Substituted diaryl compounds, their production methods and uses

Abstract

The present invention relates to the field of medicinal chemistry, specifically to a class of substituted diaryl compounds as shown in formula (I), their preparation method, and drug formulations containing the same and their medical uses. The results of pharmacological tests show that the substituted diaryl compounds of the present invention have good inhibitory effects on human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells. JPEG2024522403000097.jpg50161

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, specifically to a class of substituted diaryl compounds, methods for their preparation, and drug formulations containing same and their pharmaceutical uses. [Background technology]

[0002] 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol, CAS number 2125657-10-3, molecular formula C 28 H 42 N 2 O 5 , structural formula: [ka]

[0003] The currently disclosed literature documents only describe the physicochemical properties of the compound, and do not disclose its pharmacological action, nor does any literature report that it has an antitumor action. Summary of the Invention

[0004] The technical problem that the present invention seeks to solve is to provide a class of substituted diaryl compounds and their pharma- ceutically acceptable salts, optical isomers, methods for their preparation, pharmaceutical compositions and their use in the manufacture of medicaments for treating cancer.

[0005] In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0006] The first aspect of the technical solution of the present invention is to provide a compound represented by general formula (I) or a pharma- ceutically acceptable salt or an optical isomer thereof: [ka] However, R 1 -OC2 H 5 , -H, -CH(CH 3 ) 2 , -Br, -CF 3 , -OCH 3 , -F, -Cl, or -CH 3 and R 2 -F, -CF 3 , -Br, -NHCOCH 3 , -Cl, -H, -OCH 3 , or -CH(CH 3 ) 2 and R 3 -H, -CH 3 , -Cl, -Br, -NHCOCH 3 , -C 3 H 7 , -F, -C 14 H 29 , or -OCH 3 and R 4 -H, -Br, -CF 3 or -Cl, R 5 is -H, -Cl, -I, or -Br; R 6 teeth, [ka] It is.

[0007] Preferably, in the above compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, R 1 -H, -CH(CH 3 ) 2 , -Br, or -Cl; R 2 -F, -Br, -Cl, -H, -CH(CH 3 ) 2 , or -CF 3 and R 3 -H, -CH 3 , -Cl, -Br, or -C 14 H 29 and R 4 -H, -Br, -CF 3 or -Cl, R 5 is -H, -Cl, -I, or -Br; R 6 teeth, [ka] It is.

[0008] More preferably, in the above compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, R 1 -H,R 2 -CF 3 , R 3 -Br,R 4 -H,R 5 -H, R 6 teeth [ka] and Or, R 1 -H,R 2 -H,R 3 -C 14 H 29 , R 4 -H,R 5 -H, R 6 teeth [ka] and Or, R 1 -H,R 2 -H,R 3 -Cl, R 4 -Br,R 5 -H, R 6 teeth [ka] and Or, R 1 -Br,R 2 -H,R 3 -Br,R 4 -H,R 5 -Br, R 6 teeth [ka] It is.

[0009] More preferably, in the above compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, R 1 -H,R 2 -CF 3 , R 3 -Br,R 4 -H,R 5 -H, R 6 teeth [ka] and Or, R 1 -H,R 2 -H,R 3 -C 14 H 29 , R 4 -H,R 5 -H, R 6 teeth [ka] and Or, R 1 -Br,R 2 -H,R 3 -Br,R 4 -H,R 5 -Br, R 6 teeth [ka] It is.

[0010] More preferably, in the above compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, R 1 -H,R 2 -CF 3 , R 3 -Br,R 4 -H,R 5 -H, R 6 teeth [ka] and Or, R 1 -Br,R 2 -H,R 3 -Br,R 4 -H,R 5 -Br, R 6 teeth [ka] It is.

[0011] Pharmaceutically acceptable salts of any of the above compounds of the present invention are organic acid salts, inorganic acid salts, organic base salts or inorganic base salts, where organic acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, succinic acid, tartaric acid, citric acid, fumaric acid, inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, organic bases include meglumine, glucosamine, and inorganic bases include basic compounds of sodium, potassium, barium, calcium, magnesium, zinc, and lithium.

[0012] Any of the above compounds of the present invention is a racemate, and its optical isomer is its L-racemate or D-racemate.

[0013] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound described in the first aspect, and the compound of general formula (I) of the present invention can be prepared by the following method: [ka] However, R 1 -OC 2 H 5 , -H, -CH(CH 3 ) 2 , -Br, -CF 3 , -OCH 3 , -F, -Cl, or -CH 3 and R 2 -F, -CF 3 , -Br, -NHCOCH 3 , -Cl, -H, -OCH 3 , or -CH(CH 3 ) 2 and R 3 -H, -CH 3 , -Cl, -Br, -NHCOCH 3 , -C 3 H 7 , -F, -C 14 H 29 , or -OCH 3 and R 4 -H, -Br, -CF 3 or -Cl, R 5 is -H, -Cl, -I, or -Br; R 6 teeth, [ka] It is.

[0014] Synthesis of compounds of general formula (I): Dissolve substituted phenoxymethyloxirane (7) (1.0 mmol) and compound (5) (1.2 mmol) in isopropanol (15 mL), add a catalytic amount of pyridine under nitrogen gas protection, heat to reflux for 6 h, and detect the disappearance of raw materials by TLC. Dilute the reaction solution with ethyl acetate, wash the organic phase with water and saturated saline in sequence, dry with anhydrous sodium sulfate, filter, and remove the solvent by vacuum distillation, and separate and purify the crude product by silica gel column chromatography (mobile phase: dichloromethane-methanol = 20:1) to obtain the target compound (I), with a yield of 80% to 90%.

[0015] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition comprising a compound according to the first aspect, a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, and one or more pharmaceutical carriers and / or excipients, in any clinically or pharma- ceutical acceptable dosage form, preferably an oral formulation or an injectable.

[0016] A fourth aspect of the technical solution of the present invention provides a use of the compound according to the first aspect and the pharmaceutical composition according to the third aspect in the manufacture of a medicament for treating cancer, the cancer being lung cancer or ovarian cancer or melanoma or colon cancer.

[0017] The compound according to the present invention may be administered orally, by injection, etc. The clinical dose of the compound according to the present invention is 0.01 to 1000 mg / day, but may deviate from this range depending on the severity of the disease or the dosage form.

[0018] Beneficial technical effect: The present invention provides a series of compounds with novel structures and anti-cancer effects, which are effective against lung cancer or ovarian cancer or melanoma or colon cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In order to enable those skilled in the art to better understand the present invention, the present invention will be further described below based on specific embodiments, which are not intended to limit the present invention.

[0020] Synthesis of the target compound of the present invention: Dissolve substituted phenoxymethyloxirane (7) (1.0 mmol) and compound (5) (1.2 mmol) in isopropanol (15 mL), add a catalytic amount of pyridine under nitrogen gas protection, heat to reflux for 6 h, and detect the disappearance of the raw material by TLC. Dilute the reaction solution with ethyl acetate, wash the organic phase with water and saturated saline in turn, dry with anhydrous sodium sulfate, filter, and remove the solvent by distillation under reduced pressure, and separate and purify the crude product by silica gel column chromatography (mobile phase: dichloromethane-methanol = 20:1) to obtain the target compound. [ka]

[0021] Compound (5) is synthesized via a four-step reaction using vanillin (1) as a raw material. [ka]

[0022] The four compounds (5) obtained are shown in the table below.

[0023] [Table 1]

[0024] Substituted phenoxymethyloxiranes (7) were synthesized by nucleophilic substitution reaction of epoxybromopropane with phenols having different substituents on the benzene ring, and the resulting series of compounds are shown in the table below. [ka]

[0025] [Table 2] EXAMPLES

[0026] Example 1: Synthesis of 1-(2-ethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (SAMS10) [ka]

[0027] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0028] As compound 7, 2-((2-ethoxyphenoxy)methyl)oxirane (7-1) was used.

[0029] 2-((2-ethoxyphenoxy)methyl)oxirane (7-1) (194 mg, 1.0 mmol) and 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) (354 mg, 1.2 mmol) were dissolved in isopropanol (15 mL), and a catalytic amount of pyridine (8.0 μL, 0.1 mmol) was added under nitrogen gas protection, and the mixture was heated under reflux for 6 h. The disappearance of the raw material was detected by TLC (developing solvent: dichloromethane-methanol = 10:1). The reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated saline in sequence, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (mobile phase: dichloromethane-methanol = 20:1) to obtain a colorless oil (437.9 mg, 90%).

[0030] 1 H NMR (CDCl 3, 600 MHz) δ (ppm): 6.89 (m,7H), 4.09 (m, 7H), 3.84 (s, 3H), 3.59 (d, J = 19.80 Hz, 1H), 3.47 (d, J = 19.80 Hz, 1H), 3.05 (d, J = 17.40 Hz, 2H), 2.90 (t, J = 9.60 Hz, 2H), 2.61 (m, 2H), 2.28 (s, 3H), 2.19 (m, 2H), 1.66 (d, J = 21.0 Hz, 2H), 1.38 (m, 6H), 0.94 (d,J = 8.40 Hz, 3H). 13 C NMR (CDCl 3 , 150 MHz) δ (ppm): 149.49, 149.39, 148.72, 147.33, 131.62, 122.12, 121.27, 121.10, 115.80, 113.84, 113.16, 112.48, 72.91, 66.61 (2C), 64.51, 62.45, 59.60, 57.25, 55.94, 54.37 (2C), 42.43, 33.84 (2C), 30.39, 21.76, 14.93. IR (KBr, cm -1 ): 2924, 2871, 2851, 2794, 2360, 2340, 1592, 1512, 1494, 1460, 1419, 1368, 1321, 1272, 1217, 1138, 1035, 980, 863, 803, 772, 670. HRMS (ESI): m / z calcd for C 28 H 43 N 2 O 5 (M+H) + : 487.3172. found: 487.3199.

[0031] The preparation methods of compounds CHJ02029 to CHJ05004 in Examples 2 to 58 are the same as those in Example 1, except that different compounds 5 and 7 are used for synthesis. The raw materials of compounds 5 and 7 used in each specific Example are described in the corresponding Example.

[0032] Example 2: Synthesis of 1-(2,6-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ02029) [ka]

[0033] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0034] As compound 7, 2-((2,6-dichlorophenoxy)methyl)oxirane (7-2) was used.

[0035] Colorless oil, yield 88%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm):7.36 (d,J= 8.0 Hz, 2H), 7.08 (t,J= 8.0 Hz, 1H), 7.01 (s, 1H), 6.87 (m, 2H), 4.15 (m, 3H), 3.99 (m, 2H), 3.80 (s, 3H), 3.59 (m, 2H), 3.14 (d, J= 11.20 Hz, 2H), 2.92 (t, J= 5.60 Hz, 2H), 2.74 (m, 1H), 2.59 (dd, J= 12.80, 7.60Hz, 1H), 2.32 (m, 5H), 1.70 (d, J= 12.80 Hz, 2H), 1.45 (s, 1H), 1.30 (m, 2H), 0.95 (d, J= 6.4 Hz, 3H). 13 CNMR (CD 3OD,100 MHz)δ (ppm):151.27, 149.68, 147.30, 131.70, 129.04, 128.89 (3C), 125.31, 121.62, 113.84, 113.09, 75.76, 67.86, IR (KBr, cm -1 ): 2947, 2926, 2872, 2841, 2792, 2360, 2340, 1651, 1592, 1511, 1475, 1455, 1367, 1286, 1262, 1230, 1127, 1036, 979, 937, 863, 807, 670. HRMS (ESI): m / z calcd for C 26 H 37 Cl 2 N 2 O 4 (M+H) + : 511.2130. found: 511.2047.

[0036] Example 3: Synthesis of 1-(4-bromo-3-(trifluoromethyl)phenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ02049) [ka]

[0037] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0038] As compound 7, 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3) was used.

[0039] Colorless oil, yield 87%, 1 H NMR (CD3 OD, 400 MHz)δ (ppm):7.64 (d,J= 8.80 Hz, 1H), 7.26 (s, 1H), 7.02 (d,J= 8.80 Hz, 1H), 6.95 (s, 1H), 6.83 (q, J= 8.0 Hz, 2H), 4.08 (m, 4H), 3.91 (m, 1H), 3.75 (s, 3H), 3.50 (q,J= 12.80 Hz, 2H), 3.03 (d,J= 11.60 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.62 (dd, J= 12.40, 5.60 Hz, 1H), 2.48 (dd, J= 12.40, 6.40 Hz, 1H), 2.32 (s, 3H), 2.17 (t, J= 11.60 Hz, 2H), 1.66 (d, J= 12.40 Hz, 2H), 1.39 (s, 1H), 1.29 (m, 2H), 0.94 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3 OD,100 MHz)δ (ppm):158.33, 149.62, 147.45, 135.7 (2C), 131.91, 121.46 (2C), 118.91, 114.35, 114.29, 113.48, 113.06, 70.99, 67.29, 66.69, 62.29, 58.70, 57.12, 54.94, 54.00 (2C), 42.25, 33.48 (2C), 33.25, 20.75. IR (KBr, cm -1 ): 2926, 2872, 2849, 2793, 2370, 2323, 1684, 1651, 1556, 1512, 1474, 1455, 1419, 1367, 1330, 1313, 1260, 1235, 1139, 1035, 980, 936, 879, 809, 753. HRMS (ESI): m / z calcd for C 27 H 37 BrF 3 N 2 O 4 (M+H) +: 589.1889. found: 589.2404.

[0040] Example 4: Synthesis of 1-(2,5-bis(trifluoromethyl)phenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ02050) [ka]

[0041] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0042] As compound 7, 2-((2,5-bis(trifluoromethyl)phenoxy)methyl)oxirane (7-4) was used.

[0043] White solid, yield 85%, mp: 70-72℃, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.77 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.83 (q, J = 8.0 Hz, 2H), 4.13 (m, 5H), 3.76 (s, 3H), 3.51 (m, 2H), 3.03 (d, J = 11.20 Hz, 2H), 2.80 (t, J = 5.60 Hz, 2H), 2.63 (m, 2H), 2.30 (s, 3H), 2.17 (t, J = 11.60 Hz, 2H), 1.66 (d, J = 12.40 Hz, 2H), 1.40 (s, 1H), 1.29 (m, 2H), 0.94 (d, J = 6.40 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz) δ (ppm): 157.29, 149.66, 147.41, 131.89, 127.72, 127.67, 121.67, 121.40, 116.72, 116.68, 113.59, 112.97, IR (KBr, cm -1 ): 3562, 3354, 2945, 2877, 2831, 2800, 1624, 1595, 1517, 1463, 1435, 1330, 1259, 1232, 1174, 1132, 1087, 1043, 1022, 962, 910, 866, 833, 804, 750, 673.HRMS (ESI): m / z calcd for C 28 H 37 F 6 N 2 O 4 (M+H) + : 579.2658. found: 579.2549.

[0044] Example 5: Synthesis of 1-(3-bromophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03001) [ka]

[0045] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0046] As compound 7, 2-((3-bromophenoxy)methyl)oxirane (7-5) was used.

[0047] Colorless oil, yield 86%, 1H NMR (CDCl 3 , 400 MHz)δ (ppm): 7.10 (m,3H), 6.82 (m, 4H), 4.14 (m, 3H), 3.94 (d,J = 4.80 Hz, 2H), 3.85 (s, 3H), 3.62 (d, J= 13.60 Hz, 1H), 3.45 (d, J= 13.20 Hz, 1H), 2.98 (d, J= 11.20 Hz, 2H), 2.84 (t, J= 6.0 Hz, 2H), 2.62 (m, 1H), 2.49 (dd, J= 12.40, 3.60 Hz, 1H), 2.29 (s, 3H), 2.11 (t, J= 11.60 Hz, 2H), 1.64 (d, J = 12.40 Hz, 2H), 1.30 (m, 3H), 0.93 (d, J= 4.0 Hz, 3H). 13 CNMR (CDCl 3 , 100 MHz) δ (ppm): 159.54, 149.44, 147.60, 131.18, 130.53, 124.07, 122.76, 121.30, 117.86, 113.58, 112.97, 112.49, 70.63, 66.81, 66.04, 62.37, 59.25, 57.40, 55.97, 54.49 (2C), 42.26, 34.19 (2C), 30.57, 21.87. IR (KBr, cm -1 ): 2947, 2924, 2871, 2846, 2792, 2360, 2340, 1651, 1591, 1572, 1512, 1476, 1463, 1459, 1368, 1324, 1283, 1261, 1229, 1157, 1138, 1090, 1035, 991, 936, 861, 804, 800, 674. HRMS (ESI): m / z calcd for C 26 H 38 BrN 2 O 4 (M+H) + : 521.2015. found: 521.1945.

[0048] Example 6: Synthesis of 1-(2-bromophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03003) [ka]

[0049] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0050] As compound 7, 2-((2-bromophenoxy)methyl)oxirane (7-6) was used.

[0051] Colorless oil, yield 90%, 1 H NMR (CDCl 3 , 400 MHz)δ (ppm): 7.52 (d,J = 7.60 Hz,1H), 7.23 (d,J = 8.0 Hz,1H), 6.85 (m, 5H), 4.14 (t, J = 6.0 Hz, 3H), 4.03 (d,J= 4.40 Hz, 2H), 3.84 (s, 3H), 3.72 (q, J= 7.20 Hz, 1H), 3.63 (d, J= 12.80 Hz, 1H), 3.47 (d, J= 12.80 Hz, 1H), 2.98 (d, J= 11.20 Hz, 2H), 2.84 (t, J= 6.40 Hz, 2H), 2.72 (m, 1H), 2.59 (dd, J= 12.0, 3.60 Hz, 1H), 2.31 (s, 3H), 2.11 (t, J= 11.20 Hz, 2H), 1.64 (d, J= 12.40 Hz, 2H), 1.27 (m, 3H), 0.93 (d, J= 6.0 Hz, 3H). 13 CNMR (CDCl 3, 100 MHz)δ (ppm): 155.10, 149.41, 147.54, 133.30, 131.32, 128.46, 122.19, 121.33, 113.54, 112.94, 112.52, 112.41, 71.39, 66.74, 66.25, 62.47, 59.35, 58.43, 57.39, 55.96, 54.47, 42.43, 34.17, 30.57, 21.86, 18.45. -1 ): 2947, 2924, 2871, 2844, 2792, 2361, 2340, 1589, 1513, 1480, 1462, 1417, 1368, 1323, 1276, 1261, 1232, 1158, 1138, 1084, 1053, 1030, 979, 939, 872, 806, 749. HRMS (ESI): m / zcalcd for C 26 H 38 BrN 2 O 4 (M+H) + : 521.2015. found: 521.1943.

[0052] Example 7: Synthesis of 1-(2-isopropylphenoxy)-3-((3-methoxy-4-(2-(4-(methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03004) [ka]

[0053] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0054] As compound 7, 2-((2-isopropylphenoxy)methyl)oxirane (7-7) was used.

[0055] Colorless oil, yield 87%, 1H NMR (CDCl 3 , 400 MHz)δ (ppm): 7.2(d,J = 7.60 Hz,1H), 7.13 (t,J = 7.60 Hz,1H), 6.92 (t,J = 7.20 Hz,1H), 6.82 (m, 4H), 4.14(m, 3H), 3.99 (m, 2H), 3.84 (s, 3H), 3.65 (d, J= 13.20 Hz, 1H), 3.45 (d, J= 12.80 Hz, 1H), 3.26 (m, 1H), 2.98 (d, J= 11.20 Hz, 2H), 2.84 (t, J= 6.40 Hz, 2H), 2.69(m, 1H), 2.53 (dd, J= 12.0, 3.20 Hz, 1H), 2.31 (s, 3H), 2.11 (t, J= 11.2 Hz, 2H), 1.64 (d, J= 12.0 Hz, 2H), 1.30 (m, 3H), 1.19 (d, J= 6.80 Hz, 6H), 0.96 (d, J= 6.0 Hz, 3H). 13 CNMR (CDCl 3 , 100 MHz)δ (ppm): 155.82, 149.43, 147.56, 137.05, 131.31, 126.55, 126.07, 121.26, 120.89, 112.93, 112.45, 111.30, 70.34, 66.78, 66.35, 62.47, 59.67, 57.40, 55.94, 54.48 (2C), 42.36, 34.19 (2C), 30.57, 26.90, 22.64 (2C), 21.88.IR (KBr, cm -1 ): 2950, 2925, 2870, 2792, 2360, 2340, 1597, 1513, 1491, 1452, 1418, 1365, 1323, 1261, 1238, 1193, 1138, 1088, 1033, 1030, 980, 937, 878, 822, 805, 751. HRMS (ESI): m / z calcd for C 29 H 45 N 2 O 4 (M+H)+ : 485.3379. found: 485.3330.

[0056] Example 8: Synthesis of 1-(4-bromo-2-methoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03005) [ka]

[0057] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0058] As compound 7, 2-((4-bromo-2-methoxyphenoxy)methyl)oxirane (7-8) was used.

[0059] Colorless oil, yield 90%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.06 (s, 1H), 7.00 (d, J = 8.40 Hz,1H), 6.95(s,1H), 6.83 (m, 3H), 4.10 (m, 3H), 3.96 (dd, J = 9.60, 5.60 Hz, 1H), 3.85 (dd, J = 9.60, 5.60 Hz, 1H), 3.77 (d, J = 12.0 Hz, 6H), 3.53 (m, 2H), 3.06 (d, J = 11.60 Hz, 2H), 2.83 (t, J = 5.88 Hz, 2H), 2.63 (dd, J = 13.44, 5.60 Hz, 1H), 2.49 (dd, J = 13.44, 6.80 Hz, 1H), 2.31 (s, 3H), 2.20 (t, J = 11.60 Hz, 2H), 1.67 (d, J = 12.80 Hz, 2H), 1.40 (s, 1H), 1.28 (m, 2H), 0.94 (d, J = 6.40 Hz, 3H).13 C NMR (CD 3 OD, 100 MHz) δ (ppm): 150.42, 149.62, 147.91, 147.36, 131.88, 123.29, 121.47, 115.25, 114.88, 113.54, 113.05, 112.79, 71.91, 67.50, 66.61, 62.22, 58.89, 57.07, 55.34, 54.94, 53.96 (2C), 42.13, 33.39 (2C), 30.18, 20.71. IR (KBr, cm -1 ): 2946, 2924, 2843, 2792, 2360, 2340, 1589, 1556, 1539, 1506, 1459, 1418, 1398, 1364, 1324, 1255, 1225, 1183, 1136, 1084, 1029, 936, 857, 797, 670. HRMS (ESI): m / z calcd for C 27 H 40 BrN 2 O 5 (M+H) + : 551.2101. found: 551.2094.

[0060] Example 9: Synthesis of 1-((3-methoxy-4-(2-(4-(methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(2-methoxy-4-propylphenoxy)propan-2-ol (CHJ03011) [ka]

[0061] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0062] As compound 7, 2-((2-methoxy-4-propylphenoxy)methyl)oxirane (7-9) was used.

[0063] White solid, yield 83%, mp: 45~47℃, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 6.97 (s, 1H), 6.87 (d, J = 8.0 Hz,1H), 6.80 (m,3H), 6.69 (d, J = 8.0 Hz, 1H), 4.10 (m, 3H), 3.96 (dd, J = 9.60, 3.60 Hz, 1H), 3.84 (dd, J = 9.60, 6.40 Hz, 1H), 3.78 (d, J = 13.60 Hz, 6H), 3.54 (m, 2H), 3.05 (d, J = 11.60 Hz, 2H), 2.82 (t, J = 5.60 Hz, 2H), 2.61 (dd, J = 12.80, 5.20 Hz, 1H), 2.51 (q, J = 7.20 Hz, 3H), 2.30 (s, 3H), 2.19 (t, J = 11.60 Hz, 2H), 1.63 (m, 4H), 1.40 (s, 1H), 1.28 (m, 2H), 0.94 (d, J = 7.20 Hz, 6H). 13 C NMR (CD 3 OD, 100 MHz) δ (ppm): 149.66, 149.33, 147.40, 146.45, 136.10, 131.85, 121.50, 120.41, 113.95, 113.60, 113.07, 112.54, 72.26, 67.62, 66.67, 62.16, 59.08, 57.08, 55.14, 54.96, 53.97 (2C), 42.01, 37.26, 33.41 (2C), 30.19, 24.48, 20.71, 12.68. IR (KBr, cm -1 ): 2922, 2868, 2791, 2360, 2340, 1597, 1516, 1458, 1419, 1371, 1330, 1261, 1230, 1138, 1091, 1031, 970, 850, 804, 750, 646, 553, 489. HRMS (ESI): m / zcalcd for C 30 H47 N 2 O 5 (M+H) + : 515.3485. found: 515.3423.

[0064] Example 10: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(4-pentadecylphenoxy)propan-2-ol (CHJ03012) [ka]

[0065] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0066] As compound 7, 2-((4-pentadecylphenoxy)methyl)oxirane (7-10) was used.

[0067] White solid, yield 85%, mp: 40-42℃, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.13 (t, J = 7.60 Hz,1H), 6.97 (s, 1H), 6.84 (m, 2H), 6.72 (m, 3H), 4.11 (m, 3H), 3.98 (m, 1H), 3.86 (m, 1H), 3.76 (s, 3H), 3.55 (m, 2H), 3.05 (d, J = 11.60 Hz, 2H), 2.81 (t, J = 5.60 Hz, 2H), 2.59 (m, 4H), 2.30 (m, 3H), 2.18 (t, J = 11.60 Hz, 2H), 1.64 (m, 4H), 1.28 (s, 27H), 0.94 (d, J = 6.40 Hz, 3H), 0.89 (t, J = 6.0 Hz, 3H). 13 C NMR (CD 3OD, 100 MHz) δ (ppm): 159.02, 149.69, 147.42, 144.23, 131.93, 128.79, 121.47, 120.62, 114.35, 113.65, 113.08, 111.38, 70.34, 67.53, 66.71, 62.22, 59.19, 57.11, 54.98, 53.98 (2C), 53.38, 42.07, 35.56, 33.43 (2C), 31.67, 31.21, 30.21, 29.35 (6C), 29.20, 29.07, 28.91, 22.33, 20.72, 13.04.IR (KBr, cm -1 ): 2924, 2852, 2794, 2360, 2340, 1591, 1514, 1458, 1367, 1325, 1263, 1151, 1085, 1035, 937, 869, 806, 775, 694. HRMS (ESI): m / z calcd for C 41 H 69 N 2 O 4 (M+H) + : 653.5257. found: 653.5163.

[0068] Example 11: Synthesis of 1-(2,3-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03013) [ka]

[0069] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0070] As compound 7, 2-((2,3-dichlorophenoxy)methyl)oxirane (7-11) was used.

[0071] Colorless oil, yield 88%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.20 (t,J = 8.11 Hz,1H), 7.08 (t,J = 8.08 Hz,1H), 6.96 (m,2H), 6.82 (q, J = 8.05 Hz, 2H), 4.05 (m, 5H), 3.75 (s, 3H), 3.52 (s, 2H), 3.03 (d, J= 11.43 Hz, 2H), 2.80 (t, J= 5.65 Hz, 2H), 2.69 (dd, J= 12.82, 5.4 Hz, 1H), 2.56 (dd, J= 12.73, 7.02 Hz, 1H), 2.32 (s, 3H), 2.17 (t, J= 11.7 Hz, 2H), 1.65 (d, J= 12.71 Hz, 2H), 1.38 (s, 1H), 1.27 (m, 2H), 0.93 (d, J= 6.28 Hz, 3H). 13 CNMR (CD 3 OD, 100 MHz) δ (ppm): 155.92, 149.65, 147.41, 133.15, 131.90, 127.52, 121.91, 121.45, 121.32, 113.56, 113.03, 111.43, 71.63, 67.36, 66.65, 62.35, 58.90, 57.11, 54.97, 53.97 (2C), 42.20, 33.46 (2C), 30.22, 20.76. IR (KBr, cm -1 ): 2947, 2926, 2872, 2841, 2792, 2360, 2340, 1651, 1592, 1511, 1475, 1455, 1367, 1286, 1262, 1230, 1127, 1036, 979, 937, 863, 807, 670. HRMS (ESI): m / z calcd for C 26 H 37 Cl 2 N 2 O 4 (M+H) + : 511.2130. found: 511.2095.

[0072] Example 12: Synthesis of 1-(4-bromophenoxy)-3-((3-methoxy-4-(2-(4-(methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03014) [ka]

[0073] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0074] As compound 7, 2-((4-bromophenoxy)methyl)oxirane (7-12) was used.

[0075] Colorless oil, yield 81%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.35 (d,J= 8.0 Hz, 2H), 6.95 (s, 1H), 6.82 (m, 4H), 4.10 (t, J= 5.60 Hz, 2H), 4.05 (m, 1H), 3.95 (dd,J= 9.60, 3.20 Hz, 1H), 3.84 (dd,J= 9.60, 6.0 Hz, 1H), 3.77 (s, 3H), 3.50 (q, J= 12.80 Hz, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.61 (dd, J= 12.83, 6.0 Hz,1H), 2.48 (dd, J= 12.80, 7.20 Hz, 1H), 2.30 (s, 3H), 2.17 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.80 Hz, 2H), 1.40 (s, 1H), 1.28 (m, 2H), 0.93 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz) δ (ppm): 158.28, 149.64, 147.44, 131.89 (2C), 131.89, 121.49, 116.19 (2C), 113.56, 113.10, 112.35, 70.66, IR (KBr, cm -1 ): 2947, 2925, 2871, 2844, 2792, 2360, 2331, 1591, 1556, 1512, 1489, 1458, 1418, 1368, 1322, 1285, 1245, 1157, 1074, 1034, 980, 937, 879, 863, 821, 756, 647. HRMS (ESI): m / z calcd for C 26 H 38 BrN 2 O 4 (M+H) + : 521.2015. found: 521.1975.

[0076] Example 13: Synthesis of 1-(3-isopropylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03015) [ka]

[0077] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0078] As compound 7, 2-((3-isopropylphenoxy)methyl)oxirane (7-13) was used.

[0079] Colorless oil, yield 89%, 1 H NMR (CD3 OD, 400 MHz) δ (ppm): 7.15 (t,J= 7.60 Hz, 1H), 6.97 (s, 1H), 6.82 (m, 4H), 6.69 (d,J= 8.0 Hz, 1H), 4.10 (m, 3H), 3.97 (m, 1H), 3.86 (m, 1H), 3.76 (s, 3H), 3.54 (m, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.82 (m, 3H), 2.63 (dd, J= 12.80, 5.60 Hz, 1H), 2.51 (dd, J= 12.40, 6.8 Hz, 1H), 2.30 (s, 3H), 2.17 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.40 Hz, 2H), 1.40 (s, 1H), 1.24 (m, 8H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR(CD 3 OD,100 MHz) δ (ppm): 159.09, 150.37, 149.68, 147.44, 131.90, 128.90, 121.47, 118.55, 113.62, 113.09, 112.54, 111.36, 70.39, 67.54, 66.74, 62.21, 59.25, 57.12, 54.99 (3C), 42.05, 34.05, 33.46 (2C), 30.23, 23.03 (2C), 20.75. IR (KBr, cm -1 ): 2952, 2925, 2871, 2844, 2792, 2360, 2340, 1606, 1588, 1513, 1486, 1460, 1418, 1366, 1320, 1262, 1233, 1286, 1138, 1088, 1037, 1003, 980, 940, 870, 804, 789, 754, 700. HRMS (ESI): m / zcalcd for C 29 H 45 N 2 O 4 (M+H) + : 485.3379. found: 485.3296.

[0080] Example 14: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(3-methoxyphenoxy)propan-2-ol (CHJ03017) [ka]

[0081] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0082] As compound 7, 2-((3-methoxyphenoxy)methyl)oxirane (7-14) was used.

[0083] Colorless oil, yield 83%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.13 (t,J= 8.0 Hz, 1H), 6.96 (s, 1H), 6.83 (m, 2H), 6.48 (m, 3H), 4.09 (m, 3H), 3.96 (dd, J= 9.60, 6.80 Hz, 1H), 3.85 (dd, J= 9.20, 6.0 Hz, 1H), 3.75 (d,J= 7.60 Hz, 6H), 3.52 (m, 2H), 3.03 (d, J= 11.60 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.61(dd, J= 12.80, 5.60 Hz, 1H), 2.49 (dd, J= 12.80, 7.20 Hz, 2H), 2.30 (s, 3H), 2.16 (t, J= 11.60 Hz, 2H), 1.65 (dd, J= 12.40 Hz, 2H), 1.40 (s, 1H), 1.27 (m, 2H), 0.93 (d, J= 6.40 Hz, 3H). 13 CNMR(CD 3OD,100 MHz) δ (ppm): 160.97, 160.23, 149.65, 147.42, 131.90, 129.48, 121.46, 113.58, 113.05, 106.35, 106.02, 100.65, 70.42, 67.48, 66.69, 62.23, 59.13, 57.12, 54.98, 54.28, 53.99 (2C), 42.10, 33.46 (2C), 30.23, 20.76.IR (KBr, cm -1 ): 2947, 2925, 2872, 2837, 2792, 2360, 2340, 1593, 1559, 1513, 1492, 1455, 1418, 1368, 1334, 1287, 1264, 1231, 1201, 1154, 1083, 1036, 980, 940, 834, 807, 762, 687. HRMS (ESI): m / z calcd for C 27 H 41 N 2 O 5 (M+H) + : 473.3015. found: 473.2947.

[0084] Example 15: Synthesis of 1-(5-bromo-2-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03018) [ka]

[0085] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0086] As compound 7, 2-((5-bromo-2-fluorophenoxy)methyl)oxirane (7-15) was used.

[0087] Colorless oil, yield 85%,1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.23 (d,J= 7.20 Hz, 1H), 7.02 (m, 3H), 6.85 (dd,J= 22.0, 8.0 Hz, 2H), 4.09 (m, 4H), 3.94 (dd,J= 10.0, 5.60 Hz, 1H), 3.78 (s, 3H), 3.50 (m, 2H), 3.05 (d, J= 11.60 Hz, 2H), 2.81 (t , J= 5.60 Hz, 2H), 2.63 (dd,J= 12.80, 5.60 Hz, 1H), 2.50 (dd, J= 12.85, 6.51 Hz, 1H), 2.31 (s, 3H), 2.18 (t, J= 12.0 Hz, 2H), 1.66 (d, J= 13.20 Hz, 2H), 1.41 (s, 1H) ,1.28 (m, 2H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR(CD 3 OD,100 MHz) δ (ppm): 150.62, 149.66, 147.40, 131.94, 123.66, 123.59, 121.44, 118.06, 117.16, 116.96, 115.94, 113.59, 112.97, 72.04, 67.36, 66.68, 62.24, 58.85, 57.10, 54.98, 53.98 (2C), 42.10, 33.44 (2C), 30.22, 20.72. IR (KBr, cm -1 ): 2947, 2925, 2872, 2845, 2794, 2360, 2340, 1607, 1511, 1459, 1417, 1404, 1369, 1323, 1303, 1262, 1231, 1138, 1117, 1090, 1020, 962, 935, 877, 837, 803, 755, 627. HRMS (ESI): m / zcalcd for C 26 H 37 BrFN 2 O 4 (M+H) +: 539.1921. found: 539.1911.

[0088] Example 16: Synthesis of 1-(3,4-dimethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03019) [ka]

[0089] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0090] As compound 7, 2-((3,4-dimethoxyphenoxy)methyl)oxirane (7-16) was used.

[0091] Colorless oil, yield 87%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 6.97 (s, 1H), 6.84 (m, 3H), 6.54 (s, 1H), 6.40 (d,J= 8.55 Hz, 1H), 4.08 (m, 3H), 3.93 (dd,J= 9.57, 3.33 Hz, 1H), 3.83 (m, 1H), 3.77 (d, J= 8.88 Hz, 9H), 3.52 (q, J= 12.85 Hz, 2H), 3.05 (d, J= 11.47 Hz, 2H), 2.82 (t, J= 5.55 Hz, 2H), 2.62 (dd,J= 12.84, 5.5 Hz, 1H), 2.49 (dd, J= 12.77, 7.05 Hz, 1H), 2.31 (s, 3H), 2.19 (t, J= 11.69 Hz, 2H), 1.66 (d, J= 12.59 Hz, 2H), 1.40 (s, 1H), 1.27 (m, 2H), 0.94 (d, J= 6.29 Hz, 3H). 13 CNMR(CD 3OD,100 MHz) δ (ppm): 153.95, 150.09, 149.63, 147.39, 143.54, 131.88, 121.48, 113.57, 113.07, 112.86, 104.22, 100.91, 70.91, 67.53, 66.61, 62.22, 59.10, 57.08, 55.91, 54.97 (2C), 53.97 (2C), 42.12, 33.39 (2C), 30.18, 20.72. IR (KBr, cm -1 ): 2926, 2871, 2850, 2794, 2360, 2340, 1700, 1651, 1611, 1596, 1513, 1418, 1368, 1320, 1261, 1229, 1199, 1162, 1138, 1029, 981, 943, 875, 804, 764. HRMS (ESI): m / zcalcd for C 28 H 43 N 2 O 6 (M+H) + : 503.3121. found: 503.2817.

[0092] Example 17: Synthesis of 1-(3-bromo-4-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03043) [ka]

[0093] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0094] As compound 7, 2-((3-bromo-4-chlorophenoxy)methyl)oxirane (7-17) was used.

[0095] Colorless oil, yield 89%, 1H NMR (CDCl 3 , 400 MHz)δ (ppm): 7.30 (m, 1H), 7.17 (s, 1H), 6.81 (m, 4H), 4.11 (m, 3H), 3.91 (m, 2H), 3.84 (s, 3H), 3.61 (d,J= 12.0 Hz, 1H), 3.45 (d, J= 12.80 Hz, 1H), 2.98 (d, J= 11.20 Hz, 2H), 2.84 (t,J= 6.40 Hz, 2H), 2.61 (m, 1H), 2.47 (dd, J= 12.40, 3.60 Hz, 1H), 2.29 (s, 3H), 2.11 (t, J= 11.20 Hz, 2H), 1.63 (d, J= 12.40 Hz, 2H), 1.29 (m, 3H), 0.93 (d, J= 6.0 Hz, 3H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 157.74, 149.48, 147.66, 131.13, 130.47, 126.18, 122.53, 121.31, 119.57, 115.31, 113.07, 112.55, 71.00, 66.93, 65.99, 62.37, 59.10, 57.39, 55.99, 54.50 (2C), 42.29, 34.21 (2C), 30.56, 21.87.IR (KBr, cm -1 ): 2923, 2846, 2360, 2340, 1700, 1651, 1613, 1590, 1559, 1539, 1511, 1470, 1460, 1418, 1373, 1337, 1288, 1262, 1229, 1157, 1138, 1083, 1035, 931, 859, 805, 669. HRMS (ESI): m / z calcd for C 26 H 37 BrClN 2 O 4 (M+H) + : 555.1625. found: 555.1610.

[0096] Example 18: Synthesis of 1-(3-bromo-4-methylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04010) [ka]

[0097] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0098] As compound 7, 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18) was used.

[0099] Colorless oil, yield 82%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.15 (d,J= 8.40 Hz, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.82 (m, 3H), 4.11 (t,J= 5.60 Hz, 2H), 4.04 (m, 1H), 3.95 (m, 1H), 3.83 (m, 1H), 3.77 (s, 3H), 3.51 (q,J= 12.80 Hz, 2H), 3.03 (d, J= 11.60 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.60 (dd,J= 12.40, 5.60Hz, 1H), 2.48 (dd,J= 13.20, 6.80Hz, 1H), 2.30 (d, J= 2.40 Hz, 6H), 2.17 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.40 Hz, 2H), 1.40 (s, 1H), 1.27 (m, 2H), 0.94 (d, J= 6.40 Hz, 3H). 13 CNMR(CD 3OD,100 MHz)δ (ppm): 157.77, 149.67, 147.44, 131.94, 130.79, 129.42, 124.18, 121.46, 117.97, 113.65, 113.61, 113.06, 70.79, 67.42, 66.75, 62.25, 59.98, 57.13, 55.00, 53.99 (2C), 42.14, 33.47 (2C), 30.24, 20.74, 20.50.IR (KBr, cm -1 ): 2946, 2923, 2871, 2792, 2360, 2340, 1651, 1604, 1579, 1539, 1511, 1492, 1458, 1418, 1368, 1323, 1289, 1262, 1236, 1158, 1138, 1086, 1030, 1003, 932, 866, 838, 806, 757, 671. HRMS (ESI): m / zcalcd for C 27 H 40 BrN 2 O 4 (M+H) + : 535.2171. found: 535.2149.

[0100] Example 19: Synthesis of 1-(2-bromo-5-(trifluoromethyl)phenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04011) [ka]

[0101] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0102] As compound 7, 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19) was used.

[0103] Colorless oil, yield 85%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.71 (d,J= 8.0 Hz, 1H), 7.27 (s, 1H), 7.16 (d,J= 8.40 Hz, 1H), 6.95 (s, 1H), 6.82 (q, J= 8.0 Hz, 3H), 4.09 (m, 5H), 3.74 (s, 3H), 3.53 (s, 2H), 3.04 (d,J= 11.20 Hz, 2H), 2.81 (t,J= 5.60 Hz, 2H), 2.72 (dd, J= 12.40, 4.80 Hz, 1H), 2.58 (dd, J= 12.80, 6.40 Hz, 1H), 2.33 (s, 3H), 2.18 (t,J= 12.0 Hz, 2H), 1.66 (d, J= 12.80 Hz, 2H), 1.40 (s, 1H), 1.29 (m, 2H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR(CD 3 OD,100 MHz)δ (ppm): 155.81, 149.65, 147.39, 133.69, 131.95, 121.42, 118.16, 118.12, 116.09, 113.57, 112.96, 109.59, 109.55, 71.58, 67.30, 66.67, 62.39, 58.82, 57.10, 54.91, 53.97 (2C), 42.13, 33.45 (2C), 30.22, 20.73. IR (KBr, cm -1 ): 3560, 3354, 2927, 2868, 2818, 1591, 1516, 1462, 1421, 1371, 1332, 1255, 1226, 1165, 1130, 1080, 1041, 1020, 935, 904, 862, 802, 752. HRMS (ESI): m / z calcd for C 27 H 37 F 3 N 2 O 4 (M+H) +: 589.1889. found: 589.1827.

[0104] Example 20: Synthesis of 1-(3,5-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04012) [ka]

[0105] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0106] As compound 7, 2-((3,5-dichlorophenoxy)methyl)oxirane (7-20) was used.

[0107] Colorless oil, yield 88%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 6.96 (d,J= 9.60 Hz, 2H), 6.84 (m, 4H), 4.10 (t, J= 5.60 Hz, 2H), 4.02 (m, 2H), 3.87 (m, 1H), 3.78 (s, 3H), 3.48 (m, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.80 (t, J= 6.40 Hz, 2H), 2.60 (dd, J= 12.80, 6.0 Hz, 1H), 2.46 (dd,J=12.80, 6.40 Hz,1H), 2.31 (s, 3H), 2.17 (t, J= 12.0 Hz, 2H), 1.65 (d, J= 12.75 Hz, 2H), 1.40 (s, 1H), 1.27 (m, 2H), 0.94 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz)δ (ppm): 160.34, 149.66, 147.46, 135.12, 131.94, 121.46, 120.38, 113.52, 113.42 (3C), 113.04, 70.04, 67.26, IR (KBr, cm -1 ): 2948, 2925, 2872, 2843, 2793, 2360, 2340, 1590, 1571, 1513, 1442, 1424, 1368, 1323, 1303, 1262, 1192, 1157, 1138, 1039, 980, 938, 853, 831, 800, 756, 670. HRMS (ESI): m / z calcd for C 26 H 37 Cl 2 N 2 O 4 (M+H) + : 511.2130. found: 511.2075.

[0108] Example 21: Synthesis of 1-(3-bromo-4-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04020) [ka]

[0109] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0110] As compound 7, 2-((3-bromo-4-fluorophenoxy)methyl)oxirane (7-21) was used.

[0111] Colorless oil, yield 90%, 1H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.10 (m, 2H), 6.95 (s, 1H), 6.84 (m, 3H), 4.10 (m, 3H), 3.96 (m, 1H), 3.84 (m, 1H), 3.77 (s, 3H), 3.50 (q, J= 12.0 Hz, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.80 (t, J= 5.20 Hz, 2H), 2.60 (dd,J= 12.80, 6.0 Hz, 1H), 2.47 (dd, J= 11.20, 6.80 Hz, 1H), 2.31 (s, 3H), 2.17 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.40 Hz, 2H), 1.41(s, 1H), 1.28 (m, 2H), 0.93 (d, J= 6.0 Hz, 3H). 13 C NMR(CD 3 OD,100 MHz)δ (ppm): 155.71, 149.65, 147.44, 131.92, 121.47, 118.73, 116.32, 116.08, 114.95, 114.88, 113.55, 113.07, 71.29, 67.38, 66.71, 62.27, 58.86, 57.12, 55.01, 54.00 (2C), 42.21, 33.47 (2C), 30.23, 20.76. IR (KBr, cm -1 ): 2947, 2925, 2872, 2843, 2793, 2360, 2340, 1591, 1513, 1493, 1458, 1418, 1368, 1322, 1262, 1220, 1203, 1157, 1138, 1088, 1035, 979, 938, 862, 840, 806, 774. HRMS (ESI): m / z calcd for C 26 H 37 BrFN 2 O 4 (M+H) + : 539.1921. found: 539.1888.

[0112] Example 22: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(2,4,6-tribromophenoxy)propan-2-ol (CHJ04022) [ka]

[0113] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0114] As compound 7, 2-((2,4,6-tribromophenoxy)methyl)oxirane (7-22) was used.

[0115] Colorless oil, yield 90%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.75 (s, 2H), 6.98 (s, 1H), 6.85 (m, 2H), 4.10 (t, J= 5.69 Hz, 2H), 4.22 (m, 1H), 4.12 (t,J= 5.61 Hz, 2H), 3.79 (s, 3H), 3.54 (q, J= 12.80 Hz, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.72 (dd, J= 13.20, 5.20 Hz, 1H), 2.54 (dd, J= 12.80, 7.20 Hz, 1H), 2.32 (s, 3H), 2.16 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.40 Hz, 2H), 1.39 (s, 1H), 1.30 (m, 2H), 0.93 (d, J= 6.40 Hz, 3H). 13 CNMR(CD 3OD,100 MHz)δ (ppm): 152.75, 149.67, 147.45, 134.96 (3C), 131.75, 121.55, 118.54, 117.13, 113.66, 113.14, 75.83, 67.96, IR (KBr, cm -1 ): 2923, 2846, 2360, 2340, 1700, 1651, 1613, 1590, 1559, 1539, 1511, 1470, 1460, 1418, 1373, 1337, 1288, 1262, 1229, 1157, 1138, 1083, 1035, 931, 859, 805. HRMS (ESI): m / z calcd for C 26 H 36 Br 3 N 2 O 4 (M+H) + : 677.0225. found: 677.0256.

[0116] Example 23: Synthesis of 1-(3-bromo-5-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04023) [ka]

[0117] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0118] As compound 7, 2-((3-bromo-5-fluorophenoxy)methyl)oxirane (7-23) was used.

[0119] Colorless oil, yield 85%, 1H NMR (CD 3 OD, 400 MHz)δ (ppm): 6.95 (s, 1H), 6.85 (m, 4H), 6.65 (d, J= 10.80 Hz, 1H), 4.11 (t, J= 5.60 Hz, 2H), 4.02 (m, 2H), 3.87 (m, 1H), 3.78 (s, 3H), 3.50 (q, J= 12.80 Hz, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.81 (t, J= 5.60 Hz, 2H), 2.60 (dd,J= 12.40, 5.60 Hz, 1H), 2.46 (dd, J= 12.80, 6.40 Hz, 1H), 2.31 (s, 3H), 2.17 (t, J= 12.0 Hz, 2H), 1.65 (d, J= 12.80 Hz, 2H), 1.40 (s, 1H), 1.29 (m, 2H), 0.93 (d, J= 6.0 Hz, 3H). 13 CNMR(CD 3 OD,100 MHz)δ (ppm): 164.64, 162.18, 161.02, 149.65, 147.45, 131.93, 122.34, 121.46, 113.83, 113.29, 110.85, 101.17, 71.09, 67.25, 66.68, 62.28, 58.72, 57.12, 55.00, 53.99 (2C), 42.23, 33.46 (2C), 30.23, 20.76. IR (KBr, cm -1 ): 2947, 2925, 2872, 2841, 2792, 2360, 2340, 1605, 1583, 1512, 1454, 1418, 1367, 1318, 1280, 1263, 1231, 1280, 1263, 1231, 1146, 1084, 1039, 980, 941, 833. HRMS (ESI): m / z calcd for C 26 H 37 BrFN 2 O 4 (M+H) + : 539.1921. found:539.1879.

[0120] Example 24: Synthesis of 1-(3-chlorophenoxy)-3-((3-methoxy-4-(2-(4(methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04024) [ka]

[0121] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0122] As compound 7, 2-((3-chlorophenoxy)methyl)oxirane (7-24) was used.

[0123] Colorless oil, yield 83%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.21 (t,J= 8.40 Hz, 1H), 6.88 (m, 6H), 4.09 (m, 3H), 3.98 (m, 1H), 3.86 (m, 1H), 3.77 (s, 3H), 3.51 (q, J= 12.80 Hz, 1H), 3.03 (d, J= 11.20 Hz, 1H), 2.80 (t, J= 5.60 Hz, 2H), 2.61 (dd, J= 12.80, 6.80 Hz, 2H), 2.49 (dd, J= 12.80, 6.80 Hz, 2H), 2.30(s, 3H), 2.16 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.80 Hz, 2H), 1.39 (s, 1H), 1.28 (m, 2H), 0.93 (d, J= 6.0 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz)δ (ppm): 159.91, 149.66, 147.45, 134.44, 131.93, 130.12, 121.47, 120.46, 114.57, 113.58, 113.06, 112.81, 70.71, 67.38, 66.72, 62.26, 58.98, 57.13, 55.00, 53.99 (2C), 42.16, 33.48 (2C), 30.24, 20.76. IR (KBr, cm -1 ): 2947, 2925, 2872, 2843, 2792, 2360, 2340, 1651, 1595, 1580, 1539, 1511, 1470, 1459, 1419, 1367, 1326, 1283, 1260, 1231, 1192, 1157, 1138, 1091, 1036, 979, 935, 870, 807, 770, 681. HRMS (ESI): m / z calcd for C 26 H 38 ClN 2 O 4 (M+H) + : 477.2520. found: 477.2476.

[0124] Example 25: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(3-(trifluoromethyl)phenoxy)propan-2-ol (CHJ04025) [ka]

[0125] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0126] As compound 7, 2-((3-(trifluoromethyl)phenoxy)methyl)oxirane (7-25) was used.

[0127] Colorless oil, yield 83%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.44 (t,J= 8.0 Hz, 1H), 7.17 (m, 3H), 6.97 (s, 1H), 6.85 (m, 2H), 4.09 (m, 4H), 3.93 (m, 1H), 3.76 (s, 3H), 3.53 (m, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.63 (dd, J= 12.40, 5.20 Hz, 1H), 2.51 (dd, J= 12.80, 6.80 Hz, 1H), 2.31 (s, 3H), 2.17 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.80 Hz, 2H), 1.40 (s, 1H), 1.28 (m, 2H), 0.93 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3 OD, 100 MHz) δ (ppm): 159.32, 149.66, 147.45, 131.92, 131.39, 131.55, 130.01, 121.46, 117.96, 116.91, 113.57, 113.06, 110.96, 70.71, 67.38, 66.72, 62.26, 58.98, 57.13, 55.00, 53.99 (2C), 42.16, 33.48 (2C), 30.24, 20.76. IR (KBr, cm -1 ): 2947, 2926, 2873, 2845, 2794, 2360, 2340, 1651, 1593, 1557, 1539, 1513, 1493, 1453, 1419, 1367, 1330, 1289, 1262, 1234, 1165, 1096, 1065, 1037, 979, 934, 880, 794, 753, 698. HRMS (ESI): m / z calcd for C 27 H 38 F 3 N 2 O 4 (M+H) +: 511.2784. found: 511.2765.

[0128] Example 26: Synthesis of 1-(3,4-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04026) [ka]

[0129] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0130] As compound 7, 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26) was used.

[0131] Colorless oil, yield 81%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.36 (d,J= 9.20 Hz, 1H), 7.05 (s, 1H), 6.95 (s, 1H), 6.84 (m, 3H), 4.10 (t, J= 5.60 Hz, 2H), 4.04 (m, 1H), 3.97 (m, 1H), 3.86 (m, 1H), 3.77 (s, 3H), 3.50 (q,J= 12.80 Hz, 1H), 3.03 (d, J= 11.60 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.61 (dd, J= 12.80, 6.0 Hz, 1H), 2.47 (dd, J = 12.80, 6.80 Hz,1H), 2.31 (s, 3H), 2.16 (t, J = 11.60 Hz, 2H), 1.65 (d, J= 12.80 Hz, 2H), 1.40 (s, 1H), 1.27 (m, 2H), 0.94 (d, J= 6.40 Hz, 3H). 13 C NMR (CD 3OD, 100 MHz)δ (ppm): 158.36, 149.64, 147.45, 132.25, 131.93, 130.48, 123.33, 121.47, 116.16, 114.57,113.52, 113.07, 70.99,67.33,66.70,62.29,58.76,57.13,54.98,54.00 (2C),42.26,33.48 (2C), 30.24, 20.76. -1 ): 2947, 2926, 2872, 2841, 2792, 2360, 2340, 1651, 1592, 1570, 1539, 1511, 1475, 1455, 1419, 1367, 1286, 1262, 1230, 1191, 1156, 1127, 1092, 1036, 979, 937, 861, 807, 757, 670. HRMS (ESI): m / z calcd for C 26 H 37 Cl 2 N 2 O 4 (M+H) + : 511.2130. found: 511.2115.

[0132] Example 27: Synthesis of 1-(2-iodophenoxy)-3-((3-methoxy-4-(2-(4-(methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04027) [ka]

[0133] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0134] As compound 7, 2-((2-iodophenoxy)methyl)oxirane (7-27) was used.

[0135] Colorless oil, yield 90%,1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.72 (d,J= 7.60 Hz, 1H), 7.30 (t,J= 8.0 Hz, 1H), 6.96 (s, 1H), 6.90 (d,J= 8.40 Hz, 1H), 6.83 (q,J= 8.0 Hz, 2H), 6.70 (t,J= 7.60 Hz, 1H), 4.09 (m, 3H), 3.98 (m, 2H), 3.74 (s, 3H), 3.55 (q, J= 12.80 Hz, 2H), 3.03 (d, J= 11.20 Hz, 2H), 2.80 (t, J= 5.60 Hz, 2H), 2.74 (d, J= 5.20 Hz, 1H), 2.64 (dd, J= 12.80, 7.60 Hz, 1H), 2.32 (s, 3H), 2.17 (t, J= 11.60 Hz, 2H), 1.65 (d, J= 12.80 Hz, 2H), 1.40(s, 1H), 1.29 (m, 2H), 0.94 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3 OD, 100 MHz) δ (ppm): 157.53, 149.66, 147.40, 139.11, 131.94, 129.30, 122.32, 121.47, 113.60, 113.07, 112.12, 85.66, 71.22, 67.40, 62.42, 59.28, 57.11, 55.00, 53.97 (3C), 42.07, 33.47 (2C), 30.23, 20.75. IR (KBr, cm -1 ): 2946, 2923, 2871, 2844, 2792, 2360, 2340, 1584, 1513, 1471, 1441, 1418, 1368, 1323, 1261, 1231, 1192, 1158, 1138, 1084, 1050, 1030, 1019, 979, 962, 938, 873, 822, 806, 749. HRMS (ESI): m / z calcd for C 26 H 38 IN 2 O4 (M+H) + : 569.1876. found: 569.1842.

[0136] Example 28: Synthesis of 1-(4-bromo-2,6-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04033) [ka]

[0137] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0138] As compound 7, 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28) was used.

[0139] Colorless oil, yield 84%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.56 (s, 2H), 6.97 (s, 1H), 6.85 (m, 2H), 4.16 (m, 1H), 4.12 (t,J= 5.60 Hz, 2H), 3.99 (m, 2H), 3.79 (s, 3H), 3.52 (m, 2H), 3.04 (d, J= 11.20 Hz, 2H), 2.81 (t, J= 5.60 Hz, 2H), 2.67 (dd, J= 13.20, 4.80 Hz, 1H), 2.55 (dd, J= 13.20, 7.60 Hz, 1H), 2.30 (s, 3H), 2.17 (t, J= 12.0 Hz, 2H), 1.65 (d, J= 12.40 Hz, 2H), 1.40 (s, 1H), 1.29 (m, 2H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz)δ (ppm): 150.93, 149.67, 147.43, 131.79, 131.46 (3C), 129.99, 121.50, 116.13, 113.67, 113.08, 76.07, 67.97, IR (KBr, cm -1 ): 2947, 2924, 2872, 2840, 2794, 2360, 2340, 1544, 1511, 1459, 1419, 1375, 1320, 1259, 1231, 1193, 1158, 1138, 1084, 1031, 994, 933, 856, 803. HRMS (ESI): m / z calcd for C 26 H 36 BrCl 2 N 2 O 4 (M+H) + : 589.1236. found: 589.1220.

[0140] Example 29: Synthesis of 1-(3-bromo-5-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04034) [ka]

[0141] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0142] As compound 7, 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29) was used.

[0143] Colorless oil, yield 85%, 1 H NMR (CD3 OD, 400 MHz)δ (ppm): 7.12 (s, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 6.91 (s, 1H), 6.83 (m, 2H), 4.10 (t,J= 5.60 Hz, 2H), 4.02 (m, 2H), 3.87 (m, 1H), 3.78(s, 3H), 3.48 (m, 2H), 3.04 (d, J= 11.60 Hz, 2H), 2.81 (t, J= 5.60 Hz, 2H), 2.60 (dd,J= 12.40, 6.0 Hz, 1H), 2.46 (dd,J= 12.40, 6.0 Hz, 1H), 2.31 (s, 3H), 2.18 (t, J= 12.0 Hz, 2H), 1.66 (d, J= 12.80 Hz, 2H), 1.40 (s, 1H), 1.27 (m, 2H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR(CD 3 OD,100 MHz)δ (ppm): 160.39, 149.66, 147.44, 135.27, 131.85, 123.18, 122.49, 121.46, 116.33, 113.87, 113.54, 113.04, 71.04, 67.26, 66.67, 62.29, 58.67, 57.11, 55.01, 53.99 (2C), 42.26, 33.45 (2C), 30.22, 20.74. IR (KBr, cm -1 ): 2947, 2926, 2870, 2840, 2793, 2360, 2331, 1588, 1563, 1539, 1512, 1459, 1437, 1420, 1367, 1335, 1319, 1301, 1230, 1259, 1190, 1156, 1138, 1091, 1038, 978, 930, 912, 864, 831, 770, 670. HRMS (ESI): m / z calcd for C 26 H 37 BrClN 2 O 4 (M+H) +: 555.1625. found: 555.1600.

[0144] Example 30: Synthesis of 1-(2-bromo-5-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04036) [ka]

[0145] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0146] As compound 7, 2-((2-bromo-5-fluorophenoxy)methyl)oxirane (7-30) was used.

[0147] Colorless oil, yield 82%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.48 (m, 1H), 6.95 (s, 1H), 6.82 (m, 3H), 6.63 (t,J= 8.40 Hz, 1H), 4.11 (t,J= 5.6 Hz, 3H), 4.01 (m, 2H), 3.76 (s, 3H), 3.53 (s, 2H), 3.04 (d, J= 11.20 Hz, 2H), 2.81 (t, J= 5.60 Hz, 2H), 2.71 (dd, J= 12.80, 5.20 Hz, 1H), 2.58 (dd, J= 12.80, 7.20 Hz, 1H), 2.32 (s, 3H), 2.18 (t, J= 11.60 Hz, 2H), 1.66 (d, J= 12.80 Hz, 2H), 1.41 (s, 1H), 1.29 (m, 2H), 0.94 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz)δ (ppm): 164.01, 161.58, 156.35, 149.65, 147.40, 133.34, 131.93, 121.47, 113.59, 107.89, 106.05, 101.44, 71.52, 67.28, 66.65, 62.36, 58.95, 57.09, 54.96, 53.96 (2C), 42.01, 33.43 (2C), 30.21, 20.73. IR (KBr, cm -1 ): 3529, 3277, 3088, 2929, 2852, 2796, 2769, 2428, 1681, 1604, 1514, 1477, 1452, 1417, 1371, 1286, 1259, 1224, 1151, 1101, 1037, 960, 871, 833, 790, 748, 609, 451. HRMS (ESI): m / z calcd for C 26 H 37 BrFN 2 O 4 (M+H) + : 539.1921. found: 539.1914.

[0148] Example 31: Synthesis of N-(3-(2-hydroxy-3-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propoxy)phenyl)acetamide (CHJ04058) [ka]

[0149] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0150] As compound 7, N-(3-(oxiran-2-ylmethoxy)phenyl)acetamide (7-31) was used.

[0151] White solid, yield 90%, mp: 60-62℃,1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.27 (s, 1H), 7.17 (t,J= 8.0 Hz, 1H), 7.05 (m, 2H), 6.86 (m, 2H), 6.63 (d, J= 8.0 Hz, 1H), 4.11 (m, 3H), 3.97 (m, 1H), 3.87 (m, 1H), 3.78 (s, 3H), 3.55 (s, 2H), 3.13 (d, J= 11.20 Hz, 2H), 2.91 (t, J= 5.20 Hz, 1H), 2.65 (dd, J= 12.40, 6.80 Hz, 1H), 2.53 (dd,J=12.40, 6.80 Hz,1H), 2.32 (m, 5H), 2.11 (s, 3H), 1.70 (d, J= 13.20 Hz, 2H), 1.46 (s, 1H), 1.32 (m, 3H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR (CD 3 OD, 100 MHz)δ (ppm): 170.23, 159.35, 149.61, 147.25, 139.66, 131.87, 129.11, 121.58, 113.73, 113.06, 112.11, 109.83, 106.29, 70.42, 67.37, 66.13, 62.12, 59.09, 56.86, 55.00, 53.79 (2C), 42.01, 33.02 (2C), 29.92, 22.53, 20.59. IR (KBr, cm -1 ): 2924, 2852, 2360, 2340, 1699, 1670, 1651, 1616, 1556, 1540, 1510, 1491, 1458, 1419, 1373, 1286, 1265, 1230, 1198, 1156, 1083, 1034, 980, 871, 768, 686, 669. HRMS (ESI): m / z calcd for C 28 H 42 N 3 O 5 (M+H) +: 500.3124. found: 500.3071.

[0152] Example 32: Synthesis of 1-(2,4-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04059) [ka]

[0153] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0154] As compound 7, 2-((2,4-dichlorophenoxy)methyl)oxirane (7-32) was used.

[0155] Colorless oil, yield 81%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.37 (s, 1H), 7.23 (d, J= 8.40 Hz, 1H), 7.00 (d, J= 8.80 Hz, 1H), 6.94 (s, 1H), 6.82 (q,J= 8.0 Hz, 2H), 4.11 (t, J= 5.60 Hz, 3H), 4.00 (m, 2H), 3.75 (s, 3H), 3.52 (s, 2H), 3.06 (d, J= 11.60 Hz, 2H), 2.82 (t, J= 5.60 Hz, 2H), 2.69 (dd, J= 12.80, 5.60 Hz, 1H), 2.54 (dd, J= 12.80, 6.80 Hz, 1H), 2.32 (s, 3H), 2.19 (t, J= 12.0Hz, 2H), 1.67 (d, J= 12.80 Hz, 2H), 1.41 (s,1H), 1.29 (m, 2H), 0.94 (d, J= 6.40Hz, 3H). 13 CNMR(CD 3OD, 100 MHz)δ (ppm): 153.47, 149.61, 147.37, 131.88, 129.29, 127.46, 125.32, 123.37, 121.45, 114.33, 113.50, 112.98, 71.53, 67.36, 66.58, 62.33, 58.86, 57.07, 54.92, 53.96 (2C), 42.19, 33.41 (2C), 30.20, 20.73. IR (KBr, cm -1 ): 2947, 2924, 2872, 2845, 2360, 2339, 1590, 1513, 1484, 1458, 1419, 1389, 1368, 1323, 1290, 1263, 1232, 1156, 1060, 1028, 1007, 938, 867, 846, 804, 745, 653. HRMS (ESI): m / z calcd for C 26 H 37 Cl 2 N 2 O 4 (M+H) + : 511.2130. found: 511.2120.

[0156] Example 33: Synthesis of 1-(5-bromo-2-methylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04060) [ka]

[0157] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0158] As compound 7, 2-((5-bromo-2-methylphenoxy)methyl)oxirane (7-33) was used.

[0159] Colorless oil, yield 82%,1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 6.97 (m, 4H), 6.82 (q, J= 8.0 Hz, 2H), 4.10 (t, J= 5.20 Hz, 3H), 3.97 (dd,J= 9.60, 2.80 Hz, 1H), 3.89 (dd,J=9.20, 5.2Hz,1H), 3.74 (s, 3H), 3.51 (q,J= 12.8 Hz, 2H), 3.04 (d, J= 11.20 Hz, 2H), 2.81 (t, J= 5.20 Hz, 2H), 2.66 (dd, J= 12.80, 6.0 Hz, 1H), 2.49 (dd, J= 12.80, 6.0 Hz, 1H), 2.33 (s, 3H), 2.18 (t, J= 11.60 Hz, 2H), 2.05 (s, 3H), 1.66 (d, J= 12.80 Hz, 2H), 1.41 (s, 1H), 1.27(m, 2H), 0.94 (d, J= 6.0 Hz, 3H). 13 CNMR(CD 3 OD, 100 MHz)δ (ppm): 157.70, 149.65, 147.37, 131.99, 131.30, 125.78, 122.88, 121.36, 119.06, 113.96, 113.48, 112.83, 70.39, 67.47, 66.64, 62.41, 58.80, 57.10, 54.91, 53.98 (2C), 42.28, 33.45 (2C), 30.23, 20.72, 14.59. IR (KBr, cm -1 ): 2947, 2923, 2871, 2844, 2360, 2340, 1592, 1555, 1513, 1491, 1458, 1417, 1398, 1373, 1260, 1239, 1191, 1129, 1084, 1034, 984, 939, 870, 836, 800, 756. HRMS (ESI): m / z calcd for C 27 H 40 BrN 2 O 4 (M+H) +: 535.2171. found: 535.2170.

[0160] Example 34: Synthesis of N-(4-(2-hydroxy-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propoxy)phenyl)acetamide (CHJ04061) [ka]

[0161] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0162] As compound 7, N-(4-(oxiran-2-ylmethoxy)phenyl)acetamide (7-34) was used.

[0163] White solid, yield 90%, mp: 60-62℃, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.41 (d, J= 8.0 Hz, 2H), 6.98 (s, 1H), 6.86 (m, 4H), 4.14 (m, 3H), 3.96 (m, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 3.54 (d, J= 5.60 Hz, 2H), 3.14 (d, J= 11.20 Hz, 2H), 2.92 (t, J= 5.20 Hz, 1H), 2.64 (dd, J= 12.80, 7.20 Hz, 1H), 2.52 (dd,J=12.80, 7.20 Hz, 1H), 2.32 (m, 5H), 2.09 (s, 3H), 1.70 (d, J= 13.20 Hz, 2H), 1.46 (s, 1H), 1.32 (m, 3H), 0.95 (d, J= 6.40 Hz, 3H). 13 CNMR (CD 3OD, 100 MHz)δ (ppm): 170.23, 159.35, 149.61, 147.25, 139.66, 131.87, 129.11, 121.58, 113.73, 113.06, 112.11, 109.83, IR (KBr, cm) -1 ): 2922, 2848, 2362, 2340, 2044, 1681, 1602, 1548, 1512, 1460, 1417, 1369, 1325, 1259, 1240, 1136, 1031, 931, 819, 750, 686, 669. HRMS (ESI): m / z calcd for C 28 H 42 N 3 O 5 (M+H) + : 500.3124. found: 500.3074.

[0164] Example 35: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(2-(trifluoromethyl)phenoxy)propan-2-ol (CHJ04082) [ka]

[0165] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0166] As compound 7, 2-((2-(trifluoromethyl)phenoxy)methyl)oxirane (7-35) was used.

[0167] Colorless oil, yield 83%, 1 H NMR (CDCl3 , 400 MHz) δ (ppm): 7.55 (d, J= 7.60 Hz, 1H), 7.47 (t,J=8.0 Hz,1H), 7.00 (t,J= 8.40 Hz, 2H), 6.81 (m, 3H), 4.10 (m, 5H), 3.84 (s, 3H), 3.62 (d, J= 12.80 Hz, 1H), 3.47 (d, J= 12.80 Hz, 1H), 3.00 (d, J= 10.80 Hz, 2H), 2.86 (t,J= 6.0 Hz, 2H), 2.68 (m, 1H), 2.59 (m, 1H), 2.30 (s, 3H), 2.15 (t,J= 10.80 Hz, 2H), 1.64 (d,J= 12.0 Hz, 2H), 1.31 (m, 3H), 0.93 (d,J= 5.60 Hz, 3H). 13 C NMR(CDCl 3 ,100 MHz) δ (ppm): 156.61, 149.49, 147.54, 133.28, 131.37, 127.08, 121.34 (2C), 120.33 (2C), 113.18, 112.96, 112.61, 70.86, 66.82, 66.17, 62.45, 59.40, 57.34, 55.95, 54.43 (2C) , 42.43, 34.08 (2C), 30.50, 21.81. IR (KBr, cm -1 ): 2939, 2873, 2841, 2794, 2362, 1602, 1510, 1460, 1363, 1323, 1269, 1132, 1033, 974, 948, 879, 808, 758, 650. HRMS (ESI): m / z calcd for C 27 H 38 F 3 N 2 O 4 (M+H) + : 511.2784. found: 511.2741.

[0168] Example 36: Synthesis of 1-(4-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04083) [ka]

[0169] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0170] As compound 7, 2-((4-chlorophenoxy)methyl)oxirane (7-36) was used.

[0171] Colorless oil, yield 90%, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.22 (d,J= 15.2 Hz, 2H), 6.81 (m, 5H), 4.16 (t,J= 6.0 Hz, 2H), 4.09 (m, 1H), 3.92 (d,J= 4.40 Hz, 2H), 3.84 (s, 3H), 3.62 (d, J= 13.20 Hz, 1H), 3.45 (d, J= 13.20 Hz, 1H), 2.99 (d, J= 10.8 Hz, 2H), 2.85 (t,J= 6.0 Hz, 2H), 2.63 (t,J= 11.60 Hz, 1H), 2.50 (m, 1H), 2.29 (s, 3H), 2.14 (t,J= 10.80 Hz, 2H), 1.64 (d,J= 12.40 Hz, 2H), 1.32 (m, 3H), 0.93 (d,J= 5.60 Hz, 3H). 13 CNMR(CDCl 3,100 MHz) δ (ppm): 157.41, 149.51, 147.62, 131.25, 129.30 (2C), 125.84, 121.32, 115.88 (2C), 113.16, 112.59, 70.74, 66.91, 66.11, 62.37, 59.29, 57.36, 55.99, 54.47 (2C), 42.28, 34.12 (2C), 30.52, 21.83. -1 ): 2947, 2925, 2872, 2843, 2792, 2360, 2325, 1651, 1595, 1539, 1511, 1492, 1458, 1418, 1367, 1322, 1283, 1246, 1157, 1138, 1092, 1035, 1008, 824, 672. HRMS (ESI): m / z calcd for C 26 H 38 ClN 2 O 4 (M+H) + : 477.2520. found: 477.2471.

[0172] Example 37: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(4-methoxyphenoxy)propan-2-ol (CHJ04084) [ka]

[0173] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0174] As compound 7, 2-((4-methoxyphenoxy)methyl)oxirane (7-37) was used.

[0175] Colorless oil, yield 90%, 1 HNMR (CDCl 3, 400 MHz) δ (ppm): 6.82 (m, 7H), 4.17 (t,J= 6.0 Hz, 2H), 4.09 (m, 1H), 3.91 (d,J= 4.40 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.62 (d, J= 12.80 Hz, 1H), 3.46 (d, J= 12.80 Hz, 1H), 3.01 (d,J= 12.40 Hz, 2H), 2.86 (t,J= 6.0 Hz, 2H), 2.63 (t,J=11.20 Hz,1H), 2.51 (m, 1H), 2.28 (s, 3H), 2.16 (t,J= 11.20 Hz, 2H), 1.65 (d,J= 12.0 Hz, 2H), 1.31 (m, 3H), 0.93 (d,J= 5.48 Hz, 3H). 13 C NMR(CDCl 3 ,100 MHz) δ (ppm): 154.01, 152.97, 149.49, 147.52, 131.40, 121.31, 115.55 (2C), 114.64 (2C), 113.17, 112.57, 71.16, 66.78, 66.29, 62.37, 59.53, 57.34, 55.98, 55.73, 54.43 (2C), 42.25, 34.04 (2C), 30.48, 21.80. IR (KBr, cm -1 ): 2947, 2925, 2871, 2834, 2792, 2360, 2325, 1595, 1510, 1459, 1418, 1368, 1322, 1262, 1231, 1156, 1138, 1036, 980, 937, 878, 824, 748. HRMS (ESI): m / z calcd for C 27 H 41 N 2 O 5 (M+H) + : 473.3015. found: 473.2975.

[0176] Example 38: Synthesis of 1-(2-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04085) [ka]

[0177] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0178] As compound 7, 2-((2-chlorophenoxy)methyl)oxirane (7-38) was used.

[0179] Colorless oil, yield 83%, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.34 (d,J= 8.0 Hz, 1H), 7.19 (t,J= 7.60 Hz, 1H), 6.86 (m, 5H), 4.15 (t,J= 6.0 Hz, 3H), 4.03 (d,J= 4.40 Hz, 2H), 3.84 (s, 3H), 3.63 (d, J= 13.2 Hz, 1H), 3.47 (d, J= 13.2 Hz, 1H), 3.00 (d, J= 13.14 Hz, 2H), 2.85 (t,J= 6.40 Hz, 2H), 2.70 (m, 1H), 2.58 (m, 1H), 2.30 (s, 3H), 2.13 (t,J= 11.22 Hz, 2H), 1.64 (d,J= 12.06 Hz, 2H), 1.30 (m, 3H), 0.93 (d,J= 5.80 Hz, 3H). 13 CNMR(CDCl 3,100 MHz) δ (ppm): 154.31, 149.41, 147.52, 131.30, 130.25, 127.69, 123.15, 121.72, 121.34, 113.80, 112.97, 112.53, 71.46, 66.64, 66.24, 62.42, 59.34, 57.36, 55.95, 54.41 (2C), 42.40, 34.08 (2C), 30.58, 21.83. IR (KBr, cm -1 ): 2925, 2872, 2845, 2792, 2360, 2325, 1591, 1512, 1486, 1455, 1418, 1368, 1322, 1276, 1258, 1232, 1158, 1137, 1084, 1061, 980, 937, 877, 807, 749, 693. HRMS (ESI): m / z calcd for C 26 H 38 ClN 2 O 4 (M+H) + : 477.2520. found: 477.2506.

[0180] Example 39: Synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(2-methoxyphenoxy)propan-2-ol (CHJ04086) [ka]

[0181] As compound 5, 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-1) was used.

[0182] As compound 7, 2-((2-methoxyphenoxy)methyl)oxirane (7-39) was used.

[0183] Colorless oil, yield 85%, 1 H NMR (CDCl 3, 400 MHz) δ (ppm): 6.86 (m, 7H),4.16 (t,J= 6.0 Hz, 3H), 4.02 (m, 2H), 3.84 (s, 6H), 3.60 (d,J= 13.20 Hz, 1H), 3.47 (d, J= 13.20 Hz, 1H), 3.03 (d, J= 11.20 Hz, 2H), 2.87 (t,J= 6.0 Hz, 2H), 2.63 (m,1H), 2.54 (m, 1H), 2.28 (s, 3H), 2.16 (t,J= 10.8 Hz, 2H), 1.65 (d,J= 12.0 Hz, 2H), 1.33 (m, 3H), 0.94 (d,J= 5.60 Hz, 3H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 149.80, 149.37, 148.39, 147.38, 131.50, 121.78, 121.30, 120.93, 114.58, 112.97, 112.50, 112.04, 72.39, 66.46, 66.41, 62.38, 59.50, 57.31, 55.88 (2C), 54.33 (2C), 42.35, 33.89 (2C), 30.45, 21.77. IR (KBr, cm -1 ): 2925, 2872, 2838, 2792, 2360, 2340, 1593, 1556, 1510, 1458, 1418, 1368, 1328, 1250, 1226, 1258, 1157, 1125, 1090, 1030, 980, 939, 876, 807, 744. HRMS (ESI): m / z calcd for C 27 H 41 N 2 O 5 (M+H) + : 473.3015. found: 473.2972.

[0184] Example 40: Synthesis of 1-(3-bromo-4-methylphenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04064) [ka]

[0185] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0186] As compound 7, 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18) was used.

[0187] Colorless oil, yield 80%, 1 H NMR (CD 3 OD, 400 MHz)δ (ppm): 7.15 (d, J= 8.40 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.83 (m, 3H), 4.13 (t, J= 5.20 Hz, 2H), 4.05 (m, 1H), 3.96 (m, 1H), 3.82 (m, 4H), 3.54 (m, 2H), 3.04 (t, J= 5.20 Hz, 2H), 2.83 (s, 4H), 2.61 (dd, J= 12.40, 5.6 Hz, 1H), 2.49 (dd, J=12.80, 6.80 Hz,1H), 2.30 (d, J= 6.80 Hz, 6H), 1.87 (s, 4H). 13 CNMR (CD 3OD, 100 MHz)δ (ppm): 157.76, 149.69, 147.25, 132.08, 130.80, 129.43, 124.18, 121.47, 117.94, 113.75, 113.64, 112.98, 70.76, 67.36, 67.27, 62.21, 58.95, 54.94, 54.50, 54.23 (2C), 42.08, 22.77 (2C), 20.50. IR (KBr, cm -1 ): 2924, 2873, 2850, 2793, 2360, 2339, 1604, 1513, 1492, 1459, 1418, 1369, 1325, 1263, 1235, 1139, 1031, 976, 928, 863, 805, 750, 669. HRMS (ESI): m / z calcd for C 25 H 36 BrN 2 O 4 (M+H) + : 507.1858. found: 507.1858.

[0188] Example 41: Synthesis of 1-(2-bromo-5)-(trifluoromethyl)phenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04065) [ka]

[0189] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0190] As compound 7, 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19) was used.

[0191] Colorless oil, yield 82%, 1 H NMR (CD 3OD, 400 MHz)δ (ppm): 7.71 (d, J= 8.0 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.97 (s, 1H), 6.84 (m, 2H), 4.10 (m, 5H), 3.75 (s, 3H), 3.55 (s, 2H), 3.07 (t, J= 5.20 Hz, 2H), 2.87 (s, 4H), 2.73 (dd, J= 12.80, 4.80 Hz, 1H), 2.60 (dd,J=12.40, 6.40 Hz,1H), 2.34 (s, 3H), 1.89 (s, 4H). 13 CNMR (CD 3 OD, 100 MHz)δ (ppm): 155.80, 149.68, 147.16, 133.70, 132.16, 130.42, 121.44, 118.14, 116.09, 113.78, 112.88, 109.57, 71.55, 67.09, 62.34, 58.80, 54.86, 54.45, 54.22 (2C), 42.08, 23.39, 22.76 (2C), 12.54. IR (KBr, cm -1 ): 2968, 2938, 2879, 2793, 2361, 2323, 1734, 1700, 1518, 1492, 1459, 1419, 1398, 1328, 1268, 1252, 1167, 1137, 1080, 1035, 977, 935, 906, 861, 748, 670. HRMS (ESI): m / z calcd for C 25 H 33 BrF 3 N 2 O 4 (M+H) + : 561.1576. found: 561.1569.

[0192] Example 42: Synthesis of 1-(3,5-dichlorophenoxy)-3-((3-methoxy-4-(2(pyrrolidine-1-ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04066) [ka]

[0193] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0194] As compound 7, 2-((3,5-dichlorophenoxy)methyl)oxirane (7-20) was used.

[0195] Colorless oil, yield 84%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 6.98 (d, J= 3.60 Hz, 2H), 6.87 (m, 3H), 6.82 (d, J= 8.40 Hz, 1H), 4.13 (t, J= 4.80 Hz, 2H), 4.03 (m, 2H), 3.88 (m, 1H), 3.79 (s, 3H), 3.52 (q, J= 12.80 Hz, 2H), 3.06 (t, J= 5.20 Hz, 2H), 2.85 (s, 4H), 2.62 (dd, J= 12.40, 6.0 Hz, 1H), 2.47 (dd,J=12.40, 6.40Hz,1H), 2.32 (s, 3H), 1.88 (s, 4H). 13 CNMR (CD 3 OD, 100 MHz) δ (ppm): 160.34, 149.67, 147.23, 135.12, 132.16, 121.46, 120.37, 113.68, 113.40 (3C), 112.94, 71.00, 67.21, 67.17, 62.25, 58.63, 54.92, 54.48, 54.24 (2C), 42.20, 22.76 (2C). -1): 2933, 2877, 2843, 2787, 2361, 2340, 1591, 1514, 1454, 1421, 1330, 1290, 1261, 1230, 1165, 1130, 1089, 1028, 964, 908, 875, 808, 752, 692, 661, 617. HRMS (ESI): m / z calcd for C 24 H 33 Cl 2 N 2 O 4 (M+H) + : 483.1817. found: 483.1801.

[0196] Example 43: Synthesis of 1-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(2,4,6-tribromophenoxy)propan-2-ol (CHJ04068) [ka]

[0197] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0198] As compound 7, 2-((2,4,6-tribromophenoxy)methyl)oxirane (7-22) was used.

[0199] White solid, yield 84%, mp: 60-70℃, 1 H NMR (CD 3OD, 400 MHz) δ (ppm): 7.76 (s, 2H), 6.99 (s, 1H), 6.86 (m, 2H), 4.23 (m, 1H), 4.11 (t, J= 5.20 Hz, 2H), 3.97 (s, 2H), 3.79 (s, 3H), 3.54 (q, J= 12.80 Hz, 2H), 2.94 (t, J= 5.60 Hz, 2H), 2.72 (s, 5H), 2.55 (dd, J= 12.80, 7.60 Hz, 1H), 2.32 (s, 3H), 1.83 (s, 4H). 13 CNMR (CD 3 OD, 100 MHz) δ (ppm): 152.74, 149.66, 147.42, 134.96 (2C), 134.96, 131.75, 121.53, 118.54, 117.14, 113.56, 113.07, 75.82, 67.94, 67.68, 62.12, 59.35, 55.01, 54.58, 54.23 (2C), 42.05, 22.83 (2C).IR (KBr, cm -1 ): 3103, 2924, 2873, 2808, 1695, 1597, 1514, 1435, 1371, 1334, 1253, 1138, 1031, 989, 852, 798, 734, 684, 570. HRMS (ESI): m / z calcd for C 24 H 32 Br 3 N 2 O 4 (M+H) + : 648.9912. found: 648.9938.

[0200] Example 44: Synthesis of 1-(3,4-dichlorophenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04072) [ka]

[0201] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0202] As compound 7, 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26) was used.

[0203] Colorless oil, yield 85%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.37 (d, J= 8.80 Hz, 1H), 7.06 (s, 1H), 6.96 (s, 1H), 6.85 (m, 3H), 4.11 (t, J= 5.20 Hz, 2H), 4.04 (m, 1H), 3.98 (m, 1H), 3.86 (m, 1H), 3.77 (s, 3H), 3.51 (q, J= 12.80 Hz, 2H), 2.97 (t, J= 5.20 Hz, 2H), 2.76 (s, 4H), 2.61 (dd, J= 12.80, 6.0 Hz, 1H), 2.47 (dd, J= 12.80, 6.80 Hz, 1H), 2.32 (s, 3H), 1.85 (s, 4H). 13 CNMR(CD 3 OD,100 MHz) δ (ppm): 158.36, 149.64, 147.37, 132.25, 131.99, 130.48, 123.32, 121.45, 116.13, 114.57, 113.50, 112.99, 70.96, 67.30, 62.27, 58.73, 54.92, 54.56, 54.24 (2C), 53.40, 42.22, 22.81 (2C).IR (KBr, cm -1): 2926, 2875, 2851, 2802, 2361, 2340, 1736, 1651, 1593, 1563, 1512, 1475, 1462, 1418, 1368, 1328, 1284, 1262, 1230, 1127, 1035, 976, 932, 902, 860, 805, 752, 671. HRMS (ESI): m / z calcd for C 24 H 33 Cl 2 N 2 O 4 (M+H) + : 483.1817. found: 483.1790.

[0204] Example 45: Synthesis of 1-(4-bromo-2,6-dichlorophenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04074) [ka]

[0205] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0206] As compound 7, 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28) was used.

[0207] Colorless oil, yield 85%, 1 H NMR (CD 3OD, 400 MHz) δ (ppm): 7.59 (s, 2H), 7.00 (s, 1H), 6.91 (d, J= 8.04 Hz, 1H), 6.85 (d, J= 8.09 Hz, 1H), 4.16 (m, 3H), 4.00 (m, 2H), 3.81 (s, 3H), 3.56 (d, J= 6.47 Hz, 2H), 3.09 (t, J= 5.24 Hz, 2H), 2.89 (s, 4H), 2.69 (dd, J= 5.54, 4.71 Hz, 1H), 2.57 (dd, J= 12.76, 7.5 Hz, 1H), 2.32 (s, 3H), 1.90 (s, 4H). 13 CNMR(CD 3 OD,100 MHz) δ (ppm): 150.90, 149.71, 147.19, 131.98, 131.46 (3C), 129.99, 121.53, 116.16, 113.92, 113.01, 76.00, 67.88, 67.09, 62.06, 59.18, 54.95, 54.44, 54.23 (2C), 41.93, 22.75 (2C). -1 ): 2953, 2920, 2866, 2765, 1726, 1651, 1593, 1516, 1458, 1419, 1373, 1327, 1261, 1230, 1136, 1085, 1028, 964, 875, 842, 800, 752, 557. HRMS (ESI): m / z calcd for C 24 H 32 BrCl 2 N 2 O 4 (M+H) + :561.0923. found: 561.0882.

[0208] Example 46: Synthesis of 1-(3-bromo-5-chlorophenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04075) [ka]

[0209] As compound 5, 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethylamine (5-2) was used.

[0210] As compound 7, 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29) was used.

[0211] Colorless oil, yield 87%, 1 H NMR (CD 3 OD, 400 MHz) δ (ppm): 7.13 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.90 (m, 2H), 6.82 (d, J= 8.08 Hz, 1H), 4.15 (t, J= 5.54 Hz, 2H), 4.03 (m, 2H), 3.88 (m, 1H), 3.80 (s, 3H), 3.52 (q, J= 12.86 Hz, 2H), 3.12 (t, J= 5.24 Hz, 2H), 2.92 (s, 4H), 2.62 (dd, J= 12.72, 6.12 Hz, 1H), 2.48 (dd, J= 12.71, 6.44 Hz, 1H), 2.33 (s, 3H), 1.91 (s, 4H). 13 CNMR(CD 3 OD,100 MHz) δ (ppm): 160.38, 149.69, 147.13, 135.27, 132.25, 123.18, 122.49, 121.48, 116.32, 113.84 (2C), 112.93, 70.99, 67.18, 62.23, 58.61, 54.94, 54.42, 54.25 (2C), 42.19, 22.74 (2C), 12.54.IR (KBr, cm -1): 2974, 2934, 2379, 2309, 1716, 1651, 1593, 1557, 1539, 1510, 1475, 1419, 1393, 1339, 1231, 1124, 1038, 854, 670, 520. HRMS (ESI): m / z calcd for C 24 H 33 BrClN 2 O 4 (M+H) + :527.1312. found: 527.1275.

[0212] Example 47: Synthesis of 1-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl)(methyl)amino)-3-(2-isopropylphenoxy)propan-2-ol (CHJ04089) [ka]

[0213] As compound 5, N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3) was used.

[0214] As compound 7, 2-((2-isopropylphenoxy)methyl)oxirane (7-7) was used.

[0215] Colorless oil, yield 82%, 1 H NMR (CDCl 3, 400 MHz) δ (ppm): 7.20 (d,J= 7.60 Hz, 1H), 7.13 (t,J= 8.0 Hz, 1H), 6.93 (t,J=7.20 Hz,1H), 6.82 (m, 4H), 4.11 (m, 3H), 3.98 (m, 2H), 3.84 (s, 3H), 3.65 (d, J= 12.80 Hz, 1H), 3.46 (d, J= 12.80 Hz, 1H), 3.26 (m, 1H), 2.94 (t,J= 6.80 Hz, 2 H), 2.66 (m, 5H), 2.54 (m, 1H), 2.31 (s, 3H), 1.20 (d,J= 7.20 Hz, 6H), 1.08 (t,J= 7.20 Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 155.82, 149.38, 147.59, 137.05, 131.20, 126.55, 126.07, 121.26, 120.89, 112.69, 112.41, 111.30, 70.35, 67.24, 66.34, 62.47, 59.66, 55.94, 51.66, 47.85 (2C), 42.36, 26.89, 22.63 (2C), 11.78 (2C). IR (KBr, cm -1 ): 3035, 2965, 2933, 2871, 2360, 1598, 1513, 1491, 1451, 1417, 1368, 1286, 1261, 1239, 1197, 1139, 1088, 1034, 983, 938, 881, 823, 751. HRMS (ESI): m / z calcd for C 27 H 43 N 2 O 4 (M+H) + : 459.3223. found: 459.3166.

[0216] Example 48: Synthesis of 1-(2-bromo-5-(trifluoromethyl)phenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-(methoxybenzyl)(methyl)amino)propan-2-ol (CHJ04090) [ka]

[0217] As compound 5, N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3) was used.

[0218] As compound 7, 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19) was used.

[0219] Colorless oil, yield 81%, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.63 (d, J= 8.40 Hz, 1H), 7.10 (m, 2H), 6.81 (m, 3H), 4.11 (m, 5H), 3.84 (s, 3H), 3.65 (d,J= 12.80 Hz, 1H), 3.47 (d, J= 13.20 Hz, 1H), 2.94 (t, J= 6.80 Hz, 2H), 2.67 (m, 5H), 2.55 (m,1H), 2.32 (s, 3H), 1.08 (t,J= 7.20 Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 155.44, 149.39, 147.63, 133.70 (2C), 131.09, 121.31 (2C), 118.73, 116.43, 112.73, 112.45, 109.89, 71.63, 67.28, 66.10, 62.48, 58.95, 55.94, 51.65, 47.85 (2C), 42.42, 11.77 (2C).IR (KBr, cm -1): 2969, 2936, 2876, 2837, 2360, 2340, 1651, 1597, 1539, 1512, 1488, 1461, 1420, 1329, 1296, 1263, 1231, 1169, 1128, 1081, 1036, 979, 934, 857, 814, 751, 656, 565. HRMS (ESI): m / z calcd for C 25 H 35 BrF 3 N 2 O 4 (M+H) + : 563.1732. found: 563.1676.

[0220] Example 49: Synthesis of 1-(3,4-dichlorophenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-(methoxybenzyl)(methyl)amino)propan-2-ol (CHJ04091) [ka]

[0221] As compound 5, N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3) was used.

[0222] As compound 7, 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26) was used.

[0223] Colorless oil, yield 85%, 1 H NMR (CDCl 3, 400 MHz) δ (ppm): 7.31 (d, J= 8.8 Hz, 1H), 7.00 (s, 1H), 6.80 (m, 4H), 4.09 (m, 3H), 3.91 (m, 2H), 3.85 (s, 3H), 3.62 (d, J= 12.80 Hz, 1H), 3.45 (d, J= 12.80 Hz, 1H), 2.95 (t, J= 6.40 Hz, 2H), 2.67 (m, 5H), 2.47 (m,1H), 2.29 (s, 3H), 1.08 (t,J= 7.20 Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 157.83, 149.37, 147.63, 132.81, 131.03, 130.65, 124.20, 121.31, 116.45, 114.63, 112.73, 112.46, 70.97, 67.20, 65.97, 62.37, 59.08, 55.96, 51.65, 47.80 (2C), 42.28, 11.70 (2C). IR (KBr, cm -1 ): 2970, 2936, 2874, 2832, 2360, 2326, 1700, 1651, 1593, 1559, 1539, 1511, 1475, 1459, 1418, 1337, 1285, 1263, 1230, 1158, 1126, 1090, 1126, 1035, 930, 865, 806, 671. HRMS (ESI): m / z calcd for C 24 H 35 Cl 2 N 2 O 4 (M+H) + : 485.1974. found: 485.1904.

[0224] Example 50: Synthesis of 1-(3-bromo-4-fluorophenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl(methyl)amino)propan-2-ol (CHJ04092) [ka]

[0225] As compound 5, N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3) was used.

[0226] As compound 7, 2-((3-bromo-4-fluorophenoxy)methyl)oxirane (7-21) was used.

[0227] Colorless oil, yield 82%, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.09 (m, 1H), 7.02 (t, J= 8.80 Hz, 1H), 6.81 (m, 4H), 4.09 (m, 3H), 3.90 (m, 2H), 3.85 (s, 3H), 3.62 (d, J= 12.80 Hz, 1H), 3.46 (d, J= 12.80 Hz, 1H), 2.95 (t, J= 6.40 Hz, 2H), 2.67 (m, 5H), 2.47 (m,1H), 2.29 (s, 3H), 1.09 (t,J= 7.20 Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 155.25, 149.38, 147.62, 131.06, 121.3 (2C), 119.02 (2C), 116.52, 114.98, 112.58, 109.01, 71.29, 67.19, IR (KBr, cm -1): 2969, 2936, 2875, 2832, 2360, 2340, 1651, 1592, 1556, 1539, 1511, 1493, 1459, 1418, 1373, 1333, 1262, 1220, 1203, 1158, 1139, 1092, 1036, 929, 864, 805, 752. HRMS (ESI): m / z calcd for C 24 H 35 BrFN 2 O 4 (M+H) + : 513.1764. found: 513.1710.

[0228] Example 51: Synthesis of 1-(4-bromo-3)-(trifluoromethyl)phenoxy)-3-((4-(2-(diethylamino)ethoxy)-3(methoxybenzyl)(methyl)amino)propan-2-ol (CHJ04093) [ka]

[0229] As compound 5, N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3) was used.

[0230] As compound 7, 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3) was used.

[0231] Colorless oil, yield 83%, 1 H NMR (CDCl 3, 400 MHz) δ (ppm): 7.57 (d, J= 8.80 Hz, 1H), 7.24 (s, 1H), 6.92 (d, J= 8.80 Hz, 1H), 6.82 (m, 3H), 4.11 (t, J= 6.40 Hz, 3H), 3.96 (m, 2H), 3.84 (s, 3H), 3.63 (d, J= 12.80 Hz, 1H), 3.46 (d, J= 12.80 Hz, 1H), 2.97 (t, J= 6.4 Hz, 2H), 2.67 (m, 5H), 2.48 (m,1H), 2.30 (s, 3H), 1.10 (t,J= 7.20 Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 157.82, 149.40, 147.62, 135.72 (2C), 131.02, 121.32 (2C), 118.88 (2C), 114.64, 112.77, 110.18, 71.29, 67.19, 66.04, 62.37, 59.14, 55.96, 51.64, 47.80 (2C), 42.27, 11.69 (2C). -1 ): 2969, 2936, 2875, 2800, 2360, 2340, 1603, 1512, 1475, 1462, 1419, 1373, 1330, 1313, 1260, 1233, 1171, 1139, 1097, 1036, 1017, 980, 932, 880, 810, 752, 702. HRMS (ESI): m / z calcd for C 25 H 35 BrF 3 N 2 O 4 (M+H) + : 563.1732. found: 563.1695.

[0232] Example: 52: Synthesis of 1-(4-bromo-2,6-dichlorophenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl(methyl)amino)propan-2-ol (CHJ04094) [ka]

[0233] As compound 5, N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3) was used.

[0234] As compound 7, 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28) was used.

[0235] Colorless oil, yield 87%, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.44 (s, 2H), 6.81 (m, 3H), 4.06 (m, 5H), 3.84 (s, 3H), 3.61 (d, J= 12.80 Hz, 1H), 3.49 (d, J= 12.80 Hz, 1H), 2.96 (t, J= 6.80 Hz, 2H), 2.69 (m, 5H), 2.59 (m, 1H), 2.28 (s, 3H), 1.09 (t,J= 7.20 Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 150.74, 149.36, 147.52, 131.62 (3C), 131.24, 130.16, 121.30, 116.51, 112.76, 112.45, 71.29, 67.19, IR (KBr, cm -1 ): 2966, 2935, 2875, 2800, 2362, 2340, 1597, 1548, 1514, 1456, 1375, 1328, 1261, 1134, 1031, 995, 929, 854, 802, 748, 702, 569. HRMS (ESI): m / z calcd for C 24 H 34 BrCl2 N 2 O 4 (M+H) + : 563.1079. found: 563.1039.

[0236] Example 53: Synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-(3-methoxybenzyl)(methyl)amino)-3-(4-bromo-3-trifluoromethyl)phenoxy)propan-2-ol (CHJ04097) [ka]

[0237] As compound 5, 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethylamine (5-4) was used.

[0238] As compound 7, 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3) was used.

[0239] White solid, 85% yield, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.64 (s, 1H),7.56(d, J=8.80Hz, 1H),7.23(s,1H),7.10(s, 1H),7.05(s, 1H),6.92(d,J=8.8Hz, 1H),6.84(s, 1H),6.74 (m,2H), 4.34 (m,2H), 4.24(m, 2H),4.10(m, 1H), 3.96(m, 2H),3.84 (s,3H),3.62 (d, J=12.80Hz, 1H),3.46 (d,J=12.80Hz, 1H),2.62 (t,J=11.20Hz, 1H), 2.49 (m, 1H), 2.30 (s, 3H). 13 CNMR(CDCl 3,100 MHz) δ (ppm): 157.80, 149.88, 146.88, 137.64, 135.73, 132.45, 130.69, 129.26, 121.25, 119.59, 118.87, 114.63, IR (KBr, cm -1 ): 3111, 2929, 2877, 2787, 2362, 2340, 1600, 1514, 1473, 1419, 1321, 1261, 1230, 1170, 1138, 1093, 1026, 962, 908, 871, 810, 759, 663. HRMS (ESI): m / z calcd for C 24 H 28 BrF 3 N 3 O 4 (M+H) + : 558.1215. found: 558.1172.

[0240] Example 54: Synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-(3-methoxybenzyl)(methyl)amino)-3-(2-bromo-5-trifluoromethyl)phenoxy)propan-2-ol (CHJ04099) [ka]

[0241] As compound 5, 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethylamine (5-4) was used.

[0242] As compound 7, 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19) was used.

[0243] White solid, 90% yield, 1H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.62(d, J=12.40 Hz, 2H),7.08(m, 4H), 6.85(s,1H),6.78(d, J=8.0 Hz, 1H),6.71(d, J=8.0 Hz, 1H), 4.34 (m,2H), 4.23(m, 2H),4.09 (m, 3H),3.83 (s,3H),3.64 (d, J=12.80Hz,1H),3.47 (d,J=13.20Hz, 1H), 2.73 (t,J=11.60Hz,1H), 2.55 (m,1H), 2.32 (s,3H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 155.41, 149.90, 146.85, 137.67, 133.71, 132.57, 130.71, 129.39, 122.28, 121.25, 119.58, 118.81, IR (KBr, cm -1 ): 3118, 2879, 2845, 2787, 2362, 2340, 1676, 1595, 1516, 1460, 1421, 1388, 1332, 1290, 1259, 1138, 1114, 1085, 1029, 964, 906, 819, 752. HRMS (ESI): m / z calcd for C 24 H 28 BrF 3 N 3 O 4 (M+H) + : 558.1215. found: 558.1160.

[0244] Example 55: Synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-(3-methoxybenzyl)(methyl)amino)-3-(4-bromophenoxy)propan-2-ol (CHJ05001) [ka]

[0245] As compound 5, 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethylamine (5-4) was used.

[0246] As compound 7, 2-((4-bromophenoxy)methyl)oxirane (7-12) was used.

[0247] White solid, 85% yield, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.63(s, 1H),7.35(d, J=8.40 Hz, 2H), 7.08(d,J=14.80 Hz, 2H), 6.78(m, 5H),4.34 (m,2H), 4.23(m, 2H),4.09 (m, 1H),3.92 (d, J=4.40 Hz, 2H), 3.83 (s,3H),3.61 (d, J=13.20Hz,1H),3.45 (d,J=12.80 Hz, 1H), 2.62 (t,J=11.60Hz,1H), 2.49 (m,1H), 2.29 (s,3H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 157.89, 149.88, 146.84, 137.67, 132.56, 132.24 (2C), 129.38, 121.23, 119.58, 116.36 (2C), 114.19, 113.12,112.81,70.60,68.95,66.12,62.34,59.31,55.96,46.65,42.34.IR (KBr, cm -1): 3111, 2931, 2879, 2843, 2771, 2362, 2340, 1712, 1587, 1514, 1487, 1456, 1419, 1355, 1325, 1242, 1139, 1099, 1064, 1028, 999, 960, 910, 883, 858, 819, 754, 692, 663, 615. HRMS (ESI): m / z calcd for C 23 H 29 BrN 3 O 4 (M+H) + :490.1341. found: 490.1341.

[0248] Example 56: Synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-(3-methoxybenzyl)(methyl)amino)-3-(3-bromo-4-chlorophenoxy)propan-2-ol (CHJ05002) [ka]

[0249] As compound 5, 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethylamine (5-4) was used.

[0250] As compound 7, 2-((3-bromo-4-chlorophenoxy)methyl)oxirane (7-17) was used.

[0251] White solid, 90% yield, 1 H NMR (CDCl 3, 400 MHz) δ (ppm): 7.63(s, 1H),7.30(d, J=8.80 Hz, 1H), 7.16(s, 1H),7.08(d,J=16.0 Hz, 2H), 6.78(m, 4H),4.34 (m,2H), 4.23(m, 2H),4.09 (m, 1H),3.92 (m, 2H), 3.84 (s,3H),3.61 (d, J=13.2 Hz,1H),3.45 (d,J=13.2 Hz, 1H), 2.61 (t,J=11.60 Hz,1H), 2.48 (m,1H), 2.29 (s,3H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 157.73, 149.89, 146.87, 137.67, 132.50, 130.48, 129.37, 126.16, 122.52, 121.24, 119.55 (2C), 115.30, 114.19,112.81,70.74,68.95,66.04,62.35,59.12,55.97,46.66,42.37.IR (KBr, cm -1 ): 3113, 2927, 2877, 2845, 2785, 2362, 2340, 1589, 1564, 1512, 1467, 1419, 1384, 1323, 1261, 1239, 1141, 1089, 1029, 960, 906, 858, 808, 754, 666. HRMS (ESI): m / z calcd for C 23 H 28 BrClN 3 O 4 (M+H) + :524.0952. found: 524.0916.

[0252] Example 57: Synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-(3-methoxybenzyl)(methyl)amino)-3-(3-bromo-4-methylphenoxy)propan-2-ol (CHJ05003) [ka]

[0253] As compound 5, 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethylamine (5-4) was used.

[0254] As compound 7, 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18) was used.

[0255] White solid, 90% yield, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.64(s, 1H),7.10(s, 3H), 7.06(s, 1H),6.86(s, 1H), 6.73(m, 3H),4.34 (m, 2H), 4.24(m, 2H),4.09 (m, 1H),3.92 (m, 2H), 3.84 (s,3H),3.61 (d, J=12.80Hz,1H),3.46 (d,J=13.20 Hz, 1H), 2.62 (t,J=12.0Hz,1H), 2.48 (m, 1H), 2.30 (d,J=10.40Hz, 6H). 13 CNMR(CDCl 3 ,100 MHz) δ (ppm): 157.34, 149.86, 146.83, 137.67, 132.49, 130.99, 130.04, 129.37, 124.80, 121.24, 119.60, 118.30, IR (KBr, cm -1 ): 3112, 2924, 2877, 2844, 2777, 2361, 2340, 1605, 1564, 1511, 1492, 1454, 1418, 1264, 1239, 1226, 1158, 1141, 1091, 1029, 962, 896, 866, 815, 800, 764, 739, 658, 614. HRMS (ESI): m / z calcd for C24 H 31 BrN 3 O 4 (M+H) + :504.1498. found: 504.1460.

[0256] Example 58: Synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-(3-methoxybenzyl)(methyl)amino)-3-(3-bromo-5-chlorophenoxy)propan-2-ol (CHJ05004) [ka]

[0257] As compound 5, 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethylamine (5-4) was used.

[0258] As compound 7, 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29) was used.

[0259] White solid, 88% yield, 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 7.63(s, 1H), 7.10(s, 2H), 7.06(s, 1H), 6.96(s, 1H),6.84(s, 2H),6.73(m, 2H),4.35 (m,2H), 4.24(m, 2H),4.07 (m, 1H),3.93 (m, 2H), 3.84 (s,3H),3.61 (d, J=12.94Hz,1H),3.45 (d,J=13.35 Hz, 1H), 2.60 (t,J=11.55Hz,1H), 2.47 (m,1H), 2.29 (s,3H). 13 CNMR(CDCl 3,100 MHz) δ (ppm): 159.85, 149.91, 146.89, 137.67, 135.53, 132.46, 129.39 124.03, 122.83, 121.24, 119.58, 116.57, 114.21 (2C), 112.79, 70.90, 68.95, 65.96, 62.35, 59.05, 55.97, 46.66, 42.37. HRMS (ESI): m / z calcd for C 23 H 28 BrClN 3 O 4 (M+H) + :524.0952. found: 524.0913.

[0260] Inhibitory activity experiment of the compounds of the present invention against tumor cell proliferation 1. Materials for the experiment CHJ compounds were dissolved in dimethyl sulfoxide (DMSO, final concentration 0.4%) and adjusted to 1 mg / mL in RPMI-1640 medium containing 15% fetal bovine serum for use. When administering to groups, the compounds were doubled in the medium to the required concentration.

[0261] [Table 3]

[0262] Cell lines: Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375), and human colon cancer (LOVO) cell lines were purchased from the Cell Bank of the Chinese Academy of Sciences. They were cultured in DMEM (High Glucose) medium containing 15% fetal bovine serum at 37°C and 5% CO. 2 The cells were cultured in an incubator.

[0263] 2. Experimental method 2.1 Principle of MTT experiment and preparation method MTT is an oxidative yellow dye, and its chemical name is 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide. The MTT method, also known as the MTT colorimetric method, can detect cell viability and growth, and is a simple method and easy to operate, and is often used to screen substances with cytotoxic activity. The basic principle of detection is that succinate dehydrogenase can reduce exogenous MTT to water-insoluble blue-purple crystallized formazan, which is deposited in cells. Succinate dehydrogenase exists in the mitochondria of living cells, but does not exist in dead cells. Therefore, this color reaction occurs only in living cells.

[56] The blue-purple crystallized formazan in the cells is then dissolved with dimethyl sulfoxide (DMSO) and its absorbance is measured with a microplate reader, thereby indirectly reflecting the number of live cells. The amount of blue-purple crystallized formazan formed has a positive correlation with the number of live cells within a given cell number range.

[0264] The MTT method has the advantages of being highly efficient, accurate, simple, economical, and reproducible, and is widely used in screening antitumor drugs, detecting the activity of medical bioactive factors, testing and measuring cytotoxicity, and assessing tumor radiation sensitivity.

[0265] Preparation of 5 mg / mL MTT solution: 500.0 mg of MTT powder was weighed out and dissolved in 100 mL of warmed PBS, and the solution was filtered through a Millipore filter with a pore size of 0.22 μm to remove bacteria to obtain a filtrate. The filtrate was dispensed in small aliquots into centrifuge tubes sterilized by high pressure and frozen at -20°C in the dark.

[0266] 2.2 Cell culture and experimental methods The cryopreservation tubes in which the tumor cells were stored were removed from liquid nitrogen and quickly placed in a 37°C incubator and shaken until the cells were dissolved. After wiping the rim of the lid of the cryopreservation tube with 75% alcohol, the cell suspension was aspirated and transferred to a 10 mL centrifuge tube, which was then supplemented with 5 mL of medium. The tubes were centrifuged at low speed (25°C, 3000 r / min, 5 min), the supernatant was discarded, medium was added, and the centrifugation washing was repeated once more. After diluting the cells by adding an appropriate amount of medium, the cells were dispersed with a pipette to form a suspension, transferred to a culture flask, and incubated at 37°C, 5% CO 2 The cells were then cultured in a cell incubator. The next day, the culture medium was replaced and the cells were incubated at 37°C, 5% CO 2 The cells were placed in a cell incubator and cultured.

[0267] Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375), and human colon cancer (LOVO) cells are all adherent cells. Depending on the tumor cell proliferation rate, adherent tumor cells in the logarithmic growth phase were washed, digested with 0.25% EDTA pancreatin, and the cell number was reduced to 1 × 10 5 The solution was adjusted to 100 µL / mL and inoculated into a 96-well plate, and incubated at 37 °C in CO at 100 µL per well. 2 The cells were cultured in an incubator and treated after 24 h. The treatment groups were divided into five groups: 100, 10, 1, 0.1, and 0.01 μmol / L, with three parallel wells for each concentration. A blank control, a DMSO (0.8%) solvent control, and a cisplatin positive control were also included. The cells were incubated at 37°C, 5% CO 2 After culturing in an incubator for 48 h, the OD value was measured by the MTT method, and the cell inhibition rate was calculated.

[0268] 2.3 IC 50 Calculating values Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375), and human colon cancer (LOVO) cells were incubated for 48 h, then stopped and 10 μL of 0.5% MTT solution was added to each well and incubated with CO. 2Place them in an incubator, remove the liquid from each well after 4 h, add 0.2 mL of DMSO solution to each well, shake thoroughly at low frequency on a shaker to fully dissolve the blue-purple crystallized formazan, place them in a microplate reader, record the OD value at a wavelength of 490 nm, calculate the average OD value of three parallel wells at different concentrations, and calculate the cell inhibition rate and IC of each test drug at different concentrations based on the average value. 50 values ​​were calculated. Inhibition rate (%) = [1-OD value of test item / OD value of negative control group] x 100%

[0269] 3. Experimental results [Table 4-1]

[0270] [Table 4-2]

[0271] Observing the above experimental data, it can be seen that most of the target compounds have good inhibitory effects on human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells. The data also show that the compounds with tetramethylpiperidine on the right side have generally higher anticancer activity than the compounds with tetrahydropyrrole, diethylamino group and pyrrole on the right side. Increasing the length of the hydrophobic side chain on the left side of the compound (CHJ03011 and CHJ03012) still has excellent anticancer effect, but introducing a compound with high polarity on the left aromatic ring (CHJ04068 and CHJ04061) can obviously reduce the anticancer activity of the compound. It should be noted that the compounds with three Br atoms substituted on the left aromatic ring (CHJ04022 and CHJ04068) have the highest activity, which is equivalent to the control cisplatin.

Claims

1. A compound represented by general formula (I), or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, 【Chemistry 1】 However, R 1 -OC 2 H 5 , -H, -CH(CH 3 ) 2 , -Br, -CF 3 , -OCH 3 , -F, -Cl, or -CH 3 and R 2 -F, -CF 3 , -Br, -NHCOCH 3 , -Cl, -H, -OCH 3 , or -CH(CH 3 ) 2 and R 3 -H, -CH 3 , -Cl, -Br, -NHCOCH 3 , -C 3 H 7 , -F, -C 14 H 29 , or -OCH 3 and R 4 -H, -Br, -CF 3 or -Cl, R 5 is -H, -Cl, -I, or -Br; R 6 teeth, 【Chemistry 2】 and R6 is 【Chemistry 3】 then at least one of R 1 to R 5 is -OCH 3 , -OC 2 H 5 , -CH(CH 3 ) 2 , -Br, -CF 3 , -F, -Cl, -NHCOCH 3 , -C 14 H 29 , or -I; R6 is 【Chemistry 4】 then at least one of R 1 to R 5 is -CH(CH 3 ) 2 , -Br, -CF 3 , -F, -Cl, -NHCOCH 3 , -C 14 H 29 , or -I; A compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof.

2. R 1 -H, -CH (CH 3 ) 2 , -Br, or -Cl; R 2 -F, -Br, -Cl, -H, -CH (CH 3 ) 2 , or -CF 3 and R 3 -H, -CH 3 , -Cl, -Br, or -C 14 H 29 and R 4 -H, -Br, -CF 3 or -Cl, R 5 is -H, -Cl, -I, or -Br; R 6 teeth, 【Chemistry 5】 and At least one of R 1 to R 5 is -OCH 3 , -OC 2 H 5 , -CH(CH 3 ) 2 , -Br, -CF 3 , -F, -Cl, -NHCOCH 3 , -C 14 H 29 , or -I; 2. The compound according to claim 1, or a pharma- ceutically acceptable salt or optical isomer thereof.

3. A compound represented by general formula (I), or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, 【Chemistry 6】 R 1 -H,R 2 -CF 3 , R 3 -Br,R 4 -H,R 5 -H, R 6 teeth 【Chemistry 7】 and Or, R 1 -H,R 2 -H,R 3 -C 14 H 29 , R 4 -H,R 5 -H, R 6 teeth 【Chemistry 8】 and Or, R 1 -H,R 2 -H,R 3 -Cl, R 4 -Br,R 5 -H, R 6 teeth 【Chemistry 9】 and Or, R 1 -Br,R 2 -H,R 3 -Br,R 4 -H,R 5 -Br, R 6 teeth 【Chemistry 10】 That is, A compound, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof.

4. R 1 -H,R 2 -CF 3 , R 3 -Br,R 4 -H,R 5 -H, R 6 teeth 【Chemistry 11】 and Or, R 1 -H,R 2 -H,R 3 -C 14 H 29 , R 4 -H,R 5 -H, R 6 teeth 【Chemistry 12】 and Or, R 1 -Br,R 2 -H,R 3 -Br,R 4 -H,R 5 -Br, R 6 teeth 【Chemistry 13】 That is, 4. The compound according to claim 3, or a pharma- ceutically acceptable salt or optical isomer thereof.

5. R 1 -H,R 2 -CF 3 , R 3 -Br,R 4 -H,R 5 -H, R 6 teeth 【Chemistry 14】 That is, 4. The compound according to claim 3, or a pharma- ceutically acceptable salt or optical isomer thereof.

6. R 1 -Br,R 2 -H,R 3 -Br,R 4 -H,R 5 -Br, R 6 teeth 【Chemistry 15】 That is, 4. The compound according to claim 3, or a pharma- ceutically acceptable salt or optical isomer thereof.

7. A method for producing the compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, or an optical isomer thereof, comprising the steps of: 【Chemistry 16】 However, R 1 -OC 2 H 5 , -H, -CH(CH 3 ) 2 , -Br, -CF 3 , -OCH 3 , -F, -Cl, or -CH 3 and R 2 -F, -CF 3 , -Br, -NHCOCH 3 , -Cl, -H, -OCH 3 , or -CH(CH 3 ) 2 and R 3 -H, -CH 3 , -Cl, -Br, -NHCOCH 3 , -C 3 H 7 , -F, -C 14 H 29 , or -OCH 3 and R 4 -H, -Br, -CF 3 or -Cl, R 5 is -H, -Cl, -I, or -Br; R 6 teeth, 【Chemistry 17】 and R6 is 【Chemistry 18】 then at least one of R 1 to R 5 is -OCH 3 , -OC 2 H 5 , -CH(CH 3 ) 2 , -Br, -CF 3 , -F, -Cl, -NHCOCH 3 , -C 14 H 29 , or -I; R6 is 【Chemistry 19】 then at least one of R 1 to R 5 is -CH(CH 3 ) 2 , -Br, -CF 3 , -F, -Cl, -NHCOCH 3 , -C 14 H 29 , or -I; The synthesis of the compound of general formula (I) includes the steps of dissolving the substituted phenoxymethyloxirane (7) and compound (5) in isopropanol, adding a catalytic amount of pyridine under nitrogen gas protection, heating under reflux for 6 hours, and detecting the disappearance of the raw material by TLC; diluting the reaction solution with ethyl acetate, washing the organic phase with water and saturated saline in turn, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to remove the solvent, and separating the crude product by silica gel column chromatography to obtain the target compound. Manufacturing method.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt or optical isomer thereof, and a pharma- ceutically acceptable carrier or excipient.

9. Use of the compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt or optical isomer thereof, or the pharmaceutical composition according to claim 8, in the manufacture of a medicament for treating cancer.

10. 10. The use according to claim 9, wherein the cancer is lung cancer, ovarian cancer, melanoma or colon cancer.

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