DEZOCINE ANALOGUE

Abstract

Disclosed in the present disclosure is a Dezocine analogue, and particularly disclosed are compounds represented by formula (I), (II) and (III), a pharmaceutically acceptable salt or tautomer thereof.

##STR00001##

Claims

1. A compound represented by formula (I), (II) and (III), a pharmaceutically acceptable salt or tautomer thereof, ##STR00148## wherein, each of X.sub.1, X.sub.2, X.sub.3 is independently selected from single bond, CH.sub.2, C(RR), NH, N(R), O, or S; R.sub.12 is selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, or the group consisting of C.sub.1-6 alkyl or heteroalkyl, 3-7 membered cycloalkyl or heterocycloalkyl, 5-7 membered aryl or heteroaryl, each of which is optionally substituted by 1, 2, or 3 R; and, when X is CH.sub.2, R.sub.12 is not H; each of R.sub.22 and R.sub.32 is independently selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, or the group consisting of C.sub.1-6 alkyl or heteroalkyl, 3-7 membered cycloalkyl or heterocycloalkyl, and 5-7 membered aryl or heteroaryl, each of which is optionally substituted by 1, 2, or 3 R; n is 1, 2, or 3; each of R.sub.11, R.sub.21 and R.sub.31 is independently selected from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 heteroalkyl, each of which is optionally substituted by 1, 2, or 3 R; R.sub.23 is selected from the group consisting of C.sub.1-12 alkyl, C.sub.1-12 heteroalkyl, C.sub.3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, or 3 R; L is selected from the group consisting of C.sub.1-12 alkyl, C.sub.1-12 heteroalkyl, C.sub.3-7 cycloalkyl, or 3-7 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, or 3 R; said hetero represents O, S, or N, the number of which is selected from 1, 2 or 3 in any of the above cases; said R is selected from F, Cl, Br, I, CN, OH, NH.sub.2, C.sub.1-3 alkyl, or C.sub.1-3 heteroalkyl; said C.sub.1-3 alkyl or C.sub.1-3 heteroalkyl are each optionally substituted by 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, I, CN, OH, NH.sub.2; two geminal or ortho R optionally connect to the same atom forming 3-6 membered cycloalkyl or heterocycloalkyl.

2. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.12 is selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, or the group consisting of C.sub.1-5 alkyl or heteroalkyl, 3-5 membered cycloalkyl or heterocycloalkyl, and 5-6 membered aryl or heteroaryl, each of which is optionally substituted by 1, 2, or 3 R; and, when X is CH.sub.2, R.sub.12 is not H.

3. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 2, wherein R.sub.12 is selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, Me, ##STR00149## and, when X is CH.sub.2, R.sub.12 is not H.

4. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 2, wherein R.sub.12 is selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, Me, ##STR00150## and, when X is CH.sub.2, R.sub.12 is not H.

5. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein each of R.sub.22 and R.sub.32 is independently selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, or the group consisting of C.sub.1-5 alkyl or heteroalkyl, 3-5 membered cycloalkyl or heterocycloalkyl and 5-6 membered aryl or heteroaryl, each of which is optionally substituted by 1, 2, or 3 R.

6. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 5, wherein each of R.sub.22 and R.sub.32 is independently selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, Me, ##STR00151##

7. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 6, wherein each of R.sub.22 and R.sub.32 is independently selected from H, F, Cl, Br, I, CN, OH, NH.sub.2, Me, ##STR00152##

8. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein each of R.sub.11, R.sub.21 and R.sub.31 is independently selected from Me, ##STR00153## trifluoromethyl, monofluoromethyl, ##STR00154##

9. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein L is selected from (CH.sub.2).sub.4, (CH.sub.2).sub.5, (CH.sub.2).sub.6, (CH.sub.2).sub.7, (CH.sub.2).sub.8, (CH.sub.2).sub.9, (CH.sub.2).sub.10, ##STR00155##

10. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1, wherein R.sub.23 is selected from ##STR00156##

11. The compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1, which are selected from the group consisting of ##STR00157## ##STR00158## wherein, L, R.sub.11, R.sub.12, R.sub.21, R.sub.22, R.sub.23, R.sub.31 and R.sub.32 are defined as in claim 1.

12. A compound selected from the group consisting of ##STR00159## ##STR00160## ##STR00161## ##STR00162##

13. A compound selected from the group consisting of ##STR00163## ##STR00164## ##STR00165##

14. A method for treating pain in a subject in need thereof, comprising: administering an effective amount of the compound, the pharmaceutically acceptable salt or tautomer thereof according to claim 1 to the subject.

Description

DETAILED DESCRIPTION

[0108] The present disclosure will be specifically described below by way of examples, but the scope of the present disclosure is not limited thereto.

Example 1: Preparation of Compound 1

[0109] ##STR00035## ##STR00036##

[0110] Step 1: Preparation of Compound 1-2

[0111] Under nitrogen atmosphere, a solution of MeMgBr in ether (16.33 mL, 48.99 mmol) was slowly added dropwise to a solution of compound 1-1 (5.00 g, 19.60 mmol) in toluene (100 mL) at 0 C. After the reaction temperature was slowly raised to 25 C., the mixture was further stirred for 3 hours. The reaction was quenched with saturated NH.sub.4Cl solution (100 mL) and the aqueous phase was extracted with ethyl acetate (150 mL3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to approximately 100 mL. The remaining solution was added with aqueous HCl (6M, 20 mL), the mixture was stirred vigorously at 25 C. for 3 hours and extracted with ethyl acetate (200 mL3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=30/1 to 20/1) to give product 1-2 as a colorless oil (4.00 g, yield: 80.62%). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.97 (d, J=2.4 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 5.92 (dt, J.sub.1=1.2 Hz, J.sub.2=4.4 Hz, 1H), 3.82 (s, 3H), 2.84 (t, J=8.0 Hz, 2H), 2.27 (ddt, J.sub.1=2.0 Hz, J.sub.2=4.4 Hz, J.sub.3=8.0 Hz, 2H), 2.04 (q, J=1.6 Hz, 3H).

[0112] The following compounds were synthesized according to a method similar to that of compound 1-2:

TABLE-US-00001 Coumpound number Structure Spectrogram 2-2 [00037] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.06-7.04 (d, J = 8.0 Hz, 1H), 6.82-6.81 (d, J = 2.4 Hz, 1H), 6.71-6.68 (dd, J.sub.1 = 2.8 Hz, J.sub.2 = 2.4 Hz, 1H), 5.89-5.87 (m, 1H), 3.81 (s, 1H), 2.72-2.66 (m, 2H), 2.24-2.22 (m, 2H), 2.05-2.04 (m, 3H). 3-2 [00038] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.77 (d, J = 2.8 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 5.92 (s, 1H), 3.81 (s, 3H), 2.82 (t, J = 8.0 Hz, 2H), 2.23-2.28 (m, 2H), 2.03 (d, J = 1.6 Hz, 3H). 4-2 [00039] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.84 (t, J = 8.4 Hz, 1H), 6.74 (t, J = 8.0 Hz, 1H), 5.88-5.90 (m, 1H), 3.87 (s, 3H), 2.64 (t, J = 7.2 Hz, 2H), 2.15-2.22 (m, 5H). 5-2 [00040] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.82 (s, 1H), 6.72 (s, 1H), 5.78 (m, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 2.73 (t, J = 8.0 Hz, 2H), 2.27 (ddt, J.sub.1 = 2.0 Hz, J.sub.2 = 4.4 Hz, J.sub.3 = 8.0 Hz, 2H), 2.06 (s, 3H). 6-2 [00041] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.63 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 10.0 Hz, 1H), 6.54 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 10.8 Hz, 1H), 5.93 (t, J = 4.4 Hz, 1H), 3.84 (s, 3H), 2.75-2.67 (m, 2H), 2.23 (td, J.sub.1 = 2.0 Hz, J.sub.2 = 6.4 Hz, 2H), 2.03 (q, J = 1.6 Hz, 3H). 7-2 [00042] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.01 (d, J = 1.6 Hz, 1H), 6.90 (s, 1H), 5.91-5.85 (m, 1H), 3.82 (s, 3H), 2.70 (t, J = 8.0 Hz, 2H), 2.27 (ddt, J.sub.1 = 2.0 Hz, J.sub.2 = 4.4 Hz, J.sub.3 = 8.0 Hz, 2H), 2.01 (s, 3H).

[0113] Step 2: Preparation of Compound 1-3

[0114] M-chloroperoxybenzoic acid (4.1 g, 18.96 mmol) was added to a solution of compound 1-2 (4.00 g, 15.80 mmol) in dichloromethane (80 mL) at 0 C. The mixture was stirred at 0 C. for 30 minutes, and then the reaction was quenched by sequential addition of Na.sub.2SO.sub.3 and saturated solution of NaHCO.sub.3 (1:1, 15 mL). The aqueous phase was extracted with dichloromethane (100 mL3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to approximately 50 mL. Boron trifluoride etherate complex (0.2 mL) was added to the remaining solution at 0 C. and the mixture was further stirred at 0 C. for 1 hour. After the reaction was quenched by addition of saturated solution of Na.sub.2CO.sub.3 (10 mL), the aqueous phase was extracted with dichloromethane (100 mL3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=30/1 to 20/1) to give product 1-3 as a white solid (3.00 g, yield: 70.05%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.04-7.05 (d, J=2.8 Hz, 1H), 6.74-6.73 (d, J=2.8 Hz, 1H), 3.81 (s, 3H), 3.51 (m, 1H), 3.31-3.29 (m, 1H), 3.11 (m, 1H), 2.64-2.51 (m, 2H), 1.47 (d, J=7.2 Hz, 3H).

[0115] The following compounds were synthesized according to a method similar to that of compound 1-3:

TABLE-US-00002 Compound number Structure Spectrogram 2-3 [00043] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.15-7.11 (dd, J.sub.1 = 2.8 Hz, J.sub.2 = 2.4 Hz, 1H), 6.77-6.75 (m, 2H), 3.81 (s, 3H), 3.53- 3.49 (m, 1H), 3.05-3.01 (m, 2H), 2.64-2.59 (m, 1H), 2.52-2.48 (m, 1H), 1.48-1.46 (d, J = 6.8 Hz, 3H). 3-3 [00044] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.85 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.54-3.45 (m, 1H), 3.48-3.25 (m, 1H), 3.24-3.23 (m, 1H), 3.09-3.05 (m, 1H), 2.61-2.45 (m, 2H), 1.45 (d, J = 7.2 Hz, 3H). 4-3 [00045] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.92 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.79-3.75 (m, 1H), 3.18-3.07 (m, 1H), 3.01-2.91 (m, 1H), 2.77-2.73 (m, 1H), 2.52-2.48 (m, 1H), 1.43 (d, J = 7.6 Hz, 3H). 5-3 [00046] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.74 (m, 2H), 3.90 (s, 6H), 3.49-3.41 (m, 1H), 3.10-3.05 (m, 2H), 2.65-2.49 (m, 2H), 1.47 (d, J = 7.2 Hz, 3H). 6-3 [00047] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.57-6.48 (m, 2H), 3.79 (s, 3H), 3.49 (d, J = 7.2 Hz, 1H), 3.22-3.05 (m, 1H), 3.03- 2.86 (m, 1H), 2.67-2.37 (m, 2H), 1.45 (s 3H). 7-3 [00048] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.96 (s, 1H), 6.91 (s, 1H), 3.84 (s, 3H), 3.51-3.41 (m, 1H), 3.17-3.10 (m, 1H), 2.96-2.88 (m, 1H), 2.64-2.42 (m, 2H), 1.47 (d, J = 7.2 Hz, 3H).

[0116] Step 3: Preparation of Compound 1-4

[0117] Under nitrogen atmosphere, tetrabutylammonium bromide (492.79 mg, 1.86 mmol) was added to a mixture solution of compound 1-3 (5.00 g, 18.58 mmol) and 1,5-dibromopentane (12.82 g, 55.73 mmol) in toluene (50 mL) at 25 C. After the mixture was cooled to 0 C. under an ice bath, 35% aqueous solution of NaOH (36 g, 315.80 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 C. for 2 hours, then warmed to 25 C. and stirred for 14 hours. The aqueous phase was extracted with ethyl acetate (100 mL3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=30/1 to 20/1) to give product 1-4 as a colorless oil (4.50 g, yield: 57.9%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.07 (d, J=2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 3.83 (s, 3H), 3.33 (t, J=6.8 Hz, 2H), 3.26-3.14 (m, 1H), 3.09-2.98 (m, 1H), 2.77-2.65 (m, 1H), 2.65-2.55 (m, 1H), 2.14 (ddd, J.sub.1=13.2 Hz, J.sub.2=12.0 Hz, J.sub.3=4.4 Hz, 1H), 1.76 (quin, J=7.2 Hz, 2H), 1.65 (dd, J.sub.1=12.4 Hz, J.sub.2=4.4 Hz, 1H), 1.40 (s, 3H), 1.38-1.30 (m, 2H), 1.08-0.83 (m, 2H).

[0118] The following compounds were synthesized according to a method similar to that of compound 1-4:

TABLE-US-00003 Compound number Structure Spectrogram 2-4 [00049] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.09 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.76 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 8.4 Hz, 1H), 3.82 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 3.01- 2.96 (m, 2H), 2.73-2.64 (m, 1H), 2.61-2.53 (m, 1H), 2.16-2.06 (m, 1H), 1.74 (quin, J = 7.2 Hz, 2H), 1.68- 1.59 (m, 1H), 1.39 (s, 3H), 1.35-1.27 (m, 2H), 1.03- 0.88 (m, 2H). 3-4 [00050] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.87 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.41-3.29 (m, 1H), 3.24-3.10 (m, 1H), 3.05-2.95 (m, 1H), 2.70- 2.50 (m, 2 H), 2.15-2.05 (m, 1H), 1.79-1.50 (m, 3H), 1.41-1.24 (m, 5H), 1.00-0.83 (m, 2H). 4-4 [00051] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.93-6.80 (m, 2H), 3.89 (s, 3H), 3.31 (t, J = 7.2 Hz, 2H), 3.04-2.88 (m, 2H), 2.82-2.71 (m, 1H), 2.58-2.50 (m, 1H), 2.25- 2.21 (m, 1H), 2.08-1.94 (m, 1H), 1.74 (m, 2H), 1.51 (s, 3H), 1.44-1.25 (m, 2H), 1.05-0.98 (m, 1H), 0.87- 0.73 (m, 1H). 5-4 [00052] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.74 (s, 1H), 6.65 (s, 1H), 3.89 (s, 6H), 3.31 (t, J = 6.8 Hz, 2H), 3.05-2.95 (m, 2H), 2.72-2.57 (m, 2H), 2.14 (ddd, J.sub.1 = 13.2 Hz, J.sub.2 = 12.0 Hz, J.sub.3 = 4.4 Hz, 1H), 1.80-1.7 (m, 2H), 1.65- 1.55 (m, 1H), 1.49-1.25 (m, 5H), 1.08-0.83 (m, 2H). 6-4 [00053] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.68-6.47 (m, 2H), 3.83 (s, 3H), 3.33 (t, J = 6.8 Hz, 2H), 3.06 (s, 1H), 2.97- 2.83 (m, 1H), 2.73-2.48 (m, 2H), 2.13 (dd, J.sub.1 = 4.8 Hz, J.sub.2 = 13.2 Hz, 1H), 1.82-1.71 (m, 2H), 1.69-1.59 (m, 1H), 1.41 (s, 3H), 1.30 (s, 2H), 1.09-0.83 (m, 2H). 7-4 [00054] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.98 (s, 1H), 6.84 (s, 1H), 3.80 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 3.10-3.01 (m, 1H), 2.81-2.75 (m, 1H), 2.65-2.45 (m, 2H), 2.14 (ddd, J.sub.1 = 13.2 Hz, J.sub.2 = 12.0 Hz, J.sub.3 = 4.4 Hz, 1H), 1.80- 1.6 (m, 3H), 1.40 (s, 3H), 1.38-1.30 (m, 2H), 1.08- 0.83 (m, 2H). 8-1 [00055] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.10 (d, J = 8.4 Hz, 1H), 6.82-6.75 (m, 2H), 3.82 (s, 3H), 3.60-3.34 (m, 2H), 3.33-3.31 (m, 2H), 3.23-3.20 (m, 2H), 3.10-3.00 (m, 1H), 3.00-2.90 (m, 1H), 2.75-2.66 (m, 2H), 2.66- 2.54 (m, 1H), 1.92-1.87 (m, 1H), 1.43 (s, 3H).

[0119] Step 4: Preparation of Compound 1-5

[0120] Under nitrogen atmosphere, NaH (60% wt, 688.6 mg, 17.23 mmol) was added to a solution of compound 1-4 (4.00 g, 9.57 mmol) in DMF (80 mL) at 25 C. The reaction mixture was stirred at room temperature for 10 minutes, then heated to 60 C. and stirred for 1 hour. After being cooled to room temperature, the reaction solution was poured into ice water (400 mL). The aqueous phase was extracted with ethyl acetate (400 mL3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=30/1 to 20/1) to give product 1-5 (1.50 g, yield: 46.48%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.06 (d, J=2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 3.82 (s, 3H), 3.26 (dd, J.sub.1=4.4 Hz, J.sub.2=16.8 Hz, 1H), 3.08-2.99 (m, 1H), 2.79 (dd, J.sub.1=4.0 Hz, J.sub.2=9.6 Hz, 1H), 2.45-2.35 (m, 1H), 1.94-1.83 (m, 1H), 1.82-1.72 (m, 2H), 1.70-1.48 (m, 4H), 1.42-1.30 (m, 5H).

[0121] The following compounds were synthesized according to a method similar to that of compound 1-5:

TABLE-US-00004 Compound number Structure Spectrogram 2-5 [00056] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.07 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.74 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 8.0 Hz, 1H), 3.85-3.79 (m, 3H), 3.08-2.97 (m, 2H), 2.76 (qd, J.sub.1 = 5.2 Hz, J.sub.2 = 9.6 Hz, 1H), 2.48-2.36 (m, 1H), 1.95-1.85 (m, 1H), 1.79-1.70 (m, 2H), 1.65-1.50 (m, 4H), 1.37 (s, 3H), 1.34-1.24 (m, 2H). 3-5 [00057] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.85 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 3.21 (dd, J.sub.1 = 17.2 Hz, J.sub.2 = 4.8 Hz, 1H), 3.01 (dd, J.sub.1 = 16.4 Hz, J.sub.2 = 5.6 Hz, 1H), 2.79-2.70 (m, 1H), 2.45-2.30 (m, 1H), 1.95-1.70 (m, 3H), 1.64-1.45 (m, 3H), 1.29-1.26 (m, 5H). 4-5 [00058] MS (m/z): 276.9 (M + 1). 5-5 [00059] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.73 (s, 1H), 6.64 (s, 1H), 3.88 (s, 6H), 3.12-3.03 (m, 1H), 2.98-2.90 (m, 1H), 2.81-2.72 (m, 1H), 2.41-2.29 (m, 1H), 2.00- 1.86 (m, 1H), 1.82-1.71 (m, 2H), 1.66-1.47 (m, 4H), 1.36 (s, 3H), 1.35-1.28 (m, 2H), 0.92-0.81 (m, 1H). 6-5 [00060] MS (m/z): 277.0 (M + 1). 7-5 [00061] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.03 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 3.85 (s, 3H), 3.15 (dd, J.sub.1 = 3.6 Hz, J.sub.2 = 17.6 Hz, 1H), 2.87-2.75 (m, 2H), 2.40- 2.30 (m, 1H), 1.94-1.72 (m, 3H), 1.70-1.48 (m, 4H), 1.42-1.30 (m, 5H). 8-2 [00062] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.09 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.78-6.75 (m, 1H), 3.82 (s, 3H), 3.80-3.71 (m, 2H), 3.49-3.46 (m, 1H), 3.35- 3.25 (m, 1H), 3.08-3.06 (m, 1H), 3.00-2.98 (m, 1H), 2.98-2.84 (m, 1H), 2.50-2.43 (m, 1H), 2.12-2.08 (m, 2H), 2.05-1.90 (m, 1H), 1.40 (s, 3H).

[0122] Step 5: Preparation of Compound 1-6

[0123] Under nitrogen atmosphere, the mixed solution of compound 1-5 (400.00 mg, 1.19 mmol), MeB(OH).sub.2 (142.47 mg, 2.38 mmol), K.sub.2CO.sub.3 (493.41 mg, 3.57 mmol) and Pd(dppf)Cl.sub.2 (87.07 mg, 119.00 umol) in dioxane (8 mL) was heated to 100 C. and the mixture was stirred for 2 hours. After being cooled down, the reaction solution was diluted with 50 mL water. The aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to give product 1-6 as a yellow oil (250.00 mg, yield 77.13%). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.66 (m, 2H), 3.80 (s, 3H), 2.94 (dq, J.sub.1=5.2 Hz, J.sub.2=16.4 Hz, 2H), 2.76 (dd, J.sub.1=4.4 Hz, J.sub.2=9.6 Hz, 1H), 2.40 (ddd, J.sub.1=2.0 Hz, J.sub.2=8.0 Hz, J.sub.3=14.4 Hz, 1H), 2.28 (s, 3H), 1.98-1.85 (m, 1H), 1.81-1.67 (m, 2H), 1.65-1.46 (m, 3H), 1.41-1.29 (m, 5H).

[0124] The following compounds were synthesized according to a method similar to that of compound 1-6:

TABLE-US-00005 Compound number Structure Spectrogram 9-1 [00063] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.71-6.63 (m, 2H), 3.08- 2.98 (m, 1H), 2.94 (d, J = 5.6 Hz, 1H), 2.76 (d, J = 5.2 Hz, 1H), 2.63 (dd, J.sub.1 = 4.0 Hz, J.sub.2 = 7.6 Hz, 2H), 2.40 (br. s., 1H), 2.00-1.82 (m, 1H), 1.81-1.66 (m, 3H), 1.65-1.44 (m, 5H), 1.39-1.29 (m, 6H), 1.20 (t, J = 7.6 Hz, 3H). 10-1 [00064] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.76 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.22 (s, 1H), 4.86 (s, 1H), 3.83 (s, 3H), 3.08-2.95 (m, 2H), 2.75 (m, 1H), 2.48 (m, 1H), 2.03 (s, 3H), 1.87 (m, 2H), 1.84-1.59 (m, 6H), 1.39- 1.29 (m, 7H). 11-1 [00065] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.46-7.40 (m, 2H), 7.39- 7.34 (m, 1H), 7.33-7.28 (m, 2H), 6.86 (d, J = 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 3.83 (s, 3H), 2.93-2.87 (m, 2H), 2.69-2.60 (m, 1H), 2.57-2.47 (m, 1H), 1.90-1.72 (m, 2H), 1.69-1.45 (m, 6H), 1.45- 1.41 (m, 3H), 1.41-1.22 (m, 2H).

[0125] Step 6: Preparation of Compound 1-7

[0126] The mixed solution of compound 1-6 (250.00 mg, 0.92 mmol) and NH.sub.2OHHCl 63.78 mg, 0.92 mmol) in pyridine (8 mL) was heated at reflux for 24 hours. After being cooled to 25 C., the reaction solution was poured into ice water (100 mL). The aqueous phase was acidified with dilute hydrochloric acid (1M) and extracted with dichloromethane (100 mL3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give product 1-6 (118.00 mg, yield 44.73%). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.75 (d, J=2.8 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 3.81 (s, 3H), 3.76 (d, J=7.2 Hz, 1H), 2.92-2.77 (m, 2H), 2.36-2.30 (m, 1H), 2.28 (s, 3H), 2.15-2.03 (m, 1H), 1.69-1.55 (m, 8H), 1.54 (s, 3H).

[0127] The following compounds were synthesized according to a method similar to that of compound 1-7:

TABLE-US-00006 Compound number Structure Spectrogram 2-6 [00066] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.05-7.03 (d, J = 8.0 Hz, 1H), 6.85-6.83 (d, J = 2.4 Hz, 1H), 6.73-6.70 (dd, J.sub.1 = 2.8 Hz, J.sub.2 = 2.8 Hz, 1H), 3.80 (s, 3H), 3.80- 3.73 (m, 1H), 3.01-2.96 (m, 1H), 2.89-2.83 (m, 1H), 2.32-2.31 (m, 1H), 2.09-2.05 (m, 1H), 1.80- 1.70 (m, 1H), 1.62- 1.57 (m, 5H), 1.55 (s, 3H). 3-6 [00067] MS (m/z): 307.9 (M + 1). 4-6 [00068] MS (m/z): 292.1 (M + 1). 5-6 [00069] MS (m/z): 304.1 (M + 1). 6-6 [00070] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.68 (d, J = 1.6 Hz, 1H), 6.51 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 11.2 Hz, 1H), 3.80 (m, 4H), 3.01-2.79 (m, 2H), 2.35-2.21 (m, 1H), 2.16- 2.02 (m, 1H), 1.68-1.55 (m, 12H), 1.53 (s, 3H). 8-3 [00071] MS (m/z): 276.0 (M + 1). 9-2 [00072] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.74 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 3.77- 3.67 (m, 1H), 3.11-2.92 (m, 1H), 2.88 (dd, J.sub.1 = 4.4 Hz, J.sub.2 = 7.2 Hz, 2H), 2.62 (q, J = 7.6 Hz, 2H), 2.38- 2.22 (m, 1H), 1.58 (m, 11H), 1.19 (t, J = 7.6 Hz, 3H). 10-2 [00073] MS (m/z): 314.0 (M + 1). 11-2 [00074] MS (m/z): 349.9 (M + 1).

[0128] Step 7: Preparation of Compound 1-8

[0129] Under nitrogen atmosphere, Raney-Ni (0.5 g, 50% wt) was added to a solution of compound 1-7 (100.00 mg, 347.95 umol) in ethanol (15 mL). The reaction system was evacuated and purged with H.sub.2 for three times. Then the reaction solution was heated to 70 C. under H.sub.2 atmosphere (50 psi) and stirred for 48 hours. The reaction mixture was filtered under suction and the filtrate was concentrated in vacuo to give crude product 1-8 (80 mg) which was used directly in the next step without further purification. MS (m/z): 274.0 (M+1).

[0130] The following compounds were synthesized according to a method similar to that of compound 1-8:

TABLE-US-00007 Compound number Structure Spectrogram 2-7 [00075] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.01-6.99 (d, J = 8.8 Hz, 1H), 6.79-6.78 (d, J = 2.8 Hz, 1H), 6.73-6.70 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 2.8 Hz, 1H), 3.77 (s, 3H), 3.15-3.08 (m, 2H), 2.70-2.66 (d, J = 16.4 Hz, 1H), 2.29-2.21 (m. 1H), 2.03-1.95 (m, 1H), 1.78-1.75 (m. 3H), 1.53- 1.37 (m, 4H), 1.37 (s, 3H), 1.11-1.08 (m, 1H), 0.90- 0.83 (m, 2H). 3-7 [00076] MS (m/z): 294.0 (M + 1). 4-7 [00077] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.84-6.78 (m, 2H), 3.86 (s, 3H), 3.19-3.09 (m, 2H), 2.71-2.65 (m, 1H), 2.24-2.15 (m, 1H), 2.09-1.95 (m, 2H), 1.90-1.45 (m, 9H), 1.31-1.20 (m, 1H), 0.98-0.79 (m, 3H). 5-7 [00078] MS (m/z): 289.9 (M + 1). 6-7 [00079] MS (m/z): 278.2 (M + 1). 8-4 [00080] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.99 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H). 6.72-6.69 (m, 1H), 3.81- 3.78 (m, 4H), 3.68-3.65 (m, 1H), 3.31-3.25 (m, 1H), 3.12-3.06 (m, 3H), 2.60-2.56 (m, 1H), 2.26-2.23 (m, 2H), 2.05 (brs, 2H), 1.74-1.71 (m, 3H), 1.34 (s, 3H). 9-3 [00081] MS (m/z): 289.1 (M + 1). 10-3 [00082] MS (m/z): 302.0 (M + 1). 11-3 [00083] MS (m/z): 336.1 (M + 1).

[0131] Step 8: Preparation of Compound 1

[0132] The mixture of crude compound 1-8 (80.00 mg) and aqueous hydrobromic acid (5 mL, 48% wt) was heated to 100 C. and stirred for 1 hour. After being cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by HPLC preparative column to give product 1 (50 mg, two-step yield: 55.39%). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.58 (s, 1H), 3.65 (d, J=5.2 Hz, 1H), 2.99-2.89 (m, 1H), 2.81-2.70 (m, 1H), 2.57 (d, J=5.2 Hz, 1H), 2.23 (s, 3H), 2.02-1.88 (m, 2H), 1.80-1.64 (m, 2H), 1.64-1.50 (m, 3H), 1.46 (s, 3H), 1.20 (d, J=12.0 Hz, 1H), 1.04-0.78 (m, 2H). MS (m/z): 260.0 (M+1).

[0133] Compounds 26 and Compounds 811 were prepared according to method of Compound 1:

TABLE-US-00008 Compound number Structure Spectrogram Compound 2 (Reference compound) [00084] .sup.1H-NMR (CD.sub.3OD, 400 MHz): 6.90-6.88 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.58-6.55 (d, J = 8.4 Hz, 1H), 3.13-3.07 (m, 2H), 2.66-2.62 (d, J = 16.4 Hz, 1H), 2.28-2.24 (m, 1H), 1.96-1.93 (m, 1H), 1.77-1.73 (m, 3H), 1.54-1.50 (m, 1H), 1.49-1.46 (m, 2H), 1.34 (s, 3H), 1.09-1.07 (m, 1H), 0.93-0.90 (m, 2H). MS (m/z): 246.1 (M + 1). Compound 3 [00085] .sup.1H NMR (CD.sub.3OD, 400 MHz): 6.79 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 3.64-3.63 (m, 1H), 3.05-2.90 (m, 2H), 2.58-2.50 (m, 1H), 2.02-1.91 (m, 2H), 1.70-1.45 (m, 8H), 1.20-1.17 (m, 1H), 0.92- 0.82 (m, 2H). MS (m/z): 280.1 (M + 1). Compound 4 [00086] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.85-6.79 (m, 2H), 3.65-3.63 (m, 1H), 3.26-3.20 (m, 2H), 2.80-2.76 (m, 1H), 2.45-2.35 (m, 1H), 2.26-2.19 (m, 1H), 2.04-1.96 (m, 1H), 1.71-1.45 (m, 7H), 1.25-1.14 (m, 1H), 0.91-0.80 (m, 2H). MS (m/z): 263.9 (M + 1). Compound 5 [00087] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.67 (s, 1H), 6.54 (s, 1H), 3.62 (d, J = 5.2 Hz, 1H), 3.17 (dd, J.sub.1 = 7.2 Hz, J.sub.2 = 16.8 Hz, 1H), 2.65 (d, J = 16.8 Hz, 1H), 2.46 (br. s., 1H), 2.05-1.82 (m, 2H), 1.77-1.64 (m, 2H), 1.63- 1.48 (m, 3H), 1.44 (s, 3H), 1.19 (d, J = 11.6 Hz, 1H), 1.08-0.84 (m, 2H). MS (m/z): 262.0 (M + 1). Compound 6 [00088] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.56 (s, 1H), 6.36 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 11.2 Hz, 1H), 3.67 (d, J = 5.2 Hz, 1H), 2.95-2.80 (m, 2H), 2.60-2.51 (m, 1H), 2.05- 1.91 (m, 2H), 1.84-1.55 (m, 5H), 1.48 (s, 3H), 1.28- 1.15 (m, 1H), 1.02-0.80 (m, 2H). MS (m/z): 264.0 (M + 1). Compound 8 [00089] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.95 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 6.65-6.63 (m, 1H), 3.77- 3.74 (m, 2H), 3.60-3.55 (m, 2H), 3.40-3.30 (m, 1H), 3.09-3.04 (m, 1H), 2.70-2.66 (m, 1H), 2.45- 2.35 (m, 1H), 2.18-2.14 (m, 1H), 2.03-1.99 (m, 2H), 1.63-1.62 (m, 1H), 1.39 (s, 3H). MS (m/z): 248.0 (M + 1). Compound 9 [00090] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.59 (d, J = 1.6 Hz, 1H), 3.66 (d, J = 5.2 Hz, 1H), 3.06-2.94 (m, 1H), 2.91- 2.80 (in, 1H), 2.70-2.48 (m, 3H), 2.04-1.90 (m, 2H), 1.79-1.65 (m, 2H), 1.64-1.50 (m, 3H), 1.47 (s, 3H), 1.22 (t, J = 7.6 Hz, 4H), 1.06-0.78 (m, 2H). MS (m/z): 274.0 (M + 1). Compound 10 [00091] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.69 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 3.66 (d, J = 5.2 Hz, 1H), 3.17 (quin, J = 6.8 Hz, 1H), 3.08-2.86 (m, 2H), 2.55 (br. s., 1H), 2.06-1.87 (m, 2H), 1.80-1.65 (m, 2H), 1.64-1.49 (m, 3H), 1.47 (s, 3H), 1.23 (t, J = 6.4 Hz, 7H), 1.08-0.82 (m, 2H). MS (m/z): 288.0 (M + 1). Compound 11 [00092] .sup.1H NMR (400 MHz, CD.sub.3OD): 7.47-7.39 (m, 2H), 7.39-7.32 (m, 1H), 7.26 (d, J = 6.8 Hz, 2H), 6.77 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 3.70 (d, J = 5.2 Hz, 1H), 2.98 (dd, J.sub.1 = 7.2 Hz, J.sub.2 = 17.2 Hz, 1H), 2.53 (d, J = 17.2 Hz, 1H), 2.39 (br. s., 1H), 2.06-1.96 (m, 1H), 1.85-1.69 (m, 2H), 1.67-1.57 (m, 3H), 1.55 (s, 3H), 1.53-1.42 (m, 1H), 1.21 (d, J = 10.4 Hz, 1H), 1.10-0.84 (m, 2H).

Example 7: Preparation of Compound 7

[0134] ##STR00093##

[0135] Step 1: Preparation of Compound 7-6

[0136] Under nitrogen atmosphere, the mixture of compound 7-5 (100.00 mg, 296.52 umol), potassium hydroxide (83.19 mg, 1.48 mmol), di-tert-butyl[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (25.18 mg, 59.30 umol) and Pd.sub.2(dba).sub.3 (27.15 mg, 29.65 umol) in water (3 mL) and dioxane (4 mL) was heated to 100 C. and stirred for 3.5 hours. After being cooled down, the reaction solution was diluted by 20 mL water. The aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give 7-6 (60.00 mg, yield 73.76%). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.35 (dd, J=2.0 Hz, J.sub.2=12.4 Hz, 1H), 3.83 (s, 3H), 3.52 (s, 1H), 3.10 (dd, J=4.0 Hz, J.sub.2=16.8 Hz, 1H), 2.91-2.81 (m, 1H), 2.75 (dd, J=4.0 Hz, J.sub.2=9.6 Hz, 1H), 2.44-2.32 (m, 1H), 1.99-1.85 (m, 1H), 1.82-1.69 (m, 2H), 1.68-1.48 (m, 5H), 1.44-1.24 (m, 5H).

[0137] Step 2: Preparation of Compound 7-7

[0138] The mixed solution of compound 7-6 (70.00 mg, 255.15 umol) and NH.sub.2OHHCl (88.65 mg, 1.28 mmol) in pyridine (5 mL) was heated at reflux for 24 hours. After being cooled to 25 C., the reaction mixture was poured into ice water (20 mL). The aqueous phase was acidified with dilute hydrochloric acid (1M) and extracted with dichloromethane (20 mL3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product 7-7 (68 mg). MS (m/z): 290.0 (M+1).

[0139] Step 3: Preparation of Compound 7

[0140] Under nitrogen atmosphere, Raney-Ni (1.00 g) was added to a solution of compound 7-7 (78.00 mg, 269.55 umol) in ethanol (20 mL). The reaction system was evacuated and purged with H.sub.2 for three times. Then the reaction solution was heated to 70 C. under H.sub.2 atmosphere and stirred for 48 hours. The reaction mixture was filtered under suction and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give 7 (30.00 mg, yield 40.42%). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.33 (s, 1H), 3.81 (s, 2H), 3.67-3.56 (m, 1H), 2.91 (s, 1H), 2.84-2.70 (m, 1H), 2.56-2.41 (m, 1H), 2.00-1.85 (m, 2H), 1.77-1.47 (m, 5H), 1.45 (s, 3H), 1.19 (d, J=12.4 Hz, 1H), 1.03-0.79 (m, 2H). MS (m/z): 276.1 (M+1).

Example 12: Preparation of Compound 12

[0141] ##STR00094##

[0142] Step 1: Preparation of Compound 12-1

[0143] Ac.sub.2O (1142 mg, 8.525 mmol) was added dropwise to a solution of compound 2-7 (552 mg, 2.131 mmol) in pyridine (15 mL) at room temperature. Then, the reaction solution was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was poured into 100 mL water and extracted with ethyl acetate (100 mL3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product 12-1 (737 mg) as a yellow oil. MS (m/z): 302.2 (M+1).

[0144] Step 2: Preparation of Compound 12-2

[0145] NBS (142 mg, 0.803 mmol) was added to a solution of compound 12-1 (220 mg, 0.730 mmol) in acetonitrile (7 mL) at room temperature. After being stirred at room temperature for 2 hours, the reaction was quenched with addition of 30 mL water. The aqueous phase was extracted with ethyl acetate (20 mL3). The combined organic was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give crude product 12-2 (275 mg) as a yellow oil. MS (m/z): 379.9 (M+1).

[0146] Step 3: Preparation of Compound 12-3

[0147] Under nitrogen atmosphere, BBr.sub.3 (0.2 mL) was added to a solution of compound 12-2 (145 mg, 0.382 mmol) in dichloromethane (2 mL) at 0 C. The reaction solution was stirred at 0 C. for 1 hour, then 20 mL saturated aqueous solution of K.sub.2CO.sub.3 was added to quench the reaction. The aqueous phase was extracted with dichloromethane (10 mL3). The combined organic was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product 12-2 (127 mg) as a yellow oil. MS (m/z): 365.9 (M+1).

[0148] Step 4: Preparation of Compound 12

[0149] BBr.sub.3 (0.2 mL) was added to a solution of compound 12-3 (50 mg, 0.143 mmol) in dichloromethane (1 mL) at room temperature. The reaction solution was stirred at 0 C. for 1 hour, then 20 mL water was added to quench the reaction and the pH was adjusted to 9 with saturated aqueous solution of K.sub.2CO.sub.3. The aqueous phase was extracted with dichloromethane (10 mL3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by HPLC preparative column to give 12 (5 mg, yield: 10.80%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.84 (br. s., 3H), 7.23 (s, 1H), 6.89 (s, 1H), 3.70 (br. s., 1H), 3.18 (d, J=11.2 Hz, 1H), 2.83 (br. s., 1H), 2.69 (d, J=17.2 Hz, 1H), 2.23-1.98 (m, 3H), 1.89 (br. s., 2H), 1.63 (br. s., 6H), 0.88 (br. s., 2H). MS (m/z): 323.9 (M+1).

Example 13: Preparation of Compound 13

[0150] ##STR00095##

[0151] Step 1: Preparation of Compound 13-1

[0152] DMAP (50 mg) was added to a mixed solution of compound 2-7 (500 mg, 1.93 mmol), Boc.sub.2O (780 mg, 3.86 mmol) and triethylamine (585 mg, 5.79 mmol) in dichloromethane (20 mL) at room temperature. After the reaction mixture was stirred at room temperature for 2 hours, 20 mL water was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give product 13-1 as a colorless oil (203 mg, yield: 29.29%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.04-6.96 (m, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.70 (dd, J.sub.1=2.4 Hz, J.sub.2=8.4 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 4.10 (dd, J.sub.1=5.2 Hz, J.sub.2=10.4 Hz, 1H), 3.82-3.76 (m, 3H), 3.17 (dd, J.sub.1=6.8 Hz, J.sub.2=16.4 Hz, 1H), 2.62 (d, J=16.4 Hz, 1H), 1.91-1.51 (m, 8H), 1.48 (s, 9H), 1.36-1.30 (m, 3H), 0.98 (d, J=6.4 Hz, 2H).

[0153] Step 2: Preparation of Compound 13-2

[0154] NBS (163 mg, 0.919 mmol) was added to a solution of compound 13-1 (300 mg, 0.836 mmol) in acetonitrile (5 mL) at 25 C. After the reaction mixture was stirred at 25 C. for 2 hours, 20 mL water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product 13-2 (439 mg) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.28 (s, 1H), 6.73 (s, 1H), 4.94 (d, J=10.4 Hz, 1H), 4.16-4.07 (m, 1H), 3.88 (s, 3H), 3.19 (dd, J.sub.1=6.8 Hz, J.sub.2=16.8 Hz, 1H), 2.61 (d, J=16.8 Hz, 1H), 1.84-1.68 (m, 4H), 1.67-1.56 (m, 4H), 1.51 (s, 9H), 1.35 (s, 3H), 1.01 (d, J=6.8 Hz, 2H).

[0155] Step 3: Preparation of Compound 13-3

[0156] Under nitrogen atmosphere, the mixed solution of compound 13-2 (60 mg, 0.14 mmol), isopropenylboronic acid pinacol ester (69 mg, 0.41 mmol), K.sub.2CO.sub.3 (56 mg, 0.41 mmol) and Pd(dppf)Cl.sub.2 (11 mg, 0.013 mmol) in dioxane (2 mL) was heated at reflux overnight. After being cooled down, the reaction solution was filtered to remove precipitate. The filtrate was concentrated in vacuo. The residue was purified by thin-layer chromatography (eluent: petroleum ether/ethyl acetate=15/1) to give 13-3 as a brown oil (39 mg, yield: 71.0%). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.90 (s, 1H), 6.70 (s, 1H), 5.12-5.13 (m, 2H), 4.93-4.96 (m, 1H), 4.08-4.12 (m, 1H), 3.83 (s, 3H), 3.16-3.20 (m, 1H), 2.89-2.96 (m, 1H), 2.58-2.62 (m, 1H), 2.32 (s, 1H), 2.13 (s, 3H), 1.52-1.84 (m, 13H), 1.26-1.33 (m, 3H), 1.20-1.30 (m, 1H), 0.98-1.00 (m, 4H).

[0157] The following compounds were synthesized according to a method similar to that of compound 13-3:

TABLE-US-00009 Compound number Structure Spectrogram 14-1 [00096] MS (m/z): 317.9 (M + 1 56). 15-1 [00097] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.65 (s, 1H), 6.51 (s, 1H), 3.84 (s, 3H), 3.22-3.11 (m, 1H), 2.35- 2.25 (m, 1H), 2.14-2.13 (m, 1H), 2.00-1.55 (m, 2H), 1.74-1.49 (m, 15H), 1.35-1.15 (m, 5H), 1.00-0.80 (m, 5H), 0.75-0.50 (m, 2H).

[0158] Step 4: Preparation of Compound 13-4

[0159] Under hydrogen atmosphere (50 psi), a mixed solution of compound 13-3 and Pd/C (3.9 mg) in ethanol (2 mL) was heated at reflux for 2 hours. After being cooled down, the reaction solution was filtered. The filtrate was concentrated in vacuo to give crude product 13-4 (40 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.90 (s, 1H), 6.64 (s, 1H), 4.96-4.93 (m, 1H), 4.12-4.08 (m, 1H), 3.80 (s, 3H), 3.27-3.15 (m, 2H), 2.65-2.58 (m, 1H), 2.32 (brs, 1H), 1.83-1.62 (m, 6H), 1.50-1.25 (m, 19H), 1.00-0.98 (m, 3H).

[0160] Step 5: Preparation of Compound 13

[0161] BBr.sub.3 (75 mg, 0.30 mmol) was added to a solution of compound 13-4 (40 mg, 0.10 mmol) in dichloromethane (2 mL) at 0 C. After being warmed to room temperature, the reaction solution was stirred for 2 hours. After the reaction was complete, 10 mL saturated sodium bicarbonate solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane (10 mL5). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by HPLC preparative column to give the hydrochloride salt of product 13 (14 mg, yield: 50.0%). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.89 (s, 1H), 6.63 (s, 1H), 3.61 (d, J=5.2 Hz, 1H), 3.25-3.15 (m, 2H), 2.75-2.71 (m, 1H), 2.44 (brs, 1H), 1.93-1.91 (m, 2H), 1.70-1.45 (m, 8H), 1.23-1.15 (m, 7H), 0.97-0.92 (m, 2H). MS (m/z): 288.0 (M+1).

[0162] Compounds 14 and 15 were prepared according to a method similar to that of compound 4

TABLE-US-00010 Compound number Structure Spectrogram Compound 14 [00098] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.96 (br. s., 3H), 6.86 (s, 1H), 6.63 (s, 1H), 3.66 (br. s., 1H), 3.14 (dd, J.sub.1 = 6.4 Hz, J.sub.2 = 16.4 Hz, 1H), 2.70 (br. s., 1H), 2.58 (br. s., 1H), 2.22 (s, 3H), 1.97-1.63 (m, 6H), 1.59-1.54 (m, 1H), 1.49 (s, 3H), 1.14 (d, J = 11.6 Hz, 1H), 0.93 (br. s., 2H). MS (m/z): 260.0 (M + 1). Compound 15 [00099] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.78 (s, 1H), 6.62 (s, 1H), 5.98-5.92 (m, 1H), 5.00-4.89 (m, 3H), 3.60-3.58 (m, 1H), 3.16-3.10 (m, 1H), 2.70-2.66 (m, 1H), 2.40-2.39 (m, 1H), 1.91- 1.84 (m, 2H), 1.70-1.45 (m, 8H), 1.25-1.05 (m, 2H), 1.00-0.75 (m, 2H). MS (m/z): 286.1 (M + 1).

Example 5: Preparation of Compound 16

[0163] ##STR00100##

[0164] Step 1: Preparation of Compound 16-1

[0165] Concentrated hydrochloric acid (0.2 mL) was added dropwise to a solution of compound 13-1 (100 mg, 0.28 mmol) and NCS (37 mg, 0.28 mmol) in acetonitrile (2 mL) at 25 C. After being stirred at 25 C. for 2 hours, the reaction was quenched by the addition of 10 mL water. The aqueous phase was extracted with ethyl acetate (10 mL4). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product 16-1 (88 mg) as a yellow oil. MS (m/z): 293.9 (M+1).

[0166] Step 2: Preparation of Compound 16

[0167] BBr.sub.3 (0.2 mL) was added to a solution of compound 16-1 (88 mg, 0.3 mmol) in dichloromethane (1 mL) at 0 C. After being stirred at 0 C. for 2 hours, the reaction was quenched by the addition of 10 mL saturated potassium carbonate solution. The aqueous phase was extracted with dichloromethane/methanol mixed solution (8:1, 10 mL3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by HPLC preparative column to give the hydrochloride salt of product 16 (20 mg, yield: 23.81%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.11 (br. s., 3H), 7.11 (s, 1H), 6.90 (s, 1H), 3.64 (br. s., 1H), 3.17 (dd, J.sub.1=6.4 Hz, J.sub.2=16.4 Hz, 1H), 2.72 (d, J=17.2 Hz, 1H), 2.62 (br. s., 1H), 1.98-1.81 (m, 5H), 1.62 (br. s., 2H), 1.53 (s, 3H), 1.27-1.17 (m, 1H), 0.92 (br. s., 2H). MS (m/z): 279.9 (M+1).

Example 6: Preparation of Compound 17

[0168] ##STR00101##

[0169] Step 1: Preparation of Compound 17-1

[0170] A solution of n-butyllithium in tetrahydrofuran (1 mL, 2.5 mmol) was added to a solution of compound 13-2 (190.00 mg, 433.39 umol) in tetrahydrofuran (3 mL) at 78 C. After being stirred at 78 C. for 1 hour, the reaction mixture was added with a solution of NFSI (273.33 mg, 866.78 umol) in THF (3 mL), and stirred at 78 C. for another 4 hours. Then 20 mL saturated aqueous ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL4). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by HPLC preparative column to give product 17-1 as a colorless oil (20.00 mg, yield: 12.22%). MS (m/z): 322.1 (M+1-56).

[0171] Step 2: Preparation of Compound 17

[0172] BBr.sub.3 (39.38 mg, 158.94 umol) was added to a solution of compound 17-1 (20.00 mg, 52.98 umol) in dichloromethane (1 mL) at room temperature. After being stirred at room temperature for 2 hours, the reaction was quenched by addition of 10 mL water. The aqueous phase was adjusted to pH=9 with saturated potassium carbonate solution and extracted with dichloromethane (10 mL5). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by HPLC preparative column to give the hydrochloride salt of product 17 (11 mg, yield: 77.84%). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.88-6.80 (m, 2H), 3.66 (d, J=5.2 Hz, 1H), 3.21 (dd, J.sub.1=7.2 Hz, J.sub.2=16.8 Hz, 1H), 2.74 (d, J=17.2 Hz, 1H), 2.47 (d, J=5.6 Hz, 1H), 2.02-1.88 (m, 2H), 1.78-1.66 (m, 2H), 1.65-1.51 (m, 3H), 1.47 (s, 3H), 1.25-1.15 (m, 1H), 1.01-0.83 (m, 2H). MS (m/z): 264.0 (M+1).

Example 7: Preparation of Compound 18

[0173] ##STR00102## ##STR00103##

[0174] Step 1: Preparation of Compound 18-1

[0175] Under nitrogen atmosphere, triethylamine (90.01 mg, 889.56 umol) and Pd(dppf)Cl.sub.2 (21.70 mg, 29.65 umol) were added to a solution of compound 1-5 (100.00 mg, 296.52 umol) in methanol (30 mL). The reaction system was evacuated and purged with CO for three times. Then the reaction solution was heated to 70 C. under CO atmosphere (50 psi) and stirred for 24 hours. The reaction mixture was filtered under suction and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 18-1 (70.00 mg, yield: 74.61%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.27 (d, J=2.8 Hz, 1H), 6.99 (d, J=2.8 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.44 (dd, J.sub.1=4.4 Hz, J.sub.2=17.2 Hz, 1H), 3.22 (dd, J.sub.1=5.6 Hz, J.sub.2=17.2 Hz, 1H), 2.75 (td, J=5.2 Hz, J.sub.2=9.6 Hz, 1H), 2.51-2.31 (m, 1H), 1.94-1.64 (m, 4H), 1.35 (s, 3H), 1.33-1.23 (m, 3H).

[0176] Step 2: Preparation of Compound 18-2

[0177] The mixed solution of compound 18-1 (70.00 mg, 221.25 umol) and NH.sub.2OHHCl (76.87 mg, 1.11 mmol) in pyridine (4 mL) was heated at reflux for 24 hours. After being cooled to room temperature, the reaction solution was poured into ice water (100 mL). The aqueous phase was acidified with dilute hydrochloric acid (1M) and extracted with dichloromethane (100 mL3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 18-2 (45.00 mg, yield: 61.37%) as a white solid. MS (m/z): 332.5 (M+1).

[0178] Step 3: Preparation of Compound 18-3

[0179] Under nitrogen atmosphere, Raney-Ni (1.0 g, 50% wt) was added to a solution of compound 18-2 (45.00 mg, 135.78 umol) in ethanol (20 mL). The reaction system was evacuated and purged with H.sub.2 for three times. Then the reaction solution was heated to 70 C. under H.sub.2 atmosphere (50 psi) and stirred for 48 hours. The reaction mixture was filtered under suction and the filtrate was concentrated in vacuo to give crude product 18-3 (50 mg) which was used directly in the next step without further purification. MS (m/z): 318.1 (M+1).

[0180] Step 4: Preparation of Compound 18-4

[0181] Under nitrogen atmosphere, lithium tetrahydroaluminate (15.42 mg, 406.41 umol) was slowly added to a solution of compound 18-3 (43.00 mg, 135.47 umol) in tetrahydrofuran (20 mL) at 0 C. After being stirred at 0 C. for 2 hours, the reaction was quenched by the successive addition of water (45 mg) and 15% aqueous sodium hydroxide solution (15 mg). After filtration, the filtrate was concentrated in vacuo to give crude product 18-4 (35 mg) which was used directly in the next step without further purification. MS (m/z): 209.0 (M+1).

[0182] Step 5: Preparation of Compound 18-5

[0183] Under nitrogen atmosphere, BBr.sub.3 (90.89 mg, 362.82 umol) was slowly added to a solution of compound 18-4 (35.00 mg, 120.94 umol) in dichloromethane (5 mL) at 78 C. After being warmed to 0 C., the reaction solution was stirred for 1 hour. Then, water (30 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (30 mL3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give crude product 18-5 (35.00 mg) which was used directly in the next step without further purification. MS (m/z): 399.9 (M+1)

[0184] Step 6: Preparation of Compound 18-6

[0185] The mixed solution of compound 18-5 (63.00 mg, 178.82 umol) and sodium acetate (73.34 mg, 894.10 umol) in acetic acid (3 mL) was heated to reflux and stirred for 1 h. After being cooled down, the reaction solution was poured into 20 mL ice water to be diluted. The aqueous phase was extracted with dichloromethane (20 mL3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give product 18-6 as a white solid (20.00 mg, yield: 33.18%). MS (m/z): 318.1 (M+1).

[0186] Step 7: Preparation of Compound 18

[0187] The solution of compound 18-6 (10.00 mg, 31.50 umol) and lithium hydroxide (73.77 mg, 157.50 umol) in ethanol (2 mL) was stirred at 25 C. for 16 hours. After the reaction solution was concentrated in vacuo, 20 mL water was added and the mixture was acidified to pH=2 with dilute hydrochloric acid. The aqueous phase was extracted with dichloromethane (20 mL3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give product 18 (6.00 mg, yield: 60.55%). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.84 (d, J=2.4 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 4.69-4.50 (m, 3H), 3.65 (d, J=5.6 Hz, 1H), 3.08-2.82 (m, 2H), 2.54 (d, J=6.0 Hz, 1H), 1.95 (dd, J.sub.1=7.2 Hz, J.sub.2=15.6 Hz, 2H), 1.81-1.64 (m, 2H), 1.64-1.50 (m, 3H), 1.47 (s, 3H), 1.20 (d, J=11.6 Hz, 1H), 1.04-0.82 (m, 2H). MS (m/z): 276.0 (M+1).

Example 19: Preparation of Compound 19

[0188] ##STR00104##

[0189] Step 1: Preparation of Compound 19-1

[0190] Under nitrogen atmosphere, Pd(OAc).sub.2 (0.15 g) and xPhos (0.62 g) were added to a mixed solution of concentrated sulfuric acid (24 L) and dimethylacetamide (10 mL), then the mixture was heated to 80 C. and stirred for 30 minutes to obtain a dark solution A.

[0191] In another flask, the prepared solution A (1 mL) was added to a solution of compound 13-2 (50 mg, 0.139 mmol), Zn(CN).sub.2 (16 mg, 0.139 mmol) and Zn (0.5 mg, 0.008 mmol) in dimethylacetamide. Then, the reaction solution was heated to 90 C. and stirred overnight. After being cooled to room temperature, the reaction solution was filtered. The filtrate was poured into 10 mL water. The aqueous phase was extracted with ethyl acetate (10 mL4). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give product 19-1 (18.0 mg, yield: 40.91%). MS (m/z): 328.9 (M+1-56).

[0192] Step 2: Preparation of Compound 19

[0193] BBr.sub.3 (27 mg, 0.109 mmol) was slowly added to a solution of compound 19-1 (14 mg, 0.036 mmol) in dichloromethane (2 mL) at room temperature. After being stirred at room temperature for 5 hours, the reaction was quenched by addition of water (10 mL). The aqueous phase was basified with potassium carbonate to pH=9 and extracted with dichloromethane (10 mL4). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give product 19 (8 mg, yield: 80.0%). .sup.1H NMR (400 MHz, CD.sub.3OD): 7.01 (s, 1H), 6.67 (s, 1H), 3.08-2.98 (m, 2H), 2.61 (d, J=16.0 Hz, 1H), 2.27-2.19 (m, 1H), 2.00-1.92 (m, 1H), 1.80-1.72 (m, 3H), 1.71-1.58 (m, 2H), 1.51 (dd, J.sub.1=6.4 Hz, J.sub.2=13.6 Hz, 2H), 1.36-1.31 (m, 3H), 1.12-0.94 (m, 3H). MS (m/z): 271.1 (M+1).

Example 20: Preparation of Compound 20

[0194] ##STR00105##

[0195] Step 1: Preparation of Compound 20-1

[0196] Concentrated hydrochloric acid (0.4 mL) was added dropwise to a solution of compound 13-1 (80 mg, 0.223 mmol) and NCS (74 mg, 0.557 mmol) in acetonitrile (2 mL) at 25 C. After being stirred at 25 C. for 5 hours, the reaction was quenched by addition of 10 mL water. The aqueous phase was extracted with ethyl acetate (10 mL4). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give product 20-1 as a colorless oil (40.0 mg, yield: 54.79%). MS (m/z): 328.1 (M+1).

[0197] Step 2: Preparation of Compound 20

[0198] BBr.sub.3 (91 mg, 0.367 mmol) was slowly added to the a solution of compound 20-1 (14 mg, 0.036 mmol) in dichloromethane (2 mL) at 0 C. After being stirred at 0 C. for 5 hours, the reaction was quenched by addition of water (10 mL). The aqueous phase was basified with potassium carbonate to pH=9 and extracted with dichloromethane (10 mL4). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give the crude product. The crude product was separated and purified by HPLC preparative column to give product 20 (3.0 mg, yield: 7.89%). .sup.1H NMR (400 MHz, CD.sub.3OD): 7.19 (s, 1H), 4.64 (br. s., 1H), 3.63 (d, J=4.8 Hz, 1H), 2.83 (d, J=17.2 Hz, 1H), 2.60 (dd, J.sub.1=7.6 Hz, J.sub.2=16.4 Hz, 1H), 2.40 (d, J=6.4 Hz, 1H), 2.06-1.96 (m, 1H), 1.74 (s, 3H), 1.69 (br. s., 2H), 1.63-1.52 (m, 2H), 1.35-1.16 (m, 2H), 0.95 (d, J=12.8 Hz, 1H), 0.87-0.76 (m, 1H). MS (m/z): 314.1 (M+1).

Example 21: Preparation of Compound 21 and Compound 22

[0199] ##STR00106##

[0200] Compound 6 (700.00 mg, 2.66 mmol) was separated by SFC to give compound 21 (150 mg) and 22 (160 mg).

[0201] SFC separation condition: Instrument: Thar 80; Column: Chiralpak AD 25030 mm I.D., 5 um; Mobile phase: Supercritical CO.sub.2/IPA (0.1% NH.sub.3H.sub.2O)=65/35 at 50 mL/min; Column Temp: 38 C.; Nozzle Pressure: 100Bar; Nozzle Temp: 60 C.; Evaporator Temp: 20 C.; Trimmer Temp: 25 C.; Wavelength: 220 nm.

[0202] Compound 21 .sup.1H NMR (400 MHz, CD.sub.3OD): 6.54 (s, 1H), 6.36 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 3.09 (d, J=5.2 Hz, 1H), 2.80 (d, J=4.4 Hz, 2H), 2.39-2.27 (m, 1H), 2.05-1.91 (m, 1H), 1.84-1.48 (m, 6H), 1.35 (s, 3H), 1.30-1.21 (m, 1H), 1.02-0.80 (m, 2H). MS (m/z): 264.0 (M+1). []20D=43.8 (C=3.1, CH.sub.3OH).

[0203] Compound 22 1H NMR (400 MHz, CD.sub.3OD): 6.56 (s, 1H), 6.36 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 3.67 (d, J=5.2 Hz, 1H), 2.95-2.80 (m, 2H), 2.60-2.51 (m, 1H), 2.05-1.91 (m, 2H), 1.84-1.55 (m, 5H), 1.48 (s, 3H), 1.28-1.15 (m, 1H), 1.02-0.80 (m, 2H). MS (m/z): 264.0 (M+1). []20D=+39.8 (C=2.0, CH.sub.3OH).

[0204] Compounds 23-26 were isolated referring to the SFC separation method described above:

TABLE-US-00011 Compound number Structure Spectrogram Compound 23 [00107] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.72 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 2.96-2.84 (m, 2H), 2.45 (brs, 1H), 1.94-1.75 (m, 4H), 1.42- 1.25 (m, 4H), 1.58-1.54 (m, 3H), 1.19-1.10 (m, 1H), 0.95-0.75 (m, 2H). Compound 24 [00108] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.72 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 3.18-3.16 (m, 1H), 2.96-2.82 (m, 2H), 2.38 (brs, 1H), 1.94- 1.90 (m, 1H), 1.77-1.70 (m, 2H), 1.62-1.45 (m, 3H), 1.35 (s, 1H), 1.16-1.10 (m, 1H), 0.95- 0.75 (m, 2H). Compound 25 [00109] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.92 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.61 (dd, J.sub.1 = 2.0 Hz, J.sub.2 = 2.0 Hz, 1H), 3.76-3.69 (m, 2H), 3.52- 3.45 (m, 1H), 3.44-3.40 (m, 1H), 3.30-3.25 (m, 1H), 3.07-3.04 (m, 1H), 2.63 (d, J = 16.0 Hz, 1H), 2.33 (brs, 1H), 2.05-2.02 (m, 2H), 1.99- 1.85 (m, 1H), 1.63-1.52 (m, 1H), 1.36 (s, 3H). Compound 26 [00110] .sup.1H NMR (400 MHz, CD.sub.3OD): 6.93 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.61 (dd, J.sub.1 = 2.0 Hz, J.sub.2 = 2.0 Hz, 1H), 3.77-3.70 (m, 2H), 3.52- 3.45 (m, 1H), 3.45-3.43 (m, 1H), 3.27-3.26 (m, 1H), 3.07-3.05 (in, 1H), 2.64 (d, J = 15.6 Hz, 1H), 2.35 (brs, 1H), 2.06-2.03 (m, 2H), 2.03- 1.92 (m, 1H), 1.64-1.52 (m, 1H), 1.36 (s, 3H)

Example 27: Preparation of Compound 27

[0205] ##STR00111##

[0206] Step 1: Preparation of Compound 27

[0207] Under nitrogen atmosphere, the mixture of compound 7 (16.00 mg, 58.10 umol) and aqueous hydrobromic acid (48% wt, 3 mL) was heated to 100 C. and stirred for 1 hour. After being cooled to room temperature, the reaction solution was concentrated in vacuo. The residue was purified by HPLC preparative column to give product 27 (8.00 mg, yield: 46.23%). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.27-6.20 (m, 1H), 3.61 (d, J=5.2 Hz, 1H), 2.90 (s, 1H), 2.80 (d, J=7.2 Hz, 1H), 2.59-2.45 (m, 1H), 2.04-1.83 (m, 2H), 1.76-1.48 (m, 5H), 1.44 (s, 3H), 1.31-1.12 (m, 1H), 1.05-0.88 (m, 2H). MS (m/z): 262.1 (M+1).

Example 28: Preparation of Compound 28 and Compound 29

[0208] ##STR00112##

[0209] Step 1: Preparation of Compound 28-1

[0210] Compound 1-1 (2.00 g, 10.30 mmol) was dissolved in toluene (5.00 mL) and a solution of EtMgBr in tetrahydrofuran (13.73 mL, 3M, 41.19 mmol) was added dropwise at 78 C. After the dropwise addition was complete, the temperature was slowly raised to 25 C. and the reaction was continued for 2 hours. After the reaction was complete, water (10 mL) was added to quench the reaction, then HCl (10 mL, 4M) was added. The temperature was raised to 60 C., and the reaction was continued under stirring for 3 hours. After being cooled down, the reaction solution was extracted with dichloromethane (10 mL2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 28-1 as a pale yellow oil (1.50 g, yield: 70.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.64 (dd, J.sub.1=10.2 Hz, J.sub.2=2.4 Hz, 1H), 6.52 (dd, J.sub.1=10.8 Hz, J.sub.2=2.4 Hz, 1H), 5.92 (t, J=4.4 Hz, 1H), 3.82 (s, 3H), 2.68 (t, J=8.4 Hz, 2H), 2.40 (dd, J.sub.1=7.2 Hz, J.sub.2=1.2 Hz, 2H), 2.01-2.27 (m, 2H), 1.14 (t, J=7.2 Hz, 3H)

[0211] Step 2: Preparation of Compound 28-2

[0212] Compound 28-1 (1.50 g, 7.27 mmol) was dissolved in dichloromethane (4.00 mL), m-CPBA (1.51 g, 8.73 mmol) was added in portions under an ice bath, the internal temperature was maintained within 0-5 C., and the mixture was stirred for another 2 hours. The reaction was quenched by successive addition of saturated Na.sub.2SO.sub.3 (10 mL) and NaHCO.sub.3 (5 mL). The reaction solution was extracted with dichloromethane (10 mL2) and the combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and filtered. BF.sub.3.Et.sub.2O (103.22 mg, 727.24 umol) was added to the filtered solution under an ice bath, and the mixture was stirred at the same temperature for 0.5 hours. The reaction was quenched by addition of saturated NaHCO.sub.3 (10 mL) and the aqueous phase was extracted with dichloromethane (10 mL2). The combined organic phase was washed with saturated brine (10 mL2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give the product 28-2 as a pale yellow oil (1.00 g, yield: 61.9%). MS (m/z): 222.9 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.54 (dd, J.sub.1=11.04 Hz, J.sub.2=2.40 Hz, 1H), 6.49 (d, J=2.24 Hz, 1H), 3.79 (s, 3H), 3.30 (t, J=6.64 Hz, 1H), 3.08 (s, 1H), 2.86-3.01 (m, 1H), 2.57-2.71 (m, 1H), 2.33-2.53 (m, 1H), 1.84-1.94 (m, 2H), 0.89 (t, J=7.20 Hz, 3H).

[0213] Step 3: Preparation of Compound 28-3

[0214] Under an ice bath, compound 28-2 (900.0 mg, 4.05 mmol) was dissolved in THF (5.00 mL), then the reaction system was purged with nitrogen for 3 times, then potassium tert-butoxide (545.27 mg, 4.86 mmol) was added. After being stirred at the same temperature for 1 hour, the reaction solution was slowly added to a solution of cis-1,4-dichloro-2-butene (1.01 g, 8.10 mmol) in THF (5.00 mL). After reacting at 25 C. for 12 hours, t-BuOK (545.27 mg, 4.86 mmol) was added, then the temperature was raised to 60 C., and the reaction was continued for 6 hours, the reaction solution was slowly poured into water (10 mL) to be quenched. The aqueous phase was extracted with dichloromethane (10 mL2). The combined organic phase was washed with saturated brine (10 mL2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 28-3 as a pale yellow oil (800.00 mg, yield: 72.1%). MS (m/z): 275.1 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.46-6.55 (m, 2H), 5.64-5.76 (m, 1H), 5.32-5.45 (m, 1H), 3.79 (s, 3H), 3.02-3.12 (m, 1H), 2.95-3.00 (m, 2H), 2.52 (dd, J.sub.1=13.6 Hz, J.sub.2=7.2 Hz, 1H), 2.42 (dd, J.sub.1=15.6 Hz, J.sub.2=7.6 Hz, 1H), 2.12 (dd, J.sub.1=15.6 Hz, J.sub.2=2.4 Hz, 1H), 1.70 (dd, J.sub.1=13.6 Hz, J.sub.2=7.2 Hz, 1H), 1.13-1.31 (m, 2H), 0.61 (t, J=7.2 Hz, 3H).

[0215] Step 4: Preparation of Compound 28-4

[0216] Compound 28-3 (700.00 mg, 2.55 mmol) was dissolved in pyridine (5.00 mL) and hydroxylamine hydrochloride (1.06 g, 15.30 mmol) was added. After being warmed to 100 C. and reacted for 12 hours, the reaction was quenched by addition of water (5 mL) and the aqueous phase was extracted with dichloromethane (10 mL2). The combined organic phase was washed with water (5 mL2). The organic phase was adjusted to pH 5-6 with dilute hydrochloric acid, then washed with water (5 mL2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Ethyl acetate (1 mL) was added to the residue, then the mixture was allowed to stand overnight, white precipitate was precipitated. The mixture was filtered to give compound 28-4 as a white solid (600.00 mg, yield: 81.3%). MS (m/z): 289.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.65 (s, 1H), 6.50 (dd, J=11.6 Hz, J.sub.2=2.4 Hz, 1H), 5.58 (ddd, J.sub.1=11.2, J.sub.2=7.6, J.sub.3=3.6 Hz, 1H), 5.17-5.35 (m, 1H), 3.77 (s, 3H), 2.76-2.85 (m, 1H), 2.71 (d, J=7.2 Hz, 1H), 2.53-2.62 (m, 1H), 2.44-2.53 (m, 1H), 2.26-2.41 (m, 2H), 2.17-2.26 (m, 1H), 1.88-2.01 (m, 1H), 0.66 (t, J=7.2 Hz, 3H).

[0217] Step 5: Preparation of Compound 28-5

[0218] Compound 28-4 (400.00 mg, 1.38 mmol) was dissolved in ethanol (5.00 mL) then Raney nickel (236.45 mg) and NH.sub.3.H.sub.2O (4.84 mg, 138.00 umol) were added. After the reaction system was purged with nitrogen for 3 times, hydrogen gas was introduced. The reaction was carried out under 50 Psi at 70 C. for 12 hours. The reaction solution was filtered through celite and concentrated in vacuo to give crude product 28-5 (500.00 mg) as a pale yellow oil. MS (m/z): 277.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.66 (br, 1H), 6.53 (d, J=10.8 Hz, 1H), 3.77 (br, 3H), 2.66-2.81 (m, 2H), 1.82-2.13 (m, 4H), 1.32-1.72 (m, 6H), 1.05-1.22 (m, 2H), 0.58 (t, J=6.8 Hz, 3H).

[0219] Step 6: Preparation of Compound 28

[0220] Compound 28-5 (450.00 mg, 1.62 mmol) was dissolved in hydrobromic acid (2.00 mL) and the reaction solution was stirred at 100 C. for 3 hours. After being cooled down, the reaction solution was concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give trifluoroacetate salt of 28-6. Compound 28-6 was separated by SFC to give compound 28 (30 mg) at the first peak and compound 29 (35 mg) at the second peak.

[0221] SFC separation condition: Instrument: Thar 80; Column: Chiralpak AD 25030 mm I.D., 5 um; Mobile phase: Supercritical CO.sub.2/IPA (0.1% NH.sub.3H.sub.2O)=65/35 at 50 mL/min; Column Temp: 38 C.; Nozzle Pressure: 100Bar; Nozzle Temp: 60 C.; Evaporator Temp: 20 C.; Trimmer Temp: 25 C.; Wavelength: 220 nm.

[0222] Compound 28: MS (m/z): 263.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.55 (d, J=1.6 Hz, 1H), 6.35 (dd, J.sub.1=11.2 Hz, J.sub.2=2.4 Hz, 1H), 3.27 (d, J=3.2 Hz, 1H), 2.61-2.79 (m, 2H), 2.31-2.44 (m, 1H), 1.78-2.13 (m, 3H), 1.26-1.74 (m, 6H), 1.05-1.22 (m, 1H), 0.52-0.65 (m, 3H).

[0223] Compound 29: MS (m/z): 263.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.58 (s, 1H), 6.44 (dd, J.sub.1=11.2 Hz, J.sub.2=2.4 Hz, 1H), 3.79 (d, J=3.2 Hz, 1H), 2.75-2.93 (m, 2H), 2.60 (br. s., 1H), 1.68-2.07 (m, 5H), 1.27-1.67 (m, 2H), 1.09-1.26 (m, 2H), 0.67 (t, J=7.28 Hz, 3H).

Example 30: Preparation of Compound 30

[0224] ##STR00113##

[0225] Step 1: Preparation of Compound 30-1

[0226] Compound 1-1 (2.00 g, 10.30 mmol) was dissolved in toluene (10.00 mL) and a solution of PrMgBr in tetrahydrofuran (7.73 mL, 2M, 15.46 mmol) was added dropwise at 78 C. After the dropwise addition was complete, the temperature was slowly raised to 25 C. and the reaction was continued for 2 hours. After the reaction was complete, the reaction was quenched by the addition of water (10 mL), then HCl (25.75 mL, 4 M) was added. The temperature was raised to 60 C. and the reaction was continued for 3 hours under stirring. After being cooled down, the reaction solution was extracted with dichloromethane (10 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 30-1 (1.50 g, yield: 66.2%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) =6.72 (s, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.56 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 6.48 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 5.91 (t, J=4.4 Hz, 1H), 5.23 (t, J=3.2 Hz, 1H), 3.81-3.78 (m, 6H), 2.84 (br. s., 1H), 2.68 (t, J=7.2 Hz, 3H), 2.61-2.43 (m, 1H), 2.37 (t, J=7.2 Hz, 2H), 2.32-2.03 (m, 5H), 1.96-1.74 (m, 1H), 1.58-1.51 (m, 4H), 1.07 (t, J=7.6 Hz, 1H), 0.95 (t, J=7.2 Hz, 3H)

[0227] Step 2: Preparation of Compound 30-2

[0228] Compound 30-1 (1.50 g, 6.81 mmol) was dissolved in dichloromethane (5.00 mL), then Na.sub.2CO.sub.3 (1.08 g, 10.21 mmol) and m-CPBA (1.41 g, 8.17 mmol) were added successively under an ice bath, the internal temperature was maintained within 0-5 C., and the reaction was stirred for 1 hour. The reaction was quenched by addition of saturated Na.sub.2SO.sub.3 (5 mL) solution. The aqueous phase was extracted with dichloromethane (10 mL3), then the combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and filtered. The residue obtained after concentration in vacuo was dissolved in dichloromethane (10.00 mL). BF.sub.3.Et.sub.2O (150.17 mg, 1.06 mmol) was added to the dichloromethane solution under an ice bath, and the mixture was stirred at the same temperature for 0.5 hours. The reaction was quenched by addition of saturated NaHCO.sub.3 (10 mL) solution. The aqueous phase was extracted with dichloromethane (10 mL3). The combined organic phase was washed with saturated brine (10 mL2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 30-2 as a pale yellow oil (0.4 g, yield: 16%). MS (m/z): 236.8 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.53 (dd, J=2.4, 11.2 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H), 3.79 (s, 3H), 3.37 (t, J=6.8 Hz, 1H), 3.20-2.87 (m, 2H), 2.72-2.37 (m, 2H), 1.87-1.73 (m, 2H), 1.37-1.19 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

[0229] Step 3: Preparation of Compound 30-3

[0230] Compound 30-2 (300.0 mg, 1.27 mmol) was dissolved in THF (5.00 mL) under an ice bath and the reaction system was purged with nitrogen for three times, then potassium tert-butoxide (170.96 mg, 1.52 mmol) was added. After being stirred at the same temperature for 1 hour, the reaction solution was slowly added to a solution of cis-1,4-dichloro-2-butene (238.07 mg, 1.90 mmol) in THF (5.00 mL). After the mixture reacted at 25 C. for 12 hours, t-BuOK (170.96 mg. 1.52 mmol) was added, then the temperature was raised to 60 C. and the reaction was continued for 6 hours, the reaction solution was slowly poured into water (5 mL) to be quenched. The aqueous phase was extracted with dichloromethane (10 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 30-3 as a pale yellow oil (200.00 mg, yield: 54.61%). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.53 (d, J=2.4 Hz, 1H), 6.49 (dd, J.sub.1=2.0 Hz, J.sub.2=11.2 Hz, 1H), 5.77-5.63 (m, 1H), 5.50-5.25 (m, 1H), 3.79-3.77 (m, 3H), 3.64 (s, 1H), 3.57 (s, 1H), 3.06 (d, J=5.6 Hz, 1H), 2.99-2.91 (m, 2H), 2.54-2.36 (m, 2H), 2.33-2.22 (m, 2H), 2.13 (d, J=2.0 Hz, 1H), 1.12-0.93 (m, 1H), 0.85-0.82 (m, 3H).

[0231] Step 4: Preparation of Compound 30-4

[0232] Compound 30-3 (200.00 mg, 0.69 mmol) was dissolved in ethanol (5.00 mL), then hydroxylamine hydrochloride (481.9 mg, 6.94 mmol) and pyridine (548.62 mg, 6.94 mmol) were successively added. The reaction solution was heated to 80 C. and reacted for 12 hours. After the reaction was complete, the reaction was quenched by addition of water (10 mL) and the aqueous phase was extracted with dichloromethane (5 mL2). The combined organic phase was washed successively with dilute hydrochloric acid (1M, 5 mL2) and saturated brine (10 mL2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 30-4 as a white solid (150.00 mg, yield: 71.29%). MS (m/z): 304.1 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 8.29 (s, 1H), 6.60 (s, 1H), 6.46 (dd, J=2.4, 11.2 Hz, 1H), 5.70-5.52 (m, 1H), 5.30 (d, J=3.2 Hz, 1H), 4.24 (d, J=4.8 Hz, 1H), 3.78 (s, 3H), 2.88-2.62 (m, 2H), 2.51-2.20 (m, 5H), 1.90-1.75 (m, 1H), 1.38-1.24 (m, 2H), 0.95-0.86 (m, 1H), 0.85 (d, J=4.8 Hz, 3H).

[0233] Step 5: Preparation of Compound 30-5

[0234] Compound 30-4 (150.00 mg, 494.45 umol) was dissolved in ethanol (2.00 mL), then Raney Nickel (84.72 mg) and NH.sub.3.H.sub.2O (100.00 uL) were added. After the reaction system was purged with nitrogen for three times, hydrogen gas was introduced. The reaction was carried out under 50 Psi at 80 C. for 12 hours. The reaction solution was filtered through celite and concentrated in vacuo to give crude product 30-5 (180 mg) as a pale yellow oil. .sup.1H NMR (400 MHz, CD.sub.3OD) 6.67 (br. s., 1H), 6.54-6.47 (m, 1H), 3.77 (s, 3H), 3.28-3.22 (m, 1H), 2.81-2.67 (m, 2H), 2.41-2.27 (m, 1H), 2.08-1.84 (m, 5H), 1.59-1.27 (m, 7H), 1.20 (t, J=7.2 Hz, 3H).

[0235] Step 6: Preparation of Compound 30

[0236] Compound 30-5 (150 mg, 514.76 umol) was dissolved in hydrobromic acid (5.00 mL) and the reaction solution was stirred at 100 C. for 5 hours. After being cooled down, the reaction solution was concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give product 30 as a yellow oil (31.71 mg, yield: 22.21%). MS (m/z): 278.0 (M+1). 1H NMR (400 MHz, CD.sub.3OD) 6.60 (s, 1H), 6.43 (dd, J=2.4, 11.2 Hz, 1H), 3.79 (d, J=2.8 Hz, 1H), 2.88-2.73 (m, 2H), 2.59 (dd, J.sub.1=2.8 Hz, J.sub.2=5.0 Hz, 1H), 2.05-1.94 (m, 1H), 1.93-1.67 (m, 4H), 1.65-1.29 (m, 4H), 1.18 (td, J.sub.1=5.2 Hz, J.sub.2=10.0 Hz, 2H), 0.92-0.76 (m, 4H).

Example 31: Preparation of Compound 31

[0237] ##STR00114## ##STR00115##

[0238] Step 1: Preparation of Compound 31-1

[0239] Compound 1-1 (5.00 g, 25.75 mmol) was dissolved in dichloromethane (20.00 mL), then trifluoromethanesulfonic anhydride (8.72 g, 30.90 mmol) and sodium carbonate (5.46 g, 51.50 mmol) were successively added, the reaction solution was stirred at 25 C. for 12 hours. After the reaction was complete, water (30 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (30 mL2). The combined organic phase was washed with saturated brine (30 mL2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 31-1 (7.50 g, yield: 89.28%) as a pale yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.74 (d, J=2.0 Hz, 1H), 6.60 (dd, J.sub.1=2.4 Hz, J.sub.2=10.8 Hz, 1H), 6.08 (t, J=4.8 Hz, 1H), 3.80 (s, 3H), 2.88-2.73 (m, 2H), 2.52 (dt, J.sub.1=4.8 Hz, J.sub.2=8.4 Hz, 2H).

[0240] Step 2: Preparation of Compound 31-2

[0241] Compound 31-1 (3.00 g, 9.20 mmol) was dissolved in toluene (20.00 mL), then isobutylboronic acid (4.69 g, 46.00 mmol), Pd(PPh.sub.3).sub.4 (531.56 mg, 460.00 umol), KF (1.28 g, 22.08 mmol) and Cs.sub.2CO.sub.3 (2.40 g, 7.36 mmol) were successively added. The reaction system was purged with nitrogen for three times, then the reaction solution was stirred at 80 C. for 12 hours. After being cooled down, the reaction solution was filtered through celite and the filtrate was diluted with 20 mL water. The aqueous phase was extracted with dichloromethane (20 mL2). The combined organic phase was washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give compound 31-2 (600.00 mg, yield: 27.83%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.62 (d, J=2.0 Hz, 1H), 6.48 (dd, J.sub.1=11.2 Hz, J.sub.2=2.4 Hz, 1H), 5.88 (t, J=4.4 Hz, 1H), 3.82-3.78 (m, 3H), 2.69 (t, J=8.0 Hz, 2H), 2.28-2.25 (m, 2H), 2.24-2.20 (m, 2H), 1.93-1.73 (m, 2H), 0.91 (d, J=6.4 Hz, 6H).

[0242] Step 3: Preparation of Compound 31-3

[0243] Compound 31-2 (600.00 mg, 2.56 mmol) was dissolved in dichloromethane (2.00 mL), then Na.sub.2CO.sub.3 (407.11 mg, 3.84 mol) and m-CPBA (530.28 mg, 3.07 mmol) were successively added under an ice bath, the internal temperature was maintained within 0-5 C. and the mixture was stirred for 1 hour. The reaction was quenched by addition of saturated Na.sub.2SO.sub.3 (5 mL) solution. The aqueous phase was extracted with dichloromethane (10 mL3) and the combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and filtered. The residue obtained after concentration in vacuo was dissolved in dichloromethane (5.00 mL). BF.sub.3.Et.sub.2O (68.04 mg, 479.00 umol) was added to the dichloromethane solution under an ice bath, and the mixture was stirred at the same temperature for 0.5 hours. The reaction was quenched by addition of saturated NaHCO.sub.3 (3 mL) and the aqueous phase was extracted with dichloromethane (5 mL3). The combined organic phase was washed with saturated brine (10 mL2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 31-3 as a pale yellow oil (0.4 g, yield: 33.36%). MS (m/z): 251.0 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.53 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 6.46 (s, 1H), 3.79 (s, 3H), 3.44 (t, J=7.2 Hz, 1H), 3.21-2.93 (m, 2H), 2.69 (td, J=5.6 Hz, J.sub.2=17.2 Hz, 1H), 2.51-2.29 (m, 1H), 1.74-1.67 (m, 1H), 1.65-1.53 (m, 3H), 0.95 (t, J=6.8 Hz, 6H).

[0244] Step 4: Preparation of Compound 31-4

[0245] Compound 31-3 (300.00 mg, 1.20 mmol) was dissolved in THF (2.00 mL) under an ice bath. After the reaction system was purged with nitrogen for three times, potassium tert-butoxide (161.38 mg, 1.44 mmol) was added. After the reaction solution was stirred at the same temperature for 1 hour, the reaction solution was slowly added to a solution of cis-1,4-dichloro-2-butene (225.00 mg, 1.80 mmol) in THF (2.00 mL). After reacting at 25 C. for 12 hours, t-BuOK (161.38 mg, 1.44 mmol) was added, then the temperature was raised to 60 C. and the reaction was continued for 6 hours, the reaction solution was slowly poured into water (10 mL) to be quenched. The aqueous phase was extracted with dichloromethane (10 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was seperated and purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 31-4 as a pale yellow oil (200.00 mg, yield: 55.12%). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.49 (s, 2H), 5.71-5.61 (m, 1H), 5.37-5.26 (m, 1H), 3.77 (s, 3H), 3.14-3.04 (m, 1H), 3.03-2.97 (m, 2H), 2.56 (dd, J=8.4 Hz, J.sub.2=13.6 Hz, 1H), 2.40 (dd, J=7.6 Hz, J.sub.2=15.6 Hz, 1H), 2.32-2.24 (m, 2H), 2.13-2.03 (m, 1H), 1.70 (dd, J.sub.1=5.6 Hz, J.sub.2=13.6 Hz, 1H), 1.46-1.30 (m, 1H), 0.74-0.59 (m, 6H).

[0246] Step 5: Preparation of Compound 31-5

[0247] Compound 31-4 (200.00 mg, 661.42 umol) was dissolved in ethanol (1.00 mL), then hydroxylamine hydrochloride (459.62 mg, 6.61 mmol) and pyridine (523.18 mg, 6.61 mmol) were successively added. The reaction was heated to 80 C. and reacted for 12 hours, then quenched by addition of water (10 mL). The aqueous phase was extracted with dichloromethane (5 mL2). The combined organic phase was washed successively with dilute hydrochloric acid (1M, 5 mL2) and saturated brine (10 mL2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by thin layer chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 31-5 as a white solid (150.00 mg, yield: 71.45%). MS (m/z): 318.1 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.58 (s, 1H), 6.46 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 5.61-5.51 (m, 1H), 5.23 (br. s., 1H), 4.31-4.05 (m, 1H), 3.78 (s, 3H), 2.95-2.70 (m, 2H), 2.59-2.38 (m, 3H), 2.31-2.15 (m, 2H), 1.78 (dd, J.sub.1=6.4 Hz, J.sub.2=13.6 Hz, 1H), 1.63-1.58 (m, 1H), 0.78 (d, J=6.4 Hz, 3H), 0.58 (d, J=6.8 Hz, 3H).

[0248] Step 6: Preparation of Compound 31-6

[0249] Compound 31-5 (150.00 mg, 472.59 umol) was dissolved in ethanol (2.00 mL), then Raney nickel (80.97 mg) and NH.sub.3.H.sub.2O (100.00 uL) were added. After the reaction system was purged with nitrogen for three times, hydrogen gas was introduced. The reaction was carried out under 50 Psi at 80 C. for 12 hours. The reaction solution was filtered through celite and concentrated in vacuo to give the crude product 31-6 (130 mg) as a pale yellow oil. MS (m/z): 306.1 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.71 (s, 1H), 6.52 (dd, J=2.4, 11.2 Hz, 1H), 3.78 (s, 3H), 2.79-2.72 (m, 2H), 2.47-2.29 (m, 1H), 2.13-1.92 (m, 3H), 1.88-1.37 (m, 8H), 1.17 (d, J=6.4 Hz, 1H), 0.92 (d, J=6.8 Hz, 3H), 0.51 (d, J=6.8 Hz, 3H).

[0250] Step 7: Preparation of Compound 31

[0251] Compound 31-6 (100.00 mg, 327.41 umol) was dissolved in hydrobromic acid (2.00 mL) and the solution was stirred at 100 C. for 5 hours. After being cooled down, the reaction solution was concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give product 31 as yellow oil (9.12 mg, yield: 9.56%). MS (m/z): 292.0 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.66 (d, J=1.6 Hz, 1H), 6.47 (dd, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz, 1H), 3.72 (d, J=2.4 Hz, 1H), 2.8 (d, J=7.2 Hz, 1H), 2.64 (br. s., 1H), 2.57-2.43 (m, 1H), 2.15-1.88 (m, 4H), 1.84-1.70 (m, 1H), 1.68-1.41 (m, 5H), 1.19 (d, J=6.4 Hz, 3H), 1.13 (dt, J.sub.1=4.4 Hz, J.sub.2=7.5 Hz, 1H), 1.06 (d, J=6.4 Hz, 3H).

Example 32: Preparation of Compound 32 and Compound 33

[0252] ##STR00116##

[0253] Step 1: Preparation of Compound 32-1

[0254] Compound 6-3 (1.50 g, 7.20 mmol) was dissolved in THF (10.00 mL) under an ice bath, and the reaction system was purged with nitrogen for three times, then potassium tert-butoxide (969.98 mg, 8.64 mmol) was added. After being stirred at the same temperature for 1 hour, the reaction solution was slowly added to a solution of cis-1,4-dichloro-2-butene (1.80 g, 14.41 mmol) in THF (5.00 mL). After reacting at 25 C. for 12 hours, t-BuOK (1.21 g, 10.81 mmol) was added, then the temperature was raised to 60 C. and the reaction was continued for 6 hours. The reaction solution was slowly poured into water (5 mL) to be quenched. The aqueous phase was extracted with dichloromethane (5 mL2). The combined organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give product 32-1 as a pale yellow oil (1.2 g, yield: 64.0%). MS (m/z): 260.9 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.57 (s, 1H), 6.45-6.51 (m, 1H), 5.80 (ddd, J.sub.1=14.8 Hz, J.sub.2=7.6 Hz, J.sub.3=3.2 Hz, 1H), 5.38-5.59 (m, 1H), 3.78 (s, 3H), 3.02-3.07 (m, 1H), 2.93-3.01 (m, 1H), 2.34-2.47 (m, 2H), 2.26 (br. s., 1H), 2.09-2.18 (m, 1H), 1.56 (s, 3H).

[0255] Step 2: Preparation of Compound 32-2

[0256] Compound 32-1 (900.00 mg, 3.46 mmol) was dissolved in pyridine (5.00 mL), and hydroxylamine hydrochloride (2.40 g, 34.60 mmol) was added, then the temperature was raised to 100 C. and the reaction was continued for 12 hours. After the reaction was complete, the reaction was quenched by addition of water (10 mL) and the aqueous phase was extracted with dichloromethane (10 mL2). The combined organic phase was adjusted to pH 5-6 with hydrochloric acid and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Ethyl acetate (2 mL) was added and then the mixture was allowed to stand overnight, precipitate was precipitated. The mixture was filtered to give compound 32-2 as a white solid (400.00 mg, yield: 81.3%). MS (m/z): 275.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.70 (br. s., 2H), 6.55 (dd, J=11.2, 2.4 Hz, 1H), 6.44-6.50 (m, 1H), 5.67 (td, J.sub.1=7.6 Hz, J.sub.2=3.64 Hz, 1H), 5.32 (td, J.sub.1=7.6 Hz, J.sub.2=4.4 Hz, 1H), 4.05-4.37 (m, 2H), 3.75 (s, 3H), 3.78 (s, 3H), 2.74-2.80 (m, 3H), 2.41-2.57 (m, 2H), 2.18-2.32 (m, 2H), 2.03-2.16 (m, 2H), 1.60 (s, 3H), 1.44 (s, 3H), 0.77-1.24 (m, 3H).

[0257] Step 3: Preparation of Compound 32-3

[0258] Compound 32-2 (350.00 mg, 1.27 mmol) was dissolved in ethanol (2.00 mL), then Raney nickel (217.60 mg), NH.sub.3.H.sub.2O (4.45 mg, 127.00 umol) was added. After the reaction system was purged with nitrogen for three times, hydrogen gas was introduced. The reaction was carried out under 50 Psi at 70 C. for 12 hours. The reaction solution was filtered through celite and concentrated in vacuo to give the crude product 32-3 (500.00 mg) as a pale yellow oil. MS (m/z): 263.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.71 (d, J=19.2 Hz, 1H), 6.47-6.57 (m, 1H), 3.77 (d, J=2.8 Hz, 3H), 2.98-3.07 (m, 1H), 2.71-2.95 (m, 1H), 2.32-2.54 (m, 1H), 1.79-2.14 (m, 2H), 1.38-1.73 (m, 4H), 1.35 (d, J=9.2 Hz, 3H), 0.84-1.18 (m, 1H).

[0259] Step 4: Preparation of Compound 32 and Compound 33

[0260] Compound 32-3 (450.00 mg, 1.71 mmol) was dissolved in hydrobromic acid (2.00 mL) and the reaction solution was stirred at 100 C. for 2 hours. After being cooled down, the reaction solution was concentrated in vacuo to give the crude product. The crude product was purified by HPLC preparative column to give two epimers as 32 (40 mg, yield: 9.38%) and 33 (45 mg, yield: 10.56%).

[0261] Compound 32: MS (m/z): 249.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.66 (d, J=1.24 Hz, 1H), 6.43 (dd, J.sub.1=11.2 Hz, J.sub.2=2.4 Hz, 1H), 3.60 (d, J=3.2 Hz, 1H), 2.72-3.02 (m, 2H), 2.57 (br. s., 1H), 1.77-2.08 (m, 3H), 1.44-1.68 (m, 3H), 1.42 (s, 3H), 1.35-1.41 (m, 1H), 1.02-1.22 (m, 1H),

[0262] Compound 33: MS (m/z): 249.9 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 6.63 (d, J=1.20 Hz, 1H), 6.45 (dd, J.sub.1=11.2 Hz, J.sub.2=2.24 Hz, 1H), 3.59 (d, J=3.2 Hz, 1H), 2.68-2.76 (m, 2H), 2.48-2.61 (m, 1H), 2.17 (s, 1H), 1.89-2.05 (m, 1H), 1.61-1.82 (m, 2H), 1.44-1.59 (m, 2H), 1.36-1.43 (m, 3H), 1.14-1.28 (m, 1H), 0.89-1.07 (m, 1H).

Example 34: Preparation of Compound 34

[0263] ##STR00117##

[0264] Step 1: Preparation of Compound 34-1

[0265] Compound 21 (3 g, 11.39 mmol) and triethylamine (1.38 g, 13.67 mmol) were dissolved in DMF (10 mL), then (Boc).sub.2O (2.98 g, 13.67 mmol) was added. The reaction solution was stirred at 15 C. for 1 hour, then poured into water to be quenched, and the aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 20/1) to give product 34-1 (2.9 g) as a brown oil. MS (m/z): 308.1 (M-56+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.50 (s, 1H), 6.43 (dd, J.sub.1=2.0 Hz, J.sub.2=10.4 Hz, 1H), 5.44 (br. s., 1H), 4.95 (d, J=10.4 Hz, 1H), 4.05 (dd, J.sub.1=5.2 Hz, J.sub.2=10.4 Hz, 1H), 2.89-2.73 (m, 2H), 2.36 (br. s., 1H), 1.87-1.49 (m, 15H), 1.29 (s, 3H), 1.01-0.81 (m., 3H).

[0266] Step 2: Preparation of Compound 34-2

[0267] Compound 34-1 (363 mg, 998.71 umol) was dissolved in dichloromethane (2 mL), then adipoyl chloride (73 mg, 399.48 umol) and triethylamine (60 mg, 599.22 umol) were added. The reaction solution was stirred at 15 C. for 2 hours, then poured into water to be quenched, and the aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product as a dark yellow oil. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 6/1) to give product 34-2 (250 mg) as a pale yellow oil. MS (m/z): 859.8 (M+1).

[0268] The following compound was prepared according to a method similar to that of compound 34-2:

TABLE-US-00012 Compound number Structure Spectrogram 35-2 [00118] MS (m/z): 887.5 (M + 23).

[0269] Step 3: Preparation of Compound 34

[0270] Compound 34-2 (250 mg, 298.67 umol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1.5 mL) was added dropwise. After the addition was complete, the mixture was stirred at 15 C. for 1 hour. Saturated aqueous NaHCO.sub.3 solution was added to quench the reaction, the pH was adjusted to approximately 7, and the aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product as a dark yellow oil. The crude product was purified by high performance liquid phase preparative column (formic acid system) to give the formate salt of compound 34 (32 mg, yield: 16.8%). MS m/z: 659.6 [M+23].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.40-8.26 (m, 2H), 6.73 (s, 2H), 6.69 (d, J=9.6 Hz, 2H), 3.35 (br. s., 2H), 2.88 (br. s., 4H), 2.60-2.46 (br. s., 6H), 1.84-1.78 (m, 10H), 1.72-1.48 (m, 10H), 1.38 (s, 6H), 1.13-0.98 (m, 2H), 0.79 (br. s., 2H).

[0271] The following compound was prepared according to a method similar to that of compound 34:

TABLE-US-00013 Compound number Structure Spectogram Com- pound 35 [00119] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.42 (br. s., 1H), 6.76-6.60 (m, 4H), 3.42- 3.31 (m, 2H), 2.95-2.77 (m, 4H), 2.60-2.40 (m, 6H), 1.88-1.44 (br. s., 22H), 1.38 (s, 6H), 1.05 (q, J = 11.6 Hz, 2H), 0.79 (br. s., 4H), MS m/z: 333.4 [M/2 + 1].sup.+, 665.4 [M + 1].sup.+

Example 36: Preparation of Compound 36

[0272] ##STR00120##

[0273] Step 1: Preparation of Compound 36-1

[0274] Dezocine (1.00 g, 4.08 mmol) and triethylamine (824.84 mg, 8.15 mmol) were dissolved in DMF (8 mL), then (Boc).sub.2O (1.07 g, 4.89 mmol) was added. After being stirred at 25 C. for 1.5 hours, the reaction solution was poured into water to be quenched and the aqueous phase was extracted with dichloromethane (15 mL4). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8/1) to give product 36-1 (2.9 g). .sup.1H NMR (400 MHz, CD.sub.3OD): 6.92 (d, J=8.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.60 (dd, J.sub.1=2.4, Hz, J.sub.2=8.4 Hz, 1H), 6.14 (d, J=9.6 Hz, 1H), 4.04 (dd, J.sub.1=5.2 Hz, J.sub.2=10.4 Hz, 1H), 3.15 (dd, J.sub.1=7.2 Hz, J.sub.2=16.4 Hz, 1H), 2.65 (d, J=16.4 Hz, 1H), 2.24 (br. s., 1H), 1.82-1.68 (m, 4H), 1.51 (s, 12H), 1.29 (s, 3H), 1.23-1.11 (m, 1H), 1.08-0.97 (m, 1H), 0.95-0.85 (m, 2H).

[0275] Step 2: Preparation of Compound 36-2

[0276] Compound 36-1 (100.00 mg, 289.46 umol) and adipic acid (19.21 mg, 131.45 umol) were dissolved in dichloromethane (2 mL) and the solution was cooled to 25 C., 4-dimethylaminopyridine (73 mg, 399.48 umol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.00 mg, 328.63 umol) were successively added. The reaction solution was stirred at 0 C. for 5 hours, then poured into water to be quenched and the aqueous phase was extracted with dichloromethane (10 mL3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product 36-2 (108 mg). The crude product was used in the next step without further purification. MS (m/z): 823.5 (M+1).

[0277] The following compounds were prepared by similar method with Compound 36-2:

TABLE-US-00014 Compound number Structure Spectrogram 37-1 [00121] MS (m/z): 879.6 (M + 23). 38-1 [00122] MS (m/z): 915.5 (M + 23). 39-1 [00123] MS (m/z): 943.5 (M + 23). 40-1 [00124] MS (m/z): 929.5 (M + 23). 41-1 [00125] MS (m/z): 885.5 (M + 23).

[0278] Step 3: Preparation of Compound 36

[0279] Compound 36-2 (108.0 mg, 134.82 umol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (15.4 mg, 134.82 umol) was added at 10 C. The reaction solution was stirred at 10 C. for 4 hours, then quenched by addition of 5% NaHCO.sub.3 aqueous solution. The pH was adjusted to approximately 7, and the aqueous phase was extracted with dichloromethane (10 mL4). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by high performance liquid preparative column (neutral system) to give compound 36 as a colorless oil (27 mg, yield: 31.8%). MS (m/z): 601.4 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.07 (d, J=8.4 Hz, 2H), 6.92 (d, J=2.4 Hz, 2H), 6.83 (dd, J.sub.1=2.4 Hz, J.sub.2=8.4 Hz, 2H), 3.21-3.11 (m, 4H), 2.70 (d, J=17.2 Hz, 2H), 2.63 (br. s., 4H), 2.24 (br. s., 2H), 2.06-1.96 (m, 2H), 2.01-1.88 (m, 4H), 1.79-1.53 (m, 12H), 1.35 (s, 6H), 1.06-0.94 (m, 2H), 0.91-0.72 (m, 4H).

[0280] The following compounds were prepared by similar method with Compound 36:

TABLE-US-00015 Compound number Structure Spectrogram Compound 37 [00126] MS (m/z): 657.5 (M + 1). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.07 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 2.4 Hz, 2H), 6.82 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 8.4 Hz, 2H), 3.19-3.10 (m, 4H), 2.70 (d, J = 16.8 Hz, 2H), 2.54 (t, J = 7.6 Hz, 4H), 2.24 (br. s., 2H), 2.05-1.96 (m, 2H), 1.82- 1.61 (m, 12H), 1.56-1.42 (m, 12H), 1.35 (s, 6H), 1.07-0.95 (m, 2H), 0.92-0.75 (m, 4H). Compound 38 [00127] MS (m/z): 715.4 (M + 1). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.75-6.61 (m, 4H), 3.35 (d, J = 4.4 Hz, 3H), 2.93-2.80 (m, 4H), 2.58-2.40 (m, 6H), 1.79- 1.45 (m, 18H), 1.45-1.27 (m, 14H), 1.07-1.04 (m, 2H), 0.81-0.78 (m, 4H). Compound 39 [00128] MS (m/z): 721.4 (M + 1). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.79 (s, 2H), 6.75-6.68 (m, 2H), 3.61 (br. s., 2H), 2.31- 2.95 (m, 4H), 2.60-2.57 (m, 6H), 2.23-2.05 (m, 4H), 1.95- 1.90 (m, 6H), 1.81-1.73 (m, 4H), 1.68-1.56 (m, 10H), 1.49-1.19 (m, 14H), 0.86 (br. s., 4H) Compound 40 [00129] MS (m/z): 729.4 (M + 1). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.84 (s, 2H), 6.72 (dd, J.sub.1 = 2.0 Hz, J.sub.2 = 10.0 Hz, 2H), 3.60 (br. s., 2H), 3.04-2.91 (m, 4H), 2.55 (br. s., 2H), 1.98-1.90 (m, 4H), 1.85-1.44 (s, 22H), 1.36 (s. 12H), 1.24-1.12 (m, 2H), 0.86-0.82 (m, 4H). Compound 41 [00130] MS (m/z): 663.4 (M + 1). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.73 (s, 2H), 6.69-6.64 (m, 2H), 3.22 (d, J = 5.2 Hz, 2H), 2.94-2.82 (m, 4H), 2.40 (br. s., 2H), 2.28 (d, J = 7.6 Hz, 4H), 2.02-1.48 (m, 22H), 1.37 (s, 6H), 1.11-0.96 (m, 2H), 0.84-0.81 (m, 2H).

Example 42: Preparation of Compound 42

[0281] ##STR00131##

[0282] Step 1: Preparation of Compound 42-2

[0283] Compound 42-1 (20.00 g, 192.03 mmol) was dissolved in ethyl acetate (200 mL). Triethylamine (8.16 g, 80.65 mmol) and triphenylchloromethane (11.24 g, 40.33 mmol) were successively added under stirring. The solution was slowly heated to reflux, then stirred for 5 hours. After being cooled down, the reaction solution was quenched by being poured into 100 mL water and the aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phases were washed with 30 mL water and 30 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 3/1) to give 42-2 (20 g) as a colorless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.46-7.20 (m, 15H), 3.63 (t, J=6.4 Hz, 2H), 3.07 (t, J=6.4 Hz, 2H), 1.76-1.38 (m, 6H).

[0284] Step 2: Preparation of Compound 42-3

[0285] Compound 42-2 (12.00 g, 34.64 mmol) was dissolved in dichloromethane (200 mL), then 4-dimethylaminopyridine (846 mg, 6.93 mmol), triethylamine (4.56 g, 45.03 mmol) and p-toluenesulfonyl chloride (7.92 g, 41.56 mmol) were successively added. After being stirred at 15 C. for 16 hours, the reaction solution was quenched by being poured into 100 mL water and the aqueous phase was extracted with dichloromethane (50 mL2). The combined organic phases were washed with 50 mL water and 50 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 3/1) to give compound 42-3 as a pale yellow viscous liquid (12 g, yield: 69.2%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.78 (d, J=8.4 Hz, 2H), 7.45-7.17 (m, 17H), 4.00 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.43 (s, 3H), 1.67-1.49 (m, 4H), 1.45-1.34 (m, 2H).

[0286] Step 3: Preparation of Compound 42-4

[0287] Compound 42-2 (7.00 g, 20.20 mmol) was dissolved in THF (50 mL). Sodium hydride (1.62 g, 40.40 mmol, 60% purity) was added at 0 C. The solution was heated to 15 C., and stirred for 15 minutes. A solution of 42-3 (12.03 g, 24.04 mmol) in DMF (100 mL) was added. After being stirred at 15 C. for 16 hours, the reaction solution was quenched by being poured into 100 mL water, then the aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phases were washed with 20 mL water and 30 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give compound 42-4 as a colorless liquid (12.0 g). MS m/z: 697.5 (M+23). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48-7.20 (m, 30H), 3.38 (t, J=6.8 Hz, 4H), 3.08 (t, J=6.4 Hz, 4H), 1.71-1.60 (m, 4H), 1.59-1.49 (m, 4H), 1.48-1.37 (m, 4H).

[0288] Step 4: Preparation of Compound 42-5

[0289] Compound 42-4 (12.0 g, 17.78 mmol) was dissolved in the mixed solution of THF (50 mL) and methanol (50 mL), then p-toluenesulfonic acid (612 mg, 3.56 mmol) was added. After being stirred at 15 C. for 16 hours, the reaction solution was concentrated directly under vacuum to give the crude product. The crude product was purified by silica gel column chromatograph (eluent: dichloromethane/methanol=20/1 to 10/1) to give compound 42-5 as a pale yellow liquid (2.50 g, yield: 73.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.64 (t, J=6.4 Hz, 4H), 3.42 (t, J=6.4 Hz, 4H), 1.84-1.55 (m, 8H), 1.49-1.36 (m, 4H).

[0290] Step 5: Preparation of Compound 42-6

[0291] Periodic acid (3.29 g, 14.45 mmol) was added to acetonitrile (45 mL) and the solution was vigorously stirred at 15 C. for 15 minutes. Then the solution was cooled to 0 C. and added with 42-5 (1.10 g, 5.78 mmol) and PCC (25 mg, 115.60 umol, 0.02 eq). The mixture was heated to 15 C., and stirred for 16 hours. After the precipitate was filtered off, the filtrate was poured into 50 mL half-saturated brine, and the aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phases were washed with 40 mL saturated aqueous NaHSO.sub.3 solution and 30 mL saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product 42-6 (800.0 mg) as a pale yellow solid. The crude product was directly used in the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.47-3.41 (m, 4H), 2.47-2.37 (m, 4H), 1.83-1.57 (m, 8H).

[0292] Step 6: Preparation of Compound 42-7

[0293] Compound 42-6 (300 mg, 1.37 mmol) was dissolved in dichloromethane (20 mL). 4-dimethylaminopyridine (167 mg, 1.37 mmol), 34-1 (1.07 g, 2.95 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (735 mg, 3.84 mmol) were successively added. The reaction solution was stirred at 15 C. for 16 hours, then quenched by being poured into 30 mL water, and the aqueous phase was extracted with dichloromethane (20 mL3). The combined organic phases were washed with 10 mL water and 10 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 3/1) to give compound 42-7 as a colorless viscous solid (323 mg, yield: 26.0%). MS m/z: 931.7 (M+23).

[0294] Step 7: Preparation of Compound 42

[0295] Compound 42-7 (430 mg, 472.97 umol) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (1.8 mL) was added. After reacting at 15 C. for 16 hours, the reaction solution was poured to 50 mL ethyl acetate to be diluted poured into, then a saturated aqueous solution of sodium bicarbonate was slowly added to adjust the pH to approximately 7, and the aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phases were washed with 20 mL water and 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by high performance liquid phase preparative column (HCl system) to give the hydrochloride salt of compound 42 (200 mg, yield: 54.1%). MS m/z: 709.3 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.94 (s, 2H), 6.82 (d, J=9.8 Hz, 2H), 3.73 (d, J=4.4 Hz, 2H), 3.53 (t, J=6.0 Hz, 4H), 3.11-2.91 (m, 4H), 2.72-2.55 (m, 6H), 2.04-1.92 (m, 4H), 1.85-1.68 (m, 12H), 1.61 (d, J=9.2 Hz, 6H), 1.51 (s, 6H), 1.30-1.20 (m, 2H), 0.90-0.75 (m, 4H).

Example 43: Preparation of Compound 43

[0296] ##STR00132##

[0297] Step 1: Preparation of Compound 43-1

[0298] Compound 34-1 (200 mg, 550 umol) was dissolved in dichloromethane (10 mL), then hexanoyl chloride (74 mg, 550 umol) and triethylamine (83 mg, 825 umol) were added. The reaction solution was stirred at 15 C. for 2 hours, then poured into water to be quenched, and the aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product as a dark yellow oil. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give product 43-1 as a white solid (180 mg, yield: 70.9%). MS (m/z): 484.3 (M+23).

[0299] The following compounds were prepared by similar method with Compound 43-1:

TABLE-US-00016 Compound number Structure Spectrogram 44-1 [00133] MS (m/z): 512.1 (M + 23). 45-1 [00134] MS (m/z): 540.5 (M + 23). 46-1 [00135] MS (m/z): 554.5 (M + 23). 47-1 [00136] MS (m/z): 470.4 (M + 23). 48-1 [00137] MS (m/z): 498.4 (M + 23). 49-1 [00138] MS (m/z): 496.2 (M + 23).

[0300] Step 2: Preparation of Compound 43

[0301] Compound 43-1 (150 mg, 324 umol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (500 uL) was added dropwise. After the addition was completed, stirring was continued at 15 C. for 2 hours. The reaction solution was diluted with 20 mL dichloromethane, then saturated aqueous NaHCO.sub.3 was added to adjust the pH to approximately 7. The mixture was let stand to portion, and the organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product as a pale yellow oil. The crude product was purified by high performance liquid phase preparative column (formic acid system) to obtain the formate salt of product 43 (58 mg, yield: 49.4%). MS (m/z): 362.1 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 8.54 (s, 1H), 6.92 (s, 1H), 6.81 (dd, J.sub.1=2.0 Hz, J.sub.2=10.0 Hz, 1H), 3.63 (d, J=5.2 Hz, 1H), 3.05-2.95 (m, 2H), 2.65-2.51 (m, 3H), 2.01-1.90 (m, 2H), 1.86-1.55 (m, 7H), 1.48 (s, 3H), 1.45-1.37 (m, 4H), 1.28-1.13 (m, 1H), 0.97 (t, J=7.2 Hz, 3H), 0.92-0.79 (m, 2H).

[0302] The following compounds were prepared by similar method with Compound 43:

TABLE-US-00017 Compound number Structure Spectrogram Compound 44 [00139] MS (m/z): 390.2 (M + 1), .sup.1H NMR (400 MHz, CD.sub.3OD) 8.37 (br.s., 1H), 6.93 (s, 1H), 6.82 (dd, J.sub.1 = 2.0 Hz, J.sub.2 = 10.0 Hz, 1H), 3.68 (d, J = 5.2 Hz, 1H), 3.05- 2.98 (m, 2H), 2.65-2.54 (m, 3H), 2.00- 1.92 (m, 2H), 1.83-1.70 (m, 4H), 1.68- 1.55 (m, 3H), 1.50 (s, 3H), 1.46-1.30 (m, 8H), 1.26-1.20 (m, 1H), 0.98-0.90 (m, 5H) Compound 45 [00140] MS (m/z): 459.2 (M + 42), .sup.1H NMR (400 MHz, CDCl.sub.3) 8.45 (s, 1H), 6.75- 6.62 (m, 2H), 3.45 (d, J = 4.8 Hz, 1H), 2.95- 2.81 (m, 2H), 2.62-2.41 (m, 3H), 1.90- 1.76 (m, 3H), 1.73-1.62 (m, 3H), 1.60- 1.46 (m, 3H), 1.40 (s, 3H), 1.38-1.15 (m, 12H), 1.14-0.97 (m, 1H), 0.89-0.66 (m, 5H) Compound 46 [00141] MS (m/z): 432.4 (M + 1), .sup.1H NMR (400 MHz, CD.sub.3OD) 8.51 (br. s., 1H), 6.85 (s, 1H), 6.77 (dd, J = 2.0 Hz, J = 10.0 Hz, 1H), 3.70 (d, J = 4.8 Hz, 1H), 3.11- 2.93 (m, 2H), 2.58 (br. s., 1H), 2.07-1.91 (m, 2H), 1.85-1.58 (m, 7H), 1.50 (s, 3H), 1.43-1.29 (m, 18H), 1.28-1.13 (m, 1H), 0.99-0.78 (m, 5H). Compound 47 [00142] MS (m/z): 348.6 (M + 1), .sup.1H NMR (400 MHz, CDCl.sub.3) 8.45 (br. s., 1H), 6.74- 6.61 (m, 2H), 3.51 (d, J = 4.8 Hz, 1H), 2.99-2.81 (m, 2H), 2.58 (br. s., 1H), 1.94- 1.66 (m,4H), 1.65-1.50 (m,3H), 1.48 (s, 3H), 1.32 (s, 9H), 1.22-1.04 (m, 1H), 0.93-0.70 (m, 2H) Compound 48 [00143] MS (m/z): 376.3 (M + 1), .sup.1H NMR (400 MHz, CD.sub.3OD) 6.85 (s, 1H), 6.79- 6.72 (m, 1H), 3.63 (d, J = 4.8 Hz, 1H), 3.08-2.92 (m, 2H), 2.56 (br. s., 1H), 1.96- 1.90 (m, 2H), 1.87-1.54 (m, 8H), 1.49 (s, 3H), 1.45-1.36 (m, 2H), 1.33 (s, 6H), 1.26-1.14 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H), 0.95-0.77 (m, 2H). Compound 49 [00144] MS (m/z): 374.3 (M + 1), .sup.1H NMR (400 MHz, CD.sub.3OD) 8.55 (s, 1H), 6.91 (s, 1H), 6.80 (dd, J = 1.6 Hz, J = 10.0 Hz, 1H), 3.68 (d, J = 4.8 Hz, 1H), 3.10-2.92 (m, 2H), 2.69-2.51 (m, 2H), 2.07 (d, J = 12.4 Hz, 2H), 1.95-1.82 (m, 2H), 1.88-1.78 (m, 3H), 1.77-1.67 (m, 2H), 1.66- 1.52 (m, 5H), 1.49 (s, 3H), 1.46-1.14 (m, 4H), 0.99-0.75 (m, 2H).

Example 50: Preparation of Compound 50

[0303] ##STR00145##

[0304] Step 1: Preparation of Compound 50-2

[0305] Compound 50-1 (2 g, 17 mmol) was dissolved in THF (25 mL), then TMSCl (2.28 g, 21 mmol) and CuI (333 mg, 1.75 mmol) were added under N.sub.2. The solution was cooled to 15 C., added with n-pentylmagnesium bromide solution (20.4 mmol, 38.8 mL), then heated to 20 C. and stirred for 16 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride (50 mL) and the aqueous phase was extracted with ethyl acetate (20 mL3). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product 50-2 (3.30 g) as a yellow oil. The crude product was used directly in the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.64 (s, 3H), 2.17 (s, 2H) 1.35-1.24 (m, 8H), 0.98 (s, 6H), 0.88 (t, J=7.2 Hz, 3H).

[0306] Step 2: Preparation of Compound 50-3

[0307] Compound 50-2 (3.3 g, 17.71 mmol) was dissolved in methanol (10 mL), then a solution of potassium hydroxide (1 g, 17.82 mmol) in water (2 mL) was added. After stirring at 20 C. for 16 hours, dilute hydrochloric acid solution (2M, 10 mL) was added to adjust the pH to approximately 4, followed by addition of ethyl acetate (50 mL), then the mixture was let stand to portion. The organic phase was washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product 50-3 (2.5 g) as a pale yellow oil. The crude product was used directly in the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) 2.23 (s, 2H), 1.34-1.24 (m, 8H), 1.02 (s, 6H), 0.89 (t, J=7.2 Hz, 3H).

[0308] Step 3: Preparation of Compound 50-4

[0309] Compound 50-3 (150 mg, 870.78 umol) was dissolved in dichloromethane (10 mL), then oxalyl chloride (221 mg, 1.74 mmol) and DMF (6 mg, 87 umol) were successively added. After being stirred at 20 C. for 0.5 h, the reaction solution was concentrated in vacuo to give crude product 50-4 (170.00 mg) as a white solid. The crude product was used directly in the next step without further purification.

[0310] Step 4: Preparation of Compound 50-5

[0311] Compound 34-1 (220 mg, 605.28 umol) was dissolved in dichloromethane (5 mL), followed by successive addition of 50-4 (115 mg, 605.28 umol) and triethylamine (122 mg, 1.21 mmol). After being stirred at 20 C. for 1 hour, the reaction solution was directly concentrated under vacuum to give the crude product as a dark yellow oil. The crude product was purified by silica gel preparative plate (developing solvent: petroleum ether/ethyl acetate=20/1) to give product 50-5 as a white solid (210 mg, yield: 67.0%). MS (m/z): 540.4 (M+1).

[0312] Step 5: Preparation of Compound 50

[0313] Compound 50-5 (210 mg, 405 umol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (500 uL) was added. After being stirred at 20 C. for 16 hours, the reaction solution was diluted with 20 mL methylene chloride, then saturated aqueous NaHCO.sub.3 solution was added to adjust the pH to approximately 7 and the mixture was let stand to portion. The organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product as pale yellow oil. The crude product was purified by high performance liquid phase preparative column (formic acid system) to obtain the formate salt of compound 50 (85.00 mg, yield: 50.2%). MS (m/z): 418.4 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 8.55 (br. s., 1H), 6.88 (s, 1H), 6.79 (dd, J=2.0, 10.0 Hz, 1H), 3.64 (d, J=4.4 Hz, 1H), 3.08-2.93 (m, 2H), 2.56 (br. s., 1H), 2.48 (s, 2H), 2.03-1.89 (m, 2H), 1.87-1.54 (m, 5H), 1.49 (s, 3H), 1.44-1.16 (m, 9H), 1.11 (s, 6H), 0.93 (t, J=7.2 Hz, 3H), 0.89-0.77 (m, 2H).

Example 51: Preparation of Compound 51

[0314] ##STR00146##

[0315] Step 1: Preparation of Compound 51-2

[0316] Magnesium sulfate (27.96 g, 232.32 mmol) was added to dichloromethane (100 mL), then concentrated sulfuric acid (5.70 g, 58.08 mmol) was added. After vigorous stirring for 15 minutes, cyclopropanecarboxylic acid (5.00 g, 58.08 mmol) and tert-butanol (21.52 g, 290.39 mmol) were added. After stirring at 25 C. for 12 hours, saturated sodium carbonate solution was added until magnesium sulfate was dissolved. Dichloromethane (50 mL) was added and the mixture was let stand to portion. The organic phase was washed with saturated brine (50 mL3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 51-2 as a light yellow oily liquid (4.20 g, yield: 50.9%). .sup.1HNMR (400 MHz, CDCl.sub.3) 1.56-1.47 (m, 1H), 1.45 (s, 9H), 0.93-0.89 (m, 3H), 0.80-0.72 (m, 2H).

[0317] Step 2: Preparation of Compound 51-3

[0318] Compound 51-2 (3.70 g, 26.02 mmol) was dissolved in tetrahydrofuran (5 mL). After the solution was cooled to 78 C., diisopropylaminolithium in tetrahydrofuran and n-heptane (2M, 15.61 mL) was slowly added. After stirring for 0.5 hour at this temperature, 1-bromohexane (5.15 g, 31.22 mmol) was slowly added. After the addition was completed, the temperature was slowly raised to 25 C. and the reaction solution was stirred at this temperature for 12 hours. The reaction was quenched by addition of 10 mL water and the aqueous phase was extracted with 10 mL dichloromethane. The organic phase was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 51-3 (4.20 g) as a brown oily liquid. The crude product was directly used in the next step without further purification.

[0319] Step 3: Preparation of Compound 51-4

[0320] Compound 51-3 (4.2 g, 18.5 mmol) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (2.54 g, 22.27 mmol) was added. After stirring at 25 C. for 3 hours, 10 ml water and 10 ml dichloromethane were added. The mixture was let stand to portion, and the organic phase was further mixed with 10 mL saturated sodium carbonate solution and stirred. The aqueous phase was back-extracted with 10 ml dichloromethane, acidified with 5 ml of concentrated hydrochloric acid, and the aqueous phase was extracted with 10 ml dichloromethane. The organic phase was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 51-4 as a yellow oily liquid (800 mg, yield: 25.3%).

[0321] .sup.1H NMR (400 MHz, CDCl.sub.3) 1.54-1.41 (m, 4H), 1.36-1.22 (m, 8H), 0.88 (t, J=6.8 Hz, 3H), 0.75 (q, J=3.6 Hz, 2H).

[0322] Step 4: Preparation of Compound 51-5

[0323] Compound 51-4 (140.52 mg, 825.38 umol) was dissolved in dichloromethane (2 ml), then a drop of DMF and oxalyl chloride (125.72 mg, 990.45 umol) were added. After being stirred at 25 C. for 0.5 hours, the reaction solution was directly concentrated under vacuum. The residue was dissolved in dichloromethane (2 mL) and added to a solution of 34-1 (200.00 mg, 550.25 umol) in dichloromethane (2 mL). After being stirred at 25 C. for 12 hours, the reaction solution was quenched by addition of dichloromethane (5 mL) and water (5 mL). The mixture was let stand to portion, and the organic phase was washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product 51-5 (400 mg) as a yellow oil. MS m/z: 460.3 (M-56+1).

[0324] Step 5: Preparation of Compound 51

[0325] Compound 51-5 (350 mg, 678.69 umol) was dissolved in dichloromethane (3 ml), then trifluoroacetic acid (462 mg, 4.05 mmol) was added. After reacting at 25 C. for 2 hours, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to approximately 7. The organic phase was washed with saturated brine (5 ml3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by high performance liquid phase preparative column (formic acid system) to obtain the formate salt of compound 51 (120 mg, yield: 37.2%). MS (m/z): 416.3 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 8.55 (s, 1H), 6.88 (s, 1H), 6.80-6.74 (m, 1H), 3.66 (d, J=5.2 Hz, 1H), 3.13-2.87 (m, 2H), 2.71-2.45 (m, 1H), 2.09-1.87 (m, 2H), 1.85-1.53 (m, 9H), 1.49 (s, 3H), 1.42-1.29 (m, 8H), 1.27-1.07 (m, 1H), 0.98-0.76 (m, 7H).

Example 52: Preparation of Compound 52

[0326] ##STR00147##

[0327] Step 1: Preparation of Compound 52-2

[0328] Compound 52-1 (5.0 g, 48.93 mmol) was dissolved in THF (30 mL). Sodium hydride (196 mg, 4.89 mmol, 60% purity) and methyl acrylate (6.30 g, 73.18 mmol) were successively added at 0 C. The solution was slowly heated to reflux, and stirred for 16 hours. After being cooled down, the reaction solution was poured into 40 mL water to be quenched, and the aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phases were washed with 20 mL water and 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1 to 30/1) to give the crude product 52-2 (2.20 g) as a colorless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.71-3.67 (m, 5H), 3.43 (t, J=6.8 Hz, 2H), 2.59 (t, J=6.4 Hz, 2H), 1.72-1.19 (m, 8H), 0.95-0.83 (m, 3H).

[0329] Step 2: Preparation of Compound 52-3

[0330] Compound 52-2 (1.00 g, 5.31 mmol) was dissolved in a mixed solution of THF (30 mL) and H.sub.2O (30 mL), then Na.sub.2CO.sub.3 (2.25 g, 21.25 mmol) was added. After being heated to 50 C., the reaction solution was stirred for 3 hours. The reaction solution was poured into 2N aqueous NaOH solution (20 mL) to be quenched. The aqueous phase was washed with dichloromethane (40 mL), adjusted to pH 2 with 6N HCl, then extracted with dichloromethane (30 mL3). The combined organic phases were washed with 10 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 52-3 as a light yellow liquid (240 mg, yield: 25.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.70 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.8 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 1.63-1.51 (m, 2H), 1.38-1.22 (m, 6H), 0.88 (t, J=6.8 Hz, 3H).

[0331] Step 3: Preparation of Compound 52-4

[0332] Compound 52-3 (300 mg, 1.72 mmol) was dissolved in dichloromethane (15 mL), then 4-dimethylaminopyridine (210 mg, 1.72 mmol), 34-1 (750 mg, 2.06 mmol) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 2.06 mmol) were successively added. After being stirred at 15 C. for 2 hours, the reaction was poured into 40 mL water to be quenched and the aqueous phase was extracted with dichloromethane (15 mL3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=15/1 to 5/1) to give 52-4 (775 mg, yield: 86.0%) as a colorless viscous solid. MS m/z: 420.4 (M-100+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.75-6.68 (m, 2H), 4.92 (d, J=10.4 Hz, 1H), 4.22-3.98 (m, 1H), 3.80 (t, J=6.4 Hz, 2H), 3.49 (t, J=6.8 Hz, 2H), 2.90-2.85 (m, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.40 (br. s., 1H), 1.84-1.53 (m, 10H), 1.49 (s, 9H), 1.40-1.24 (m, 9H), 1.10-0.80 (m, 5H).

[0333] Step 4: Preparation of Compound 52

[0334] Compound 52-4 (700 mg, 1.35 mmol) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (2.0 mL) was added. After being stirred at 15 C. for 3 hours, the reaction solution was poured into 60 mL ethyl acetate to be diluted, then saturated aqueous sodium bicarbonate solution was slowly added to adjust the pH to approximately 7, and the aqueous phase was extracted with ethyl acetate (30 mL3). The combined organic phases were washed with 20 mL water and 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by high performance liquid preparative column to obtain the hydrochloride salt of compound 52 (250 mg, yield: 44.1%). MS m/z: 420.6 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.91 (br. s., 2H), 6.84-6.66 (m, 2H), 3.79 (t, J=6.4 Hz, 2H), 3.75-3.61 (m, 1H), 3.48 (t, J=6.8 Hz, 2H), 3.00-2.85 (m, 3H), 2.81 (t, J=6.4 Hz, 2H), 2.29-2.00 (m, 2H), 1.98-1.81 (m, 2H), 1.71-1.50 (m, 9H), 1.44-1.19 (m, 6H), 0.96-0.70 (m, 5H).

[0335] In Vitro Activity Test

[0336] Experiment Objective:

[0337] Fluorescence imaging plate reader FLIPR was used to detect changes of intracellular calcium signals. EC50 and IC50 values of the compounds were used as indicators to evaluate the activation or inhibition of the compounds on , , and opioid receptors.

[0338] Experimental Materials:

[0339] Cell lines: HEK293-, HEK293- and HEK293-, stable-transfected cell lines HEK293-, HEK293- and HEK293-; Cell culture media (DMEM, Invitrogen #11965118, 10% fetal bovine serum Invitrogen #10099141, Geneticin Selective Antibiotic (G418) 300 g/mL, Invitrogen #10131027, Blasticidin-S HCL 2 ug/mL Invitrogen #A1113902)

[0340] Pancreatic enzyme (Invitrogen, #25200-072)

[0341] DPBS (Hyclone, #SH30028.01B)

[0342] Fluo-4 Direct (Invitrogen# F10471)

[0343] HBSS (Invitrogen #14025126)

[0344] HEPES (Invitrogen #15630130)

[0345] 384 Cell plate (Greiner #781946)

[0346] 384 Compound plate (Greiner #781280)

[0347] CO.sub.2 incubator (Thermo#371)

[0348] Centrifuge (Eppendorf #5810R)

[0349] Vi-cell Cell Counter (Beckman Coulter)

[0350] POD 810 Plate Assembler Automatic Microplate Pretreatment System

[0351] Labcyte FLIPR, Molecular Device

[0352] Experimental Procedures and Methods:

[0353] 1. Cell Seeding (HEK293-, HEK293- and HEK293- Cells)

[0354] 1) Preheating medium, pancreatic enzyme, and DPBS in a 37 C. water bath. Aspirating the culture medium from the cell culture flask and washing it with 10 mL DPBS;

[0355] 2) Adding the preheated pancreatic enzyme solution to the cell culture flask, rotating the flask slightly to make the pancreatic enzymes evenly cover the cell surface of the flask, and then putting it into a 37 C., 5% CO.sub.2 incubator to digest for 1-2 minutes;

[0356] 3) Suspending the cells with 10-15 mL culture medium in each T150 cm.sup.2 cell culture flask, centrifugating at 800 rpm for 5 minutes, and resuspending the cells with 10 mL culture medium, aspirating 1 mL cell resuspension to be counted with Vi-cell;

[0357] 4) Diluting HEK293-, HEK293- and HEK293- cells to 510.sup.5/mL with culture medium, use multichannel pipette to add diluted cells into 384 plate (Greiner #781946) (50 L/well, 25000 cells/well for HEK293-, HEK293- and HEK293- cells). Placing the cell plate in a 37 C., 5% CO.sub.2 incubator overnight.

[0358] 2. Adding Compound Samples:

[0359] 1) Diluting the compound to 20 mM with DMSO, 3 fold diluted, 8 gradients, double reduplicative wells, and adding it to the compound plate using an Echo ultrasonic liquid handler device (Echo liquid handler).

[0360] 3. FLIPR Experiment:

[0361] 1) Washing off the cell culture medium in 384 plate with vacuum pump, adding 20 L Fluo-4 Direct fluorescent dye, then incubating in a 37 C., 5% CO.sub.2 incubator for 50 minutes, followed by equilibrating at room temperature for 10 minutes.

[0362] 2) EC50 test: Adding 20 uL HBSS buffer (containing 20 mM HEPES) to the compound plate, mixing well and centrifugating. Placing the cell plate and compound plate into FLIPR and reading the fluorescence value.

[0363] 3) After the EC50 test, placing the cell plate into a 37 C., 5% CO.sub.2 incubator to be incubated for 25 minutes. Calculating the EC80 value with the EC50 value of the positive agonist, preparing 4 EC80 solution, adding it to the 384 compound plate by multichannel pipette, and mixing well and centrifugating.

[0364] 4) IC50 test: In FLIPR, successively placing 4 EC80 plate, cell plate, FLIPR tip, running the program and reading the fluorescence value.

[0365] 4. Data Analyzing: Using Prism 5.0 to Analyze the Data and Calculate the EC50 and IC50 Values of the Compounds.

TABLE-US-00018 TABLE 1 In vitro activity test results Mu receptor Kapp receptor Delt receptor EC.sub.50 EC.sub.50 EC.sub.50 Test sample (uM) IC.sub.50 (uM) (uM) IC.sub.50 (uM) (uM) IC.sub.50 (uM) Compound 1 E A E B E C Compound 2 A B E C E E Compound 3 B B E B E C Compound 4 B B E C E E Compound 5 C D C D E E Compound 6 A B E C E C Compound 7 E C E C E E Compound 8 B C E C E E Compound 9 E C E C E E Compound 10 E D E D E E Compound 11 E E D E E E Compound 12 D D E E E E Compound 13 D D D D E E Compound 14 D D E D E E Compound 15 E E D E E E Hydrochloride D C E C E E of Compound 16 Hydrochloride C C E D E E of Compound 17 Compound 18 E C E E E E Compound 19 E E E E E E Compound 20 E D E D E E Compound 21 A A E C E C Compound 22 C B E C E D Compound 23 A A E C E E Compound 24 D B E C E C Compound 25 B C E C E C Compound 26 E D E E E E Compound 27 E C E D E E Compound 28 A B E B E C Compound 29 A B E C E D Compound 30 B B E B E D Compound 31 D D E D E E Compound 32 B B B B E C Compound 33 B C B B C C Note: A 0.1 uM; 0.1 uM < B 1 uM; 1 uM < C 10 uM; 10 uM < D 100 uM; E > 100 uM.

[0366] In vitro activity tests demonstrated: the compounds of the present disclosure have agonistic and antagonistic dual effect on the Mu receptor, and weaker antagonistic effect on the Kapp receptor.

[0367] Drug Metabolism Experiment

[0368] Experiment Objective:

[0369] Through the in vivo drug metabolism test in rats, values such as C.sub.max, t.sub.1/2, AUC, MRT and B/P ratio of the compound in vivo were used as indicators to evaluate the metabolism of the compound in rats.

[0370] 1. Pharmacokinetic Study of Intravenous Injection of Dezocine and Analogues Thereof in Rats

[0371] Mixing the test compound with an appropriate amount of physiological saline solution of 20% polyethylene glycol 400, followed by vortex and sonicate, and adjusting the pH to 4-5 with hydrochloric acid to obtain 5 mg/mL approximately clear solution, filtering the solution by microporous filtering film to be used. Selecting 6 to 9 weeks old SD rats (Shanghai Sleek Laboratory Animal Co., Ltd.) and intravenously injecting the test compound solution at a dose of 1 mg/kg. Collecting whole blood in certain time to prepare and obtain plasma. Analyzing drug concentrations by LC-MS/MS method and calculating pharmacokinetic parameters using Phoenix WinNonlin software (Pharsight, USA).

[0372] 2. Brain Distribution Study of Intravenous Injection of Dezocine and Analogues Thereof in Rats

[0373] Intravenously injecting the test compound solution in the same manner as example 1 at a dose of 1 mg/kg. Executing animals with carbon dioxide 15 minutes and 2 hours after dosing, collecting whole blood and brain tissue sample, centrifugating the whole blood to obtain plasma, and homogenizing the brain tissue with triple volumes of deionized water. Analyzing drug concentration of the plasma and brain homogenate samples by LC-MS/MS method, and calculating the concentration ratio of brain tissue to plasma (B/P ratio).

[0374] 3. Pharmacokinetics of Intramuscular Injection of Compound 21 and Prodrug Thereof in Rats

[0375] Mixing the test compound with an appropriate amount of sesame oil, followed by vortex and sonicate, to prepare and obtain 25 mol/mL homogeneous suspension. Selecting 6 to 9 weeks old SD rats (Shanghai Sleek Laboratory Animal Co., Ltd.), intramuscularly injecting the suspension of the test compound at a dose of 20 mol/kg or 40 mol/kg. Collecting whole blood in certain time, adding precipitant (acetonitrile, methanol and analytical internal standard) and centrifugating. Analyzing drug concentration (if the test drug is a prodrug, drug concentrations of the prodrug and hydrolyzed parent drug are simultaneously analyzed) of the supernatant solution by LC-MS/MS method, and calculating pharmacokinetic parameters using Phoenix WinNonlin software (Pharsight, USA).

TABLE-US-00019 TABLE 2 Results of intravenous pharmacokinetics test of dezocine and analogues thereof Compound number Dezocine Compound 21 Compound 23 C.sub.0 (nM) 684 493 362 T.sub.1/2 (hr) 1.26 1.42 1.60 Vd.sub.ss (L/kg) 12.2 16.2 20.6 Cl (mL/min/kg) 139 155 165 AUC.sub.0-last (nM .Math. hr) 485 387 341 MRT.sub.0-last (hr) 1.22 1.35 1.65 B/P ratio (0.25 h/2 h) 9.29/12.9 13.3/19.8 16.7/27.9 Note: All compounds were administered at dose of 1 mg/kg.

[0376] Intravenous injection pharmacokinetic data indicates that: the compounds of the present disclosure have a higher B/P ratio than dezocine and are easier to penetrate the blood-brain barrier.

TABLE-US-00020 TABLE 3 Results of intramuscular injection pharmacokinetic test of Compound 21 Compound number Compound 21 C.sub.max (nM) 1753 T.sub.max (hr) 0.50 t.sub.1/2 (hr) 4.20 AUC.sub.0-last (nM .Math. hr) 3989 MRT.sub.0-last (hr) 2.82 Note: the dose was 40 mol/kg.

TABLE-US-00021 TABLE 4 Results of intramuscular injection of Compound 21 carboxylic diester prodrug Compound number Compound 34 Compound 35 Compound 38 Parent Parent Parent Compound compound Compound compound Compound compound 34 21 25 21 38 21 C.sub.max (nM) 3.91 399 ND 222 ND 192 T.sub.max (hr) 0.25 2.33 ND 4.33 ND 2.17 t.sub.1/2 (hr) ND 7.2 ND 5.51 ND 33.7 AUC.sub.0-last 2.95 3699 ND 2660 ND 3235 (nM .Math. hr) MRT.sub.0-last (hr) 0.539 8.12 ND 9.15 ND 18.0 Note: All compounds were administered at dose of 20 mol/kg. Every 20 mol carboxylic diester prodrug theoretically hydrolyzes 40 mol active ingredient of compound 21. ND = cannot be determined (parameters cannot be determined because the end-elimination phase cannot be fully defined).

TABLE-US-00022 TABLE 5 Results of intramuscular injection of Compound 21 carboxylic monoester prodrug Compound number Compound 43 Compound 44 Compound 45 Compound Parent Compound Parent Compound Parent 43 compound 21 44 compound 21 45 compound 21 C.sub.max (nM) ND 322 ND 130 ND 48.3 T.sub.max (hr) ND 2.67 ND 3.33 ND 10.0 t.sub.1/2 (hr) ND 4.07 ND 11.9 ND 39.8 AUC.sub.0-last (nM .Math. hr) ND 2286 ND 1692 ND 1547 MRT.sub.0-last (hr) ND 5.89 ND 13.0 ND 21.9 Note: All compounds were administered at dose of 40 mol/kg. Every 40 mol carboxylic acid monoester prodrug theoretically hydrolyzes 40 mol active ingredient of compound 21. ND = cannot be determined (parameters cannot be determined because the end-elimination phase cannot be fully defined).

[0377] The results of intramuscular injection pharmacokinetic test showed that: after the sesame oil suspensions of carboxylic diester prodrug and carboxylic monoester prodrug of Compound 21 were administered by intramuscular injection, both of them can be slowly released in vivo, followed by being quickly hydrolyzed to the parent drug compound 21, which can significantly prolong the retention time of the parent drug compound 21 in rats, and reduce the C.sub.max so as to achieve the purpose of prolonging the drug action time and improving the safety.

[0378] The foregoing description of the embodiments has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but, where applicable, are interchangeable and can be used in a selected embodiment, even if not specifically shown or described. The same may also be varied in many ways. Such variations are to be regarded as a departure from the disclosure, and all such modifications are intended to be included within the scope of the disclosure.