-fluorobenzyl alcohol (4.8 g, 23.4 mmol), bis (pinacolato) diboron (7.1 g, 28.1 mmol) and potassium acetate (KOAc; 6.9 g, 70.2 mmol) After dissolving in formamide (DMF; 20 ml) [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.6 g, 0.7 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 3 hours and the reaction mixture was cooled to room temperature and then added to water (30 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate (50 ml x 2). The extracted organic layer was washed with saturated brine (30 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (4.7 g).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.87 (d, 1H), 7.73 (m, 1H), 7.04 (dd, 1H), 4.75 (d, 2H), 1.34 (s, 12H)

Step 2) (2-Fluoro-5-pyrimidin-2-ylphenyl) methyl alcohol

[2-Fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) above (1.0 g , 4.0 mmol), 2-chloropyrimidine (0.5 g, 4.8 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 98 mg, 0.1 mmol) After dissolving in dimethylformamide (DMF; 6 ml), an aqueous 2N-sodium carbonate solution (Na ₂ CO ₃ ; 5.0 ml, 1.0 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 3 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (480 mg).

Step 3) 2-Ethoxy-3- [4- (2-fluoro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester

(2-fluoro-5-pyrimidin-2-ylphenyl) methyl alcohol (480 mg, 2.4 mmol) prepared in step 2) was dissolved in dichloromethane (10 ml) and cooled to 0 ° C., and then Ethylamine (Et ₃ N; 0.5 ml, 3.6 mmol) and methanesulfonyl chloride (0.2 ml, 2.9 mmol) were added dropwise sequentially, and the reaction mixture was stirred at 0 ° C for about 1 hour. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (15 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated to give methanesulfonic acid 2-fluoro-5-pyrimidin-2-ylbenzyl ester, which was dissolved in acetonitrile (5 ml) without purification, then 2- Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (458 mg, 1.9 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 1.2 g, 3.6 mmol) were added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (15 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (25 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (550 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.78 (d, 2H), 8.65-8.63 (dd, 1H), 8.44-8.41 (m, 1H), 7.20 (d, 1H), 6.96 (d, 2H) , 5.16 (s, 2H), 4.18-4.15 (m, 2H), 3.99-3.96 (t, 1H), 3.62-3.58 (m, 1H), 3.37-3.33 (m, 1H), 2.96 (d, 2H) , 1.21 (t, 3H), 1.16 (t, 3H)

Example  22. 2-Ethoxy-3- [4- (2-fluoro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid

Example 2 using 2-ethoxy-3- [4- (2-fluoro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester (545 mg) prepared in Example 21 The title compound (320 mg) was obtained following the same method as the above.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 2H), 8.60-8.58 (dd, 1H), 8.38-8.36 (m, 1H), 7.21-7.17 (m, 4H), 6.95 (d, 2H), 5.14 (s, 2H), 4.06-4.03 (m, 2H), 3.65-3.61 (m, 1H), 3.40-3.37 (m, 1H), 3.09-3.04 (m, 1H), 2.99-2.97 ( m, 1H), 1.15 (t, 3H)

Example  23. 2- Ethoxy -3-4- [2- Fluoro -5- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Pe Nylpropanoic acid ethyl ester

Step 1) [5- (5-ethyl-pyrimidin-2-yl) -2-fluorophenyl) methyl alcohol

[2-Fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 21 (750 mg, 2.98 mmol) and 2-chloro-5-ethylpyrimidine (434 μl, 3.57 mmol) gave the title compound (400 mg) according to the same method as Step 2) of Example 21.

Step 2) 2-Ethoxy-3-4- [2-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenyl propanoic acid ethyl ester

Example 3 step 3) of Example 21 using [5- (5-ethyl-pyrimidin-2-yl) -2-fluorophenyl) methyl alcohol (400 mg, 1.72 mmol) prepared in step 1). According to the same method, the title compound (300 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.63-8.60 (m, 2H), 8.41-8.38 (m, 1H), 7.26-7.16 (m, 3H), 6.96 (d, 2H), 5.15 (s, 2H), 4.18-4.15 (m, 2H), 3.99-3.96 (m, 1H), 3.60-3.58 (m, 1H), 3.37-3.32 (m, 1H), 2.96 (d, 2H), 2.68-2.64 ( m, 2H), 1.32 (t, 3H), 1.20 (t, 3H), 1.16 (t, 3H)

Example  24. 2-Ethoxy-3-4- [2-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phen Nilpropanoic acid

Using 2-ethoxy-3-4- [2-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (293 mg) prepared in Example 23 , The title compound (220 mg) was obtained in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.67 (s, 2H), 8.55-8.53 (m, 1H), 8.35-8.32 (m, 1H), 7.20-7.17 (m, 3H), 6.96 (d, 2H), 5.14 (s, 2H), 4.05-4.02 (m, 1H), 3.65-3.60 (m, 1H), 3.40-3.37 (m, 1H), 3.04-2.97 (m, 1H), 2.98-2.96 ( d, 2H), 2.70-2.65 (m, 2H), 1.30 (t, 3H), 1.15 (t, 3H)

Example  25. 2- Ethoxy -3-4- [2- Fluoro -5- (4- Trifluoromethyl -Pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Step 1) [5- (4-Trifluoromethyl-pyrimidin-2-yl) -2-fluorophenyl) methyl alcohol

[2-Fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 21 (750 mg, 2.98 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (431 μl, 3.57 mmol), followed by the same method as Step 2) of Example 21 (400 mg). ) Was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.96 (d, 1H), 8.53 (dd, 1H), 8.35 (m, 1H), 7.46 (d, 1H), 7.08 (t, 1H), 4.80 (d , 2H), 3.28 (bs, 1H)

Step 2) 2-Ethoxy-3-4- [2-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Example 21 step, using [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-fluorophenyl) methyl alcohol (400 mg, 1.47 mmol) prepared in step 1) above The title compound (450 mg) was obtained in the same manner as 3).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.99 (d, 1H), 8.70-8.67 (m, 1H), 8.49-8.46 (m, 1H), 7.21-7.16 (m, 3H), 6.95 (d, 2H), 5.15 (s, 2H), 4.19-4.10 (m, 2H), 4.00-3.97 (m, 1H), 3.63-3.61 (m, 1H), 3.38-3.35 (m, 1H), 2.96 (d, 2H), 1.21 (t, 3H), 1.17 (t, 3H)

Example  26. 2-ethoxy-3-4- [2-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

2-Ethoxy-3-4- [2-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester prepared in Example 25 (445 mg) Using, to obtain the title compound (360 mg) in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.02 (d, 1H), 8.70-8.68 (m, 1H), 8.51-8.48 (m, 1H), 7.51 (d, 1H), 7.26-7.20 (m, 3H), 6.96 (d, 2H), 5.17 (s, 2H), 4.07-4.05 (m, 1H), 3.62-3.60 (m, 1H), 3.47-3.43 (m, 1H), 3.12-3.07 (m, 1H), 2.97-2.94 (m, 1H), 1.20 (t, 3H), 1.17 (t, 3H)

Example  27. 2- Ethoxy -3- [4- (2- Chloro -5-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid ethyl ester

Step 1) [2-Chloro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol

5-bromo-2-chlorobenzyl alcohol (2.0 g, 9.0 mmol), bis (pinacolato) diboron (2.7 g, 10.8 mmol) and potassium acetate (KOAc; 2.6 g, 27.0 mmol) were dried with anhydrous dimethyl After dissolving in formamide (DMF; 10 ml) [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.2 g, 0.3 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 3 hours, the reaction mixture was cooled to room temperature and added to water (15 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate (30 ml x 2). The extracted organic layer was washed with saturated brine (20 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.8 g).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.90 (s, 1H), 7.67 (dd, 1H), 7.37 (d, 1H), 4.79 (s, 2H), 1.34 (s, 12H)

Step 2) (2-Chloro-5-pyrimidin-2-ylphenyl) methyl alcohol

[2-Chloro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) (600 mg, 2.2 mmol), 2-chloropyrimidine (305 mg, 2.7 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 54 mg, 0.07 mmol) After dissolving in methylformamide (DMF; 3 ml), an aqueous 2N-sodium carbonate solution (Na ₂ CO ₃ ; 2.8 ml, 5.6 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 3 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (310 mg).

Step 3) 2-Ethoxy-3- [4- (2-chloro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester

(2-chloro-5-pyrimidin-2-ylphenyl) methyl alcohol (310 mg, 1.4 mmol) prepared in step 2) was dissolved in dichloromethane (5 ml), cooled to 0 ° C., and triethyl An amine (Et ₃ N; 293 μl, 2.1 mmol) and methanesulfonyl chloride (130 μl, 1.7 mmol) were added dropwise sequentially, and the reaction mixture was stirred at 0 ° C. for about 1 hour. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (15 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The obtained residue was dissolved in acetonitrile (5 ml), and then 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (267 mg, 1.1 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 685 mg , 2.1 mmol) was added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (20 ml x 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (220 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.75 (d, 2H), 8.60-8.55 (m, 1H), 8.40-8.37 (m, 1H), 7.20 (d, 1H), 6.96 (d, 2H) , 5.14 (s, 2H), 4.18-4.15 (m, 2H), 3.99-3.96 (t, 1H), 3.62-3.58 (m, 1H), 3.37-3.33 (m, 1H), 2.96 (d, 2H) , 1.21 (t, 3H), 1.16 (t, 3H)

Example  28. 2- Ethoxy -3- [4- (2- Chloro -5-pyrimidine-2- Ilbenzyloxy ) Phenyl Propanoic acid

Example 2 was prepared using 2-ethoxy-3- [4- (2-chloro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester (210 mg) prepared in Example 27. The title compound (130 mg) was obtained following the same method.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.73 (d, 2H), 8.57 (d, 1H), 8.40-8.37 (m, 1H), 7.20 (d, 2H), 6.96 (d, 2H), 5.20 (s, 2H), 3.99-3.94 (m, 1H), 3.58-3.52 (m, 1H), 3.37-3.32 (m, 1H), 2.96 (d, 2H), 1.15 (t, 3H)

Example  29.2- Ethoxy -3-4- [2- Chloro -5- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Phenyl Propanoic acid ethyl ester

Step 1) [5- (5-ethyl-pyrimidin-2-yl) -2-chlorophenyl) methyl alcohol

[2-Chloro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 27 600 mg, 2.22 mmol) and 2-chloro-5-ethylpyrimidine (328 μl, 2.7 mmol) gave the title compound (380 mg) in the same manner as in step 2) of Example 27.

Step 2) 2-Ethoxy-3-4- [2-chloro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Using [5- (5-ethyl-pyrimidin-2-yl) -2-chlorophenyl) methyl alcohol (380 mg, 1.5 mmol) prepared in step 1), the same as in step 3) of Example 27 The title compound (170 mg) was obtained according to the method.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.64-8.62 (m, 3H), 8.33-8.01 (d, 1H), 7.49 (d, 1H), 7.27 (d, 1H), 7.18 (d, 2H) , 6.98 (d, 2H), 5.19 (d, 2H), 4.18-4.14 (m, 2H), 3.98-3.96 (m, 1H), 3.60-3.58 (m, 1H), 3.36-3.33 (m, 2H) , 2.98 (d, 2H), 2.68-2.62 (m, 2H), 1.26 (t, 3H), 1.16 (t, 3H)

Example  30. 2-Ethoxy-3-4- [2-chloro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenyl Propanoic acid

Using 2-ethoxy-3-4- [2-chloro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (167 mg) prepared in Example 29 , The title compound (140 mg) was obtained in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.66 (s, 2H), 8.48-8.43 (m, 1H), 8.32-8.29 (m, 1H), 7.22-7.18 (m, 3H), 6.96 (d, 2H), 5.18 (s, 2H), 4.04-4.02 (m, 1H), 3.68-3.64 (m, 1H), 3.42-3.37 (m, 1H), 3.00-2.95 (m, 1H), 2.94-2.90 ( d, 2H), 2.70-2.65 (m, 2H), 1.31 (t, 3H), 1.15 (t, 3H)

Example  31.2- Ethoxy -3-4- [2- Chloro -5- (4- Trifluoromethyl -Pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Step 1) [5- (4-Trifluoromethyl-pyrimidin-2-yl) -2-chlorophenyl) methyl alcohol

[2-Chloro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 27 The title compound (740 mg) according to the same method as Step 2) of Example 27, using 800 mg, 2.98 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (434 μl, 3.6 mmol). Obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.00 (d, 2H), 8.58 (s, 1H), 8.29 (d, 1H), 7.50 (d, 1H), 7.41 (d, 1H), 4.83 (s , 2H), 3.05 (bs, 1H)

Step 2) 2-Ethoxy-3-4- [2-chloro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyl oxy] phenylpropanoic acid ethyl ester

Example 27, except that [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-chlorophenyl) methyl alcohol (740 mg, 2.6 mmol) prepared in step 1) was used The title compound (260 mg) was obtained in the same manner as step 3).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.02 (d, 1H), 8.72 (s, 1H), 8.41 (d, 1H), 7.54-7.50 (m, 2H), 7.20 (d, 2H), 6.97 (d, 2H), 5.20 (s, 2H), 4.19-4.17 (m, 2H), 3.99-3.97 (m, 1H), 3.63-3.59 (m, 1H), 3.38-3.36 (m, 1H), 2.96 (d, 2H), 1.24 (t, 3H), 1.16 (t, 3H)

Example  32. 2- Ethoxy -3-4- [2- Chloro -5- (4- Trifluoromethyl -Pyrimidin-2-yl) benzyloxy] phenylpropanoic acid

2-Ethoxy-3-4- [2-chloro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (254 mg) prepared in Example 31 was prepared. Using the same method as in Example 2, the title compound (180 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.04 (d, 1H), 8.72 (s, 1H), 8.43-8.40 (dd, 1H), 7.55-7.51 (m, 2H), 7.24 (d, 2H) , 7.18 (d, 2H), 7.00 (d, 2H), 5.20 (s, 2H), 4.01-4.05 (m, 1H), 3.62-3.96 (m, 1H), 3.47-3.43 (m, 1H), 3.12 -3.09 (m, 1H), 3.00-2.94 (m, 1H), 1.19 (t, 3H)

Example  33. 2- Ethoxy -3-4- [2- Methoxy -5- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Phenyl Propanoic acid ethyl ester

Step 1) [2-methoxy-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol

5-bromo-2-methoxybenzyl alcohol (5.0 g, 23.0 mmol), bis (pinacolato) diboron (7.0 g, 27.6 mmol) and potassium acetate (KOAc; 6.8 g, 69.0 mmol) were anhydrous dimethyl After dissolving in formamide (DMF; 20 ml) [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.6 g, 0.7 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 3 hours and the reaction mixture was cooled to room temperature and then added to water (30 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate (50 ml x 2). The extracted organic layer was washed with saturated brine (50 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (2.5 g).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.75 (s, 1H), 7.74 (dd, 1H), 6.84 (d, 1H), 4.67 (s, 2H), 3.83 (s, 3H), 1.32 (s , 12H)

Step 2) [5- (5-ethyl-pyrimidin-2-yl) -2-methoxyphenyl) methyl alcohol

[2-methoxy-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) above (300 mg) , 1.1 mmol), 2-chloro-5-ethylpyrimidine (158 μl, 1.3 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 27 mg, 0.03 mmol) was dissolved in dimethylformamide (DMF; 2 ml) and 2N-sodium carbonate aqueous solution (Na ₂ CO ₃ ; 1.4 ml, 2.8 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 3 hours, cooled to room temperature and water (5 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (10 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (250 mg).

Step 3) 2-Ethoxy-3-4- [2-methoxy-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

[5- (5-ethyl-pyrimidin-2-yl) -2-methoxyphenyl) methyl alcohol (250 mg, 1.0 mmol) prepared in step 2) was dissolved in dichloromethane (5 ml), and then 0. After cooling to ° C, triethylamine (Et ₃ N; 209 μl, 1.5 mmol) and methanesulfonyl chloride (93 μl, 1.2 mmol) were added dropwise sequentially, and the reaction mixture was stirred at 0 ° C for about 1 hour. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (10 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The obtained residue was dissolved in acetonitrile (5 ml), and then 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (191 mg, 0.8 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 489 mg) , 1.5 mmol) was added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (110 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.60 (s, 2H), 8.54 (s, 1H), 7.32-7.29 (m, 1H), 7.21-7.15 (m, 3H), 6.99-6.95 (m, 3H), 5.12 (s, 2H), 4.18-4.4.16 (m, 2H), 3.99-3.98 (m, 1H), 3.92 (s, 3H), 3.82-3.79 (m, 1H), 3.38-3.34 ( m, 1H), 2.96-2.94 (d, 2H), 2.68-2.64 (m, 2H), 1.30 (t, 3H), 1.29 (t, 3H), 1.17 (t, 3H)

Example  34. 2- Ethoxy -3-4- [2- Methoxy -5- (5-ethyl-pyrimidin-2-yl) Benzyloxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [2-methoxy-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester (100 mg) prepared in Example 33 , The title compound (80 mg) was obtained in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.60 (s, 2H), 8.48 (s, 1H), 8.33 (d, 1H), 7.26-7.17 (d, 2H), 7.00-6.92 (m, 3H) , 5.07 (s, 2H), 4.11-3.96 (m, 1H), 3.90 (s, 3H), 3.52-3.47 (m, 1H), 3.39-3.30 (m, 1H), 3.03-2.91 (m, 2H) , 2.65-2.60 (m, 2H), 1.19 (t, 3H)

Example  35. 2-Ethoxy-3-4- [2-methoxy-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Step 1) [5- (4-Trifluoromethyl-pyrimidin-2-yl) -2-methoxyphenyl) methyl alcohol

[2-methoxy-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] methyl alcohol prepared in step 1) of Example 33 (300 mg, 1.14 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (169 μl, 1.4 mmol) were used for the title compound (300 mg) according to the same method as Step 2) of Example 33). ) Was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.91 (d, 1H), 8.42 (d, 1H), 8.38 (dd, 1H), 7.38 (d, 1H), 6.92 (d, 1H), 4.74 (s , 2H), 3.88 (s, 3H), 2.89 (bs, 1H)

Step 2) 2-Ethoxy-3-4- [2-methoxy-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester

Example 33 step, using [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-methoxy phenyl) methyl alcohol (300 mg, 1.0 mmol) prepared in step 1) above The title compound (170 mg) was obtained in the same manner as 3).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.98 (d, 1H), 8.63 (d, 1H), 8.50-8.47 (dd, 1H), 7.43 (d, 1H), 7.18-7.16 (d, 2H) , 7.03-6.96 (m, 3H), 5.13 (s, 2H), 4.19-4.15 (m, 2H), 3.99-3.95 (m, 4H), 3.62-3.56 (m, 1H), 3.37-3.33 (m, 1H), 2.96 (d, 2H), 1.21 (t, 3H), 1.16 (t, 3H)

Example  36. 2-Ethoxy-3-4- [2-methoxy-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid

Use of 2-ethoxy-3-4- [2-methoxy-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester of Example 35 (160 mg) Thus, the title compound (140 mg) was obtained in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.98 (d, 1H), 8.61 (s, 1H), 8.47 (d, 1H), 7.42 (d, 1H), 7.18 (d, 2H), 7.03-6.97 (d, 3H), 5.14 (s, 2H), 4.08-4.06 (m, 1H), 3.95 (s, 3H), 3.61-3.58 (m, 1H), 3.49-3.45 (m, 1H), 3.10-3.06 (m, 1H), 2.99-2.95 (m, 1H), 1.19 (t, 3H)

Example  37. 2- Ethoxy -3-4- [2- (4-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid  Ethyl ester

Step 1) 2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol

4-bromophenethyl alcohol (2.0 g, 9.9 mmol), bis (pinacolato) diboron (3.0 g, 11.9 mmol) and potassium acetate (KOAc; 2.9 g, 29.7 mmol) were dissolved in anhydrous dimethylformamide (DMF; After dissolving in 15 ml), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.5 g, 0.6 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 4 hours, the reaction mixture was cooled to room temperature, added to water (30 ml) to terminate the reaction, and the aqueous layer was extracted with ethyl acetate (50 ml × 2). The extracted organic layer was washed with saturated brine (50 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (2.2 g).

Rf = 0.33 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, 2H), 7.25 (d, 2H), 3.86 (m, 2H), 2.89 (t, 2H), 1.34 (s, 12H)

Step 2) 2- (4-Pyrimidin-2-yl-phenyl) ethyl alcohol

2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol prepared in step 1) (400 mg, 1.6 mmol ), 2-chloropyrimidine (220 mg, 1.9 mmol) and [1,1-?-Bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 39 mg, 0.05 mmol) After dissolving in amide (DMF; 3 ml), an aqueous 2N-sodium carbonate solution (Na ₂ CO ₃ ; 2.0 ml, 3.0 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (210 mg).

Rf = 0.24 (n-Hex: EtOAc = 1: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 2H), 8.38 (d, 2H), 7.36 (d, 2H), 7.18 (t, 1H), 3.92 (t, 2H), 2.95 (t , 2H).

Step 3) 2-Ethoxy-3-4- [2- (4-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- (4-pyrimidin-2-yl-phenyl) ethyl alcohol (210 mg, 1.0 mmol), triphenyl phosphine (PPh ₃ ; 315 mg, 1.2 mmol) prepared in step 2), 2-ethoxy 3- (4-hydroxyphenyl) propanoic acid ethyl ester (214 mg, 0.9 mmol) was dissolved in anhydrous tetrahydrofuran (THF; 2 ml), cooled to 0 ° C., and then diisopropyl azodicarboxylate (DIAD; 295 μl, 1.5 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (164 mg).

Rf = 0.30 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.79 (d, 2H), 8.39 (d, 2H), 7.41 (d, 2H), 7.13-7.18 (m, 3H), 6.82 (d, 2H), 4.13 -4.22 (m, 4H), 3.96 (t, 1H), 3.57-3.60 (m, 1H), 3.33-3.37 (m, 1H), 3.16 (t, 2H), 2.94 (d, 2H), 1.22 (t , 3H), 1.16 (t, 3H)

Example  38. 2- Ethoxy -3-4- [2- (4-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid

The same method as in Example 2, using the 2-ethoxy-3-4- [2- (4-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester (160 mg) in Example 37. According to the title compound (91 mg).

Rf = 0.04 (n-Hex: EtOAc = 1: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.87 (d, 2H), 8.32 (d, 2H), 7.47 (d, 2H), 7.41 (t, 1H), 7.14 (d, 2H), 6.83 ( d, 2H), 4.22 (t, 2H), 3.99 (dd, 1H), 3.58 (m, 1H), 3.33-3.36 (m, 1H), 3.14 (t, 2H), 2.96 (dd, 1H), 2.87 (dd, 1H), 1.11 (t, 3H)

Example  39.2- Ethoxy -3-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid  Ethyl ester

Step 1) 2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol

3-bromophenethyl alcohol (1.5 g, 7.5 mmol), bis (pinacolato) diboron (2.1 g, 8.2 mmol) and potassium acetate (KOAc; 2.2 g, 22.5 mmol) were dissolved in anhydrous dimethylformamide (DMF; After dissolving in 15 ml), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.2 g, 0.2 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 5 hours, the reaction mixture was cooled to room temperature, added to water (30 ml) to terminate the reaction, and the aqueous layer was extracted with ethyl acetate (40 ml × 2). The extracted organic layer was washed with saturated brine (50 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.2 g).

Rf = 0.30 (n-Hex: EtOAc = 3: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 7.67-7.69 (m, 2H), 7.30-7.34 (m, 2H), 3.87 (t, 2H), 2.88 (t, 2H), 1.35 (s, 12H)

Step 2) 2- (3-Pyrimidin-2-yl-phenyl) ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (400 mg, 1.6 mmol) prepared in step 1) above ), 2-chloropyrimidine (220 mg, 1.9 mmol) and [1,1-?-Bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 39 mg, 0.05 mmol) After dissolving in amide (DMF; 3 ml), an aqueous 2N-sodium carbonate solution (Na ₂ CO ₃ ; 2.0 ml, 3.0 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (195 mg).

Rf = 0.22 (n-Hex: EtOAc = 1: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.31 (d, 2H), 7.45 (t, 1H), 7.37 (d, 1H), 7.20 (t, 1H), 3.94 (t , 2H), 2.98 (t, 2H)

Step 3) 2-Ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (195 mg, 1.0 mmol) prepared in step 2), triphenyl phosphine (PPh ₃ ; 315 mg, 1.2 mmol), 2-ethoxy 3- (4-hydroxyphenyl) propanoic acid ethyl ester (214 mg, 0.9 mmol) was dissolved in anhydrous tetrahydrofuran (THF; 2 ml), cooled to 0 ° C. and then diisopropyl azodicarboxylate (DIAD 295 μl, 1.5 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (150 mg).

Rf = 0.33 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.37 (s, 1H), 8.33 (d, 1H), 7.43-7.45 (m, 2H), 7.20 (t, 1H), 7.14 (d, 2H), 6.83 (d, 2H), 4.22 (t, 2H), 4.16 (q, 2H), 3.96 (t, 1H), 3.57-3.59 (m, 1H), 3.34-3.36 (m, 1H ), 3.19 (t, 2H), 2.94 (d, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  40. 2- Ethoxy -3-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid

Example 2 was prepared by using 2-ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester (142 mg) prepared in Example 39. According to the same method, the title compound (72 mg) was obtained.

Rf = 0.07 (n-Hex: EtOAc = 1: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.88 (d, 2H), 8.34 (s, 1H), 8.24 (d, 1H), 7.45-7.48 (m, 2H), 7.41 (t, 1H), 7.14 (d, 2H), 6.83 (d, 2H), 4.23 (t, 2H), 3.98 (t, 1H), 3.58 (m, 1H), 3.34 (m, 1H), 3.16 (t, 2H), 2.95 (dd, 1H), 2.88 (dd, 1H), 1.12 (t, 3H)

Example  41. 2 (S) - Ethoxy -3-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid  Ethyl ester

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (500 mg, 2.5 mmol) prepared in step 2) of Example 39 was dissolved in dichloromethane (10 ml), and then cooled to 0 ° C., Triethylamine (Et ₃ N; 523 μl, 3.8 mmol) and methanesulfonyl chloride (233 μl, 3.0 mmol) were added dropwise sequentially, and the reaction mixture was stirred at 0 ° C. for about 2 hours. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (15 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. Obtained residue After dissolving in acetonitrile (5 ml), 2 (S) -ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (536 mg, 2.2 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 1.2 g 3.8 mmol) was added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (80 mg).

Rf = 0.13 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 2H), 8.37 (s, 1H), 8.32 (d, 1H), 7.42-7.47 (m, 2H), 7.13-7.19 (m, 3H) , 6.83 (d, 2H), 4.13-4.23 (m, 4H), 3.96 (t, 1H), 3.57-3.61 (m, 1H), 3.32-3.36 (m, 1H), 3.19 (t, 2H), 2.94 (d, 2H), 1.21 (t, 3H), 1.16 (t, 3H)

Example  42. 2 (S) - Ethoxy -3-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid

It was carried out using 2 (S) -ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester (80 mg) prepared in Example 41. The title compound (78 mg) was obtained in the same manner as the Example 2.

Rf = 0.25 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.78 (d, 2H), 8.32 (s, 1H), 8.22-8.23 (m, 1H), 7.39-7.41 (m, 2H), 7.28 (t, 1H ), 7.11 (d, 2H), 6.79 (d, 2H), 4.16 (t, 2H), 3.95-3.99 (m, 1H), 3.54-3.58 (m, 1H), 3.31-3.33 (m, 1H), 3.09 (t, 2H), 2.93 (dd, 1H), 2.84 (dd, 1H), 1.09 (t, 3H)

Example  43. 2- Ethoxy -3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl Ropanic acid ethyl ester

Step 1) 2- [3- (5-ethyl-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (500 mg) prepared in step 1) of Example 39) , 2.0 mmol) and 2-chloropyrimidine in place of 2-chloro-5-ethylpyrimidine (291 μl, 2.4 mmol), following the same method as in Step 2 of Example 39, the title compound (301 mg) Obtained.

Rf = 0.13 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (s, 2H), 8.27-8.28 (m, 2H), 7.44 (t, 1H), 7.34 (d, 1H), 3.94 (t, 2H), 2.98 (t, 2H), 2.69 (q, 2H), 1.31 (t, 3H)

Step 2) 2-Ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

In the same manner as in step 3) of Example 39, using 2- [3- (5-ethyl-pyrimidin-2-yl) phenyl] ethyl alcohol (300 mg, 1.3 mmol) prepared in step 1) above According to the title compound (288 mg).

Rf = 0.54 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (s, 2H), 8.33 (s, 1H), 8.29 (d, 1H), 7.39-7.45 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H), 4.21 (t, 2H), 4.16 (q, 2H), 3.58 (m, 1H), 3.34 (m, 1H), 3.19 (t, 2H), 2.94 (d, 2H), 2.69 ( q, 2H), 1.32 (t, 3H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  44.2- Ethoxy -3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester (275 mg) prepared in Example 43 , The title compound (125 mg) was obtained in the same manner as in Example 2.

Rf = 0.23 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.72 (s, 2H), 8.30 (s, 1H), 8.20 (d, 1H), 7.40-7.44 (m, 2H), 7.14 (d, 2H), 6.84 (d, 2H), 4.23 (t, 2H), 3.98 (dd, 1H), 3.58 (m, 1H), 3.33-3.36 (m, 1H), 3.15 (t, 2H), 2.94-2.96 (m, 1H), 2.86-2.88 (m, 1H), 2.72 (q, 2H), 1.32 (t, 3H), 1.11 (t, 3H)

Example  45. 2 (S) -Ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [3- (5-ethyl-pyrimidin-2-yl) phenyl] ethyl alcohol (1.5 g, 6.6 mmol) prepared in step 1) of Example 43 and 2 (S) -ethoxy-3- ( Using the 4-hydroxyphenyl) propanoic acid ethyl ester (1.2 g, 5.3 mmol), the title compound (3.0 g) was obtained in the same manner as in Example 41.

Rf = 0.36 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (s, 2H), 8.33 (s, 1H), 8.29 (d, 1H), 7.39-7.45 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H), 4.21 (t, 2H), 4.16 (q, 2H), 3.95 (t, 1H), 3.57-3.59 (m, 1H), 3.34-3.36 (m, 1H), 3.18 (t, 2H ), 2.94 (d, 2H), 2.69 (q, 2H), 1.32 (t, 3H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  46. 2 (S) - Ethoxy -3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenylpropanoic acid

2 (S) -Ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester prepared in Example 45 (3.0 g) Using, to obtain the title compound (2 g) in the same manner as in Example 2.

Rf = 0.20 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.71 (s, 2H), 8.30 (s, 1H), 8.20 (d, 1H), 7.40-7.44 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H), 4.22 (t, 2H), 3.97-3.98 (m, 1H), 3.58-3.60 (m, 1H), 3.33-3.35 (m, 1H), 3.15 (t, 2H), 2.95 ( dd, 1H), 2.86 (dd, 1H), 2.72 (q, 2H), 1.31 (t, 3H), 1.11 (t, 3H)

Example  47. 2- Ethoxy -3-4- [2- (3- (4- Trifluoromethyl Pyrimidin-2-yl) Phenyl ) on Methoxy] phenyl propanoic acid ethyl ester

Step 1) 2- [3- (4-trifluoromethyl-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (500 mg) prepared in step 1) of Example 39) , 2.0 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (290 μl, 2.4 mmol) gave the title compound (404 mg) according to the same method as Step 2) of Example 39. It was.

Rf = 0.24 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.04 (d, 1H), 8.38-8.40 (m, 2H), 7.45-7.51 (m, 2H), 7.42 (d, 1H), 3.95 (t, 2H) , 3.00 (t, 2H)

Step 2) 2-Ethoxy-3-4- [2- (3- (4-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

Example 3 step 3) of Example 39 using 2- [3- (4-trifluoromethyl-pyrimidin-2-yl) phenyl] ethyl alcohol (404 mg, 1.5 mmol) prepared in step 1). The same method gave the title compound (350 mg).

Rf = 0.38 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.03 (d, 1H), 8.44 (s, 1H), 8.38 (m, 1H), 7.50 (d, 1H), 7.46 (d, 2H), 7.14 (d , 2H), 6.83 (d, 2H), 4.22 (t, 2H), 4.16 (q, 2H), 3.95 (t, 1H), 3.57-3.59 (m, 1H), 3.34-3.36 (m, 1H), 3.20 (t, 2H), 2.94 (d, 2H), 1.22 (t, 3H), 1.15 (t, 3H)

Example  48. 2- Ethoxy -3-4- [2- (3- (4- Trifluoromethyl Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl propanoic acid

2-Ethoxy-3-4- [2- (3- (4-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester prepared in Example 47 (335 mg) Using, to obtain the title compound (192 mg) in the same manner as in Example 2.

Rf = 0.18 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.12 (d, 1H), 8.46 (s, 1H), 8.35 (d, 1H), 7.71 (d, 1H), 7.47-7.51 (m, 2H), 7.14 (d, 2H), 6.84 (d, 2H), 4.24 (t, 2H), 3.97 (dd, 1H), 3.58-3.60 (m, 1H), 3.33-3.35 (m, 1H), 3.17 (t, 2H), 2.95 (m, 1H), 2.88 (m, 1H), 1.11 (t, 3H)

Example  49.2- Ethoxy -3-4- [2- (3- (4- Methoxy Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl Propanoic acid ethyl ester

Step 1) 2- [3- (4-methoxy-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (500 mg) prepared in step 1) of Example 39) , 2.0 mmol) and 2-chloro-4-methoxypyrimidine (347 mg, 2.4 mmol) gave the title compound (272 mg) according to the same method as Step 2) of Example 39.

Rf = 0.13 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.50 (d, 1H), 8.32 (d, 2H), 7.43 (t, 1H), 7.36 (d, 1H), 6.64 (d, 1H), 4.10 (s , 3H), 3.93 (t, 2H), 2.98 (t, 2H)

Step 2) 2-Ethoxy-3-4- [2- (3- (4-methoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

The same method as Step 3) of Example 39, using 2- [3- (4-methoxy-pyrimidin-2-yl) phenyl] ethyl alcohol (272 mg, 1.2 mmol) prepared in step 2) above. According to the title compound (211 mg).

Rf = 0.53 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.50 (d, 1H), 8.36 (s, 1H), 8.32 (d, 1H), 7.44 (d, 2H), 7.14 (d, 2H), 6.83 (d , 2H), 6.63 (d, 1H), 4.21 (t, 2H), 4.16 (q, 2H), 4.09 (s, 3H), 3.96 (t, 1H), 3.57-3.59 (m, 1H), 3.34- 3.36 (m, 1H), 3.19 (t, 2H), 2.94 (d, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  50. 2-ethoxy-3-4- [2- (3- (4-methoxy-pyrimidin-2-yl) phenyl) ethoxy] phenyl Propanoic acid

2-Ethoxy-3-4- [2- (3- (4-methoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester (200 mg) prepared in Example 49 was used The title compound (96 mg) was obtained in the same manner as in Example 2.

Rf = 0.18 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.49 (d, 1H), 8.34 (s, 1H), 8.25 (d, 1H), 7.42-7.45 (m, 2H), 7.14 (d, 2H), 6.84 (d, 2H), 6.75 (d, 1H), 4.24 (t, 2H), 4.07 (s, 3H), 3.97 (dd, 1H), 3.58 (m, 1H), 3.33-3.34 (m, 1H) , 3.16 (t, 2H), 2.94-2.95 (m, 1H), 2.86-2.88 (m, 1H), 1.11 (t, 3H)

Example  51.2- Ethoxy -3-4- [2- (4- (4,6- Dimethoxy Pyrimidin-2-yl) Phenyl ) Etok Phenyl propanoic acid ethyl ester

Step 1) 2- [4- (4,6-Dimethoxy-pyrimidin-2-yl-phenyl) ethyl alcohol

2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (247 mg) prepared in step 1) of Example 37 , 1.0 mmol) and 2-chloro-4,6-dimethoxypyrimidine (209 mg, 1.2 mmol) gave the title compound (106 mg) in the same manner as in Step 2) of Example 37. .

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.35 (d, 2H), 7.27 (d, 2H), 5.92 (s, 1H), 4.00 (s, 6H), 3.83 (t, 2H), 2.89 (t , 2H)

Step 2) 2-Ethoxy-3-4- [2- (4- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [4- (4,6-dimethoxy-pyrimidin-2-yl-phenyl) ethyl alcohol (106 mg, 0.4 mmol) prepared in step 1) and 2-ethoxy-3- (4- Using hydroxyphenyl) propanoic acid ethyl ester (71 mg, 0.3 mmol), The title compound (32 mg) was obtained in the same manner as in Example 41.

Rf = 0.26 (n-Hex: EtOAc = 8: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.39 (d, 2H), 7.37 (d, 2H), 7.14 (d, 2H), 6.82 (d, 2H), 5.96 (s, 1H), 4.13-4.20 (m, 4H), 4.04 (s, 6H), 3.96 (t, 1H), 3.57-3.60 (m, 1H), 3.34-3.36 (m, 1H), 3.15 (t, 2H), 2.94 (d, 2H ), 1.20 (t, 3H), 1.16 (t, 3H)

Example  52. 2- Ethoxy -3-4- [2- (4- (4,6- Dimethoxy Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl propanoic acid

2-Ethoxy-3-4- [2- (4- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester prepared in Example 51 (30 mg ), To give the title compound (24 mg) in the same manner as in Example 2.

Rf = 0.07 (n-Hex: EtOAc = 1: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.34 (d, 2H), 7.38 (d, 2H), 7.13 (d, 2H), 6.81 (d, 2H), 5.98 (s, 1H), 4.18 ( t, 2H), 4.00 (s, 6H), 3.96-3.99 (m, 1H), 3.55-3.57 (m, 1H), 3.30-3.32 (m, 1H), 3.10 (t, 2H), 2.94 (dd, 1H), 2.85 (dd, 1H), 1.11 (t, 3H)

Example  53. 2- Ethoxy -3-4- [2- (3- (4,6- Dimethoxy Pyrimidin-2-yl) Phenyl ) Etok Phenyl propanoic acid ethyl ester

Step 1) 2- [3- (4,6-Dimethoxy-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (500 mg) prepared in step 1) of Example 39) , 2.0 mmol) and 2-chloro-4,6-dimethoxypyrimidine (419 mg, 2.4 mmol) gave the title compound (325 mg) in the same manner as in Step 2) of Example 39. .

 Rf = 0.24 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.31-8.34 (m, 2H), 7.42 (t, 1H), 7.35 (d, 1H), 5.98 (s, 1H), 4.05 (s, 6H), 3.93 (t, 2H), 2.98 (t, 2H)

Step 2) 2-Ethoxy-3-4- [2- (3- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [3- (4,6-dimethoxy-pyrimidin-2-yl-phenyl) ethyl alcohol (110 mg, 0.4 mmol) prepared in step 1) and 2-ethoxy-3- (4- Using the hydroxyphenyl) propanoic acid ethyl ester (76 mg, 0.3 mmol), the title compound (128 mg) was obtained in the same manner as in Example 41.

Rf = 0.39 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.37 (s, 1H), 8.33-8.35 (m, 1H), 7.38-7.43 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H) , 5.96 (s, 1H), 4.13-4.22 (m, 4H), 4.03 (s, 6H), 3.95 (t, 1H), 3.60 (m, 1H), 3.34-3.36 (m, 1H), 3.18 (t , 2H), 2.94 (d, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  54. 2- Ethoxy -3-4- [2- (3- (4,6- Dimethoxy Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl propanoic acid

2-Ethoxy-3-4- [2- (3- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester prepared in Example 53 (128 mg ), To give the title compound (107 mg) in the same manner as in Example 2.

Rf = 0.24 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.38 (s, 1H), 8.28 (d, 1H), 7.40-7.42 (m, 2H), 7.14 (d, 2H), 6.84 (d, 2H), 6.02 (s, 1H), 4.23 (t, 2H), 4.02 (s, 6H), 3.97-4.00 (m, 1H), 3.52-3.56 (m, 1H), 3.33-3.36 (m, 1H), 3.15 ( t, 2H), 2.95 (dd, 1H), 2.88 (dd, 1H), 1.11 (t, 3H)

Example  55. 2- Ethoxy -3-4- [2- (3- (4- Cyano Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl Propanoic acid ethyl ester

Step 1) 2- [3- (4-cyano-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (500 mg) prepared in step 1) of Example 39) , 2.0 mmol) and 2-chloro-pyrimidine-4-carbonitrile (335 mg, 2.4 mmol) gave the title compound (63 mg) in the same manner as in Step 2) of Example 39.

  Rf = 0.19 (n-Hex: EtOAc = 3: 2, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.00 (d, 1H), 8.34-8.35 (m, 2H), 7.42-7.50 (m, 3H), 3.96 (t, 2H), 3.00 (t, 2H)

Step 2) 2-Ethoxy-3-4- [2- (3- (4-cyano-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

The same method as Step 3) of Example 39, using 2- [3- (4-cyano-pyrimidin-2-yl) phenyl] ethyl alcohol (63 mg, 0.3 mmol) prepared in step 1) above. According to the title compound (8 mg).

Rf = 0.28 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.00 (d, 1H), 8.40 (s, 1H), 8.35 (d, 1H), 7.46-7.50 (m, 3H), 7.15 (d, 2H), 6.83 (d, 2H), 4.22 (t, 2H), 4.15 (q, 2H), 3.96 (t, 1H), 3.60 (t, 1H), 3.38 (t, 1H), 3.19 (t, 2H), 2.94 ( d, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  56. 2- Ethoxy -3-4- [2- (3- (4- Cyano Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenylpropanoic acid

2-Ethoxy-3-4- [2- (3- (4-cyano-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester (5 mg) prepared in Example 55 was used Thus, the title compound (3 mg) was obtained in the same manner as in Example 2.

Rf = 0.36 (CH ₂ Cl ₂ : MeOH = 20: 1 → 10: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.05 (d, 1H), 8.52 (s, 1H), 8.41 (d, 1H), 7.93 (d, 1H), 7.46-7.48 (m, 2H), 7.16 (d, 2H), 6.82 (d, 2H), 4.24 (t, 2H), 3.83 (m, 1H), 3.59 (td, 1H), 3.28 (td, 1H), 3.18 (t, 2H), 2.94 (m, 1 H), 2.82 (m, 1 H), 1.09 (t, 3 H)

Example  57. 2- Ethoxy -3-4- [2- (3- (5- Fluoro Pyrimidin-2-yl) Phenyl ) Ethoxy ] Pe  Nylpropanoic acid ethyl ester

Step 1) 2- [3- (5-Fluoro-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (374 mg) prepared in step 1) of Example 39 , 1.51 mmol) and 2-chloro-5-fluoropyrimidine (240 mg, 1.8 mmol) gave the title compound (374 mg) according to the same method as Step 2) of Example 39.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (s, 2H), 8.25 (d, 1H), 7.44 (t, 1H), 7.36 (d, 1H), 3.93 (t, 2H), 2.97 (t , 2H), 1.67 (bs, 1H)

Step 2) 2-Ethoxy-3-4- [2- (3- (5-fluoro-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [3- (5-fluoro-pyrimidin-2-yl) phenyl] ethyl alcohol (374 mg, 1.5 mmol) prepared in step 1) and 2-ethoxy-3- (4-hydroxyphenyl Using the propanoic acid ethyl ester (322 mg, 1.4 mmol), the title compound (50 mg) was obtained in the same manner as in Example 41.

Rf = 0.55 (n-Hex: EtOAc = 3: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.66 (s, 2H), 8.31 (s, 1H), 8.26 (dd, 1H), 7.46-7.40 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H), 4.21 (t, 2H), 4.16 (q, 2H), 3.96 (t, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.18 (t, 2H), 2.94 ( m, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  58. 2- Ethoxy -3-4- [2- (3- (5- Fluoro Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenylpropanoic acid

2-Ethoxy-3-4- [2- (3- (5-fluoro-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester (45 mg) prepared in Example 57 was used The title compound (35 mg) was obtained in the same manner as the Example 2.

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.77 (s, 2H), 8.34 (s, 1H), 8.24 (d, 1H), 7.44-7.41 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H), 4.22 (t, 2H), 3.95 (dd, 1H), 3.58 (m, 1H), 3.31 (m, 1H), 3.15 (t, 2H), 2.96 (dd, 1H), 2.84 (dd, 1H), 1.11 (t, 3H)

Example  59. 2-Ethoxy-3-4- [2- (3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

Step 1) 2- [3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (136 mg) prepared in step 1) of Example 39) , 0.55 mmol) and 2-chloro-5- (trifluoromethyl) pyrimidine (120 mg, 0.6 mmol) were prepared for the title compound (90 mg) according to the same method as Step 2) of Example 39. Obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.02 (s, 2H), 8.38-8.36 (m, 2H), 7.49-7.42 (m, 2H), 3.80 (t, 2H), 2.84 (t, 2H)

Step 2) 2-Ethoxy-3-4- [2- (3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl] ethyl alcohol (90 mg, 0.3 mmol) prepared in step 1) and 2-ethoxy-3- (4-hydro Using oxyphenyl) propanoic acid ethyl ester (64 mg, 0.3 mmol), the title compound (30 mg) was obtained in the same manner as in Example 41.

Rf = 0.56 (n-Hex: EtOAc = 3: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.03 (s, 2H), 8.46 (s, 1H), 8.39 (dd, 1H), 7.49-7.47 (m, 2H), 7.14 (d, 2H), 6.83 (d, 2H), 4.22 (t, 2H), 4.16 (q, 2H), 3.96 (t, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.20 (t, 2H), 2.95- 2.93 (m, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  60. 2- Ethoxy -3-4- [2- (3- (5- Trifluoromethyl Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl propanoic acid

2-Ethoxy-3-4- [2- (3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester prepared in Example 59 (25 mg) Using, to obtain the title compound (15 mg) in the same manner as in Example 2.

¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.15 (s, 2H), 8.49 (s, 1H), 8.38 (dd, 1H), 7.54-7.45 (m, 2H), 7.17 (d, 2H), 6.81 (d, 2H), 4.23 (t, 2H), 3.78 (m, 1H), 3.58 (m, 1H), 3.22 (m, 1H), 3.16 (t, 2H), 2.93 (dd, 1H), 2.78 (dd, 1H), 1.08 (t, 3H)

Example  61. 2-Ethoxy-3-4- [2- (3- (4-phenyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

Step 1) 2- [3- (4-phenyl-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (176 mg) prepared in step 1) of Example 39) , 0.71 mmol) and 2-chloro-4-phenylpyrimidine (150 mg, 0.8 mmol) gave the title compound (43 mg) according to the same method as Step 2) of Example 39.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 1H), 8.42-8.43 (m, 2H), 8.20-8.23 (m, 2H), 7.59 (d, 1H), 7.53-7.54 (m, 3H), 7.46 (t, 1H), 7.38 (d, 1H), 3.94 (t, 2H), 2.99 (t, 2H)

Step 2) 2-Ethoxy-3-4- [2- (3- (4-phenyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [3- (4-phenyl-pyrimidin-2-yl) phenyl] ethyl alcohol (45 mg, 0.2 mmol) and 2-ethoxy-3- (4-hydroxyphenyl) prepared in step 1) above. Using the propanoic acid ethyl ester (43 mg, 0.2 mmol), the title compound (30 mg) was obtained in the same manner as in Example 41.

Rf = 0.29 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.84 (d, 1H), 8.50 (s, 1H), 8.47 (d, 1H), 8.22-8.24 (m, 2H), 7.61 (d, 1H), 7.54 -7.55 (m, 3H), 7.45-7.48 (m, 2H), 7.15 (d, 2H), 6.85 (d, 2H), 4.23 (t, 2H), 4.16 (q, 2H), 3.96 (t, 1H ), 3.57-3.59 (m, 1H), 3.33-3.36 (m, 1H), 3.22 (t, 2H), 2.94 (d, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  62.2- Ethoxy -3-4- [2- (3- (4- Phenyl Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [2- (3- (4-phenyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester (29 mg) prepared in Example 61 , The title compound (27 mg) was obtained in the same manner as in Example 2.

Rf = 0.15 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.79 (d, 1H), 8.46 (s, 1H), 8.32 (m, 1H), 8.25-8.27 (m, 2H), 7.78 (d, 1H), 7.52-7.54 (m, 3H), 7.44 (d, 2H), 7.13 (d, 2H), 6.83 (d, 2H), 4.21 (t, 2H), 3.95-3.97 (m, 1H), 3.52-3.54 ( m, 1H), 3.30-3.32 (m, 1H), 3.15 (t, 2H), 2.94 (dd, 1H), 2.86 (dd, 1H), 1.09 (t, 3H)

Example  63. 2- Ethoxy -3-4- [2- (3- (4- methyl Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenyl Ropanic acid ethyl ester

Step 1) 2- [3- (4-Methyl-pyrimidin-2-yl) phenyl] ethyl alcohol

2- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol (114 mg) prepared in step 1) of Example 39 , 0.46 mmol) and 2-chloro-4-methylpyrimidine (66 mg, 0.5 mmol) gave the title compound (11 mg) according to the same method as Step 2) of Example 39.

Rf = 0.17 (n-Hex: EtOAc = 3: 2, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.64 (d, 1H), 8.30-8.31 (m, 2H), 7.43 (t, 1H), 7.35 (d, 1H), 7.06 (d, 1H), 3.93 (t, 2H), 2.97 (t, 2H), 2.59 (s, 3H)

Step 2) 2-Ethoxy-3-4- [2- (3- (4-methyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- [3- (4-methyl-pyrimidin-2-yl) phenyl] ethyl alcohol (11 mg, 0.05 mmol) and 2-ethoxy-3- (4-hydroxyphenyl) prepared in step 1) above. Using the propanoic acid ethyl ester (11 mg, 0.04 mmol), the title compound (10 mg) was obtained in the same manner as in Example 41.

Rf = 0.28 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.65 (d, 1H), 8.35 (s, 1H), 8.31 (d, 1H), 7.42-7.44 (m, 2H), 7.14 (d, 2H), 7.07 (d, 1H), 6.83 (d, 2H), 4.14-4.23 (m, 4H), 3.96 (t, 1H), 3.57-3.59 (m, 1H), 3.34-3.36 (m, 1H), 3.19 (t , 2H), 2.94 (d, 2H), 2.60 (s, 3H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  64. 2- Ethoxy -3-4- [2- (3- (4- methyl Pyrimidin-2-yl) Phenyl ) Ethoxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [2- (3- (4-methyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester (10 mg) prepared in Example 63 , The title compound (8 mg) was obtained in the same manner as in Example 2.

Rf = 0.12 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.65 (d, 1H), 8.32 (s, 1H), 8.22 (d, 1H), 7.42-7.44 (m, 2H), 7.24 (d, 1H), 7.14 (d, 2H), 6.83 (d, 2H), 4.22 (t, 2H), 3.96-3.99 (m, 1H), 3.57-3.59 (m, 1H), 3.30-3.33 (m, 1H), 3.15 ( t, 2H), 2.85 (dd, 1H), 2.58 (s, 3H), 1.11 (t, 3H)

Example  65. 2- Ethoxy -3-4- [2- (2- Fluoro -5-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenyl Propanoic acid ethyl ester

Step 1) 2- [2-Fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol

5-bromo-2-fluorophenethyl alcohol (2.1 g, 9.6 mmol), bis (pinacolato) diboron (3.6 g, 14.4 mmol) and potassium acetate (KOAc; 2.8 g, 28.8 mmol) After dissolving in methylformamide (DMF; 50 ml), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 0.2 g, 0.3 mmol) was added. The reaction mixture was stirred at 90 ° C. for about 3 hours and the reaction mixture was cooled to room temperature and then added to water (50 ml) to terminate the reaction. The aqueous layer was extracted with ethyl acetate (80 ml x 2). The extracted organic layer was washed with saturated brine (100 ml), dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (2.2 g).

Step 2) 2- (2-Fluoro-5-pyrimidin-2-yl-phenyl) ethyl alcohol

2- [2-fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol prepared in step 1) ( 500 mg, 1.9 mmol), 2-chloropyrimidine (320 g, 2.8 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl ₂ (dppf); 46 mg, 0.06 mmol ) Was dissolved in dimethylformamide (DMF; 5 ml) and 2N-sodium carbonate aqueous solution (Na ₂ CO ₃ ; 1.9 ml, 3.8 mmol) was added dropwise. The reaction mixture was stirred at 90 ° C. for about 3 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (320 mg).

Step 3) 2-Ethoxy-3-4- [2- (2-fluoro-5-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester

2- (2-fluoro-5-pyrimidin-2-yl-phenyl) ethyl alcohol (320 mg, 1.5 mmol) prepared in step 2) was dissolved in dichloromethane (5 ml) and cooled to 0 ° C. Triethylamine (Et ₃ N; 418 μl, 3.0 mmol) and methanesulfonyl chloride (174 μl, 2.2 mmol) were added dropwise sequentially, and the reaction mixture was stirred at 0 ° C. for about 1 hour. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (10 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated to give methanesulfonic acid 2- (2-fluoro-5-pyrimidin-2-yl-phenyl) ethyl ester with no acetonitrile (5 ml) without purification. After dissolving in 2-Ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (322 mg, 1.4 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 733 mg, 2.2 mmol) were added. The reaction mixture was stirred at 80 ° C. for about 2 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (70 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 2H), 8.43-8.41 (m, 1H), 8.35-8.31 (m, 1H), 7.30-7.14 (m, 4H), 6.84 (d, 2H), 4.23 ~ 4.13 (m, 4H), 3.95 ~ 3.93 (m, 1H), 3.62 ~ 3.56 (m, 1H), 3.37 ~ 3.32 (m, 1H), 3.20 ~ 3.16 (m, 1H), 2.94 ( d, 2H), 1.22 (t, 3H), 1.15 (t, 3H)

Example  66. 2- Ethoxy -3-4- [2- (2- Fluoro -5-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [2- (2-fluoro-5-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester (70 mg) prepared in Example 65 , To obtain the title compound (50 mg) in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.80 (d, 2H), 8.38 to 8.35 (m, 2H), 7.26 to 7.72 (m, 4H), 6.84 (d, 2H), 4.25 to 4.22 (m, 2H), 4.05 ~ 4.03 (m, 1H), 3.60 ~ 3.55 (m, 1H), 3.47 ~ 3.43 (m, 1H), 3.23 ~ 3.19 (m, 1H), 3.13 (s, 1H), 3.05 ~ 3.02 ( m, 1H), 2.97-2.95 (m, 1H), 1.16 (t, 3H)

Example  67. 2- Ethoxy -3- (4-2- [5- (5-ethyl-pyrimidin-2-yl) -2- Fluoro - Phenyl ] on Methoxyphenyl) propanoic acid ethyl ester

Step 1) 2- [5- (5-ethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethyl alcohol

2- [2-fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl] ethyl alcohol in step 1) of Example 65) (100 mg, 0.38 mmol) and the title compound (300 mg) were prepared according to the same method as step 2) of Example 65, except that 2-chloro-5-ethylpyrimidine (288 μl, 2.4 mmol) was used. Obtained.

Step 2) 2-Ethoxy-3- (4-2- [5- (5-ethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid ethyl ester

Example 65 step, using 2- [5- (5-ethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethyl alcohol (200 mg, 0.8 mmol) prepared in step 1) above. The title compound (200 mg) was obtained in the same manner as 3).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.61-8.58 (m, 2H), 8.38-8.35 (m, 1H), 7.26-7.12 (m, 3H), 6.96 (d, 2H), 4.23-4.20 ( m, 2H), 4.05-4.01 (m, 1H), 3.60-3.55 (m, 1H), 3.47-3.43 (m, 1H), 3.23-3.19 (m, 1H), 3.13 (s, 1H), 3.05- 3.02 (m, 1H), 2.97-2.95 (m, 1H), 2.68-2.63 (m, 2H), 1.21 (t, 3H), 1.16 (t, 3H)

Example  68. 2- Ethoxy -3- (4-2- [5- (5-ethyl-pyrimidin-2-yl) -2- Fluoro - Phenyl ] Ethoxyphenyl Propanoic acid

2-Ethoxy-3- (4-2- [5- (5-ethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid ethyl ester prepared in Example 67 ( 190 mg) was used to obtain the title compound (150 mg) according to the same method as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.59-8.55 (m, 2H), 8.40-8.37 (m, 1H), 7.26-7.12 (m, 3H), 6.96 (d, 2H), 4.23-4.20 ( m, 2H), 4.05-4.01 (m, 1H), 3.55-3.51 (m, 1H), 3.46-3.41 (m, 1H), 3.24-3.22 (m, 1H), 3.15 (s, 1H), 3.08- 3.05 (m, 1H), 2.99-2.96 (m, 1H), 1.15 (t, 3H)

Example  69. 2- Ethoxy -3- (4-2- [5- (4- Trifluoromethyl -Pyrimidin-2-yl) -2- Influenza Oro-phenyl] ethoxyphenyl) propanoic acid ethyl ester

Step 1) 2- [5- (4-Trifluoromethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethyl alcohol

2- [2-fluoro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) phenyl prepared in step 1) of Example 65] Using ethyl alcohol (100 mg, 0.38 mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (69 μl, 0.6 mmol), follow the same procedure as in step 2) of Example 65. 92 mg) was obtained.

Step 2) 2-Ethoxy-3- (4-2- [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid ethyl ester

Example using 2- [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethyl alcohol (92 mg, 0.3 mmol) prepared in step 1) above The title compound (30 mg) was obtained in the same manner as in step 3) of 65.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 9.01 (d, 1H), 8.69-8.65 (m, 1H), 8.50-8.48 (m, 1H), 7.51 (d, 1H), 7.25-7.20 (m, 3H), 6.97 (d, 2H), 4.34-4.30 (m, 2H), 4.07-4.03 (m, 1H), 3.65-3.61 (m, 1H), 3.49-3.45 (m, 1H), 3.23-3.19 ( m, 1H), 3.17 (s, 1H), 3.05-3.02 (m, 1H), 2.97-2.95 (m, 1H), 1.21 (t, 3H), 1.15 (t, 3H)

Example  70. 2- Ethoxy -3- (4-2- [5- (4- Trifluoromethyl -Pyrimidin-2-yl) -2- Fluoro -Phenyl] ethoxyphenyl) propanoic acid

2-Ethoxy-3- (4-2- [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid prepared in Example 69 Using ethyl ester (28 mg), the title compound (20 mg) was obtained in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.96 (d, 1H), 8.47-8.42 (m, 2H), 7.26-7.12 (m, 4H), 6.84 (d, 2H), 4.25-4.22 (m, 2H), 4.05-4.03 (m, 1H), 3.60-3.55 (m, 1H), 3.47-3.43 (m, 1H), 3.23-3.19 (m, 1H), 3.13 (s, 1H), 3.05-3.02 ( m, 1H), 2.97-2.95 (m, 1H), 1.16 (t, 3H)

Example  71.2- Ethoxy -3-4- [3- (3-pyrimidin-2-yl- Phenyl ) Propoxy ] Phenylpropanoic acid  Ethyl ester

Step 1) 3- (3-Pyrimidin-2-yl-phenyl) propiononitrile

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (960 mg, 4.79 mmol), triphenyl phosphine (PPh ₃ ; 520 mg, 7.67 mmol) and already prepared in step 2) of example 39 Dazole (1.88 g, 7.18 mmol) was dissolved in anhydrous tetrahydrofuran (THF; 50 ml), stirred for about 30 minutes and iodine (I ₂ ; 1.46 g, 5.75 mmol) was added. The reaction mixture was stirred at room temperature for about 3 hours and after confirming that the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 ml), washed with water (30 ml x 2) and saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. Obtained residue Dissolved in anhydrous dimethylsulfoxide (DMSO; 20 ml) without purification and potassium cyanide (KCN; 374 mg, 5.75 mmol) was added. The reaction mixture was stirred at room temperature for about 1 hour and after confirming that the reaction was completed, it was concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 ml), washed with water (20 ml × 2) and saturated brine, dehydrated with magnesium sulfate (MgSO 4), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (280 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.79 (d, 2H), 8.36 (d, 1H), 8.32 (s, 1H), 7.47 (t, 1H), 7.36 (d, 1H), 7.18 (t , 1H), 3.05 (t, 2H), 2.68 (t, 2H)

Step 2) 3- (3-Pyrimidin-2-yl-phenyl) propanoic acid methyl ester

3- (3-pyrimidin-2-yl-phenyl) propiononitrile (280 mg, 1.34 mmol) prepared in step 1) was dissolved in 1,4-dioxane (25 ml), followed by methyl alcohol (5.5 ml ) Was added dropwise and stirred at room temperature for about 30 minutes. Acetyl chloride (10 ml) was added dropwise to the reaction mixture, followed by stirring at room temperature for 2 hours. After confirming that the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 ml), washed with water (10 ml) and saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (250 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.78 (d, 2H), 8.31-8.29 (m, 2H), 7.42 (t, 1H), 7.33 (d, 1H), 7.15 (t, 1H), 3.67 (s, 3H), 3.05 (t, 2H), 2.71 (t, 2H)

Step 3) 3- (3-Pyrimidin-2-yl-phenyl) propan-1-ol

3- (3-pyrimidin-2-yl-phenyl) propanoic acid methyl ester (250 mg, 1.03 mmol) prepared in step 2) was dissolved in anhydrous tetrahydrofuran (THF; 30 ml) and cooled to 0 ^° C. Then lithium aluminum hydride (LiAlH ₄ ; 78 mg, 2.06 mmol) was added slowly. The reaction mixture was stirred at 0 ^° C. for 2 hours, ice was added to terminate the reaction, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (220 mg).

Step 4) 2- [3- (3-iodo-propyl) phenyl] pyrimidine

3- (3-pyrimidin-2-yl-phenyl) propan-1-ol (220 mg, 1.03 mmol) prepared in step 3), triphenyl phosphine (PPh ₃ ; 430 mg, 1.64 mmol) and already Doazole (100 mg, 1.54 mmol) was dissolved in anhydrous tetrahydrofuran (THF; 50 ml), stirred for about 30 minutes and then iodine (I ₂ ; 310 mg, 1.23 mmol) was added. The reaction mixture was stirred at room temperature for about 3 hours and after confirming that the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), washed with water (15 ml × 2) and saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (270 mg).

Step 5) 2-Ethoxy-3-4- [3- (3-pyrimidin-2-yl-phenyl) propoxy] phenylpropanoic acid ethyl ester

2- [3- (3-iodo-propyl) phenyl] pyrimidine (190 mg, 0.59 mmol) prepared in step 4), 2-ethoxy-3- (4-hydroxyphenyl) propanoic acid ethyl ester (120 mg, 0.53 mmol) was dissolved in dimethylformamide (DMF; 20 ml) and potassium carbonate (K ₂ CO ₃ ; 160 mg, 1.17 mmol) was added. The reaction mixture was stirred at room temperature for about 3 hours, cooled to room temperature and water (10 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (15 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (60 mg).

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.82 (d, 2H), 8.32-8.27 (m, 2H), 7.44-7.42 (m, 1H), 7.40-7.35 (m, 1H), 7.19-7.16 ( m, 1H), 7.14 (d, 2H), 6.81 (d, 2H), 4.19-4.14 (m, 2H), 3.99-3.94 (m, 3H), 3.62-3.56 (m, 1H), 3.37-3.34 ( m, 1H), 2.95-2.89 (m, 4H), 2.19-2.15 (m, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  72. 2- Ethoxy -3-4- [3- (3-pyrimidin-2-yl- Phenyl ) Propoxy ] Phenylpropanoic acid

Using 2-ethoxy-3-4- [3- (3-pyrimidin-2-yl-phenyl) propoxy] phenylpropanoic acid ethyl ester (58 mg) prepared in Example 71, According to the same method, the title compound (40 mg) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.82 (d, 2H), 8.32-8.27 (m, 2H), 7.44-7.42 (m, 1H), 7.40-7.35 (m, 1H), 7.19-7.16 ( m, 1H), 7.14 (d, 2H), 6.81 (d, 2H), 4.19-4.14 (m, 2H), 3.99-3.94 (m, 3H), 3.62-3.56 (m, 1H), 3.37-3.34 ( m, 1H), 2.95-2.89 (m, 4H), 2.19-2.15 (m, 2H), 1.22 (t, 3H), 1.16 (t, 3H)

Example  73. 2-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Benzyl Butane  Ethyl ester

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (75 mg, 0.38 mmol) prepared in step 2 of Example 39 was dissolved in dichloromethane (10 ml), and then cooled to 0 ° C., and Ethylamine (Et ₃ N; 78 μl, 0.57 mmol) and methanesulfonyl chloride (35 μl, 0.45 mmol) were added dropwise sequentially, and the reaction mixture was stirred at 0 ° C. for about 2 hours. After diluting the reaction mixture with dichloromethane (10 ml), the organic layer was washed with water (15 ml) and again with saturated brine. The organic layer was dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. Obtained residue After dissolving in acetonitrile (2 ml), 2- (4-hydroxybenzyl) butanoic acid ethyl ester (72 mg, 0.4 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 176 g, 0.5 mmol) were added. The reaction mixture was stirred at 80 ° C. for about 4 hours, cooled to room temperature and water (5 ml) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate (10 ml × 3) and the organic layer was washed with saturated brine, dehydrated with magnesium sulfate (MgSO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (95 mg).

Rf = 0.25 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.36 (s, 1H), 8.32 (d, 1H), 7.43-7.45 (m, 2H), 7.20 (t, 1H), 7.05 (d, 2H), 6.81 (d, 2H), 4.21 (t, 2H), 4.04-4.07 (m, 2H), 3.19 (t, 2H), 2.85 (dd, 1H), 2.66 (dd, 1H), 2.52 (m, 1H), 1.53-1.61 (m, 2H), 1.16 (t, 3H), 0.90 (t, 3H)

Example  74. 2-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Benzyl Butane

Using 2-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] benzylbutanoic acid ethyl ester (90 mg) prepared in Example 73, according to the same method as in Example 2 Compound (86 mg) was obtained.

Rf = 0.23 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.78 (d, 2H), 8.32 (s, 1H), 8.22-8.24 (m, 1H), 7.41 (m, 2H), 7.29 (t, 1H), 7.05 (d, 2H), 6.79 (d, 2H), 4.16 (t, 2H), 3.10 (t, 2H), 2.80 (dd, 1H), 2.65 (dd, 1H), 2.48 (td, 1H), 1.52 -1.56 (m, 2H), 0.91 (t, 3H)

Example  75. 2- methyl -2-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenoxypropanoic acid  Ethyl ester

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (53 mg, 0.27 mmol) and 2- (4-hydroxyphenoxy) -2-methyl-propane prepared in step 2) of Example 39) Using the acid ethyl ester (73 mg, 0.3 mmol), the title compound (96 mg) was obtained in the same manner as in Example 73.

Rf = 0.19 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.36 (s, 1H), 8.33 (d, 1H), 7.43-7.45 (m, 2H), 7.20 (t, 1H), 6.77 -6.83 (m, 4H), 4.23 (q, 2H), 4.18 (t 2H), 3.18 (t, 2H), 1.53 (s, 6H), 1.27 (t, 3H)

Example  76. 2- methyl -2-4- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenoxypropionic acid

Example 2 was prepared by using 2-methyl-2-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenoxypropanoic acid ethyl ester (90 mg) prepared in Example 75. The same method gave the title compound (61 mg).

Rf = 0.19 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.87 (d, 2H), 8.33 (s, 1H), 8.24 (d, 1H), 7.45-7.48 (m, 2H), 7.41 (t, 1H), 6.81-6.88 (m, 4H), 4.21 (t, 2H), 3.16 (t, 2H), 1.48 (s, 6H)

Example  77. 2- methyl -2-3- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenoxypropionic acid  Ethyl ester

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (53 mg, 0.27 mmol) and 2- (3-hydroxyphenoxy) -2-methyl-propane prepared in step 2) of Example 39) Using the acid ethyl ester (73 mg, 0.3 mmol), the title compound (104 mg) was obtained in the same manner as in Example 73.

Rf = 0.20 (n-Hex: EtOAc = 4: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.81 (d, 2H), 8.33 (s, 1H), 8.30 (d, 1H), 7.43 (dd, 2H), 7.18 (t, 1H), 7.10 (t , 1H), 6.55 (d, 1H), 6.43 (s, 1H), 6.40 (d, 1H), 4.19-4.23 (m, 4H), 3.18 (t, 2H), 1.58 (s, 6H), 1.22 ( t, 3H)

Example  78.2- methyl -2-3- [2- (3-pyrimidin-2-yl- Phenyl ) Ethoxy ] Phenoxypropanoic acid

Example 2, using 2-methyl-2-3- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenoxypropanoic acid ethyl ester (90 mg) prepared in Example 77; According to the same method, the titled compound (71 mg) was obtained.

Rf = 0.28 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.84 (d, 2H), 8.34 (s, 1H), 8.25 (d, 1H), 7.44-7.46 (m, 2H), 7.36 (t, 1H), 7.11 (t, 1H), 6.59 (d, 1H), 6.45-6.49 (m, 2H), 4.21 (t, 2H), 3.15 (t, 2H), 1.54 (s, 6H)

Example 79. 2- Methyl - 2 - phenoxy- 3-4- [2- (3-pyrimidin-2-yl- phenyl ) ethoxy ] phenylpropanoic acid ethyl ester

2- (3-pyrimidin-2-yl-phenyl) ethyl alcohol (53 mg, 0.27 mmol) and 3- (4-hydroxyphenyl) -2-methyl-2- prepared in step 2) of Example 39). Using the phenoxy-propanoic acid ethyl ester (97 mg, 0.3 mmol), the title compound (78 mg) was obtained in the same manner as in Example 73.

Rf = 0.37 (n-Hex: EtOAc = 2: 1, v / v)

¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.78 (d, 2H), 8.38 (s, 1H), 8.33 (d, 1H), 7.43-7.44 (m, 2H), 7.19-7.23 (m, 2H) , 7.14 (d, 3H), 6.96 (t, 1H), 6.82-6.85 (m, 4H), 4.17-4.23 (m, 4H), 3.26 (d, 1H), 3.19 (t, 2H), 3.10 (d , 1H), 1.39 (s, 3H), 1.20 (t, 3H)

Example 80. 2- Methyl - 2 - phenoxy- 3-4- [2- (3-pyrimidin-2-yl- phenyl ) ethoxy ] phenylpropanoic acid

Using 2-methyl-2-phenoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester (70 mg) prepared in Example 79, The title compound (41 mg) was obtained in the same manner as in Example 2.

Rf = 0.36 (CH ₂ Cl ₂ : MeOH = 20: 1, v / v)

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.83 (d, 2H), 8.35 (s, 1H), 8.22 (d, 1H), 7.44-7.46 (m, 2H), 7.35 (t, 1H), 7.16-7.24 (m, 4H), 6.96 (t, 1H), 6.84-6.87 (m, 4H), 4.24 (t, 2H), 3.23 (d, 1H), 3.16 (t, 2H), 3.09 (d, 1H), 1.33 (s, 3H)

Test Example  1. Human Peroxysome Multiplier Activating receptor-alpha ( PPAR -α) activation test

Human PPAR-alpha was transiently expressed in CV-1 (monkey kidney cells) cells to evaluate the ability of the compounds of the present invention to activate PPAR-alpha to induce transcriptional activation (transactivation assay). Chimeric receptor systems were used to rule out interference due to endogenous receptor activation [Jian-Shen Q. et al, Mol Cell Biol (1995) 15 (3), 1817-1825. A correction vector expressing a respective expression vector and a Renilla luciferase expressing a chimeric PPAR-alpha receptor in the form of a ligand-binding domain of human PPAR-alpha fused to a DNA binding site of the yeast transcription factor GAL4. DNA constructs containing five copies of the DNA binding region of GAL4 capable of inducing the expression of firefly luciferase were transiently transfected into CV-1 cells [Motomura W. et al. , Int J Cancer (2004) 108 (1), 41-6]. After reacting for 3 hours, DMEM medium containing 10% fetal calf serum containing the compound of the present invention was exchanged. After reacting for 24 hours, the luciferase activity of the firefly was measured. Positive controls for PPAR-alpha include 3-4- [2- (2-phenyl-4-methyl-1,3-oxazole) ethyloxy] phenyl- (2S)-[(1-methyl-3- Oxo-3-phenyl) propenyl] aminopropanoic acid (GW-409544) was used.

Evaluation of the activity of a compound of the present invention is performed by measuring the percentage (Relative Response%) of the maximum effect of the positive control at the initial single concentration, followed by multiple concentrations of the compound of the present invention exhibiting at least 50% activity Evaluation was performed to calculate concentrations (EC ₅₀ ) which caused 50% activation for maximal effect using nonlinear regression analysis. The results are shown in Table 1.

compound hPPAR-α
(EC ₅₀ , uM) compound hPPAR-α
(EC ₅₀ , uM) Example 1 0.723 Example 36 2.158 Example 4 0.460 Example 44 1.016 Example 6 0.282 Example 46 0.957 Example 12 0.442 Example 48 3.858 Example 18 1.180 Example 50 4.022 Example 20 0.369 Example 58 2.298 Example 22 0.963 Example 58 0.868 Example 24 1.882 Example 62 3.531 Example 26 0.367 Example 68 3.451 Example 32 4.234 Example 70 1.784

From the results of Table 1, the compound of formula 1 of the present invention is shown to increase the activity of human peroxysomal proliferator-activated receptor-alpha, a transcription factor associated with obesity or diabetes, by 50% or more at a concentration of 100 uM or less It can be seen that it has an excellent activity increasing effect on the peroxysomal proliferator-activated receptor-alpha (PPAR-α).

Test Example  2. Human Peroxysome Multiplier Activating receptor-gamma ( PPAR -γ) activation test

Human PPAR-gamma was transiently expressed in CV-1 (monkey kidney cells) cells to evaluate the ability of the compounds of the present invention to induce transcriptional activation by activating PPAR-gamma (transactivation assay). Chimeric receptor systems were used to rule out interference due to endogenous receptor activation [Jian-Shen Q. et al, Mol Cell Biol (1995) 15 (3), 1817-1825. A correction vector expressing each of the chimeric PPAR-gamma receptors expressing a fusion form of the ligand binding domain of human PPAR-gamma to the DNA binding site of the yeast transcription factor GAL4 and Renilla luciferase The DNA construct containing five copies of the DNA binding region of GAL4 and capable of inducing Firefly luciferase expression was transiently transfected into CV-1 cells [Motomura W. et al. , Int J Cancer (2004) 108 (1), 41-6]. After reacting for 3 hours, DMEM medium containing 10% fetal calf serum containing the compound of the present invention was exchanged. After reacting for 24 hours, the luciferase activity of the firefly was measured. Positive controls for PPAR-gamma include 3-4- [2- (2-phenyl-4-methyl-1,3-oxazole) ethyloxy] phenyl- (2S)-[(1-methyl-3- Oxo-3-phenyl) propenyl] aminopropanoic acid (GW-409544) was used.

Evaluation of the activity of a compound of the present invention is performed by measuring the percentage (Relative Response%) of the maximum effect of the positive control at the initial single concentration, followed by multiple concentrations of the compound of the present invention exhibiting at least 50% activity. Evaluation was performed to calculate concentrations (EC ₅₀ ) which caused 50% activation for maximal effect using nonlinear regression analysis. The results are shown in Table 2.

compound hPPAR-γ
(EC ₅₀ , uM) compound hPPAR-γ
(EC ₅₀ , uM) Example 1 1.274 Example 36 0.812 Example 2 0.576 Example 44 0.736 Example 4 0.191 Example 46 0.511 Example 6 2.339 Example 48 0.546 Example 8 1.185 Example 50 1.041 Example 10 4.655 Example 58 2.298 Example 12 0.528 Example 58 3.475 Example 24 0.968 Example 62 0.803 Example 26 0.400 Example 68 0.699 Example 32 0.574 Example 70 0.548

From the results in Table 2, it was shown that the compound of formula 1 of the present invention increases the activity of the peroxysomal proliferator-activated receptor-gamma, which is a transcription factor associated with obesity or diabetes, by 50% or more at a concentration of 100 uM or less. In addition, it can be seen that it has an excellent effect of increasing the activity against peroxysomal proliferator-activated receptor-gamma (PPAR-γ).

Test Example  3. Diabetic rats  ( db Of db  Hypoglycemic test using mouse)

About 12 weeks old male db mice (C57BLKS / J-db / db) were divided into three groups of five rats and tested in comparison with the normal rat group. Each group is divided into a control group (db mouse control), a test group and a positive control group, and the test group contains 0.1 to 10 mg / 5 ml / kg of the compound of the present invention suspended in 0.5% methyl cellulose (MC). Oral administration was performed for 5 days at once daily intervals. The control group was 0.5% methyl cellulose (MC) aqueous solution only, the positive control group was orally administered a commercial drug (Rosiglitazone, Avandia ™, GSK) in the same manner.

Drug efficacy was assessed by measuring whole blood glucose and insulin levels before and after the last dose. Each item was used to measure whole blood glucose from the blood collected from the vein on the day of final administration using an Accu-check compact and to assist the mouse insulin kit (Japan shibayagi co., ltd) was used to measure insulin concentration. The results are shown in Table 3.

compound Dosage
(mg / kg, once / day, oral) Hypoglycemic effect compared to control (%) db mouse Control - 0 Rosiglitazone 10 -43.5 Example 4 10 -49.8 Example 26 3 -49.3 Example 40 10 -56.7 Example 44 10 -69.6 Example 44 3 -46.0 Example 48 10 -69.6 Example 46 3 -61.4 Example 66 3 -57.5 Example 66 One -43.4

From the results of Table 3, it can be seen that the compound according to the present invention has a very good activity in the hypoglycemic test using diabetic mice (db / db mice).

Test Example  4. Assessment of body dynamics

As a result of oral or intravenous administration of the compound according to an embodiment of the present invention to mice and rats at a dose of 3 mg / kg, respectively, the maximum plasma concentration (Cmax) was 5,000 to 100,000 ng / ml, and the plasma concentration-time curve was lower. The area (AUC) was 10,000 to 500,000 ng-hr / mL and the half-life (T _1/2 ) was about 5 to 48 hours, and the bioavailability was 30 to 100% compared with the same dose of intravenous administration. Therefore, it can be seen from the above results that the compound of Formula 1 according to the present invention has excellent body dynamics and bioavailability.

The 2-phenylpyrimidine derivatives of the present invention or pharmaceutically acceptable salts thereof have an excellent effect on peroxysomal proliferator-activated receptors (PPARs) alpha and gamma, and have a very good hypoglycemic effect and biologic upon oral administration. Has utilization.

Claims (6)

2-phenylpyrimidine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

Where Q is -O- or-(CH ₂ ) m-, where m is an integer from 1 to 3, n is an integer from 1 to 5; R is hydrogen or C ₁ -C ₅ alkyl, R ₁ and R ₂ are independently of each other hydrogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or phenoxy, provided that R ₁ and R ₂ cannot be hydrogen at the same time, R ₃ is hydrogen, C ₁ -C ₅ alkoxy or halogen, R ₄ and R ₅ independently of one another are hydrogen, halogen, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, trifluoromethyl or phenyl. The method of claim 1, Q is -O- or -CH _2- , n is an integer from 1 to 3; R is hydrogen or C ₁ -C ₃ alkyl, R ₁ and R ₂ are independently of each other hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or phenoxy, R ₃ is hydrogen, C ₁ -C ₃ is alkoxy or halogen, R ₄ and R ₅ are independently hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, characterized in that the methyl or phenyl, 2-trifluoromethyl-phenyl each other Pyrimidine derivatives or pharmaceutically acceptable salts thereof. The method of claim 1, 2-ethoxy-3- [4- (4-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester; 2-ethoxy-3- [4- (4-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid; 2-ethoxy-3- [4- (3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester; 2-ethoxy-3- [4- (3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid; 2-ethoxy-3-4- [3- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [3- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [3- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [3- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [3- (4-methoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [3- (4-methoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [3- (4,6-dimethoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [3- (4,6-dimethoxy-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [3- (4-cyano-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [3- (4-cyano-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3- [4- (4-fluoro-3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester; 2-ethoxy-3- [4- (4-fluoro-3-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid; 2-ethoxy-3-4- [4-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [4-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [4-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [4-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3- [4- (2-fluoro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester; 2-ethoxy-3- [4- (2-fluoro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid; 2-ethoxy-3-4- [2-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2-fluoro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [2-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2-fluoro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3- [4- (2-chloro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid ethyl ester; 2-ethoxy-3- [4- (2-chloro-5-pyrimidin-2-ylbenzyloxy) phenyl] propanoic acid; 2-ethoxy-3-4- [2-chloro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2-chloro-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [2-chloro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2-chloro-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [2-methoxy-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2-methoxy-5- (5-ethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [2-methoxy-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2-methoxy-5- (4-trifluoromethyl-pyrimidin-2-yl) benzyloxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (4-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (4-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid; 2 (S) -ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2 (S) -ethoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2 (S) -ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2 (S) -ethoxy-3-4- [2- (3- (5-ethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (4-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (4-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (4-methoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (4-methoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (4- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (4- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (4,6-dimethoxy-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (4-cyano-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (4-cyano-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (5-fluoro-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (5-fluoro-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (5-trifluoromethyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (4-phenyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (4-phenyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (3- (4-methyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (3- (4-methyl-pyrimidin-2-yl) phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3-4- [2- (2-fluoro-5-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [2- (2-fluoro-5-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid; 2-ethoxy-3- (4-2- [5- (5-ethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid ethyl ester; 2-ethoxy-3- (4-2- [5- (5-ethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid; 2-ethoxy-3- (4-2- [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid ethyl ester; 2-ethoxy-3- (4-2- [5- (4-trifluoromethyl-pyrimidin-2-yl) -2-fluoro-phenyl] ethoxyphenyl) propanoic acid; 2-ethoxy-3-4- [3- (3-pyrimidin-2-yl-phenyl) propoxy] phenylpropanoic acid ethyl ester; 2-ethoxy-3-4- [3- (3-pyrimidin-2-yl-phenyl) propoxy] phenylpropanoic acid; 2-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] benzylbutanoic acid ethyl ester; 2-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] benzylbutanoic acid; 2-methyl-2-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenoxypropanoic acid ethyl ester; 2-Methyl-2-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenoxypropanoic acid; 2-methyl-2-3- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenoxypropanoic acid ethyl ester; 2-methyl-2-3- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenoxypropanoic acid; 2-methyl-2-phenoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropanoic acid ethyl ester; And 2-Methyl-2-phenoxy-3-4- [2- (3-pyrimidin-2-yl-phenyl) ethoxy] phenylpropionic acid A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. A process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof by reacting a compound of formula 2 with a compound of formula 3:

Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Q are the same as defined in claim 1, Y is hydroxy, methanesulfonyl, benzenesulfonyl, toluenesulfonyl or halogen Indicates. The method of claim 4, wherein the compound of Formula 2 is prepared by reacting the compound of Formula 4 with the compound of Formula 5.

In Scheme 2, R ₃ , R ₄ , R ₅ are the same as defined in claim 1, Y is the same as defined in claim 4, X represents a halogen, Z is halogen, boronic acid or trifluoromethane Sulfonyl. Diabetes, dyslipidemia, hyperlipidemia, obesity, hypertension, comprising a therapeutically effective amount of a compound of formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof , Composition for preventing or treating arteriosclerosis of the arteries, coagulation disorders, cardiovascular disease or bulimia nervosa.