Biphenyl compound as CCR2/CCR5 receptor antagonist

Abstract

Provided is a CCR2/CCR5 receptor antagonist and the use thereof in the preparation of a drug for treating diseases associated with the CCR2/CCR5. In particular, disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. ##STR00001##

Claims

1. A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, wherein, ##STR00609## R.sub.1 is selected from the group consisting of C.sub.1-6 alkoxy and 5-6 membered heterocycloalkyl, each of which is optionally substituted by 1, 2 or 3 R; each of R.sub.2, R.sub.3 and R.sub.4 is independently H, halogen, OH, CN, or selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkyl-S(═O)—, C.sub.1-6 alkyl-S(═O).sub.2.sub.− and C.sub.3-6 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 R; each of R.sub.5 and R.sub.6 is independently H, or C.sub.1-3 alkyl, which is optionally substituted by 1, 2 or 3 R ring A is ##STR00610## R.sub.7 is C.sub.1-6 alkyl, which is optionally substituted by 1, 2 or 3 R; R.sub.8 is H, or C.sub.1-6 alkyl, which is optionally substituted by 1, 2 or 3 R; L is —S(═O)— or —S(═O).sub.2—; R is halogen, OH, or selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl and C.sub.3-6 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 R′; R′ is F, Cl, Br, I, OH, CH.sub.2F, CHF.sub.2 or CF.sub.3; each of the “hetero” in the 5-6 membered heterocycloalkyl is independently —NH—, —O— or N; in any of the above cases, the number of the heteroatom or the heteroatom group is independently 1, 2 or 3.

2. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R is F, Cl, Br, I, OH, or selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy and C.sub.3-6 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 R′.

3. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 2, wherein, R is F, Cl, Br, I, OH, or selected from the group consisting of Me, ##STR00611## each of which is optionally substituted by 1, 2 or 3 R′.

4. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 3, wherein, R is F, Cl, Br, I, OH, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, ##STR00612##

5. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.1 is selected from the group consisting of C.sub.1-4 alkoxy and pyrrolidinyl, each of which is optionally substituted by 1, 2 or 3 R.

6. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 5, wherein, R.sub.1 is selected from the group consisting of ##STR00613## each of which is optionally substituted by 1, 2 or 3 R.

7. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 6, wherein, R.sub.1 is ##STR00614##

8. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, each of R.sub.2, R.sub.3 and R.sub.4 is independently H, halogen, OH, CN, or selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-3 alkyl-S(═O)—, C.sub.1-3 alkyl-S(═O).sub.2— and C.sub.4-5 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 R.

9. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 8, wherein, each of R.sub.2, R.sub.3 and R.sub.4 is independently H, F, Cl, Br, I, OH, CN, or selected from the group consisting of Me, ##STR00615## each of which is optionally substituted by 1, 2 or 3 R.

10. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 9, wherein, each of R.sub.2, R.sub.3 and R.sub.4 is independently H, F, Cl, Br, I, OH, CN, Me, ##STR00616##

11. The compound as shown in formula (I) or the pharmaceutically accentahle salt thereof according to claim 10, wherein, R.sub.2 is H, F, Cl, OH, CN, Me, ##STR00617##

12. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 10, wherein, R.sub.3 is H, F, Cl, Me or ##STR00618##

13. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 10, wherein, R.sub.4 is H or Cl.

14. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, each of R.sub.5 and R.sub.6 is independently H or Me.

15. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.7 is selected from the group consisting of Me, ##STR00619## each of which is optionally substituted by 1, 2 or 3 R.

16. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 15, wherein, R.sub.7 is Me, ##STR00620##

17. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.8 is H, or selected from the group consisting of Me and ##STR00621## each of which is optionally substituted by 1, 2 or 3 R.

18. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 17, wherein, R.sub.8 is H, Me or ##STR00622##

19. The compound as shown in formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein, ring A is ##STR00623##

20. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of ##STR00624## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are as defined in claim 1.

21. A compound shown as the following formula or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of ##STR00625## ##STR00626## ##STR00627## ##STR00628## ##STR00629## ##STR00630## ##STR00631## ##STR00632## ##STR00633## ##STR00634## ##STR00635## ##STR00636## ##STR00637## ##STR00638## ##STR00639## ##STR00640## ##STR00641##

22. A compound or the pharmaceutically acceptable salt thereof, which is selected from the group consisting of ##STR00642## ##STR00643## ##STR00644## ##STR00645## ##STR00646## ##STR00647## ##STR00648## ##STR00649## ##STR00650## ##STR00651## ##STR00652## ##STR00653## ##STR00654## ##STR00655## ##STR00656## ##STR00657## ##STR00658## ##STR00659## ##STR00660## ##STR00661## ##STR00662## ##STR00663## ##STR00664## ##STR00665## ##STR00666## ##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671## ##STR00672## ##STR00673## ##STR00674##

23. A pharmaceutical composition, comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

24. A method of treating CCR2 and/or CCR5 related disease in a subject in need thereof, comprising administering a pharmaceutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1.

25. A method of treating CCR2 and/or CCR5 related disease in a subject in need thereof, comprising administering a pharmaceutically effective amount of the pharmaceutical composition according to claim 23 to the subject.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Reference Example 1: Fragment BB-1A

(1) ##STR00081##

(2) Synthesis Pathway:

(3) ##STR00082##

Step 1: Synthesis of Compound BB-1A-2

(4) Compound BB-1A-1 (100 g, 0.846 mol), p-toluenesulfonyl chloride (146.67 g, 769.31 mmol) and triethylamine (233.54 g, 2.31 mol) were dissolved in dichloromethane (0.5 L), and stirred at room temperature for 12 hours. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure, followed by addition of water (400 mL) to dissolve the residue. The aqueous phase was extracted with ethyl acetate three times (1.5 L). The combined organic phase was washed with saturated brine twice (400 mL), and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was removed under reduced pressure to obtain a brown oil BB-1A-2 (170.10 g, 624.54 mmol, yield 81.18%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.81 (t, J=7.40 Hz, 3H) 1.16-1.27 (m, 3H) 1.35-1.44 (m, 2H) 2.37 (s, 3H) 3.30 (t, J=6.53 Hz, 2H) 3.50-3.55 (m, 2H) 4.05-4.10 (m, 2H) 7.27 (d, J=8.03 Hz, 2H) 7.73 (d, J=8.28 Hz, 2H). MS m/z: 273.9 [M+H].sup.+.

Step 2: Synthesis of Compound BB-1A

(5) Compound BB-1A-2 (170.10 g, 624.54 mmol), p-hydroxyphenyl borate (137.44 g, 624.54 mmol) was dissolved in acetonitrile (1.6 L), followed by addition of potassium carbonate (86.32 g, 624.54 mmol) and potassium iodide (10.37 g, 62.45 mmol) at room temperature. The resulting solution was heated to reflux and reacted with stirring for 12 hours at 60° C. under nitrogen protection. After cooling to room temperature, the solvent was removed under reduced pressure, followed by addition of water (500 mL) to dissolve the residue. The aqueous phase was extracted with ethyl acetate three times (2 L). After combining, the solvent was removed under reduced pressure. Other impurities were removed by column chromatography to obtain a yellow oil Compound BB-1A (99.30 g, 310.09 mmol, 49.65% yield). .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ ppm 0.93 (t, J=7.40 Hz, 4H) 1.28-1.36 (m, 13H) 1.39 (dd, J=15.18, 7.40 Hz, 1H) 1.51-1.65 (m, 3H) 3.54 (t, J=6.65 Hz, 2H) 3.75-3.88 (m, 2H) 4.06-4.25 (m, 2H) 6.92 (d, J=8.53 Hz, 2H) 7.75 (d, J=8.53 Hz, 2H).

(6) The reference examples in the following table were synthesized according to the synthesis method of the steps 1-2 in Reference Example 1.

(7) TABLE-US-00001 Reference Example Fragment 1 Fragment 2 Structure 2 3 4 0 41

Reference Example 5: Fragment BB-1B

(8) ##STR00095##

(9) Synthesis Pathway:

(10) ##STR00096##

Step 1: Synthesis of Compound BB-1B

(11) Compound BB-1A-1 (6 g, 27.26 mmol), n-bromobutane (5.6 g, 40.89 mmol) was dissolved in acetonitrile (50 mL), followed by addition of potassium carbonate (11.3 g, 81.78 mmol) at room temperature. The resulting solution was heated to reflux and reacted with stirring for 6 hours at 80° C. under nitrogen protection. After cooling to room temperature, the solvent was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate three times (600 mL). After combining, the solvent was removed under reduced pressure to obtain a red oil Compound BB-1B (7.05 g, 25.53 mmol, yield 93.64%). .sup.1H NMR (400 MHz, CDCl.sub.3-d) 6=7.76 (d, J=8.5 Hz, 2H), 7.11-6.70 (m, 2H), 4.00 (t, J=6.5 Hz, 2H), 1.82-1.74 (m, 2H), 1.56-1.47 (m, 2H), 1.38-1.32 (m, 11H), 0.99 (t, J=7.4 Hz, 3H); MS m/z: 279.1 [M+H].sup.+.

(12) The reference examples in the following table were synthesized according to the synthesis method of the step 1 in Reference Example 5

(13) TABLE-US-00002 Reference Example Fragment 1 Structure 6 7 00 8 01 02

Reference Example 9: Fragment BB-2A

(14) ##STR00103##

Step 1: Synthesis of Compound BB-1B

(15) ##STR00104##

(16) Compound BB-2A-1 (10.00 g, 49.75 mmol) was dissolved in N,N-dimethylformamide (30.00 mL) at room temperature, followed by addition of potassium carbonate (20.63 g, 149.25 mmol) and methyl iodide (25.80 g, 181.77 mmol). The reaction mixture was stirred at room temperature for 15 hours. After completion of the reaction, 100 mL of ice water was added to the reaction solution, and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine (300 mL×2), and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the product BB-2A (10.50 g, yield 98.15%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ=10.38 (s, 1H), 7.91 (d, J=2.8 Hz, 1H), 7.63 (dd, J=2.6, 8.9 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 3.92 (s, 3H).

(17) The reference examples in the following table were synthesized according to the synthesis method of the step 1 in Reference Example 9.

(18) TABLE-US-00003 Reference Example Fragment 1 Structure 10 05 06 11 07 08 12 09 0 13 14

Reference Example 15: Fragment BB-2B

(19) ##STR00115##

Step 1: Synthesis of Compound BB-2B

(20) ##STR00116##

(21) Compound 1 (1.51 g, 7.49 mmol), diethyl bromofluoromethyl phosphate (3.00 g, 11.24 mmol) and potassium carbonate (2.07 g, 14.99 mmol) were sequentially added to a mixture of acetonitrile (10.00 mL) and water (1.00 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 0.5 hour at 0° C. under nitrogen protection. After completion of the reaction, water (50 mL) was added to the mixture, and extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound BB-2B (2.11 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.26 (s, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.65 (dd, J=9.0, 2.5 Hz, 1H), 7.09 (d, J=8.53 Hz, 1H), 7.09 (d, J=8.53 Hz, 1H), 6.77-6.40 (t, J=72.4 Hz, 1H).

Reference Example 16: Fragment BB-2H

(22) ##STR00117##

(23) Synthesis Pathway:

(24) ##STR00118##

Step 1: Synthesis of Compound BB-2H-2

(25) ##STR00119##

(26) Compound BB-2H-1 (11.50 g, 58.66 mmol) was dissolved in carbon tetrachloride (150 mL) at room temperature, followed by addition of N-bromobutanimide (31.32 g, 175.98 mmol) and benzoyl peroxide (1.42 g, 5.87 mmol). After completion of the addition, the reaction mixture was heated to 85° C. and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, followed by filtration. The filter cake was wash with ethyl acetate (50 mL). The filtrate was combined and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the title compound BB-2H-2 (pale-yellow solid, 20.00 g). The crude product was used directly in the next step without purification. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.18 (d, J=1.8 Hz, 1H), 7.60 (dd, J=1.8, 8.3 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.92 (s, 1H).

Step 2: Synthesis of Compound BB-2H

(27) ##STR00120##

(28) Compound BB-2H-2 (5.00 g, 14.13 mmol) was dissolved in acetonitrile (20 mL) at room temperature, followed by addition of a solution prepared by silver nitrate (6.72 g, 39.56 mmol) and water (10 mL). After completion of the addition, the reaction mixture was heated to 80° C. and stirred for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, and filtered to remove the yellow silver bromide precipitate. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20-1/5) to obtain the title compound BB-2H (1.20 g, yield: 40.44%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.31 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.90 (dd, J=1.9, 8.2 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H).

Reference Example 42: Fragment BB-2I

(29) ##STR00121##

Step 1: Synthesis of Compound BB-2I

(30) ##STR00122##

(31) Compound BB-2I-1(20.00 g, 98.52 mmol) and isopropyl mercaptan (11.25 g, 147.78 mmol, 13.72 mL) were dissolved in N,N-dimethylformamide (200 mL) at room temperature, followed by addition of potassium carbonate (40.85 g, 295.56 mmol). After completion of the addition, the reaction mixture was heated to 60° C. and stirred for 12 hours. After completion of the reaction, the reaction miture was cooled to room temperature, followed by addition of 1000 mL of saturated sodium carbonate solution, and extraction with ethyl acetate (800 mL). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the product BB-2I (10.50 g, yield 98.15%). .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=10.47 (s, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.70-7.58 (m, 1H), 7.39 (d, J=8.3 Hz, 1H), 4.11 (q, J=7.0 Hz, 1H), 3.44-3.26 (m, 1H), 3.47-3.22 (m, 1H), 1.32 (d, J=6.8 Hz, 7H), 1.28-1.23 (m, 1H); MS m/z: 260.9 [M+H].sup.+.

Reference Example 43: Fragment BB-2J

(32) ##STR00123##

Step 1: Synthesis of Compound BB-2J

(33) ##STR00124##

(34) Compound BB-2I (5.00 g, 19.29 mmol) was dissolved in dichloromethane (30.00 mL), followed by dropwise addition of a solution prepared by potassium hydrogencarbonate (5.79 g, 57.87 mmol) and water (10.00 mL) at 0° C. After stirring for 10 minutes, liquid bromine (4.62 g, 28.93 mmol, 1.49 mL) was added dropwise to the reaction mixture at 0° C. The reaction was carried out for 50 minutes at room temperature. The reaction was quenched with saturated sodium sulfite solution (40 mL). 100 mL of water was added to the reaction solution, and extracted with dichloromethane (00 mL). The organic phase was combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1, 5/1) to obtain the product BB-2J (2.00 g, yield 37.68%). .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=10.00 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 8.06-8.04 (m, 1H), 7.98-7.94 (m, 1H), 3.02 (quin, J=7.0 Hz, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H); MS m/z: 276.7 [M+H].sup.+.

Reference Example 17: Fragment BB-3A

(35) ##STR00125##

(36) Synthesis Pathway:

(37) ##STR00126##

Step 1: Synthesis of Compound BB-3A-2

(38) Compound BB-3A-1 (150 g, 1.57 mol), 1,3-dihydroxyacetone (110.28 g, 1.22 mol) and potassium thiocyanate (178.46 g, 1.84 mol) were dissolved in n-butanol (2 L), followed by addition of acetic acid (133.74 mL, 2.34 mol) at room temperature, and stirred for 16 hours at room temperature. 60 mL of water was added to the reaction solution, and stirred for 30 minutes at room temperature, followed by filtration. The filter cake was washed with water and dried to obtain a white powdery compound BB-3A-2 (210 g, yield 77.7%). MS m/z: 173.0 [M+H].sup.+.

Step 2: Synthesis of Compound BB-3A-3

(39) BB-3A-2 (210.00 g, 1.22 mol, 1.00 eq) was suspended in n-butanol (2.00 L) at 20° C., and hydrogen peroxide (207.32 g, 1.83 mol, 175.69 mL, 1.50 eq, purity 30%) was added dropwise to the suspension at 0° C. The reaction solution was naturally warmed to 20° C. and stirred for 16 hours. The reaction solution was quenched with 100 mL of saturated sodium sulfite, and concentrated obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol=40:1 to 20:1) to obtain compound BB-3A-3 (70.00 g, yield 40.93%). MS m/z: 141.0 [M+H].sup.+.

Step 3: Synthesis of Compound BB-3A-4

(40) BB-3A-3 (40.00 g, 285.35 mmol, 1.00 eq) was dissolved in dichloromethane (150 mL), and dichlorosulfoxide (82.15 g, 690.55 mmol, 50.09 mL, 2.42 eq) was added dropwise to the solution at room temperature. The reaction solution was heated to 40° C. and stirred for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. 300 mL of ethyl acetate was added to the crude product, followed by filtration. The filter cake was collected to obtain compound BB-3A-4 (33.00 g, 169.15 mmol, hydrochloride, yield: 59.3%). .sup.1H NMR (400 MHz, DMSO-d6): 9.31 (d, J=1.5 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H), 5.03 (s, 2H), 4.29-4.12 (m, 2H), 1.93-1.82 (m, 2H), 0.90 (t, J=7.4 Hz, 3H).

Step 4: Synthesis of Compound BB-3A-5

(41) 4-Aminothiophenol (52.94 g, 422.88 mmol, 2.5 eq) and triethylamine (51.35 g, 507.45 mmol, 70.34 mL, 3.00 eq) were dissolved in isopropanol (1.00 L), followed by addition of a solution of BB-3A-4 (33.00 g, 169.15 mmol, 1.00 eq, hydrochloride) in water (100 mL) at room temperature, and stirred for 16 hours at room temperature. The mixture was diluted with water (100 mL) and extracted with (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude material. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=50:1-10:1) to obtain BB-3A-5 (15.00 g, 60.64 mmol, yield 35.85%). .sup.1H NMR (400 MHz, CHLOROFORM-d) □=7.41 (s, 1H), 7.10-7.03 (m, 2H), 6.62 (s, 1H), 6.57-6.52 (m, 2H), 3.91-3.83 (m, 4H), 1.80 (sxt, J=7.4 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H).

Step 5: Synthesis of Compound BB-3A-6

(42) BB-3A-5 (10.00 g, 40.43 mmol, 1.00 eq) was dissolved in methyl isobutyl ketone (600 mL) and toluene (1.2 L), followed by addition of p-dimethylbenzoyl-D-tartaric acid (15.62 g, 40.43 mmol, 1.00 eq) at room temperature. The mixture was stirred for 10 hours at room temperature, and cooled to 0° C., followed by dropwise addition of H.sub.2O.sub.2 (13.75 g, 121.29 mmol, 11.65 mL, 30% purity, 3.00 eq) at room temperature. The mixture was stirred for 96 hours at room temperature. The mixture was quenched with saturated aqueous solution of sodium sulfite, followed by addition of water (200 mL), sodium hydroxide (3.08 g, 76.96 mmol, 1.00 eq) and ethyl acetate (500 mL), and stirred for 30 minutes at room temperature. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude material was dissolved in water (100 mL) and ethylene glycol dimethyl ether (100 mL), and concentrated after stirring for 14 hours at room temperature. The crude product was washed with acetonitrile:water=1:1 (80 mL) and filtered to obtain BB-3A-6 (8.00 g, 12.31 mmol, yield 40.53%).

Step 6: Synthesis of Compound BB-3A

(43) BB-3A-6 (8.00 g, 12.31 mmol, 1.00 eq) was dissolved in water (100 mL) and ethyl acetate (100 mL), and adjusted to pH=3 with 1N hydrochloric acid. The mixture was stirred for 30 minutes at room temperature. The aqueous phase was collected, and adjusted to pH=10 with a saturated aqueous solution of sodium carbonate. The mixture was extracted with dichloromethane: isopropyl alcohol=10:1 (3*200 mL), and the organic phase was concentrated under reduced pressure to obtain BB-3A (2.80 g, 10.63 mmol, yield 86.37%). .sup.1H NMR (400 MHz, METHANOL-d4) □=7.66 (s, 1H), 7.22-7.17 (m, 2H), 6.77-6.70 (m, 3H), 4.24 (s, 2H), 3.75 (dt, J=1.5, 7.3 Hz, 2H), 1.72 (sxt, J=7.3 Hz, 2H), 0.90 (t, J=7.5 Hz, 3H).

(44) The reference examples in the following table were synthesized according to the synthesis method of the steps 1-4 in Reference Example 17.

(45) TABLE-US-00004 Reference Example Fragment 1 Compound structure 18 19 0 20 21

Reference Example 22: Fragment BB-3B-4

(46) ##STR00135##

(47) Synthesis Pathway:

(48) ##STR00136##

Step 1: Synthesis of Compound BB-3B-4-2

(49) BB-3B-4-1 (4.50 g, 43.23 mmol) was added dropwise to a solution of hydrazine hydrate (2.80 g, 47.55 mmol) in ethanol (20.00 mL) at 0° C. After the reaction mixture was stirred at room temperature for 15 hours, 1-propyl isocyanate (4.37 g, 43.18 mmol) was added dropwise to the reaction system. The system was raised to 40° C. and the reacted for 15 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude compound BB-3B-4-2 (9.5 g, yield: 82.69%). .sup.1H NMR (400 MHz, DMSO-d6) δ=9.63 (s, 1H), 9.08 (br s, 1H), 7.77 (br s, 1H), 5.27 (br s, 1H), 3.93 (d, J=5.8 Hz, 2H), 3.42-3.36 (m, 2H), 1.54-1.45 (m, 2H), 0.88-0.78 (m, 3H).

Step 2: Synthesis of Compound BB-3B-4-3

(50) Compound BB-3B-4-2 (9.50 g, 35.76 mmol) was dissolved in n-butanol (40.00 mL). The reaction solution was heated to 80° C. and stirred for 15 hours. After completion of the reaction, the temperature was cooled to 25° C., and the product BB-3B-4-3 was stored in n-butanol for direct use in the next reaction. MS-ESI (m/z): 173.8 (M+H).sup.+.

Step 3: Synthesis of Compound BB-3B-4

(51) A solution of compound BB-3B-4-3 (35.70 mmol) in n-butanol (30.00 mL) was added dropwise to 30% hydrogen peroxide (12.14 g, 107.10 mmol) at 0° C. The reaction solution was stirred for 15 hours at room temperature. After completion of the reaction, the reaction was quenched with a saturated solution of sodium sulfite (15 mL). After separation, the aqueous phase was extracted with dichloromethane (20 mL×5). The organic phases were combined, washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtrate to remove the desiccant, and concentrated under reduced pressure to obtain the title compound BB-3B-4 (3 g, crude).

Reference Example 23: Fragment BB-3B-3

(52) ##STR00137##

(53) Synthesis Pathway:

(54) ##STR00138##

Step 1: Synthesis of Compound BB-3B-2

(55) Triphenylphosphine (47.64 g, 181.64 mmol) and diisopropyl azodicarboxylate (36.73 g, 181.64 mmol) were dissolved in tetrahydrofuran (120.00 mL) at 0° C. under a nitrogen atmosphere, followed by sequential addition of compound 1 (10.00 g, 90.82 mmol) and n-propanol (10.91 g, 181.64 mmol). The mixture was warmed to 25° C. and stirred for 12 hours under a nitrogen atmosphere. After completion of the reaction, dilute hydrochloric acid (1 M) was added to the mixture to adjust to pH=1 and extracted with ethyl acetate (50 mL×3). The aqueous phase was adjusted to pH=13 with sodium hydroxide (1M) and extracted with ethyl acetate (50 mL×4). The organic phases were combined, washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether: ethyl acetate=20:1-5:1) to obtain the title compound BB-3H-2 ((12.00 g, pale-yellow oily liquid, yield: 27.60%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 9.81 (s, 1H), 7.50 (s, 1H), 4.19 (t, J=7.1 Hz, 2H), 2.49 (s, 3H), 1.98-1.74 (m, 2H), 0.89 (t, J=7.5 Hz, 3H).

Step 2: Synthesis of Compound BB-3B-3

(56) Sodium borohydride (3.28 g, 86.74 mmol) was added to a solution of compound 2 (11.00 g, 72.28 mmol) in ethanol (30.00 mL) at 0° C. under a nitrogen atmosphere, and then the mixture was warmed to 25° C. and stirred for 2 hours under nitrogen protection. After completion of the reaction, the mixture was quenched with concentrated hydrochloric acid (12.5 mL), and then adjusted to pH=12-13 with sodium hydroxide solid. Dichloromethane (20 mL) was added to the mixture, filtered and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound BB-3H-3 (7.50 g, yield: 67.22%). MS-ESI m/z: 155 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.26 (s, 1H), 4.54 (s, 2H), 3.91-3.87 (m, 2H), 2.06 (s, 3H), 1.81-1.76 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).

(57) The reference examples in the following table were synthesized according to the synthesis method of the steps 1-2 in Reference Example 23.

(58) TABLE-US-00005 Reference Example Fragment 1 Compound structure 24 0

(59) The reference examples in the following table were synthesized according to the synthesis method of the steps 2-4 in Reference Example 17.

(60) TABLE-US-00006 Reference Example Fragment 2 Compound structure 25 26

Reference Example 27: BB-3C

(61) ##STR00145##

(62) Synthesis Pathway:

(63) ##STR00146##

Step 1: Synthesis of Compound BB-3C

(64) Compound BB-3C-1 (450.00 mg, 1.93 mmol) was dissolved in 4-methyl-2-pentanone (5.00 mL), followed by dropwise addition of 30% hydrogen peroxide (555.86 μL, 5.79 mmol) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. After completion of the reaction, the reaction mixture was cooled to 0-5° C., quenched with 2 mL of saturated sodium sulfite solution, and concentrated under reduced pressure to remove the solvent. The obtained crude was isolated by silica gel plate (developing agent: dichloromethane/methanol=10/1) to obtain the compound BB-3C (150.00 mg, yield 28.15% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=7.48 (s, 1H), 7.20-7.14 (m, 2H), 6.73-6.67 (m, 2H), 6.61 (s, 1H), 4.09-3.97 (m, 4H), 3.89-3.78 (m, 2H), 1.38 (t, J=7.4 Hz, 3H); MS-ESI (m/z): 250.0 (M+H).sup.+.

(65) The reference examples in the following table were synthesized according to the synthesis method of the step 1 in Reference Example 27.

(66) TABLE-US-00007 Reference Example Fragment 1 Structure 28 29 0 30 31 32 33 34 0 56

Reference Example 57: BB-3A′

(67) ##STR00163##

(68) Synthesis Pathway:

(69) ##STR00164##

Step 1: Synthesis of Compound BB-3A′

(70) Compound BB-3A′-1 was isolated by supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 150×4.6 mm I.D., 3 μm, mobile phase: A: CO.sub.2 B: ethanol (0.05% DEA), gradient: 5%-40% B, 5 min, keeping 40% for 2.5 min, then keeping 5% B for 2.5 min, flow rate: 2.5 mL/min, column temperature: 35° C., wavelength: 220 nm) to obtain the isomers BB-3A′ (retention time: 4.238 min) and BB-3A (retention time: 4.602 min). MS-ESI (m/z): 264.0 (M+H).sup.+.

Reference Example 35: BB-3G

(71) ##STR00165##

(72) Synthesis Pathway:

(73) ##STR00166##

Step 1: Synthesis of Compound BB-3G

(74) Compound BB-3G-1 (200.00 mg, 808.54 μmol) was dissolved in 4-methyl 2-pentanone (5.00 mL), followed by dropwise addition of 30% hydrogen peroxide (776.79 μL, 8.09 mmol) at room temperature. The reaction mixture was stirred for 96 hours at room temperature. After completion of the reaction, the temperature was decreased to 0 to 5° C., and the reaction was quenched by 2 mL of saturated sodium sulfite solution. The solvent was removed by concentration under reduced pressure. The obtained crude product was isolated by silica gel plate (developing agent: dichloromethane/methanol=10/1) to obtain compound BB-3G (30.00 mg, yield 13.28% yield). MS-ESI m/z: 279.9 (M+H).sup.+.

Reference Example 36: BB-3K, BB-3K′

(75) ##STR00167##

(76) Synthesis Pathway:

(77) ##STR00168##

Step 1: Synthesis of Compound BB-3K, BB-3K′

(78) Compound BB-3I was isolated by supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 150×4.6 mm I.D., 3 μm, mobile phase: A: CO.sub.2 B: ethanol (0.05% DEA), gradient: 5%-40% B, 5.5 min, keeping 40% for 3 min, then keeping 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 40° C., wavelength: 220 nm) to obtain the isomers BB-3K (retention time: 5.828 min) and BB-3K′ (retention time: 6.163 min). MS-ESI (m/z): 264.0 (M+H).sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.43 (s, 1H), 7.15-7.10 (m, 2H), 6.71-6.66 (m, 2H), 4.07-3.95 (m, 4H), 3.85 (dq, J=1.9, 7.3 Hz, 2H), 1.70 (s, 3H), 1.39 (t, J=7.3 Hz, 3H).

Reference Example 45: BB-3J, BB-3J′

(79) ##STR00169##

(80) Synthesis Pathway:

(81) ##STR00170##

Step 1: Synthesis of Compound BB-3J, BB-3J′

(82) Compound BB-3H was isolated by supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 150×4.6 mm I.D., 3 μm, mobile phase: A: CO.sub.2 B: ethanol (0.05% DEA), gradient: 5%-40% B, 5.5 min, keeping 40% for 3 min, then keeping 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 40° C., wavelength: 220 nm) to obtain the isomers BB-3J (retention time: 4.775 min) and BB-3J′ (retention time: 4.521 min). MS-ESI m/z: 277.9 (M+H)+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 0.56 (br s, 3H) 1.27-1.37 (m, 8H) 1.39 (br d, J=7.03 Hz, 3H) 3.41 (br s, 2H) 3.59-3.76 (m, 5H) 6.35 (br d, J=6.53 Hz, 4H) 6.70-6.80 (m, 4H) 7.05 (s, 2H).

Reference Example 46: BB-3L

(83) ##STR00171##

(84) Synthesis Pathway:

(85) ##STR00172##

Step 1: Synthesis of Compound BB-3L-2

(86) Compound BB-3L-1 (5.00 g, 31.74 mmol) and N,N-dimethylformamide (1.07 g, 14.60 mmol, 1.12 mL) were dissolved in dichloromethane (50 ml), followed by addition of oxalyl chloride (10.07 g, 79.35 mmol, 6.94 mL) at room temperature. The reaction solution was stirred at room temperature for 3 hours under nitrogen atmosphere, followed by addition of methanol (10 mL). The reaction mixture was concentrated to obtain compound BB-3L-2 (5.40 g, yield: 99.16%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ:9.32 (s, 1H), 9.09 (d, J=6.0 Hz, 1H), 8.07 (d, J=6.0 Hz, 1H), 4.05 (s, 3H).

Step 2: Synthesis of Compound BB-3L-3

(87) Compound BB-3L-2 (5.00 g, 29.14 mmol) and potassium vinyl fluoroborate (3.90 g, 29.14 m mol) were dissolved in dioxane (45 mL) and water (15 mL), followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (213.22 mg, 291.40 u mol) and potassium carbonate (8.06 g, 58.28 mmol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, and water (10 mL) was added to the mixture, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain the title compound BB-3L-3 (2.50 g, yield 52.58%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 9.00 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 7.48-7.39 (m, 1H), 7.37 (d, J=5.3 Hz, 1H), 5.79 (d, J=17.6 Hz, 1H), 5.50-5.44 (m, 1H), 3.85 (s, 3H).

Step 3: Synthesis of Compound BB-3L-4

(88) Compound BB-3L-3 (1.00 g, 6.13 mmol) was dissolved in tetrahydrofuran (10.00 mL), and wet palladium on carbon catalyst (1.8 g, palladium content 10%, water content 50%) was added thereto at room temperature. The reaction system was displaced with argon three times, followed by displacing with hydrogen three times. The reaction mixture was stirred for 3 hours at room temperature under hydrogen atmosphere (15 psi), followed by filtration to remove the catalyst. The filtrate was concentrated under reduced pressure to obtain the title compound BB-3L-4 (880.00 mg, yield: 86.95%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.94 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 7.12 (d, J=5.0 Hz, 1H), 3.83 (s, 3H), 2.91 (q, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H).

Step 4: Synthesis of Compound BB-3L-5

(89) Compound BB-3L-4 (880.00 mg, 5.33 mmol) was dissolved in tetrahydrofuran (10.00 mL), followed by slow addition of lithium tetrahydroaluminum (303.25 mg, 7.99 mmol) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with sodium sulfate decahydrate (10 g), followed by addition of water (10 mL) and extraction with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered to remove desiccant. The filtrate was concentrated under reduced pressure to obtain the compound BB-3L-5 (470.00 mg, yield: 64.39%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.36 (s, 1H), 8.32 (d, J=5.0 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 4.66 (s, 2H), 2.67 (q, J=7.5 Hz, 2H), 2.26-2.14 (m, 1H), 1.18 (t, J=7.5 Hz, 3H).

Step 5: Synthesis of Compound BB-3L-6

(90) Compound BB-3L-5 (470.00 mg, 3.43 mmol) was dissolved in dichloromethane (5.00 mL), followed by addition of thionyl chloride (2.04 g, 17.13 mmol, 1.24 mL, 5.00 eq) at room temperature. The mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound BB-3L-6 (670.00 mg, hydrochloride, yield 96.81%). MS-ESI m/z: 156.0 (M+H).sup.+.

Step 6: Synthesis of Compound BB-3L-7

(91) Compound BB-3L-6 (670.00 mg, 3.49 mmol, hydrochloride) and p-aminothiophenol (1.31 g, 10.47 mmol) were dissolved in dichloromethane (5.00 mL) and followed by addition of triethylamine (1.06 g, 10.47 mmol, 1.45 mL) at room temperature. The mixture was stirred for 4 hours at room temperature under nitrogen atmosphere. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatograph (eluent: ethyl acetate/petroleum ether=1/4-1/0) to obtain the title compound BB-3L-7 (630.00 mg, yield 48.54%). MS-ESI m/z: 245.0 (M+H).sup.+.

Step 7: Synthesis of Compound BB-3L

(92) Compound BB-3L-7 (630.00 mg, 2.58 mmol) was dissolved in dichloromethane (10.00 m L), followed by dropwise addition of hydrogen peroxide (2.92 g, 25.78 mmol, 2.48 mL, 30% purity) at room temperature. The reaction solution was heated to 40° C. and stirred for 18 hours under nitrogen atmosphere. After cooling to room temperature, sodium sulfite (10 g) was added to the reaction solution, and stirred for 0.5 hour, followed by filtration. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel plate to obtain the compound BB-3L (320.00 mg, yield 47.64% yield). MS-ESI m/z: 261.1 (M+H).sup.+.

(93) The reference examples in the following table were synthesized according to the synthesis method of the steps 2-7 in Reference Example 46.

(94) TABLE-US-00008 Reference Example Fragment 1 Structure 47

(95) The reference examples in the following table were synthesized according to the synthesis method of the steps 5-7 in Reference Example 46.

(96) TABLE-US-00009 Reference Example Fragment 2 Structure 48

Reference Example 37: BB-4A

(97) ##STR00177##

(98) Synthesis Pathway:

(99) ##STR00178##

Step 1: Synthesis of Compound BB-4A-2

(100) Compound BB-4A-1 (1.00 g, 4.65 mmol) and N,N-dimethylformamide (33.99 mg, 465.00 μmol) were dissolved in dichloromethane (10.00 mL) under nitrogen atmosphere, followed by dropwise addition of oxalyl chloride (1.48 g, 11.63 mmol) at 0° C. The reaction mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. Methanol (1.49 g, 46.50 mmol) was added dropwise to the reaction solution. The reaction solution was concentrated under reduced pressure to remove solvent to give the crude compound BB-4A-2 (1.00 g, yield 93.88%).

Step 2: Synthesis of Compound BB-4A-3

(101) Compound BB-4A-2 (1.00 g, 4.37 mmol), compound BB-1A (1.40 g, 4.37 mmol) and potassium carbonate (1.81 g, 13.10 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (356.50 mg, 436.55 μmol). The reaction mixture was stirred for 10 hours at 90° C. under nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, followed by addition of water (10 mL) and extraction with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=100/1, 9/1) to obtain the title compound BB-4A-3 (yellow solid, 1.00 g, yield 59.74%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.03 (d, J=2.0 Hz, 1H), 7.51 (dd, J=1.9, 7.9 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.21-7.17 (m, 1H), 6.93 (d, J=8.8 Hz, 2H), 4.11-4.08 (m, 2H), 3.84 (s, 3H), 3.74 (t, J=4.9 Hz, 2H), 3.48 (t, J=6.7 Hz, 2H), 2.55 (s, 3H), 1.55-1.50 (m, 2H), 1.36-1.28 (m, 2H), 0.86 (t, J=7.4 Hz, 3H).

Step 3: Synthesis of Compound BB-4A

(102) Compound BB-4A-3 was dissolved in tetrahydrofuran (10 mL) under nitrogen atmosphere, and lithium tetrahydroaluminum (299.23 mg, 7.89 mmol) was added portionwise to the reaction solution at 0-5° C. The reaction mixture was stirred for 15 hours at room temperature under nitrogen protection. After completion of the reaction, the reaction was quenched by the addition of 0.5 mL of water and 0.5 mL of saturated sodium carbonate solution, followed by filtration. The filtrate was added to water (10 ml), and extracted with ethyl acetate (20 mL*3). The organic phases were combined washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was isolated by silica gel column (eluent: petroleum ether/ethyl acetate=50/1, 10/1) to obtain the compound BB-4A (695.00 mg, yield 79.84%). .sup.1H NMR (400 MHz, DMSO-d6) δ=7.58 (br s, 1H), 7.54 (br d, J=8.5 Hz, 2H), 7.37 (br d, J=7.5 Hz, 1H), 7.16 (br d, J=7.8 Hz, 1H), 7.00 (br d, J=8.5 Hz, 2H), 5.10 (br t, J=5.3 Hz, 1H), 4.52 (br d, J=4.8 Hz, 2H), 4.13-4.06 (m, 2H), 3.74-3.65 (m, 2H), 3.44 (br t, J=6.5 Hz, 2H), 2.24 (s, 3H), 1.53-1.45 (m, 2H), 1.31 (qd, J=7.3, 14.7 Hz, 2H), 0.87 (br t, J=7.3 Hz, 3H).

(103) The reference examples in the following table were synthesized according to the synthesis method of the steps 1-3 in Reference Example 37.

(104) TABLE-US-00010 Reference Example Fragment 2 Structure 38 0 39 49 50 51

Reference Example 40: BB-4D

(105) ##STR00189##

(106) Synthesis Pathway:

(107) ##STR00190##

Step 1: Synthesis of Compound BB-4D-2

(108) Compound BB-4D-1 (10.00 g, 35.35 mmol) and pyrrolidine (2.77 g, 38.89 mmol) were dissolved in N,N-dimethylformamide (100 mL) at room temperature under nitrogen atmosphere, followed by addition of cuprous iodide (673.24 mg, 3.54 mmol), L-proline (813.97 mg, 7.07 mmol) and cesium carbonate (13.82 g, 42.42 mmol). After completion of the addition, the reaction mixture was heated to 120° C. and stirred for 10 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, quenched with saturated brine (200 mL), and extracted with ethyl acetate (500 mL×3). The organic phases were combined, washed with water (200 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain the title compound BB-4D-2 (white solid, 4.01 g, yield: 50.17%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.29 (d, J=9.0 Hz, 2H), 6.43 (d, J=9.0 Hz, 2H), 3.25 (t, J=6.7 Hz, 4H), 2.01 (td, J=3.4, 6.6 Hz, 4H).

Step 2: Synthesis of Compound BB-4D

(109) Compound BB-4D-2 (1.00 g, 4.42 mmol) and 3-formylbenzeneboronic acid (663.13 mg, 4.42 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (360.95 mg, 4.42 mmol), potassium carbonate (916.33 mg, 6.63 mmol) and water (3 mL). The reaction mixture was heated to 80° C. and stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, the mixture is cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: ethyl acetate/petroleum ether=1/100-1/20) to obtain the title compound BB-4D (yellow liquid, 489.00 mg, yield: 44.02%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.08 (s, 1H), 8.07 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.58-7.52 (m, 3H), 6.66 (d, J=8.8 Hz, 2H), 3.39-3.32 (m, 4H), 2.05 (td, J=3.4, 6.5 Hz, 4H).

Reference Example 52: BB-4H

(110) ##STR00191##

(111) Synthesis Pathway:

(112) ##STR00192##

Step 1: Synthesis of Compound BB-4H-3

(113) Compound BB-4H-1 (4.00 g, 15.16 mmol) and compound BB-4H-2 (2.80 g, 14.40 mmol) were dissolved in 1,4-dioxane (50 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (1.24 g, 1.52 mmol), potassium carbonate (3.14 g, 22.74 mmol) and water (15 mL). The reaction mixture was stirred for 12 hours at room temperature under nitrogen protection. After completion of the reaction, saturated brine (50 mL) was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by column chromatography (eluent: ethyl acetate/petroleum ether=0/10-1/10) to obtain the title compound BB-4H-3 (3.40 g, yield: 89.31%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.04 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.57 (dd, J=2.1, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 5.69 (quin, J=2.2 Hz, 1H), 2.68 (qt, J=2.3, 7.4 Hz, 2H), 2.53 (qt, J=2.4, 7.5 Hz, 2H), 2.02 (quin, J=7.5 Hz, 2H).

Step 2: Synthesis of Compound BB-4H-5

(114) Compound BB-4H-3 (2.00 g, 7.96 mmol) and compound BB-4H-5 (2.68 g, 8.36 mmol) were dissolved in 1,4-dioxane (45 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (650.05 mg, 796.00 μmol), potassium carbonate (1.65 g, 11.94 mmol) and water (15 mL). The reaction mixture was heated to 80° C. u and stirred for 10 hours under nitrogen atmosphere. After completion of the reaction, saturated brine (100 mL) was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by flash silica gel column chromatography (eluent: ethyl acetate/petroleum ether=0/10-1/10) to obtain the title compound BB-4H-5 (1.89 g, yield: 65.14%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.25 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.75 (dd, J=2.0, 8.0 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 5.86-5.72 (m, 1H), 4.29-4.10 (m, 2H), 3.86-3.79 (m, 2H), 3.56 (t, J=6.7 Hz, 2H), 2.80 (dt, J=2.0, 7.5 Hz, 2H), 2.63 (dt, J=2.4, 7.3 Hz, 2H), 2.12 (quin, J=7.5 Hz, 2H), 1.66-1.59 (m, 2H), 1.46-1.37 (m, 2H), 0.94 (t, J=7.3 Hz, 3H).

Step 3: Synthesis of Compound BB-4H

(115) Compound BB-4H-5 (1.89 g, 5.19 mmol) was dissolved in methanol (100 mL) at room temperature, and wet palladium on carbon catalyst (70.00 mg, palladium content 10%, water content 50%) was added thereto. The system was displaced with argon three times, followed by displacing with hydrogen three times. The reaction mixture was stirred for 24 hours at room temperature under hydrogen atmosphere (30 psi). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product BB-4H (white solid, 1.70 g, yield 88.89%). The crude product was used directly in the next reaction without purification. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.55 (d, J=2.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.49 (dd, J=2.0, 8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.5 Hz, 2H), 4.82 (d, J=5.8 Hz, 2H), 4.19-4.15 (m, 2H), 3.84-3.80 (m, 2H), 3.56 (t, J=6.7 Hz, 2H), 3.38-3.27 (m, 1H), 2.13-2.06 (m, 2H), 1.92-1.83 (m, 2H), 1.79-1.70 (m, 2H), 1.67-1.63 (m, 2H), 1.61 (br d, J=8.0 Hz, 2H), 1.40 (qd, J=7.4, 14.9 Hz, 2H), 0.94 (t, J=7.4 Hz, 3H).

Reference Example 53: BB-5A

(116) ##STR00193##

(117) Synthesis Pathway:

(118) ##STR00194##

Step 1: Synthesis of Compound BB-5A

(119) Compound BB-5A-1 (800.00 mg, 2.08 mmol) and trimethyltrifluoromethylsilane (887.62 mg, 6.24 mmol) were dissolved in toluene (10 mL) under nitrogen atmosphere, followed by addition of silver trifluoromethanesulfonate (2.67 g, 10.40 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.47 g, 4.16 mmol), cesium fluoride (948.24 mg, 6.24 mmol) and 2-fluoropyridine (1.01 g, 10.40 mmol). The reaction mixture was stirred for 12 hours at room temperature under nitrogen protection. After completion of the reaction, saturated brine (20 mL) was added to the mixture to quench the reaction, followed by extraction with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by column chromatography (eluent: ethyl acetate/petroleum ether=1/50-1/5) to obtain the title compound BB-5A (yellow oily liquid, 122.00 mg, yield: 12.96%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.95 (d, J=16.1 Hz, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.57 (dd, J=2.3, 8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.34 (dd, J=1.3, 8.5 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.56 (d, J=16.1 Hz, 1H), 4.30 (q, J=7.3 Hz, 2H), 4.22-4.14 (m, 2H), 3.87-3.78 (m, 2H), 3.57 (t, J=6.7 Hz, 2H), 1.68-1.60 (m, 2H), 1.47-1.39 (m, 2H), 1.36 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).

Reference Example 53: BB-5B

(120) ##STR00195##

(121) Synthesis Pathway:

(122) ##STR00196##

Step 1: Synthesis of Compound BB-5B

(123) Compound BB-5B-1 (400.00 mg, 903.73 μmol, 1.00 eq) was dissolved in dichloromethane (5.00 mL), followed by addition of m-chloroperoxybenzoic acid at room temperature (779.78 mg, 3.61 mmol, 80% purity, 4.00 eq). The reaction was carried at room temperature for 3 hours, and quenched with 8 mL of saturated sodium sulfite, followed by addition of water (20 mL) and extraction with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=50/1, 3/1) to obtain the title compound BB-5B (400.00 mg, 842.80 μmol, 93.26% yield). MS-ESI m/z: 497.2[M+Na].sup.+; .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=8.64 (d, J=16.1 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.72 (dd, J=1.8, 8.3 Hz, 1H), 7.63-7.51 (m, 2H), 7.10-6.99 (m, 2H), 6.46 (d, J=15.8 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 4.22-4.17 (m, 2H), 3.86-3.80 (m, 2H), 3.57 (t, J=6.7 Hz, 2H), 3.25 (td, J=6.8, 13.7 Hz, 1H), 1.67-1.61 (m, 3H), 1.45-1.39 (m, 2H), 1.36 (t, J=7.2 Hz, 4H), 1.31 (d, J=7.0 Hz, 6H), 0.94 (t, J=7.3 Hz, 3H).

Reference Example 55: BB-5C

(124) ##STR00197##

(125) Synthesis Pathway:

(126) ##STR00198##

Step 1: Synthesis of Compound BB-5C-2

(127) Phosphorus oxychloride (4.62 mL, 49.74 mmol) was carefully added to N,N-dimethylacetamide (6.91 mL, 74.61 mmol) at 0° C., and the mixture was stirred for 0.5 hour at 0° C., followed by addition of compound BB-5C-1 (5.00 g, 24.87 mmol) to the above mixture. After completion of the addition, the reaction mixture was heated to 70° C. and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature. After saturated sodium hydrogen carbonate solution (30 mL) was added thereto, the mixture was heated to 60° C. and stirred for 0.5 hour to quench the reaction. The mixture was then cooled again to room temperature, adjusted to pH=2 with concentrated hydrochloric acid, and extracted with dichloromethane (15 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/50-1/5) to obtain the title compound BB-5C-2 (1.50 g, yield: 26.80%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.71-7.61 (m, 3H), 7.27-7.22 (m, 1H), 6.48 (br d, J=9.5 Hz, 1H).

Step 2: Synthesis of Compound BB-5C-4

(128) Compound BB-5C-2 (1.00 g, 4.44 mmol) and compound BB-5C-3 (1.56 g, 4.88 mmol) were dissolved in 1,4-dioxane (15 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (362.59 mg, 444.00 μmol), potassium carbonate (920.48 mg, 6.66 mmol) and water (3.00 mL). After completion of the addition, the reaction mixture was heated to 80° C. and stirred for 4 hours. After completion of the reaction, saturated brine (40 mL) was added to the mixture to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/40-1/2) to obtain the title compound BB-5C-4 (1.25 g, yield: 83.19%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.74 (br dd, J=9.2, 18.4 Hz, 2H), 7.63 (s, 1H), 7.51 (br d, J=7.8 Hz, 2H), 7.39 (br d, J=8.3 Hz, 1H), 7.03 (br d, J=7.5 Hz, 2H), 6.47 (br d, J=9.5 Hz, 1H), 4.18 (br s, 2H), 3.83 (br s, 2H), 3.57 (br t, J=6.4 Hz, 2H), 1.68-1.59 (m, 2H), 1.41 (qd, J=7.1, 14.5 Hz, 2H), 0.94 (br t, J=7.2 Hz, 3H).

Step 3: Synthesis of Compound BB-5C

(129) Compound BB-5C-4 (150.00 mg, 443.26 μmol) was dissolved in dimethyl sulfoxide (1 mL) at room temperature, and then hydrazine hydroxide octahydrate (279.66 mg, 886.52 μmol) was added thereto. After completion of the addition, the reaction mixture was carefully heated to 40° C. and stirred for 3 hours, followed by addition of methyl iodide (251.67 mg, 1.77 mmol) to the above mixture. After completion of the addition, the reaction mixture was stirred for 0.5 hour at this temperature. After completion of the reaction, the reaction mixture was cooled to room temperature, and nitrogen was introduced thereto to remove the excess methyl iodide. Saturated brine (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, washed with saturated brine (20 mL) dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure to obtain the title compound BB-5C (148.00 mg, yield: 86.85%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.78 (d, J=2.3 Hz, 1H), 7.52-7.46 (m, 3H), 7.20 (d, J=12.5 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H), 6.02 (d, J=12.5 Hz, 1H), 4.19-4.13 (m, 2H), 3.87 (s, 3H), 3.83-3.79 (m, 2H), 3.69 (s, 3H), 3.56 (t, J=6.7 Hz, 2H), 1.66-1.60 (m, 2H), 1.40 (qd, J=7.5, 14.9 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H).

Example 1:WX017

(130) ##STR00199##

(131) Synthesis Pathway:

(132) ##STR00200##

Step 1: Synthesis of Compound WX017-2

(133) Triethylphosphorylacetate (25.02 g, 111.60 mmol) was dissolved in tetrahydrofuran under nitrogen atmosphere, followed by portionwise addition of sodium hydride (4.46 g, 111.60 mmol) of 60% purity at 0° C. The reaction mixture was stirred a for 0.5 hourt 0-5° C., followed by addition of a solution of compound BB-2A (16.00 g, 74.40 mmol) in tetrahydrofuran (20.00 mL). The reaction mixture was stirred for 1.5 hours at room temperature under nitrogen protection. After completion of the reaction, the reaction solution was slowly poured into 50 mL of saturated aqueous solution of ammonium chloride. The organic phase and the aqueous phase were separated, and the aqueous phase was extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with saturated brine (120 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure to obtain the product WX017-2 (21.00 g, yield 98.99%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.89 (d, J=16.3 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.43 (dd, 8.8 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 6.49 (d, J=16.1 Hz, 1H), 4.27 (q, J=7.3 Hz, 2H), 3.87 (s, 3H), 1.34-1.31 (m, 3H).

Step 2: Synthesis of Compound WX017-3

(134) Compound WX017-2 (10.00 g, 35.07 mmol), compound BB-1A (10.11 g, 31.56 mmol) and potassium carbonate (14.54 g, 105.21 mmol) were dissolved in 1,4-dioxane (80.00 mL) and water (15.00 mL) under nitrogen atmosphere followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (2.57 g, 3.51 mmol). The reaction mixture was heated to 80° C. and stirred for 5 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, followed by addition of water (60 mL) and extraction with ethyl acetate (60 mL×2). The organic phases were combined, washed with saturated brine (120 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration and the obtained residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate=100/1, 20/1) to obtain the title compound WX017-3 (8.60 g, yield 58.89%). MS-ESI m/z: 399.1 (M+H)+; .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=7.95 (d, J=16.3 Hz, 1H), 7.60 (d, J=2.3 Hz, 1H), 7.44 (dd, J=2.3, 8.5 Hz, 1H), 7.40-7.35 (m, 2H), 6.94-6.86 (m, 3H), 6.52 (d, J=16.1 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.11-4.06 (m, 2H), 3.84 (s, 3H), 3.75-3.71 (m, 2H), 3.48 (t, J=6.8 Hz, 2H), 1.56-1.49 (m, 2H), 1.32 (dd, J=7.4, 15.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).

Step 3: Synthesis of Compound WX017-4

(135) The compound WX017-3 was dissolved in methanol, tetrahydrofuran and water, followed by addition of sodium hydroxide at room temperature. The reaction mixture was stirred for 15 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. 10 mL of water and 4 M hydrochloric acid were added to adjust the pH to 4-5 by, and then extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (120 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure to obtain the compound WX017-4 (600.00 mg, yield 40.29%). .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=8.16 (d, J=16.3 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.57 (dd, J=2.3, 8.5 Hz, 1H), 7.57-7.55 (m, 2H), 7.02-6.98 (m, 3H), 6.63 (d, J=16.1 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 3.84-3.81 (m, 2H), 3.58-3.55 (m, 2H), 1.66-1.59 (m, 2H), 1.43-1.38 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Step 4: Synthesis of Compound WX017

(136) Compound WX017-4 (80.00 mg, 215.96 μmol) was dissolved in dichloromethane (5 mL) at room temperature. The solution was cooled to 0° C., and N,N-dimethylformamide (789.23 ug, 10.80 μmol) and oxalyl chloride (82.24 mg, 647.88 μmol) were added to the above solution. The reaction mixture was stirred for 0.5 hour at 0-5° C. under nitrogen atmosphere. After completion of the reaction, nitrogen was introduced to the mixture to remove the organic solvent. The mixture was mixed in 3 mL of tetrahydrofuran, and added dropwise to a mixture of compound BB-3A (56.21 mg, 213.43 μmol) and triethylamine (64.79 mg, 640.29 μmol) in tetrahydrofuran (5 mL) at 0° C. After completion of the addition, the reaction mixture was warmed to room temperature and stirred for 15 hours under nitrogen atmosphere. After completion of the reaction, methanol (5 mL) was added to the mixture to quench the reaction, and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to give the compound WX017. MS-ESI m/z: 616.1; 617.1[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 9.33 (s, 1H), 8.05 (d, J=15.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.61 (d, J=2.3 Hz, 1H), 7.50 (br d, J=2.3 Hz, 1H), 7.48 (s, 1H), 7.44-7.39 (m, 2H), 7.29 (d, J=8.8 Hz, 2H), 6.98-6.93 (m, 3H), 6.88 (d, J=15.8 Hz, 1H), 6.55 (s, 1H), 4.15 (d, J=4.8 Hz, 2H), 4.14-4.13 (m, 1H), 4.13 (d, J=2.8 Hz, 1H), 3.97 (d, J=14.1 Hz, 1H), 3.86 (s, 3H), 3.83-3.79 (m, 1H), 3.79-3.79 (m, 1H), 3.76 (dt, J=4.0, 7.3 Hz, 2H), 3.56 (t, J=6.8 Hz, 2H), 1.73-1.66 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.35 (m, 2H), 0.93 (t, J=7.4 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H).

(137) The reference examples in the following table were synthesized according to the synthesis method of the steps 1-4 in Example 1.

(138) TABLE-US-00011 Example Fragment 1 Fragment 2 Fragment 3 Fragment 4  2 01 02 03 04  3 05 06 07 08  4 09 0  5  6 0  7  8  9 0 10 11 0 12 13 14 0 15 16 0 17 18 19 0 20 21 0 22 23 24 0 25 26 00 27 01 02 03 04 28 05 06 07 08 29 09 0 30 31 0 32 33 34 0 35 36 0   .sup. 37A 38 39 0 48 49 0 50 51 52 0 56 57 0 58 61 62 0 63 64 00 65 01 02 03 04 66 05 06 07 08 67 09 0 68 69 0 74 75 76 0 79 80 0 81 82 85 0 86 87 0 88 89 90 0 91 92 0 Example Structure Compound  2 WX001  3 WX002  4 WX003  5 WX004  6 WX007  7 WX008  8 WX009  9 WX010 10 WX012 11 0 WX013 12 WX014 13 WX015 14 WX016 15 WX018 16 WX019 17 WX020 18 WX021 19 WX022 20 WX023 21 00 WX024 22 01 WX025 23 02 WX026 24 03 WX027 25 04 WX028 26 05 WX029 27 06 WX030 28 07 WX031 29 08 WX032 30 09 WX033 31 0 WX034 32 WX035 33 WX036 34 WX038 35 WX044 36 WX045   .sup. 37A   WX039-1 38 WX046 39 WX047 48 WX048 49 0 WX049 50 WX050 51 WX051 52 WX052 56 WX056 57 WX057 58 WX058 61 WX061 62 WX062 63 WX063 64 0 WX064 65 WX065 66 WX066 67 WX067 68 WX068 69 WX069 74 WX074 75 WX075 76 WX076 79 WX079 80 0 WX080 81 WX081 82 WX082 85 WX085 86 WX086 87 WX087 88 WX088 89 WX089 90 WX090 91 WX091 92 0 WX092

Example 37: WX039, WX040

(139) ##STR00551##

Step 1: Synthesis of Compound WX039 and WX040

(140) Compound WX039-1 was isolated by supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 50×4.6 mm I.D., 3 μm, mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2, flow rate: 2.5 mL/min, column temperature: 40° C., wavelength: 220 nm) to obtain the isomers WX039 (retention time: 1.982 min) and WX040 (retention time: 2.416 min). MS-ESI m/z: 603.1; 604.1; 605.1 [M+H].sup.+; .sup.1H NMR (WX039,400 MHz, CDCl.sub.3) δ: 9.37 (s, 1H) 8.05 (d, J=15.5 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.61 (d, J=2.3 Hz, 1H), 7.51 (s, 1H), 7.49 (dd, J=8.7 Hz, J=2.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.96-6.92 (m, 3H), 6.88 (d, J=15.5 Hz, 1H), 6.55 (s, 1H), 4.15-4.13 (m, 2H), 4.11-3.94 (m, 2H), 3.86 (s, 3H), 3.84-3.82 (m, 2H), 3.80-3.69 (m, 2H), 3.56 (t, J=6.8 Hz, 2H), 1.63-1.59 (m, 2H), 1.42-1.38 (m, 3H), 1.36-1.32 (m, 2H), 0.93 (t, J=7.4 Hz, 3H); .sup.1H NMR (WX040, 400 MHz, CDCl.sub.3) δ: 9.07 (br s, 1H) 8.05 (d, J=15.5 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.62 (d, J=2.3 Hz, 1H), 7.53 (s, 1H), 7.50 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 6.97-6.94 (m, 3H), 6.88 (d, J=15.5 Hz, 1H), 6.56 (br s, 1H), 4.16-4.13 (m, 2H), 4.11-3.95 (m, 2H), 3.88 (s, 3H), 3.85-3.74 (m, 4H), 3.56 (t, J=6.8 Hz, 2H), 1.63-1.59 (m, 2H), 1.42-1.36 (m, 3H), 1.36-1.32 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).

Example 86: WX086

(141) ##STR00552##

Step 1: Synthesis of Compound WX086

(142) Compound WX086-1 was isolated by supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 50×4.6 mm I.D., 3 μm, mobile phase A: CO.sub.2, B: 40% of ethanol (0.05% DEA). flow rate: 2.5 mL/min, column temperature: 40° C., wavelength: 220 nm) to obtain the isomers WX086′ (retention time: 2.247 min) and WX086 (retention time: 3.248 min). MS-ESI m/z: 613.0, 614.0, 615.0 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ:8.35 (d, J=5.0 Hz, 1H), 8.02 (d, J=16.1 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=9.0 Hz, 2H), 7.77 (d, J=2.0 Hz, 1H), 7.60 (dd, 8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.44 (d, J=9.0 Hz, 2H), 7.32 (d, J=5.0 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.02 (d, J=8.5 Hz, 2H), 6.97 (d, J=15.6 Hz, 1H), 4.43-4.24 (m, 2H), 4.19-4.11 (m, 2H), 3.97 (s, 3H), 3.82-3.78 (m, 2H), 3.57 (s, 2H), 2.73-2.55 (m, 2H), 1.64-1.55 (m, 2H), 1.48-1.38 (m, 2H), 1.21 (t, J=7.5 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H).

Example 87: WX087

(143) ##STR00553##

Step 1: Synthesis of Compound WX087

(144) Compound WX087-1 was isolated by supercritical fluid chromatography (separation condition: Column: Chiralpak AS-3 50×4.6 mm I.D., 3 μm, mobile phase A: CO.sub.2, B: 40% of ethanol (0.05% DEA). flow rate: 2.5 mL/min, column temperature: 40° C., wavelength: 220 nm) to obtain the isomers WX087′ (retention time: 2.409 min) and WX087 (retention time: 3.392 min). MS-ESI m/z: 627.2, 628.2, 629.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.41 (br d, J=4.5 Hz, 1H), 8.06 (d, J=15.6 Hz, 1H), 7.94 (br d, J=10.3 Hz, 2H), 7.76 (br d, J=8.5 Hz, 2H), 7.67 (d, J=1.8 Hz, 1H), 7.53 (dd, J=2.0, 8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.36 (br d, J=8.3 Hz, 2H), 7.12 (br d, J=4.5 Hz, 1H), 6.99 (dd, J=2.9, 8.7 Hz, 3H), 6.78 (d, J=15.6 Hz, 1H), 4.23-4.14 (m, 3H), 4.10-4.04 (m, 1H), 3.93 (s, 3H), 3.82 (t, J=4.8 Hz, 2H), 3.57 (t, J=6.7 Hz, 2H), 2.61-2.53 (m, 2H), 1.64-1.58 (m, 4H), 1.44-1.37 (m, 2H), 1.01-0.96 (m, 2H), 0.96-0.91 (m, 3H).

Example 40: WX006

(145) ##STR00554##

(146) Synthesis Pathway:

(147) ##STR00555##

Step 1: Synthesis of Compound WX006-2

(148) Compound WX006-1 (500.00 mg, 1.89 mmol) and potassium isopropenyl trifluoroborate (195.78 mg, 1.32 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (154.34 mg, 189.00 μL), potassium carbonate (522.43 mg, 3.78 mmol) and water (4 mL). The reaction mixture was heated to 50° C. and stirred for 12 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, followed by addition of water (50 mL) and extraction with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by flash silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/9) (eluent: ethyl acetate/petroleum ether=0/9-1/9) to obtain the title compound WX006-2 (colorless liquid, 500.00 mg, yield: 77.78%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.07 (s, 1H), 7.96 (s, 1H), 7.59-7.57 (d, J=6 Hz, 1H), 7.17-7.15 (d, J=8 Hz, 1H), 5.38 (s, 1H), 4.85 (s, 1H), 2.11 (s, 3H).

Step 2: Synthesis of Compound WX006-4

(149) Compound WX006-2 (500.00 g, 1.47 mmol) and compound WX006-3 (616.18 mg, 1.91 mmol) were dissolved in 1,4-dioxane (6 mL) under nitrogen atmosphere, followed by addition of (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride dichloromethane complex (120.05 mg, 147.00 μmol), potassium carbonate (406.34 g, 2.94 mmol) and water (3 mL). The reaction mixture was heated to 50° C. and stirred for 16 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, followed by addition of water (50 mL) to quenched the reaction, and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The insoluble material was removed by filtration, and the obtained residue was purified by flash silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/9) to obtain the title compound WX006-4 (yellow oily liquid, 232.00 mg, yield: 46.63%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.26 (s, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.78-7.74 (m, 1H), 7.57 (d, J=7.5 Hz, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.05-7.00 (m, 2H), 5.46 (t, J=1.6 Hz, 1H), 4.97-4.94 (m, 1H), 4.19-4.16 (m, 2H), 4.15 (s, 1H), 3.83 (d, J=5.0 Hz, 2H), 3.59-3.55 (m, 2H), 2.22 (s, 3H), 1.66-1.61 (m, 2H), 1.61-1.57 (m, 5H), 1.46-1.36 (m, 3H), 1.34 (s, 1H), 0.98-0.95 (m, 1H), 0.96-0.93 (m, 1H), 0.95-0.93 (m, 1H).

Step 3: Synthesis of Compound WX006-5

(150) Compound WX006-4 (120.00 mg, 354.57 μmol) was dissolved in ethyl acetate (3 mL) at room temperature, and wet palladium on carbon catalyst (100.00 mg, palladium content 10%, water content 50%) was added thereto. The system was displaced with argon three times, followed by displacing with hydrogen three times. The reaction mixture was heated to 50° C. and stirred for 4 hours under hydrogen atmosphere (15 psi). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound WX006-5 (pale-yellow oily liquid, 110.00 mg). The crude product was used directly in the next step without purification.

Step 4: Synthesis of Compound WX006-6

(151) Compound WX006-5 (100.00 mg, 292.00 μmol) was dissolved in dichloromethane (3 mL) at room temperature, and active manganese dioxide (253.86 mg, 2.92 mmol) was added thereto. The reaction mixture was stirred for 16 hours at room temperature under nitrogen protection. After completion of the reaction, manganese dioxide was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (developing solvent: ethyl acetate/petroleum ether=1/15) to obtain the title compound WX006-6 (pale-yellow solid, 170.00 mg, yield: 85.50%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 10.43 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.75 (dd, J=2.1, 8.2 Hz, 1H), 7.58-7.45 (m, 2H), 7.38-7.32 (m, 1H), 7.05-6.96 (m, 2H), 4.20-4.14 (m, 2H), 4.04-3.94 (m, 1H), 3.85-3.79 (m, 2H), 3.60-3.52 (m, 2H), 1.70-1.57 (m, 2H), 1.51-1.37 (m, 2H), 1.35 (d, J=6.8 Hz, 4H), 1.04-0.98 (m, 1H), 0.98-0.88 (m, 3H).

Step 5: Synthesis of Compound WX006-8

(152) Compound WX008-7 (210.72 mg, 939.94 μmol) was dissolved in tetrahydrofuran (2 mL) at room temperature. The solution was cooled to 0° C., and sodium hydride (22.56 mg, 939.94 μmol, purity 60%) was added to the above solution. The reaction mixture was warmed to room temperature and stirred for 0.5 hour. A solution prepared by the compound WX006-6 (160.00 mg, 469.97 μmol) and tetrahydrofuran (2 mL) was added to the above mixture. After completion of the addition, the mixture was further stirred for 5 hours. After completion of the reaction, water (25 mL) was added to the mixture to quenched the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL×3), and dried over anhydrous sodium sulfate, followed by filtration to remove the desiccant. The filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (developing solvent: ethyl acetate/petroleum ether=1/15) to obtain the title compound WX006-8 (pale-yellow solid, 160.00 mg, yield 82.93%).

Step 6: Synthesis of Compound WX006-9

(153) Compound WX006-8 (150.00 mg, 365.37 μmol) was dissolved in ethanol (2 mL) at room temperature, and 8 M aqueous sodium hydroxide solution (1.5 mL) was added to the above solution. The reaction mixture was heated to 50° C. and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, and adjusted to pH=4 with 4 M hydrochloric acid solution, followed by filtration. The precipitate was collected and purified by preparative thin layer chromatography (developing solvent: ethyl acetate/petroleum ether=1/15) to obtain the title compound WX006-9 (pale-yellow solid, 90.00 mg, yield 64.40%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.36-8.24 (m, 1H), 7.73 (s, 1H), 7.64-7.46 (m, 3H), 7.46-7.36 (m, 1H), 7.08-6.98 (m, 2H), 6.45 (d, J=15.8 Hz, 1H), 4.26-4.10 (m, 2H), 3.91-3.73 (m, 2H), 3.57 (t, J=6.7 Hz, 2H), 3.47-3.30 (m, 1H), 1.79-1.52 (m, 2H), 1.46-1.37 (m, 2H), 1.37-1.21 (m, 6H), 0.94 (t, J=7.4 Hz, 3H).

Step 7: Synthesis of Compound WX006

(154) Compound WX006-9 (60.00 mg, 227.83 μmol) was dissolved in dichloromethane (2 mL). The solution was cooled to 0° C., and oxalyl chloride (74.57 mg, 587.46 μmol) and N,N-dimethylformamide (21.47 mg, 293.73 μmol) were added to the above solution. After completion of the addition, the reaction mixture was warmed to room temperature and stirred for 2.5 hours under nitrogen atmosphere. A nitrogen stream was introduced to the reaction mixture to remove the solvent. The obtained residue was dissolved in tetrahydrofuran (1 mL), and added to a solution prepared by compound BB-3A (69.62 mg, 264.36 μmol), triethylamine (59.45 mg, 587.46 μmol) and tetrahydrofuran (1 mL). After completion of the addition, the reaction mixture was stirred for 2.5 hours at room temperature. After completion of the reaction, methanol (2 mL) was added to the mixture to quench the reaction, the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain the compound WX006. MS-ESI m/z: 628.1; 629.1; 630.1[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.84 (br s, 1H), 8.33-8.20 (m, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.67-7.29 (m, 8H), 6.99 (d, J=8.8 Hz, 2H), 6.61 (d, J=15.1 Hz, 1H), 6.53 (s, 1H), 4.23-4.11 (m, 3H), 3.99 (d, J=14.1 Hz, 1H), 3.87-3.74 (m, 4H), 3.57 (t, J=6.8 Hz, 2H), 3.45-3.36 (m, 1H), 1.79-1.65 (m, 1H), 1.41 (qd, J=7.3, 14.9 Hz, 2H), 1.29 (d, J=7.0 Hz, 5H), 1.26 (br s, 1H), 1.00-0.83 (m, 6H).

(155) The reference examples in the following table were synthesized according to the synthesis method of the steps 1-7 in Example 40.

(156) TABLE-US-00012 Example Fragment 1 Structure Compound 41 WX005

(157) The reference examples in the following table were synthesized according to the synthesis method of the steps 4-7 in Example 40.

(158) TABLE-US-00013 Example Fragment 2 Fragment 3 Fragment 5 Structure Compound 42 0 WX011 43 WX042 44 WX043 45 N/A WX037 46 0 WX041 53 WX053 59 WX059 60 0 WX060 70 WX070 71 WX071 72 0 WX072 73 WX073 87 WX087 88 WX088

(159) The reference examples in the following table were synthesized according to the synthesis method of the steps 6-7 in Example 40.

(160) TABLE-US-00014 Example Fragment 4 Fragment 5 Structure Compound 54 00 01 02 WX054 55 03 04 05 WX055 78 06 07 08 WX078

(161) NMR and MS data for each example

(162) TABLE-US-00015 Example Comound NMR MS m/z: 2 WX001 .sup.1H NMR (400 MHz, Methanol-d4) δ: 7.88 (d, J = 8.5 Hz, 586.1, 2H), 7.82-7.74 (m, 2H), 7.67 (s, 1H), 7.64-7.54 (m, 587.1 4H), 7.50-7.44 (m, 3H), 7.05 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 15.6 Hz, 1H), 6.66 (s, 1H), 4.42-4.35 (m, 1H), 4.29-4.21 (m, 1H), 4.19-4.14 (m, 2H), 3.84-3.75 (m, 4H), 3.57 (t, J = 6.7 Hz, 2H), 1.72 (q, J = 7.4 Hz, 2H), 1.64- 1.54 (m, 2H), 1.48-1.36 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H) 3 WX002 .sup.1H NMR (400 MHz, CDCl3) δ = 9.52 (br s, 1H), 7.85- 500.2, 7.77 (m, 3H), 7.64 (s, 1H), 7.57-7.46 (m, 4H), 7.43- 501.1 7.36 (m, 2H), 7.30 (br d, J = 8.3 Hz, 2H), 6.98 (br d, J = 8.5 Hz, 2H), 6.76 (br d, J = 15.6 Hz, 1H), 6.51 (br s, 1H), 4.20 (br d, J = 14.3 Hz, 1H), 3.97 (br d, J = 14.3 Hz, 1H), 3.90- 3.75 (m, 5H), 1.71 (br d, J = 7.0 Hz, 2H), 0.89 (br t, J = 7.3 Hz, 3H) 4 WX003 .sup.1H NMR (400 MHz, Methanol-d4) δ: 7.90-7.83 (m, 604.1, 3H), 7.82-7.77 (m, 2H), 7.66 (s, 1H), 7.63-7.56 (m, 605.1 1H), 7.56-7.51 (m, 2H), 7.44 (dd, J = 1.6, 8.7 Hz, 2H), 7.26-7.17 (m, 1H), 7.06-6.92 (m, 3H), 6.65 (s, 1H), 4.41-4.32 (m, 1H), 4.27-4.20 (m, 1H), 4.17-4.09 (m, 2H), 3.79 (d, J = 6.0 Hz, 4H), 3.56 (dt, J = 1.3, 6.5 Hz, 2H), 1.77-1.67 (m, 2H), 1.64-1.54 (m, 2H), 1.45-1.34 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H) 5 WX004 .sup.1H NMR (400 MHz, CDCl3) δ: 7.90-7.76 (m, 3H), 7.71 514.0, (s, 1H), 7.63-7.42 (m, 6H), 7.37 (d, J = 8.0 Hz, 2H), 7.00 515.0, (d, J = 8.8 Hz, 2H), 6.69-6.52 (m, 2H), 4.18-3.99 (m, 516.0 4H), 3.80 (t, J = 7.3 Hz, 2H), 1.80-1.69 (m, 2H), 1.47 (t, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H) 41 WX005 .sup.1H NMR (400 MHz, CDCl3) δ: 9.74 (br s, 1H), 8.13 (d, 614.1 J = 15.3 Hz, 1H), 7.81 (br d, J = 8.5 Hz, 2H), 7.63 (s, 1H), 615.1 7.52-7.41 (m, 4H), 7.32-7.27 (m, 3H), 6.97 (d, J = 8.5 616.1 Hz, 2H), 6.72 (d, J = 15.3 Hz, 1H), 6.50 (s, 1H), 4.28- 3.89 (m, 4H), 3.88-3.72 (m, 4H), 3.57 (t, J = 6.7 Hz, 2H), 2.82 (q, J = 7.4 Hz, 2H), 1.74-1.57 (m, 4H), 1.41 (qd, J = 7.3, 15.0 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 0.98-0.90 (m, 3H), 0.86 (t, J = 7.4 Hz, 3H) 40 WX006 .sup.1H NMR (400 MHz, CDCl3) δ: 8.84 (br s, 1H), 8.33- 628.1, 8.20 (m, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.67-7.29 (m, 629.1, 8H), 6.99 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 15.1 Hz, 1H), 630.1 6.53 (s, 1H), 4.23-4.11 (m, 3H), 3.99 (d, J = 14.1 Hz, 1H), 3.87-3.74 (m, 4H), 3.57 (t, J = 6.8 Hz, 2H), 3.45- 3.36 (m, 1H), 1.79-1.65 (m, 1H), 1.41 (qd, J = 7.3, 14.9 Hz, 2H), 1.29 (d, J = 7.0 Hz, 5H), 1.26 (br s, 1H), 1.00- 0.83 (m, 6H) 6 WX007 .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.88-7.77 (m, 3H), 7.69 527.7, (s, 1H), 7.60-7.39 (m, 6H), 7.35 (d, J = 8.5 Hz, 2H), 6.98 528.7 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 15.3 Hz, 1H), 6.56 (s, 1H), 4.62 (quin, J = 6.0 Hz, 1H), 4.22-4.12 (m, 1H), 4.01 (d, J = 14.1 Hz, 1H), 3.82 (dt, J = 2.5, 7.2 Hz, 2H), 1.74 (sxt, J = 7.3 Hz, 2H), 1.39 (d, J = 6.0 Hz, 7H), 0.91 (t, J = 7.4 Hz, 3H) 7 WX008 .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ: 7.88 (d, J = 8.5 Hz, 600.1, 2H), 7.66 (s, 1H), 7.62 (br. s., 1H), 7.59-7.52 (m, 3H), 601.1 7.51-7.36 (m, 5H), 7.03 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 4.43-4.34 (m, 1H), 4.29-4.20 (m, 1H), 4.17-4.11 (m, 2H), 3.86-3.72 (m, 4H), 3.56 (t, J = 6.5 Hz, 2H), 2.21 (s, 3H), 1.80-1.67 (m, 2H), 1.63-1.51 (m, 2H), 1.47-1.33 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H) 8 WX009 .sup.1H NMR (400 MHz, CDCl3) δ: 8.08 (s, 1H), 7.87-7.76 541.7, (m, 3H), 7.71 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.52 (d, 542.7 J = 8.8 Hz, 2H), 7.50-7.47 (m, 2H), 7.46-7.42 (m, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 15.6 Hz, 1H), 6.59 (s, 1H), 4.19-4.11 (m, 1H), 4.05- 4.00 (m, 3H), 3.81 (t, J = 7.2 Hz, 2H), 1.86-1.71 (m, 4H), 1.56-1.48 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H) 9 WX010 .sup.1H NMR (400 MHz, CDCl3) δ = 8.62 (s, 1H), 8.14 (s, 587.0, 1H), 7.85-7.76 (m, 3H), 7.69 (br s, 1H), 7.55 (br d, 588.0, J = 6.5 Hz, 1H), 7.51 (br d, J = 8.5 Hz, 2H), 7.47-7.42 (m, 589.0 2H), 7.40 (br d, J = 8.3 Hz, 2H), 7.01 (br d, J = 8.3 Hz, 2H), 6.71 (br d, J = 15.6 Hz, 1H), 4.35-4.12 (m, 4H), 3.97 (br t, J = 7.2 Hz, 2H), 3.83 (br d, J = 4.3 Hz, 2H), 3.56 (br t, J = 6.5 Hz, 2H), 1.84-1.73 (m, 2H), 1.63-1.56 (m, 2H), 1.47-1.33 (m, 2H), 0.94 (br t, J = 7.2 Hz, 6H) 42 WX011 .sup.1H NMR (400 MHz, CDCl3) δ: 10.10 (br s, 1H), 8.06 600.0, (d, J = 15.6 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 601.0 7.48 (s, 1H), 7.41 (br d, J = 8.5 Hz, 3H), 7.27 (s, 1H), 7.25 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 15.3 Hz, 1H), 6.47 (s, 1H), 4.21-4.16 (m, 1H), 4.16-4.12 (m, 2H), 3.91 (d, J = 14.3 Hz, 1H), 3.84- 3.80 (m, 2H), 3.80-3.70 (m, 2H), 3.56 (t, J = 6.7 Hz, 2H), 2.43 (s, 3H), 1.73-1.56 (m, 4H), 1.40 (sxt, J = 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H) 10 WX012 .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.43 (br s, 1H), 7.76 (d, 600.1, J = 8.5 Hz, 2H), 7.62 (s, 1H), 7.56-7.38 (m, 6H), 7.33 601.1, (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.56 (s, 1H), 602.1 6.30 (s, 1H), 4.18 (t, J = 4.8 Hz, 2H), 4.15-4.09 (m, 1H), 4.02-3.96 (m, 1H), 3.85-3.74 (m, 4H), 3.57 (t, J = 6.7 Hz, 2H), 2.70 (s, 3H), 1.76 (s, 1H), 1.62-1.55 (m, 2H), 1.41 (sxt, J = 7.5 Hz, 2H), 0.97-0.86 (m, 6H) 11 WX013 .sup.1H NMR (400 MHz, CDCl.sub.3) δ:8.59 (br s, 1H), 7.86- 543.7, 7.77 (m, 3H), 7.69 (s, 1H), 7.58-7.41 (m, 6H), 7.35 (d, 544.7 J = 8.5 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 15.6 Hz, 1H), 6.57 (s, 1H), 4.21-4.14 (m, 3H), 4.01 (d, J = 14.1 Hz, 1H), 3.85-3.77 (m, 4H), 3.49 (s, 3H), 1.79- 1.69 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H) 12 WX014 .sup.1H NMR (400 MHz, METHANOL-d4) δ: 7.87-7.78 618.1, (m, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.55-7.47 (m, 4H), 619.1, 7.45-7.35 (m, J = 8.8 Hz, 2H), 7.22-7.09 (m, 1H), 6.99 620.0 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 6.30-6.24 (m, 1H), 4.33 (d, J = 14.3 Hz, 1H), 4.19 (d, J = 14.6 Hz, 1H), 4.15-4.07 (m, 2H), 3.82-3.70 (m, 4H), 3.53 (t, J = 6.7 Hz, 2H), 2.57 (s, 3H), 1.74-1.64 (m, 2H), 1.61-1.51 (m, 2H), 1.44- 1.26 (m, 2H), 0.95-0.82 (m, 6H) 13 WX015 .sup.1H NMR (400 MHz, CDCl3) δ: 8.13 (s, 1H), 7.89 (br s, 543.2, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.57-7.43 (m, 8H), 7.32 544.3, (br d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 4.36-4.17 545.2 (m, 2H), 3.98 (t, J = 6.7 Hz, 4H), 2.27 (s, 3H), 1.90-1.82 (m, 2H), 1.81-1.70 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H) 14 WX016 .sup.1H NMR (400 MHz, CDCl3) δ: 8.17 (d, J = 15.6 Hz, 1H), 620.2, 7.80 (d, J = 8.5 Hz, 2H), 7.69 (br s, 1H), 7.51-7.41 (m, 621.1 5H), 7.31 (br d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.77 (br d, J = 15.6 Hz, 1H), 6.51 (br s, 1H), 4.22-4.14 (m, 3H), 3.96 (br d, J = 14.1 Hz, 1H), 3.88-3.75 (m, 5H), 3.57 (t, J = 6.8 Hz, 2H), 1.78-1.66 (m, 2H), 1.62-1.56 (m, 2H), 1.46-1.37 (m, 2H), 0.97-0.86 (m, 6H) 1 WX017 .sup.1H NMR (400 MHz, CDCl3) δ: 9.33 (s, 1H), 8.05 (d, 616.1, J = 15.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 2.3 617.1 Hz, 1H), 7.50 (br d, J = 2.3 Hz, 1H), 7.48 (s, 1H), 7.44- 7.39 (m, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.98-6.93 (m, 3H), 6.88 (d, J = 15.8 Hz, 1H), 6.55 (s, 1H), 4.15 (d, J = 4.8 Hz, 2H), 4.14-4.13 (m, 1H), 4.13 (d, J = 2.8 Hz, 1H), 3.97 (d, J = 14.1 Hz, 1H), 3.86 (s, 3H), 3.83-3.79 (m, 1H), 3.79-3.79 (m, 1H), 3.76 (dt, J = 4.0, 7.3 Hz, 2H), 3.56 (t, J = 6.8 Hz, 2H), 1.73-1.66 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.35 (m, 2H), 0.93 (t, J = 7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H) 15 WX018 .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 9.85 (br s, 608.0, 1H), 7.98 (d, J = 15.8 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 609.0. 7.66 (d, J = 2.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.41 (d, 610.0 J = 8.8 Hz, 2H), 7.29 (s, 2H), 7.19 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 15.8 Hz, 1H), 6.73-6.35 (m, 2H), 4.20 (d, J = 14.1 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.94 (d, J = 14.1 Hz, 1H), 3.88-3.73 (m, 2H), 1.84-1.77 (m, 2H), 1.71-1.67 (m, 2H), 1.52 (qd, J = 7.5, 14.9 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H) 16 WX019 .sup.1H NMR (400 MHz, CDCl3) δ: 8.66 (s, 1H), 7.83 (d, 572.0, J = 15.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H), 573.0 7.56 (br d, J = 7.3 Hz, 1H), 7.54 (s, 1H), 7.52-7.49 (m, 2H), 7.48-7.40 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.03- 6.99 (m, 2H), 6.70 (d, J = 15.6 Hz, 1H), 6.56 (s, 1H), 4.20- 4.16 (m, 2H), 4.16-3.98 (m, 2H), 3.90 (q, J = 7.4 Hz, 2H), 3.84-3.80 (m, 2H), 3.59-3.54 (m, 2H), 1.61-1.58 (m, 2H), 1.44-1.36 (m, 5H), 0.94 (t, J = 7.4 Hz, 3H) 17 WX020 .sup.1H NMR (400 MHz, CDCl3) δ: 9.70 (s, 1H), 8.15 (d, 562.0, J = 15.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 563.0, 7.53 (s, 1H), 7.45-7.42 (m, 3H), 7.41 (s, 1H), 7.28 (d, 564.0 J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 15.6 Hz, 1H), 6.48 (s, 1H), 4.22-4.01 (m, 2H), 4.00-3.92 (m, 2H), 3.89 (q, J = 7.4 Hz, 2H), 1.84-1.77 (m, 2H), 1.52 (qd, J = 7.5, 14.9 Hz, 2H), 1.36 (t, J = 7.4 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H) 18 WX021 .sup.1H NMR (400 MHz, CDCl3) δ: 9.64 (s, 1H), 8.17 (d, 588.0, J = 15.6 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 589.0, 7.69 (s, 1H), 7.46-7.43 (m, 4H), 7.31 (d, J = 8.4 Hz, 2H), 590.0 6.96 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 15.6 Hz, 1H), 6.52 (s, 1H), 4.22-4.02 (m, 2H), 4.01-4.00 (m, 2H), 3.72 (q, J = 7.4 Hz, 2H), 1.84-1.80 (m, 2H), 1.59-1.51 (m, 2H), 1.12-1.04 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H), 0.66-0.64 (m, 2H), 0.33-0.32 (m, 2H). 19 WX022 .sup.1H NMR (400 MHz, CDCl3) δ: 9.49 (s, 1H), 8.08 (d, 580.0, J = 15.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 581.0, 7.43 (s, 1H), 7.37-7.35 (m, 4H), 7.21 (d, J = 8.8 Hz, 2H), 582.0 6.88 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 15.6 Hz, 1H), 6.41 (s, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.56 (t, J = 5.6 Hz, 1H), 4.14-4.06 (m, 3H), 3.86 (d, J = 14 Hz, 1H), 3.75-3.72 (m, 2H), 2.18-2.10 (m, 2H), 1.66-1.62 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H). 20 WX023 .sup.1H NMR (400 MHz, CDCl3) δ: 8.73 (s, 1H), 7.70-7.69 598.0, (m, 3H), 7.52 (d, J = 8.8 Hz, 2H), 7.47-7.44 (m, 3H), 599.0 7.35 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 15.6 Hz, 1H), 6.59 (s, 1H), 4.23-4.06 (m, 4H), 3.84 (d, J = 4.8 Hz, 2H), 3.83-3.60 (m, 2H), 3.58 (d, J = 6.8 Hz, 2H), 1.47-1.43 (m, 2H), 1.43-1.31 (m, 2H), 1.39-1.38 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H), 0.35- 0.33 (m, 2H), 0.33-0.32 (m, 2H). 21 WX024 .sup.1H NMR (400 MHz, CDCl3) δ: 10.46 (s, 1H), 7.94-7.83 618.1, (m, 4H), 7.63-7.47 (m, 6H), 7.2-6.99 (m, 4H), 6.52 (s, 619.0, 1H), 4.76-4.62 (m, 2H), 4.33-4.15 (m, 4H), 4.01 (t, 620.0 J = 6.4 Hz, 2H), 3.8 (m, 2H), 2.3-2.1 (m, 2H), 1.72-1.45 (m, 6H), 0.95 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H). 22 WX025 .sup.1H NMR (400 MHz, CDCl3) δ: 10.19 (br s, 1H), 8.16 576.0, (br d, J = 15.3 Hz, 1H), 7.91-7.74 (m, J = 7.5 Hz, 2H), 577.0 7.66 (br s, 1H), 7.51 (br s, 1H), 7.48-7.37 (m, 4H), 7.29 (br s, 2H), 6.96 (br d, J = 7.5 Hz, 2H), 6.91-6.76 (m, 1H), 6.47 (br s, 1H), 4.22 (br d, J = 14.1 Hz, 1H), 4.02 (br s, 2H), 3.99-3.89 (m, 1H), 3.89-3.69 (m, 2H), 1.82 (br s, 2H), 1.77-1.64 (m, 2H), 1.63-1.44 (m, 2H), 1.10-0.95 (m, 3H), 0.95-0.79 (m, 3H) 23 WX026 .sup.1H NMR (400 MHz, CDCl3) δ: 9.08 (br s, 1H), 8.04 (d, 622.0, J = 15.6 Hz, 1H), 7.80 (br d, J = 8.5 Hz, 2H), 7.65 (s, 1H), 623.0 7.54-7.47 (m, 2H), 7.47-7.40 (m, 2H), 7.31 (br d, J = 8.5 Hz, 2H), 6.99-6.91 (m, 3H), 6.85 (d, J = 15.6 Hz, 1H), 6.53 (s, 1H), 6.32-6.23 (m, 1H), 6.17-6.10 (m, 1H), 5.99 (s, 1H), 4.27 (dt, J = 3.9, 12.9 Hz, 2H), 4.22-4.12 (m, 1H), 4.07-3.94 (m, 3H), 3.87-3.73 (m, 2H), 1.86- 1.71 (m, 4H), 1.53 (qd, J = 7.5, 15.0 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H) 24 WX027 .sup.1H NMR (400 MHz, CDCl3) δ: 9.44 (br s, 1H), 8.15 (d, 590.0 J = 15.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.68 (s, 1H), 591.1, 7.51-7.40 (m, 5H), 7.29 (d, J = 8.5 Hz, 2H), 6.95 (d, 592.1 J = 8.8 Hz, 2H), 6.78 (d, J = 15.6 Hz, 1H), 6.50 (s, 1H), 4.16 (d, J = 14.1 Hz, 1H), 4.04-3.95 (m, 3H), 3.82 (dt, J = 3.6, 7.3 Hz, 2H), 1.85-1.75 (m, 2H), 1.64-1.59 (m, 2H), 1.52 (qd, J = 7.4, 14.9 Hz, 2H), 1.27 (qd, J = 7.4, 15.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H) 25 WX028 .sup.1H NMR (400 MHz, CDCl3) δ: 9.34 (br s, 1H), 7.88- 600.1, 7.59 (m, 4H), 7.57-7.45 (m, 4H), 7.44-7.37 (m, 2H), 601.1 7.35-7.28 (m, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 15.6 Hz, 1H), 6.53 (s, 1H), 4.20-4.12 (m, 3H), 4.04- 3.95 (m, 1H), 3.85-3.78 (m, 4H), 3.56 (t, J = 6.8 Hz, 2H), 1.73-1.53 (m, 4H), 1.46-1.35 (m, 2H), 1.33-1.23 (m, 2H), 0.98-0.85 (m, 6H) 26 WX029 .sup.1H NMR (400 MHz, CDCl3) δ: 9.58 (br s, 1H), 7.84- 600.1, 7.77 (m, 3H), 7.63 (s, 1H), 7.52 (br d, J = 6.5 Hz, 1H), 601.1 7.49-7.44 (m, 3H), 7.43-7.36 (m, 2H), 7.34-7.27 (m, 2H), 6.99 (br d, J = 8.5 Hz, 2H), 6.76 (br d, J = 15.3 Hz, 1H), 6.51 (s, 1H), 4.22-4.11 (m, 3H), 4.00 (br d, J = 14.1 Hz, 1H), 3.81 (br t, J = 4.8 Hz, 2H), 3.75-3.60 (m, 2H), 3.56 (br t, J = 6.7 Hz, 2H), 1.93 (td, J = 6.8, 13.6 Hz, 1H), 1.61 (quin, J = 7.1 Hz, 2H), 1.40 (qd, J = 7.4, 14.9 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.86 (br dd, J = 6.8, 10.5 Hz, 6H) 27 WX030 .sup.1H NMR (400 MHz, CDCl3) δ: 9.79-9.51 (m, 1H), 8.15 590.1, (d, J = 15.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.65 (s, 1H), 591.0 7.47-7.39 (m, 5H), 7.28 (d, J = 8.5 Hz, 2H), 6.94 (d, 592.0 J = 8.5 Hz, 2H), 6.78 (d, J = 15.6 Hz, 1H), 6.47 (s, 1H), 4.16 (d, J = 14.1 Hz, 1H), 4.05-3.93 (m, 3H), 3.75-3.53 (m, 2H), 1.96-1.85 (m, 1H), 1.84-1.75 (m, 2H), 1.52 (qd, J = 7.5, 14.9 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.83 (dd, J = 6.7, 13.9 Hz, 6H) 28 WX031 .sup.1H NMR (400 MHz, CDCl3) δ: 9.08 (br s, 1H), 7.85 (s, 602.0, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.59 (d, J = 8.5 603.0 Hz, 2H), 7.55-7.50 (m, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.44-7.39 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 15.6 Hz, 1H), 6.54 (s, 1H), 4.36 (s, 2H), 4.20-4.15 (m, 2H), 3.99 (t, J = 7.4 Hz, 2H), 3.85-3.79 (m, 2H), 3.56 (t, J = 6.7 Hz, 2H), 1.83-1.73 (m, 2H), 1.58 (br s, 2H), 1.43-1.37 (m, 2H), 0.94 (t, J = 7.4 Hz, 6H) 29 WX032 .sup.1H NMR (400 MHz, CDCl3) δ: 9.56 (br s, 1H), 8.10 (d, 630.1, J = 15.8 Hz, 1H), 7.80 (br d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 631.1, 7.50-7.36 (m, 4H), 7.27 (br d, J = 8.8 Hz, 2H), 6.98- 632.1 6.80 (m, 4H), 6.53 (s, 1H), 4.17-3.92 (m, 6H), 3.80 (br t, J = 4.8 Hz, 2H), 3.77-3.66 (m, 2H), 3.55 (t, J = 6.7 Hz, 2H), 1.73-1.55 (m, 4H), 1.45-1.33 (m, 5H), 0.92 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H) 30 WX033 .sup.1H NMR (400 MHz, CDCl3) δ: 8.463-8.644 (m, 1 H) 644.1, 8.065-8.224 (m, 1 H) 7.860 (br d, J = 8.533 Hz, 2 H) 645.1, 7.603-7.748 (m, 2 H) 7.442-7.558 (m, 3 H) 7.316 (d, 646.1 J = 8.282 Hz, 2 H) 7.000 (d, J = 8.784 Hz, 3 H) 6.854 (d, J = 15.560 Hz, 1 H) 6.535-6.673 (m, 1 H) 4.586-4.788 (m, 1 H) 4.108-4.218 (m, 3 H) 3.947-4.040 (m, 1 H) 3.831 (s, 4 H) 3.577 (s, 2 H) 1.698-1.766 (m, 2 H) 1.583- 1.679 (m, 2 H) 1.433 (d, J = 6.023 Hz, 8 H) 0.870-1.056 (m, 6 H) 31 WX034 .sup.1H NMR (400 MHz, CDCl3) δ: 8.072 (d, J = 15.560 Hz, 1 658.1, H) 7.869-7.926 (m, 1 H) 7.681-7.753 (m, 2 H) 7.586- 659.0, 7.632 (m, 1 H) 7.367-7.453 (m, 4 H) 7.278 (d, J = 8.784 660.2 Hz, 2 H) 6.881-6.940 (m, 3 H) 6.642-6.725 (m, 1 H) 6.524 (s, 1 H) 4.072-4.121 (m, 2 H) 3.918-4.064 (m, 2 H) 3.666-3.796 (m, 6 H) 3.491 (t, J = 6.776 Hz, 2 H) 2.127 (dd, J = 12.925, 6.400 Hz, 1 H) 1.590-1.711 (m, 2 H) 1.263-1.441 (m, 2 H) 1.024 (d, J = 6.776 Hz, 6 H) 0.848 (dt, J = 16.187, 7.341 Hz, 6 H) 32 WX035 .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 9.44 (br s, 646.0, 1H), 8.04 (br d, J = 15.8 Hz, 1H), 7.80 (br d, J = 8.3 Hz, 647.1. 2H), 7.49 (br s, 1H), 7.43 (br d, J = 8.5 Hz, 2H), 7.30 (br d, J = 8.3 Hz, 2H), 7.22 (s, 1H), 7.07 (s, 1H), 6.98 (br d, J = 8.5 Hz, 2H), 6.86 (br d, J = 15.6 Hz, 1H), 6.54 (br s, 1H), 4.23-4.10 (m, 3H), 4.06-3.96 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.85-3.80 (m, 2H), 3.80-3.73 (m, 2H), 3.57 (br t, J = 6.7 Hz, 2H), 1.74-1.67 (m, 2H), 1.62 (td, J = 6.9, 14.3 Hz, 2H), 1.40 (qd, J = 7.4, 14.9 Hz, 2H), 0.94 (br t, J = 7.4 Hz, 3H), 0.87 (br t, J = 7.3 Hz, 3H) 33 WX036 .sup.1H NMR (400 MHz, CDCl3) δ: 8.249-8.360 (m, 1 H) 630.1, 7.978 (d, J = 15.560 Hz, 1 H) 7.705 (d, J = 8.533 Hz, 2 H) 631.1, 7.401 (s, 1 H) 7.341 (d, J = 2.008 Hz, 1 H) 7.253 (d, 632.1 J = 8.784 Hz, 2 H) 7.205-7.224 (m, 1 H) 7.026 (s, 1 H) 6.844-6.918 (m, 1 H) 6.773 (d, J = 2.510 Hz, 1 H) 6.728- 6.749 (m, 1 H) 6.693-6.728 (m, 1 H) 6.657-6.680 (m, 1 H) 6.489-6.520 (m, 1 H) 4.080 (s, 2 H) 3.997- 4.043 (m, 1 H) 3.895-3.970 (m, 1 H) 3.853 (s, 3 H) 3.717-3.760 (m, 2 H) 3.654-3.717 (m, 2 H) 3.488 (t, J = 6.776 Hz, 2 H) 1.605-1.758 (m, 3 H) 1.477-1.559 (m, 4 H) 1.246-1.407 (m, 2 H) 0.844 (dt, J = 19.011, 7.309 Hz, 6 H) 45 WX037 .sup.1H NMR (400 MHz, CDCl3) δ: 9.34 (br s, 1H), 7.87- 270.1 7.76 (m, 3H), 7.66 (s, 1H), 7.55 (br d, J = 6.3 Hz, 1H), (M/2 + H).sup.+ 7.52-7.44 (m, 3H), 7.43-7.34 (m, 2H), 7.31 (br d, J = 8.3 Hz, 2H), 6.73 (br d, J = 15.3 Hz, 1H), 6.63 (br d, J = 8.5 Hz, 2H), 6.59-6.50 (m, 1H), 4.22-4.10 (m, 1H), 4.08-3.94 (m, 1H), 3.87-3.71 (m, 2H), 3.34 (br t, J = 6.1 Hz, 4H), 2.04 (br t, J = 6.3 Hz, 5H), 1.79-1.63 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H) 34 WX038 .sup.1H NMR (400 MHz, CDCl3) δ: 8.83 (br s, 1H), 8.05 (d, 630.1, J = 15.8 Hz, 1H), 7.79 (br d, J = 8.5 Hz, 2H), 7.62 (s, 1H), 631.1, 7.51 (br d, J = 8.5 Hz, 1H), 7.46-7.39 (m, 3H), 7.29 (s, 632.1 2H), 7.02-6.93 (m, 3H), 6.83 (d, J = 15.6 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H), 4.11-3.99 (m, 2H), 3.89 (s, 3H), 3.84- 3.74 (m, 4H), 3.56 (t, J = 6.7 Hz, 2H), 1.65-1.53 (m, 7H), 1.40 (qd, J = 7.4, 14.9 Hz, 2H), 0.91 (td, J = 7.3, 17.7 Hz, 6H) 37 WX039 .sup.1H NMR (400 MHz, CDCl3) δ: 9.37(s, 1 H) 8.05(d, 603.1 J = 15.5 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 2.3 604.1 Hz, 1H), 7.51(s, 1H), 7.49(dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 605.1 7.41(d, J = 8.8 Hz, 2H), 7.29(d, J = 8.5 Hz, 2H), 6.96- 6.92(m, 3H), 6.88(d, J = 15.5 Hz, 1H), 6.55(s, 1H), 4.15- 4.13(m, 2H), 4.11-3.94 (m, 2H), 3.86(s, 3H), 3.84-3.82 (m, 2H), 3.80-3.69(m, 2H), 3.56(t, J = 6.8 Hz, 2H), 1.63- 1.59(m, 2H), 1.42-1.38(m, 3H), 1.36-1.32(m, 2H), 0.93(t, J = 7.4 Hz, 3H). 37 WX040 .sup.1H NMR (400 MHz, CDCl3) δ: 9.07(br s, 1 H) 8.05(d, 603.1 J = 15.5 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 2.3 604.0 Hz, 1H), 7.53(s, 1H), 7.50 (dd, J = 8.7 Hz, J = 2.1 Hz, 1H), 605.0 7.43(d, J = 8.5 Hz, 2H), 7.30(d, J = 8.3 Hz, 2H), 6.97- 6.94(m, 3H), 6.88(d, J = 15.5 Hz, 1H), 6.56(br s, 1H), 4.16-4.13(m, 2H), 4.11-3.95 (m, 2H), 3.88 (s, 3H), 3.85-3.74 (m, 4H), 3.56 (t, J = 6.8 Hz, 2H), 1.63-1.59 (m, 2H), 1.42-1.36 (m, 3H), 1.36-1.32(m, 2H), 0.93(t, J = 7.4 Hz, 3H). 46 WX041 .sup.1H NMR (400 MHz, CDCl3) δ: 8.68 (S, 1 H), 7.79 (d, 586.0, J = 8.8 Hz, 2 H), 7.68 (d, J = 1.8 Hz, 1 H), 7.51 (s, 1 H), 587.0 7.47 (d, J = 8.5 Hz, 2H), 7.44 (s, 1 H), 7.33 (d, J = 8.8 Hz, 588.1 1 H), 7.27 (s, 1 H), 6.99 (d, J = 8.8 Hz, 2H), 6.62(d, J = 15.3 Hz, 1 H), 6.55 (s, 1 H), 4.18-4.15 (m, 2 H), 4.12-3.98 (m, 2 H), 3.88-3.84 (m, 2 H), 3.83-3.81(m, 2 H), 3.56(t, J = 6.8 Hz, 2 H), 2.48(s, 1H), 1.43-1.25 (m, 7H), 0.94 (t, J = 7.4 Hz, 3 H). 43 WX042 .sup.1H NMR (400 MHz, CDCl3) δ: 9.08 (s, 1 H), 7.97 (d, 630.0, J = 15.6 Hz, 1 H), 7.73(d, J = 8.8 Hz, 2H), 7.43-7.41 (m, 631.0, 2 H), 7.36-7.34 (m, 2H), 7.30 (d, J = 1.7 Hz, 1H), 7.24 632.0 (d, J = 8.5 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 15.8 Hz, 1 H), 6.46 (s, 1H), 4.10-4.08 (m, 2 H), 4.07- 3.9 (m, 2H), 3.76-3.73 (m, 2 H), 3.70 (s, 3H), 3.49 (t, J = 6.8 Hz, 2 H), 2.29 (s, 3H), 1.66-1.62 (m, 2H), 1.56- 1.52 (m, 2H), 1.36-1.30 (m, 2H), 0.87 (t, J = 7.4 Hz, 3 H), 0.81 (t, J = 7.3 Hz, 3H) 44 WX043 .sup.1H NMR (400 MHz, CDCl3) δ: 9.14 (br s, 1H), 7.88 (br 650.0, d, J = 15.6 Hz, 1H), 7.70 (br d, J = 8.3 Hz, 2H), 7.40 (s, 651.0, 1H), 7.32 (s, 1H), 7.23 (br s, 1H), 7.22 (br s, 3H), 6.92 652.0 (br s, 1H), 6.91-6.87 (m, 2H), 6.73 (br d, J = 15.6 Hz, 1H), 6.44 (s, 1H), 4.09 (br s, 2H), 4.05 (br s, 1H), 3.88 (br d, J = 14.3 Hz, 1H), 3.80 (s, 3H), 3.75 (br s, 2H), 3.70 (br d, J = 6.5 Hz, 2H), 3.49 (br t, J = 6.4 Hz, 2H), 1.64- 1.58 (m, 2H), 1.57-1.51 (m, 2H), 1.37-1.29 (m, 2H), 0.87 (br t, J = 7.2 Hz, 3H), 0.81 (br t, J = 7.2 Hz, 3H) 35 WX044 .sup.1H NMR (400 MHz, CHLOROFORM-d) δ: 10.28 (br s, 611.1, 1H), 7.98 (d, J = 15.8 Hz, 1H), 7.81 (br d, J = 8.3 Hz, 612.0 2H), 7.76-7.65 (m, 2H), 7.59 (br d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.48 (br d, J = 8.5 Hz, 2H), 7.29 (br d, J = 9.0 Hz, 2H), 7.09 (br d, J = 15.6 Hz, 1H), 7.01 (br d, J = 8.8 Hz, 2H), 6.49 (s, 1H), 4.29-4.13 (m, 3H), 3.97 (br d, J = 14.1 Hz, 1H), 3.88-3.70 (m, 4H), 3.57 (t, J = 6.7 Hz, 2H), 1.72 (qd, J = 7.3, 14.6 Hz, 1H), 1.78-1.66 (m, 1H), 1.40 (qd, J = 7.4, 14.9 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.89 (br t, J = 7.3 Hz, 3H) 36 WX045 .sup.1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J = 15.6 Hz, 2H), 616.3, 7.78(d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.48-7.31 (m, 6H), 614.3 7.01-6.98(m, 3H), 6.82(d, J = 15.6 Hz, 1H), 4.18-4.07 (m, 4H), 3.94 (s, 3H), 3.84-3.81 (m, 4H), 3.58-3.55(m, 2H), 1.45-1.37(m, 7H), 0.93(t, J = 7.4 Hz, 3H). 38 WX046 .sup.1H NMR (400 MHz, CDCl3) δ: 10.53 (br s, 1 H) 7.84- 652.0, 7.94 (m, 1 H) 7.76 (br d, J = 8.03 Hz, 2 H) 7.53 (s, 1 H) 653.0 7.40 (s, 2 H) 7.31 (d, J = 7.5 Hz, 2 H) 7.16 (d, J = 8.0 Hz, 2 H) 7.11 (s, 1 H) 6.76-6.95 (m, 3 H) 6.21-6.66 (m, 1 H) 3.89-4.15 (m, 3 H) 3.79-4.15 (m, 3 H) 3.75 (s, 2 H) 3.49 (t, J = 6.2 Hz, 2 H) 1.49-1.60 (m, 2 H) 1.40 (s, 3 H) 1.34 (br s, 2 H) 1.29 (t, J = 6.7 Hz, 3 H) 0.86 (t, J = 7.0 Hz, 3 H). 39 WX047 1H NMR (400 MHz, CDCl3) δ: 9.92 (br s, 1H), 8.03 (br 630.1, d, J = 15.8 Hz, 1H), 7.75 (br d, J = 8.3 Hz, 2H), 7.50 (br s, 631.1 1H), 7.43-7.36 (m, 2H), 7.31 (br d, J = 8.5 Hz, 2H), 7.20- 7.15 (m, 2H), 6.87 (br d, J = 8.5 Hz, 2H), 6.83 (br s, 1H), 6.79 (br d, J = 15.6 Hz, 1H), 4.07 (br dd, J = 3.9, 9.2 Hz, 3H), 4.01 (q, J = 6.8 Hz, 2H), 3.89-3.80 (m, 3H), 3.77- 3.71 (m, 2H), 3.52-3.45 (m, 2H), 1.57-1.51 (m, 2H), 1.47 (s, 3H), 1.33 (br d, J = 6.5 Hz, 5H), 1.30-1.25 (m, 3H), 0.91-0.84 (m, 3H) 48 WX048 1H NMR (400 MHz, CDCl3) δ: 9.07 (br s, 1H), 8.06 (d, 572.0 J = 15.8 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 2.0 573.0 Hz, 1H), 7.53-7.48 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.54-7.40 (m, 1H), 7.55-7.39 (m, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.99-6.92 (m, 3H), 6.88 (d, J = 15.8 Hz, 1H), 6.56 (s, 1H), 4.15 (d, J = 14.1 Hz, 1H), 4.18-3.96 (m, 1H), 4.02-3.96 (m, 2H), 3.88 (s, 3H), 3.78 (dt, J = 3.8, 7.2 Hz, 2H), 1.75 (br d, J = 12.5 Hz, 2H), 1.72-1.66 (m, 2H), 1.52 (qd, J = 7.4, 14.9 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H) 49 WX049 1H NMR (400 MHz, CDCl3) δ: 9.33 (s, 1H), 8.05 (d, 602.0 J = 15.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 2.3 603.0 Hz, 1H), 7.50 (br d, J = 2.3 Hz, 1H), 7.48 (s, 1H), 7.44- 7.39 (m, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.98-6.93 (m, 3H), 6.88 (d, J = 15.8 Hz, 1H), 6.55 (s, 1H), 4.15 (d, J = 4.8 Hz, 2H), 4.14-4.13 (m, 1H), 4.13 (d, J = 2.8 Hz, 1H), 3.97 (d, J = 14.1 Hz, 1H), 3.83-3.79 (m, 1H), 3.79-3.79 (m, 1H), 3.76 (dt, J = 4.0, 7.3 Hz, 2H), 3.56 (t, J = 6.8 Hz, 2H), 1.73-1.66 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.35 (m, 2H), 0.93 (t, J = 7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H)∘ 50 WX050 1H NMR (400 MHz, CDCl3) δ: 9.08 (s, 1H), 8.06 (d, 602.0 J = 15.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.3 603.1 Hz, 1H), 7.52-7.49 (m, 1H), 7.49 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 6.0 Hz, 2H), 6.96-6.94 (m, 1H), 6.88 (d, J = 15.8 Hz, 1H), 6.57 (s, 1H), 4.19-4.16 (m, 2H), 4.14 (d, J = 7.5 Hz, 1H), 3.99 (d, J = 14.1 Hz, 1H), 3.88 (s, 3H), 3.84-3.81 (m, 2H), 3.78 (dt, J = 2.8, 7.3 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H), 1.75- 1.71 (m, 2H), 1.67-1.61 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 51 WX051 1H NMR (400 MHz, CDCl3) δ: 9.14 (br s, 1 H) 7.93 (d, 652.0 J = 15.5 Hz, 1 H) 7.73 (d, J = 8.7 Hz, 2 H) 7.63 (d, J = 2.0 653.0 Hz, 1 H) 7.45 (dd, J = 8.6, 2.1 Hz, 1 H) 7.42 (s, 1 H) 7.37 654.0 (d, J = 8.7 Hz, 2 H) 7.24 (d, J = 8.5 Hz, 2 H) 7.14 (d, J = 8.5 Hz, 1 H) 6.92 (d, J = 8.5 Hz, 2 H) 6.77 (d, J = 15.8 Hz, 1 H) 6.31-6.67 (m, 2 H) 3.66-4.17 (m, 8 H) 3.49 (t, J = 6.6 Hz, 2 H) 1.65 (d, J = 7.2 Hz, 2 H) 1.33 (d, J = 7.5 Hz, 2 H) 0.78-0.91 (m, 6 H) 52 WX052 1H NMR (400 MHz, CDCl3) δ: 9.90 (br s, 1 H) 7.98 (d, 594.0 J = 15.5 Hz, 1 H) 7.81 (d, J = 8.7 Hz, 2 H) 7.65 (d, J = 2.2 595.0 Hz, 1 H) 7.47-7.52 (m, 2 H) 7.37-7.45 (m, 2 H) 7.29 596.1 (s, 1 H) 7.19 (d, J = 8.5 Hz, 1 H) 6.95 (d, J = 8.7 Hz, 2 H) 6.88 (d, J = 15.5 Hz, 1 H) 6.31-6.74 (m, 2 H) 3.90-4.26 (m, 4 H) 3.81 (d, J = 13.05 Hz, 2 H) 1.79-1.91 (m, 2 H) 1.62-1.71 (m, 2 H) 1.06 (t, J = 7.4 Hz, 3 H) 0.87 (t, J = 7.4 Hz, 3 H) 53 WX053 1H NMR (400 MHz, CDCl3) δ: 10.35 (s, 1H), 7.96 (d, 651.0 J = 16 Hz, 1H), 7.82(d, J = 8.0 Hz, 2H), 7.53-7.27(m, 7H), 652.0 6.96(d, J = 8.4 Hz, 3H), 6.48(s, 1H), 4.24-3.55(m, 13H), 1.40(d, J = 7.6 Hz, 2H), 0.96-0.86(m, 6H). 54 WX054 1H NMR (400 MHz, CDCl3) δ: 9.84 (br s, 1H), 8.00 (d, 670.0 J = 15.6 Hz, 1H), 7.82 (br d, J = 8.3 Hz, 2H), 7.68 (s, 671.0 1H), 7.53 (dd, J = 1.9, 8.4 Hz, 1H), 7.48 (s, 1H), 7.43 (br d, J = 8.5 Hz, 2H), 7.37-7.28 (m, 3H), 7.00 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 15.8 Hz, 1H), 4.21-4.11 (m, 3H), 4.00-3.90 (m, 3H), 3.86-3.80 (m, 2H), 3.57 (t, J = 6.8 Hz, 2H), 1.65 (br d, J = 2.8 Hz, 2H), 1.53 (s, 3H), 1.46- 1.35 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H) 55 WX055 1H NMR (400 MHz, CDCl3) δ: 10.03 (br s, 1H), 7.99 (br 670.0 d, J = 15.6 Hz, 1H), 7.82 (br d, J = 8.3 Hz, 3H), 7.67 (s, 671.0 1H), 7.53 (br d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.42 (br d, J = 8.5 Hz, 3H), 6.99 (br d, J = 8.5 Hz, 3H), 6.85 (br d, J = 15.8 Hz, 1H), 4.21-4.14 (m, 3H), 3.99-3.90 (m, 3H), 3.83 (br t, J = 4.6 Hz, 2H), 3.57 (br t, J = 6.7 Hz, 2H), 1.64 (br d, J = 6.8 Hz, 2H), 1.52 (s, 3H), 1.45-1.35 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H) 56 WX056 1H NMR (400 MHz, CDCl3) δ: 8.38 (br s, 1H), 8.06 (br 599.0 d, J = 15.8 Hz, 1H), 7.92 (br s, 2H), 7.76 (br d, J = 7.8 Hz, 600.0 2H), 7.67 (br s, 1H), 7.54 (br d, J = 8.5 Hz, 1H), 7.47 (br d, J = 8.3 Hz, 2H), 7.35 (br d, J = 7.5 Hz, 2H), 7.11 (br s, 1H), 7.00 (br d, J = 8.3 Hz, 4H), 6.78 (br d, J = 15.8 Hz, 1H), 4.21-4.08 (m, 4H), 3.94 (s, 3H), 3.89-3.78 (m, 2H), 3.87-3.77 (m, 1H), 3.57 (t, J = 6.7 Hz, 3H), 2.26 (br s, 4H), 1.62 (td, J = 6.9, 14.5 Hz, 6H), 1.46-1.36 (m, 6H) 57 WX057 1H NMR (400 MHz, CDCl3) δ: 8.07-7.92 (m, 2H), 4.20- 675.9 4.17 (m, 2H), 3.98-3.92 (m, 2H), 3.84 (br t, J = 3.9 Hz, 676.0 2H), 3.58 (dt, J = 1.6, 6.7 Hz, 2H), 2.96-2.86 (m, 1H), 1.64 (br d, J = 7.0 Hz, 2H), 1.52 (s, 3H), 1.47-1.40 (m, 2H), 1.40-1.36 (m, 3H), 1.30 (dd, J = 2.8, 7.0 Hz, 4H), 1.27 (br s, 2H), 1.13 (dd, J = 1.9, 6.7 Hz, 3H), 0.99-0.91 (m, 3H) 58 WX058 1H NMR (400 MHz, CDCl3) δ: 9.41 (br s, 1H), 8.22 (d, 659.9 J = 15.6 Hz, 1H), 7.61 (br d, J = 8.8 Hz, 1H), 7.49 (br d, 662.0 J = 1.3 Hz, 1H), 7.36-7.27 (m, 3H), 7.11-7.07 (m, 1H), 6.77 (br d, J = 8.5 Hz, 1H), 6.52 (d, J = 15.6 Hz, 1H), 6.33 (s, 1H), 3.96 (t, J = 4.8 Hz, 1H), 3.93-3.75 (m, 1H), 3.62 (t, J = 4.6 Hz, 1H), 3.58-3.52 (m, 1H), 3.36 (t, J = 6.7 Hz, 1H), 3.19-3.10 (m, 1H), 1.53-1.45 (m, 1H), 1.45-1.39 (m, 1H), 1.25-1.17 (m, 1H), 1.08 (d, J = 6.8 Hz, 1H), 0.77-0.69 (m, 4H), 0.70-0.63 (m, 1H) 59 WX059 1H NMR (400 MHz, CDCl3) δ: 0.93 (dt, J = 16.00, 7.43 599.8. Hz, 6 H) 1.41 (dq, J = 14.90, 7.41 Hz, 2 H) 1.62-1.67 600.8 (m, 2 H) 1.73 (sxt, J = 7.33 Hz, 2 H) 2.42 (s, 3 H) 3.57 (t, J = 6.78 Hz, 2 H) 3.75-3.89 (m, 4 H) 4.01 (d, J = 14.05 Hz, 1 H) 4.12-4.22 (m, 3 H) 6.56 (s, 1 H) 6.68 (d, J = 15.56 Hz, 1 H) 7.00 (d, J = 8.78 Hz, 2 H) 7.32-7.39 (m, 3 H) 7.46-7.54 (m, 4 H) 7.76-7.85 (m, 3 H) 8.64 (s, 1 H) 60 WX060 1H NMR (400 MHz, CDCl3) δ: 10.70 (s, 1H), 8.16-8.08 654.0, (m, 1H), 7.83-7.75 (m, J = 8.5 Hz, 2H), 7.72-7.65 (m, 655.0 2H), 7.55 (br d, J = 8.0 Hz, 1H), 7.49-7.39 (m, 3H), 7.26- 7.18 (m, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 15.6 Hz, 1H), 6.44 (s, 1H), 4.23-4.17 (m, 1H), 4.17-4.10 (m, 2H), 3.93-3.84 (m, 1H), 3.82 (t, J = 4.8 Hz, 2H), 3.80-3.69 (m, 2H), 3.56 (t, J = 6.8 Hz, 2H), 1.71-1.57 (m, 4H), 1.45-1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H) 61 WX061 1H NMR (400 MHz, CDCl3) δ: 10.58 (br s, 1 H) 7.88 (d, 652.0 J = 15.8 Hz, 1 H) 7.75 (d, J = 8.5 Hz, 2 H) 7.53 (d, J = 2.2 653.0 Hz, 1 H) 7.36-7.43 (m, 2 H) 7.30 (d, J = 8.5 Hz, 2 H) 654.0 7.16 (d, J = 8.7 Hz, 2 H) 7.09 (d, J = 8.5 Hz, 1 H) 6.88 (d, J = 8.5 Hz, 2 H) 6.83 (d, J = 15.8 Hz, 1 H) 6.19-6.64 (m, 1 H) 3.79-4.15 (m, 6 H) 3.69-3.78 (m, 2 H) 3.49 (t, J = 6.6 Hz, 2 H) 1.49-1.60 (m, 2 H) 1.40 (s, 3 H) 1.31- 1.36 (m, 2 H) 1.28 (t, J = 7.2 Hz, 3 H) 0.86 (t, J = 7.4 Hz, 3 H) 62 WX062 1H NMR (400 MHz, CDCl3) δ: 10.49 (br s, 1 H) 7.89 (d, 594.0 J = 15.8 Hz, 1 H) 7.76 (d, J = 8.2 Hz, 2 H) 7.54 (d, J = 1.7 595.0 Hz, 1 H) 7.37-7.44 (m, 2 H) 7.32 (d, J = 8.5 Hz, 2 H) 7.16 596.0 (d, J = 8.5 Hz, 2 H) 7.10 (d, J = 8.53 Hz, 1 H) 6.87 (b d, J = 8.53 Hz, 2 H) 6.83 (d, J = 15.8 Hz, 1 H) 6.22-6.64 (m, 1 H) 3.78-4.15 (m, 6 H) 1.70-1.78 (m, 2 H) 1.40 (s, 3 H) 1.29 (t, J = 7.2 Hz, 3 H) 0.99 (t, J = 7.4 Hz, 3 H) 63 WX063 1H NMR (400 MHz, CDCl3) δ: 10.43 (br s, 1 H) 7.89 (d, 594.0 J = 15.81 Hz, 1 H) 7.76 (br d, J = 8.53 Hz, 2 H) 7.54 (d, 595.0 J = 2.01 Hz, 1 H) 7.38-7.45 (m, 2 H) 7.32 (d, J = 8.53 Hz, 596.0 2 H) 7.17 (d, J = 8.78 Hz, 2 H) 7.10 (d, J = 8.53 Hz, 1 H) 6.87 (d, J = 8.53 Hz, 2 H) 6.82 (d, J = 15.81 Hz, 1 H) 6.23- 6.66 (m, 1 H) 3.80-4.14 (m, 6 H) 1.77-1.83 (m, 2 H) 1.40 (s, 3 H) 1.29 (t, J = 7.40 Hz, 3 H) 0.99 (t, J = 7.40 Hz, 3 H) 64 WX064 1H NMR (400 MHz, CDCl3) δ: 10.14 (br s, 1 H) 7.97 (d, 638.0 J = 15.8 Hz, 1 H) 7.80 (d, J = 8.5 Hz, 2 H) 7.64 (d, J = 2.0 639.0 Hz, 1 H) 7.45-7.53 (m, 2 H) 7.40 (d, J = 8.5 Hz, 2 H) 640.0 7.26 (d, J = 3.5 Hz, 1 H) 7.18 (d, J = 8.5 Hz, 1 H) 6.96 (d, J = 8.7 Hz, 2 H) 6.90 (d, J = 15.8 Hz, 1 H) 6.29-6.76 (m, 2 H) 3.70-4.24 (m, 8 H) 3.52 (t, J = 6.7 Hz, 2 H) 1.56- 1.75 (m, 4 H) 0.95 (t, J = 7.4 Hz, 3 H) 0.86 (t, J = 7.4 Hz, 3 H) 65 WX065 1H NMR (400 MHz, CDCl3) δ: 9.98 (br s, 1H), 8.05 (d, 602.1, J = 15.8 Hz, 1H), 7.83 (br d, J = 8.5 Hz, 2H), 7.57 (d, J = 1.5 603.0, Hz, 1H), 7.50-7.45 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 604.0 7.27-7.23 (m, 2H), 6.98-6.93 (m, 3H), 6.90 (d, J = 12.0 Hz, 1H), 4.18-4.11 (m, 3H), 3.97-3.88 (m, 3H), 3.84- 3.79 (m, 5H), 3.52 (t, J = 6.8 Hz, 2H), 1.70-1.62 (m, 2H), 1.55 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H) 66 WX066 1H NMR (400 MHz, CDCl3) δ: 9.83 (br s, 1H), 9.81- 602.1, 9.72 (m, 1H), 8.05 (d, J = 15.6 Hz, 1H), 7.83 (br d, J = 8.3 603.0, Hz, 2H), 7.58 (d, J = 1.8 Hz, 1H), 7.50-7.45 (m, 2H), 604.0 7.40 (br d, J = 8.5 Hz, 2H), 7.30-7.25 (m, 2H), 6.99- 6.86 (m, 4H), 4.18-4.15 (m, 2H), 4.14-3.93 (m, 2H), 3.93-3.88 (m, 2H), 3.84 (s, 3H), 3.83-3.79 (m, 2H), 3.52 (t, J = 6.8 Hz, 2H), 1.71-1.62 (m, 2H), 1.56 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H) 67 WX067 1H NMR (400 MHz, CDCl3) δ: 8.64 (br s, 1H), 8.13 (br 616.1, d, J = 15.6 Hz, 1H), 7.81 (br d, J = 8.0 Hz, 2H), 7.67 (s, 617.1, 1H), 7.54-7.49 (m, 2H), 7.46 (br d, J = 7.5 Hz, 2H), 7.34 618.1 (br d, J = 7.8 Hz, 2H), 7.02-6.95 (m, 3H), 6.83 (br d, J = 15.1 Hz, 1H), 6.59 (s, 1H), 4.18 (br s, 2H), 4.17-4.15 (m, 2H), 4.14-3.99 (m, 2H), 3.84 (br s, 2H), 3.79 (br t, J = 7.2 Hz, 2H), 3.54 (br t, J = 6.5 Hz, 2H), 1.76-1.70 (m, 2H), 1.67 (br d, J = 7.5 Hz, 2H), 1.49 (br t, J = 6.8 Hz, 3H), 0.97 (br t, J = 7.4 Hz, 3H), 0.90 (br t, J = 7.2 Hz, 3H) 68 WX068 1H NMR (400 MHz, CDCl3) δ: 9.22 (br s, 1H), 8.03 (d, 630.1 J = 15.6 Hz, 1H), 7.74 (br d, J = 8.5 Hz, 2H), 7.54 (s, 1H), 631.1 7.43-7.32 (m, 4H), 7.21 (s, 1H), 6.94-6.82 (m, 3H), 6.76 (d, J = 15.6 Hz, 1H), 4.11-4.06 (m, 2H), 4.06-4.02 (m, 2H), 4.11-3.89 (m, 1H), 3.84-3.77 (m, 1H), 3.81 (q, J = 7.0 Hz, 1H), 3.74 (br t, J = 4.8 Hz, 2H), 3.49 (t, J = 6.8 Hz, 2H), 1.61-1.55 (m, 4H), 1.53 (s, 3H), 1.36 (br t, J = 7.0 Hz, 4H), 1.32-1.27 (m, 1H), 1.33-1.26 (m, 3H), 0.90-0.83 (m, 1H), 0.87 (t, J = 7.3 Hz, 2H) 69 WX069 1H NMR (400 MHz, CDCl3) δ: 8.54 (br s, 1H), 8.11 (d, 630.1, J = 15.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 2.3 631.1, Hz, 1H), 7.49 (dd, J = 2.3, 8.5 Hz, 1H), 7.44 (d, J = 8.8 Hz, 632.1, 2H), 7.41 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 6.79 (d, J = 15.8 Hz, 1H), 4.19- 4.16 (m, 2H), 4.15-4.11 (m, 2H), 4.10-4.01 (m, 2H), 3.84-3.80 (m, 2H), 3.77 (t, J = 7.3 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 1.76-1.65 (m, 4H), 1.63 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H) 70 WX070 1H NMR (400 MHz, CDCl3) δ: 11.10 (br s, 1H), 8.17- 654.0 8.09 (m, 1H), 7.82 (br d, J = 8.0 Hz, 2H), 7.68 (d, J = 7.5 655.0 Hz, 1H), 7.67-7.65 (m, 1H), 7.56 (br d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 15.6 Hz, 1H), 4.23-4.11 (m, 3H), 3.98-3.79 (m, 5H), 3.57 (t, J = 6.8 Hz, 2H), 1.67-1.58 (m, 2H), 1.47-1.31 (m, 8H), 0.94 (t, J = 7.3 Hz, 3H) 71 WX071 1H NMR (400 MHz, CDCl3) δ: 11.15 (br s, 1H), 8.13 (br 654.0 d, J = 15.1 Hz, 1H), 7.82 (br d, J = 8.5 Hz, 2H), 7.72-7.60 655.0 (m, 2H), 7.55 (br d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.44- 7.36 (m, J = 8.5 Hz, 2H), 7.24-7.17 (m, J = 8.5 Hz, 2H), 6.96 (br d, J = 8.5 Hz, 2H), 6.83 (br d, J = 15.6 Hz, 1H), 4.27-4.08 (m, 3H), 3.94 (q, J = 7.0 Hz, 2H), 3.89-3.78 (m, 3H), 3.57 (br t, J = 6.5 Hz, 2H), 1.62 (quin, J = 7.0 Hz, 2H), 1.48-1.29 (m, 8H), 0.94 (t, J = 7.3 Hz, 3H) 72 WX072 1H NMR (400 MHz, CDCl3) δ: 8.36 (br s, 1H), 8.28 (d, 654.1 J = 15.1 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 655.0 1.8 Hz, 1H), 7.53 (dd, J = 1.9, 8.2 Hz, 1H), 7.51-7.45 (m, 3H), 7.40 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.05-6.96 (m, 2H), 6.56 (d, J = 15.3 Hz, 1H), 4.21- 4.16 (m, 2H), 4.13-3.99 (m, 2H), 3.93-3.85 (m, 2H), 3.85-3.81 (m, 2H), 3.57 (t, J = 6.8 Hz, 2H), 3.42 (td, J = 8.7, 17.3 Hz, 1H), 2.14-2.04 (m, 2H), 1.90-1.80 (m, 2H), 1.79-1.71 (m, 2H), 1.67-1.61 (m, 3H), 1.45-1.37 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H) 73 WX073 1H NMR (400 MHz, CDCl3) δ: 8.29 (d, J = 15.3 Hz, 654.1 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 1.8 Hz, 1H), 655.0 7.56-7.52 (m, 1H), 7.51-7.45 (m, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 15.1 Hz, 1H), 4.21-4.15 (m, 2H), 4.13- 4.00 (m, 2H), 3.88 (q, J = 7.0 Hz, 2H), 3.85-3.81 (m, 2H), 3.57 (t, J = 6.8 Hz, 2H), 3.47-3.38 (m, 1H), 2.14- 2.04 (m, 2H), 1.91-1.81 (m, 2H), 1.80-1.69 (m, 2H), 1.67-1.61 (m, 6H), 1.44-1.36 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H) 74 WX074 1H NMR (400 MHz, CDCl3) δ: 10.80 (br s, 1 H) 7.95 (d, 638.0 J = 15.8 Hz, 1 H) 7.83 (d, J = 8.5 Hz, 2 H) 7.59 (d, J = 2.0 639.0 Hz, 1 H) 7.43-7.49 (m, 2 H) 7.37 (d, J = 8.5 Hz, 2 H) 640.0 7.23 (d, J = 8.5 Hz, 2 H) 7.16 (d, J = 8.2 Hz, 1 H) 6.96 (d, J = 8.7 Hz, 2 H) 6.91 (d, J = 15.8 Hz, 1 H) 6.29-6.71 (m, 1 H) 3.86-4.23 (m, 6 H) 3.78-3.85 (m, 2 H) 3.52 (t, J = 6.7 Hz, 2 H) 1.58-1.73 (m, 2 H) 1.45 (s, 3 H) 1.36 (s, 3 H) 0.95 (t, J = 7.4 Hz, 3 H) 75 WX075 1H NMR (400 MHz, CDCl3) δ: 0.82 (t, J = 7.40 Hz, 3 H) 629.8, 0.87 (t, J = 7.40 Hz, 3 H) 1.33 (dq, J = 15.09, 7.43 Hz, 2 630.1 H) 1.53 (s, 3 H) 1.59 (br s, 3 H) 1.61-1.69 (m, 2 H) 3.49 (t, J = 6.65 Hz, 2 H) 3.68-3.77 (m, 4 H) 3.80 (s, 3 H) 3.91-4.06 (m, 2 H) 4.07-4.11 (m, 2 H) 6.78 (d, J = 15.81 Hz, 1 H) 6.89-6.92 (m, 2 H) 7.18-7.24 (m, 3 H) 7.33- 7.37 (m, 3 H) 7.43 (dd, J = 8.53, 2.26 Hz, 1 H) 7.54 (d, J = 2.01 Hz, 1 H) 7.73 (d, J = 8.53 Hz, 2 H) 7.98 (d, J = 15.56 Hz, 1 H) 9.07 (br s, 1 H) 76 WX076 1H NMR (400 MHz, CDCl3) δ: 0.82 (t, J = 7.40 Hz, 3 H) 629.8, 0.87 (t, J = 7.40 Hz, 3 H) 1.33 (dq, J = 15.09, 7.43 Hz, 2 630.1 H) 1.53 (s, 3 H) 1.59 (br s, 3 H) 1.61-1.69 (m, 2 H) 3.49 (t, J = 6.65 Hz, 2 H) 3.68-3.77 (m, 4 H) 3.80 (s, 3 H) 3.91-4.06 (m, 2H) 4.07-4.11 (m, 2 H) 6.78 (d, J = 15.81 Hz, 1 H) 6.89-6.92 (m, 2 H) 7.18-7.24 (m, 3 H) 7.33- 7.37 (m, 3 H) 7.43 (dd, J = 8.53, 2.26 Hz, 1 H) 7.54 (d, J = 2.01 Hz, 1 H) 7.73 (d, J = 8.53 Hz, 2 H) 7.98 (d, J = 15.56 Hz, 1 H) 9.07 (br s, 1 H) 78 WX078 1H NMR (400 MHz, CDCl3) δ: 8.58 (d, J = 15.6 Hz, 1H), 692.0 8.07 (d, J = 8.3 Hz, 1H), 7.86-7.73 (m, 3H), 7.70 (d, 693.0 J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 7.32 (br d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 15.3 Hz, 1H), 6.52 (s, 1H), 4.24-3.95 (m, 4H), 3.87- 3.77 (m, 5H), 3.58 (t, J = 6.7 Hz, 2H), 3.36-3.24 (m, 1H), 1.80-1.69 (m, 3H), 1.67-1.62 (m, 2H), 1.46-1.38 (m, 2H), 1.33 (d, J = 6.8 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H) 79 WX079 1H NMR (400 MHz, CDCl3) δ: 0.96 (br s, 4 H) 1.22- 615.8, 1.48 (m, 2 H) 1.58 (br s, 6 H) 2.33 (br s, 2 H) 3.45-3.74 616.8 (m, 1 H) 3.74-4.00 (m, 9 H) 4.16 (br s, 2 H) 6.97 (br s, 4 H) 7.35-7.45 (m, 2 H) 7.49 (br s, 2 H) 7.59 (br s, 1 H) 7.74-7.96 (m, 2 H) 8.07 (br s, 1 H) 10.11 (br s, 1 H) 9.82-10.38 (m, 1 H) 80 WX080 1H NMR (400 MHz, CDCl3) δ: 10.42 (br s, 1 H) 7.89 (d, 652.1 J = 15.5 Hz, 1 H) 7.75 (d, J = 8.5 Hz, 2 H)) 7.53 (d, J = 2.01 653.0 Hz, 1 H) 7.36 (s, 1 H) 7.31 (d, J = 8.5 Hz, 2 H) 7.16 (d, 654.0 J = 8.5 Hz, 2 H) 7.10 (d, J = 8.5 Hz, 1 H) 6.89 (d, J = 8.5 Hz, 2 H) 6.83 (d, J = 15.5 Hz, 1 H) 6.20-6.68 (m, 1 H) 3.72-4.12 (m, 8 H) 3.45 (t, J = 6.7 Hz, 2 H) 1.51-1.68 (m, 4 H) 1.41 (s, 3 H) 0.88 (t, J = 7.2 Hz, 3 H) 0.79 (t, J = 7.2 Hz, 3 H) 81 WX081 1H NMR (400 MHz, CDCl3) δ: 10.25 (br s, 1 H) 7.90 (d, 666.0 J = 15.5 Hz, 1 H) 7.75 (d, J = 8.5 Hz, 2 H) 7.55 (s, 1 H) 667.1 7.41 (d, J = 8.5 Hz, 1 H) 7.37 (s, 1 H) 7.32 (d, J = 8.5 Hz, 668.2 2 H) 7.16 (d, J = 8.5 Hz, 2 H) 7.11 (d, J = 8.5 Hz, 1 H) 6.89 (d, J = 8.5 Hz, 2 H) 6.83 (d, J = 15.5 Hz, 1 H) 6.20-6.67 (m, 1 H) 3.67-4.15 (m, 8 H) 3.49 (t, J = 6.7 Hz, 2 H) 1.59- 1.68 (m, 2 H) 1.49-1.58 (m, 2 H) 1.42 (s, 3 H) 1.25- 1.38 (m, 2 H) 0.86 (t, J = 7.2 Hz, 3 H) 0.80 (t, J = 7.5 Hz, 3 H) 82 WX082 1H NMR (400 MHz, CDCl3) δ: 9.78 (br s, J = 17.5 Hz, 1 666.0 H) 7.91 (d, J = 15.5 Hz, 1 H) 7.74 (d, J = 8.5 Hz, 2 H) 7.58 667.1 (d, J = 2.0 Hz, 1 H) 7.42 (dd, J = 8.5, 2.0 Hz, 1 H) 7.36 (s, 668.2 1 H) 7.34 (d, J = 8.5 Hz, 2 H) 7.17 (s, 1 H) 7.13 (s, 2 H) 6.90 (d, J = 8.5 Hz, 2 H) 6.80 (d, J = 16.0 Hz, 1 H) 6.46 (s, 1 H) 3.83-4.19 (m, 4 H) 3.65-3.81 (m, 4 H) 3.44-3.53 (m, 2 H) 1.62-1.68 (m, 5 H) 1.52-1.58 (m, 2 H) 1.33 (d, J = 15.06, 7.5 Hz, 2 H) 0.85-0.91 (m, 3 H) 0.78-0.84 (m, 3 H) 83 WX083 1H NMR (400 MHz, CDCl3) δ: 10.18 (br s, 1H), 8.15 668.0 (dd, J = 2.0, 15.3 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.75- 690.0 7.68 (m, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.48-7.42 (m, 3H), 7.29-7.22 (m, 3H), 7.00 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 15.3 Hz, 1H), 4.22-3.94 (m, 1H), 3.86-3.82 (m, 1H), 3.90-3.76 (m, 1H), 3.58 (t, J = 6.8 Hz, 2H), 1.67- 1.59 (m, 4H), 1.50 (s, 3H), 1.46-1.37 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H) 84 WX084 1H NMR (400 MHz, CDCl3) δ: 10.29 (br s, 1H), 7.99 (br 668.0 d, J = 13.8 Hz, 1H), 7.65 (br d, J = 8.3 Hz, 2H), 7.57-7.51 690.0 (m, 2H), 7.42 (br d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.14- 7.05 (m, 3H), 6.83 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 15.3 Hz, 1H), 4.02 (t, J = 4.6 Hz, 1H), 4.05-3.90 (m, 1H), 3.78-3.71 (m, 1H), 3.78-3.71 (m, 1H), 3.68 (br t, J = 4.8 Hz, 1H), 3.70-3.66 (m, 1H), 3.42 (t, J = 6.8 Hz, 2H), 1.56-1.50 (m, 2H), 1.50-1.44 (m, 3H), 1.32 (s, 3H), 1.28-1.22 (m, 2H), 0.82-0.75 (m, 4H), 0.69 (t, J = 7.4 Hz, 3H) 85 WX085 1H NMR (400 MHz, CDCl3) δ: 0.69-0.95 (m, 7 H) 1.32 615.8, (br d, J = 6.53 Hz, 2 H) 1.45-1.68 (m, 4 H) 3.48 (br s, 2 616.1 H) 3.62-3.80 (m, 8 H) 3.92 (br d, J = 13.55 Hz, 1 H) 4.06 (br s, 4 H) 6.48 (br s, 1 H) 7.15-7.57 (m, 8 H) 7.74 (br d, J = 7.03 Hz, 2 H) 7.98 (br d, J = 15.56 Hz, 1 H) 9.59 (br s, 1 H) 86 WX086 1H NMR (400 MHz, CDCl3) δ: 8.35 (d, J = 5.0 Hz, 1H), 613.0, 8.02 (d, J = 16.1 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 9.0 Hz, 614.0 2H), 7.77 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 2.0, 8.5 Hz, 615.0 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 15.6 Hz, 1H), 4.43-4.24 (m, 2H), 4.19-4.11 (m, 2H), 3.97 (s, 3H), 3.82-3.78 (m, 2H), 3.57 (s, 2H), 2.73-2.55 (m, 2H), 1.64-1.55 (m, 2H), 1.48-1.38 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H) 87 WX087 1H NMR (400 MHz, CDCl3)δ: 8.41 (br d, J = 4.5 Hz, 627.2, 1H), 8.06 (d, J = 15.6 Hz, 1H), 7.94 (br d, J = 10.3 Hz, 2H), 628.2 7.76 (br d, J = 8.5 Hz, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.53 629.2 (dd, J = 2.0, 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.36 (br d, J = 8.3 Hz, 2H), 7.12 (br d, J = 4.5 Hz, 1H), 6.99 (dd, J = 2.9, 8.7 Hz, 3H), 6.78 (d, J = 15.6 Hz, 1H), 4.23-4.14 (m, 3H), 4.10-4.04 (m, 1H), 3.93 (s, 3H), 3.82 (t, J = 4.8 Hz, 2H), 3.57 (t, J = 6.7 Hz, 2H), 2.61-2.53 (m, 2H), 1.64-1.58 (m, 4H), 1.44-1.37 (m, 2H), 1.01-0.96 (m, 2H), 0.96-0.91 (m, 3H) 88 WX088 .sup.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.04-7.95 634.1 (m, 1H), 8.00 (d, J = 15.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.44 (s, 1H), 7.42 (s, 2H), 7.33-7.29 (m, 3H), 7.00 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 16.4 Hz, 1H), 4.20-4.14 (m, 2H), 4.12 (s, 1H), 4.01 (s, 1H), 3.98 (s, 3H), 3.92 (q, J = 7.4 Hz, 2H), 3.85-3.81 (m, 2H), 3.57 (t, J = 6.6 Hz, 2H), 1.67-1.62 (m, 2H), 1.60 (br s, 4H), 1.46-1.37 (m, 5H), 0.98-0.92 (m, 1H), 0.95 (t, J = 7.4 Hz, 2H) 89 WX089 1H NMR (400 MHz, DMSO-d6) δ = 10.56 (s, 1H), 7.92- 648.1 7.78 (m, 3H), 7.75-7.58 (m, 5H), 7.44 (br d, J = 8.5 Hz, 2H), 7.13-6.98 (m, 3H), 4.33 (br d, J = 14.3 Hz, 1H), 4.23-4.07 (m, 5H), 3.91 (br d, J = 6.8 Hz, 2H), 3.80- 3.63 (m, 2H), 3.50-3.43 (m, 2H), 1.63 (s, 3H), 1.51 (quin, J = 6.9 Hz, 2H), 1.41-1.26 (m, 8H), 0.89 (t, J = 7.4 Hz, 3H) 90 WX090 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.89 (t, J = 7.40 630.1 Hz, 3 H) 1.23-1.30 (m, 3 H) 1.30-1.39 (m, 2 H) 1.47- 1.55 (m, 2 H) 1.60 (s, 3 H) 2.34 (s, 3 H) 3.46 (t, J = 6.65 Hz, 2 H) 3.70-3.73 (m, 2 H) 3.74 (s, 3 H) 3.82-3.92 (m, 2 H) 4.13 (t, J = 4.64 Hz, 2 H) 4.17 (s, 1 H) 4.24- 4.30 (m, 1 H) 6.97-7.04 (m, 2 H) 7.05 (s, 1 H) 7.42 (d, J = 8.78 Hz, 2 H) 7.56 (s, 2 H) 7.61 (d, J = 8.78 Hz, 2 H) 7.70 (d, J = 1.76 Hz, 1 H) 7.80 (s, 1 H) 7.83-7.88 (m, 2 H) 10.51 (s, 1 H) 91 WX091 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ = 10.59 (s, 1H), 7.95 604.1 (br d, J = 5.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.75-7.69 (m, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.39-7.35 (m, 1H), 7.10-7.02 (m, 3H), 4.31-4.23 (m, 1H), 4.18-4.10 (m, 3H), 3.97-3.79 (m, 2H), 3.75-3.68 (m, 2H), 3.46 (t, J = 6.4 Hz, 2H), 1.60 (s, 3H), 1.55-1.46 (m, 2H), 1.38-1.30 (m, 2H), 1.30-1.25 (m, 3H), 0.88 (t, J = 7.4 Hz, 3H) 92 WX092 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ = 10.49 (s, 1H), 7.85 (d, 600.1 J = 8.5 Hz, 2H), 7.72-7.62 (m, 4H), 7.56 (s, 1H), 7.51 (s, 1H), 7.46-7.37 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 15.6 Hz, 1H), 4.32-4.22 (m, 1H), 4.20-4.10 (m, 3H), 3.93-3.82 (m, 2H), 3.78-3.68 (m, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H), 1.61 (s, 3H), 1.56-1.46 (m, 2H), 1.40-1.24 (m, 5H), 0.89 (t, J = 7.3 Hz, 3H)

Experimental Example 1: CCR2/CCR5 In Vitro Test

(163) Experimental Purpose:

(164) The intracellular calcium signal was detected by FLIPR, and the IC.sub.50 value of the compound was used as an index to evaluate the inhibitory effect of the compound on CCR2 and CCR5 receptors.

(165) Experimental Materials:

(166) 1. Cell line: The cells were inoculated and incubated in a 5% CO.sub.2 incubator at 37° C. overnight.

(167) CCR2/CCR5 density: 1 M (20 k/well)

(168) TABLE-US-00016 Target Clone# Passage# Host CCR2 C7 P6 HEK293 CCR5 C13 P4 HEK293

(169) 2. Reagents: Fluo-4 Direct, (Invitrogen, Cat #F10471)

(170) 3. Equipment and Devices:

(171) 384 well Poly-D-Lysine protein coating plate, Greiner #781946

(172) 384 compound plate, Greiner #781280

(173) FLIPR, Molecular Device

(174) ECHO, Labcyte

(175) 4. Compounds:

(176) The compound was dissolved in DMSO to prepare a 10 mM solution, and the compound solution was placed in a nitrogen box.

(177) TABLE-US-00017 Compound_ID Purity Amount_In_mg Cenicriviroc 97.00 1.15

(178) Agonist reference compounds:

(179) TABLE-US-00018 MCP-1 Sigma SRP3109 10 uM stock in H.sub.2O RANTES Sigma SRP3269 10 uM stock in H.sub.2O

(180) Experimental Procedures and Methods:

(181) Preparation of probenecid in FLIPR assay buffer: 1 mL of FLIPR assay buffer was added to 77 mg of probenecid to prepare a 250 mM solution, which is prepared fresh daily.

(182) 2× (8 μM) Fluo-4 Direct™ Loading Buffer (per 10 mL) Thaw a bottle of Fluo-4 Direct™ crystal (F10471). Add 10 mL of FLIPR assay buffer to the vial. Add 0.2 mL of probenecid to each 10 mL of Fluo-Direct. The final concentration of the assay was 2.5 mM. Rotate it and place for >5 minutes (in absence of light). Prepare fresh daily.

(183) Experimental Procedures:

(184) (a) Prepare agonist compound:

(185) MCP-1 was diluted in FLIPR assay buffer 1:2 into 10 points, starting at 0.5 uM (final 100 nM). RANTES was diluted in FLIPR assay buffer 1:3 into 10 points, starting at 0.5 uM (final 100 nM). 20 uL of serially diluted compound buffer was added to each well of the DRC plate according to the compound plate map.

(186) (b) Prepare antagonist compound: antagonist reference compound

(187) Standard compound was diluted in DMSO 1:3 into 11 points, starting at 1 mM. Test compound was diluted in DMSO 1:3 into 11 points, starting at 2 mM. 250 nL of compound solution was transferred into a cell plate using Echo (Greiner #781946).

(188) (c) Take the cell plate out of the incubator, and gently dispense 20 uL of 2× Fluo-4 Direct wash-free loading buffer into a 384-well cell culture plate using a pipette. The final cell plate is 40 μL in volume.

(189) (d) Incubate for 50 minutes at 37° C. under 5% CO.sub.2, and for 10 minutes at room temperature.

(190) (e) Take the cell plate out of the incubator, and place it in FLIPR. Place the composite plate and the tip box in FLIPR.

(191) (f) For DRC plate: 1) Run the program on FLIPRTETRA. 2) Read the fluorescent signal. 3) Transfer 10 μL of compound from the DRC plate to the cell plate. 4) Read the fluorescent signal. 5) Calculate the “maximum−minimum” from Read 90 to the maximum allowed. Use FLIPR to calculate the EC80 value of each cell line. 6) Prepare 5×EC.sub.80 concentration of the agonist reference compound.

(192) (g) For the composite plate (1-add): 1) Run the program on FLIPRTETRA. 2) Transfer 10 μl, of 5×EC80 concentration of the agonist reference compound from the composite plate to the cell plate. 3) Read the fluorescent signal. 4) Calculate the “maximum−minimum” from Read 90 to the maximum allowed.

(193) (h) Analyze the data using Prism, and calculate the IC.sub.50 value of the compound.

(194) The experimental results are shown in Table 1:

(195) TABLE-US-00019 TABLE 1 IC.sub.50 (nM) test results detected by FLIPR Compound CCR2 CCR5 WX001 29.9 9.3 WX002 318.6 113.2 WX003 21.6 3.0 WX004 152.8 7.1 WX005 12.1 3.4 WX006 32.1 3.3 WX007 65.2 6.4 WX008 17.3 1.5 WX009 63.2 9.4 WX010 214.2 17.2 WX011 61.0 2.6 WX012 51.0 5.4 WX013 983.7 14.2 WX014 257.8 7.9 WX015 62.0 65.1 WX016 75.1 4.5 WX017 13.0 7.9 WX018 43.5 7.3 WX019 9.3 50.9 WX020 68.1 8.2 WX021 64.5 8.8 WX022 204.9 10.1 WX023 37.1 53.3 WX024 63.1 1.3 WX025 127.0 7.4 WX026 175.4 3.2 WX027 207.2 13.6 WX028 86.4 15.5 WX029 167.5 34.2 WX030 300.3 15.9 WX031 237.3 95.9 WX032 28.6 8.1 WX033 56.3 11.8 WX034 30.0 10.0 WX035 214.6 16.1 WX036 64.9 13.3 WX037 62.2 44.2 WX038 42.5 12.5 WX039 70.1 760.0 WX040 11.3 10.5 WX041 22.5 21.4 WX042 52.8 4.0 WX043 249.6 9.1 WX044 293.2 16.1 WX045 77.6 14.8 WX046 1.1 2.8 WX047 8.2 6.7 WX048 11.8 2.6 WX049 13.3 9.2 WX050 12.6 20.8 WX051 5.5 1.4 WX052 80.8 11.9 WX053 5.9 1.3 WX054 43.4 9.2 WX055 7.6 6.4 WX056 71.1 16.6 WX057 24.7 3.5 WX058 28.2 5.7 WX059 9.9 8.5 WX060 18.5 4.1 WX061 8.9 15.2 WX062 84.5 20.5 WX063 9.4 1.4 WX064 12.8 6.1 WX065 49.6 68.0 WX066 6.5 10.1 WX067 16.8 0.9 WX068 36.0 18.4 WX069 35.3 1.0 WX070 39.2 8.4 WX071 4.5 3.4 WX072 11.9 5.9 WX073 11.9 6.5 WX074 5.4 3.5 WX075 17.3 2.4 WX076 42.2 8.5 WX078 25.4 1.3 WX079 5.6 5.8 WX080 25.1 15.1 WX081 12.5 5.5 WX082 53.4 11.4 WX083 28.9 2.1 WX084 51.2 4.6 WX085 5.2 5.6 WX086 13.0 1.8 WX087 66.0 2.1 WX088 3.5 4.3 WX089 15.0 ND WX090 5.5 6.9 WX091 4.7 4.4 WX092 3.9 10.1

(196) Conclusion: The compounds of the present invention have significant antagonism to CCR2 and CCR5 receptors.

Experimental Example 2: Comparative Pharmacokinetics Study in Rats

(197) SD male rats were used as the test animals in this study. The drug concentrations in plasma of the rats by intravenous or oral administration of test compounds WX017, WX047, WX079, WX088 and reference compound at different time points were quantitatively determined by LC/MS/MS, which were used to evaluate the pharmacokinetic profile of the two test drugs in rats.

(198) A clear solution of the test compound was injected into SD rats via the tail vein (overnight fasting, 7-10 weeks old), and the test compound was orally administered to the SD rats (overnight fasting, 7-10 weeks old). Approximately 200 μL of blood was collected from the jugular vein or tail vein of the animals 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, and was placed in an anticoagulant tube containing EDTA-K2. The plasma was collected by centrifugation at 3000 g for 15 minutes at 4° C. The plasma concentration was determined by LC-MS/MS. The pharmacokinetic parameters were calculated by the non-compartment model linear logarithmic trapezoidal method using WinNonlin™ Version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software.

(199) Table 2 shows the pharmacokinetic parameters of the test compounds WX017, WX047, WX079 and the reference compound in rats.

(200) TABLE-US-00020 TABLE 2 Pharmacokinetic parameters in rats Intravenous injection (2 mg/kg) Oral (10 mg/kg) Area Area Under a Under a Plasma Half- Curve Peak Peak Curve clearance life (0-inf, concentrationn time (0-inf/0-last, (mL/min/kg) (h) nM .Math. h) (M) (h) nM .Math. h) Bioavailability Reference 1.57 5.48 31344 3323 4.0 31956 20.4% Compound (Cenicriviroc) WX017 0.4 3.69 135732 30750 1.5 331778 48.9% WX047 0.520 3.06 101904 20750 5.0 204785 40.4% WX079 0.224 9.47 255072 27300 3.0 404142 32.6% WX088 0.328 6.63 150423 12185 3.0 122101 15.7%

(201) The experimental results showed that the plasma clearance of WX017, WX047, WX079 and WX088 was lower than that of the reference compound, which was 25%, 33%, 14% and 21% of the reference compound, respectively; the oral plasma system of exposure (AUC.sub.0-inf) of WX017, WX047, WX079 and WX088 was 10.4, 6.4, 12.6 and 3.8 times, as that of the reference compound, respectively. Therefore, in rodent rats, the pharmacokinetics of WX017, WX047, WX079 and WX088 are significantly better than that of the reference compound.

Experimental Example 3: Comparative Pharmacokinetics Study in Cynomolgus Monkeys

(202) Male cynomolgus monkeys were used as the test animals in this study. The drug concentrations in plasma of the cynomolgus monkeys by intravenous or oral administration of test compound WX047 and reference compound at different time points were quantitatively determined by LC/MS/MS, which were used to evaluate the pharmacokinetic profile of the two test drugs in cynomolgus monkeys.

(203) A clear solution of the test compound was injected into cynomolgus monkeys via t the cephalic or saphenous vein (overnight fasting, 2.5-7 kg), and the test compound was intragastrically administered to the cynomolgus monkeys (overnight fasting, 7-10 weeks old). Approximately 400 μL of blood was collected from the peripheral vein of the animals 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after administration, and transferred into an commercial centrifuge tube containing EDTA-K2*2H.sub.2O anticoagulation. The plasma was collected by centrifugation at 3000 g for 10 minutes at 4° C. The plasma concentration was determined by LC-MS/MS. The pharmacokinetic parameters were calculated by the non-compartment model linear logarithmic trapezoidal method using WinNonlin™ Version 6.3 (Pharsight, Mountain View, Calif.) pharmacokinetic software.

(204) Table 3 shows the pharmacokinetic parameters of the test compound WX047 and the reference compound in cynomolgus monkeys.

(205) TABLE-US-00021 TABLE 3 Pharmacokinetic parameters in rats Intravenous injection (1 mg/kg) Oral (3 mg/kg) Area Area Under a Under a Plasma Half- Curve Peak Peak Curve clearance life (0-inf, concentrationn time (0-inf/0-last, (mL/min/kg) (h) nM .Math. h) (M) (h) nM .Math. h) Bioavailability Reference 8.74 5.37 2766 99.6 2.0 424 5.11 Compound (Cenicriviroc) WX047 9.11 1.66 3149 1080 2.0 3678 38.9

(206) The experimental results showed that the bioavailability of WX047 was 7.6 times as that of the reference compound; the oral plasma system of exposure (AUC.sub.0-inf) of WX047 was 10.8 times as that of the reference compound. Therefore, the pharmacokinetic of WX047 in cynomolgus monkeys are significantly better than that of the reference compound.

Experimental Example 4 Inhibition Effect on the Activity of Human Liver Microsomal Cytochrome P450 Isoezymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4)

(207) A total of 5 specific probe substrates for CYP's five isozymes, Phenacetin (CYP1A2), Diclofenac (CYP2C9), (S)-Mexantine (S)-Mephenytoin, CYP2C19), Dextromethorphan (CYP2D6) and Midazolam (CYP3A4) were incubated with human liver microsomes and test compounds, respectively, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the sample was processed and liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to quantitatively detect the eight metabolites produced by the specific substrate, Acetaminophen and 4′-hydroxydiclofenac, 4′-hydroxymephenytoin, Dextrorphan and 1′-hydroxymidazolam, in order to calculate the corresponding half maximal inhibitory concentration (IC.sub.50).

(208) TABLE-US-00022 TABLE 4 IC.sub.50 (μM) Compound ID CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4-M Reference Compound >50 >50 >50 >50 5.6 (Cenicriviroc) WX047 >50 >50 >50 >50 >50 WX079 >50 >50 >50 >50 28.3

(209) Experimental Conclusion: The reference compound has a weak inhibitory effect on CYP3A4, while WX047 and WX079 have no risk on inhibiting five isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450, which are better than the reference compound.