SUBSTITUTED DIARYL COMPOUND AS WELL AS PREPARATION METHOD AND APPLICATION THEREOF

Abstract

The invention relates to the field of medicinal chemistry, in particular to a substituted diaryl compound shown as a formula (I), a preparation method of the substituted diaryl compound, a medicinal preparation containing the substituted diaryl compound and medical application of the substituted diaryl compound. Pharmacological test results show that the substituted diaryl compound disclosed by the invention has a good inhibition effect on cells of human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO). The formula (I) is shown in the specification:

##STR00001##

Claims

1. A compound of general formula (I), or lts pharmaceutically acceptable salt or its optical isomer, ##STR00121## Wherein, R.sub.1 represents OC.sub.2H.sub.5, H, CH(CH.sub.3).sub.2, Br, CF.sub.3OCH.sub.3,F, Cl, CH.sub.3 R.sub.2 represents F, CF.sub.3, Br, NHCOCH.sub.3, Cl, H, OCH.sub.3, CH(CH.sub.3).sub.2 R.sub.3 represents H, CH.sub.3, Cl, Br, NHCOCH.sub.3, C.sub.3H.sub.7, F, C.sub.14H.sub.29, OCH.sub.3 R.sub.4 represents H, Br, CF.sub.3, Cl R.sub.5 represents H, Cl, I, Br, R.sub.6 represents ##STR00122##

2. The compound described in claim 1 or its pharmaceutically acceptable salt or its optical isomer is characterized in that: The described R.sub.1 represents H, CH(CH.sub.3).sub.2, Br, Cl R.sub.2 represents F, Br, Cl, H, CH(CH.sub.3).sub.2, CF.sub.3 R.sub.3 represents H, CH.sub.3, Cl, Br, C.sub.14H.sub.29 R.sub.4 represents H, Br, CF.sub.3, Cl R.sub.5 represents H, Cl, I, Br, R.sub.6 represents ##STR00123##

3. The compound described in claim 2 or its pharmaceutically acceptable salt or its optical isomer is characterized in that: The described R.sub.1 represents H; R.sub.2 represents CF.sub.3; R.sub.3 represents Br; R.sub.4 represents H; R.sub.5 represents H; R.sub.6 represents ##STR00124## Or R.sub.1 represents H; R.sub.2 represents H; R.sub.3 represents C.sub.14H.sub.29; R.sub.4 represents H; R.sub.5 represents H; R.sub.6 represents ##STR00125## Or R.sub.1 represents H; R.sub.2 represents H; R.sub.3 represents Cl; R.sub.4 represents Br; R.sub.5 represents H; R.sub.6 represents ##STR00126## Or R.sub.1 represents Br; R.sub.2 represents H; R.sub.3 represents Br; R.sub.4 represents H; R.sub.5 represents Br; R.sub.6 represents ##STR00127##

4. The compound described in claim 3 or its pharmaceutically acceptable salt or its optical isomer is characterized. in that: The described R.sub.1 represents H; R, represents CF.sub.3; R.sub.3 represents Br; R.sub.4 represents H; R.sub.5 represents H; R.sub.6 represents ##STR00128## Or R.sub.1 represents H; R.sub.2 represents C.sub.14H.sub.29; R.sub.4 represents H; R.sub.5 represents H; R.sub.6 represents ##STR00129## Or R.sub.1 represents Br; R.sub.2 represents H; R.sub.3 represents Br; R.sub.4 represents H; R.sub.5 represents Br; R.sub.6 represents ##STR00130##

5. the compound described in claim 3 or its pharmaceutically acceptable salt or its optical isomer is characterized in that: The described R.sub.1 represents H; represents CF.sub.3; R.sub.3 represents Br; R.sub.4 represents H; R.sub.5 represents H; R.sub.6 represents ##STR00131##

6. The compound described in claim 3 or its pharmaceutically acceptable salt or its optical isomer is characterized in that: The described R.sub.1 represents Br; R.sub.2 represents H; R.sub.3 represents Br; R.sub.4 represents H; R.sub.5 represents Br; R.sub.6 represents ##STR00132##

7. Use of the compound of any one of claims 1 or a phamiaceutically acceptable salt thereof, an optical isomer thereof in the preparation of a drug for treating cancer.

8. Based on the application shown it claim 7, it characteristics lie in that the described cancer is lung cancer car ovarian cancer or melanoma or colon cancer.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0019] The following specific embodiments will further illustrate the present invention so that those skilled in the art can better understand the present invention, but do not limit the present invention in this way.

[0020] Synthesis of the target compound in the embodiment of present invention: Dissolve substituted phenoxymethyloxirane (7) (1.0 mmol) and compound. (5) (1.2 mmol) in isopropanol (15 mL) under nitrogen protection , add a catalytic amount of pyridine, heat to reflux for 6 hours, and detect the disappearance of the raw material by TIC. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: dichloromethane-methanol=20:1) to obtain target compound.

##STR00017##

[0021] Compound (5) is synthesized through 4 steps of reaction using vanilline (1) as the raw material.

##STR00018##

[0022] The 4 types of compound (5) obtained is shown in the following table;

TABLE-US-00001 TABLE 1 Detailed Structure of Compound (5) No Structure 5-1 [00019] 5-2 [00020] 5-3 [00021] 5-4 [00022]

[0023] Substituted phenoxyl methyloxirane (7) is synthesized from the nucleophilic substitution between the phenol of different substitutions on the benzene ring and epibromohydrin. The compound series obtained is shown in the following table:

##STR00023##

TABLE-US-00002 TABLE 2 Detailed Structure of Compound (7) No Structure 7-1 [00024] 7-2 [00025] 7-3 [00026] 7-4 [00027] 7-5 [00028] 7-6 [00029] 7-7 [00030] 7-8 [00031] 7-9 [00032] 7-10 [00033] 7-11 [00034] 7-12 [00035] 7-13 [00036] 7-14 [00037] 7-15 [00038] 7-16 [00039] 7-17 [00040] 7-18 [00041] 7-19 [00042] 7-20 [00043] 7-21 [00044] 7-22 [00045] 7-23 [00046] 7-24 [00047] 7-25 [00048] 7-26 [00049] 7-27 [00050] 7-28 [00051] 7-29 [00052] 7-30 [00053] 7-31 [00054] 7-32 [00055] 7-33 [00056] 7-34 [00057] 7-35 [00058] 7-36 [00059] 7-37 [00060] 7-38 [00061] 7-39 [00062]

EMBODIMENT 1

[0024] synthesis of 1-(2-ethoxyphenoxy)-3-((3-methoxy-44 -(4-tnethylpiperidin-1yl)ethoxy)benzyl)(methyl)amino)propan-2ol (SAMS10)

##STR00063##

[0025] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1.1).

[0026] Compound 7 used is 2(2-methoxyphenoxy)methyl)oxirane(7-1).

[0027] Dissolve 2-((2-ethoxylphenoxyl) methyl) oxirane (7-1) (194 mg, 1.0 mmol) and 1-(3-methoxyl-4-(2-(4-methyl piperidine-1-base) ethoxyl) phenyl)-N-methyl methylamine (5-1) (354 mg, 1.2 mmol) in isopropanol (15 mL), and, with the protection of nitrogen, add pyridine (8.0?L, 0.1 mmol.) of catalyst dosage. Apply heating reflux for 6 h and the TLC test (developer: dichloramethane-methanol=10:1) raw material disappears. Dilute the reaction liquid with ethyl acetate, and wash the organic phase with. water and saturated saline solution in order. Dry it with anhydrous sodium sulfate and filter it. The solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (mobile phase: dichloromethane-methanol=20:1), a colorless oily substance (437.9 mg 90%) was obtained. .sup.1H NMR (CDCl.sub.3, 600 MHz,) ? (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). .sup.13C NMR (CDCl.sub.3, 150 MHz) ? (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.sup.?1): 2924, 2871, 2851, 2794, 2360, 2340, 1592, 1512, 1494, 1460, 1419, 1368, 1321, 1272, 1217, 1138, 1035, 980, 863, 803, 772, 670. HRMS (t SI):. m/z calcd. for C.sub.28H.sub.43N.sub.2O.sub.5 (M?H).sup.?: 487.3172. found: 487.3199.

[0028] The preparation method of compounds CHJ02029-CHJ05004 in Examples 2-58 is the same as that in Example 1. The difference is that different compounds 5 and 7 are used for synthesis. Specifically, the raw materials of compound 5 and compound 7. used in each embodiment are as follows in the corresponding embodiment record.

EMBODIMENT 2

[0029] synthesis of 1-(2,6-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ02029)

##STR00064##

[0030] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperldin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0031] Compound 7 used is 2((2,6-dichlorophenoxy)methyl)oxirane (7-2).

[0032] Colorless oil, yield 88%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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). .sup.13CNMR (CD.sub.3OD,100 MHz)? (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, 66.25, 62,02, 59.27, 56.86, 55.00, 53.81 (2C), 41.86, 33.04 (2C), 29.92, 20.60. IR (KBr, cm.sup.?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.sub.26H.sub.37Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 511.2130. found: 511.2047.

EMBODIMENT 3

[0033] 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)

##STR00065##

[0034] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperdin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0035] Compound 7 used is 2-((4bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3).

[0036] Colorless oil, yield 87%, .sup.1H NMR (CD.sub.2OD, 400 MHz)? (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, 3 H), 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, 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). .sup.13CNMR (CD.sub.3OD,100 MHz)? (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.sup.?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.sub.27H.sub.37BrF.sub.3N.sub.2O.sub.4 (M+H).sup.+: 589.1889. found: 589.2404.

EMBODIMENT 4

[0037] 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)

##STR00066##

[0038] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0039] Compound 7 used is 2-((2,5-bis(trifluoromethyl)phenoxy)methyl)oxirane (7-4).

[0040] White s(olid, yield 85%, mp: 7072? C., .sup.1H NMR (CD.sub.3OD, 400 MHz)? (ppm): 7.77 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.38 (d, J=8.0 Hz, 6.96 (s, 1H), 6.83 (q, J8.0 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, J5.60 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), .sup.13CNMR (CD3OD, 100 MHz) ? (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, 109.94, 109.90, 71.45, 67.17, 66.71, 62.28, 59.06, 57.11, 54.90, 53.98 (2C), 41,93, 33.46 (2C), 30.24, 20.73, IR (KBr, cm.sup.?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. (EST): calcd for C.sub.28H.sub.37F.sub.6N.sub.2O.sub.4 (M+4).sup.+: 579.2658. found: 579.2549.

EMBODIMENT 5

[0041] synthesis of 1-(3-bromophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ03001)

##STR00067##

[0042] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0043] Compound 7 used is 2-((3-bromophenoxy)methyl)oxirane (7-5).

[0044] Colorless oil, yield 86%,.sup.1H NMR (CDCl.sub.3, 400 MHz)? (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). .sup.13CNMR (CDCl.sub.3, 100 MHz) ? (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.sup.?1): 2947, 2924, 2871, 2846, 2792, 2360, 2340, 11651, 1591, 1572, 1512, 1476, 1463, 1459, 1368, 1324, 1283, 1261, 1229, 1157, 1138, 1090, 1035, 991, 936, 861, 804, 800, 674. HRMS (ESI); calcd for C.sub.26H.sub.38BrN.sub.2O.sub.4 (M+H).sup.+: 521.2015. found: 521.1945.

EMBODIMENT 6

[0045] synthesis of 1-(2-bromophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ03003)

##STR00068##

[0046] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin -1yl)ethon)phenyl)-N-methylmethanamine (5-1).

[0047] Compound 7 used is 2-((2-bromophenox methyl)oxirane (7-6).

[0048] Colorless oil,yield 90%, .sup.1H NMR (CDCl.sup.3, 400 MHz)? (ppm): 7.52 (d,J=7.60 Hz,1H), 7.23 (dJ=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). .sup.13CNMR (CDCl.sub.3, 100 MHz)? (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. IR (KBr, em.sup.?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/zcalcdfir C.sub.26H.sub.38BrN.sub.2O.sub.4 (M+H).sup.+: 521.2015. found: 521,1943.

EMBODIMENT 7

[0049] synthesis of 1(2-isopropylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ03004)

##STR00069##

[0050] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin -1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0051] Compound 7 used is 2-((2-isopropylphenoxy)methyl)oxirane (7-7).

[0052] Colorless oil,yield 87%, .sup.1H NMR (CDCl.sup.3, 400 MHz)? (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), 3.00 (m, 2H), 3.94 (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). .sup.13CNMR (CDCl.sub.3, 100 MHz)? (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.sup.?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 calcdfor C.sub.29H.sub.45N.sub.2O.sub.4 (M+H).sup.+: 485.3379. found: 485.3330.

EMBODIMENT 8

[0053] synthesis of 1-(4-bromo-2-methoxypbenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy) benzyl)(methyl)amino)propan-2-ol (CHJ03005)

##STR00070##

[0054] Compound 5 used is 1-(3-Methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine(5-1).

[0055] Compound. 7 used is 2-((4-bromo-2-methoxyphenoxy)methyl)oxirane (7-8).

[0056] Colorless oil,yield 90%, 1H NMR (CD.sub.3OD, 400 MHz)? (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). .sup.13C NMR (CD.sub.3OD, 100 MHz)? (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.sup.?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 calcdfor C.sub.27H.sub.40BrN.sub.2O.sub.5 (M+H).sup.+: 551.2101. found: 551.2094.

EMBODIMENT 9

[0057] synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(2-methoxy-4-propylphenoxy)propan-2-ol (CHJ03011)

##STR00071##

[0058] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1),

[0059] Compound 7 used is 2-((2-methoxy-4-propylphenoxy)mathyl)oxirane (7-9).

[0060] White solid,yield 83%,mp: 45-47? C., .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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). .sup.13C NMR (CD.sub.3OD, 100 MHz)? (ppm): 1.49.66, 149,33, 147.40, 146.45, 136.1.0, 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 (1(KBr, cm.sup.?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 (EST); m/zcalcdfor C.sub.30H.sub.47N.sub.2dO.sub.5 (M+H).sup.+: 515.3485. found: 515.3423.

EMBODIMENT 10

[0061] synthesis of 1((3-methoxy-4-(2-(4-methylpiperidin-1- yl)ethoxy)benzyl)(methyl)amino -3-(4-pentadecylphenoxy)propan-2-ol (CHJ03012)

##STR00072##

[0062] Compound 5 used is 1-(3-methoxy-4(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0063] Compound 7 used is 2-((4-pentadecylphenoxy)methyl)oxirane (7-10).

[0064] White solid,yield 85%,mp: 40-42? C., .sup.1H NMR (CD.sub.3OD, 400 MHz)? (ppm): 7.13 (t, K=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, 4), 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), .sup.13C NMR (CD.sub.3OD, 100 MHz)? (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. (KBr, cm.sup.?1): 2924, 2852, 2794, 2360, 2340, 1591, 1514, 1458, 1367, 1325, 1263, 1151, 1085, 1035, 937, 869, 806, 775, 694. HRMS (ESI): m/z calcdfor C.sub.41H.sub.69N.sub.2O.sub.4 (M+H).sup.+: 653.5257, found: 653.5163.

EMBODIMENT 11

[0065] synthesis of 1-(2,3-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03013)

##STR00073##

[0066] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0067] Compound 7 used is 2-((2,3-diellorophenoxy)methyl)oxirane (7-11).

[0068] Colorless oil,yield 88% .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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). .sup.13CNMR (CD.sub.3O D, 100 MHz) ? (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), 30.2.2, 20.76. IR (KBr, cm.sup.?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): calcd for C(.sub.26H.sub.37Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 511.2130. found: 511.2095.

EMBODIMENT 12

[0069] synthesis of 1-(4-bromophenoxy)-3-((3-methoxy-4-(2-)4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ03014)

##STR00074##

[0070] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1),

[0071] Compound 7 used is 2-((4-hromophenoxy)methyl)oxirane (7-12).

[0072] Colorless oil,yield 81%, .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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). .sup.13CNMR (CD.sub.3OD, 100 MHz) ? 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, 67.42, 66.70, 62.27, 58.96, 57,12, 54.88, 53.99 (2C). 42.21. 33.47 (2C), 30.23. 20.76. IR (KBr, cm.sup.?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 (ES!): calcdfor C.sub.26H.sub.38BrN.sub.2O.sub.4 (M+H).sup.+: 521.2015. found: 521.1975.

EMBODIMENT 13

[0073] synthesis of 1-(3-isopropylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ03015)

##STR00075##

[0074] Compound. 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0075] Compound 7 used is 2-((3-isopropylphenoxy)methyl)oxirane (7-13).

[0076] Colorless oil,yield 89%, .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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, .sup.3H). .sup.13CNMR(CD.sub.3OD, 100 MHz) ? (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.sup.?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/zealed for C.sub.29H.sub.45N.sub.2O.sub.4 (M+H).sup.30 : 485.3379. found: 485.3296.

EMBODIMENT 14

[0077] synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(3-methoxyphenoxy)propan2-ol (CHJ03017)

##STR00076##

[0078] Compound 5 used is 1-(3methoxy-4-(2(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0079] Compound 7 used is 2-((3-methoxyphenoxy)methyl)oxirane (7-14).

[0080] Colorless oil,yield 83%, .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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, 720 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). .sup.13CNMR(CD.sub.3OD,100 MHz) ? (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.sup.?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): calcdfor C.sub.27H.sub.41N.sub.2O.sub.5 (M+J).sup.+: 473.3015. found: 473.2947.

EMBODIMENT :15

[0081] 1-(5-bromo-2-fluorophenoxy)-3-(3-methoxy-4-(2-(4-methylpiperidin-1yl)ethoxy) benzyl)(methyl)amino)propan-2-ol (CHJ03018)

##STR00077##

[0082] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0083] Compound 7 used is 2((5-bromo-2-fluorophenoxy)methyl)oxirane (7-15).

[0084] Colorless oil,yield 85%,.sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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, 3 H). .sup.1CNMR(CD.sub.3OD),100 MHz) ? (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.sup.?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/calcdfor C.sub.26H.sub.37BrFN.sub.2O.sub.4 (M+H).sup.+: 539.1921. found: 539.1911.

EMBODIMENT 16

[0085] synthesis of 1-(3,4-dimethoxyphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ03019)

##STR00078##

[0086] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0087] Compound 7 used is 2((3,4-dimethoxyphenoxy)methyl)oxirane (7-16).

[0088] Colorless oil,yield 87%,.sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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, 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). .sup.13CNMR(CD.sub.3OD,100 MHz) ? (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 (20, 42.12, 33.39 (2C), 30.18, 20.72. IR (KBr, cm.sup.?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 (EST): m/zcalcdfor C.sub.28H.sub.43N.sub.2O.sub.6 (M+H).sup.+: 503.3121. tbund: 501.2817.

EMBODIMENT 17

[0089] synthesis of 1-(3-bromo-4-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidia-1-yl)ethoxy) benzyl)(methyl)amino)propan-2-ol (CHJ03043)

##STR00079##

[0090] Compound 5 used is 1-(3-methoxy4(2-4-methylpiperidin-1-yl)ethoxY)phenyl)-N-methylmethanamine (5-1),

[0091] Compound 7 used is 2-((3-bromo-4-chlorophenoxy)methyl)oxitane(7-17).

[0092] Colorless oil,yield 89%, .sup.1H NMR (CDCl.sub.3, 400 MHz)? (ppm): 730 (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). .sup.13CNMR(CDCl.sub.3,100 MHz) ? (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, 21.87IR (KBr, cm.sup.?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 calcdfor C.sub.26H.sub.37BrClN.sub.2O.sub.4 (M+H).sup.+: 555.1.625. found: 555.1610.

EMBODIMENT 8

[0093] synthesis of 1-(3-bromo-4-methylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy) benzyl)(methyl)amino)propan-2-ol (CHJ04010)

##STR00080##

[0094] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1),

[0095] Compound 7 used is 2-((3-bromo-4-methylphenoxy)methyl)oxirane (7-18).

[0096] Colorless oil,yield 82%, .sup.1H NMR (CD.sub.3OD, 400 MHZ)? (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, 6.80 Hz, 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). .sup.13CNMR(CD.sub.3OD,100 MHz)? (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, 20,50.1IR (KBr, cm.sup.?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.sub.27H.sub.40BrN.sub.2O.sub.O (M+H).sup.+: 535.2171. found: 535.2149.

EMBODIMENT 19

[0097] 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)

##STR00081##

[0098] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0099] Compound 7 used is 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane (7-19).

[0100] Colorless oil,yield 85%,.sup.1H NMR (CD.sub.3OD 400 MHz)? (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), (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). .sup.13CNMR(CD.sub.3OD,100 MHz)? (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.sup.?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 calcdfor C.sub.27H.sub.37BrF.sub.3N.sub.2O.sub.4 (M+H).sup.+: 589.1889. found: 589.18.27.

EMBODIMENT 20

[0101] synthesis of 1-(3,5-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ04012)

##STR00082##

[0102] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0103] Compound 7 used is 2-((3,5-dichlorophenoxy)methyl)oxirane (7-20).

[0104] Colorless oil,yield 88%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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=12.806.40 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). .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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, 66.70, 62.29, 58.68, 57.13, 54.99, 54.00 (2C), 42.25, 33.47 (2C), 30.24, 20.75. IR(KBr, cm.sup.?1): 2948, 2925, 2872, 2843, 2793, 2360, 2340, 1590, 1571, 1513, 1442, 1424, 1368, 13.23, 1303, 1262, 1192, 1157, 1138, 1039, 980, 938, 853, 831, 800, 756, 670. HRMS (ESI): m/z calcd for C.sub.26H.sub.37Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 511.2130. found: 511.2075.

EMBODIMENT 21

[0105] synthesis of 1-(3-bromo-4-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy) benzyl)(methyl)amino)propan-2-ol (CHJ04020)

##STR00083##

[0106] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0107] Compound 7 used is 2-((3-bromo-4-fluorophenoxy)methyl)oxirane (7-21).

[0108] Colorless oil,yield 90%, .sup.1H NMR (CD.sub.3ODD, 400 MHz)? (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,=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, 12.40 Hz, 2H), 1.41(s, 1H), 1,28 (m, 2H), 0.93 (d, J=6.0 Hz, 3H). .sup.13C NMR(CD.sub.3OD,100 MHz)? (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.sup.?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); calcdfor C.sub.26H.sub.37BrFN.sub.2O.sub.4 (M+H).sup.+: 539.1921. found: 539.1888.

EMBODIMENT 22

[0109] synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methy)amino)-3-(2,4,6-tribromnophenoxy)propan-2-ol (CHJ04022)

##STR00084##

[0110] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0111] Compound 7 used is 2-((2.4,6-tribromophenoxy)metbyl)oxirane(7-22.

[0112] Colorless oii,yieid 90%, .sup.1H NMR. (CD.sub.3OD, 400 MHz)? (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 3H), (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) .sup.13CNMR(CD.sub.3OD,100 MHz)? (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, 66.75, 62.14, 59.34, 57.11, 55.06, 53.99 (2C), 42.08, 33.48 (2C), 30.24, 20.77. IR (KBr, cm.sup.?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.sub.26H.sub.36Br.sub.3N.sub.2O.sub.4 (M+H).sup.+: 677.0225. found: 677.0256.

EMBODIMENT 23

[0113] synthesis of 1-(3-bromo-5-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl) benzyl)(methyl)amino)propan-2-ol (CHJ04023)

##STR00085##

[0114] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin1-yl)ethoxy)phenyl)-N-methylmethanamine (5-1).

[0115] Compound 7 used is 2-((3-bromo-5-fluorophenoxy)metbyl)oxirane(7-23 .

[0116] Colorless oil,yield 85%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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, 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). .sup.13CNMR(CD.sub.3OD,100 MHz)? (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.sup.?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 calcdfor C.sub.26H.sub.37BrFN.sub.2O.sub.4 (M+H).sup.+: 539.1921. found:539.1879.

EMBODIMENT 24

[0117] synthesis of 1-(3-chlorophenoxyl-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ04024)

##STR00086##

[0118] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0119] Compound 7 used is 2-((3-chlorophenoxy)methyl)oxirane (7-24).

[0120] Colorless oil,yield 83%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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, 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), .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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.sup.?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 calcdfor C.sub.26H.sub.38ClN.sub.2O.sub.4 (M+H).sup.+: 477.2520. found; 477.2476.

EMBODIMENT 25

[0121] synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(3-(trifluoromethyl)phenoxy)propan-2-ol (CHJ04025)

##STR00087##

[0122] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0123] Compound 7 used is 2-((3-(trifluoromethyl)phenoxy)methyl)oxirane (7-25).

[0124] Colorless oil,yield 83%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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), .sup.13CNMR (CD.sub.3OD, 100 MHz) ? (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.sup.?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 calcdfor C.sub.27H.sub.38F.sub.3N.sub.2O.sub.4 (M+H).sup.+: 511.2784. found: 511.2765.

EMBODIMENT 26

[0125] synthesis of 1-(3,4-dichlophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ04026)

##STR00088##

[0126] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0127] Compound 7 used is 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26).

[0128] Colorless oil,yield 81%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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 Hz1H), 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). .sup.13C NMR (CD.sub.3OD, 100 MHz)? (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. IR (KBr, cm.sup.?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 calcdfor C.sub.26H.sub.37Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 511.2130. found: 511.2115.

EMBODIMENT 27

[0129] synthesis of 1-(2-iodophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyp(methyl)amino)propan-2-ol (CHJ04027)

##STR00089##

[0130] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0131] Compound 7 used is 2-((2-iodophenoxy)methyl)oxirane (7-27).

[0132] Colorless oil,yield 90%,.sup.1H NMR (CD.sub.3OD, 400 MHz)? (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, 12.80 Hz, 2H), 1.40(s, 1H), 1,29 (m, 2H), 0.94 (d, J=6.40 Hz, 3H) .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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.sup.?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 calcdfor C.sub.26H.sub.38IN.sub.2O.sub.4 (M+H).sup.+: 569.1876. found: 569.1842.

EMBODIMENT 28

[0133] 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)

##STR00090##

[0134] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0135] Compound 7 used is 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28).

[0136] Colorless oil,yield 84%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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), .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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, 66.71, 62,14, 59.26, 57.09, 55.02. 53.97 (2C), 42.01, 33.44 (2C), 30.21, 20,.76. IR. (KBr, cm.sup.?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): for C.sub.26H.sub.36BrCl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 589.1236. found: 589.1220.

EMBODIMENT 29

[0137] synthesis of 1-(3-bromo-5-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin1-yl)ethoxy) benzyl)(methyl)amino)propan-2-ol. (CHJ04034)

##STR00091##

[0138] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0139] Compound 7 used is 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29).

[0140] Colorless oil,yield 85%,.sup.1H NMR (CD.sub.3OD, 400 MHz)? (ppm): 7.12 (s, 1H), 7.02 , 6.95 (s, 1H ), 6.91 (s, 1H), 6.83 (m, 2H), 4.10 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 G), 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). .sup.13CNMR(CD.sub.3OD, 100 MHz)? (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.sup.?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.sub.26H.sub.37BrClN.sub.2O.sub.4 (M+H).sup.+: 555.1625. found: 555.1600.

EMBODIMENT 30

[0141] synthesis of 1-(2-bromo-5-fluorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxybenzyl)(methyl)amino))propan-2-ol (CHJ04036)

##STR00092##

[0142] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0143] Compound 7 used is 2-((2-bromo-5-fluorophenoxy)methyl)oxirane (7-30).

[0144] Colorless oil,yield 82%, .sup.1H NMR (CD.sub.3OD, 400 MHz)? (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=5.6 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). .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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.sup.?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.sub.26H.sub.37BrFN.sub.2O.sub.4 (M+H).sup.+: 539.1921. found: 539.1914.

EMBODIMENT 31

[0145] synthesis of N-(3-(2-hydroxy-3((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propoxy)phenyl)acetamide (CHJ04058)

##STR00093##

[0146] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0147] Compound 7 used is N-(3-oxirane-2-ylmethoxy)phenyl)acetamide (7-31).

[0148] White solid,yield 90%,mp: 60-62? C.,.sup.1H NMR (CD.sub.3OD, 400 MHz)? (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 (dd,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), .sup.13CNMR (CD.sub.1OD, 100 MHz)? (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.sub.28H.sub.42N.sub.3O.sub.5 (M+H).sup.+: 500.3124. found: 500.3071.

EMBODIMENT 32

[0149] synthesis of 1-(2,4-dichlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ04059)

##STR00094##

[0150] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0151] Compound 7 used is 2-((2,4-dichlorophenoxy)methyl)oxirane (7-32).

[0152] Colorless oil,yield 81%,.sup.1H NMR. (CD.sub.3OD, 400 MHz)? (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 (tmJ=12.0 Hz, 2H), 1.67 (d,J=12.80 Hz, 2H ) (s,1H ), 1.29 (m, 2H), 0.94 (d,J=6.40 Hz, 3H). .sup.13CNMR(CD.sub.3OD, 100 MHz)? (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): calcd for C.sub.26H.sub.37Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 511.2130, found: 511.2120.

EMBODIMENT 33

[0153] synthesis of 1-(5-bromo-2-methylphenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04060)

##STR00095##

[0154] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0155] Compound 7 used is 2-((5-bromo-2-methylphenoxy)methyl)oxirane (7-33).

[0156] Colorless oil,yield 82%. 1H NMR (CD.sub.3OD, 400 MHz)? (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). .sup.13CNMR(CD.sub.3OD, 100 MHz)? (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, (KBr, cm.sup.?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): calcd for C.sub.27H.sub.40BrN.sub.2O.sub.4 (M+H).sup.+: 535.2171. found: 535,2170.

EMBODIMENT 34

[0157] synthesis of N-(4-2-hydroxy 3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propoxy)phenypacetamide (CHJ04061)

##STR00096##

[0158] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0159] Compound 7 used is N-(4-(oxiran-2-ylmethoxy)phenyl)acetamide (7-34).

[0160] White solid,yield 90%,mp: 60-62? C., .sup.1H NMR (CD.sub.3OD, 400 MHz)? (ppm): 7.41 (d,J=8.0 Hz, 2H), 6.98 (s,1H ), 6.86 (m, 4H), 4.14 (m, 3M), 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), .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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.sup.?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.sub.28H.sub.42N.sub.3O.sub.5 (M+H).sup.+: 500.3124. found: 500.3074.

EMBODIMENT 35

[0161] synthesis of 14(3-methoxy-4-(2(4-methylpiperidin1-y;)ethoxy)benzyl)(methyl)amino)-3-(2-(trifluoromethyl)phenoxy)propan-2-ol (CHJ04082)

##STR00097##

[0162] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0163] Compound 7 used is 2-((2-trifluoromethyl)phenoxy)methyl)orirane (7-35).

[0164] Colorless oil,yield 83%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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). .sup.C NMR(CDCl.sub.3,100 MHz) ? (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.sup.?1): 2039, 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.sub.27H.sub.38F.sub.3N.sub.2O.sub.4 (M+H).sup.+: 511.2784. found: 511.2741.

EMBODIMENT 36

[0165] synthesis of 1-(4-chlorophenoxy)-3((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04083)

##STR00098##

[0166] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0167] Compound 7 used is 2-((4-methoxyphenoxy)methyl)oxirane (7-36).

[0168] Colorless oil,yield 90%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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), .sup.13CNMR(CDCl.sub.3,100 MHz) ? (ppm): 157.41, 149.51, 147.6.2, 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. IR (KBr cm.sup.?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): calcd for C.sub.26H.sub.38ClN.sub.2O.sub.4 (M+H).sup.+: 477.2520. found: 477.2471.

EMBODIMENT 37

[0169] synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino)-3-(4-methoxyphenoxy)propan-2-ol (CHJ04084)

##STR00099##

[0170] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0171] Compound 7 used is 2-((4-methoxyphenoxylmethyl)oxirane (7-37).

[0172] Colorless oil,yield 90%, .sup.1HNMR (CDCl.sub.3, 400 MHz) ? (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=11.20 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), .sup.C NMR(CDCl.sub.3,100 MHz) ? (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.sup.?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.sub.27H.sub.41N.sub.2O.sub.5 (M+H).sup.+: 473.3015. found: 473.2975.

EMBODIMENT 38

[0173] synthesis of 1-(2-chlorophenoxy)-3-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol(CHJ04085)

##STR00100##

[0174] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0175] Compound 7 used is 2((2-chlorophenoxy)methyl)oxirane (7-38).

[0176] Colorless oil,yield 83%, .sup.1H NMR (COCl.sub.3, 400 MHz) ? (ppm): 7.34 (d,J=8.0 Hz, 1 H), 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). .sup.13CNMR(CDCl.sub.3,100 MHz) ? 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.sup.?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.sub.26H.sub.38ClN.sub.2O.sub.4 (M+H).sup.+: 477.2520. found: 477.2506.

EMBODIMENT 39

[0177] synthesis of 1-((3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)benzyl)(methyl)amino-3-(2-methoxyphenoxy)propan-2-ol (CHJ04086)

##STR00101##

[0178] Compound 5 used is 1-(3-methoxy-4-(2-(4-methylpiperidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (51).

[0179] Compound 7 used is 2-((2-methoxyphenoxy)methyl)oxirane (7-39).

[0180] Colorless oil,yield 85%,.sup.1H NMR (CDCl.sub.3, 400 MHz) ? (ppm): 6.86 (m, 7H), 4.16 (t,J=6.0 Hz, 3H), 4.02 (m, 2), 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). .sup.13CNMR(CDCl.sub.3100 MHz)? (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.sup.?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): (ESI): m/z calcd for C.sub.27H.sub.41N.sub.2O.sub.5 (M+H).sup.+: 473.2972. found: 473.2972.

EMBODIMENT 40

[0181] synthesis of 1-(3-bromo-4-methylphenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl) (methyl)amino)propan-2-ol (CHJ04064)

##STR00102##

[0182] Compound 5 used is 1-(3-methoxy-4-(2(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (52).

[0183] Compound 7 used is 2-((3-bromo-4-methylphenoxy)methyl)oxirane 7-18).

[0184] Colorless oil,yield80%,.sup.1H NMR (CD.sub.3OD, 400 MHz) ? (ppm): 7.15 (d,J=8.40 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.3 (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). .sup.13CNMR (CD.sub.3OD, 100 MHz)? (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.sup.?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): (ESI): m/z calcd for C.sub.25H.sub.36BrN.sub.2O.sub.4 (M+H).sup.+: 507.1858. found: 507.1858.

EMBODIMENT 41

[0185] synthesis of 1-(-bromo-5-(trifluoromethyl)phenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy) benzyl)(methyl)amino)propan-2-ol(CHJ04065)

##STR00103##

[0186] Compound 5 used is 1-(3-methoxy-4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (52).

[0187] Compound 7 used is 2-((2-bromo-5-(trifluoromethyl)phenoxy)methyl)oxirane 7-19).

[0188] Colorless oil,yield 82%,.sup.1H NMR (CD.sub.3OD, 400 MHz)? (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), 13CNMR (CD30D, 100 MHz) ? (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, IRl (KBr, cm.sup.?1): 2968, 2938, 2879, 2793, 2361, 2323, 1734, 1700, 1518, 1492, 1459, 1419, 1398, 1328, 1268, 1252, 1167, 1137, 1080, 1035, 977, 906, 861, 748, 670. HRMS (ESI): m/z calcd for C.sub.25H.sub.33BrF.sub.3N.sub.2O.sub.4 (M+H).sup.+: 561.1576. found: 561.1569.

EMBODIMENT 42

[0189] synthesis of 1-(3,5-dichlorophenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl) amino)propan-2-ol (CHJ04066)

##STR00104##

[0190] Compound 5 used is 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (52).

[0191] Compound 7 used is 2-((3,5-dichlorophenoxy)methyl)oxirane 7-20).

[0192] Colorless oil,yield 84%, .sup.1H NMR (CD.sub.3OD 400 MHz) ? (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, 6.40 Hz, 1H), 2.32 (s, 3H), 1.88 (s, 4H). .sup.13CNMR (CD.sub.3OD, 100 MHz) ? (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). IR (KBr, cm?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.sub.24H.sub.33Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 483.1817. found: 483.1801.

EMBODIMENT 43

[0193] synthesis of 1-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)henzyl)(methyl)amino)-3-(2,4,6-tribromophenoxy)propan-2-ol (CHJ04068)

##STR00105##

[0194] Compound 5 used is 1-(3-methoxy-4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (52).

[0195] Compound 7 used is 2-((2,4,6-tribromophenoxy)methyl)oxirane 7-22).

[0196] White solid,yield 84%,mp: 60-70? C.,.sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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). .sup.13CNMR (CD3OD, 100 MHz) ? (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.sup.?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.sub.24H.sub.32Br.sub.3N.sub.2O.sub.4 (M+H).sup.+: 648.9912. found: 648.9938.

EMBODIMENT 44

[0197] synthesis of 1-(3,4-dichlorophenoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl) amino)propan-2-ol (CHJ04072)

##STR00106##

[0198] Compound 5 used is 1-(3-methoxy-4-(2-(pyrrolidin-1yl)ethoxy)phenyl)-N-methylmethanamine (5-2).

[0199] Compound 7 used is 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26).

[0200] Colorless oil,yield 85%, .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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=6.0 Hz, 1H), 2.47 (dd, J=12.80, 6.80 Hz, 1H), 2.32 (s, 3H), 1.85 (s, 4H). .sup.13CNMR(CD.sub.3OD, 100 MHz) ? (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.sup.?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.sub.24H.sub.33Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 483.1817. found: 483.1790.

EMBODIMENT 45

[0201] synthesis of 1-(4-bromo-2,6-dichlorophonoxy)-3-((3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)(methyl)amino)propan-2-ol (CHJ04074)

##STR00107##

[0202] Compound 5 used is 1-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2),

[0203] Compound 7 used is 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28).

[0204] Colorless oil,yield 85%, .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (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). .sup.13CNMR (CD.sub.3OD, 100 MHz) ? (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). IR (KBr, cm?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.sub.24H.sub.32BrCl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 561.0923. found: 561.0882.

EMBODIMENT 46

[0205] synthesis of 1-(3-bromo-5-chlorophenoxyl-3-((3-metboxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl)methyl)aminopropan-2-ol (CHJ04075)

##STR00108##

[0206] Compound 5 used is 1-(3-methoxy-4-(2-pyrrolidin-1-yl)ethoxy)phenyl)-N-methylmethanamine (5-2).

[0207] Compound 7 used is 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29).

[0208] Colorless oil,yield 87%, .sup.1H NMR (CD.sub.3OD, 400 MHz) ? (ppm); 7.13 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.90 (m, 2H), 6.82 (d, J=8.07 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), .sup.13CNMR (CD.sub.36l OD, 100 MHz) ? (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.sup.?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.sub.24H.sub.33BrClN.sub.2O.sub.4 (M+H).sup.+: 527.1312. found: 527.1275.

EMBODIMENT 47

[0209] synthesis of 1-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl)(methyl)amino)-3-(2-isopropylphenoxy)propan-2-ol (CHJ04089)

##STR00109##

[0210] Compound 5 used is N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine 5-3),

[0211] Compound 7 used is 2-((2-isopropylphenoxy)methyl)oxirane (7-7).

[0212] Colorless oil,yield 82%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (ppm): 7.20 (d, J=7.60 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.93 (t, J=07.20 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). .sup.13CNMR(CDCl.sub.3,100 MHz) ? (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.sub.27H.sub.43N.sub.2O.sub.4 (M+H).sup.+: 459.3223. found: 459.3166.

EMBODIMENT 48

[0213] synthesis of 1-(2-bromo-5-(trifluoromethyl)phenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-methoxy benzyl)(methyl)amino)propan-2-ol (CHJ04090)

##STR00110##

[0214] Compound 5 used is N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan1-amine (5-3).

[0215] Compound 7 used is 2-((2bromo-5-(trifluoromethl)phenoxy)methyl)oxirane (7-19).

[0216] Colorless oil,yield 81%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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.). .sup.13CNMR (CDCl.sub.3, 100 MHz) ? (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.sup.?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.sub.25H.sub.35BrF.sub.3N.sub.2O.sub.4 (M+H).sup.+: 563.1676. found: 563.1676.

EMBODIMENT 49

[0217] synthesis of 1-(3,4-dichlorophenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl)(methyl) amino)propan-2-ol (CHJ04091)

##STR00111##

[0218] Compound 5 used is N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3),

[0219] Compound 7 used is 2-((3,4-dichlorophenoxy)methyl)oxirane (7-26).

[0220] Colorless oil,yield 85%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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). .sup.13CNMR(CDCl.sub.3,100 MHz) ? (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.sub.24H.sub.35Cl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 485.1974. found: 485.1904.

EMBODIMENT 50

[0221] synthesis of 1-(3-bromo-4-fluorophenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl)(methyl)amino)propan-2-ol (CHJ04092)

##STR00112##

[0222] Compound 5 used is N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).

[0223] Compound 7 used is 2-((3-bromo-4-fluorophenoxy)metyl)oxirane (7-21).

[0224] Colorless oil,yield 82%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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=7.20 Hz, 2H), 2.67 (m, 5H), 2.47 (m, 1H), 2.29 (s, 3H), 1.09 (t, J=7.20 Hz, 6H). .sup.13CNMR(CDCk.sub.3, 100 MHz) ? (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, 66.04 62.37, 59.14, 55.96, 51.64, 47.80 (2C), 42.27, 11.69 (2C). IR (KBr, cm.sub.?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.sub.24H.sub.35BfFN.sub.2O.sub.4 (M+H).sup.+: 513.1764. found: 513.1710.

EMBODIMENT 51

[0225] synthesis of 1-(4-bromo-3trifluoromethyl)phenoxy)-3-(( 4-(2-(diethylamino)ethoxy)-3-methoxybenzyl)(methyl)amino)propan-2-ol (CHJ04093)

##STR00113##

[0226] Compound 5 used is N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).

[0227] Compound 7 used is 2((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane (7-3).

[0228] Colorless oil,yield 83%, .sup.1H NMR (CDCl.sub.3400 MHz) ? (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), .sup.13CNMR(CDCl.sub.3, 100 MHz) ? (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). IR (KBr, cm.sup.?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.sub.25H.sub.35BrF.sub.3N.sub.2O.sub.4 (M+H).sup.+: 563.1732. found: 563.1695.

EMBODIMENT 52

[0229] synthesis of1-(4-bromo-2,6-dichlorophenoxy)-3-((4-(2-(diethylamino)ethoxy)-3-methoxybenzyl) (methyl)amino)propan-2-ol (CHJ04094)

##STR00114##

[0230] Compound 5 used is N,N-diethyl-2-(2-methoxy-4-((methylamino)methyl)phenoxy)ethan-1-amine (5-3).

[0231] Compound 7 used is 2-((4-bromo-2,6-dichlorophenoxy)methyl)oxirane (7-28).

[0232] Colorless oil,yield 87%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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). .sup.13CNMR(CDCl.sub.3, 100 MHz) ? (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, 66.04, 62.37, 59.14, 55.96, 51.64, 47.80 (2C), 42.27, 11.69 (2C). IR, (KBr, cm.sup.?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.sub.24H.sub.34BrCl.sub.2N.sub.2O.sub.4 (M+H).sup.+: 563.1079. found: 563.1039.

EMBODIMENT 53

[0233] synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzyl)(methyl)amino)-3-(4-bromo-3-(trifluoromethyl)phenoxy)propari-ol (CHJ04097)

##STR00115##

[0234] Compound 5 used is 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).

[0235] Compound 7 used is 2-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)oxirane. (7-3).

[0236] White solid,yield 85%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (ppm): 7.64 (s, 1H), 7.56(d, J=8.80 Hz, 1H), 7.23(s1H), 7.10(s, 1H),7.05(s, 1H),6.92(d,J=8.8 Hz, 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=12.80 Hz, 1H), 3.46 (d,J=12.80 Hz, 1H), 2.62 (t, J=11.20 Hz, 1H), 2.49 (m, 1H), 2.30 (s, 3H). .sup.13CNMR(CDCl.sub.3,100 MHz) ? (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, 114.58, 114.18, 112.82, 110.21, 70.88, 68.92, 66.00, 62.35, 59.07, 55.95, 46.69, 42.35. IR (KB, cm.sup.?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.sub.24H.sub.28BrF.sub.3N.sub.3O.sub.4 (M+H).sup.+: 558.1215. found: 558.1172.

EMBODIMENT 54

[0237] synthesis of 1-((4-(2-(1H-imidazol-1yl)ethoxy)-3-methoxybenzyl)(methyl)amino)-3-(2-bromo-5-(trifluoromethyl)phenoxy)propan-2-ol (CHJ04099)

##STR00116##

[0238] Compound 5 used is 1-(4-(2-(1H-imidazol-1-yl)ethoxv)-3-methoxyphenyl)-N-methylmethanamine (5-4),

[0239] Compound 7 used is 2-((2-bromo-5-(trifluormethyl)phenoxy)methyl)oxirane (7-19)

[0240] White solid,yield 90%, .sup.1H NMR (CDCl.sup.3, 400 MHz) ? (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=12.80 Hz, 1H), 3.47 (d. J=13.20 Hz, 1H), 2.73 (t,J=11.60 Hz, 1H), 2.55 (m, 1H), 2.32 (s, 3H). .sup.13CNMR(CDCl.sub.3,100 MHz) ? (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, 116.41, 114.19, 112.80, 109.89, 71.55, 68.94, 66.15, 62.45, 58.93, 55.94, 46.65, 42.52. IR (KBr, cm.sup.?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.sub.24H.sub.28BrF.sub.3N.sub.3O.sub.4 (M+H).sup.+: 558.1215. found: 558.1160.

EMBODIMENT 55

[0241] synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzyl)(methyl)amino-3-(4-bromophenoxy)propan-2-ol (CHJ05001)

##STR00117##

[0242] Compound 5 used is 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).

[0243] Compound 7 used is 2-((4-bromophenoxy)methyl)oxirane (7-12).

[0244] White solid,yield 85%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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=13.20 Hz, 1H), 3.45 (d, J=12.80 Hz, 1H), 2.62 (t, J=11.60 Hz, 1H), 2.49 (m, 1H), 2.29 (s, 3H). .sup.13CNMR(CDCl.sub.3, 100 MHz) ? (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.sup.?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.sub.23H.sub.29BrN.sub.3O.sub.4 (M+H).sup.+: 490.1341. found: 490.1341.

EMBODIMENT56

[0245] synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzyl)(methyl)amino)-3-(3-bromo-4-methylphenoxy)propan-2-ol (CHJ05002)

##STR00118##

[0246] Compound 5 used is 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).

[0247] Compound 7 used is 2-((3-bromo-4-chlorophenoxy)methyl)oxirane (7-17).

[0248] White solid,yield 90%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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). .sup.13CNMR(CDCl.sub.3, 100 MHz) ? (ppm): 157.73, 1.49.89, 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.sub.23H.sub.28BrClN.sub.3O.sub.4 (M+H).sup.+: 524.0952. found: 524.0916.

EMBODIMENT 57

[0249] synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)03-methoxybenzyl)(methyl)amino)-3-(3-bromo-4-methylphenoxy)propan-2-ol (CHJ05003)

##STR00119##

[0250] Compound 5 used is 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).

[0251] Compound 7 used is 2((3-bromo-4-methylphenoxy)methyl)oxirane (7-18).

[0252] White solid,yield 90%,.sup.1H NMR CDCl.sub.3, 400 MHz) ? (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=12.80 Hz, 1H),3.46 (d, J=13.20 Hz, 1H ), 2.62 (t, J=12.0 Hz, 1H), 2.48 (m, 1H ), 2.30 (d,J=10.40 Hz, 6H), .sup.13CNMR(CDCl.sub.3,100 MHz) ? (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. 114.15, 113.90, 112.77, 70.68, 68.93, 66.11, 62.33, 59.30, 55.96, 46.64, 42.30, 21.84. 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 C.sub.24H.sub.31BrN.sub.3O.sub.4 (M+H).sup.+: 504.1498. found: 504.1460.

EMBODIMENT 58

[0253] synthesis of 1-((4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzyl)(methyl)amino)-3-(3-5-chlorophenoxy)propan-2-ol (CHJ05004)

##STR00120##

[0254] Compound 5 used is 1-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxyphenyl)-N-methylmethanamine (5-4).

[0255] Compound 7 used is 2-((3-bromo-5-chlorophenoxy)methyl)oxirane (7-29),

[0256] White solid,yield 88%, .sup.1H NMR (CDCl.sub.3, 400 MHz) ? (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=12.94 Hz,1H ),3.45 (d, J=13.35 Hz, 1H ), 2.60 (t, J=11.55 Hz, 1H), 2.47 (m, 1H), 2.29 (s, 3H). .sup.13CNMR(CDCl.sub.3, 100 MHz) ? (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.sub.23H.sub.28BrClN.sub.3O.sub.4 (M+H).sup.+:524.0952. found: 524.0913.

Experiment on Compounds in the Invention in Inhibiting the Activity of Tumor Cell Growth

1 Experiment Materials

[0257] Dissolve CHJ compound series with dimethyl sultbxide (DMSO, final concentration 0.4%), and use RPMI-1640 culture medium containing 15% fetal calf serum to prepare 1 mg/mL solution for future use. During drug administration in groups, use the culture medium to dilute it to the concentration needed.

TABLE-US-00003 Experiment reagent Reagent name Specification Manufacturer Cis-platinum 10 mg/bottle Qilu Pharmaceutical Co., Ltd. DMEM (High 500 mL Biological Industries in Glucose) Isreal Fetal calf serum 500 mL Biological Industries in Isreal Dimethyl sulfoxide 50 mL Beijing Solarbio Life Sciences Co., Ltd.: MTT 5 mL Sigma in America EDTA pancreatic 100 mL Beijing Solarbio Life enzyme Sciences Co., Ltd.:

[0258] Cell lines: human lung cancer (A549), Inman ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cell lines, all purchased from the Cell Bank of the Chinese Academy of Sciences, DMEM containing 15% fetal bovine serum (High Glucose) culture medium, placed in a 37? C., 5% CO2 incubator.

2. Experimental Methods

[0259] MTT is an oxidizing yellow dye with the chemical name of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazoliumbromide tetrazole bromide. The MMT method, also known as the MTT colorimetric method, can test the survival and growth of cells. The method is simple and easily accessible and often used to screet the substance with cytotoxic activity. The basic principle of testing, is that succinodehydrogenase can reduce exogenous MIT so that MTT is reduced to blueviolet crystal Formazan insoluble to water. The crystal deposits in cells. The succinodehydrogenase exists in the mitochondria of living cells, not in the dead cells. Therefore, the chromogenic reaction can only take place in living cells. Then, dissolve the blueviolet crystal Formazan contained in cells with dimethyl sulfoxide (DMSO), and measure its absorbancy with microplate reader so that the count of living cells is reflected indirectly. Within the scope of certain cell count, the amount of blueviolet crystal Formazan formed is positively correlated to the count of living cells.

[0260] MTT is efficient, accurate, convenient, economical and highly repeatable. It has been extensively applied to the screening of antitumor drugs, activity detection of medical bioactive factor, cytotoxic activity test, and the measurement of tumor radiosensitivity.

[0261] Preparation of 5 mg/mL MTT solution: weigh 500.0 mg MTT powder and dissolve it in 100 ml warm PBS. Use the millipore filter of 0.22 ?m aperture to screen the bacteria and obtain the filtrate. Divide the filtrate into small doses and put them the centrifugal tube which has gone through autoclaved sterilization. Freeze them in a dark place under ?20? C.

[0262] Fetch the frozen tube containing the tumor cells from ligrt d. nitrogen and put it swiftly into the 37? C. incubator. Keep shaking till it melts. Rub the rim of the cover of frozen tube with 75% alcohol, suck in the cell suspension and transfer it to 10 mL centrifugal tube. Add 5 ml culture medium. Apply low-speed centrifugation (25? C. 3000r/min, 5 min), discard the supernatant, add culture medium, and then repeat the centrifugation once more. After proper amount of culture medium is added for the purpose of dilution, blow away the cells with straw to form suspension. Transfer the suspension to the culture bottle, and place the bottle in the 37? C. cell incubator containing 5% CO.sub.2. Change the culture solution the next day and place the bottle in the 37? C. cell incubator containing 5% CO.sup.2 for continued culture.

[0263] Human lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) ceilsare all adherent. Based on the growth rate of tumor cells, wash the adherent tumor cells in the logarithmic phase and digest them in 0.25% EDTA pancreatic enzyme. Adjust the cell count to 1?105/mL and inoculate the cells in 96-pore plate, each pore containing 100 ?L. Culture the cells in the 37? C. CO.sub.2 incubator, and administer the drug 24 h later. Add pharmaceutical (CJH compound series) of different concentrations to the administration group. Set up 5 dosage groups for each pharmaceutical, respectively 100, 10, 1, 0.1, 0.01 ?mol/L. Set up three complex pores for each concentration. Set up blank control, DMSO (0.8%) solvent control and cis-platinum positive control. After 48 h of culture in the 37 ? C. incubator containing 5% CO.sub.2, measure the OD value through MTT method and calculate the cell inhibition ratio.

2.3 Calculation of IC.SUB.50

[0264] After 48 h of culture of human lung cancer (A549), human ovarian cancer (SKOV3). human melanoma (A375) and human colon cancer (LOVO) cells, stop it and add 10 ?L 0.5% MTT solution to each pore. Place it in the CO.sub.2 incubator for 4 h. Remove the liquid from each pore, respectively add 0.2 mL DMSO solution, and oscillate it adequately on the table concentrator under low frequency so that the blueviolet crystal Formazan is dissolved adequately. Place it in the microplate reader and record the OD value at the wavelength of 490 mm. Calculate the average OD value of three parallel pores of different concentrations, and calculate the cell inhibition ratio and IC.sub.50 of each tested pharmaceutical under different concentrations based on the average.

[0265] Inhibition ratio (%)=[1-tested sample OD/negative control group OD]?100%.

TABLE-US-00004 IC.sub.50 value of target compound against cancer cell proliferation IC.sub.50 (?M) Compound A549 SKOV3 A375 LOVO SAMS10 14.64 ? 0.06 21.07 ? 0.18 27.11 ? 0.66 8.48 ? 0.07 CHJ02029 3.55 ? 0.06 6.30 ? 0.16 2.43 ? 0.12 1.87 ? 0.02 CHJ02049 0.52 ? 0.23 0.62 ? 0.08 0.62 ? 0.04 1.25 ? 0.03 CHJ02050 1.09 ? 1.55 4.04 ? 0.06 1.87 ? 0.07 3.88 ? 1.80 CHJ03001 1.30 ? 1.03 2.48 ? 10.63 1.95 ? 0.33 1.26 ? 0.53 CHJ03003 6.08 ? 0.90 3.00 ? 0.99 5.95 ? 0.42 0.70 ? 0.26 CHJ03004 2.10 ? 1.25 6.19 ? 0.25 0.72 ? 0.80 2.54 ? 0.10 CHJ03005 15.58 ? 0.16 3.99 ? 0.21 5.60 ? 0.81 6.66 ? 0.11 CHJ03011 10.56 ? 0.02 21.21 ? 1.08 1.82 ? 1.23 15.19 ? 1.78 CHJ03012 2.19 ? 1.04 3.54 ? 1.02 0.16 ? 0.33 1.95 ? 0.43 CHJ03014 1.09 ? 0.06 6.19 ? 0.62 1.63 ? 0,72 0.53 ? 0.15 CHJ03015 1.03 ? 0.13 4.47 ? 1.62 3.22 ? 0,42 0.55 ? 0.21 CHJ03017 17.25 ? 0.79 6.21 ? 1.04 8.68 ? 0.11 2.44 ? 0.03 CHJ03018 18.76 ? 1.06 1.79 ? 0.23 3.13 ? 0.06 1.72 ? 1.58 CHJ03043 2.50 ? 1.32 2.90 ? 0.19 0.54 ? 0.26 0.95 ? 0.41 CHJ04010 4.51 ? 1,29 4.96 ? 1.26 0.45 ? 0.46 2.78 ? 0.23 CHJ04011 4.05 ? 1.12 2.41 ? 1.03 0.48 ? 0.28 1.01 ? 0.08 CHJ04012 6.38 ? 0.07 4.34 ? 0.32 1.24 ? 1.01 2.12 ? 0.04 CHJ04020 1.38 ? 1.14 3.40 ? 1.17 1.60 ? 0.92 3.83 ? 1.80 CHJ04022 1.88 ? 0.19 1.03 ? 0.24 0.05 ? 0.01 0.69 ? 0.03 CHJ04023 5.44 ? 2.54 8.03 ? 2.77 0.81 ? 0.33 3.07 ? 1.62 CHJ04024 5.45 ? 1.03 1.37 ? 0.34 0.98 ? 0.76 18.61 ? 3.22 CHJ04025 4.21 ? 2.24 3.32 ? 1.02 2.34 ? 1.63 2.55 ? 1.65 CHJ04026 0.97 ? 0.21 7.45 ? 2.26 1.50 ? 0.06 0.82 ? 0.42 CHJ04027 6.22 ? 1.34 3.02 ? 1.76 0.73 ? 0.13 2.35 ? 1.04 CHJ04033 0.95 ? 0.37 6.22 ? 3.05 0.92 ? 0.07 2.23 ? 1.26 CHJ04034 0.86 ? 0.45 3.06 ? 1.10 0.65 ? 0.14 1.16 ? 0.94 CHJ04036 17.84 ? 3.62 15.5 ? 2.56 18.36 ? 1.10 3.67 ? 0.41 CHJ04058 245.31 ? 2.40 101.71 ? 1.48 56.21 ? 0.55 53.96 ? 2.14 CHJ04059 10.63 ? 3.37 3.26 ? 1.21 3.23 ? 0.49 3.92 ? 0.56 CHJ04060 CHJ04061 333.10 ? 2.7 143.47 ? 3.1 62.13 ? 4,21 97.14 ? 4.21 CHJ04064 21.50 ? 3.65 17.05 ? 0.24 9.24 ? 2.65 3.55 ? 2.14 CHJ04065 25.48 ? 2.11 27.07 ? 1.62 10.82 ? 1,79 3.14 ? 1.06 CHJ04066 29.90 ? 2.45 77.07 ? 4.07 10.29 ? 1.40 2.50 ? 0.65 CHJ04068 5.46 ? 1.76 4.21 ? 1.23 1.54 ? 1.34 0.52 ? 0.40 CHJ04072 12.53 ? 2.44 9.62 ? 4.23 2.26 ? 0.37 5.21 ? 2.31 CHJ04082 22.26 ? 1.98 28.54 ? 5.22 7.51 ? 2.62 2.82 ? 1.05 CHJ04083 13.35 ? 2.02 10.36 ? 1.43 2.44 ? 1.03 1.23 ? 0.17 CHJ04084 42.69 ? 3.06 96.38 ? 2.72 16.70 ? 2.48 7.54 ? 1.02 CHJ04085 28.83 ? 5.12 49.22 ? 1.97 7.32 ? 1.80 1.94 ? 0.79 CHJ04086 34.7 ? 3.42 CHJ04089 27.78 ? 1.73 42.71 ? 2.61 15.03 ? 2.37 49.50 ? 3.54 CHJ04090 35.01 ? 2.21 36.4 ? 2.17 11.70 ? 2.12 34.05 ? 2.59 CHJ04091 11.05 ? 1.33 17.8 ? 3.11 4.01 ? 3.11 10.63 ? 3.20 CHJ04092 30.16 ? 2.76 34.5 ? 2.70 11.23 ? 1.05 47.91 ? 3.43 CHJ04093 20.12 ? 2.01 10.24 ? 1.69 2.60 ? 1.22 14.45 ? 2.14 CHJ04094 18.40 ? 3.17 15.86 ? 2.11 2.05 ? 1.01 28.51 ? 4.42 CHJ04097 24.38 ? 2.78 33.59 ? 2.47 14.85 ? 2.77 32.10 ? 3.39 CHJ04098 35.92 ? 2.09 47.40 ? 3.20 19.48 ? 2.15 29.80 ? 3.72 CHJ04099 23.10 ? 2.58 37.39 ? 2.48 16.16 ? 2.11 38.24 ? 2.94 CHJ05001 30.69 ? 3.12 40.12 ? 3.02 15.78 ? 1.73 49.10 ? 2.71 CHJ05002 35.66 ? 2.71 42.96 ? 2.37 13.66 ? 2.06 33.10 ? 3.27 CHJ05003 33.97 ? 2.11 35.11 ? 1.35 24.92 ? 1.93 52.49 ? 1.22 cisplatin 4.21 ? 1.31 1.91 ? 0.43 5.91 ? 1.64 2.64 ? 1.12

3. Experiment Result

[0266] It is found by observing the above experiment data that the majority of the target compounds perform well in inhibitinghuman lung cancer (A549), human ovarian cancer (SKOV3), human melanoma (A375) and human colon cancer (LOVO) cells. Moreover, it can be seen from the data that the compounds with tetramethyl piperidine on the right are usually more active than those with tetrahydropyrrole, diethylin or pyrrole on the right in fighting off cancer. When the length of chain on the hydrophobic side increases on the left of the compound (CHJ03011 and CHJ03012), the compound is still effective against cancer. Nonetheless, the anti-cancer activity of compound can be lowered prominently by introducing large polar compound to the aromatic ring on the left (CHJ04068 and CHJ04061). It is worth noting that the compound with 3 Br atoms as substitute on the aromatic ring on the left (CHJ04022 and CHJ04068) are the most active, as active as the cis-platinum in the control group.