PYRROLIDINE DERIVATIVES AS PPAR AGONISTS

Abstract

The present invention discloses a class of pyrrolidine derivatives as PPAR agonist, and their use for the treatment of some diseases of PPAR receptor-associated pathways (such as nonalcoholic steatohepatitis and concurrent fibrosis, insulin resistance, primary biliary cholgangitis, dyslipidenmia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity or the like). In particular, the present invention discloses a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A compound of Formula (I), ##STR00193## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from H, NH.sub.2, or from C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.3-6 cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl each of which is optionally substituted with 1, 2, or 3 R; R.sub.2, R.sub.3 are independently selected from H, halogen, OH, NH.sub.2, or from C.sub.1-3 alkyl optionally substituted with 1, 2, or 3 R; X is selected from NH, O, S; when X is selected from O or S, R.sub.4 is selected from H or from C.sub.1-6 alkyl optionally substituted with 1, 2, or 3 R; when X is selected from NH, R.sub.4 is selected from H, C.sub.1-6 alkyl, or from C.sub.1-6 alkyl-S(O).sub.2, C.sub.1-6 alkyl-S(O).sub.2OH optionally substituted with 1, 2, or 3 R; or, a structural unit R.sub.4X is selected from: ##STR00194## ##STR00195## R.sub.5 is selected from H, halogen, OH, NH.sub.2, CN, COOH, or from C.sub.1-6 alkyl, C.sub.1-6 alkyl-S(O), C.sub.1-6 alkyl-S(O).sub.2, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio each of which is optionally substituted with 1, 2, or 3 R; n is selected from 0, 1, 2 or 3; a ring A is selected from phenyl, naphthyl, 5-6-membered heteroaryl; L.sub.1 is selected from a single bond, C(O), O, NH, C(O)O, C(O)NH, S(O).sub.2, S(O), (CRR).sub.1-3; L.sub.2 is selected from a single bond, (CRR).sub.1-3, C(O), O, S, NH, C(O)O, C(O)NH, S(O).sub.2, S(O); L.sub.3 is selected from (CRR), C(O); L.sub.4 is selected from a single bond, (CRR).sub.1-3; R is selected from H, F, Cl, Br, I, OH, CN, NH.sub.2, COOH, C(O)NH.sub.2, or from C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl each of which is optionally substituted with 1, 2, or 3 R; R is selected from F, Cl, Br, I, OH, CN, NH.sub.2, COOH, Me, Et, CF.sub.3, CHF.sub.2, CH.sub.2F, NHCH.sub.3, N(CH.sub.3).sub.2; hetero- refers to a heteroatom or a heteroatomic group, and is selected from C(O)NH, NH, C(NH), S(O).sub.2 NH, S(O) NH, O, S, O, S, ON, C(O)O, C(O), C(S), S(O), S(O).sub.2 and NHC(O)NH; in any one of the cases defined above, the number of the heteroatoms or heteroatomic groups is independently selected from 1, 2 or 3.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from H, F, Cl, Br, I, OH, CN, NH.sub.2, COOH, C(O)NH.sub.2, or from C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-3 alkylamino, N,N-di(C.sub.1-3 alkyl)amino each of which is optionally substituted with 1, 2, or 3 R.

3. (canceled)

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1 is selected from H, NH.sub.2, or from C.sub.1-6 alkyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrazolyl, pyridyl, cyclohexyl each of which is optionally substituted with 1, 2, or 3 R.

5. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein R.sub.1 is selected from H, NH.sub.2, or from Me, Et, ##STR00196## each of which is optionally substituted with 1, 2, or 3 R.

6. (canceled)

7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.2, R.sub.3 are independently selected from H, F, Cl, Br, I, OH, NH.sub.2, or from Me, Et each of which is optionally substituted with 1, 2, or 3 R.

8. (canceled)

9. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein when X is selected from O or S, R.sub.4 is selected from H, or from Me, Et, ##STR00197## each of which is optionally substituted with 1, 2, or 3 R.

10. (canceled)

11. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein when X is selected from NH, R.sub.4 is selected from H, C.sub.1-4 alkyl, or from C.sub.1-4 alkyl-S(O).sub.2, C.sub.1-3 alkyl-S(O).sub.2OH each of which is optionally substituted with 1, 2, or 3 R.

12. (canceled)

13. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.5 is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, COOH, or from Me, Et, ##STR00198## each of which is optionally substituted with 1, 2, or 3 R.

14.-16. (canceled)

17. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit ##STR00199## is selected from: ##STR00200##

18. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the ring A is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl.

19. (canceled)

20. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit ##STR00201## is selected from ##STR00202##

21. (canceled)

22. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L.sub.3 is selected from CH.sub.2, C(O).

23. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein a structural unit-L.sub.1-L.sub.2- is selected from: a single bond, CH.sub.2, C(O), S(O).sub.2, C(O)O, C(O)NH, C(O)CH.sub.2, C(O)OCH.sub.2, CH.sub.2CH.sub.2O.

24. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L.sub.4 is selected from a single bond, CH.sub.2, CH.sub.2CH.sub.2.

25. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is selected from: ##STR00203## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, L.sub.1, L.sub.2, L.sub.3, L.sub.4 are as defined in claim 1.

26. The compound according to claim 1, which is selected from: ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220##

27. The compound according to claim 26, which is selected from: ##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252## ##STR00253##

28. A pharmaceutical composition comprising therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, as well as a pharmaceutically acceptable carrier.

29. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for treating a PPAR receptor-associated disorders.

30. The use according to claim 29, wherein the disorder is selected from nonalcoholic steatohepatitis and concurrent fibrosis, insulin resistance, primary biliary cholgangitis, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

Example 1: Compound 1

[0125] ##STR00098##

Step 1: Compound 1-c

[0126] A solution of Compound 1-a (5.00 g, 30.08 mmol, 1.00 eq) and Compound 1-b (4.52 g, 30.08 mmol, 1.00 eq) in HCl/MeOH (4 N, 40.01 mL, 5.32 eq) was stirred at 20 C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was washed with dichloromethane/MeOH solution (1:1, 50 mL) to give Compound 1-c.

[0127] MS m/z (ESI): 298.9 [M+1].

Step 2: Compound 1-e

[0128] A solution of Compound 1-c (2.00 g, 6.70 mmol, 1.00 eq), Compound 1-d (2.99 g, 13.40 mmol, 2.49 mL, 2.00 eq), potassium carbonate (1.85 g, 13.40 mmol, 2.00 eq) and potassium iodide (111.26 mg, 670.00 mol, 0.10 eq) in dimethylsulfoxide (30.00 mL) was stirred under nitrogen protection at 90 C. for 12 h. Water (30 mL) was added into the reaction mixture, and extracted with ethyl acetate (30 mL3). The combined organic phase was washed with water (20 mL2) and saturated brine (20 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate=3/1) to give Compound 1-e.

[0129] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.98-7.94 (m, 2H), 7.71 (d, J=15.8 Hz, 1H), 7.42 (d, J=15.8 Hz, 1H), 7.34-7.29 (m, 2H), 7.28 (s, 2H), 2.55 (s, 3H), 2.28 (s, 6H), 1.52 (s, 9H), 1.46 (s, 6H).

Step 3: Compound 1-f

[0130] A solution of Compound 1-e (300.00 mg, 680.91 mol, 1.00 eq), 2-(methylamino)acetic acid (151.65 mg, 1.70 mmol, 2.50 eq) and paraformaldehyde (368.02 mg, 4.09 mmol, 6.00 eq) in toluene (10.00 mL) was stirred under nitrogen protection at 110 C. for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 1-f.

[0131] MS m/z (ESI): 498.3 [M+1].

[0132] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 6.86 (s, 2H), 3.93-3.85 (m, 1H), 3.66 (q, J=7.0 Hz, 1H), 3.03 (t, J=8.7 Hz, 2H), 2.97-2.91 (m, 1H), 2.80-2.73 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.18 (s, 6H), 1.51 (s, 9H), 1.41 (s, 6H).

Step 4: Compound 1

[0133] Under nitrogen protection, a solution of Compound 1-f (100.00 mg, 200.93 mol, 1.00 eq) in dichloromethane (5.00 mL) was added dropwise with trifluoroacetic acid (1.50 mL) at 0 C. The mixture was stirred at 20 C. for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL). The organic phase was washed with water (10 mL2) and saturated brine (10 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:2) to give Compound 1.

[0134] MS m/z (ESI): 442.1 [M+1].

[0135] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.74 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 6.91 (s, 2H), 4.02 (td, J=6.7, 9.0 Hz, 1H), 3.63 (q, J=7.4 Hz, 1H), 3.07 (t, J=9.3 Hz, 1H), 2.99 (t, J=8.4 Hz, 1H), 2.77 (dd, J=6.0, 9.3 Hz, 1H), 2.60 (t, J=8.3 Hz, 1H), 2.51 (br. s., 3H), 2.31 (s, 3H), 2.12 (s, 6H), 1.34 (s, 6H).

Example 2: Compound 2

[0136] ##STR00099##

Step 1: Compound 2-b

[0137] Under nitrogen protection, a solution of Compounds 1-e (200.00 mg, 453.94 mol, 1.00 eq) and 2-a (129.32 mg, 544.73 mol, 1.20 eq) in toluene (3.00 mL) was added dropwise with trifluoroacetic acid (50.00 L) at 0 C. The mixture was stirred at 20 C. for 1 h. The mixture was adjusted with a saturated solution of sodium bicarbonate to pH-7. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give Compound 2-b.

[0138] MS m/z (ESI): 574.3 [M+1].

[0139] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.67 (d, J=8.5 Hz, 2H), 7.40-7.36 (m, 2H), 7.32 (t, J=7.3 Hz, 2H), 7.26-7.22 (m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.88 (s, 2H), 3.93-3.85 (m, 1H), 3.75-3.62 (m, 3H), 3.11 (t, J=8.9 Hz, 1H), 3.01 (t, J=8.7 Hz, 1H), 2.89 (dd, J=6.9, 9.2 Hz, 1H), 2.82 (dd, J=6.3, 9.3 Hz, 1H), 2.48 (s, 3H), 2.18 (s, 6H), 1.50 (s, 9H), 1.41 (s, 6H).

Step 2: Compound 2

[0140] A HCl/ethyl acetate solution (4 N, 217.85 L, 5.00 eq) was added into a solution of Compound 2-b (100.00 mg, 174.28 mol, 1.00 eq) in ethyl acetate (2.00 mL) at 20 C. The mixture was stirred at 20 C. for 8 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative High Performance Liquid Chromatography to give Compound 2.

[0141] MS m/z (ESI): 518.3 [M+1].

[0142] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.62-7.55 (m, 4H), 7.53-7.47 (m, 3H), 7.14 (d, J=8.5 Hz, 2H), 6.94 (s, 2H), 4.49 (s, 2H), 4.46-4.40 (m, 1H), 3.90-3.81 (m, 1H), 3.79-3.71 (m, 2H), 3.61-3.50 (m, 2H), 2.49 (s, 3H), 2.19 (s, 6H), 1.42 (s, 6H).

Example 3: Compound 3

[0143] ##STR00100##

Step 1

Compound 3-a

[0144] A solution of Compound 2-b (1.00 g, 1.74 mmol, 1.00 eq) and 1-chloroethyl methylclhlorofonmate (746.30 mg, 5.22 mmol, 3.00 eq) in 1,2-dichloroethane (10.00 mL) was stirred at 80 C. for 8 h. The mixture was concentrated under reduced pressure. Then, methanol (10.00 mL) was added into the residue, heated to 80 C., and stirred for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give Compound 3-a.

[0145] MS m/z (ESI): 442.1 [M+1].

[0146] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.57 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.91 (s, 2H), 4.22 (q, J=8.2 Hz, 1H), 3.94-3.74 (m, 6H), 3.71-3.52 (m, 2H), 2.47 (s, 3H), 2.11 (s, 6H), 1.40 (d, J=4.8 Hz, 6H).

Step 2: Compound 3

[0147] A sodium hydroxide solution (2 N, 339.69 L, 3.00 eq) was added into a solution of Compound 3-a (100.00 mg, 226.46 mol, 1.00 eq) in ethanol (3.00 mL) at 20 C. The mixture was stirred at 20 C. for 1 h. The mixture was neutralized with a HCl solution (1 N) to pH-7, and then concentrated under reduced pressure. Methanol (20 mL) was added into the residue. The mixture was stirred at 20 C. for 10 min and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 3.

[0148] MS m/z (ESI): 428.2 [M+1].

[0149] .sup.1H NMR (400 MHz, MeOD-d.sub.4) S ppm 7.64 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 6.93 (s, 2H), 4.40 (q, J=7.8 Hz, 1H), 3.87-3.68 (m, 3H), 3.53-3.43 (m, 2H), 2.51 (s, 3H), 2.20 (s, 6H), 1.39 (s, 6H).

Examples 4 and 5: Compounds 4 and 5

[0150] ##STR00101## ##STR00102##

Step 1: Compound 4-a

[0151] Under nitrogen protection, methyl chloroformate (12.35 mg, 130.71 mol, 1.50 eq) was added into a solution of Compound 2-b (50.00 mg, 87.14 mol, 1.00 eq) in 1,2-dichloroethane (10.00 mL) at 20 C. The mixture was stirred at 80 C. for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give Compound 4-a.

[0152] MS m/z (ESI): 564.3 [M+23].

[0153] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.70 (t, J=8.9 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 6.81 (s, 2H), 4.07-3.82 (m, 3H), 3.76-3.50 (m, 6H), 2.50 (s, 3H), 2.16 (s, 6H), 1.49 (s, 9H), 1.39-1.35 (m, 6H).

Step 2: Compound 4-b

[0154] Trifluoroacetic acid (500.00 L) was added into a solution of Compound 4-a (100.00 mg, 184.60 mol, 1.00 eq) in dichloromethane (2.00 mL) at 20 C. The mixture was stirred at 20 C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give Compound 4-b.

[0155] MS m/z (ESI): 486.2 [M+1].

[0156] .sup.1H NMR (400 MHz, MeOD-d.sub.4) S ppm 7.76 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 6.93 (s, 2H), 4.39-4.28 (m, 1H), 3.96-3.86 (m, 2H), 3.74 (s, 3H), 3.66 (dd, J=8.9, 10.7 Hz, 1H), 3.60-3.52 (m, 2H), 2.52 (s, 3H), 2.16 (s, 6H), 1.38 (s, 6H).

Step 3: Compounds 4 and 5

[0157] Compound 4-b (35 mg) was subjected to chiral separation to give Compound 4; Compound 5.

[0158] Compound 4:

[0159] MS m/z (ESI): 508.1 [M+23].

[0160] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (br. s., 2H), 7.12 (d, J=8.03 Hz, 2H), 6.78 (s, 2H), 3.96-3.84 (m, 3H), 3.66 (s, 3H), 3.60-3.48 (m, 3H), 2.42 (s, 3H), 2.08 (br. s., 6H), 1.33 (br. s., 6H).

[0161] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2.

[0162] Retention time of Compound 4: 4.766 min (peak 1).

[0163] Compound 5:

[0164] MS m/z (ESI): 508.1 [M+23].

[0165] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (br. s., 2H), 7.11 (br. s., 2H), 6.78 (br. s., 2H), 3.93-3.84 (m, 3H), 3.65-3.55 (m, 6H), 2.42 (br. s., 3H), 2.08 (br. s., 6H), 1.34 (br. s., 6H).

[0166] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2.

[0167] Retention time of Compound 5: 5.434 min (peak 2).

Example 6: Compound 6

[0168] ##STR00103##

Step 1: Compound 6-a

[0169] Ethyl chloroformate (378.26 mg, 3.49 mmol, 331.81 L, 2.00 eq) was slowly added into a solution of Compound 2-b (1.00 g, 1.74 mmol, 1.00 eq) in dichloromethane (10.00 mL). The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give Compound 6-a.

[0170] MS m/z (ESI): 578.2 [M+23].

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.70 (t, J=8.41 Hz, 2H), 7.17 (d, J=8.03 Hz, 2H), 6.81 (s, 2H), 4.16-4.10 (m, 2H), 3.99-3.91 (m, 3H), 3.66-3.53 (m, 3H), 2.49 (s, 3H), 2.15 (br. s., 6H), 1.48 (s, 9H), 1.36 (br. s., 6H), 1.27-1.24 (m, 3H).

Step 2: Compound 6-b

[0172] Trifluoroacetic acid (923.40 mg, 8.10 mmol, 599.61 L, 11.54 eq) was slowly added into a solution of Compound 6-a (390.00 mg, 701.78 mol, 1.00 eq) in dichloromethane (10.00 mL). The mixture was stirred at 20 C. for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative High Performance Liquid Chromatography to give Compound 6-b.

[0173] MS m/z (ESI): 500.2 [M+1].

[0174] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.76-7.72 (m, 2H), 7.20 (d, J=8.28 Hz, 2H), 6.88 (s, 2H), 4.17 (q, J=7.03 Hz, 2H), 4.01-3.92 (m, 3H), 3.61-3.53 (m, 1H), 2.50 (s, 3H), 2.18 (br. s., 6H), 1.46 (s, 6H), 1.27 (t, J=7.03 Hz, 3H).

Step 3: Compound 6

[0175] Compound 6-b (100 mg) was subjected to chiral separation to give Compound 6 (24.30 mg, yield: 24.30%).

[0176] MS m/z (ESI): 522.1 [M+23].

[0177] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.72 (t, J=8.16 Hz, 2H), 7.19 (d, J=8.03 Hz, 2H), 6.86 (br. s., 2H), 4.17 (q, J=7.03 Hz, 2H), 4.01-3.91 (m, 3H), 3.62-3.53 (m, 3H), 2.50 (s, 3H), 2.16 (br. s., 6H), 1.45 (br. s., 6H), 1.27 (t, J=7.03 Hz, 3H).

[0178] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2.

[0179] Retention time of Compound 6: 5.198 min (peak 2).

Example 7: Compound 7

[0180] ##STR00104##

Step 1: Compound 7-a

[0181] Under nitrogen protection, isopropyl chloroformate (426.47 mg, 3.48 mmol, 484.63 L, 2.00 eq) was added into a solution of Compound 2-b (1.00 g, 1.74 mmol, 1.00 eq) in dichloromethane (10.00 mL) at 20 C. The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (30.6%, ethyl acetate/petroleum ether) to give Compound 7-a.

[0182] MS m/z (ESI): 592.2 [M+23].

[0183] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.73-7.68 (m, 2H), 7.18 (d, J=8.28 Hz, 2H), 6.81 (s, 2H), 4.95 (dt, J=12.30, 6.15 Hz, 1H), 4.05-3.88 (m, 3H), 3.71-3.51 (m, 3H), 2.50 (s, 3H), 2.15 (br. s., 6H), 1.48 (s, 9H), 1.37 (d, J=2.76 Hz, 6H), 1.28-1.26 (m, 6H).

Step 2: Compound 7-b

[0184] Trifluoroacetic acid (3.09 g, 27.09 mmol, 2.01 mL, 19.29 eq) was added into a solution of Compound 7-a (800.00 mg, 1.40 mmol, 1.00 eq) in dichloromethane (10.00 mL). The mixture was stirred at 25 C. for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 7-b.

[0185] MS m/z (ESI): 514.2 [M+1].

[0186] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.76-7.74 (m, 2H), 7.20 (d, J=8.28 Hz, 2H), 6.88 (s, 2H), 4.97-4.94 (m, 1H), 4.02-3.90 (m, 1H), 3.58-3.55 (m, 1H), 2.50 (s, 3H), 2.17 (br. s., 6H), 1.46 (s, 6H), 1.25 (br. s., 6H).

Step 3: Compound 7

[0187] Compound 7-b (100 mg) was subjected to chiral separation to give Compound 7.

[0188] MS m/z (ESI): 536.1 [M+23].

[0189] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.74 (t, J=9.29 Hz, 2H), 7.21 (d, J=8.28 Hz, 2H), 6.88 (br. s., 2H), 4.97 (dt, J=12.30, 6.15 Hz, 1H), 4.07-3.92 (m, 3H), 3.64-3.53 (m, 3H), 2.52 (s, 3H), 2.18 (d, J=4.27 Hz, 6H), 1.47 (br. s., 6H), 1.27 (br. s., 6H).

[0190] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2.

[0191] Retention time of Compound 7: 4.639 min (peak 2).

Example 8: Compound 8

[0192] ##STR00105##

Step 1: Compound 8-b

[0193] A solution of Compound 1-c (7.00 g, 23.46 mmol, 1.00 eq), Compound 8-a (18.30 g, 93.84 mmol, 13.76 mL, 4.00 eq), potassium carbonate (9.73 g, 70.38 mmol, 3.00 eq) and potassium iodide (1.17 g, 7.04 mmol, 0.30 eq) in dimethylsulfoxide (30.00 mL) was stirred under nitrogen protection at 110 C. for 16 h. Ethyl acetate (70.00 mL) was added into the reaction mixture, and washed with water (400 mL3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to give Compound 8-b.

[0194] MS m/z (ESI): 413.1 [M+1].

[0195] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.95 (d, J=8.28 Hz, 2H), 7.71 (d, J=15.56 Hz, 1H), 7.42 (d, J=15.56 Hz, 1H), 7.31-7.28 (m, 4H), 4.30 (q, J=7.28 Hz, 2H), 2.54 (s, 3H), 2.25 (s, 6H), 1.50 (s, 6H), 1.36 (t, J=7.15 Hz, 3H).

Step 2: Compound 8-c

[0196] Under nitrogen protection, trifluoroacetic acid (1.53 g, 13.45 mmol, 0.73 eq) was added into a solution of Compound 8-b (7.60 g, 18.42 mmol, 1.00 eq) and N-methoxymethyl-1-phenyl-N-(trimethylsilylethyl)methylamine (5.25 g, 22.10 mmol, 1.20 eq) in dichloromethane (40.00 mL) at 0 C. The mixture was stirred at 25 C. for 16 h. The mixture was neutralized with a saturated solution of sodium bicarbonate to pH=7, and then treated with water and dichloromethane (1:1, 200 mL).

[0197] The aqueous phase was extracted with dichloromethane (200 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (23.1%, ethyl acetate/petroleum ether) to give Compound 8-c.

[0198] MS m/z (ESI): 546.6 [M+1].

[0199] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.67 (d, J=8.53 Hz, 2H), 7.39-7.37 (m, 2H), 7.32 (t, J=7.53 Hz, 2H), 7.30-7.24 (m, 1H), 7.14 (d, J=8.53 Hz, 2H), 6.88 (s, 2H), 4.28 (q, J=7.03 Hz, 2H), 3.90-3.88 (m, 1H), 3.71-3.65 (m, 3H), 3.11 (t, J=9.03 Hz, 1H), 3.02 (t, J=8.78 Hz, 1H), 2.90 (dd, J=9.03, 7.03 Hz, 1H), 2.82 (dd, J=9.29, 6.27 Hz, 1H), 2.48 (s, 3H), 2.15 (s, 6H), 1.45 (s, 6H), 1.35 (t, J=7.03 Hz, 3H).

Step 3: Compound 8-d

[0200] Compound 8-c (1.00 g, 1.83 mmol, 1.00 eq), 1,2-dichloroethane (2.00 mL) and benzyl chloroformate (937.77 mg, 5.50 mmol, 781.48 L, 3.00 eq) was added into a dried flask. The mixture was stirred at 80 C. for 16 h, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (32.5%, ethyl acetate/petroleum ether) to give Compound 8-d.

[0201] MS m/z (ESI): 590.3 [M+1].

Step 4: Compound 8-e

[0202] Compound 8-d (680.00 mg, 1.15 mmol, 1.00 eq) and 1,4-dioxane (5.00 mL) was added into a dried flask. Then, lithium hydroxide (82.63 mg, 3.45 mmol, 3.00 eq) and water (1.00 mL) was added. The mixture was stirred at 25 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=3, and treated with water and ethyl acetate (1:1, 50 mL). The aqueous phase was extracted by ethyl acetate (20 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 8-e.

[0203] MS m/z (ESI): 562.2 [M+1].

[0204] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.75 (dd, J=15.18, 8.16 Hz, 2H), 7.40-7.35 (m, 5H), 7.21 (t, J=7.65 Hz, 2H), 6.89 (s, 2H), 5.19 (d, J=3.51 Hz, 2H), 4.06-3.98 (m, 2H), 3.75-3.61 (m, 2H), 2.52 (s, 3H), 2.19 (s, 6H), 1.48 (d, J=1.76 Hz, 6H).

Step 5: Compound 8

[0205] Compound 8-e (50 mg) was subjected to chiral separation to give Compound 8.

[0206] MS m/z (ESI): 584.1 [M+23].

[0207] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.72 (dd, J=15.56, 8.28 Hz, 2H), 7.37-7.33 (m, 5H), 7.19 (t, J=7.40 Hz, 2H), 6.86 (s, 2H), 5.17-5.13 (m, 2H), 4.04-3.95 (m, 3H), 3.76-3.59 (m, 3H), 2.50 (s, 3H), 2.16 (s, 6H), 1.45 (br. s., 6H).

[0208] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0209] Retention time of Compound 8: 4.956 min (peak 2).

Example 9: Compound 9

[0210] ##STR00106##

Step 1: Compound 9-a

[0211] Under nitrogen protection, phenyl chloroformate (294.47 mg, 1.88 mmol, 235.57 L, 2.00 eq) was slowly added into a solution of Compound 8-c (500.00 mg, 940.36 mol, 1.00 eq) in dichloromethane (10.00 mL). The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (40.6%, ethyl acetate/petroleum ether) to give Compound 9-a.

[0212] MS m/z (ESI): 576.2 [M+1].

Step 2: Compound 9

[0213] Compound 9-a (500.00 mg, 868.48 mol, 1.00 eq), ethanol (3.00 mL) and 1,4-dioxane (1.00 mL) was added into a flask. Then, lithium hydroxide (62.40 mg, 2.61 mmol, 3.00 eq) and H.sub.2O (1.00 mL) was added. The mixture was stirred at 40 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=2, and then treated with water/ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (50 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane), and the product was subjected to chiral separation to give Compound 9.

[0214] MS m/z (ESI): 570.1 [M+23].

[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.75 (t, J=7.78 Hz, 2H), 7.40-7.36 (m, 2H), 7.24-7.16 (m, 5H), 6.88 (d, J=6.78 Hz, 2H), 4.16-4.10 (m, 3H), 3.88-3.71 (m, 3H), 2.49 (br. s., 3H), 2.12 (br. s., 6H), 1.33 (br. s., 6H).

[0216] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0217] Retention time of Compound 9: 4.709 min (peak 2).

Example 10: Compound 10

[0218] ##STR00107##

Step 1: Compound 10-a

[0219] 1-chloroethyl chloroformate (3.93 g, 27.48 mmol, 3.00 eq) was added into a solution of Compound 8-c (5.00 g, 9.16 mmol, 1.00 eq) in toluene (50.00 mL) at 25 C. The mixture was stirred at 80 C. for 16 h. Then, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (50.00 mL). The solution was stirred at 80 C. for 1 h. The mixture was directly concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-85:15) to give Compound 10-a.

[0220] MS m/z (ESI): 456.3 [M+1].

[0221] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.59 (d, J=8.53 Hz, 2H), 7.12 (d, J=8.53 Hz, 2H), 6.93 (s, 2H), 4.32-4.26 (m, 2H), 4.23-4.21 (m, 1H), 3.91-3.65 (m, 5H), 2.50 (s, 3H), 2.15 (s, 6H), 1.42 (d, J=5.52 Hz, 6H), 1.36 (t, J=7.03 Hz, 3H).

Step 2: Compound 10-b

[0222] Isopropyl chloroformate (140.32 mg, 1.32 mmol, 137.57 L, 1.50 eq) and triethylamine (177.68 mg, 1.76 mmol, 243.39 L, 2.00 eq) was added into a solution of Compound 10-a (400.00 mg, 877.94 mol, 1.00 eq) in dichloromethane (10.00 mL) at 0 C. The mixture was stirred at 20 C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-80:20) to give Compound 10-b.

[0223] MS m/z (ESI): 526.2 [M+1].

[0224] 1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (d, J=8.53 Hz, 1H), 7.58 (d, J=8.53 Hz, 1H), 7.11 (dd, J=8.53, 17.57 Hz, 2H), 6.75 (d, J=9.54 Hz, 2H), 4.11-3.41 (m, 7H), 2.66-2.47 (m, 2H), 2.43 (d, J=1.51 Hz, 3H), 2.06 (d, J=12.05 Hz, 6H), 1.38-1.30 (m, 6H), 1.27 (t, J=7.28 Hz, 3H), 1.15-1.05 (m, 11H).

Step 3: Compound 10-c

[0225] Lithium hydroxide (13.67 mg, 570.67 mol, 3.00 eq) was added into a solution of Compound 10-b (100.00 mg, 190.22 mol, 1.00 eq) in ethanol (5.00 mL) and water (5.00 mL) at 0 C. The mixture was stirred at 20 C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-80:20) to give Compound 10-c.

[0226] MS m/z (ESI): 498.1 [M+1].

Step 4: Compound 10

[0227] The compound was isolated by chiral supercritical chromatography to give Compound 10.

[0228] MS m/z (ESI): 498.2 [M+1].

[0229] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.77 (d, J=8.28 Hz, 1H), 7.68 (d, J=8.53 Hz, 1H), 7.20 (dd, J=8.53, 17.57 Hz, 2H), 6.86 (d, J=12.30 Hz, 2H), 4.18-3.85 (m, 4H), 3.67-3.62 (m, 2H), 2.69 (qd, J=6.55, 12.99 Hz, 1H), 2.51 (d, J=2.01 Hz, 3H), 2.17 (d, J=13.80 Hz, 6H), 1.46-1.43 (m, 6H), 1.18 (dd, J=6.78, 10.04 Hz, 6H).

[0230] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0231] Retention time of Compound 10: 4.188 min (peak 2).

Example 11: Compound 11

[0232] ##STR00108##

Step 1: Compound 11-a

[0233] Compound 10-a (300.00 mg, 658.46 mol, 1.00 eq), triethylamine (199.89 mg, 1.98 mmol, 273.82 L, 3.00 eq) and dichloromethane (10.00 mL) was added into a dried round-bottom flask of 100 mL. Then, n-pentyl chloroformate (247.91 mg, 1.65 mmol, 2.50 eq) was added. The mixture was stirred at 15 C. for 2 h. The mixture was diluted with dichloromethane (20 mL), added with a saturated solution of sodium bicarbonate (10 mL), and then stirred for 10 min. The organic phase was washed with saturated brine (10 mL2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-3:1) to give Compound 11-a.

[0234] MS m/z (ESI): 592.1 [M+23].

[0235] 1H NMR (400 MHz, CDCl.sub.3) 7.63 (t, J=11.2 Hz, 2H), 7.10 (d, J=7.6 Hz, 2H), 6.75 (s, 2H), 4.08-3.44 (m, 10H), 2.43 (s, 3H), 2.06 (br s, 6H), 1.57 (t, J=6.8 Hz, 6H), 1.34-1.25 (m, 7H), 0.83 (t, J=6.4 Hz, 3H).

Step 2: Compound 11-b

[0236] Lithium hydroxide (73.65 mg, 1.76 mmol, 5.00 eq) was added into a solution of Compound 11-a (200.00 mg, 351.03 mol, 1.00 eq) in ethanol (2.00 mL), tetrahydrofuran (2.00 mL) and H.sub.2O (1.00 mL). The mixture was stirred at 50 C. for 3 h. The mixture was adjusted with a saturated potassium bisulfate solution to pH=2-3, and then added with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL2). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate=15:1) to give Compound 11-b.

[0237] MS m/z (ESI): 564.1 [M+23].

[0238] 1H NMR (400 MHz, CDCl.sub.3) 7.74 (t, J=8.8 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.87 (d, J=2.8 Hz, 2H), 4.13-3.14 (m, 8H), 2.51 (s, 3H), 2.18 (d, J=5.2 Hz, 6H), 2.02 (s, 4H), 1.67-1.64 (m, 2H), 1.35-1.27 (m, 6H), 0.92 (br.s., 3H).

Step 3: Compound 11

[0239] The compound was isolated by chiral supercritical chromatography to give Compound 11.

[0240] MS m/z (ESI): 536.1 [M+23].

[0241] 1H NMR (400 MHz, CDCl.sub.3) 7.65 (br s, 2H), 7.11 (br d, J=7.28 Hz, 2H), 6.78 (br s, 2H), 4.08-3.37 (m, 10H), 2.42 (s, 3H), 2.07 (br s, 6H), 1.56 (br d, J=7.04 Hz, 3H), 1.31 (br s, 4H), 0.94-0.67 (m, 6H).

[0242] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2.

[0243] Retention time of Compound 11: 5.294 min (peak 2).

Example 12: Compound 12

[0244] ##STR00109##

Step 1

Compound 12-a

[0245] (2-chlorophenyl) chloroformate (83.85 mg, 438.97 mol, 61.20 L, 2.00 eq) and triethylamine (44.42 mg, 438.97 mol, 60.85 L, 2.00 eq) was slowly added into a solution of Compound 10-a (100.00 mg, 219.49 mol, 1.00 eq) in dichloromethane (5.00 mL). The mixture was stirred at 25 C. for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (52.6%, ethyl acetate/petroleum ether) to give Compound 12-a.

[0246] MS m/z (ESI): 632.1 [M+23].

Step 2: Compound 12

[0247] Compound 12-a (180.00 mg, 295.00 mol, 1.00 eq) and ethanol (6.00 mL) was added into a flask. Then, lithium hydroxide (21.20 mg, 885.00 mol, 3.00 eq) and water (2.00 mL) were added. The mixture was stirred at 40 C. for 5 h. The mixture was adjusted with 1N diluted HCl to pH=3, and treated with water/ethyl acetate (1:1, 20 mL). The aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 12.

[0248] MS m/z (ESI): 604.1 [M+23].

[0249] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.69 (dd, J=8.53, 6.78 Hz, 2H), 7.36 (dd, J=8.03, 1.25 Hz, 1H), 7.20 (s, 2H), 7.16-7.13 (m, 3H), 6.86 (d, J=7.28 Hz, 2H), 4.15-4.03 (m, 3H), 3.79-3.65 (m, 3H), 2.44 (s, 3H), 2.12 (d, J=4.77 Hz, 6H), 1.40-1.39 (m, 6H).

Examples 13 and 14: Compounds 13 and 14

[0250] ##STR00110##

Step 1: Compound 13-a

[0251] Under nitrogen protection, a solution of triphosgene (97.70 mg, 329.23 mol, 1.00 eq) in tetrahydrofuran (3 mL) was added dropwise into a solution of 4-chlorophenol (42.33 mg, 329.23 mol, 32.31 L, 1.00 eq) in tetrahydrofuran (15.00 mL) 0 C., and then triethylamine (33.31 mg, 329.23 mol, 45.63 L, 1.00 eq) was slowly added into it. The mixture was stirred at 25 C. for 2 h. After the reaction finished, the mixture was filtered, and the filter cake was washed with tetrahydrofuran (5 mL2). Compound 10-a (150.00 mg, 329.23 mol, 1.00 eq) and triethylamine (33.31 mg, 329.23 mol, 45.63 L, 1.00 eq) was added into the filtrate at 25 C. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/petroleum ether=22.7%) to give Compound 13-a.

[0252] MS m/z (ESI): 610.1 [M+1].

Step 2: Compound 13-b

[0253] Lithium hydroxide (21.20 mg, 885.00 mol, 3.00 eq) and H.sub.2O (2.00 mL) was added into a solution of Compound 13-a (255.00 mg, 417.92 mol, 1.00 eq) in ethanol (6.00 mL). The mixture was stirred at 40 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=2, and treated with water/ethyl acetate (1:1, 20 mL). The aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 13-b.

[0254] MS m/z (ESI): 604.1 [M+23].

[0255] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.69 (dd, J=8.53, 6.78 Hz, 2H), 7.36 (dd, J=8.03, 1.25 Hz, 1H), 7.20 (s, 2H), 7.16-7.13 (m, 3H), 6.86 (d, J=7.28 Hz, 2H), 4.15-4.02 (m, 3H), 3.79-3.65 (m, 3H), 2.44 (s, 3H), 2.12 (d, J=4.77 Hz, 6H), 1.40-1.39 (m, 6H).

Step 3: Compounds 13 and 14

[0256] Compound 13-b (30.00 mg, 51.54 mol, 1.00 eq) was isolated and purified by chiral supercritical fluid chromatography to give Compound 13; Compound 14.

[0257] Compound 13:

[0258] MS m/z (ESI): 582.1 [M+1].

[0259] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.67 (t, J=8.66 Hz, 2H), 7.26-7.24 (m, 2H), 7.13 (dd, J=8.53, 4.02 Hz, 2H), 7.03 (d, J=7.94 Hz, 2H), 6.83 (d, J=6.27 Hz, 2H), 4.07-4.00 (m, 3H), 3.79-3.65 (m, 3H), 2.43 (s, 3H), 2.11 (d, J=5.77 Hz, 6H), 1.39 (br s, 6H).

[0260] Conditions of the chiral resolution: chiral column: Lux Cellulose-2 1504.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.5 mL/min; column temperature: 40 C.

[0261] Retention time of Compound 13: 5.715 min (peak 1).

[0262] Compound 14:

[0263] MS m/z (ESI): 582.1 [M+1].

[0264] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (t, J=8.41 Hz, 2H), 7.27-7.24 (m, 2H), 7.13 (dd, J=8.53, 4.02 Hz, 2H), 7.03 (d, J=7.94 Hz, 2H), 6.84 (d, J=6.27 Hz, 2H), 4.06-4.00 (m, 3H), 3.79-3.63 (m, 3H), 2.43 (s, 3H), 2.12 (d, J=5.52 Hz, 6H), 1.39-1.38 (m, 6H).

[0265] Conditions of the chiral resolution: chiral column: Lux Cellulose-2 1504.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.5 mL/min; column temperature: 40 C.

[0266] Retention time of Compound 14: 9.994 min (peak 2).

Example 15: Compound 15

[0267] ##STR00111##

Step 1: Compound 15-a

[0268] Compound 10-a (300.00 mg, 658.46 mol, 1.00 eq), di-iso-propyl ethylamine (170.20 mg, 1.32 mmol, 230.00 L, 2.00 eq) and trichloromethane (5.00 mL) was added into a 50 mL dried round-bottom flask at 20 C. Then, p-methoxy phenyl chloroformate (184.29 mg, 987.69 mol, 147.43 L, 1.50 eq) was added. The mixture was stirred at 20 C. for 2 h. A saturated solution of sodium bicarbonate (5 mL) was added into the mixture, and stirred for 10 min. The aqueous phase was extracted with dichloromethane (10 mL3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1 to 2:1) to give Compound 15-a.

[0269] MS m/z (ESI): 606.2 [M+23].

[0270] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (dd, J=10.4, 9.2 Hz, 2H), 7.12 (dd, J=8.8, 4.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.81-6.78 (m, 4H), 4.08-3.99 (m, 5H), 3.75-3.59 (m, 7H), 2.43 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.55 (b.r.s., 1H), 1.35-1.34 (m, 6H), 1.19 (t, J=6.8 Hz, 1H).

Step 2: Compound 15

[0271] Compound 15-a (150.00 mg, 247.63 mol, 1.00 eq), lithium hydroxide (59.31 mg, 2.48 mmol, 10.00 eq), ethanol (2.00 mL), tetrahydrofuran (2.00 mL) and water (1.00 mL) was added into a reaction flask. The mixture was stirred at 20 C. for 20 h. Lithium hydroxide (59.31 mg, 2.48 mmol, 10.00 eq) was added, and the mixture was stirred at 20 C. for 30 h. The mixture was diluted with water (5 mL), adjusted with a saturated potassium bisulfate solution to pH=2-3, and then added with ethyl acetate (10 mL3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate) to give Compound 15.

[0272] MS m/z (ESI): 578.2 [M+1].

[0273] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.64 (dd, J=8.4, 6.8 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.94 (dd, J=10.0, 8.0 Hz, 2H), 6.85-6.80 (m, 4H), 4.31-4.00 (m, 1H), 3.86-3.85 (m, 1H), 3.84-3.50 (m, 7H), 2.39 (s, 3H), 2.06 (b.r.s, 6H), 1.38-1.36 (m, 6H).

Examples 16 and 17: Compounds 16 and 17

[0274] ##STR00112##

Step 1: Compound 16-a

[0275] Benzoyl chloride (185.12 mg, 1.32 mmol, 152.99 L, 1.50 eq) and triethylamine (177.68 mg, 1.76 mmol, 243.39 L, 2.00 eq) was added into a solution of Compound 10-a (400.00 mg, 877.94 mol, 1.00 eq) in dichloromethane (10.00 mL) at 0 C. The mixture was stirred at 20 C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-80:20) to give Compound 16-a.

[0276] MS m/z (ESI): 560.1 [M+1].

[0277] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.71 (d, J=8.53 Hz, 1H), 7.58-7.28 (m, 7H), 7.17-6.99 (m, 2H), 6.82-6.68 (m, 2H), 4.19 (br d, J=7.28 Hz, 2H), 4.01-3.51 (m, 5H), 2.42 (d, J=18.57 Hz, 3H), 2.05 (s, 6H), 1.36-1.30 (m, 6H), 1.29-1.23 (m, 3H).

Step 2: Compound 16-b

[0278] Lithium hydroxide (213.95 mg, 8.93 mmol, 10.00 eq) was added into a solution of Compound 16-a (500.00 mg, 893.30 mol, 1.00 eq) in ethanol (10.00 mL) and H.sub.2O (5.00 mL) at 20 C. The mixture was stirred at 20 C. for 2 h. The mixture was extracted with dichloromethane (20 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-80:20) to give Compound 16-b.

[0279] MS m/z (ESI): 532.1 [M+1].

Step 3: Compounds 16 and 17

[0280] Compound 18-b (400 mg, 752.36 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 16; Compound 17.

[0281] Compound 16:

[0282] MS m/z (ESI): 532.5 [M+1].

[0283] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.80 (d, J=8.28 Hz, 1H), 7.62-7.55 (m, 3H), 7.44-7.41 (m, 3H), 7.23 (d, J=8.28 Hz, 1H), 7.11 (d, J=8.28 Hz, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 4.31 (dd, J=11.92, 8.91 Hz, 1H), 4.18-4.15 (m, 1H), 3.99-3.93 (m, 3H), 3.77-3.64 (m, 1H), 2.49 (d, J=19.32 Hz, 3H), 2.15 (s, 6H), 1.43 (br. s., 6H).

[0284] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0285] Retention time of Compound 16: 6.673 min (peak 2).

[0286] Compound 17:

[0287] MS m/z (ESI): 532.1 [M+1].

[0288] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.80 (d, J=8.28 Hz, 1H), 7.63-7.54 (m, 3H), 7.44-7.41 (m, 3H), 7.24 (d, J=8.28 Hz, 1H), 7.12 (d, J=8.53 Hz, 1H), 6.87 (d, J=28 Hz, 2H), 4.32-4.15 (m, 2H), 3.96-3.93 (m, 2H), 3.78-3.66 (m, 2H), 2.50 (d, J=19.58 Hz, 3H), 2.16 (s, 6H), 1.44 (br. s., 6H).

[0289] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0290] Retention time of Compound 17: 4.992 min (peak 1).

Example 18: Compound 18

[0291] ##STR00113##

Step 1: Compound 18-a

[0292] Mesyl chloride (201.14 mg, 1.76 mmol, 135.91 L, 2.00 eq) and triethylamine (177.68 mg, 1.76 mmol, 243.40 L, 2.00 eq) was added into a solution of Compound 10-a (400.00 mg, 877.94 mol, 1.00 eq) in dichloromethane (5.00 mL). The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (46.1%, ethyl acetate/petroleum ether) to give Compound 18-a.

[0293] MS m/z (ESI): 534.1 [M+1].

Step 2: Compound 18

[0294] Compound 18-a (110.00 mg, 206.11 mol, 1.00 eq) and dioxane (1.00 mL) was added into a round-bottom flask. Then, lithium hydroxide (14.81 mg, 618.33 mol, 3.00 eq) and water (1.00 mL) were added. The mixture was stirred at 40 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=3, and was added with water/ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography. The resulted product was subjected to chiral separation to give Compound 18.

[0295] MS m/z (ESI): 528.1 [M+23].

[0296] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.75 (d, J=8.53 Hz, 2H), 7.22 (d, J=8.28 Hz, 2H), 6.95 (s, 2H), 4.62-4.35 (m, 1H), 3.86-3.82 (m, 2H), 3.73-3.68 (m, 1H), 3.57-3.52 (m, 2H), 3.04 (s, 3H), 2.51 (s, 3H), 2.22 (s, 6H), 1.36 (d, J=5.27 Hz, 6H).

[0297] Conditions of the chiral resolution: chiral column: Chiralpak OJ-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2.

[0298] Retention time of Compound 18: 5.853 min (peak 2).

Example 19: Compound 19

[0299] ##STR00114##

Step 1: Compound 19-a

[0300] Compound 10-a (400.03 mg, 878.00 mol, 1.00 eq) was added into a solution of sulfuryl diamide (421.90 mg, 4.39 mmol, 262.05 L, 5.00 eq) in dioxane (10.00 mL) at 25 C. The mixture was stirred at 110 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-80:20) to give Compound 19-a.

[0301] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.71 (d, J=8.04 Hz, 2H), 7.20 (d, J=8.04 Hz, 2H), 6.88 (s, 2H), 4.72 (s, 2H), 4.48-4.38 (m, 1H), 4.29 (q, J=7.04 Hz, 2H), 3.84-3.56 (m, 9H), 2.52 (s, 3H), 2.17 (s, 6H), 1.45 (d, J=4.02 Hz, 6H), 1.37-1.34 (m, 3H).

Step 2: Compound 19-b

[0302] Lithium hydroxide (291.15 mg, 12.16 mmol, 10.00 eq) was added into a solution of Compound 19-a (650.00 mg, 1.22 mmol, 1.00 eq) in ethanol (10.00 mL) and water (5 mL) at 20 C. The mixture was stirred at 20 C. for 2 h. The mixture was extracted with dichloromethane (20 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-80:20) to give Compound 19-b.

[0303] MS m/z (ESI): 507.1 [M+1].

Step 3: Compound 19

[0304] Compound 19-b (400.00 mg, 789.51 mol, 1.00 eq) was subjected to chiral separation to give Compound 19.

[0305] MS m/z (ESI): 507.1 [M+1].

[0306] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.71 (d, J=8.04 Hz, 2H), 7.20 (d, J=8.04 Hz, 2H), 6.88 (s, 2H), 4.72 (s, 2H), 4.48-4.38 (m, 1H), 4.29 (q, J=7.04 Hz, 2H), 3.91-3.47 (m, 9H), 2.52 (s, 3H), 2.17 (s, 6H), 1.45 (d, J=4.02 Hz, 6H), 1.38-1.32 (m, 3H).

[0307] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0308] Retention time of Compound 19: 4.227 min (peak 2).

Example 20: Compound 20

[0309] ##STR00115##

Step 1: Compound 20-a

[0310] Triethylamine (177.68 mg, 1.76 mmol, 243.39 L, 2.00 eq) and carbonyl diimidazole (213.54 mg, 1.32 mmol, 1.50 eq) was added into a solution of Compound 10-a (400.00 mg, 877.94 mol, 1.00 eq) in toluene (10.00 mL) at 25 C. The mixture was stirred at 80 C. for 16 h. Then, tetrahydropyrrole (93.66 mg, 1.32 mmol, 110.19 L, 1.50 eq) was added. The mixture was stirred at 80 C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-75:25) to give Compound 20-a.

[0311] MS m/z (ESI): 553.3 [M+1]

Step 2: Compound 20-b

[0312] Lithium hydroxide (194.99 mg, 8.14 mmol, 10.00 eq) was added into a solution of Compound 20-a (450.00 mg, 814.16 mol, 1.00 eq) in ethanol (5.00 mL) and water (5 mL) at 20 C. The mixture was stirred at 45 C. for 16 h. The mixture was extracted with dichloromethane (20 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:methanol=100:0-75:25) to give Compound 20-b.

[0313] MS m/z (ESI): 525.1 [M+1].

Step 3: Compound 20

[0314] Compound 20-b (100.00 mg, 319.58 mol, 1.00 eq) was subjected to chiral separation to give Compound 20-c (70.0 mg, yield: 17.50%); Compound 20.

[0315] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.72 (d, J=8.54 Hz, 2H), 7.18 (d, J=8.28 Hz, 2H), 6.89 (s, 2H), 4.03-3.85 (m, 3H), 3.75-3.63 (m, 3H), 3.39 (br dd, J=5.52, 10.78 Hz, 4H), 2.49 (s, 3H), 2.15 (s, 6H), 1.85 (br dd, J=5.90, 13.68 Hz, 4H), 1.43 (br s, 6H).

[0316] Conditions of the chiral resolution: chiral column: Chiralpak OJ-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0317] Retention time of Compound 20: 3.362 min (peak 2).

Example 21: Compound 21

[0318] ##STR00116##

Step 1: Compound 21-a

[0319] Compound 10-a (500.00 mg, 1.10 mmol, 1.00 eq), dichloromethane (5.00 mL), acetylchloride (86.15 mg, 1.10 mmol, 78.32 L, 1.00 eq) and triethylamine (222.10 mg, 2.19 mmol, 304.24 L, 2.00 eq) was added into a dried round-bottom flask. The mixture was stirred at 25 C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate) to give Compound 21-a.

[0320] MS m/z (ESI): 498.1 [M+1].

Step 2: Compound 21

[0321] Compound 21-a (130.00 mg, 261.23 mol, 1.00 eq) and dioxane (1.00 mL) was added into a round-bottom flask. Then, lithium hydroxide (18.77 mg, 783.68 mol, 3.00 eq) and water (1.00 mL) were added. The mixture was stirred at 40 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=3, and was added with water/ethyl acetate (1:1, 20 mL). The aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (11.3%, dichloromethane/MeOH). The resulted product was subjected to chiral separation to give Compound 21.

[0322] MS m/z (ESI): 470.1 [M+1].

[0323] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (d, J=8.03 Hz, 1H), 7.61 (d, J=8.03 Hz, 1H), 7.15-7.09 (m, 2H), 6.81-6.77 (m, 2H), 4.11-4.06 (m, 1H), 3.95-3.91 (m, 1H), 3.81-3.79 (m, 2H), 3.58-3.48 (m, 2H), 2.44 (s, 3H), 2.12-2.03 (m, 9H), 1.40-1.38 (m, 6H).

[0324] Conditions of the chiral resolution: chiral column: Chiralpak OJ-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0325] Retention time of Compound 21: 3.430 min (peak 2).

Examples 22 and 23: Compounds 22 and 23

[0326] ##STR00117##

Step 1: Compound 22-a

[0327] Sodium borohydride (34.66 mg, 916.20 mol, 1.00 eq) was added into a solution of Compound 8-c (500.00 mg, 916.20 mol, 1.00 eq) in ethanol (5.00 mL) at 0 C. The mixture was stirred at 50 C. for 2 h. Ethyl acetate/water (1:1, 50 mL) was added into the mixture. The aqueous phase was extracted with ethyl acetate (20 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 22-a.

[0328] MS m/z (ESI): 548.1 [M+1].

[0329] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.34 (br d, J=4.27 Hz, 6H), 7.24 (br d, J=8.03 Hz, 2H), 7.18-7.14 (m, 3H), 4.30-4.23 (m, 3H), 3.32-3.18 (m, 3H), 3.03 (br d, J=9.03 Hz, 1H), 2.71-2.69 (m, 1H), 2.46 (s, 3H), 2.42-2.33 (m, 3H), 2.04 (s, 6H), 1.40 (s, 6H), 1.33 (t, J=7.15 Hz, 3H).

Step 2: Compound 22-b

[0330] Triethylsilicane (636.86 mg, 5.48 mmol, 872.41 L, 5.00 eq) was added into a solution of Compound 22-a (600.00 mg, 1.10 mmol, 1.00 eq) in dichloromethane (5.00 mL), and then trifluoroacetic acid (624.48 mg, 5.48 mmol, 405.51 L, 5.00 eq) was added. The mixture was stirred at 25 C. for 3 h. The mixture was added with a saturated solution of sodium carbonate (30 mL), and was extracted with ethyl acetate (30 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give Compound 22-b.

[0331] MS m/z (ESI): 532.1 [M+1].

[0332] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.29-7.27 (m, 2H), 7.24-7.17 (m, 3H), 7.03 (d, J=8.28 Hz, 2H), 6.92 (d, J=8.03 Hz, 2H), 6.65 (s, 2H), 4.21 (q, J=7.28 Hz, 2H), 3.63-3.50 (m, 2H), 2.89-2.77 (m, 1H), 2.75-2.68 (m, 3H), 2.58-2.55 (m, 2H), 2.37 (s, 3H), 2.07 (s, 6H), 1.60 (br s, 2H), 1.38 (s, 6H), 1.30-1.27 (m, 3H).

Step 3: Compound 22-c

[0333] Compound 22-b (185.00 mg, 347.91 mol, 1.00 eq), dichloromethane (5.00 mL) and methyl chloroformate (164.39 mg, 1.74 mmol, 134.75 L, 5.00 eq) was added into a dried round-bottom flask. The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (34.6%, ethyl acetate/petroleum ether) to give Compound 22-c.

[0334] MS m/z (ESI): 522.1 [M+23].

Step 4: Compounds 22 and 23

[0335] Compound 22-c (89.00 mg, 178.12 mol, 1.00 eq) and ethanol (5.00 mL) was added into a dried round-bottom flask. Then, lithium hydroxide (12.80 mg, 534.36 mol, 3.00 eq) and water (1.00 mL) were added. The mixture was stirred at 40 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=3, and then was added with water/ethyl acetate (1:1, 30 mL). The aqueous phase was extracted with ethyl acetate (30 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give a compound, which was subjected to chiral separation to give Compound 22; Compound 23.

[0336] Compound 22:

[0337] MS m/z (ESI): 472.1 [M+1].

[0338] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.15 (d, J=8.03 Hz, 2H), 7.03 (br d, J=6.78 Hz, 2H), 6.93 (s, 2H), 3.79 (dd, J=8.28, 10.54 Hz, 1H), 3.68 (s, 3H), 3.56-3.53 (m, 1H), 3.12 (t, J=10.16 Hz, 1H), 2.94-2.92 (m, 1H), 2.69 (br d, J=13.05 Hz, 1H), 2.45-2.43 (m, 5H), 2.27 (s, 6H), 1.43 (s, 6H).

[0339] Compound 23:

[0340] MS m/z (ESI): 494.1 [M+23].

[0341] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.09-7.06 (m, 2H), 6.91 (br d, J=7.03 Hz, 2H), 6.79 (br d, J=2.76 Hz, 2H), 3.79-3.72 (m, 1H), 3.61 (s, 3H), 3.54-3.49 (m, 1H), 3.31-3.25 (m, 1H), 3.07-3.01 (m, 1H), 2.83-2.78 (m, 1H), 2.65 (br d, J=14.05 Hz, 1H), 2.39-2.32 (m, 5H), 2.16 (s, 6H), 1.45 (s, 6H).

[0342] Conditions of the chiral resolution: chiral column: Chiralpak OJ-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2.

[0343] Retention time of Compound 22: 4.092 min (peak 1); retention time of Compound 23: 4.594 min (peak 2)

Example 24: Compound 24

[0344] ##STR00118##

Step 1: Compound 24-b

[0345] Compound 1-a (20.42 g, 122.83 mmol, 1.00 eq) was added into a solution of Compound 24-a (15.00 g, 122.83 mmol, 1.00 eq) in HCl/MeOH (4 N, 100.00 mL) at 20 C. The mixture was stirred at 20 C. for 2 h. The mixture was filtered, and the filter cake was dissolved in ethyl acetate (500 mL), added with water (1000 mL), and extracted with ethyl acetate (200 mL3). The combined organic phase was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 24-b.

[0346] MS m/z (ESI): 270.9 [M+1].

[0347] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.04 (d, J=8.54 Hz, 2H), 7.71 (d, J=2.26 Hz, 2H), 7.41 (d, J=8.54 Hz, 2H), 7.32-7.21 (m, 2H), 7.16 (s, 1H), 6.89 (d, J=7.78 Hz, 1H), 2.60-2.53 (s, 3H).

Step 2: Compound 24-c

[0348] A compound tert-butyl bromo-isopropionate (12.38 g, 55.47 mmol, 3.00 eq) and potassium carbonate (7.67 g, 55.47 mmol, 3.00 eq) was added into a solution of Compound 24-b (5.00 g, 18.49 mmol, 1.00 eq) in acetonitrile (30.00 mL) at 20 C. The mixture was stirred at 80 C. for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:0-80:20) to give Compound 24-c.

[0349] MS m/z (ESI): 413.0 [M+1].

[0350] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.96 (d, J=8.54 Hz, 2H), 7.75 (d, J=15.56 Hz, 1H), 7.48 (d, J=15.56 Hz, 1H), 7.35-7.27 (m, 3H), 7.26-7.23 (m, 1H), 7.16 (s, 1H), 6.91 (td, J=1.22, 7.84 Hz, 1H), 2.56 (s, 3H), 1.61 (s, 6H), 1.46 (s, 9H).

Step 3: Compound 24-d

[0351] N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (6.10 g, 25.70 mmol, 2.00 eq) and TFA (2.20 g, 19.28 mmol, 1.43 mL, 1.50 eq) was added into a solution of Compound 24-c (5.30 g, 12.85 mmol, 1.00 eq) in dichloromethane (25.00 mL) at 0 C. The mixture was stirred at 20 C. for 16 h. The mixture was directly concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 24-d.

[0352] MS m/z (ESI): 546.1 [M+1].

[0353] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.69 (d, J=8.53 Hz, 2H), 7.42-7.36 (m, 2H), 7.32 (t, J=7.40 Hz, 2H), 7.26-7.21 (m, 1H), 7.18-7.08 (m, 3H), 6.94-6.87 (m, 2H), 6.71-6.66 (m, 1H), 3.99-3.89 (m, 1H), 3.80-3.62 (m, 3H), 3.14 (t, J=9.03 Hz, 1H), 3.02 (t, J=8.66 Hz, 1H), 2.89-2.80 (m, 2H), 2.52-2.43 (m, 3H), 1.55 (s, 6H), 1.43 (s, 9H).

Step 4: Compound 24-e

[0354] Phenyl chloroformate (3.44 g, 21.99 mmol, 2.75 mL, 3.00 eq) was added into a solution of Compound 24-d (4.00 g, 7.33 mmol, 1.00 eq) in dichloromethane (30.00 mL) at 20 C. The mixture was stirred at 20 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 24-e.

[0355] MS m/z (ESI): 598.0 [M+23].

[0356] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.78 (dd, J=5.02, 8.54 Hz, 2H), 7.43-7.35 (m, 2H), 7.26-7.12 (m, 6 h), 6.96-6.82 (m, 2H), 6.72 (dd, J=2.14, 8.16 Hz, 1H), 4.25-4.04 (m, 3H), 3.97-3.67 (m, 3H), 2.52 (s, 3H), 1.55 (d, J=5.02 Hz, 6H), 1.44 (s, 9H).

Step 5: Compound 24-f

[0357] Trifluoroacetic acid (11.88 g, 104.22 mmol, 7.72 mL, 20.00 eq) was added into a solution of Compound 24-e (3.00 g, 5.21 mmol, 1.00 eq) in dichloromethane (20.00 mL) at 20 C. The mixture was stirred at 20 C. for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:0-90:10) to give Compound 24-f.

[0358] MS m/z (ESI): 520.0 [M+1].

Step 6: Compound 24

[0359] Compound 24-f (1.00 g, 1.92 mmol, 1.00 eq) was subjected to chiral separation to give Compound 24.

[0360] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.70 (t, J=7.54 Hz, 2H), 7.37-7.25 (m, 2H), 7.18-7.05 (m, 6 h), 6.91 (d, J=7.78 Hz, 1H), 6.80 (s, 1H), 6.73 (t, J=5.90 Hz, 1H), 4.15-3.92 (m, 3H), 3.88-3.58 (m, 3H), 2.43 (s, 3H), 1.55-1.40 (m, 6H).

[0361] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0362] Retention time of Compound 24: 6.698 min (peak 2)

Examples 25, 26: Compounds 25, 26

[0363] ##STR00119## ##STR00120##

Step 1: Compound 25-a

[0364] Trimethylchlorosilicane (23.53 g, 216.55 mmol, 27.36 mL, 1.20 eq) was added into a solution of Compound 1-a (30.00 g, 180.46 mmol, 1.00 eq) in dichloromethane (200.00 mL) at 20 C. The mixture was stirred at 20 C. for 1 h. Then, N-bromosuccinimide (38.54 g, 216.55 mmol, 1.20 eq) was added. The mixture was stirred at 20 C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100/1-100/30) to give Compound 25-a.

[0365] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88-7.85 (m, 2H), 7.27-7.24 (m, 2H), 4.40 (s, 2H), 2.52 (s, 3H).

Step 2: Compound 25-b

[0366] Triphenylphosphine (32.10 g, 122.38 mmol, 1.00 eq) was added into a solution of Compound 25-a (30.00 g, 122.38 mmol, 1.00 eq) in toluene (250.00 mL) at 20 C. The mixture was stirred at 80 C. for 17 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (250 mL3). The organic phases were combined and concentrated to give Compound 25-b.

[0367] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.99 (d, J=8.5 Hz, 2H), 7.89-7.70 (m, 15H), 7.44 (d, J=8.5 Hz, 2H), 6.17 (d, J=13.1 Hz, 2H), 2.57 (s, 3H).

Step 3: Compound 25-c

[0368] Potassium carbonate (110.44 g, 799.05 mmol, 3.00 eq), ethyl 2-bromo-isobutyrate (207.81 g, 1.07 mol, 156.25 mL, 4.00 eq) and potassium iodide (44.21 g, 266.35 mmol, 1.00 eq) was added into a solution of Compound 1-b (40.00 g, 266.35 mmol, 1.00 eq) in dimethylsulfoxide (400.00 mL) at 20 C. The mixture was stirred at 130 C. for 4 h. Water (1 L) was added into the mixture, and extracted with ethyl acetate (200 mL6). The combined organic phase was washed with water (1 L) and saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-100:50) to give Compound 25-c.

[0369] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.85 (s, 1H), 7.50 (s, 2H), 4.31-4.23 (m, 2H), 2.25 (s, 6H), 1.45 (s, 6H), 1.33 (t, J=7.2 Hz, 1H).

Step 4: Compound 25-e

[0370] Potassium tert-butoxide (19.10 g, 170.25 mmol, 1.50 eq) was added into a solution of Compound 25-d (58.36 g, 170.25 mmol, 1.50 eq) in tetrahydrofuran (50.00 mL) at 0 C. The mixture was stirred at 0 C. for 30 min. Then, Compound 25-c (30.00 g, 113.50 mmol, 1.00 eq) was added. The mixture was stirred at 20 C. for 17 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography petroleum ether/ethyl acetate=100/1-100/20) to give Compound 25-e.

Step 5: Compound 25-f

[0371] Camphorsulfonic acid (17.88 g, 76.95 mmol, 3.00 eq) was added into a solution of Compound 25-e (15 g, 51.30 mmol, 1.00 eq) in tetrahydrofuran (200.00 mL) at 20 C. The mixture was stirred at 20 C. for 17 h. A saturated sodium carbonate (500 mL, 4 N) solution was added into the mixture, and extracted with ethyl acetate (500 mL2). The combined organic phase was washed with saturated brine (500 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 25-f.

[0372] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.80-9.69 (m, 1H), 9.62 (s, 1H), 6.75 (s, 2H), 4.21 (br d, J=4.0 Hz, 2H), 4.20 (s, 1H), 3.25 (s, 2H), 2.12-2.10 (m, 6H), 1.40-1.38 (m, 6H), 1.28 (d, J=1.8 Hz, 2H), 1.28-1.27 (m, 1H).

Step 6: Compound 25-g

[0373] Under nitrogen protection, potassium tert-butoxide (1.11 g, 9.85 mmol, 1.00 eq) was added into a solution of Compound 25-b (5.00 g, 9.85 mmol, 1.00 eq) in tetrahydrofuran (50.00 mL). The mixture was stirred at 20 C. for 1 h. Then, Compound 25-f (2.74 g, 9.85 mmol, 1.00 eq) was added. The mixture was stirred at 50 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100/1-100/30) to give Compound 25-g.

[0374] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85 (d, J=8.5 Hz, 2H), 7.28-7.27 (m, 2H), 7.22-7.14 (m, 1H), 7.02 (s, 1H), 6.83 (s, 2H), 4.30 (s, 2H), 3.53 (d, J=6.8 Hz, 2H), 2.55 (s, 3H), 2.21 (s, 6H), 1.49 (s, 6H), 1.38 (s, 3H).

Step 7: Compound 25-h

[0375] N-(methoxymethyl)-1-phenyl-N-(trimethylsilyl)methylamine (3.33 g, 14.04 mmol, 6.00 eq) and trifluoroacetic acid (1.60 g, 14.04 mmol, 1.04 mL, 6.00 eq) was added into a solution of Compound 25-g (1.00 g, 2.34 mmol, 1.00 eq) in dichloromethane (60.00 mL) at 20 C. The mixture was stirred at 40 C. for 17 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/1-100/30) to give Compound 25-h.

[0376] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.71 (d, J=8.5 Hz, 1H), 7.31-7.20 (m, 9H), 6.71 (s, 1H), 4.30-4.23 (m, 2H), 3.76-3.36 (m, 6H), 3.07-2.96 (m, 2H), 2.68 (t, J=7.3 Hz, 2H), 2.51 (s, 3H), 2.10-2.03 (m, 6H), 1.36-1.22 (m, 9H).

Step 8: Compound 25-i

[0377] Phenyl chloroformate (375.00 mg, 2.40 mmol, 300.00 L, 3.12 eq) was added into a solution of Compound 25-h (430.00 mg, 768.19 mol, 1.00 eq) in dichloromethane (20.00 mL) at 20 C. The mixture was stirred at 20 C. for 17 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/1 to 100/50) to give Compound 25-i.

[0378] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.66 (dd, J=4.0, 8.3 Hz, 2H), 7.41-7.33 (m, 2H), 7.23-7.08 (m, 5H), 6.79 (d, J=2.0 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.93-3.60 (m, 4H), 3.48-3.32 (m, 1H), 2.97-2.84 (m, 1H), 2.67 (d, J=7.8 Hz, 2H), 2.57-2.49 (m, 3H), 2.25-2.13 (m, 6H), 1.46 (s, 6H), 1.36 (t, J=7.2 Hz, 3H).

Step 9: Compound 25-j

[0379] Water (8.00 mL) and lithium hydroxide (81.22 mg, 3.39 mmol, 20.00 eq) was added into a solution of Compound 25-i (100.00 mg, 169.57 mol, 1.00 eq) in ethanol (8.00 mL) at 20 C. The mixture was stirred at 20 C. for 17 h. A diluted HCl (1N, 10 mL) was added into the mixture, and extracted with dichloromethane (50 mL3). The combined organic phase was washed with saturated brine (50 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 25-j.

[0380] MS m/z (ESI): 584.1 [M+23].

[0381] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.65 (d, J=6.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.29-7.22 (m, 3H), 7.16 (t, J=7.2 Hz, 2H), 6.87 (s, 2H), 4.13-3.92 (m, 2H), 3.89-3.80 (m, 1H), 3.69 (dd, J=5.4, 10.7 Hz, 1H), 3.58-3.49 (m, 1H), 2.81 (d, J=14.1 Hz, 2H), 2.71-2.63 (m, 1H), 2.55 (s, 3H), 2.23 (s, 6H), 1.43 (s, 6H).

Step 10: Compounds 25 and 26

[0382] Compound 25-j (25.00 mg, 44.51 mol, 1.00 eq) was subjected to chiral separation to give Compound 25; Compound 26.

[0383] Compound 25: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.73 (d, J=8.28 Hz, 2H), 7.41-7.33 (m, 2H), 7.27-7.18 (m, 3H), 7.15 (d, J=8.28 Hz, 2H), 6.83 (d, J=5.52 Hz, 2H), 4.02-3.64 (m, 4H), 3.50-3.32 (m, 1H), 3.08-2.88 (m, 1H), 2.81-2.61 (m, 2H), 2.55 (s, 3H), 2.20 (d, J=3.51 Hz, 6H).

[0384] Compound 26: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.73 (d, J=8.28 Hz, 2H), 7.42-7.34 (m, 2H), 7.27-7.18 (m, 3H), 7.15 (d, J=8.54 Hz, 2H), 6.83 (d, J=5.78 Hz, 2H), 4.05-3.64 (m, 4H), 3.50-3.32 (m, 1H), 3.07-2.88 (m, 1H), 2.83-2.62 (m, 2H), 2.55 (s, 3H), 2.20 (d, J=3.52 Hz, 6H).

[0385] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0386] Retention time of Compound 25: 2.018 min (peak 1); Retention time of Compound 26: 2.410 min (peak 2).

Example 27: Compound 27

[0387] ##STR00121##

Step 1: Compound 27-a

[0388] Chloromethyl 1-chloroformate (3.32 g, 23.22 mmol, 2.00 eq) was added into a solution of Compound 25-h (6.50 g, 11.61 mmol, 1.00 eq) in toluene (60.00 mL) at 25 C. The mixture was stirred under nitrogen protection at 100 C. for 8 h. The mixture was concentrated under reduced pressure. Methanol (50.00 mL) was added into the residue. The mixture was stirred at 70 C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give Compound 27-a.

[0389] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.57 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.77 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.96-3.86 (m, 1H), 3.74 (dd, J=3.3, 7.0 Hz, 1H), 3.69-3.59 (m, 1H), 3.53-3.36 (m, 1H), 3.32-3.20 (m, 1H), 2.88 (br d, J=7.0 Hz, 1H), 2.76 (dd, J=2.6, 7.9 Hz, 2H), 2.52-2.49 (m, 3H), 2.14-2.09 (m, 6H), 1.42 (d, J=2.8 Hz, 6H), 1.34 (t, J=7.2 Hz, 3H).

Step 2: Compound 27-b

[0390] A solution of Compound 27-a (250.00 mg, 532.32 mol, 1.00 eq), di-iso-propyl ethylamine (137.59 mg, 1.06 mmol, 185.93 L, 2.00 eq) and dichloromethane (5.00 mL) was added into a 50 mL reaction flask. Then, (4-chlorophenyl) methyl chloroformate (152.52 mg, 798.48 mol, 1.50 eq) was added. The mixture was stirred at 25 C. for 2 h. A saturated solution of sodium bicarbonate (5 mL) was added into the mixture. The aqueous phase was extracted with dichloromethane (310 mL). The combined organic phase was washed with a saturated aqueous solution of potassium bisulfate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1 to 5:1) to give Compound 27-b.

[0391] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.56 (dd, J=8.8, 4.0 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.02 (dd, J=9.2, 4.0 Hz, 2H), 6.70 (d, J=2.4 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.82-3.53 (m, 4H), 3.38-3.30 (m, 1H), 2.85-2.77 (m, 1H), 2.59-2.46 (m, 2H), 2.46 (s, 3H), 2.10 (s, 6H), 1.39 (s, 6H), 1.29 (t, J=7.2 Hz, 3H).

Step 3: Compound 27-c

[0392] Lithium hydroxide (29.93 mg, 1.25 mmol, 3.00 eq) was added into a solution of Compound 27-b (260.00 mg, 416.54 mol, 1.00 eq) in ethanol (2.00 mL), tetrahydrofuran (2.00 mL) and water (1.00 mL). The mixture was stirred at 25 C. for 60 h. The mixture was adjusted with a saturated aqueous solution of potassium bisulfate to pH=2-3, and extracted with ethyl acetate (10 mL3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2) to give Compound 27-c.

[0393] MS m/z (ESI): 618.0 [M+23].

Step 4: Compound 27

[0394] Compound 27-c (100.00 mg) was subjected to chiral separation to give Compound 27.

[0395] MS m/z (ESI): 618.0 [M+23].

[0396] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.65 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.17 (t, J=8.8 Hz, 2H), 6.87 (s, 2H), 4.01-3.96 (m, 2H), 3.82-3.81 (m, 1H), 3.70-3.67 (m, 1H), 3.53-3.51 (m, 1H), 2.82-2.68 (m, 3H), 2.67 (s, 3H), 2.24 (s, 6H), 1.42 (s, 6H).

[0397] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 504.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 4 mL/min; column temperature: 40 C.

[0398] Retention time of Compound 27: 1.148 min (peak 1)

Example 28: Compound 28

[0399] ##STR00122##

Step 1: Compound 28-a

[0400] A solution of Compound 27-a (250.00 mg, 532.32 mol, 1.00 eq), di-iso-propyl ethylamine (137.59 mg, 1.06 mmol, 185.93 L, 2.00 eq) and dichloromethane (5.00 mL) was added into a 50 mL reaction flask. Then, (4-fluorophenyl) methyl chloroformate (139.38 mg, 798.48 mol, 104.80 L, 1.50 eq) was added. The mixture was stirred at 25 C. for 2 h. A saturated solution of sodium bicarbonate (5 mL) was added into the mixture. The aqueous phase was extracted with dichloromethane (310 mL), and the combined organic phase was washed with a saturated aqueous solution of potassium bisulfate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-5:1) to give Compound 28-a.

[0401] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.57 (dd, J=8.4, 4.4 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.03-6.96 (m, 4H), 6.71 (d, J=2.8 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.83-3.66 (m, 4H), 3.64-3.36 (m, 1H), 2.78-2.76 (m, 1H), 2.61-2.56 (m, 2H), 2.46 (s, 3H), 2.09 (s, 6H), 1.39 (s, 6H), 1.29 (t, J=7.2 Hz, 3H).

Step 2: Compound 28-b

[0402] Lithium hydroxide (30.74 mg, 1.28 mmol, 3.00 eq) was added into a solution of Compound 28-a (260.00 mg, 416.54 mol, 1.00 eq) in ethanol (2.00 mL), tetrahydrofuran (2.00 mL) and water (1.00 mL). The mixture was stirred at 25 C. for 60 h. The mixture was adjusted with a saturated aqueous solution of potassium bisulfate to pH=2-3, and extracted with ethyl acetate (10 mL3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2) to give Compound 28-b.

[0403] MS m/z (ESI): 602.1 [M+23].

Step 3: Compound 28

[0404] Compound 28-b (100.00 mg) was subjected to chiral separation to give Compound 28.

[0405] MS m/z (ESI): 602.1 [M+23].

[0406] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.65 (dd, J=8.4, 2.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.17-7.13 (m, 4H), 6.88 (s, 2H), 4.02-3.97 (m, 2H), 3.82-3.80 (m, 1H), 3.67-3.65 (m, 1H), 3.53-3.50 (m, 1H), 2.84-2.67 (m, 3H), 2.56 (s, 3H), 2.19 (s, 6H), 1.45 (s, 6H).

[0407] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 504.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 4 mL/min; column temperature: 40 C.

[0408] Retention time of Compound 28: 1.867 min (peak 1)

Examples 29 and 30: Compounds 29 and 30

[0409] ##STR00123##

Step 1: Compound 29-a

[0410] A solution of Compound 27-a (250.00 mg, 532.32 mol, 1.00 eq), di-iso-propyl ethylamine (137.60 mg, 1.06 mmol, 2.00 eq) and trichloromethane (5.00 mL) was added into a 50 mL reaction flask. Then, (4-bromo phenyl) methyl chloroformate (188.02 mg, 798.50 mol, 113.95 L, 1.50 eq) was added. The mixture was stirred at 25 C. for 18 h. A saturated solution of sodium bicarbonate (5 mL) was added into the mixture. The aqueous phase was extracted with dichloromethane (2*10 mL), and the combined organic phase was washed with a saturated aqueous solution of potassium bisulfate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to give Compound 29-a.

[0411] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.55 (dd, J=8.8, 3.2 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 6.71 (d, J=2.4 Hz, 2H), 4.22 (q, J=7.6 Hz, 2H), 3.82-3.66 (m, 4H), 3.37-3.30 (m, 1H), 2.85-2.80 (m, 1H), 2.77 (d, J=6.4 Hz, 2H), 2.45 (s, 3H), 2.09 (s, 6H), 1.39 (s, 6H), 1.29 (t, J=7.6 Hz, 1H).

Step 2: Compound 29-b

[0412] Lithium hydroxide (29.01 mg, 1.21 mmol, 3.00 eq) was added into a solution of Compound 29-a (270.00 mg, 403.80 mol, 1.00 eq) in ethanol (2.00 mL), tetrahydrofuran (2.00 mL) and water (1.00 mL). The mixture was stirred at 25 C. for 60 h. The mixture was adjusted with a saturated aqueous solution of potassium bisulfate to pH=2-3, and extracted with ethyl acetate (10 mL3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:3) to give Compound 29-b.

[0413] MS m/z (ESI): 664.0 [M+23].

Step 3: Compounds 29 and 30

[0414] Compound 29-b (100.00 mg) was subjected to chiral separation to give Compound 29; Compound 30.

[0415] Compound 29:

[0416] MS m/z (ESI): 664.0 [M+23].

[0417] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.65 (dd, J=8.0, 2.0 Hz, 2H), 7.53 (d, J=9.2 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 7.12 (dd, J=8.8, 2.4 Hz, 2H), 6.88 (s, 2H), 3.98-3.95 (m, 2H), 3.84-3.80 (m, 1H), 3.69-3.67 (m, 1H), 3.53-3.51 (m, 1H), 2.82-2.66 (m, 3H), 2.55 (s, 3H), 2.23 (s, 6H), 1.42 (s, 6H).

[0418] Compound 30:

[0419] MS m/z (ESI): 664.0 [M+23].

[0420] .sup.1H NMR (400 MHz, MeOD-d.sub.4) S ppm 7.66 (d, J=6.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.12 (dd, J=8.8, 2.8 Hz, 2H), 6.88 (s, 2H), 4.02-3.84 (m, 2H), 3.84-3.82 (m, 1H), 3.69-3.66 (m, 1H), 3.53-3.51 (m, 1H), 2.83-2.79 (m, 4H), 2.67 (s, 3H), 2.23 (s, 6H), 1.43 (s, 6H).

[0421] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 504.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 4 mL/min; column temperature: 40 C.

[0422] Retention time of Compound 29: 1.376 min (peak 1); Retention time of Compound 30: 2.462 min (peak 2).

Examples 31 and 32: Compounds 31 and 32

[0423] ##STR00124##

Step 1: Compound 31-a

[0424] Compound 22-b (850.00 mg, 1.60 mmol, 1.00 eq) and dichloromethane (10.00 mL) was added into a dried round-bottom flask. Then, (4-chlorophenyl)chloroformate (610.66 mg, 3.20 mmol, 445.74 L, 2.00 eq) was added. The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (40.6%, ethyl acetate/petroleum ether) to give Compound 31-a.

[0425] MS m/z (ESI): 596.1 [M+1].

Step 2: Compounds 31 and 32

[0426] Lithium hydroxide (8.03 mg, 335.47 mol, 1.00 eq) and water (1.00 mL) was added into a solution of Compound 31-a (200.00 mg, 335.47 mol, 1.00 eq) in tetrahydrofuran (3 mL) and ethanol (2.00 mL). The mixture was stirred at 25 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=2, and then water/ethyl acetate (1:1, 50 mL) was added. The aqueous phase was extracted with ethyl acetate (50 mL2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (50.7%, ethyl acetate/petroleum ether) to give a compound, which was subjected to chiral separation to give Compound 31; Compound 32.

[0427] Compound 31:

[0428] MS m/z (ESI): 590.1 [M+23].

[0429] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.24-7.21 (m, 2H), 7.08 (t, J=6.7 Hz, 2H), 6.99-6.94 (m, 4H), 6.83 (s, 2H), 3.94-3.85 (m, 1H), 3.70-3.69 (m, 1H), 3.45-3.38 (m, 1H), 3.21-3.15 (m, 1H), 2.90-2.88 (m, 1H), 2.70-2.67 (m, 1H), 2.52-2.50 (m, 2H), 2.39 (d, J=1.5 Hz, 3H), 2.18 (s, 6H), 1.45 (s, 6H).

[0430] Compound 32:

[0431] MS m/z (ESI): 590.1 [M+23].

[0432] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.23 (dd, J=2.0, 8.8 Hz, 2H), 7.08 (t, J=6.8 Hz, 2H), 6.99-6.94 (m, 4H), 6.83 (s, 2H), 3.94-3.85 (m, 1H), 3.70-3.69 (m, 1H), 3.45-3.39 (m, 1H), 3.21-3.15 (m, 1H), 2.90-2.88 (m, 1H), 2.70-2.67 (m, 1H), 2.52-2.50 (m, 2H), 2.39 (d, J=1.5 Hz, 3H), 2.18 (s, 6H), 1.45 (s, 6H).

[0433] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1504.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 2.5 mL/min; column temperature: 40 C.

[0434] Retention time of Compound 31: 2.644 min (peak 1); Retention time of Compound 32: 3.026 min (peak 2).

Examples 33 and 34: Compounds 33 and 34

[0435] ##STR00125##

Step 1: Compound 33-a

[0436] Under nitrogen protection, (4-chlorophenyl)chloroformate (5.25 g, 27.48 mmol, 3.83 mL, 2.00 eq) was slowly added into a solution of Compound 2-b (7.50 g, 13.74 mmol, 1.00 eq) in dichloromethane (60.00 mL). The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (41.5%, ethyl acetate/petroleum ether) to give Compound 33-a.

[0437] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (dd, J=5.3, 8.5 Hz, 2H), 7.26-7.24 (m, 2H), 7.15-7.03 (m, 5H), 6.87-6.82 (m, 2H), 6.63 (dd, J=2.3, 8.3 Hz, 1H), 4.11-3.96 (m, 3H), 3.82-3.70 (m, 1H), 3.68-3.60 (m, 2H), 2.43 (s, 3H), 1.46 (d, J=4.8 Hz, 6H), 1.35 (s, 9H)

Step 2: Compounds 33 and 34

[0438] In a flask, trifluoroacetic acid (23.10 g, 202.60 mmol, 15.00 mL, 16.94 eq) was slowly added into a solution of Compound 33-a (7.30 g, 11.96 mmol, 1.00 eq) in dichloromethane (60.00 mL). The mixture was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (40.6%, ethyl acetate/petroleum ether), and the resulted product was subjected to chiral separation to give Compound 33, yield: 3.65%; Compound 34.

[0439] Compound 33:

[0440] MS m/z (ESI): 576.0 [M+23].

[0441] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.78-7.75 (m, 2H), 7.33-7.31 (m, 2H), 7.23-7.12 (m, 5H), 6.93-6.86 (m, 2H), 6.79 (t, J=7.1 Hz, 1H), 4.08-3.97 (m, 3H), 3.81-3.77 (m, 3H), 2.50 (s, 3H), 1.56-1.53 (m, 6H)

[0442] Compound 34:

[0443] MS m/z (ESI): 576.0 [M+23].

[0444] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.69 (dd, J=6.0, 8.3 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.15-7.03 (m, 5H), 6.83 (br t, J=6.5 Hz, 1H), 6.78 (s, 1H), 6.75-6.72 (m, 1H), 4.01-3.91 (m, 3H), 3.73-3.69 (m, 3H), 2.42 (s, 3H), 1.47-1.45 (m, 6H)

[0445] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2.

[0446] Retention time of Compound 33: 5.039 min (peak 1); Retention time of Compound 34: 6.986 min (peak 2).

Example 35: Compound 35

[0447] ##STR00126##

Step 1: Compound 35-b

[0448] Under nitrogen protection, Compound 10-a (150.00 mg, 329.23 mol, 1.00 eq), di-iso-propyl ethylamine (85.10 mg, 658.46 mol, 115.00 L, 200 eq) and 35-a (68.96 mg, 395.07 mol, 51.85 L, 1.20 eq) were stirred at 20 C. for 12 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 35-b.

[0449] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.77-7.72 (m, 2H), 7.23-7.21 (m, 2H), 7.13-7.12 (m, 2H), 7.08-7.06 (m, 2H), 6.88-6.87 (m, 2H), 4.32-4.17 (m, 2H), 4.15-4.09 (m, 3H), 3.84-3.77 (m, 3H), 2.53 (s, 3H), 2.16 (t, J=6.53 Hz, 6H), 1.44 (s, 6H), 1.38-1.34 (m, 3H).

Step 2: Compound 35-c

[0450] A solution of Compound 35-b (180.00 mg, 303.18 mol, 1.00 eq) and lithium hydroxide (127.22 mg, 3.03 mmol, 10.00 eq) in ethanol (9.00 mL) and water (3.00 mL) was stirred at 25 C. for 12 h. The mixture was adjusted with 1N diluted HCl to pH=3, and treated with water and ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phase was washed with saturated brine (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give Compound 35-c.

[0451] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.67-7.65 (m, 2H), 7.45-7.39 (m, 1H), 7.13-7.02 (m, 5H), 6.87-6.86 (m, 2H), 4.35-4.31 (m, 1H), 4.06-4.03 (m, 1H), 3.88-3.78 (m, 2H), 3.54-3.51 (m, 2H), 2.40 (s, 3H), 2.06-2.05 (m, 6H), 1.26 (d, J=2.80 Hz, 6H).

Step 3: Compound 35

[0452] Compound 35-c (120 mg) was subjected to chiral separation to give Compound 35.

[0453] MS m/z (ESI): 588.1 [M+23].

[0454] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (t, J=8.41 Hz, 2H), 7.13 (dd, J=4.02, 8.53 Hz, 2H), 7.03-7.02 (m, 2H), 6.99-6.97 (m, 2H), 6.84 (d, J=6.53 Hz, 2H), 4.08-4.01 (m, 3H), 3.70-3.65 (m, 3H), 2.44 (s, 3H), 2.12 (d, J=5.52 Hz, 6H), 1.40 (s, 6H).

[0455] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0456] Retention time of Compound 35: 2.429 min (peak 2).

Example 36: Compound 36

[0457] ##STR00127##

Step 1: Compound 36-b

[0458] Under nitrogen protection, a solution of Compound 10-a (150.00 mg, 329.23 mol, 1.00 eq), triethylamine (66.63 mg, 658.46 mol, 91.27 L, 2.00 eq), oxy-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylureahexafluorophosphonate (187.77 mg, 493.85 mol, 1.50 eq) and 36-a (84.25 mg, 493.85 mol, 1.50 eq) in dichloromethane (10.00 mL) was stirred at 20 C. for 12 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 36-b.

[0459] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (d, J=8.4 Hz, 2H), 7.53-7.52 (m, 1H), 7.24-7.09 (m, 6H), 6.67 (d, J=4.8 Hz, 2H), 3.97-3.89 (m, 3H), 3.60-3.58 (m, 5H), 2.43 (s, 3H), 2.03 (d, J=8.0 Hz, 6H), 1.34-1.31 (m, 6H), 1.29-1.25 (m, 3H).

Step 2: Compound 36-c

[0460] A solution of Compound 36-b (120.00 mg, 197.31 mol, 1.00 eq) and lithium hydroxide (82.79 mg, 1.97 mmol, 10.00 eq) in ethanol (9.00 mL) and water (3.00 mL) was stirred at 25 C. for 12 h. The mixture was adjusted with 1N diluted HCl to pH=3, and treated with water and ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phase was washed with saturated brine (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give Compound 36-c.

[0461] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.78-7.75 (m, 2H), 7.36-7.31 (m, 4H), 7.24-7.21 (m, 2H), 6.89 (s, 2H), 4.09-3.91 (m, 3H), 3.77-3.50 (m, 5H), 2.51 (d, J=2.8 Hz, 3H), 2.16 (s, 6H), 1.36 (s, 6H).

Step 3: Compound 36

[0462] Compound 36-c (80 mg) was separated by High Performance Liquid Chromatography to give Compound 36.

[0463] MS m/z (ESI): 602.1 [M+23].

[0464] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.67 (d, J=8.53 Hz, 1H), 7.56 (d, J=8.53 Hz, 1H), 7.22-7.21 (m, 2H), 7.18-7.09 (m, 4H), 6.70 (d, J=5.02 Hz, 2H), 4.03-3.98 (m, 1H), 3.91-3.89 (m, 1H), 3.80 (d, J=8.03 Hz, 1H), 3.72 (d, J=7.78 Hz, 1H), 3.61-3.60 (m, 3H), 3.59-3.56 (m, 1H), 2.43 (s, 3H), 2.07 (d, J=9.54 Hz, 6H), 1.39-1.35 (m, 6H).

Example 37: Compound 37

[0465] ##STR00128##

Step 1: Compound 37-b

[0466] Under nitrogen protection, a solution of Compound 10-a (400.00 mg, 877.94 mol, 1.00 eq), triphosgene (208.42 mg, 702.35 mol, 0.80 eq), di-iso-propyl ethylamine (226.93 mg, 1.76 mmol, 306.66 L, 2.00 eq) and 37-a (134.40 mg, 1.05 mmol, 1.20 eq) in tetrahydrofuran (20.00 mL) was stirred at 25 C. for 12 h. The reaction mixture was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 37-b.

[0467] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65-7.62 (m, 2H), 7.30-7.27 (m, 3H), 7.17-7.10 (m, 3H), 6.79 (d, J=6.4 Hz, 2H), 4.22-4.05 (m, 5H), 3.93-3.58 (m, 3H), 2.43 (s, 3H), 2.05 (s, 6H), 1.33-1.25 (m, 8H).

Step 2: Compound 37-c

[0468] A solution of Compound 37-b (200.00 mg, 328.32 mol, 1.00 eq) and lithium hydroxide (13.78 mg, 328.32 mol, 1.00 eq) in ethanol (6.00 mL) and water (3.00 mL) was stirred at 25 C. for 12 h. The mixture was adjusted with 1N diluted HCl to pH=3, and treated with water and ethyl acetate (1:1.50 mL). The aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phase was washed with saturated brine (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give Compound 37-c.

[0469] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.82 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2 Hz), 7.46 (d, J=8.8 Hz, 1H), 7.32-7.27 (m, 4H), 6.97 (s, 1H), 4.49-4.45 (m, 1H), 4.02-3.93 (m, 2H), 3.62-3.60 (m, 1H), 3.49-3.45 (m, 2H), 2.56 (s, 3H), 2.08 (s, 6H), 1.25 (d, J=3.6 Hz, 6H).

Step 3: Compound 37

[0470] Compound 37-c (110 mg) was separated by HPLC to give Compound 37.

[0471] MS m/z (ESI): 603.0 [M+23].

[0472] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.35 (s, 1H), 7.82 (d, J=8.53 Hz, 2H), 7.54 (d, J=7.70 Hz, 2H), 7.28-7.23 (m, 4H), 6.96 (s, 2H), 4.47-4.43 (m, 3H), 3.98-3.90 (m, 3H), 2.48 (br s, 3H), 2.08 (s, 6H), 1.26 (d, J=3.51 Hz, 6H).

Example 38: Compound 38

[0473] ##STR00129##

Step 1: Compound 38-a

[0474] Under nitrogen protection, a solution of Compound 38-a (1.00 g, 7.78 mmol, 819.67 L, 1.00 eq), triphosgene (1.85 g, 6.22 mmol, 0.80 eq) and triethylamine (787.26 mg, 7.78 mmol, 1.08 mL, 1.00 eq) in tetrahydrofuran (20.00 mL) was stirred at 0 C. for 15 min, warmed to 20 C., and stirred for 1 h. The reaction solution was filtered and concentrated, and the resulted crude product was dissolved in tetrahydrofuran (5.00 mL), and then 10-a (1.00 g, 2.19 mmol, 1.00 eq) and di-iso-propyl ethylamine (424.55 mg, 3.29 mmol, 573.72 L, 1.50 eq) were added and stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 38-b.

[0475] MS m/z (ESI): 610.2 [M+1].

[0476] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.78 (dd, J=3.52, 8.54 Hz, 2H), 7.44-7.38 (m, 1H), 7.32-7.24 (m, 4H), 7.18-7.12 (m, 1H), 6.97 (d, J=2.76 Hz, 2H), 4.55-4.38 (m, 1H), 4.13 (q, J=7.28 Hz, 2H), 3.97-3.84 (m, 1H), 3.67-3.43 (m, 3H), 2.50 (s, 3H), 2.04 (s, 6H), 1.28 (s, 6H), 1.20 (t, J=7.04 Hz, 3H)

Step 2: Compound 38-c

[0477] A solution of Compound 38-b (1.00 g, 1.64 mmol, 1.00 eq) and lithium hydroxide (117.83 mg, 4.92 mmol, 3.00 eq) in ethanol (20.00 mL) and water (5.00 mL) was stirred at 20 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=4, and treated with water and ethyl acetate (1:1.50 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 38-c.

[0478] MS m/z (ESI): 582.2 [M+1].

Step 3: Compound 38

[0479] Compound 38-c (200 mg) was subjected to chiral separation to give Compound 38.

[0480] MS m/z (ESI): 604.0 [M+23].

[0481] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.74 (t, J=8.66 Hz, 2H), 7.32-7.27 (m, 1H), 7.23-7.15 (m, 4H), 7.09-7.03 (m, 1H), 6.90 (br d, J=5.52 Hz, 2H), 4.19-4.02 (m, 3H), 3.90-3.64 (m, 3H), 2.50 (s, 3H), 2.19 (br d, J=5.52 Hz, 6H), 1.46 (br s, 6H).

[0482] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 504.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 4.0 mL/min; column temperature: 40 C.

[0483] Retention time of Compound 38: 1.667 min (peak 2).

Example 39: Compound 39

[0484] ##STR00130##

Step 1: Compound 39-b

[0485] Under nitrogen protection, a solution of Compound 39-a (1.00 g, 9.25 mmol, 1.00 eq), triphosgene (2.20 g, 7.40 mmol, 0.80 eq) and triethylamine (1.12 g, 11.10 mmol, 1.54 mL, 1.20 eq) in tetrahydrofuran (20.00 mL) was stirred at 0 C. for 15 min, warmed to 20 C. and stirred for 1 h. The reaction solution was filtered and concentrated, and the resulted crude product was dissolved in tetrahydrofuran (20.00 mL), 10-a (1.00 g, 2.19 mmol, 1.00 eq) and di-iso-propyl ethylamine (424.55 mg, 3.29 mmol, 573.72 L, 1.50 eq) were added and stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 39-b.

[0486] MS m/z (ESI): 612.1 [M+23].

Step 2: Compound 39-c

[0487] A solution of Compound 39-b (200.00 mg, 339.13 mol, 1.00 eq) and lithium hydroxide (81.22 mg, 3.39 mmol, 10.00 eq) in ethanol (20.00 mL) and water (5.00 mL) was stirred at 20 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=4, and treated with water and ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 39-c.

[0488] MS m/z (ESI): 562.2 [M+1].

Step 3: Compound 39

[0489] Compound 39-c (200 mg) was subjected to chiral separation to give Compound 39.

[0490] MS m/z (ESI): 562.2 [M+1].

[0491] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.77 (t, J=8.16 Hz, 2H), 7.25-7.15 (m, 4H), 7.04 (d, J=8.28 Hz, 2H), 6.93 (d, J=6.54 Hz, 2H), 4.21-4.05 (m, 3H), 3.92-3.65 (m, 3H), 2.53 (s, 3H), 2.21 (br d, J=5.52 Hz, 6H), 1.49 (s, 6H)

[0492] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0493] Retention time of Compound 39: 3.697 min (peak 2).

Example 40: Compound 40

[0494] ##STR00131## ##STR00132##

Step 1: Compound 40-a

[0495] Under nitrogen protection, a solution of Compound 40-a (1.00 g, 7.34 mmol, 1.00 eq), triphosgene (1.74 g, 5.87 mmol, 0.80 eq) and triethylamine (891.28 mg, 8.81 mmol, 1.22 mL, 1.20 eq) in tetrahydrofuran (20.00 mL) was stirred at 0 C. for 15 min, warmed to 20 C. and stirred for 1 h. The reaction solution was filtered and concentrated, and the resulted crude product was dissolved in tetrahydrofuran (20.00 mL), and then 10-a (1.00 g, 2.19 mmol, 1.00 eq) and di-iso-propyl ethylamine (424.55 mg, 3.29 mmol, 573.72 L, 1.50 eq) were added and stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 40-b.

[0496] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.81 (d, J=7.54 Hz, 2H), 7.26 (dd, J=8.54, 13.30 Hz, 4H), 7.11-6.94 (m, 4H), 4.58-4.41 (m, 1H), 4.20-4.09 (m, 2H), 3.99-3.82 (m, 1H), 3.43-3.72 (m, 3H), 2.89 (q, J=6.74, 13.69 Hz, 1H), 2.50-2.48 (m, 3H), 2.14-2.01 (m, 6H), 1.30 (s, 6H), 1.25-1.18 (m, 9H).

Step 2: Compound 40-c

[0497] A solution of Compound 40-b (1.00 g, 1.62 mmol, 1.00 eq) and lithium hydroxide (387.67 mg, 16.20 mmol, 10.00 eq) in ethanol (20.00 mL) and water (5.00 mL) was stirred at 20 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=4, and treated with water and ethyl acetate (1:1.50 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 40-c.

[0498] MS m/z (ESI): 612.2 [M+23].

Step 3: Compound 40

[0499] Compound 40-c (200 mg) was subjected to chiral separation to give Compound 40.

[0500] MS m/z (ESI): 612.1 [M+23].

[0501] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.66 (br t, J=8.78 Hz, 2H), 7.15-7.08 (m, 4H), 6.98 (d, J=8.54 Hz, 2H), 6.82 (br d, J=7.28 Hz, 2H), 4.13-3.95 (m, 3H), 3.84-3.56 (m, 3H), 2.88-2.77 (m, 1H), 2.41 (s, 3H), 2.10 (br d, J=6.54 Hz, 6H), 1.37 (br s, 6H), 1.16 (d, J=6.78 Hz, 6H).

[0502] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of iso-propanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0503] Retention time of Compound 40: 2.240 min (peak 2).

Example 41: Compound 41

[0504] ##STR00133## ##STR00134##

Step 1: Compound 41-b

[0505] Under nitrogen protection, a solution of Compound 41-a (1.00 g, 6.13 mmol, 1.00 eq), triphosgene (1.46 g, 4.90 mmol, 0.80 eq) and triethylamine (620.80 mg, 6.13 mmol, 850.41 L, 1.00 eq) in tetrahydrofuran (20.00 mL) was stirred at 0 C. for 15 min, warmed to 20 C. and stirred for 1 h. The reaction solution was filtered and concentrated, and the resulted crude product was dissolved in tetrahydrofuran (20.00 mL), and then 10-a (1.00 g, 2.19 mmol, 1.00 eq) and di-iso-propyl ethylamine (424.55 mg, 3.29 mmol, 573.72 L, 1.50 eq) were added and stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 41-b.

[0506] MS m/z (ESI): 644.1 [M+1].

[0507] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.82-7.73 (m, 3H), 7.45 (dt, J=2.51, 8.66 Hz, 1H), 7.40-7.36 (m, 1H), 7.27 (d, J=8.28 Hz, 2H), 6.97 (d, J=3.52 Hz, 2H), 4.56-4.42 (m, 1H), 4.13 (q, J=7.04 Hz, 2H), 3.96-3.83 (m, 1H), 3.42-3.79 (m, 4H), 2.06-2.02 (m, 6H), 1.28 (d, J=1.76 Hz, 6H), 1.20 (t, J=7.16 Hz, 3H)

Step 2: Compound 41-c

[0508] A solution of Compound 41-b (1.00 g, 1.55 mmol, 1.00 eq) and lithium hydroxide (111.46 mg, 4.65 mmol, 3.00 eq) in ethanol (20.00 mL) and water (5.00 mL) was stirred at 20 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=4, and treated with water and ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 41-c.

[0509] MS m/z (ESI): 616.1 [M+1].

Step 3: Compound 41

[0510] Compound 41-c (200 mg) was subjected to chiral separation to give Compound 41.

[0511] MS m/z (ESI): 616.1 [M+1].

[0512] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.69 (t, J=8.16 Hz, 2H), 7.37 (d, J=2.26 Hz, 1H), 7.18 (d, J=2.26 Hz, 1H), 7.16-7.11 (m, 3H), 6.84 (d, J=7.28 Hz, 2H), 4.15-3.62 (m, 6 h), 2.44 (s, 3H), 2.12 (d, J=5.02 Hz, 6H), 1.44-1.35 (m, 6H)

[0513] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 504.6 mm I.D., 3 m; mobile phase: 40% of iso-propanol (0.05% DEA) in CO.sub.2; flow rate: 4.0 mL/min; column temperature: 40 C.

[0514] Retention time of Compound 41: 1.899 min (peak 2).

Example 42: Compound 42

[0515] ##STR00135## ##STR00136##

Step 1: Compound 42-b

[0516] Under nitrogen protection, a solution of Compound 42-a (1.00 g, 6.82 mmol, 1.00 eq), triphosgene (1.62 g, 5.46 mmol, 0.80 eq) and triethylamine (690.48 mg, 6.82 mmol, 945.86 L, 1.00 eq) in tetrahydrofuran (20.00 mL) was stirred at 0 C. for 15 min, warmed to 20 C. and stirred for 1 h. The reaction solution was filtered and concentrated, and the resulted crude product was dissolved in tetrahydrofuran (20.00 mL), and then 10-a (1.00 g, 2.19 mmol, 1.00 eq) and di-iso-propyl ethylamine (424.55 mg, 3.29 mmol, 573.72 L, 1.50 eq) were added and stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 42-b.

[0517] MS m/z (ESI): 628.1 [M+1].

[0518] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.78 (d, J=7.28 Hz, 2H), 7.60 (dd, J=2.38, 10.16 Hz, 1H), 7.41-7.21 (m, 5H), 6.97 (d, J=3.76 Hz, 2H), 4.56-4.41 (m, 1H), 4.13 (q, J=7.18 Hz, 2H), 3.97-3.81 (m, 1H), 3.74-3.40 (m, 4H), 2.51-2.50 (m, 3H), 2.06-2.01 (m, 6H), 1.28 (d, J=1.52 Hz, 6H), 1.20 (t, J=7.16 Hz, 3H).

Step 2: Compound 42-c

[0519] A solution of Compound 42-b (1.00 g, 1.59 mmol, 1.00 eq) and lithium hydroxide (114.24 mg, 4.77 mmol, 3.00 eq) in ethanol (20.00 mL) and water (5.00 mL) was stirred at 20 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=4, and treated with water and ethyl acetate (1:1.50 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 42-c.

[0520] MS m/z (ESI): 622.1 [M+23].

Step 3: Compound 42

[0521] Compound 42-c (200 mg) was subjected to chiral separation to give Compound 42.

[0522] MS m/z (ESI): 600.1 [M+1].

[0523] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.72 (d, J=7.54 Hz, 2H), 7.21-7.12 (m, 5H), 6.89 (s, 2H), 4.21-4.00 (m, 3H), 3.83-3.64 (m, 3H), 2.49 (s, 3H), 2.18 (s, 6H), 1.25 (s, 6H)

[0524] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of iso-propanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0525] Retention time of Compound 42: 3.045 min (peak 2).

Example 43: Compound 43

[0526] ##STR00137## ##STR00138##

Step 1: Compound 43-b

[0527] Under nitrogen protection, a solution of Compound 43-a (1.00 g, 6.13 mmol, 1.00 eq), triphosgene (1.46 g, 4.90 mmol, 0.80 eq) and triethylamine (620.80 mg, 6.13 mmol, 850.41 L, 1.00 eq) in tetrahydrofuran (20.00 mL) was stirred at 0 C. for 15 min, warmed to 20 C. and stirred for 1 h. The reaction solution was filtered and concentrated, and the resulted crude product was dissolved in tetrahydrofuran (20.00 mL), and then 10-a (1.00 g, 2.19 mmol, 1.00 eq) and di-iso-propyl ethylamine (424.55 mg, 3.29 mmol, 573.72 L, 1.50 eq) were added and stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 43-b.

[0528] MS m/z (ESI): 644.1 [M+1].

[0529] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.78 (dd, J=4.02, 8.54 Hz, 2H), 7.65 (d, J=8.78 Hz, 1H), 7.55 (d, J=2.52 Hz, 1H), 7.38 (d, J=8.78 Hz, 1H), 7.29-7.18 (m, 3H), 6.96 (d, J=2.52 Hz, 3H), 6.75 (dd, J=2.76, 8.78 Hz, 1H), 4.55-4.39 (m, 1H), 4.12 (q, J=7.20 Hz, 2H), 3.84-3.97 (m, 1H), 3.45-3.67 (m, 3H), 2.50-2.50 (m, 3H), 2.02-2.07 (m, 6H), 1.28 (s, 6H), 1.20 (t, J=7.04 Hz, 3H)

Step 2: Compound 43-c

[0530] A solution of Compound 43-b (1.00 g, 1.55 mmol, 1.00 eq) and lithium hydroxide (111.37 mg, 4.65 mmol, 3.00 eq) in ethanol (20.00 mL) and water (5.00 mL) was stirred at 20 C. for 16 h. The mixture was adjusted with 1N diluted HCl to pH=4, and treated with water and ethyl acetate (1:1.50 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give Compound 43-c.

[0531] MS m/z (ESI): 616.1 [M+1].

Step 3: Compound 43

[0532] Compound 43-c (200 mg) was subjected to chiral separation to give Compound 43.

[0533] MS m/z (ESI): 616.0 [M+1].

[0534] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.71-7.62 (m, 2H), 7.35 (d, J=8.78 Hz, 1H), 7.24 (br s, 1H), 7.12 (br s, 2H), 6.97 (br d, J=8.78 Hz, 1H), 6.81 (br s, 2H), 4.01 (br s, 3H), 3.81-3.56 (m, 3H), 2.43 (s, 3H), 2.11 (br s, 6H), 1.18 (s, 6H).

[0535] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 504.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 4.0 mL/min; column temperature: 40 C.

[0536] Retention time of Compound 43: 4.876 min (peak 2).

Examples 44 and 45: Compounds 44 and 45

[0537] ##STR00139## ##STR00140##

Step 1: Compound 44-a

[0538] Under nitrogen protection, a solution of Compound 1-b (20.00 g, 133.18 mmol, 1.00 eq), tert-butyl 2-bromo-isobutyrate (118.86 g, 532.72 mmol, 99.05 mL, 4.00 eq), potassium carbonate (55.22 g, 399.54 mmol, 3.00 eq) and potassium iodide (2.21 g, 13.32 mmol, 0.10 eq) in dimethylsulfoxide (250.00 mL) was stirred at 110 C. for 16 h. The mixture was filtered, and ethyl acetate/water (1:1, 300 mL) was added into the filtrate. The organic phase was washed with water (2300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (11.8%, ethyl acetate/petroleum ether) to give Compound 44-a.

[0539] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.89 (s, 1H), 7.48 (s, 2H), 2.26 (s, 6H), 1.47 (s, 9H), 1.42 (s, 6H).

Step 2: Compound 44-b

[0540] A solution of triethyl phosphonoacetate (2.30 g, 10.26 mmol, 2.04 mL, 1.50 eq) in tetrahydrofuran (5 m) was added into a solution of sodium hydride (547.25 mg, 13.68 mmol, 60% purity, 2.00 eq) in tetrahydrofuran (15.00 mL) at 0 C. The mixture was stirred at 25 C. for 1 h, and then a solution of Compound 44-a (2.00 g, 6.84 mmol, 1.00 eq) in tetrahydrofuran (10 mL) was added. The mixture was stirred for additional 4 h. Water (50 mL) was added into the mixture, and extracted with ethyl acetate (50 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 44-b.

[0541] MS m/z (ESI): 363.0 [M+1].

[0542] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.50 (d, J=15.81 Hz, 1H), 7.09 (s, 2H), 6.25 (d, J=15.81 Hz, 1H), 4.11-4.05 (m, 2H), 2.17 (s, 6 h), 1.44 (s, 9H), 1.37 (s, 6H), 1.27-1.25 (m, 3H).

Step 3: Compound 44-c

[0543] Palladium-carbon (300.00 mg, 10% purity) and anhydrous ethanol (50 mL) was added into hydrogenation flask under argon protection. Then, a solution of Compound 44-b (2.00 g, 5.52 mmol, 1.00 eq) in ethanol (50 mL) was added. The mixture was stirred at 25 C. for 4 h in hydrogen (50 psi) atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give Compound 44-c.

[0544] MS m/z (ESI): 387.1 [M+23].

[0545] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.71 (s, 2H), 4.03 (q, J=7.19 Hz, 2H), 2.74 (br t, J=7.78 Hz, 2H), 2.50-2.46 (m, 2H), 2.12 (s, 6H), 1.43 (s, 9H), 1.34 (s, 6H), 1.27 (t, J=7.03 Hz, 6H), 1.21 (br t, J=7.03 Hz, 3H).

Step 4: Compound 44-d

[0546] Under nitrogen protection, a solution of Compound 44-c (200.00 mg, 548.73 mol, 1.00 eq) in tetrahydrofuran (5 mL) was added into a solution of aluminum lithium hydride (41.65 mg, 1.10 mmol, 2.00 eq) in tetrahydrofuran (5.00 mL) at 0 C. The mixture was stirred at 0 C. for 3 h. Water (100 mL) was added into the reaction mixture, and extracted with ethyl acetate (100 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 44-d.

[0547] MS m/z (ESI): 345.0 [M+23].

Step 5: Compound 44-e

[0548] Oxalyl chloride (1.42 g, 11.16 mmol, 976.92 L, 2.00 eq) was added into a solution of dimethylsulfoxide (1.74 g, 22.32 mmol, 1.74 mL, 4.00 eq) in dichloromethane (15.00 mL) at 78 C. The mixture was stirred at 78 C. for 5 min. Then, Compound 44-d (1.80 g, 5.58 mmol, 1.00 eq) was added, and the mixture was stirred at 78 C. for 40 min. Then, triethylamine (3.39 g, 33.48 mmol, 4.64 mL, 6.00 eq) was added at 78 C., and the mixture was stirred at 0 C. for 30 min. The mixture was quenched by water (50 mL), and extracted with ethyl acetate (50 mL3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (24.3%, ethyl acetate/petroleum ether) to give Compound 44-e.

[0549] MS m/z (ESI): 343.2 [M+23].

Step 6: Compound 44-f

[0550] Sodium tert-butoxide (1.36 g, 14.18 mmol, 1.20 eq) was added into a solution of Compound 25-b (6.00 g, 11.82 mmol, 1.00 eq) in tetrahydrofuran (50.00 mL) at 20 C. The mixture was stirred at 20 C. for 30 min. Water (50 mL) was added into the reaction mixture, and extracted with ethyl acetate (30 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 44-f.

Step 7: Compound 44-g

[0551] Compound 44-f (2.06 g, 4.84 mmol, 1.00 eq) was added into a solution of Compound 44-e (1.55 g, 4.84 mmol, 1.00 eq) in tetrahydrofuran (10 mL). The mixture was stirred at 50 C. for 16 h. Water/ethyl acetate (1:1, 50 mL) was added into the mixture, and the aqueous phase was extracted with ethyl acetate (50 mL2). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography (16.5%, ethyl acetate/petroleum ether) to give Compound 44-g.

Step 8: Compound 44-h

[0552] Under nitrogen protection, trifluoroacetic acid (1.00 mL) was added into a solution of Compound 44-g (1.60 g, 3.41 mmol, 1.00 eq) and N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (972.64 mg, 4.10 mmol, 1.20 eq) in dichloromethane (150.00 mL) at 0 C. The mixture was stirred at 25 C. for 16 h. Water/dichloromethane (1:1, 100 mL) was added into the mixture, and the aqueous phase was extracted with dichloromethane (100 mL2). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography (27.3%, ethyl acetate/petroleum ether) to give Compound 44-h.

[0553] MS m/z (ESI): 602.3 [M+1].

Step 9: Compound 44-i

[0554] (4-chlorophenyl) methyl chloroformate (952.13 mg, 4.98 mmol, 694.99 L, 2.00 eq) was slowly added into a solution of Compound 44-h (1.50 g, 2.49 mmol, 1.00 eq) in dichloromethane (15.00 mL). The mixture was stirred at 25 C. for 20 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (25.6%, ethyl acetate/petroleum ether) to give Compound 44-i.

[0555] MS m/z (ESI): 610.2 [M+1].

Step 10: Compounds 44 and 45

[0556] A solution of Compound 44-i (220.00 mg, 330.20 mol, 1.00 eq) and trifluoroacetic acid (1.54 g, 13.51 mmol, 1.00 mL, 40.90 eq) in dichloromethane (5.00 mL) was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (54.2%, ethyl acetate/petroleum ether), and the resulted product was subjected to chiral separation to give Compound 44; Compound 45.

[0557] Compound 44:

[0558] MS m/z (ESI): 632.1 [M+23].

[0559] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.86 (dd, J=5.8, 8.5 Hz, 2H), 7.31-7.27 (m, 4H), 7.09-7.05 (m, 2H), 6.76 (d, J=5.3 Hz, 2H), 3.96-3.91 (m, 1H), 3.77-3.59 (m, 3H), 3.20-3.16 (m, 1H), 2.80-2.67 (m, 1H), 2.55-2.52 (m, 5H), 2.19 (d, J=4.5 Hz, 6H), 1.93-1.85 (m, 1H), 1.74-1.63 (m, 1H), 1.51-1.47 (m, 6H).

[0560] Compound 45:

[0561] MS m/z (ESI): 632.1 [M+23].

[0562] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.86 (dd, J=5.6, 8.4 Hz, 2H), 7.33-7.26 (m, 4H), 7.07-7.05 (m, 2H), 6.77-6.75 (m, 2H), 3.93 (dt, J=2.6, 10.6 Hz, 1H), 3.80-3.59 (m, 3H), 3.39-3.20 (m, 1H), 2.84-2.64 (m, 1H), 2.55-2.51 (m, 5H), 2.18 (d, J=3.5 Hz, 6H), 1.95-1.85 (m, 1H), 1.70 (br dd, J=3.8, 8.8 Hz, 1H), 1.51-1.47 (m, 6H).

[0563] Conditions of the chiral resolution: chiral column: Chiralpak IC-3 1504.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.5 mL/min; column temperature: 40 C.

[0564] Retention time of Compound 44: 5.592 min (peak 1); Retention time of Compound 45: 7.585 min (peak 1)

Example 46: Compound 46

[0565] ##STR00141##

Step 1: Compound 46-a

[0566] Under nitrogen protection, a solution of Compound 10-a (150.00 mg, 329.23 mol, 1.00 eq), di-iso-propyl ethylamine (85.10 mg, 658.46 mol, 115.00 L, 2.00 eq) and 4-bromo phenyl chloroformate (93.02 mg, 395.08 mol, 56.38 L, 1.20 eq) in dichloromethane (10 mL) was stirred at 20 C. for 12 h. The reaction solution was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give Compound 46-a.

[0567] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.76-7.71 (m, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.21 (d, J=5.2 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.86 (d, J=5.6 Hz, 2H), 4.17-4.09 (m, 5H), 3.84-3.77 (m, 3H), 2.52 (s, 3H), 2.15 (s, 6H), 1.44-1.42 (m, 6H), 1.38-1.36 (m, 3H).

Step 2: Compound 46-b

[0568] A solution of Compound 46-a (140.00 mg, 213.87 mol, 1.00 eq) and lithium hydroxide (89.74 mg, 2.14 mmol, 10.00 eq) in ethanol (9.00 mL) and water (3.00 mL) was stirred at 25 C. for 12 h. The mixture was adjusted with 1N diluted HCl to pH=3, and treated with water and ethyl acetate (1:1, 50 mL). The aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phase was washed with saturated brine (20 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give Compound 46-b.

[0569] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 7.78 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.15-7.12 (m, 2H), 6.98 (d, J=4.0 Hz, 2H), 4.17-4.14 (m, 1H), 4.00-3.97 (m, 2H), 3.92-3.90 (m, 1H), 3.66-3.64 (m, 2H), 2.52 (s, 3H), 2.17 (d, J=5.6 Hz, 6H), 1.38 (s, 6H).

Step 3: Compound 46

[0570] Compound 46-b (50 mg) was subjected to chiral separation to give Compound 46.

[0571] MS m/z (ESI): 650.0 [M+23].

[0572] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.67 (t, J=8.5 Hz, 2H), 7.41-7.39 (m, 2H), 7.13 (dd, J=4.3, 8.5 Hz, 2H), 6.99-6.97 (m, 2H), 6.83 (d, J=6.3 Hz, 2H), 4.09-4.00 (m, 3H), 3.70-3.60 (m, 3H), 2.43 (s, 3H), 2.12 (d, J=5.5 Hz, 6H), 1.39-1.38 (m, 6H).

[0573] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[0574] Retention time of Compound 46: 7.984 min (peak 2).

Example 47: Compound 47

[0575] ##STR00142## ##STR00143##

Step 1: Compound 47-b

[0576] Compound 1-(5-chlorothien-2-yl)-ethanone (10.00 g, 62.26 mmol, 1.00 eq), 47-a (23.40 g, 62.26 mmol, 1.00 eq) and dichloromethane (200.00 mL) was added into a dried round-bottom flask, and the resulted clear solution was stirred at 20 C. for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give 47-b.

[0577] MS m/z (ESI): 240.7 [M+1].

[0578] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.60 (d, J=4.0 Hz, 1H), 7.00 (d, J=4.0 Hz, 1H), 4.28 (s, 1H).

Step 2: Compound 47-c

[0579] At 20 C., Compound 47-b (13.00 g, 54.28 mmol, 1.00 eq), triphenylphosphine (14.24 g, 54.28 mmol, 1.00 eq) and toluene (100.00 mL) was added into a dried round-bottom flask, the resulted suspension was stirred at 20 C. for 2 h. The reaction system was cooled to room temperature, and produced a yellow precipitate, which was filtered. The filter cake was washed with ethyl acetate (350 mL) to give Compound 47-c.

[0580] .sup.1H NMR (CDCl.sub.3) ppm 8.91 (d, J=4.0 Hz, 1H), 7.92-7.87 (m, 6H), 7.75-7.72 (m, 2H), 7.66-7.60 (m, 6H), 7.00 (d, J=4.0 Hz, 1H), 6.13 (d, J=12.8 Hz, 1H).

Step 3: Compound 47-d

[0581] At 20 C., Compound 47-c (5.00 g, 10.27 mmol, 1.00 eq), potassium tert-butoxide (1.73 g, 15.41 mmol, 1.50 eq) and tetrahydrofuran (30.00 mL) was added into a dried round-bottom flask and the resulted suspension was stirred at 20 C. for 1 h. The reaction system was cooled to room temperature, and diluted with water (50 mL) and ethyl acetate (20 mL). After phase separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (320 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue so as to give Compound 47-d.

[0582] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.71-7.68 (m, 6H), 7.66-7.63 (m, 3H), 7.51-7.48 (m, 7H), 7.26 (s, 1H), 6.82 (d, J=4.0 Hz, 1H).

Step 4: Compound 47-e

[0583] At 20 C., Compound 44-e (2.00 g, 6.24 mmol, 1.00 eq), 47-d (2.63 g, 6.24 mmol, 1.00 eq) and tetrahydrofuran (20.00 mL) was added into a dried round-bottom flask, the resulted clear solution was stirred at 65 C. for 16 h. The reaction solution was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 47-e.

[0584] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.45 (d, J=4.0 Hz, 1H), 7.10 (td, J=6.8, 15.2 Hz, 1H), 6.98-6.94 (m, 1H), 6.78 (br s, 2H), 6.66 (d, J=15.3 Hz, 1H), 2.83 (s, 2H), 2.72 (s, 2H), 2.21-2.20 (m, 6H), 1.51-1.50 (m, 9H), 1.41-1.40 (m, 6H).

Step 5: Compound 47-f

[0585] At 20 C., Compound 47-e (1.00 g, 2.16 mmol, 1.00 eq), trifluoroacetic acid (12.31 mg, 108.00 mol, 7.99 L, 0.05 eq) was added into a dried round-bottom flask. The reaction mixture was heated to 80 C., and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (1.54 g, 6.48 mmol, 1.66 mL, 3.00 eq) was slowly added dropwise to the reaction system, which was stirred at 80 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-60:40) to give Compound 47-f.

[0586] MS m/z (ESI): 596.3 [M+1].

[0587] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.38-7.33 (m, 2H), 7.38-7.21 (m, 4H), 6.78 (s, 2H), 4.41-4.28 (m, 2H), 4.08-3.94 (m, 1H), 3.74-3.69 (m, 2H), 3.08 (dd, J=6.5, 11.0 Hz, 1H), 2.77-2.48 (m, 3H), 2.20 (s, 6H), 1.96-1.84 (m, 1H), 1.81-1.66 (m, 2H), 1.53-1.51 (m, 9H), 1.41 (s, 6H).

Step 6: Compound 47-g

[0588] At 20 C., Compound 47-f (1.10 g, 1.84 mmol, 1.00 eq), phenyl chloroformate (1.44 g, 9.20 mmol, 1.15 mL, 5.00 eq) and chloroform (10.00 mL) was added into a dried round-bottom flask, the resulted clear solution was stirred at 80 C. for 16 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 47-g.

[0589] MS m/z (ESI): 648.1 [M+23].

Step 7: Compound 47-h

[0590] Compound 47-g (220.00 mg, 348.20 mol, 1.00 eq) and dichloromethane (6.00 mL), and then trifluoroacetic acid (397.02 mg, 3.48 mmol, 257.81 L, 10.00 eq) was added into a 100 mL reaction flask. The mixture was stirred at 25 C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol=10:1) to give Compound 47-h.

Step 8: Compound 47

[0591] Compound 47-h (17.00 mg, 29.82 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 47.

[0592] MS m/z (ESI): 570.3 [M+1].

[0593] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.55 (br d, J=6.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.21 (br d, J=6.5 Hz, 1H), 7.15-7.11 (m, 2H), 7.02 (br d, J=4.5 Hz, 1H), 6.78 (br d, J=5.0 Hz, 2H), 3.97 (br d, J=7.5 Hz, 2H), 3.73 (br d, J=8.0 Hz, 1H), 3.39-3.34 (m, 1H), 3.16 (br d, J=10.0 Hz, 1H), 2.54 (br s, 2H), 2.21 (br d, J=4.5 Hz, 6 h), 1.86 (br s, 1H), 1.68 (br s, 2H), 1.51 (br d, J=19.6 Hz, 6H)

[0594] Conditions of the chiral resolution: chiral column: OJ (250 mm30 mm, 10 m); mobile phase: 50% of methanol (0.05% DEA) in CO.sub.2; flow rate: 80 mL/min; column temperature: 40 C.

[0595] Retention time of Compound 47: 3.760 min (peak 1).

Example 48: Compound 48

[0596] ##STR00144##

Step 1: Compound 48-b

[0597] At 20 C., hydrogen peroxide (599.71 mg, 5.29 mmol, 508.23 L, 30% purity, 1.10 eq) and sodium hydroxide (211.64 mg, 5.29 mmol, 1.10 eq) was added into a solution of Compound 48-a (1.00 g, 4.81 mmol, 1.00 eq) in tetrahydrofuran (30.00 mL). The mixture was stirred at 20 C. for 2 h. The reaction mixture was quenched by adding a saturated solution of sodium sulfite (10 mL), and extracted with ethyl acetate (5 mL3). The combined organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 48-b.

[0598] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.13 (s, 1H) 7.03 (s, 1H) 3.78 (s, 3H) 1.25 (s, 8H).

Step 2: Compound 48-c

[0599] At 0 C., Compound 48-b (400.00 mg, 4.08 mmol, 1.00 eq) and triethylamine (412.60 mg, 4.08 mmol, 565.20 L, 1.00 eq) was added into a solution of triphosgene (967.99 mg, 3.26 mmol, 0.80 eq) in tetrahydrofuran (10.00 mL). The mixture was stirred at 20 C. for 2 h. After filtration, the filtrate was concentrated under reduced pressure to give Compound 48-c.

Step 3: Compound 48-d

[0600] At 20 C., Compound 27-a (1.00 g, 2.13 mmol, 1.00 eq) and DIEA (550.38 mg, 4.26 mmol, 743.76 L, 2.00 eq) was added into a solution of 48-c (410.25 mg, 2.56 mmol, 1.20 eq) in dichloromethane (50.00 mL). The mixture was stirred at 20 C. for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100/0-40/60) to give Compound 48-d.

[0601] MS m/z (ESI): 594.3 [M+1].

Step 4: Compound 48

[0602] At 20 C., lithium hydroxide (201.69 mg, 8.42 mmol, 10.00 eq) was added into a solution of Compound 48-d (500.00 mg, 842.13 mol, 1.00 eq) in ethanol (20.00 mL) and water (5.00 mL). The mixture was stirred at 20 C. for 16 h. The mixture was acidized by 1N diluted HCl (5 mL), and then extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The residue was separated by High Performance Liquid Chromatography to give Compound 48.

[0603] MS m/z (ESI): 566.4 [M+1].

[0604] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.61 (br t, J=7.92 Hz, 2H) 7.41 (s, 1H) 7.29 (s, 1H) 7.10-7.17 (m, 2H) 6.72 (br s, 2H) 3.77 (s, 3H) 3.67 (br d, J=11.54 Hz, 2H) 3.28 (br s, 2H) 2.84 (br d, J=14.56 Hz, 2H) 2.59 (br s, 2H) 2.45 (s, 3H) 2.10 (br s, 6H) 1.41 (br s, 6H).

Examples 49 and 50: Compounds 49 and 50

[0605] ##STR00145## ##STR00146##

Step 1: Compound 49-b

[0606] A solution of sodium ethoxide (9.19 g, 135.11 mmol, 1.10 eq) in ethanol (50.00 mL) was added into a solution of Compound 49-a (15.00 g, 122.83 mmol, 1.00 eq) and ethyl 2-bromo-isobutyrate (31.15 g, 159.68 mmol, 23.42 mL, 1.30 eq) in ethanol (100.00 mL). Under nitrogen protection, the mixture was stirred at 90 C. for 8 h. The mixture was acidized by diluted HCl (1N) to pH=6-7, and then extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL3) and saturated brine (100 mL2), dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (petroleum ether:ethyl acetate=20/1) to give Compound 49-b.

[0607] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.95 (s, 1H), 7.52 (d, J=6.4 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.34 (t, J=1.2 Hz, 1H), 7.15 (s, 1H), 4.29-4.24 (q, J=7.2 Hz, 2H), 1.64 (s, 6H), 1.27 (t, J=7.2 Hz, 3H).

Step 2: Compound 49-c

[0608] Under nitrogen protection, potassium tert-butoxide (8.55 g, 76.16 mmol, 1.20 eq) was added into a solution of a compound methoxymethyl triphenylphosphine chloride (28.29 g, 82.54 mmol, 1.30 eq) in tetrahydrofuran (100.00 mL) at 0 C., and the mixture was stirred at 0 C. for 30 min. Then, a solution of Compound 49-b (15.00 g, 63.49 mmol, 1.00 eq) in tetrahydrofuran (50.00 mL) was added dropwise. The mixture was quenched by adding water (100 mL), and then extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL2), dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (petroleum ether:ethyl acetate=20/1) to give Compound 49-c.

[0609] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.10-7.04 (m, 2H), 6.93 (d, J=13.2 Hz, 1H), 6.67-6.56 (m, 1H), 6.04 (d, J=6.8 Hz, 1H), 5.68-5.07 (m, 1H), 4.19-4.13 (q, J=7.2 Hz, 2H), 3.70-3.60 (m, 3H), 1.52 (s, 6H), 1.20-1.15 (m, 3H)

Step 3: Compound 49-d

[0610] Under nitrogen protection, oxalyl chloride (19.10 g, 150.50 mmol, 13.17 mL, 2.00 eq), and then ethanol (6.93 g, 150.50 mmol, 8.77 mL, 2.00 eq) and water (2.71 g, 150.50 mmol, 2.00 eq) were added into a solution of Compound 49-c (22.00 g, 75.25 mmol, 1.00 eq) in chloroform (200.00 mL) at 0 C. The mixture was stirred 0 C. for 0.5 h. The mixture was adjusted with a saturated solution of sodium carbonate to pH 7-8. The organic phase was washed with water (50 mL2) and saturated brine (50 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (petroleum ether:ethyl acetate=30/1-10/1) to give Compound 49-d.

[0611] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.64 (t, J=2.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.5 Hz, 1H), 6.70-6.66 (m, 2H), 4.32-4.26 (m, 2H), 3.55 (d, J=2.3 Hz, 2H), 1.53 (s, 6H), 1.31 (t, J=7.2 Hz, 3H).

Step 4: Compound 49-e

[0612] Under nitrogen protection, a solution of Compound 49-d (22.00 g, 87.90 mmol, 1.00 eq) and 44-f (37.49 g, 87.90 mmol, 1.00 eq) in tetrahydrofuran (400.00 mL) was stirred at 50 C. for 12 h.

[0613] The mixture was concentrated under reduced pressure. The residue was purified by silica gel column (chromatography petroleum ether:ethyl acetate=30/1-10/1) to give Compound 49-e.

[0614] MS m/z (ESI): 399.2 [M+1].

Step 5: Compound 49-f

[0615] Under nitrogen protection, N-methoxymethyl-1-phenyl-N-(trimethyldisilanyl)methylamine (8.94 g, 37.64 mmol, 1.50 eq) was added dropwise into a solution of Compound 49-e (10.00 g, 25.09 mmol, 1.00 eq) and trifluoroacetic acid (143.05 mg, 1.25 mmol, 92.89 L, 0.05 eq) in dioxane (50.00 mL) solution at 90 C. The mixture was stirred at 90 C. for 0.5 h. The mixture was diluted with water (500 mL), and extracted with ethyl acetate (300 mL3). The combined organic phase was washed with water (300 mL3) and saturated brine (300 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20/1-5/1) to give Compound 49-f.

[0616] MS m/z (ESI): 532.2 [M+1].

Step 6: Compound 49-g

[0617] Under nitrogen protection, a solution of Compound 49-f (6.00 g, 11.28 mmol, 1.00 eq) and phenyl chloroformate (3.53 g, 22.57 mmol, 2.83 mL, 2.00 eq) in chloroform (40.00 mL) was stirred at 70 C. for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=5/1) to give Compound 49-g.

[0618] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.66 (d, J=8.5 Hz, 1H), 7.61 (br d, J=8.5 Hz, 1H), 7.35 (t, J=7.6 Hz, 2H), 7.27-7.11 (m, 6H), 6.83 (br d, J=7.5 Hz, 1H), 6.78-6.66 (m, 2H), 4.26-4.17 (m, 2H), 3.95-3.57 (m, 4H), 3.52-3.35 (m, 1H), 2.98-2.65 (m, 3H), 2.52 (s, 3H), 1.59 (d, J=2.3 Hz, 6H), 1.26-1.21 (m, 3H).

Step 7: Compounds 49 and 50

[0619] At 25 C., a solution of lithium hydroxide monohydrate (448.97 mg, 10.70 mmol, 5.00 eq) in water (2.00 mL) was added into a solution of Compound 49-g (1.20 g, 2.14 mmol, 1.00 eq) in ethanol (5.00 mL) and tetrahydrofuran (5.00 mL). The mixture was stirred at 25 C. for 8 h. The mixture was neutralized with diluted HCl (1N) to pH=5-6, and then extracted with ethyl acetate (20 mL3). The combined organic phase was washed with water (20 mL3) and saturated brine (20 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=3/1-1/1), and then the purified product was subjected to chiral separation to give Compound 49; Compound 50.

[0620] Compound 49: MS m/z (ESI): 534.3 [M+1].

[0621] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.70-7.55 (m, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.20-7.04 (m, 6H), 6.79-6.63 (m, 3H), 3.93-3.26 (m, 5H), 2.88-2.49 (m, 3H), 2.47-2.40 (m, 3H), 1.56-1.45 (m, 6 h).

[0622] Compound 50: MS m/z (ESI): 534.3 [M+1].

[0623] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.72-7.59 (m, 2H), 7.30-7.07 (m, 9H), 6.80-6.60 (m, 3H), 3.91-3.73 (m, 3H), 3.42-3.27 (m, 1H), 2.81-2.54 (m, 4H), 2.47-2.44 (m, 3H), 1.55-1.50 (m, 6H).

[0624] Conditions of the chiral resolution: chiral column: Chiralpak AD-50 mm4.6 mm I.D., 3 m; mobile phase: 40% of ethanol (0.05% DEA) in CO.sub.2; flow rate: 4 mL/min; column temperature: 40 C.

[0625] Retention time of Compound 49: 1.904 min (peak 1); Retention time of Compound 50: 2.071 min (peak 2).

Examples 51 and 52: Compounds 51 and 52

[0626] ##STR00147## ##STR00148##

Step 1: Compound 51-a

[0627] Phenyl chloroformate (156.09 mg, 996.94 mol, 124.87 L, 1.00 eq) was slowly added into a solution of Compound 44-h (600.00 mg, 996.94 mol, 1.00 eq) in chloroform (10.00 mL). The mixture was stirred at 70 C. for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (51.6%, ethyl acetate/petroleum ether) to give Compound 51-a.

[0628] MS m/z (ESI): 654.4 [M+23].

Step 2: Compounds 51 and 52

[0629] A solution of Compound 51-a (360.00 mg, 569.78 mol, 1.00 eq) and trifluoroacetic acid (2.66 g, 23.30 mmol, 1.73 mL, 40.90 eq) in dichloromethane (5.00 mL) was stirred at 25 C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (54.2%, ethyl acetate/petroleum ether), and the resulted product was subjected to chiral separation to give Compound 51; Compound 52.

[0630] Compound 51: MS m/z (ESI): 598.1 [M+23].

[0631] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.80 (dd, J=6.3, 8.3 Hz, 2H), 7.29-7.20 (m, 4H), 7.05-7.03 (m, 3H), 6.69 (d, J=5.3 Hz, 2H), 3.89-3.86 (m, 1H), 3.70-3.63 (m, 2H), 3.51-3.31 (m, 1H), 3.12 (br dd, J=8.5, 10.8 Hz, 1H), 2.80-2.60 (m, 1H), 2.49-2.45 (m, 5H), 2.12 (d, J=4.8 Hz, 6H), 1.80-1.78 (m, 1H), 1.61-1.60 (m, 1H), 1.41 (br d, J=16.8 Hz, 6H).

[0632] Compound 52: MS m/z (ESI): 598.1 [M+23].

[0633] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.80 (dd, J=6.0, 8.3 Hz, 2H), 7.29-7.20 (m, 4H), 7.07-7.05 (m, 3H), 6.70 (d, J=5.3 Hz, 2H), 3.89-3.86 (m, 1H), 3.70-3.63 (m, 2H), 3.52-3.24 (m, 1H), 3.12 (dd, J=8.5, 11.0 Hz, 1H), 2.77-2.62 (m, 1H), 2.49-2.45 (m, 5H), 2.12 (d, J=4.8 Hz, 6H), 1.80-1.78 (m, 1H), 1.61-1.52 (m, 1H), 1.42 (d, J=15.8 Hz, 6H).

[0634] Conditions of the chiral resolution: chiral column: Lux Cellulose-2 1504.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.5 mL/min; column temperature: 40 C.

[0635] Retention time of Compound 51: 8.092 min (peak 1); Retention time of Compound 52: 13.834 min (peak 2).

Example 53: Compound 53

[0636] ##STR00149##

Step 1: Compound 53-b

[0637] Under nitrogen protection, triphosgene (2.17 g, 7.33 mmol, 0.80 eq) was slowly added into a solution of Compound 53-a (1.00 g, 9.16 mmol, 1.00 eq) and triethylamine (926.90 mg, 9.16 mmol, 1.27 mL, 1.00 eq) in tetrahydrofuran (20.00 mL) at 0 C. The mixture was stirred at 20 C. for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Compound 27-a (1.00 g, 2.13 mmol, 1.00 eq) and N,N-di-iso-propyl ethylamine (550.38 mg, 4.26 mmol, 743.76 L, 2.00 eq) was added into a solution of the residue (365.47 mg, 2.13 mmol, 1.00 eq) in dichloromethane (50.00 mL) at 20 C. The mixture was stirred at 20 C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100/0-40/60) to give Compound 53-b.

[0638] MS m/z (ESI): 605.3 [M+1].

Step 2: Compound 53

[0639] At 20 C., lithium hydroxide (118.81 mg, 4.96 mmol, 10.00 eq) was added into a solution of Compound 53-b (300.00 mg, 496.06 mol, 1.00 eq) in ethanol (20.00 mL) and water (5.00 mL). The mixture was stirred at 20 C. for 16 h. The mixture was acidized by adding 1N diluted HCl (5 mL), and then extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by High Performance Liquid Chromatography to give Compound 53

[0640] MS m/z (ESI): 577.4 [M+1].

[0641] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.32 (t, J=2.76 Hz, 1H), 7.59 (dd, J=8.54, 2.76 Hz, 2H), 7.38-7.45 (m, 1H), 7.06-7.16 (m, 3H), 6.73 (s, 2H), 3.58-3.88 (m, 5H), 3.27-3.40 (m, 1H), 2.58-2.64 (m, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 2.14 (br d, J=2.26 Hz, 6H), 1.42 (br d, J=3.26 Hz, 6H).

Example 54: Compound 54

[0642] ##STR00150##

Step 1: Compound 54-b

[0643] Under nitrogen protection, triphosgene (2.08 g, 7.01 mmol, 0.80 eq) was slowly added dropwise into a solution of Compound 54-a (1.00 g, 8.76 mmol, 1.08 mL, 1.00 eq) and triethylamine (886.42 mg, 8.76 mmol, 1.21 mL, 1.00 eq) in tetrahydrofuran (10.00 mL) at 0 C. The mixture was stirred at 20 C. for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue (752.49 mg, 4.26 mmol, 2.00 eq) and N,N-di-iso-propyl ethylamine (550.38 mg, 4.26 mmol, 743.76 L, 2.00 eq) was added into a solution of Compound 27-a (1.00 g, 2.13 mmol, 1.00 eq) in dichloromethane (50.00 mL) at 20 C. The mixture was stirred at 20 C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100/0-40/60) to give Compound 54-b.

[0644] MS m/z (ESI): 610.3 [M+1].

[0645] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.61-7.71 (m, 2H), 7.22 (br dd, J=5.28, 2.76 Hz, 2H), 6.72-6.80 (m, 2H), 4.50-4.64 (m, 1H), 4.25-4.37 (m, 2H), 3.43-3.79 (m, 4H), 3.17-3.31 (m, 1H), 2.84 (br s, 1H), 2.58-2.67 (m, 2H), 2.54 (s, 3H), 2.16 (br d, J=4.02 Hz, 6H), 1.69-2.03 (m, 4H), 1.46 (s, 6H), 1.37 (t, J=7.16 Hz, 3H).

Step 2: Compound 54

[0646] At 20 C., lithium hydroxide (479.14 mg, 20.01 mmol, 10.00 eq) was added into a solution of Compound 54-b (1.22 g, 2.00 mmol, 1.00 eq) in ethanol (20.00 mL) and water (4.00 mL). The mixture was stirred at 20 C. for 2 h. The mixture was acidized by adding 1N diluted HCl (5 mL), and then extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by High Performance Liquid Chromatography to give Compound 54.

[0647] MS m/z (ESI): 582.4 [M+1].

[0648] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.56-7.65 (m, 2H), 7.09-7.17 (m, 2H), 6.67 (br s, 2H), 3.34-3.78 (m, 5H), 3.08-3.23 (m, 1H), 2.77 (br s, 1H), 2.49-2.59 (m, 2H), 2.43 (br s, 3H), 2.06 (br s, 6H), 1.90 (br s, 1H), 1.77 (br d, J=10.04 Hz, 1H), 1.63 (br d, J=13.06 Hz, 1H), 1.36 (br s, 6H), 1.06-1.26 (m, 4H), 0.89-1.02 (m, 2H), 0.80 (br d, J=6.54 Hz, 3H).

Example 55: Compound 55

[0649] ##STR00151##

Step 1: Compound 55-a

[0650] A solution of Compound 44-g (900.00 mg, 1.92 mmol, 1.00 eq), sarcosine (427.72 mg, 4.80 mmol, 2.50 eq) and paraformaldehyde (1.04 g, 11.52 mmol, 6.00 eq) in toluene (10.00 mL) was stirred at 110 C. for 16 h under nitrogen protection. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (70.2%, ethyl acetate/petroleum ether) to give Compound 55-a.

[0651] MS m/z (ESI): 526.2 [M+1].

Step 2: Compound 55

[0652] Trifluoroacetic acid (1.30 g, 11.41 mmol, 844.16 L, 30.00 eq) was added into a solution of Compound 55-a (200.00 mg, 380.42 mol, 1.00 eq) in dichloromethane (10.00 mL). The mixture was stirred at 25 C. for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (80.3%, ethyl acetate/petroleum ether), and then isolated by High Performance Liquid Chromatography to give Compound 55.

[0653] MS m/z (ESI): 470.1 [M+1].

[0654] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.95 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.67 (s, 2H), 4.06-3.99 (m, 2H), 3.44 (dd, J=3.5, 10.8 Hz, 1H), 2.92-2.83 (m, 3H), 2.72 (s, 3H), 2.51 (s, 3H), 2.49-2.29 (m, 2H), 2.15 (s, 6 h), 1.83-1.80 (m, 2H), 1.42 (d, J=8.3 Hz, 6H)

Example 56: Compound 56

[0655] ##STR00152##

Step 1: Compound 56-a

[0656] -chloroethyl chloroformate (3.56 g, 24.93 mmol, 3.00 eq) was added into a solution of Compound 44-h (5.00 g, 8.31 mmol, 1.00 eq) in toluene (50.00 mL). The reaction solution was stirred at 80 C. for 16 h. The reaction solution was concentrated, and methanol (50.00 mL) was added and stirred at 80 C. for additional 1 h. The reaction mixture was concentrated under reduced pressure, the crude product was purified by flash column chromatography (76.3%, ethyl acetate/petroleum ether) to give Compound 56-a.

[0657] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.39 (br s, 2H), 7.22 (br d, J=6.5 Hz, 2H), 6.63 (br d, J=11.0 Hz, 2H), 4.38-4.19 (m, 2H), 3.87 (br s, 1H), 3.78 (s, 3H), 3.69 (br s, 1H), 3.34 (br s, 1H), 3.18-3.02 (m, 2H), 2.65 (br s, 1H), 2.49 (d, J=3.5 Hz, 3H), 2.42-2.35 (m, 2H), 2.06 (d, J=7.5 Hz, 6H), 1.38 (d, J=4.8 Hz, 6H).

Step 2: Compound 56

[0658] Compound 56-a (500.00 mg, 1.06 mmol, 1.00 eq), lithium hydroxide (76.16 mg, 3.18 mmol, 3.00 eq), water (2.00 mL) and methanol (6.00 mL) was added into a dried reaction flask. The reaction solution was stirred at 40 C. for 16 h. The reaction solution was adjusted by 1N diluted HCl to pH=6, and treated by water and ethyl acetate (1:1, 20 mL), the aqueous phase was extracted with ethyl acetate (2*20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product. The crude product was purified by preparative High Performance Liquid Chromatography to give Compound 56.

[0659] MS m/z (ESI): 456.1 [M+1].

[0660] .sup.1H NMR (400 MHz, MeOD-d.sub.4) ppm 8.52 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 6.74 (s, 2H), 4.06-4.04 (m, 1H), 3.61-3.56 (m, 2H), 3.40 (dd, J=7.3, 11.5 Hz, 1H), 3.14-3.12 (m, 1H), 2.56-2.45 (m, 6H), 2.19 (s, 6H), 1.87-1.83 (m, 1H), 1.75-1.70 (m, 1H), 1.37 (d, J=12.0 Hz, 6H).

Example 57: Compound 57

[0661] ##STR00153##

Step 1: Compound 57-a

[0662] Methyl chloroformate (785.10 mg, 8.31 mmol, 643.52 L, 10.00 eq) was slowly added into a solution of Compound 44-h (500.00 mg, 830.79 mol, 1.00 eq) in chloroform (10 mL). The mixture was stirred at 70 C. for 32 h. The reaction solution was concentrated under reduced pressure, the crude product was purified by flash column chromatography (26.6%, ethyl acetate/petroleum ether) to give Compound 57-a.

[0663] MS m/z (ESI): 592.2 [M+23].

Step 2: Compound 57

[0664] Trifluoroacetic acid (1.86 g, 16.32 mmol, 1.21 mL, 30.00 eq) was added into a solution of Compound 57-a (310.00 mg, 544.10 mol, 1.00 eq) in dichloromethane (30.00 mL). The reaction solution was stirred at 25 C. for 4 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (73.3%, ethyl acetate/petroleum ether) to give a product. The product was subjected to chiral separation to give Compound 57.

[0665] MS m/z (ESI): 536.1 [M+23].

[0666] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.77 (d, J=8.3 Hz, 2H), 7.21-7.19 (m, 2H), 6.67 (s, 2H), 3.79-3.55 (m, 6H), 3.37-3.35 (m, 1H), 3.13-2.98 (m, 1H), 2.70-2.51 (m, 1H), 2.46-2.41 (m, 5H), 2.11 (br d, J=7.0 Hz, 6H), 1.73 (br s, 1H), 1.57-1.53 (m, 1H), 1.45-1.40 (m, 6H).

[0667] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 5 um); mobile phase: 40% of methanol (0.1% NH.sub.3H.sub.2O) in CO.sub.2; flow rate: 60 mL/min; column temperature: 40 C.

[0668] Retention time of Compound 57: 2.964 min (peak 1).

Example 58: Compound 58

[0669] ##STR00154##

Step 1: Compound 58-a

[0670] Isopropyl chloroformate (1.02 mg, 8.31 mmol, 1.16 L, 10.00 eq) was slowly added into a solution of Compound 44-h (500.00 mg, 830.79 mol, 1.00 eq) in chloroform (10.00 mL). The reaction solution was stirred at 70 C. for 32 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (47.6%, ethyl acetate/petroleum ether) to give Compound 58-a.

[0671] MS m/z (ESI): 620.3 [M+23].

Step 2: Compound 58

[0672] Trifluoroacetic acid (801.08 mg, 7.03 mmol, 520.18 L, 30.00 eq) was added into a solution of Compound 58-a (140.00 mg, 234.19 mol, 1.00 eq) in dichloromethane (30.00 mL). The reaction solution was stirred at 25 C. for 4 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (73.3%, ethyl acetate/petroleum ether) to give a product. The product was subjected to chiral separation to give Compound 58.

[0673] MS m/z (ESI): 564.1 [M+23].

[0674] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.78 (br d, J=8.3 Hz, 2H), 7.23-7.21 (m, 2H), 6.68 (s, 2H), 4.85-4.82 (m, 1H), 3.82-3.59 (m, 2H), 3.44-3.29 (m, 2H), 3.11-2.89 (m, 1H), 2.76-2.54 (m, 1H), 2.47-2.40 (m, 5H), 2.14-2.11 (m, 6H), 1.74 (br s, 1H), 1.56-1.41 (m, 7H), 1.20-1.12 (m, 6H).

[0675] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 5 um); mobile phase: 40% of methanol (0.1% NH.sub.3H.sub.2O) in CO.sub.2; flow rate: 60 mL/min; column temperature: 40 C.

[0676] Retention time of Compound 58: 6.217 min (peak 1).

Examples 59 and 60: Compounds 59 and 60

[0677] ##STR00155##

Step 1: Compound 59-a

[0678] 1-bromo-2-methoxyethane (441.99 mg, 3.18 mmol, 298.64 L, 3.00 eq) and triethylamine (321.78 mg, 3.18 mmol, 440.79 L, 3.00 eq) was added into a solution of Compound 57-a (500.00 mg, 1.06 mmol, 1.00 eq) in acetonitrile (10.00 mL). The reaction solution was stirred at 25 C. for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (80.3%, ethyl acetate/petroleum ether) to give Compound 59-a.

[0679] MS m/z (ESI): 528.4 [M+1].

Step 2: Compounds 59 and 60

[0680] Lithium hydroxide (21.10 mg, 881.16 mol, 3.00 eq) and water (2.00 mL) was added into a solution of Compound 59-a (155.00 mg, 293.72 mol, 1.00 eq) in methanol (6.00 mL). The reaction solution was stirred at 40 C. for 16 h. The reaction solution was adjusted by 1N diluted HCl to pH=6, and treated with water and ethyl acetate (1:1, 15 mL). After phase separation, the aqueous phase was extracted with ethyl acetate (215 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product which was purified by flash column chromatography (82.3%, ethyl acetate/petroleum ether) to give a product. The product was subjected to chiral separation to give Compound 59 and Compound 60.

[0681] Compound 59:

[0682] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.99 (br d, J=8.3 Hz, 2H), 7.29 (br d, J=8.5 Hz, 2H), 6.67 (s, 2H), 3.95 (br s, 2H), 3.62 (br s, 1H), 3.38-3.29 (m, 5H), 3.07 (br s, 1H), 2.98 (br t, J=9.4 Hz, 2H), 2.86 (br s, 1H), 2.75 (s, 1H), 2.51 (s, 3H), 2.39 (br dd, J=5.1, 11.9 Hz, 1H), 2.35-2.26 (m, 1H), 2.17 (s, 6H), 1.84-1.70 (m, 2H), 1.47-1.38 (m, 6H).

[0683] Compound 60:

[0684] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.99 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.67 (s, 2H), 3.97 (br s, 2H), 3.62 (br d, J=4.5 Hz, 1H), 3.40-3.28 (m, 5H), 3.15-3.07 (m, 1H), 2.98 (br t, J=10.2 Hz, 2H), 2.87 (br s, 1H), 2.79-2.69 (m, 1H), 2.51 (s, 3H), 2.45-2.35 (m, 1H), 2.34-2.23 (m, 1H), 2.17 (s, 6H), 1.89-1.68 (m, 2H), 1.48-1.37 (m, 6H).

[0685] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 5 um); mobile phase: 40% of EtOH (0.1% NH.sub.3H.sub.2O) in CO.sub.2; flow rate: 60 mL/min; column temperature: 40 C.

[0686] Retention time of Compound 59: 5.564 min (peak 1); Retention time of Compound 60: 5.981 min (peak 2).

Example 61: Compound 61

[0687] ##STR00156##

Step 1: Compound 61

[0688] At 20 C., Compound 61-a (59.05 mg, 347.40 mol, 34.74 L, 2.00 eq) and anhydrous potassium carbonate (72.02 mg, 521.10 mol, 3.00 eq) was added into a solution of Compound 52 (100.00 mg, 173.70 mol, 1.00 eq) in N,N-dimethylformamide (10.00 mL). The mixture was stirred at 20 C. for 16 h. The mixture was diluted with water (10 mL), and then extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was separated by High Performance Liquid Chromatography to give Compound 61.

[0689] MS m/z (ESI): 618.2 [M+1].

[0690] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.79 (dd, J=3.26, 8.53 Hz, 2H), 7.32-7.24 (m, 2H), 7.23-7.18 (m, 2H), 7.14-7.09 (m, 1H), 7.06 (dd, J=4.89, 7.40 Hz, 2H), 6.65 (d, J=6.27 Hz, 2H), 5.04 (spt, J=6.27 Hz, 1H), 3.96-3.47 (m, 4H), 3.33-3.19 (m, 1H), 2.79-2.57 (m, 1H), 2.53-2.34 (m, 5H), 2.08 (s, 6H), 1.85-1.71 (m, 1H), 1.66-1.60 (m, 1H), 1.34 (d, J=3.26 Hz, 6H), 1.24 (d, J=6.27 Hz, 6H).

[0691] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 50*4.6 mm I.D., 3 m; mobile phase: ethanol (0.05% DEA); flow rate: 4 mL/min; column temperature: 40 C.

[0692] Retention time of Compound 61: 1.790 min (peak 1).

Example 62: Compound 62

[0693] ##STR00157## ##STR00158##

Step 1: Compound 62-b

[0694] At 25 C., triphenylphosphine (37.37 g, 142.48 mmol, 1.00 eq) was added into a solution of Compound 62-a (28.36 g, 142.48 mmol, 1.00 eq) in toluene (300.00 mL). The mixture was stirred at 25 C. for 4 h. The reaction solution was filtered, and the filter cake was washed with dichloromethane (200 mL) and dried under reduced pressure to give Compound 62-b.

[0695] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.09 (d, J=7.6 Hz, 2H), 7.88-7.86 (m, 9H), 7.83-7.82 (m, 7H), 7.78-7.76 (m, 2H), 6.22 (d, J=13.2 Hz, 2H).

Step 2: Compound 62-c

[0696] At 20 C., potassium tert-butoxide (3.65 g, 32.52 mmol, 1.50 eq) was added into a solution of Compound 62-b (10.00 g, 21.68 mmol, 1.00 eq) in tetrahydrofuran (100 mL). The mixture was stirred at 20 C. for 0.5 h. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 62-c.

[0697] MS m/z (ESI): 381.1 [M+1].

[0698] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.01 (d, J=7.2 Hz, 2H), 7.83 (t, J=5.2 Hz, 4H), 7.51-7.49 (m, 2H), 7.48-7.38 (m, 13H).

Step 3: Compound 62-d

[0699] At 20 C., Compound 44-e (850 mg, 2.65 mmol, 1.00 eq) was slowly added into a solution of Compound 62-c (1.01 g, 2.65 mmol, 1.00 eq) in tetrahydrofuran (10.00 mL). The reaction solution was stirred at 50 C. for 5 h. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give Compound 62-d.

[0700] MS m/z (ESI): 445.2 [M+23].

[0701] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.80 (t, J=1.4 Hz, 2H), 7.90-7.83 (m, 1H), 7.61-7.41 (m, 2H), 7.09-6.77 (m, 4H), 6.77-6.76 (m, 2H), 2.83-2.81 (m, 2H), 2.72 (s, 2H), 2.20 (br s, 6H), 1.51-1.50 (m, 9H), 1.42-1.41 (m, 6H)

Step 4: Compound 62-e

[0702] At 0 C., N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (264.06 mg, 1.11 mmol, 1.00 eq) and trifluoroacetic acid (12.68 mg, 111.23 mol, 0.10 eq) was added into a solution of Compound 62-d (470.00 mg, 1.11 mmol, 1.00 eq) in dichloromethane (20.00 mL). The reaction solution was stirred at 25 C. for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-40:60) to give Compound 62-e.

[0703] MS m/z (ESI): 556.3 [M+1].

[0704] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.95 (d, J=7.2 Hz, 2H), 7.49 (d, J=7.6 Hz, 2H), 7.45-7.31 (m, 6H), 6.66 (s, 2H), 4.41-4.33 (m, 1H), 3.74-3.72 (m, 1H), 2.81-2.70 (m, 4H), 2.48-2.38 (m, 4H), 2.14 (s, 6H), 2.13-2.10 (m, 2H), 1.51 (s, 9H), 1.38 (s, 6H).

Step 5: Compound 62-f

[0705] Methyl phenyl chloroformate (394.42 mg, 2.52 mmol, 5.00 eq) was slowly added into a solution of Compound 62-e (280.00 mg, 503.82 mol, 1.00 eq) in chloroform (30.00 mL). The reaction solution was stirred at 70 C. for 4 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-30:70) to give Compound 62-f.

[0706] MS m/z (ESI): 608.4 [M+23].

[0707] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.91-7.89 (m, 2H), 7.44-7.42 (m, 2H), 7.30-7.27 (m, 3H), 7.09-7.06 (m, 3H), 6.66 (d, J=7.2 Hz, 2H), 3.92-3.80 (m, 2H), 3.35-3.32 (m, 2H), 2.95-2.83 (m, 2H), 2.50-2.46 (m, 2H), 2.16 (s, 6H), 1.68-1.63 (m, 2H), 1.44 (s, 9H), 1.36 (s, 6H).

Step 6: Compound 62-g

[0708] At 20 C., trifluoroacetic acid (778.65 mg, 6.83 mmol, 505.62 L, 40.00 eq) was added into a solution of Compound 62-f (100.00 mg, 170.73 mol, 1.00 eq) in dichloromethane (20.00 mL). The mixture was stirred at 20 C. for 1 h. The reaction solution was concentrated to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 62-g.

[0709] MS m/z (ESI): 530.4 [M+1].

Step 7: Compound 62

[0710] Compound 62-g (20.00 mg) was isolated by chiral supercritical chromatography to give Compound 62.

[0711] MS m/z (ESI): 530.1 [M+1].

[0712] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.96-7.76 (m, 1H), 7.57-7.15 (m, 5H), 7.03 (br d, J=11.54 Hz, 1H), 6.24 (s, 1H), 5.29-5.16 (m, 6H), 3.42 (s, 1H), 2.13-1.48 (m, 10H), 1.33 (br t, J=7.15 Hz, 1H), 1.21-1.17 (m, 6H).

[0713] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 50*4.6 mm I.D., 3 m; mobile phase: ethanol (0.05% DEA); flow rate: 4 mL/min; column temperature: 40 C.

[0714] Retention time of Compound 62: 1.651 min (peak 1).

Example 63: Compound 63

[0715] ##STR00159## ##STR00160##

Step 1: Compound 63-b

[0716] At 25 C., triphenylphosphine (60.43 g, 230.38 mmol, 1.00 eq) was added into a solution of Compound 63-a (50.00 g, 230.38 mmol, 1.00 eq) in toluene (300.00 mL). The mixture was stirred at 25 C. for 4 h. The reaction solution was filtered, and the filter cake was washed with dichloromethane (300 mL) and then dried under reduced pressure to give Compound 63-b.

[0717] MS m/z (ESI): 399.1 [M+1].

[0718] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.51 (dd, J=5.3, 8.8 Hz, 2H), 7.96 (dd, J=7.3, 13.3 Hz, 6H), 7.82-7.76 (m, 3H), 7.72-7.64 (m, 6H), 7.20 (t, J=8.5 Hz, 2H), 6.38 (d, J=12.0 Hz, 2H).

Step 2: Compound 63-c

[0719] At 20 C., potassium tert-butoxide (3.51 g, 31.29 mmol, 1.50 eq) was added into a solution of Compound 63-b (10.00 g, 20.86 mmol, 1.00 eq) in tetrahydrofuran (100.00 mL). The mixture was stirred at 20 C. for 0.5 h. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (100 mL3). The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 63-c.

[0720] MS m/z (ESI): 399.1 [M+1].

[0721] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.00-7.94 (m, 2H), 7.77-7.68 (m, 6H), 7.59-7.44 (m, 10H), 7.06-6.98 (m, 2H).

Step 3: Compound 63-d

[0722] At 50 C., Compound 44-e (1.00 g, 3.26 mmol, 1.00 eq) was slowly added into a solution of Compound 63-c (1.30 g, 3.26 mmol, 1.00 eq) in tetrahydrofuran (20.00 mL). Under nitrogen protection, the reaction solution was stirred at 50 C. for 16 h. The reaction solution was concentrated under reduced pressure a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=70:1) to give Compound 63-d.

[0723] MS m/z (ESI): 463.2 [M+23].

[0724] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85-7.80 (m, 2H), 7.07-7.02 (m, 2H), 6.73-6.69 (m, 4H), 2.78-2.73 (m, 2H), 2.55-2.48 (m, 2H), 2.13 (s, 6H), 1.43 (s, 9H), 1.34 (s, 6H)

Step 4: Compound 63-e

[0725] At 0 C., N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (538.93 mg, 2.27 mmol, 1.00 eq) and trifluoroacetic acid (258.83 mg, 2.27 mmol, 168.07 L, 1.00 eq) was added into a solution of Compound 63-d (999.00 mg, 2.27 mmol, 1.00 eq) in dichloromethane (20.00 mL). The reaction solution was stirred at 25 C. for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give Compound 63-e.

[0726] MS m/z (ESI): 574.3 [M+1].

[0727] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.04-7.98 (m, 2H), 7.45-7.42 (m, 5H), 7.21-7.16 (m, 1H), 7.18 (t, J=8.5 Hz, 1H), 6.63 (s, 2H), 4.37-4.30 (m, 1H), 4.28-4.22 (m, 1H), 3.92 (br s, 1H), 3.50 (br s, 1H), 3.15 (br s, 2H), 2.51-2.30 (m, 4H), 2.14 (s, 5H), 1.87 (br d, J=7.0 Hz, 1H), 1.92-1.85 (m, 1H), 1.52-1.50 (m, 9H), 1.38 (s, 6H)

Step 5: Compound 63-f

[0728] At 20 C., methyl phenyl chloroformate (559.43 mg, 3.57 mmol, 447.55 L, 5.00 eq) was slowly added into a solution of Compound 63-e (410.00 mg, 714.61 mol, 1.00 eq) in chloroform (30.00 mL). The reaction solution was stirred at 70 C. for 4 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-30:70) to give Compound 63-f.

[0729] MS m/z (ESI): 548.3 [M-56].

[0730] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.15 (dd, J=5.77, 7.78 Hz, 2H), 7.44-7.37 (m, 5H), 7.16 (br d, J=8.03 Hz, 2H), 6.82 (s, 2H), 4.14 (br dd, J=7.78, 15.81 Hz, 2H), 3.84-3.76 (m, 2H), 3.68-3.57 (m, 4H), 2.12 (s, 6H), 1.87-1.68 (m, 2H), 1.45 (d, J=1.51 Hz, 9H), 1.33 (d, J=5.02 Hz, 6H).

Step 6: Compound 63-g

[0731] At 25 C., trifluoroacetic acid (1.51 g, 13.25 mmol, 980.52 L, 40.00 eq) was added into a solution of Compound 63-f (200.00 mg, 331.28 mol, 1.00 eq) in dichloromethane (10.00 mL). The reaction solution was stirred at 25 C. for 4 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-40:60) to give Compound 63-g.

[0732] MS m/z (ESI): 548.3 [M+1].

Step 7: Compound 63

[0733] Compound 63-g (85 mg) was subjected to chiral separation to give Compound 63.

[0734] MS m/z (ESI): 548.0 [M+1].

[0735] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.01 (td, J=6.0, 8.7 Hz, 2H), 7.36 (q, J=8.0 Hz, 2H), 7.24-7.10 (m, 5H), 6.78 (br d, J=5.5 Hz, 2H), 4.02-3.93 (m, 1H), 3.57 (dd, J=8.0, 11.0 Hz, 1H), 3.39 (dd, J=8.0, 10.5 Hz, 1H), 3.23-3.18 (m, 1H), 2.83 (br dd, J=7.8, 13.3 Hz, 1H), 2.73 (td, J=4.4, 8.3 Hz, 1H), 2.55 (br t, J=7.8 Hz, 2H), 2.20 (br d, J=3.5 Hz, 6H), 1.92-1.81 (m, 1H), 1.75-1.64 (m, 1H), 1.55-1.41 (m, 6H).

[0736] Conditions of the chiral resolution: chiral column: Lux Cellulose-2 1504.6 mm I.D., 3 m; mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 2.5 mL/min; column temperature: 40 C.

[0737] Retention time of Compound 63: 3.626 min (peak 1).

Example 64: Compound 64

[0738] ##STR00161## ##STR00162##

Step 1

Compound 64-b

[0739] At 25 C., triphenylphosphine (49.54 g, 188.88 mmol, 1.05 eq) was added into a solution of Compound 64-a (50.00 g, 179.89 mmol, 1.00 eq) in toluene (500.00 mL). The reaction solution was stirred at 25 C. for 12 h. The reaction solution was filtered, and the filter cake was washed with dichloromethane (200 mL), and then dried under reduced pressure to give Compound 64-b.

[0740] MS m/z (ESI): 461 [M+1].

[0741] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.01 (d, J=8.5 Hz, 2H), 7.88-7.84 (m, 11H), 7.82-7.76 (m, 6H), 6.23 (d, J=13.1 Hz, 2H).

Step 2: Compound 64-c

[0742] At 20 C., potassium tert-butoxide (3.12 g, 27.77 mmol, 1.50 eq) was added into a solution of Compound 64-b (10.00 g, 18.51 mmol, 1.00 eq) in tetrahydrofuran (100.00 mL). The reaction solution was stirred at 20 C. for 0.5 h. The reaction solution was extracted with ethyl acetate (100 mL3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 64-C.

[0743] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.90-7.77 (m, 4H), 7.73-7.68 (m, 4H), 7.59-7.54 (m, 4H), 7.51-7.45 (m, 8H).

Step 3: Compound 64-d

[0744] At 50 C., Compound 44-e (1.00 g, 3.12 mmol, 1.00 eq) was slowly added into a solution of Compound 64-c (1.43 g, 3.12 mmol, 1.00 eq) in tetrahydrofuran (20.00 mL). The reaction solution was stirred at 50 C. for 24 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give Compound 64-d.

[0745] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.79-7.72 (m, 2H), 7.61 (d, J=8.5 Hz, 2H), 6.84-6.81 (m, 2H), 6.80-6.79 (m, 2H), 2.87-2.85 (m, 2H), 2.74-2.72 (m, 2H), 2.22 (s, 6H), 1.53 (s, 9H), 1.44 (s, 6H).

Step 4: Compound 64-e

[0746] At 0 C., N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (467.22 mg, 1.97 mmol, 1.20 eq) and trifluoroacetic acid (187.00 mg, 1.64 mmol, 121.43 L, 1.00 eq) was added into a solution of Compound 64-d (824.00 mg, 1.64 mmol, 1.00 eq) in dichloromethane (20.00 mL). The reaction solution was stirred at 25 C. for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-20:80) to give Compound 64-e.

[0747] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.81 (br d, J=8.3 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.45-7.40 (m, 5H), 6.62 (s, 2H), 4.35-4.23 (m, 2H), 3.16 (br s, 2H), 2.66 (br s, 2H), 2.47-2.35 (m, 4H), 2.13 (s, 6H), 1.94-1.83 (m, 2H), 1.50 (s, 9H), 1.37 (d, J=3.0 Hz, 6H).

Step 5: Compound 64-f

[0748] At 25 C., phenyl chloroformate (356.49 mg, 2.28 mmol, 285.19 L, 5.00 eq) was added into a solution of Compound 64-e (289.00 mg, 455.38 mol, 1.00 eq) in chloroform (20.00 mL). The reaction solution was heated to 70 C. and stirred for 48 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-40:60) to give Compound 64-f.

[0749] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.78-7.72 (m, 2H), 7.57 (dd, J=3.0, 8.5 Hz, 2H), 7.30 (br d, J=2.0 Hz, 2H), 7.11-7.03 (m, 3H), 6.66 (d, J=6.5 Hz, 2H), 3.85-3.55 (m, 4H), 3.40-3.25 (m, 1H), 2.76-2.58 (m, 1H), 2.56-2.36 (m, 2H), 2.12 (s, 6H), 1.79-1.62 (m, 2H), 1.44 (s, 9H), 1.36-1.33 (m, 6H).

Step 6: Compound 64-g

[0750] At 25 C., trifluoroacetic acid (686.22 mg, 6.02 mmol, 445.60 L, 40.00 eq) was added into a solution of Compound 64-f (100.00 mg, 150.46 mol, 1.00 eq) in dichloromethane (10.00 mL). The reaction solution was stirred at 25 C. for 1 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-40:60) to give Compound 64-g.

[0751] MS m/z (ESI): 610.1 [M+1].

Step 7: Compound 64

[0752] Compound 64-g (85.00 mg, 155.22 mol, 1.00 eq) was subjected to chiral separation to give Compound 64.

[0753] MS m/z (ESI): 610.0 [M+1].

[0754] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.86-7.78 (m, 2H), 7.64 (dd, J=5.3, 8.3 Hz, 2H), 7.35 (q, J=8.0 Hz, 2H), 7.23-7.17 (m, 1H), 7.12 (br t, J=8.8 Hz, 2H), 6.77 (d, J=5.5 Hz, 2H), 4.02-3.88 (m, 2H), 3.81-3.67 (m, 2H), 3.43-3.34 (m, 1H), 3.23-3.15 (m, 1H), 2.54 (br t, J=7.8 Hz, 2H), 2.19 (d, J=5.0 Hz, 6H), 1.86 (br d, J=7.5 Hz, 2H), 1.50 (d, J=17.6 Hz, 6H).

[0755] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 5 um); mobile phase: 0.1% NH.sub.3H.sub.2O IPA; flow rate: 60 mL/min; column temperature: 40 C.

[0756] Retention time of Compound 64: 1.915 min (peak 1).

Examples 65 and 66: Compounds 65 and 66

[0757] ##STR00163## ##STR00164##

Step 1: Compound 65-b

[0758] At 25 C., triphenylphosphine (58.97 g, 224.85 mmol, 1.05 eq) was added into a solution of Compound 65-a (50.00 g, 214.14 mmol, 1.00 eq) in toluene (500.00 mL). The reaction solution was stirred at 25 C. for 48 h under nitrogen protection. The reaction solution was filtered, and the filter cake was washed with dichloromethane (200 mL), and dried under reduced pressure to give Compound 65-b.

[0759] MS m/z (ESI): 415.0 [M+1].

[0760] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.10 (d, J=8.8 Hz, 2H), 7.91-7.81 (m, 9H), 7.80-7.74 (m, 6H), 7.72 (d, J=8.8 Hz, 2H), 6.20 (d, J=13.1 Hz, 2H).

Step 2: Compound 65-c

[0761] At 20 C., potassium tert-butoxide (3.40 g, 30.26 mmol, 1.50 eq) was added into a solution of Compound 65-b (10.00 g, 20.17 mmol, 1.00 eq) in tetrahydrofuran (100.00 mL). The reaction solution was stirred at 20 C. for 0.5 h. The reaction solution was extracted with ethyl acetate (100 mL3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 65-c.

[0762] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.92-7.87 (m, 2H), 7.84-7.76 (m, 2H), 7.74-7.67 (m, 6H), 7.57-7.54 (m, 2H), 7.51-7.48 (m, 6H), 7.33-7.29 (m, 2H).

Step 3: Compound 65-d

[0763] At 50 C., Compound 44-e (1.00 g, 3.12 mmol, 1.00 eq) was slowly added into a solution of Compound 65-c (1.29 g, 3.12 mmol, 1.00 eq) in tetrahydrofuran (20.00 mL). The reaction solution was stirred at 50 C. for 24 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give Compound 65-d.

[0764] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.76-7.71 (m, 2H), 7.35 (d, J=8.5 Hz, 2H), 6.77-6.74 (m, 2H), 6.72 (s, 2H), 2.78-2.76 (m, 2H), 2.68-2.67 (m, 2H), 2.13 (s, 6H), 1.44 (s, 9H), 1.35 (s, 6H)

Step 4: Compound 65-e

[0765] At 0 C., N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (441.99 mg, 1.86 mmol, 1.20 eq) and trifluoroacetic acid (176.89 mg, 1.55 mmol, 114.87 L, 1.00 eq) was added into a solution of Compound 65-d (709.00 mg, 1.55 mmol, 1.00 eq) in dichloromethane (20.00 mL). The reaction solution was warmed to 25 C. and stirred for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-20:80) to give Compound 65-e.

[0766] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.89 (br d, J=8.3 Hz, 2H), 7.49-7.42 (m, 7H), 6.62 (s, 2H), 4.38-4.22 (m, 2H), 3.15 (br d, J=8.8 Hz, 2H), 2.67 (br s, 2H), 2.50-2.28 (m, 4H), 2.13 (s, 4H), 2.14-2.11 (m, 1H), 2.14-2.11 (m, 1H), 1.93-1.82 (m, 2H), 1.50 (s, 9H), 1.37 (s, 6 h).

Step 5: Compound 65-f

[0767] At 25 C., phenyl chloroformate (332.94 mg, 2.13 mmol, 266.35 L, 5.00 eq) was added into a solution of Compound 65-e (251.00 mg, 425.29 mol, 1.00 eq) in chloroform (20.00 mL). The reaction solution was warmed to 70 C. and stirred for 48 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-40:60) to give Compound 65-f.

[0768] MS m/z (ESI): 642.4 [M+1].

Step 6: Compound 65-g

[0769] At 25 C., trifluoroacetic acid (588.33 mg, 5.16 mmol, 382.03 L, 40.00 eq) was added into a solution of Compound 65-f (80.00 mg, 129.00 mol, 1.00 eq) in dichloromethane (10.00 mL). The reaction solution was stirred at 25 C. for 1 h. The reaction solution was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-50:50) to give Compound 65-g.

[0770] MS m/z (ESI): 564.1 [M+1].

Step 7: Compounds 65 and 66

[0771] Compound 65-g (60.00 mg, 106.37 mol, 1.00 eq) was subjected to chiral separation to give Compound 65 and Compound 66.

[0772] Compound 65:

[0773] MS m/z (ESI): 564.1 [M+1].

[0774] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.90 (dd, J=6.0, 8.5 Hz, 2H), 7.48 (dd, J=5.5, 8.5 Hz, 2H), 7.40-7.31 (m, 2H), 7.20 (q, J=7.5 Hz, 1H), 7.12 (br t, J=8.8 Hz, 2H), 6.77 (d, J=6.0 Hz, 2H), 4.03-3.89 (m, 2H), 3.81-3.65 (m, 2H), 3.41-3.35 (m, 1H), 3.22-3.15 (m, 1H), 2.54 (br t, J=7.5 Hz, 2H), 2.19 (d, J=5.0 Hz, 6H), 1.90-1.81 (m, 2H), 1.50 (d, J=17.6 Hz, 6H).

[0775] Compound 66:

[0776] MS m/z (ESI): 564.1 [M+1].

[0777] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.90 (dd, J=6.0, 8.5 Hz, 2H), 7.48 (dd, J=5.0, 8.5 Hz, 2H), 7.35 (q, J=8.0 Hz, 2H), 7.19 (q, J=7.4 Hz, 1H), 7.12 (t, J=8.8 Hz, 2H), 6.77 (d, J=5.5 Hz, 2H), 4.04-3.89 (m, 2H), 3.80-3.64 (m, 2H), 3.38 (dd, J=7.8, 10.8 Hz, 1H), 3.19 (dd, J=8.0, 11.0 Hz, 1H), 2.60-2.48 (m, 2H), 2.19 (d, J=5.0 Hz, 6H), 1.91-1.80 (m, 2H), 1.49 (d, J=16.6 Hz, 6H).

[0778] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 5 um); mobile phase: 0.1% NH.sub.3H.sub.2O IPA; flow rate: 60 mL/min; column temperature: 40 C.

[0779] Retention time of Compound 65: 1.835 min (peak 1). Retention time of Compound 66: 1.905 min (peak 2).

Example 67: Compound 67

[0780] ##STR00165##

Step 1: Compound 67

[0781] Compound 51 (50.00 mg, 86.85 mol, 1.00 eq) and chloroform (5.00 mL) was added into a dried reaction flask. The mixture was cooled to 0 C. in an ice-water bath, and then m-chloroperbenzoic acid (14.11 mg, 69.48 mol, 0.80 eq) was slowly added. After removing the ice-water bath, the mixture was naturally warmed to 20 C., and stirred for 1 h. A saturated solution of sodium thiosulfate was added dropwise into the reaction system, which was monitored with potassium iodide test paper until the test paper did not change color. Then, the mixture was extracted with ethyl acetate (20 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified with preparative High Performance Liquid Chromatography to give Compound 67.

[0782] MS m/z (ESI): 592.2 [M+1].

[0783] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.00-7.92 (m, 2H), 7.71 (t, J=8.5 Hz, 2H), 7.40-7.33 (m, 2H), 7.24-7.17 (m, 1H), 7.14 (br dd, J=5.5, 7.0 Hz, 2H), 6.78-6.72 (m, 2H), 3.99-3.61 (m, 4H), 3.44 (ddd, J=3.8, 6.9, 10.9 Hz, 0.5H), 3.34-3.26 (m, 0.5H), 2.83-2.79 (m, 3H), 2.68-2.61 (m, 1H), 2.56-2.45 (m, 1H), 2.21-2.11 (m, 6H), 1.93-1.78 (m, 2H), 1.57-1.41 (m, 6H).

Example 68: Compound 68

[0784] ##STR00166##

Step 1: Compound 68

[0785] Compound 51 (50.00 mg, 86.85 mol, 1.00 eq) and chloroform (5.00 mL) was added into a dried reaction flask. Then, m-chloroperbenzoic acid (35.26 mg, 173.70 mol, 2.00 eq) was slowly added. The mixture was stirred at 20 C. for additional 1 h. A saturated solution of sodium thiosulfate was added dropwise to the reaction system, which was monitored with potassium iodide test paper until the test paper did not change color. Then, the mixture was extracted with ethyl acetate (320 mL). The organic phases were collected, and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by preparative High Performance Liquid Chromatography to give Compound 68.

[0786] MS m/z (ESI): 608.2 [M+1].

[0787] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.05 (d, J=4.5 Hz, 4H), 7.36 (q, J=7.5 Hz, 2H), 7.24-7.17 (m, 1H), 7.13 (t, J=7.8 Hz, 2H), 6.77 (d, J=3.5 Hz, 2H), 4.02-3.91 (m, 1H), 3.85-3.70 (m, 2.5H), 3.59 (dd, J=7.5, 11.0 Hz, 0.5H), 3.43 (dd, J=7.5, 10.5 Hz, 0.5H), 3.28 (dd, J=8.0, 11.0 Hz, 0.5H), 3.10 (s, 3H), 2.87-2.68 (m, 1H), 2.59-2.49 (m, 1H), 2.17 (d, J=4.5 Hz, 6H), 1.93-1.72 (m, 2H), 1.48 (d, J=13.6 Hz, 6H).

Example 69: Compound 69

[0788] ##STR00167## ##STR00168##

Step 1: Compound 69-a

[0789] Compound 25-f (8.70 g, 31.26 mmol, 1.00 eq) and tetrahydrofuran (100.00 mL) was added into a pre-dried flask of 250 mL. And then 63-c (12.45 g, 31.26 mmol, 1.00 eq) was added into the reaction system. The mixture was stirred at 50 C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-20:80) to give pure Compound 69-a.

[0790] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.96-7.92 (m, 2H), 7.17-7.11 (m, 3H), 7.01 (s, 1H), 6.81 (s, 2H), 4.37-4.34 (m, 2H), 3.52 (dd, J=1.0, 6.8 Hz, 2H), 2.19 (s, 6H), 1.48-1.47 (m, 6H), 1.38-1.36 (m, 3H).

Step 2: Compound 69-b

[0791] Compound 69-a (3.30 g, 8.28 mmol, 1.00 eq) and dioxane (100.00 mL) was added into a pre-dried flask of 1000 mL, purged with nitrogen gas three times followed by adding trifluoroacetic acid (83.01 mg, 728.00 mol, 53.90 L, 0.05 eq). Subsequently, the resulted clear reaction solution was heated and stirred at 80 C. for 5 min, and then a solution of N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (5.90 g, 24.84 mmol, 3.00 eq) in dioxane (10.00 mL) was slowly added, while keeping the reaction system at 80 C. After 30 min the feeding was completed, the reaction system was stirred at 80 C. for 1 h. The reaction system was cooled to room temperature, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-20:80) to give the product, pure Compound 69-b.

[0792] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.75 (dd, J=5.5, 9.0 Hz, 2H), 7.23-7.12 (m, 5H), 7.02-6.94 (m, 2H), 6.64 (s, 2H), 4.19 (q, J=7.4 Hz, 2H), 3.63-3.54 (m, 2H), 3.04-2.94 (m, 2H), 2.66-2.61 (m, 2H), 2.17-2.06 (m, 2H), 2.01-1.98 (m, 6H), 1.60-1.52 (m, 2H), 1.36 (s, 6H), 0.84-0.77 (m, 3H).

Step 3: Compound 69-c

[0793] Compound 69-b (1.53 g, 2.88 mmol, 1.00 eq) and chloroform (10.00 mL) was added into a pre-dried round-bottom flask of 50 mL. Then, phenyl chloroformate (2.25 g, 14.39 mmol, 1.80 mL, 5.00 eq) was added. Under nitrogen protection, the reaction vessel was placed in an oil bath at 70 C., and stirred for 6 h. The reaction system was cooled to room temperature, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give the product, pure Compound 69-c.

[0794] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.76 (td, J=5.9, 8.3 Hz, 2H), 7.38-7.34 (m, 2H), 7.21-7.07 (m, 5H), 6.79 (s, 2H), 4.30 (q, J=7.0 Hz, 2H), 3.97-3.83 (m, 2H), 3.77-3.62 (m, 2H), 3.51-3.36 (m, 1H), 2.97-2.83 (m, 1H), 2.73-2.60 (m, 2H), 2.17 (s, 6H), 1.47 (s, 6H), 1.37 (t, J=6.8 Hz, 3H)

Step 4: Compound 69-d

[0795] Compound 69-c (1.24 g, 2.21 mmol, 1.00 eq) was added into a pre-dried flask of 100 mL, and then was dissolved by adding ethanol (9.00 mL) and water (3.00 mL). Subsequently, lithium hydroxide (925.35 mg, 38.64 mmol, 17.50 eq) was added into the reaction system, and the mixture was stirred at 40 C. for 16 h. A saturated aqueous solution of potassium bisulfate was added dropwise to the reaction system until pH=5-6. Then the mixture was extracted with ethyl acetate (310 mL). The organic phases were combined, and successively washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-50:50) to give a crude product. The crude product was purified by preparative High Performance Liquid Chromatography to give Compound 69-d.

[0796] MS m/z (ESI): 534.3 [M+1].

Step 5: Compound 69

[0797] Compound 69-d (145.00 mg, 271.74 mmol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 70.

[0798] MS m/z (ESI): 534.3 [M+1].

[0799] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.75 (dd, J=5.5, 8.5 Hz, 2H), 7.32-7.25 (m, 2H), 7.16-7.00 (m, 5H), 6.75 (d, J=5.0 Hz, 2H), 3.95-3.81 (m, 1H), 3.79-3.64 (m, 2H), 3.59 (br dd, J=7.5, 11.0 Hz, 1H), 3.42-3.26 (m, 1H), 2.96-2.82 (m, 1H), 2.69-2.55 (m, 2H), 2.12 (d, J=3.0 Hz, 6H), 1.43 (s, 6H).

[0800] Chiral Analysis Conditions: chiral column: AS (250 mm30 mm, 10 m); mobile phase: 0.1% NH.sub.3H.sub.2O EtOH; flow rate: 80 mL/min; column temperature: 40 C.

[0801] Retention time of Compound 70: 3.561 min (peak 1).

Example 70: Compound 70

[0802] ##STR00169## ##STR00170##

Step 1: Compound 70-a

[0803] Compound 25-f (18.00 g, 64.67 mmol, 1.00 eq) and tetrahydrofuran (100.00 mL) was added into a pre-dried flask of 250 mL. Then, 65-c (26.83 g, 64.67 mmol, 1.00 eq) was added into the reaction system, and the mixture was stirred at 50 C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give Compound 70-a.

[0804] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.86 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.28 (s, 0.5H), 7.24-7.15 (m, 1H), 7.02 (s, 0.5H), 6.82 (s, 2H), 4.41-4.35 (m, 2H), 3.53 (d, J=6.5 Hz, 2H), 2.20 (s, 6H), 1.49 (s, 6H), 1.39-1.37 (m, 3H).

Step 2: Compound 70-b

[0805] Compound 70-a (4.00 g, 9.64 mmol, 1.00 eq) and dioxane (120.00 mL) was added into a dried flask, and then trifluoroacetic acid (83.01 mg, 728.00 mol, 53.90 L, 0.05 eq) was added. The solution was heated and stirred at 80 C. for 5 min, followed by slowly adding dropwise a solution of N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (6.87 g, 28.92 mmol, 3.00 eq) in dioxane (120.00 mL). After the completion of the feeding, the reaction mixture was stirred at 80 C. for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give Compound 70-b.

[0806] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.66 (d, J=8.5 Hz, 2H), 7.26-7.23 (m, 7H), 6.63 (s, 2H), 4.22-4.18 (m, 2H), 3.71-3.61 (m, 2H), 3.54-3.44 (m, 2H), 3.05-2.96 (m, 2H), 2.69-2.59 (m, 2H), 2.11 (d, J=12.0 Hz, 2H), 2.02-1.97 (m, 6H), 1.41-1.34 (m, 6H), 0.93-0.75 (m, 3H)

Step 3: Compound 70-c

[0807] Compound 70-b (1.00 g, 1.82 mmol, 1.00 eq) and chloroform (10.00 mL) was added into a pre-dried round-bottom flask of 50 mL. Then, phenyl chloroformate (1.43 g, 9.12 mmol, 1.14 mL, 5.00 eq) was added. Under nitrogen protection, the reaction vessel was placed in an oil bath at 70 C., and stirred for 6 h. The reaction system was cooled to room temperature, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give Compound 70-c.

[0808] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (dd, J=6.3, 8.3 Hz, 2H), 7.43-7.35 (m, 4H), 7.25-7.13 (m, 3H), 6.80 (s, 2H), 4.32 (q, J=7.0 Hz, 2H), 3.98-3.68 (m, 4H), 3.52-3.38 (m, 1H), 2.98-2.84 (m, 1H), 2.75-2.63 (m, 2H), 2.20-2.16 (m, 6H), 1.59 (d, J=1.0 Hz, 6H), 1.42-1.35 (m, 3H).

Step 4: Compound 70-d

[0809] Compound 70-c (560.00 mg, 968.69 mol, 1.00 eq) was added into a dried flask, and then was dissolved by adding ethanol (6.00 mL) and water (2.00 mL). Subsequently, lithium hydroxide (406.46 mg, 16.97 mmol, 17.52 eq) was added into the reaction system, and the mixture was stirred at 40 C. for 16 h. A saturated aqueous solution of potassium bisulfate was added dropwise to the reaction system until pH=5-6. Then the mixture was extracted with ethyl acetate (310 mL). The organic phases were combined, and successively washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-50:50) to give a crude product. The crude product was purified by preparative High Performance Liquid Chromatography to give Compound 70-d.

[0810] MS m/z (ESI): 550.3 [M+1].

Step 5: Compound 70

[0811] Compound 70-d (100.00 mg, 181.80 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 70.

[0812] MS m/z (ESI): 572.3 [M+23].

[0813] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.66 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.32-7.26 (m, 2H), 7.16-7.09 (m, 1H), 7.06 (br d, J=7.5 Hz, 2H), 6.75 (d, J=5.0 Hz, 2H), 3.95-3.82 (m, 1H), 3.76-3.65 (m, 2H), 3.60 (br dd, J=7.0, 11.0 Hz, 1H), 3.39-3.27 (m, 1H), 2.94-2.81 (m, 1H), 2.65-2.57 (m, 2H), 2.12 (d, J=3.0 Hz, 6H), 1.43 (s, 6H).

[0814] Chiral Analysis Conditions: chiral column: AS (250 mm30 mm, 10 m); mobile phase: 0.1% NH.sub.3H.sub.2O EtOH; flow rate: 80 mL/min; column temperature: 40 C.

[0815] Retention time of Compound 70: 3.827 min (peak 1).

Example 71: Compound 71

[0816] ##STR00171##

Step 1: Compound 71-a

[0817] Compound 44-h (5.00 g, 8.31 mmol, 1.00 eq), trifluoroacetic acid (9.47 g, 83.08 mmol, 6.15 mL, 10.00 eq) and dichloromethane (50.00 mL) was added into a dried round-bottom flask, and the resulted clear solution was stirred at 20 C. for 3 h. The reaction solution was concentrated under reduced pressure. The residue was isolated by flash column chromatography (petroleum ether:ethyl acetate=100:0-10:90) to give Compound 71-a.

[0818] MS m/z (ESI): 546.3 [M+1].

[0819] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.87 (d, J=8.4 Hz, 2H), 7.49-7.42 (m, 6H), 7.31 (s, 1H), 6.69 (s, 2H), 4.46-4.22 (m, 2H), 3.89 (s, 1H), 3.46 (s, 1H), 3.17-3.10 (m, 2H), 2.72-2.70 (m, 1H), 2.54 (s, 3H), 2.48-2.44 (m, 2H), 2.17 (s, 6H), 1.92-1.87 (m, 2H), 1.51 (s, 6H).

Step 2: Compound 71-b

[0820] 71-a (4.10 g, 7.51 mmol, 1.00 eq), oxalyl chloride (9.53 g, 75.10 mmol, 6.57 mL, 10.00 eq) and dichloromethane (40.00 mL) was added into a dried round-bottom flask, and the resulted clear solution was stirred at 20 C. for 1 h. The reaction system was concentrated under reduced pressure, and then ethanol (20.00 mL) was added. The solution was stirred at 20 C. for 1 h. A saturated aqueous solution of sodium carbonate was added dropwise into the reaction system until pH=8-9. The reaction system was extracted with ethyl acetate (100 mL) and water (100 mL). After phase separation, the organic phases were collected, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 71-b.

[0821] MS m/z (ESI): 574.3 [M+1].

[0822] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85 (t, J=8.4 Hz, 2H), 7.31-7.22 (m, 7H), 6.68 (s, 2H), 4.31-4.24 (m, 2H), 3.59-3.53 (m, 2H), 2.99-2.65 (m, 4H), 2.51 (s, 3H), 2.49-2.39 (m, 3H), 2.11 (s, 6H), 1.76-1.74 (m, 3H), 1.42 (s, 6H), 1.34 (t, J=7.2 Hz, 3H).

Step 3: Compound 71-c

[0823] At 20 C., -chloroethyl chloroformate (7.48 g, 52.30 mmol, 10.00 eq), Compound 71-b (3.00 g, 5.23 mmol, 1.00 eq) and anhydrous toluene (30.00 mL) was added into a pre-dried round-bottom flask of 100 mL, and the mixture was stirred at 80 C. for 16 h. The reaction solution was concentrated under reduced pressure, and was added with methanol (30.00 mL) and stirred at 80 C. for hours. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-10:90) to give Compound 71-c.

[0824] MS m/z (ESI): 484.2 [M+1].

[0825] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.84 (d, J=4.8 Hz, 2H), 7.28-7.25 (m, 2H), 6.66 (d, J=12.8 Hz, 2H), 4.29-4.24 (m, 2H), 3.89-3.51 (m, 4H), 3.18-3.02 (m, 1H), 2.53 (s, 1H), 2.49-2.46 (m, 2H), 2.12-2.08 (d, J=7.5 Hz, 6H), 1.40-1.32 (d, J=4.8 Hz, 6H).

Step 4: Compound 71-d

[0826] At 20 C., Compound 71-c (100.00 mg, 206.76 mol, 1.00 eq) was added into a pre-dried round-bottom flask of 100 mL, and then acetylchloride (12.98 mg, 165.41 mol, 11.80 L, 0.80 eq) and triethylamine (20.92 mg, 206.76 mol, 28.66 L, 1.00 eq) were added. The reaction system produced a substantial amount of white smoke. The reaction solution was stirred at 20 C. for 3 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (dichloromethane:methanol=100:0-30:70) to give Compound 71-d.

[0827] MS m/z (ESI): 526.3 [M+1].

Step 5: Compound 71

[0828] 71-d (50.00 mg, 95.11 mol, 1.00 eq), and then ethanol (6.00 mL) were added into a pre-dried flask of 50 mL. Next, lithium hydroxide (22.78 mg, 951.10 mol, 10.00 eq) and water (2.00 mL) were added into the reaction system. The reaction solution was stirred at 40 C. for 16 h. A saturated aqueous solution of potassium bisulfate was added dropwise to the reaction system until pH=6. The reaction mixture was extracted with ethyl acetate and water (1:1, 20 mL). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (310 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by thin layer chromatography (dichloromethane:methanol=10:1) to give a crude product which was further purified by preparative High Performance Liquid Chromatography to give Compound 71.

[0829] MS m/z (ESI): 498.3 [M+1].

[0830] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85 (br d, J=4.8 Hz, 2H), 7.30 (br d, J=8.3 Hz, 2H), 6.75 (br d, J=10.8 Hz, 2H), 3.83-3.70 (m, 3H), 3.50 (br s, 2H), 2.54 (d, J=6.0 Hz, 3H), 2.46 (br s, 3H), 2.20 (br d, J=16.8 Hz, 6H), 2.02 (br s, 3H), 1.83 (br s, 2H), 1.64-1.41 (m, 6H).

Example 72: Compound 72

[0831] ##STR00172##

Step 1: Compound 72-a

[0832] Iso-pentyl chloroformate (31.14 mg, 206.76 mol, 1.00 eq) and triethylamine (41.84 mg, 413.52 mol, 57.32 L, 2.00 eq) was added into a solution of Compound 71-c (100.00 mg, 206.76 mol, 1.00 eq) in dichloromethane (10.00 mL) The resulted clear solution was stirred at 20 C. for 1 h. The reaction solution was concentrated under reduced pressure. The residue was isolated and purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-50:50) to give Compound 72-a.

Step 2: Compound 72

[0833] Lithium hydroxide (20.03 mg, 836.40 mol, 10.00 eq) and water (2.00 mL) was added into a solution of Compound 72-a (50.00 mg, 83.64 mol, 1.00 eq) in ethanol solution (6.00 mL). The mixed solution was stirred at 40 C. for 16 h. The mixture was adjusted with a saturated aqueous solution of potassium bisulfate to pH=6, and treated by water and ethyl acetate (1:1, 20 mL). The aqueous phase was extracted with ethyl acetate (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10/1) to give a crude product which further was isolated by High Performance Liquid Chromatography to give Compound 72.

[0834] MS m/z (ESI): 570.4 [M+1].

[0835] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88-7.84 (m, 2H), 7.30 (br s, 2H), 6.74 (br s, 2H), 3.96 (br s, 2H), 3.77-3.62 (m, 4H), 2.98 (br d, J=9.3 Hz, 1H), 2.54 (s, 3H), 2.50 (br s, 2H), 2.19 (br d, J=13.1 Hz, 6H), 2.03 (br s, 2H), 1.53 (br s, 6H), 1.45 (br s, 4H), 0.89 (br d, J=3.8 Hz, 6H)

Example 73: Compound 73

[0836] ##STR00173##

Step 1: Compound 73-b

[0837] 73-a (22.35 mg, 310.14 mol, 1.50 eq) and acetic acid (1.24 mg, 20.68 mol, 1.18 L, 0.10 eq) was added into a solution of Compound 71-c (100.00 mg, 206.76 mol, 1.00 eq) in methanol (10.00 mL). The resulted clear solution was stirred at 20 C. for 1 h. Then, sodium cyanoborohydride (19.49 mg, 310.14 mol, 1.50 eq) was added into the reaction system and stirred at 20 C. for 16 h. The reaction solution was concentrated under reduced pressure. The residue was isolated and purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-10:90) to give Compound 73-b.

[0838] MS m/z (ESI): 540.3 [M+1].

Step 2: Compound 73

[0839] Lithium hydroxide (124.25 mg, 5.19 mmol, 20.00 eq) was added into a mixed solution of Compound 73-b (140.00 mg, 259.39 mol, 1.00 eq) in ethanol (10.00 mL) and water (5.00 mL). The resulted clear solution was stirred at 50 C. for 16 h. An 1N aqueous HCl solution was added dropwise to the reaction system until pH=6. The reaction system was diluted with 10 mL ethyl acetate/10 mL water. After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (10 mL3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol=10:1) to give a colorless oil crude product. The crude product was isolated and purified by preparative High Performance Liquid Chromatography to give Compound 73.

[0840] MS m/z (ESI): 512.3 [M+1].

[0841] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.92 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.72 (s, 2H), 4.79-4.71 (m, 4H), 3.97 (br s, 1H), 3.83 (br s, 1H), 3.54 (br s, 1H), 2.96 (br s, 1H), 2.84 (br s, 2H), 2.71-2.61 (m, 1H), 2.53 (s, 3H), 2.41-2.33 (m, 1H), 2.17 (s, 6H), 1.81 (br d, J=5.3 Hz, 3H), 1.48 (d, J=8.8 Hz, 6H)

Example 74: Compound 74

[0842] ##STR00174## ##STR00175##

Step 1: Compound 74-b

[0843] At 20 C., Compound 74-a (200.00 mg, 2.32 mmol, 210.53 L, 1.00 eq), triethylamine (704.91 mg, 6.97 mmol, 965.63 L, 3.00 eq) and tetrahydrofuran (10.00 mL) was added into a dried round-bottom flask, and then triphosgene (551.26 mg, 1.86 mmol, 0.80 eq) was added. The resulted suspension was stirred at 20 C. for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give Compound 74-b.

Step 2: Compound 74-c

[0844] At 20 C., Compound 74-b (46.08 mg, 310.14 mol, 1.50 eq), Compound 71-c (100.00 mg, 206.76 mol, 1.00 eq), triethylamine (41.84 mg, 413.52 mol, 57.32 L, 2.00 eq) and dichloromethane (10.00 mL) was added into a dried round-bottom flask, and the resulted clear solution was stirred at 20 C. for 1 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 74-c.

[0845] MS m/z (ESI): 596.4 [M+1].

Step 3: Compound 74-d

[0846] Compound 74-c (100.00 mg, 167.84 mol, 1.00 eq) and ethanol (6.00 mL) was added into a reaction flask and then lithium hydroxide (40.20 mg, 1.68 mmol, 10.00 eq) and water (2.00 mL) were added. The mixture was stirred at 40 C. for 16 h. An 1N aqueous HCl solution was added dropwise to the reaction system to pH=6. The reaction system was extracted with ethyl acetate (20 mL) and water (20 mL). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (310 mL). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol=10:1) to give Compound 74-d.

[0847] MS m/z (ESI): 590.2 [M+23].

Step 4: Compound 74

[0848] Compound 74-d (14.00 mg, 24.66 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 74.

[0849] MS m/z (ESI): 568.4 [M+1].

[0850] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85 (br s, 2H), 7.28-7.27 (m, 2H), 6.64 (br s, 2H), 3.89 (s, 1H), 3.70 (br s, 2H), 3.41 (br s, 1H), 3.12 (br s, 1H), 2.62 (s, 1H), 2.51 (br s, 5H), 2.03 (br s, 6H), 1.76-1.65 (m, 11H), 1.35-1.28 (m, 6H).

[0851] Chiral column: AS (250 mm30 mm, 10 m); mobile phase: 35% of methanol (0.05% DEA) in CO.sub.2; flow rate: 80 mL/min; column temperature: 40 C.

[0852] Retention time of Compound 74: 4.120 min (peak 1).

Example 75: Compound 75

[0853] ##STR00176## ##STR00177##

Step 1: Compound 75-a

[0854] At 20 C., Compound 71-c (200.00 mg, 413.51 mol, 1.00 eq), mesyl chloride (71.05 mg, 620.27 mol, 48.01 L, 1.50 eq), triethylamine (125.53 mg, 1.24 mmol, 171.96 L, 3.00 eq) and dichloromethane (10.00 mL) was added into a dried round-bottom flask, and the resulted clear solution was stirred at 20 C. for 1 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 75-a.

[0855] MS m/z (ESI): 584.2 [M+23].

[0856] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.89-7.81 (m, 2H), 7.30 (s, 2H), 6.74 (s, 2H), 4.33-4.27 (m, 2H), 3.84-3.77 (m, 2H), 3.56-3.50 (m, 1H), 3.33-3.31 (m, 2H), 2.96 (s, 3H), 2.65-2.47 (m, 6H), 2.19 (s, 6H), 1.90-1.79 (m, 2H), 1.49 (d, J=2.0 Hz, 6H), 1.37-1.35 (m, 3H).

Step 2: Compound 75-b

[0857] Compound 75-a (51.00 mg, 90.79 mol, 1.00 eq) and ethanol (6.00 mL) was added into a reaction flask of 100 mL, and then lithium hydroxide (21.74 mg, 907.88 mol, 10.00 eq) and water (2.00 mL) were added. The mixture was stirred at 40 C. for 16 h. A saturated aqueous solution of potassium bisulfate was added dropwise into the reaction system to pH=6. The reaction system was extracted with ethyl acetate (20 mL) and water (20 mL). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (310 mL). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol=10:1) to give Compound 75-b.

[0858] MS m/z (ESI): 534.3 [M+1].

Step 3: Compound 75

[0859] Compound 75-b (16.00 mg, 29.98 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 75.

[0860] MS m/z (ESI): 534.3 [M+1].

[0861] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.81 (d, J=8.5 Hz, 2H), 7.29 (s, 2H), 6.77 (s, 2H), 3.80-3.71 (m, 2H), 3.55-3.50 (m, 1H), 3.40 (dd, J=6.8, 9.8 Hz, 1H), 3.28 (dd, J=5.3, 9.8 Hz, 1H), 2.94 (s, 3H), 2.65-2.56 (m, 2H), 2.55 (s, 3H), 2.54-2.47 (m, 1H), 2.19 (s, 6H), 1.90-1.79 (m, 2H), 1.49 (d, J=2.0 Hz, 6H)

[0862] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 5 um); mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 60 mL/min; column temperature: 40 C.

[0863] Retention time of Compound 75: 4.725 min (peak 1).

Example 76: Compound 76

[0864] ##STR00178## ##STR00179##

Step 1: Compound 76-b

[0865] Cesium carbonate (388.20 g, 1.19 mol, 3.00 eq) and ethyl 2-bromo-isobutyrate (154.93 g, 794.30 mmol, 2.00 eq) was added into a solution of Compound 76-a (48.50 g, 397.15 mmol, 1.00 eq) in 1,4-dioxane (500.00 mL). The mixture was stirred at 90 C. for 1 h. The reaction mixture was filtered, and the filter cake was washed with ethanol (200 mL3). The combined filtrate was concentrated under reduced pressure to give Compound 76-b.

[0866] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.89 (s, 1H), 7.83-7.78 (m, 2H), 6.94-6.89 (m, 2H), 4.25-4.21 (m, 2H), 1.68 (s, 6H), 1.22 (t, J=7.2 Hz, 3H).

Step 2: Compound 76-c

[0867] Methoxymethyl triphenylphosphine chloride (28.29 g, 82.53 mmol, 1.50 eq) and tetrahydrofuran (200.00 mL) was added into a dried reaction flask, and then potassium tert-butoxide (10.69 g, 95.27 mmol, 1.73 eq) was added in batches at 20 C. After reacting for 1 hour, Compound 76-b (13.00 g, 55.02 mmol, 1.00 eq) was added into the reaction solution. The mixture was stirred at 20 C. for 1 h, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give Compound 76-c.

[0868] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.48-7.44 (m, 1H), 7.36-7.35 (m, 1H), 7.14-6.91 (m, 2H), 6.80-6.77 (m, 1H), 6.09-5.73 (m, 1H), 4.16-4.10 (m, 2H), 3.77-3.66 (m, 3H), 1.58 (s, 6H), 1.29-1.27 (m, 3H).

Step 3: Compound 76-d

[0869] Oxalyl chloride (15.99 g, 125.98 mmol, 11.03 mL, 2.00 eq) was slowly added into a solution of Compound 76-c (16.65 g, 62.99 mmol, 1.00 eq) in chloroform (200.00 mL) at 0 C., and then ethanol (5.80 g, 125.98 mmol, 7.34 mL, 2.00 eq) and water (2.27 g, 125.98 mmol, 2.27 mL, 2.00 eq) were added. The mixed solution was stirred at 0 C. for 1 h. A saturated aqueous sodium carbonate solution was added dropwise to the reaction system to pH 7-8. The reaction system was extracted with dichloromethane (20 mL) and water (20 mL). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (320 mL). The organic phases were combined and successively washed with water (320 mL) and saturated brine (320 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 76-d.

[0870] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.71 (t, J=2.4 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.87-6.81 (m, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.92-3.90 (m, 2H), 1.59 (s, 6H), 1.40-1.37 (m, 3H).

Step 4: Compound 76-e

[0871] Compound 44-f (23.79 g, 55.78 mmol, 1.00 eq) was added into a solution of Compound 76-d (13.96 g, 55.78 mmol, 1.00 eq) in tetrahydrofuran (150.00 mL). The mixture was stirred at 50 C. for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 76-e.

[0872] MS m/z (ESI): 399.1 [M+1].

[0873] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.93-7.83 (m, 2H), 7.30-7.27 (m, 3H), 7.21-7.06 (m, 2H), 6.85-6.76 (m, 3H), 4.27-4.21 (m, 2H), 3.84 (dd, J=1.0, 6.8 Hz, 1H), 3.57 (d, J=5.8 Hz, 1H), 2.53 (d, J=2.0 Hz, 3H), 1.59 (d, J=1.5 Hz, 6H), 1.27-1.25 (m, 3H)

Step 5: Compound 76-f

[0874] Trifluoroacetic acid (90.27 mg, 791.50 mol, 58.62 L, 0.05 eq) was added into a solution of Compound 76-e (6.31 g, 15.83 mmol, 1.00 eq) in 1,4-dioxane (350.00 mL), and then N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (11.28 g, 47.49 mmol, 3.00 eq) was slowly added. The mixture was stirred at 80 C. for 2 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 76-f.

[0875] MS m/z (ESI): 532.2 [M+1].

[0876] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.89-7.83 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.33-7.29 (m, 5H), 7.22-7.18 (m, 2H), 6.99 (d, J=8.3 Hz, 2H), 6.72-6.66 (m, 2H), 4.21-4.15 (m, 2H), 4.09-4.00 (m, 1H), 3.67-3.62 (m, 2H), 3.11-2.99 (m, 2H), 2.88-2.82 (m, 1H), 2.75-2.57 (m, 4H), 2.52-2.50 (m, 3H), 1.55-1.50 (m, 6H), 1.23-1.18 (m, 3H)

Step 6: Compound 76-g

[0877] Phenyl chloroformate (6.37 g, 40.70 mmol, 5.10 mL, 5.00 eq) was slowly added into a solution of Compound 76-f (4.33 g, 8.14 mmol, 1.00 eq) in chloroform (50.00 mL), and the mixture was stirred at 70 C. for 16 h. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 76-g.

[0878] MS m/z (ESI): 562.0 [M+1].

[0879] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.92-7.82 (m, 1H), 7.65-7.62 (m, 1H), 7.39-7.29 (m, 3H), 7.26-7.11 (m, 6H), 7.08-7.05 (m, 1H), 6.81-6.78 (m, 1H), 4.29-4.20 (m, 2H), 4.00-3.90 (m, 1H), 3.88-3.80 (m, 1H), 3.77-3.70 (m, 2H), 3.49-3.35 (m, 1H), 2.95-2.80 (m, 1H), 2.74 (dd, J=2.6, 7.7 Hz, 1H), 2.55-2.53 (m, 3H), 2.51-2.49 (m, 1H), 1.61-1.59 (m, 6H), 1.27-1.25 (m, 3H).

Step 7: Compound 76-h

[0880] Lithium hydroxide (766.40 mg, 32.00 mmol, 10.00 eq) and water (5.00 mL) was added into a solution of Compound 76-g (1.80 g, 3.20 mmol, 1.00 eq) in ethanol (15.00 mL), and the mixture was stirred at 40 C. for 4 h. A saturated aqueous solution of potassium bisulfate was added dropwise into the reaction system to pH=6. The reaction system was extracted with ethyl acetate (20 mL) and water (20 mL). After phase separation, the organic phases were collected. The aqueous phase was extracted with ethyl acetate (310 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-0:100) to give a crude product, which was further purified by High Performance Liquid Chromatography to give Compound 76-h.

[0881] MS m/z (ESI): 534.2 [M+1].

[0882] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (d, J=7.5 Hz, 2H), 7.39-7.33 (m, 2H), 7.26-7.18 (m, 3H), 7.16-7.09 (m, 4H), 6.91-6.85 (m, 2H), 4.00-3.87 (m, 1H), 3.84-3.73 (m, 2H), 3.67 (dd, J=6.5, 10.8 Hz, 1H), 3.51-3.35 (m, 1H), 3.02-2.91 (m, 1H), 2.78 (td, J=6.8, 13.9 Hz, 2H), 2.53 (s, 3H), 1.59 (br s, 6H).

Step 8: Compound 76

[0883] Compound 76-h (200.00 mg, 374.78 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 76.

[0884] MS m/z (ESI): 534.1 [M+1].

[0885] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (br dd, J=4.9, 7.9 Hz, 2H), 7.38-7.32 (m, 2H), 7.23-7.17 (m, 3H), 7.15-7.11 (m, 2H), 7.08-7.01 (m, 2H), 6.84 (br s, 2H), 3.98-3.85 (m, 1H), 3.84-3.69 (m, 2H), 3.68-3.60 (m, 1H), 3.47-3.30 (m, 1H), 2.95-2.81 (m, 1H), 2.80-2.65 (m, 2H), 2.51 (s, 3H), 1.53 (br s, 6H).

[0886] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: 55% of methanol (0.05% DEA) in CO.sub.2; flow rate: 80 mL/min; column temperature: 40 C. Retention time of Compound 76: 0.729 min (peak 1).

Example 77: Compound 77

[0887] ##STR00180##

Step 1: Compound 77-b

[0888] Cesium carbonate (179.48 g, 550.86 mmol, 3.00 eq) and ethyl 2-bromo-isobutyrate (71.63 g, 367.24 mmol, 53.86 mL, 2.00 eq) was added into a solution of Compound 77-a (25.00 g, 183.62 mmol, 1.00 eq) in 1,4-dioxane (500.00 mL), and stirred at 90 C. for 1 h. The reaction system was diluted with ethyl acetate (500 mL) and water (500 mL). The organic phase was washed with saturated brine (3500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 77-b.

[0889] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.83 (s, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.58 (dd, J=2.0, 8.5 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 4.23-4.17 (m, 2H), 2.27 (s, 3H), 1.66 (s, 6H), 1.20 (t, J=7.2 Hz, 3H).

Step 2: Compound 77-c

[0890] Methoxymethyl triphenylphosphine chloride (35.61 g, 103.88 mmol, 1.30 eq) and tetrahydrofuran (200.00 mL) was added into a dried reaction flask, and then potassium tert-butoxide (13.45 g, 119.87 mmol, 1.50 eq) was added in batches at 20 C. After reacting for 1 hour, Compound 77-b (20.00 g, 79.91 mmol, 1.00 eq) was added into the reaction solution. The mixture was stirred at 20 C. for 1 h, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-15:1) to give Compound Compound 77-c.

[0891] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.30-7.18 (m, 1H), 6.98-6.81 (m, 2H), 6.53 (dd, J=5.6, 8.4 Hz, 1H), 5.99-5.63 (m, 1H), 4.17 (dq, J=1.3, 7.1 Hz, 2H), 3.69-3.57 (m, 3H), 2.14 (d, J=3.5 Hz, 3H), 1.50 (s, 6H), 1.21-1.17 (m, 3H)

Step 3: Compound 77-d

[0892] Oxalyl chloride (12.51 g, 98.58 mmol, 8.63 mL, 2.00 eq) was slowly added into a solution of Compound 77-c (13.72 g, 49.29 mmol, 1.00 eq) in chloroform (150.00 mL) at 0 C., and then ethanol (4.54 g, 98.58 mmol, 5.75 mL, 2.00 eq) and water (1.78 g, 98.58 mmol, 1.78 mL, 2.00 eq) were added. The mixed solution was stirred 0 C. for 1 h. A saturated aqueous sodium carbonate solution was added dropwise into the reaction system to pH 7-8. Dichloromethane (20 mL) and water (20 mL) were added. After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (320 mL). The organic phases were combined and successively washed with water (320 mL) and saturated brine (320 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 77-d.

[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.69 (t, J=2.5 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.89 (dd, J=2.0, 8.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.56 (d, J=2.5 Hz, 2H), 2.23 (s, 3H), 1.59 (s, 6H), 1.27-1.24 (m, 3H).

Step 4: Compound 77-e

[0894] Compound 44-f (21.75 g, 51.00 mmol, 1.00 eq) was added into a solution of Compound 77-d (13.48 g, 51.00 mmol, 1.00 eq) in tetrahydrofuran (150.00 mL). The mixture was stirred at 50 C. for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 77-e.

[0895] MS m/z (ESI): 413.0 [M+1].

[0896] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.78-7.74 (m, 2H), 7.21-7.17 (m, 2H), 7.08 (td, J=6.8, 15.3 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.83-6.72 (m, 2H), 6.56 (d, J=8.3 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.45 (d, J=6.8 Hz, 2H), 2.44 (s, 3H), 2.14 (s, 3H), 1.51 (s, 6H), 1.20-1.17 (m, 3H).

Step 5: Compound 77-f

[0897] Trifluoroacetic acid (141.37 mg, 1.24 mmol, 91.80 L, 0.05 eq) was added into a solution of Compound 77-e (10.23 g, 24.80 mmol, 1.00 eq) in 1,4-dioxane (350.00 mL), and then N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (17.66 g, 74.39 mmol, 3.00 eq) was slowly added dropwise. The mixture was stirred at 80 C. for 2 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 77-f.

[0898] MS m/z (ESI): 546.3 [M+1].

[0899] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.27-7.20 (m, 3H), 7.17-7.15 (m, 3H), 7.10-7.07 (m, 4H), 6.58 (td, J=6.8, 10.7 Hz, 2H), 5.85 (d, J=10.5 Hz, 2H), 5.23 (s, 2H), 4.63-4.36 (m, 8H), 3.33 (br s, 3H), 2.94 (br s, 3H), 1.39-1.38 (m, 6H), 1.35-1.35 (m, 3H).

Step 6: Compound 77-g

[0900] Phenyl chloroformate (4.30 g, 27.49 mmol, 3.44 mL, 5.00 eq) was slowly added into a solution of Compound 77-f (3.00 g, 5.50 mmol, 1.00 eq) in chloroform (50.00 mL), and the mixture was stirred at 70 C. for 4 h. The mixture was concentrated under reduced pressure to give a crude product.

[0901] The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 77-g.

[0902] MS m/z (ESI): 576.1 [M+1].

[0903] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.61 (t, J=8.9 Hz, 2H), 7.38-7.33 (m, 2H), 7.22-7.18 (m, 3H), 7.16-7.12 (m, 2H), 6.96 (br s, 1H), 6.87 (br d, J=8.3 Hz, 1H), 6.61 (dd, J=2.0, 8.3 Hz, 1H), 4.25 (dq, J=2.0, 7.1 Hz, 2H), 3.94-3.88 (m, 1H), 3.86-3.78 (m, 1H), 3.76-3.58 (m, 2H), 3.49-3.36 (m, 1H), 2.91-2.78 (m, 1H), 2.72-2.67 (m, 2H), 2.52 (s, 3H), 2.19 (d, J=2.0 Hz, 3H), 1.60 (s, 6H), 1.26 (s, 3H).

Step 7: Compound 77-h

[0904] Lithium hydroxide (1.04 g, 43.40 mmol, 10.00 eq) and water (7.00 mL) was added into a solution of Compound 77-g (2.50 g, 4.34 mmol, 1.00 eq) in ethanol (21.00 mL), and the mixture was stirred at 30 C. for 1 h. A saturated aqueous solution of potassium bisulfate was added dropwise to the reaction system to pH=6. The reaction system was extracted with ethyl acetate (20 mL) and water (20 mL). After phase separation, the organic phases were collected. The aqueous phase was extracted with ethyl acetate (310 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue of 1.5 g. A crude product of 0.5 g was taken from the residue, and purified by High Performance Liquid Chromatography to give Compound 77-h.

[0905] MS m/z (ESI): 548.3 [M+1].

[0906] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.59 (br d, J=7.8 Hz, 2H), 7.27 (br d, J=7.3 Hz, 2H), 7.14 (br d, J=7.8 Hz, 3H), 7.06 (br d, J=7.3 Hz, 2H), 6.92 (br s, 1H), 6.82 (br s, 1H), 6.69 (br s, 1H), 3.91-3.80 (m, 1H), 3.73 (br s, 1H), 3.68-3.55 (m, 2H), 3.40-3.26 (m, 1H), 2.92-2.79 (m, 1H), 2.63 (br s, 2H), 2.45 (s, 3H), 2.11 (br s, 3H), 1.51 (br s, 6H).

Step 8: Compound 77

[0907] Compound 77-h (100.00 g, 182.60 mmol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 77.

[0908] MS m/z (ESI): 548.1 [M+1].

[0909] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (br s, 2H), 7.33 (br d, J=7.5 Hz, 2H), 7.18 (br s, 3H), 7.13 (br s, 2H), 7.06-7.01 (m, 1H), 6.95 (br s, 1H), 6.85 (br s, 1H), 3.88-3.54 (m, 5H), 2.84 (br s, 1H), 2.68 (br s, 2H), 2.50 (br s, 3H), 2.15 (br s, 3H), 1.52 (br s, 6H).

[0910] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: 50% of methanol (0.05% DEA) in CO.sub.2; flow rate: 80 mL/min; column temperature: 40 C.

[0911] Retention time of Compound 77: 0.564 min (peak 1).

Example 78: Compound 78

[0912] ##STR00181## ##STR00182##

Step 1: Compound 78-b

[0913] Cesium carbonate (345.33 g, 10.71 mmol, 3.00 eq) and ethyl 2-bromo-isobutyrate (137.82 g, 706.58 mmol, 2.00 eq) was added into a solution of Compound 78-a (49.5 g, 353.29 mmol, 1.00 eq) in 1,4-dioxane (500.00 mL) and N,N-dimethylformamide (200 mL) at 25 C. The mixture was stirred at 90 C. for 16 h. Water (800 mL) was added into the reaction mixture, and extracted with ethyl acetate (300 mL3). The combined organic phase was washed with water (300 mL3) and saturated brine (300 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, so as to give Compound 78-b.

[0914] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.79 (d, J=2.0 Hz, 1H), 7.54 (dd, J=2.0, 10.8 Hz, 1H), 7.51-7.44 (m, 1H), 7.51-7.44 (m, 1H), 6.89 (t, J=8.0 Hz, 1H), 4.19-4.15 (m, 2H), 1.61 (s, 6H), 1.18 (t, J=7.2 Hz, 3H)

Step 2: Compound 78-c

[0915] Under nitrogen protection, methoxymethyl triphenylphosphine chloride (26.29 g, 76.70 mmol, 1.30 eq) and tetrahydrofuran (120 mL) was added into a reaction flask, and then potassium tert-butoxide (7.94 g, 70.80 mmol, 1.20 eq) was added in batches at 0 C. The reaction system was stirred at 0 C. for 1 h. Then, a solution of Compound 78-b (15.00 g, 59.00 mmol, 1.00 eq) in tetrahydrofuran (30 mL) was added dropwise to the reaction solution. The reaction system was stirred at 0 C. for additional 30 min. The reaction mixture was quenched with a saturated solution of ammonium chloride (30 mL), and extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL3) and saturated brine (100 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-80:20) to give Compound 78-c.

[0916] MS m/z (ESI): 283.0 [M+1].

[0917] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.36 (dd, J=2.1, 12.9 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 7.05-6.75 (m, 3H), 6.04 (d, J=6.8 Hz, 1H), 5.63 (d, J=13.1 Hz, 1H), 5.06 (d, J=7.0 Hz, 1H), 4.21-4.14 (m, 2H), 3.72-3.56 (m, 3H), 1.49 (s, 6H), 1.22 (dt, J=1.3, 7.2 Hz, 3H)

Step 3: Compound 78-d

[0918] Oxalyl chloride (10.79 g, 7.44 mL, 85.02 mmol, 2.00 eq) was slowly added dropwise into a solution of Compound 78-c (12 g, 42.51 mmol, 1.00 eq) in chloroform (100 mL) at 15 C., and then ethanol (3.92 g, 4.96 mL, 85.02 mmol, 2.00 eq) and water (1.53 g, 85.02 mmol, 2.00 eq) were successively added dropwise. The reaction mixture was stirred at 15 C. for additional 30 min. The mixture was adjusted with a saturated solution of sodium bicarbonate to pH=7-8. The organic phase was washed with water (50 mL2) and saturated brine (50 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, so as to give Compound 78-d.

[0919] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.66 (t, J=2.3 Hz, 1H), 6.93-6.85 (m, 2H), 6.85-6.72 (m, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.56 (d, J=2.0 Hz, 2H), 1.51 (s, 6H), 1.21 (t, J=7.2 Hz, 3H)

Step 4: Compound 78-e

[0920] Compound 44-f (19.08 g, 44.73 mmol, 1.00 eq) was added into a solution of Compound 78-d (12 g, 44.73 mmol, 1.00 eq) in tetrahydrofuran (120 mL). The mixture was stirred at 55 C. for 12 h. The mixture was concentrated under reduced pressure to give a crude product. The residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-80:20) to give Compound 78-e.

[0921] MS m/z (ESI): 417.0 [M+1].

[0922] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85-7.73 (m, 2H), 7.23-7.17 (m, 2H), 7.11-6.29 (m, 5H), 4.18 (dq, J=3.6, 7.2 Hz, 2H), 3.77 (d, J=6.3 Hz, 1H), 3.49 (d, J=6.0 Hz, 1H), 2.45 (d, J=1.5 Hz, 3H), 1.50 (d, J=1.8 Hz, 6H), 1.21 (dt, J=4.5, 7.2 Hz, 3H).

Step 5: Compound 78-f

[0923] Trifluoroacetic acid (134.14 mg, 1.18 mmol, 0.05 eq) was added into a solution of Compound 78-e (9.8 g, 23.53 mmol, 1.00 eq) in 1,4-dioxane (250 mL), and then the reaction system was warmed to 80 C. Then, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (16.76 g, 70.59 mmol, 3.00 eq) in 1,4-dioxane (50 mL) was added dropwise into the reaction solution. The reaction mixture was stirred at 80 C. for additional 30 min. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-80:20) to give Compound 78-f.

[0924] MS m/z (ESI): 550.1 [M+1].

Step 6: Compound 78-g

[0925] Phenyl chloroformate (3.85 g, 24.57 mmol, 3.00 eq) was added into a solution of Compound 78-f (4.5 g, 8.19 mmol, 1.00 eq) in chloroform (50 mL) at 15 C. The reaction system was reacted at 70 C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-80:20) to give Compound 78-g.

[0926] MS m/z (ESI): 580.1 [M+23].

[0927] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.62 (dd, J=6.4, 8.4 Hz, 2H), 7.31-7.26 (m, 2H), 7.19-7.04 (m, 5H), 6.89-6.73 (m, 3H), 4.18 (dq, J=1.8, 7.1 Hz, 2H), 3.93-3.83 (m, 1H), 3.78-3.54 (m, 3H), 3.41-3.22 (m, 1H), 2.98-2.77 (m, 1H), 2.75-2.55 (m, 2H), 2.46 (s, 3H), 1.50 (s, 6H), 1.22-1.19 (m, 3H).

Step 7: Compound 78-h

[0928] A solution of lithium hydroxide monohydrate (434.29 mg, 10.35 mmol, 3.00 eq) in water (4.00 mL) was slowly added into a solution of Compound 78-g (2.00 g, 3.45 mmol, 1.00 eq) in tetrahydrofuran (10 mL) and ethanol (10 mL). The reaction mixture was stirred at 25 C. for 6 h. The reaction system was adjusted with a saturated aqueous solution of potassium bisulfate to pH=5-6, and extracted with ethyl acetate (20 mL3). The combined organic phase was washed with water (10 mL3) and saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 78-h.

[0929] MS m/z (ESI): 552.1 [M+23].

[0930] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.66 (d, J=8.5 Hz, 2H), 7.33-7.24 (m, 2H), 7.19-7.16 (m, 2H), 7.15-7.09 (m, 1H), 7.05 (d, J=7.5 Hz, 2H), 6.96-6.85 (m, 2H), 6.84-6.78 (m, 1H), 3.96-3.84 (m, 1H), 3.79-3.51 (m, 3H), 3.44-3.23 (m, 1H), 3.00-2.82 (m, 1H), 2.78-2.69 (m, 1H), 2.65-2.57 (m, 1H), 2.46 (s, 3H), 1.51-1.46 (m, 6H).

Step 8: Compound 78

[0931] Compound 78-h (220 mg, 398.83 mmol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 78.

[0932] MS m/z (ESI): 574.1 [M+23].

[0933] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (dd, J=2.5, 8.5 Hz, 2H), 7.31-7.23 (m, 2H), 7.19-7.08 (m, 3H), 7.04 (d, J=7.8 Hz, 2H), 6.96-6.70 (m, 3H), 3.99-3.81 (m, 1H), 3.77-3.47 (m, 3H), 3.39-3.18 (m, 1H), 2.99-2.81 (m, 1H), 2.76-2.52 (m, 2H), 2.45 (s, 3H), 1.44 (br s, 6H).

[0934] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; flow rate: 80 mL/min; column temperature: 40 C.

[0935] Retention time of Compound 78: 0.651 min (peak 1).

Example 79: Compound 79

[0936] ##STR00183## ##STR00184##

Step 1: Compound 79-b

[0937] Cesium carbonate (65.08 g, 10.71 mmol, 1.50 eq) and bromoethyl acetate (33.36 g, 199.75 mmol, 1.50 eq) was added into a solution of Compound 79-a (20 g, 133.17 mmol, 1.00 eq) in acetone (200.00 mL). The mixture was stirred at 60 C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give Compound 79-b.

[0938] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.91-9.85 (m, 1H), 7.56 (s, 2H), 4.46 (s, 2H), 4.34-4.27 (m, 2H), 2.37 (s, 6H), 1.33 (t, J=7.2 Hz, 3H).

Step 2: Compound 79-c

[0939] Sodium ethoxide (5.62 g, 82.54 mmol, 1.30 eq) was added into a solution of methoxymethyl triphenylphosphine chloride (32.65 g, 95.23 mmol, 1.50 eq) in tetrahydrofuran (120 mL) in batches at 0 C., and then a solution of 79-b (15.00 g, 63.49 mmol, 1.00 eq) in tetrahydrofuran (30 mL) was added dropwise. The reaction mixture was stirred at 20 C. for additional 12 h, and then quenched with water (100 mL), extracted with ethyl acetate (200 mL3). The combined organic phase was washed with water (100 mL3) and saturated brine (100 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:0-80:20) to give Compound 79-c.

[0940] MS m/z (ESI): 265.1 [M+1].

[0941] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.25 (s, 1H), 6.97 (d, J=13.1 Hz, 1H), 6.90 (s, 1H), 6.09 (d, J=7.0 Hz, 1H), 5.73 (d, J=13.1 Hz, 1H), 5.13 (d, J=7.0 Hz, 1H), 4.40 (s, 2H), 4.32 (q, J=7.0 Hz, 2H), 3.80-3.67 (m, 3H), 2.29 (d, J=3.5 Hz, 6H), 1.36 (t, J=7.2 Hz, 3H).

Step 3: Compound 79-d

[0942] Oxalyl chloride (3.36 g, 2.32 mL, 26.48 mmol, 2.00 eq) was added dropwise into a solution of Compound 79-c (3.5 g, 13.24 mmol, 1.00 eq) in chloroform (35 mL) at 0 C. After completion of the addition, ethanol (1.22 g, 1.54 mL, 26.48 mmol, 2.00 eq) and water (477.22 mg, 26.48 mmol, 2.00 eq) were successively added dropwise into the reaction solution. The mixture was stirred at 0 C. for additional 30 min. The mixture was adjusted with a saturated solution of sodium bicarbonate to pH=7-8. The organic phase was washed with water (200 mL2) and saturated brine (200 mL2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, so as to give Compound 79-d.

[0943] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.64 (t, J=2.4 Hz, 1H), 6.79 (s, 2H), 4.33 (s, 2H), 4.23 (q, J=7.0 Hz, 2H), 3.50 (d, J=2.3 Hz, 2H), 2.22 (s, 6H), 1.31 (t, J=7.2 Hz, 3H)

Step 4: Compound 79-e

[0944] 1-(4-(methylthio) phenyl-2-(triphenylphosphoranyl))ethanone 44-f (5.96 g, 12.57 mmol, 1.00 eq) was added into a solution of Compound 79-d (3.50 g, 13.98 mmol, 1.00 eq) in tetrahydrofuran (50 mL). The mixture was stirred at 55 C. for 12 h. The mixture was concentrated under reduced pressure to give a crude product. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 79-e.

[0945] MS m/z (ESI): 399.1 [M+1].

[0946] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88-7.73 (m, 2H), 7.24-7.18 (m, 2H), 7.11-7.03 (m, 0.5H), 6.83-6.73 (m, 2H), 6.39-6.21 (m, 0.5H), 4.33-4.29 (m, 2H), 4.27-4.18 (m, 2H), 2.45 (s, 2H), 2.23-2.19 (m, 6H), 1.29-1.23 (m, 3H).

Step 5: Compound 79-f

[0947] Trifluoroacetic acid (48.64 mg, 426.58 mol, 0.05 eq) was added into a solution of Compound 79-e (3.4 g, 8.53 mmol, 1.00 eq) in 1,4-dioxane (170 mL), and warmed to 80 C. Then, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (5.68 g, 25.59 mmol, 3.00 eq) in 1,4-dioxane (30 mL) was slowly added dropwise to the reaction system. The mixture was stirred for additional 30 min. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 79-f.

[0948] MS m/z (ESI): 532.3 [M+1].

[0949] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.55 (d, J=8.5 Hz, 2H), 7.19-7.14 (m, 5H), 7.04 (d, J=8.5 Hz, 2H), 6.59 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 4.10 (s, 2H), 3.58-3.45 (m, 3H), 2.99-2.79 (m, 2H), 2.59-2.41 (m, 5H), 2.37 (s, 3H), 2.00 (s, 6H), 1.18 (t, J=7.2 Hz, 3H)

Step 6: Compound 79-g

[0950] Phenyl chloroformate (2.30 g, 14.67 mmol, 3.00 eq) was added into a solution of Compound 79-f (2.60 g, 4.89 mmol, 1.00 eq) in chloroform (30 mL), and the reaction system was reacted at 70 C. for 1 h. The mixture was concentrated under reduced pressure to give a crude product. The residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-80:20) to give Compound 79-g.

[0951] MS m/z (ESI): 562.3 [M+1].

[0952] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.59 (dd, J=5.5, 8.5 Hz, 2H), 7.32-7.24 (m, 2H), 7.16-7.09 (m, 3H), 7.09-7.03 (m, 2H), 6.73 (d, J=4.8 Hz, 2H), 4.29 (d, J=2.3 Hz, 2H), 4.23 (dq, J=1.1, 7.2 Hz, 2H), 3.91-3.80 (m, 1H), 3.78-3.72 (m, 1H), 3.61-3.55 (m, 1H), 3.40-3.25 (m, 1H), 2.93-2.76 (m, 1H), 2.60 (br d, J=7.3 Hz, 1H), 2.45 (s, 3H), 2.17 (d, J=3.0 Hz, 6H), 1.28-1.24 (m, 3H).

Step 7: Compound 79-h

[0953] A solution of lithium hydroxide monohydrate (402.82 mg, 10.35 mmol, 3.00 eq) in water (4.00 mL) was added into a solution of Compound 79-g (1.80 g, 3.20 mmol, 1.00 eq) in tetrahydrofuran (10 mL) and ethanol (10 mL) at 0 C. The reaction mixture was stirred at 25 C. for 2 h. The reaction system was adjusted with a saturated aqueous solution of potassium bisulfate to pH=5-6, and extracted with ethyl acetate (20 mL3). The combined organic phase was washed with water (10 mL3) and saturated brine (10 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 79-h.

[0954] MS m/z (ESI): 534.1 [M+1].

[0955] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.63 (dd, J=1.5, 8.5 Hz, 2H), 7.33-7.25 (m, 2H), 7.18-7.02 (m, 5H), 6.75 (d, J=6.3 Hz, 1H), 6.79-6.72 (m, 1H), 4.34 (d, J=3.0 Hz, 2H), 3.93-3.83 (m, 1H), 3.75-3.56 (m, 3H), 3.40-3.23 (m, 1H), 2.98-2.78 (m, 1H), 2.71-2.52 (m, 2H), 2.46 (s, 3H), 2.16 (d, J=4.3 Hz, 6H).

Step 8: Compound 79

[0956] The raw material 79-h (250 mg, 468.48 mmol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 79.

[0957] MS m/z (ESI): 534.1 [M+1].

[0958] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.62 (d, J=8.5 Hz, 2H), 7.30-7.22 (m, 2H), 7.16-7.08 (m, 3H), 7.04 (br d, J=8.0 Hz, 2H), 4.19 (br s, 1H), 4.27-4.07 (m, 1H), 3.93-3.78 (m, 1H), 3.74-3.48 (m, 3H), 3.37-3.17 (m, 1H), 2.95-2.74 (m, 1H), 2.68-2.46 (m, 2H), 2.43 (s, 3H), 2.09 (br d, J=5.0 Hz, 6H).

[0959] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; flow rate: 80 mL/min; column temperature: 40 C.

[0960] Retention time of Compound 79: 0.600 min (peak 1).

Example 80: Compound 80

[0961] ##STR00185## ##STR00186##

Step 1: Compound 80-a

[0962] A saturated aqueous solution of potassium carbonate (63.49 mmol, 100.00 mL, 1.00 eq) was added into a solution of Compound 76-b (15.00 g, 63.49 mmol, 1.00 eq), ((1,3-dioxolan-2-yl)methyl)triphenylphosphine bromide (35.43 g, 82.54 mmol, 1.30 eq), 2-(2-methoxyethoxy)-N,N-di[2-(2-methoxyethoxy) ethyl]ethylamine (14.37 g, 44.44 mmol, 0.70 eq) in dichloromethane (100.00 mL). The reaction system was stirred at 40 C. for 20 h. The reaction system was diluted with (dichloromethane/water=1:1, 200 mL). The aqueous phase was extracted with dichloromethane (300 mL3), and the combined organic phase was washed with saturated brine (300 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 80-a.

[0963] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.24-7.17 (m, 2H), 6.75-6.69 (m, 2H), 6.67-6.59 (m, 1H), 6.00-5.53 (m, 1H), 5.47-5.30 (m, 1H), 4.15 (dq, J=4.0, 7.1 Hz, 2H), 4.07-3.82 (m, 4H), 1.53 (d, J=2.8 Hz, 6H), 1.20-1.12 (m, 3H).

Step 2: Compound 80-b

[0964] Under argon protection, palladium hydroxide (458.43 mg, 653.00 mol, 20% purity, 0.05 eq) was added into a solution of Compound 80-a (4.00 g, 13.06 mmol, 1.00 eq) in ethanol (50.00 mL). The reaction system was stirred at 50 C. for 5 h in hydrogen (50 psi) atmosphere. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3100 mL). The combined organic phase was concentrated under reduced pressure to give Compound 80-b.

[0965] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.06 (d, J=8.5 Hz, 2H), 6.79-6.74 (m, 2H), 4.23 (q, J=7.3 Hz, 2H), 4.03-3.83 (m, 4H), 2.72-2.64 (m, 2H), 1.98-1.88 (m, 2H), 1.57 (s, 6H), 1.25 (t, J=7.2 Hz, 3H).

Step 3: Compound 80-c

[0966] A 2N aqueous HCl solution (18.00 mL) was added into a solution of Compound 80-b (3.00 g, 9.73 mmol, 1.00 eq) in tetrahydrofuran (18.00 mL). The reaction system was stirred at 70 C. for 3 h. Water (50 mL) was added into the mixture, and extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL3) and saturated brine (100 mL3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 80-c.

[0967] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.73 (s, 1H), 7.00-6.96 (m, 2H), 6.72-6.68 (m, 2H), 4.16 (q, J=7.0 Hz, 2H), 2.86-2.78 (m, 2H), 2.70-2.62 (m, 2H), 1.50 (s, 6H), 1.18 (t, J=7.2 Hz, 3H).

Step 4: Compound 80-d

[0968] Compound 44-f (3.07 g, 7.19 mmol, 1.00 eq) was added into a solution of Compound 80-c (1.90 g, 7.19 mmol, 1.00 eq) in tetrahydrofuran (20.00 mL), and the mixture was stirred at 50 C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution: petroleum ether:ethyl acetate=100:0-90:10) to give Compound 80-d.

[0969] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85-7.79 (m, 2H), 7.29-7.26 (m, 2H), 7.10-7.02 (m, 3H), 6.87-6.77 (m, 3H), 4.26-4.20 (m, 2H), 2.81-2.76 (m, 2H), 2.64-2.57 (m, 2H), 2.53 (s, 3H), 1.58 (s, 6H), 1.25 (t, J=7.2 Hz, 3H).

Step 5: Compound 80-e

[0970] Trifluoroacetic acid (23.49 mg, 206.04 mol, 15.26 L, 0.05 eq) was added into a solution of Compound 80-d (1.7 g, 4.12 mmol, 1.00 eq) and 1,4-dioxane (100 mL), and warmed to 80 C. Then, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (2.93 g, 12.36 mmol, 3.00 eq) in 1,4-dioxane (10 mL) was slowly added dropwise into the reaction solution. After the completion of the addition, the reaction solution was stirred at 80 C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 80-e.

[0971] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.87 (d, J=8.8 Hz, 2H), 7.34-7.29 (m, 5H), 7.26-7.24 (m, 2H), 6.96 (d, J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 4.13 (q, J=7.0 Hz, 2H), 3.71-3.53 (m, 4H), 3.05-2.98 (m, 1H), 2.92-2.78 (m, 2H), 2.69-2.61 (m, 1H), 2.52 (s, 3H), 2.48-2.40 (m, 2H), 1.81-1.71 (m, 2H), 1.56 (s, 6H), 1.26-1.22 (m, 3H).

Step 6: Compound 80-f

[0972] Phenyl chloroformate (2.30 g, 14.66 mmol, 1.84 mL, 5.00 eq) was added into a solution of Compound 80-e (1.60 g, 2.93 mmol, 1.00 eq) in chloroform (20.00 mL), and stirred at 70 C. for 16 h. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 80-f.

[0973] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88 (br dd, J=3.4, 8.4 Hz, 2H), 7.43-7.28 (m, 4H), 7.25-7.11 (m, 3H), 7.06-6.98 (m, 2H), 6.82-6.74 (m, 2H), 4.28-4.19 (m, 2H), 4.03-3.54 (m, 4H), 3.43-3.27 (m, 1H), 2.89-2.71 (m, 1H), 2.67-2.51 (m, 5H), 1.93-1.65 (m, 2H), 1.60-1.54 (m, 6H), 1.30-1.26 (m, 3H).

Step 7: Compound 80-g

[0974] A solution of lithium hydroxide (270.40 mg, 11.29 mmol, 5.00 eq) in water (2.00 mL) was added into a solution of Compound 80-f (1.30 g, 2.26 mmol, 1.00 eq) in ethanol (6.00 mL) and tetrahydrofuran (6.00 mL). The mixture was stirred at 40 C. for 4 h. The reaction system was adjusted with a saturated aqueous solution of potassium bisulfate to pH=5-6, and then was extracted with ethyl acetate (310 mL). The combined organic phase was successively washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by High Performance Liquid Chromatography to give Compound 80-g.

[0975] MS m/z (ESI): 548.1 [M+1].

Step 8: Compound 80

[0976] Compound 80-g (400.00 mg, 0.73 mmol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 80.

[0977] MS m/z (ESI): 548.1 [M+1].

[0978] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.87 (dd, J=5.4, 8.4 Hz, 2H), 7.39-7.27 (m, 4H), 7.23-7.10 (m, 3H), 7.08-7.02 (m, 2H), 6.86 (d, J=8.3 Hz, 2H), 4.03-3.53 (m, 4H), 3.42-3.15 (m, 1H), 2.87-2.66 (m, 1H), 2.64-2.56 (m, 2H), 2.53 (d, J=1.8 Hz, 3H), 1.93-1.62 (m, 2H), 1.57 (d, J=9.3 Hz, 6H).

[0979] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; flow rate: 80 mL/min; column temperature: 40 C.

[0980] Retention time of Compound 80: 2.054 min (peak 1).

Example 81: Compound 81

[0981] ##STR00187## ##STR00188##

Step 1: Compound 81-a

[0982] A saturated aqueous solution of potassium carbonate (79.91 mmol, 100.00 mL, 1.00 eq) was added into a solution of Compound 77-b (20.00 g, 79.91 mmol, 1.00 eq), ((1,3-dioxolan-2-yl)methyl)triphenylphosphine bromide (44.59 g, 103.88 mmol, 1.30 eq) and 2-(2-methoxyethoxy)-N,N-di[2-(2-methoxyethoxy) ethyl]ethylamine (8.09 g, 55.94 mmol, 17.91 mL, 0.70 eq) in dichloromethane (100.00 mL). The reaction system was stirred at 40 C. for 20 h. The reaction system was diluted with (dichloromethane/water=1:1, 200 mL). The aqueous phase was extracted with dichloromethane (300 mL3), and the combined organic phase was washed with saturated brine (300 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 81-a.

[0983] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.24-7.08 (m, 2H), 6.73-6.57 (m, 2H), 6.11-5.35 (m, 2H), 4.30-4.22 (m, 2H), 4.07-3.91 (m, 4H), 2.22 (d, J=5.0 Hz, 3H), 1.60 (d, J=2.8 Hz, 6H), 1.29-1.24 (m, 3H).

Step 2: Compound 81-b

[0984] Under argon protection, palladium hydroxide (657.53 mg, 936.39 mol, 20% purity, 0.05 eq) was added into a solution of Compound 81-a (6.00 g, 18.73 mmol, 1.00 eq) in ethanol (50.00 mL). The reaction system was stirred at 50 C. for 5 h in hydrogen (50 psi) atmosphere. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3100 mL). The combined organic phase was concentrated under reduced pressure to give Compound 81-b.

[0985] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 6.98 (d, J=1.8 Hz, 1H), 6.87 (dd, J=2.0, 8.3 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 4.87 (t, J=4.8 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.02-3.84 (m, 4H), 2.68-2.61 (m, 2H), 2.21 (s, 3H), 1.96-1.90 (m, 2H), 1.57 (s, 6H), 1.26 (t, J=7.2 Hz, 3H).

Step 3: Compound 81-c

[0986] An aqueous HCl solution (2 M, 24.00 mL) was added into a solution of Compound 81-b (4.50 g, 13.96 mmol, 1.00 eq) in tetrahydrofuran (24.00 mL) at 25 C. The mixture was stirred at 70 C. for 2 h. Water (50 mL) was added into the reaction system, and was extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 81-c.

[0987] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.81 (t, J=1.4 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.85 (dd, J=2.0, 8.3 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 4.28-4.23 (m, 2H), 2.89-2.82 (m, 2H), 2.76-2.70 (m, 2H), 2.21 (s, 3H), 1.58 (s, 6H), 1.26 (t, J=7.2 Hz, 3H).

Step 4: Compound 81-d

[0988] Compound 44-f (4.75 g, 11.14 mmol, 1.00 eq) was added into a solution of Compound 81-c (3.10 g, 11.14 mmol, 1.00 eq) in tetrahydrofuran (30.00 mL), and then was stirred at 50 C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-90:10) to give Compound 81-d.

[0989] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.74 (d, J=8.3 Hz, 2H), 7.21-7.17 (m, 2H), 7.02-6.89 (m, 2H), 6.82-6.72 (m, 2H), 6.53 (d, J=8.3 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.70-2.62 (m, 2H), 2.51 (q, J=7.3 Hz, 2H), 2.45 (s, 3H), 2.14 (s, 3H), 1.50 (s, 6H), 1.20-1.16 (m, 3H).

Step 5: Compound 81-e

[0990] Trifluoroacetic acid (40.09 mg, 351.50 mol, 26.03 L, 0.05 eq) was added into a solution of Compound 81-d (3.00 g, 7.03 mmol, 1.00 eq) in 1,4-dioxane (200 mL), and warmed to 80 C. Then, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (5.01 g, 21.09 mmol, 3.00 eq) in 1,4-dioxane (20 mL) was slowly added dropwise, and stirred at 80 C. for additional 1 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 81-e.

[0991] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.81 (d, J=8.5 Hz, 2H), 7.27-7.18 (m, 7H), 6.82 (d, J=1.8 Hz, 1H), 6.71 (dd, J=2.0, 8.3 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.73-3.53 (m, 4H), 3.00-2.93 (m, 1H), 2.85-2.70 (m, 2H), 2.60 (dd, J=7.0, 9.3 Hz, 1H), 2.50-2.39 (m, 5H), 2.11 (s, 3H), 1.75-1.67 (m, 2H), 1.50 (s, 6H), 1.26-1.20 (m, 3H).

Step 6: Compound 81-f

[0992] Phenyl chloroformate (5.03 g, 32.15 mmol, 4.02 mL, 5.00 eq) was added into a solution of Compound 81-e (3.60 g, 6.43 mmol, 1.00 eq) in chloroform (40.00 mL), and stirred at 70 C. for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 81-f.

[0993] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.87 (dd, J=3.3, 8.5 Hz, 2H), 7.40-7.33 (m, 2H), 7.31-7.27 (m, 2H), 7.24-7.11 (m, 3H), 6.94-6.89 (m, 1H), 6.84-6.78 (m, 1H), 6.57 (dd, J=2.8, 8.3 Hz, 1H), 4.29-4.20 (m, 2H), 4.03-3.55 (m, 4H), 3.46-3.27 (m, 1H), 2.89-2.69 (m, 1H), 2.62-2.47 (m, 5H), 2.19 (s, 3H), 1.91-1.64 (m, 2H), 1.56 (s, 6H), 1.29-1.26 (m, 3H).

Step 7: Compound 81-g

[0994] A solution of lithium hydroxide (467.03 mg, 19.50 mmol, 5.00 eq) in water (3.00 mL) was added into a solution of Compound 81-f (2.30 g, 3.90 mmol, 1.00 eq) in ethanol (9.00 mL) and tetrahydrofuran (9.00 mL), and then was stirred at 40 C. for 4 h. The reaction system was adjusted with a saturated aqueous solution of potassium bisulfate to pH=5-6, and then the mixture was extracted with ethyl acetate (310 mL). The combined organic phase was successively washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by High Performance Liquid Chromatography to give Compound 81-g.

[0995] MS m/z (ESI): 562.1 [M+1].

Step 8: Compound 81

[0996] Compound 81-g (400.00 mg, 712.14 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 81.

[0997] MS m/z (ESI): 562.1 [M+1].

[0998] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.91-7.85 (m, 2H), 7.40-7.28 (m, 4H), 7.24-7.08 (m, 3H), 6.99-6.73 (m, 3H), 4.01-2.98 (m, 6H), 2.87-2.61 (m, 2H), 2.54 (d, J=1.5 Hz, 3H), 2.21 (d, J=3.5 Hz, 3H), 1.94-1.67 (m, 2H), 1.65-1.54 (m, 6H).

[0999] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; flow rate: 60 mL/min; column temperature: 40 C.

[1000] Retention time of Compound 81: 1.187 min (peak 1).

Example 82: Compound 82

[1001] ##STR00189## ##STR00190##

Step 1: Compound 82-a

[1002] A saturated potassium carbonate solution (83.00 mL) was added into a solution of Compound 78-a (40.00 g, 157.33 mmol, 1.00 eq), ((1,3-dioxolan-2-yl)methyl)triphenylphosphine bromide (33.77 g, 78.67 mmol, 0.50 eq) and 2-(2-methoxyethoxy)-N,N-di[2-(2-methoxyethoxy) ethyl]ethylamine (17.81 g, 55.07 mmol, 17.63 mL, 0.35 eq) in dichloromethane (83.00 mL). The mixture was stirred at 40 C. for 20 h. The reaction system was diluted with (dichloromethane/water=1:1, 500 mL). The aqueous phase was extracted with dichloromethane (100 mL3), and the combined organic phase was washed with saturated brine (100 mL1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-80:20) to give Compound 82-a.

[1003] MS m/z (ESI): 325.1 [M+1].

[1004] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.04-7.11 (m, 1H), 6.93-6.98 (m, 1H), 6.84 (q, J=8.28 Hz, 1H), 6.54-6.63 (m, 1H), 5.57-6.01 (m, 1H), 5.29-5.44 (m, 1H), 4.17 (dq, J=3.51, 7.11 Hz, 2H), 3.95-4.01 (m, 2H), 3.83-3.89 (m, 2H), 1.52 (d, J=3.51 Hz, 6H), 1.19-1.24 (m, 3H)

Step 2: Compound 82-b

[1005] Under argon protection, palladium hydroxide (1.30 g, 1.85 mmol, 20% purity, 0.10 eq) was added into a solution of Compound 82-a (6.00 g, 18.50 mmol, 1.00 eq) in ethanol (30.00 mL). The mixture was stirred at 50 C. for 16 h in hydrogen (50 psi) atmosphere. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (310 mL). The combined filtrate was concentrated under reduced pressure to give Compound 82-b.

[1006] MS m/z (ESI): 349.1 [M+23].

[1007] .sup.1H NMR (400 MHz, CDCl.sub.3) 6.72-6.89 (m, 3H), 4.80 (t, J=4.64 Hz, 1H), 4.17 (q, J=7.28 Hz, 2H), 3.88-3.93 (m, 2H), 3.76-3.82 (m, 2H), 2.56-2.66 (m, 2H), 1.81-1.91 (m, 2H), 1.43-1.53 (m, 6H), 1.21 (t, J=7.03 Hz, 3H).

Step 3: Compound 82-c

[1008] An aqueous HCl solution (2 M, 28.34 mL, 3.70 eq) was added into a solution of Compound 82-b (5.00 g, 15.32 mmol, 1.00 eq) in tetrahydrofuran (28.34 mL). The mixture was stirred at 70 C. for 3 h. Water (50 mL) was added into the mixture, and extracted with ethyl acetate (100 mL3). The combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound 82-c.

[1009] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.73 (t, J=1.13 Hz, 1H), 6.79-6.87 (m, 2H), 6.73-6.77 (m, 1H), 4.17 (q, J=7.11 Hz, 2H), 2.79-2.84 (m, 2H), 2.66-2.72 (m, 2H), 1.49 (s, 6H), 1.19-1.24 (m, 3H).

Step 4: Compound 82-d

[1010] Compound 44-f (6.65 g, 15.59 mmol, 1.00 eq) was added into a solution of Compound 82-c (4.40 g, 15.59 mmol, 1.00 eq) in tetrahydrofuran (40.00 mL), and then was stirred at 50 C. for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 82-d.

[1011] MS m/z (ESI): 431.1 [M+1].

[1012] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70-7.77 (m, 2H), 7.15-7.22 (m, 2H), 6.96 (td, J=6.78, 15.31 Hz, 1H), 6.72-6.88 (m, 4H), 4.17 (q, J=7.28 Hz, 2H), 2.66-2.72 (m, 2H), 2.48-2.57 (m, 2H), 2.45 (s, 3H), 1.49 (s, 6H), 1.18-1.23 (m, 3H).

Step 5: Compound 82-e

[1013] Trifluoroacetic acid (58.26 mg, 511.00 mol, 37.83 L, 0.05 eq) was added into a solution of Compound 82-d (4.40 g, 10.22 mmol, 1.00 eq) in 1,4-dioxane (120 mL), and warmed to 80 C. Then, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (7.28 g, 30.66 mmol, 7.84 mL, 3.00 eq) was added dropwise into the reaction mixture, followed by stirring for additional 30 min. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 82-e.

[1014] MS m/z (ESI): 564.1 [M+1].

[1015] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.72 (d, J=8.53 Hz, 2H), 7.01-7.17 (m, 7H), 6.53-6.76 (m, 3H), 4.09 (q, J=7.19 Hz, 2H), 3.37-3.46 (m, 2H), 2.83-2.91 (m, 1H), 2.62-2.74 (m, 2H), 2.49 (dd, J=7.15, 9.16 Hz, 1H), 2.36-2.40 (m, 1H), 2.37 (s, 2H), 2.22-2.34 (m, 2H), 1.58-1.66 (m, 2H), 1.36-1.42 (m, 6H), 1.14 (t, J=7.15 Hz, 3H).

Step 6: Compound 82-f

[1016] Phenyl chloroformate (1.25 g, 7.98 mmol, 999.54 L, 3.00 eq) was added into a solution of Compound 82-e (1.50 g, 2.66 mmol, 1.00 eq) in chloroform (10.00 mL), and then was stirred at 70 C. for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give Compound 82-f.

[1017] MS m/z (ESI): 594.2 [M+1].

Step 7: Compound 82-g

[1018] Compound 82-f (1.10 g, 1.85 mmol, 1.00 eq), lithium hydroxide (443.08 mg, 18.50 mmol, 10.00 eq) and ethanol (10.00 mL), water (5.00 mL) was added into a round-bottom flask at 20 C., and then stirred at 30 C. for 3 h. A saturated aqueous solution of potassium bisulfate was added dropwise into the reaction system to pH=5. Water (10 mL) was added into the mixture, and extracted with ethyl acetate (10 mL3). The organic phases were combined and washed with saturated brine (10 mL3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative High Performance Liquid Chromatography to give Compound 82-g.

[1019] MS m/z (ESI): 566.2 [M+1].

Step 8: Compound 82

[1020] Compound 82-g (500.00 mg, 883.94 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 82.

[1021] MS m/z (ESI): 566.0 [M+1].

[1022] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.74-7.83 (m, 2H), 6.98-7.32 (m, 8H), 6.63-6.90 (m, 3H), 3.61-3.95 (m, 3H), 3.39-3.60 (m, 1H), 3.04-3.32 (m, 1H), 2.56-2.79 (m, 1H), 2.37-2.53 (m, 5H), 1.49-1.82 (m, 2H), 1.39 (br d, J=7.53 Hz, 6H).

[1023] Conditions of the chiral resolution: chiral column: Chiralpak AD-3 1004.6 mm I.D., 3 m; mobile phase: 40% of iso-propanol (0.05% DEA) in CO.sub.2; flow rate: 2.8 mL/min; column temperature: 40 C.

[1024] Retention time of Compound 82: 2.772 min (peak 1).

Example 83: Compound 83

[1025] ##STR00191## ##STR00192##

Step 1: Compound 83-b

[1026] Cesium carbonate (52.32 g, 160.59 mmol, 1.50 eq) and ethyl 2-bromo-isoburtrate (52.21 g, 267.65 mmol, 39.25 mL, 2.50 eq) was added into a solution of Compound 83-a (15.00 g, 107.06 mmol, 1.00 eq) in N,N-dimethylformamide (150.00 mL). The mixture was stirred at 90 C. for 2 h. The reaction mixture was extracted with ethyl acetate (200 mL) and water (300 mL). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (100 mL3), and the combined organic phase was washed with an 1N solution of sodium hydroxide (100 mL) and a saturated solution of potassium bisulfate (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 83-b.

[1027] MS m/z (ESI): 254.9 [M+1].

[1028] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 10.20 (s, 1H), 7.77 (t, J=8.5 Hz, 1H), 6.66 (dd, J=2.5, 8.8 Hz, 1H), 6.55 (dd, J=2.3, 12.3 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 1.67 (s, 6H), 1.23 (t, J=7.2 Hz, 3H)

Step 2: Compound 83-c

[1029] Potassium tert-butoxide (10.29 g, 91.74 mmol, 1.50 eq) was added into a solution of methoxymethyl triphenylphosphine chloride (27.26 g, 79.51 mmol, 1.30 eq) in tetrahydrofuran (200.00 mL) in batches at 20 C. The mixed solution was reacted for 1 h, and Compound 83-b (15.55 g, 61.16 mmol, 1.00 eq) was added. The mixture was stirred at 20 C. for 1 h. Sodium borohydride (2.00 g, 52.87 mmol, 0.86 eq) was added into the reaction system, which was subsequently quenched by adding water (50 ml). Next, the reaction system was extracted with ethyl acetate (100 ml) and water (100 ml). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (350 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-70:30) to give Compound 83-c.

[1030] MS m/z (ESI): 282.9 [M+1].

[1031] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.95-7.32 (m, 1H), 7.15-7.03 (m, 1H), 6.61-6.15 (m, 2H), 5.81-5.36 (m, 1H), 4.24 (dq, J=2.1, 7.2 Hz, 2H), 3.79-3.67 (m, 3H), 1.59 (s, 6H), 1.26 (dt, J=1.5, 7.2 Hz, 3H).

Step 3: Compound 83-d

[1032] Compound 83-c (8.84 g, 31.31 mmol, 1.00 eq) was added into a dry reaction flask, and then chloroform (100.00 mL) was added. Next, oxalyl chloride (7.95 g, 62.62 mmol, 5.48 mL, 2.00 eq) was slowly added into the reaction system under nitrogen protection at 0 C., and then ethanol (2.88 g, 62.62 mmol, 3.65 mL, 2.00 eq), water (1.13 g, 62.62 mmol, 1.13 mL, 2.00 eq) were added into the mixture solution. The mixed solution was stirred 0 C. for 1 h. A saturated aqueous sodium carbonate solution was added dropwise into the reaction system to pH=7-8. The reaction system was extracted with dichloromethane (100 ml) and water (100 ml). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (350 mL). The organic phases were combined and were successively washed with water (350 mL) and saturated brine (350 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 83-d.

[1033] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 9.71 (q, J=1.8 Hz, 1H), 7.72-7.42 (m, 1H), 7.07-7.00 (m, 1H), 6.65-6.61 (m, 1H), 4.24 (q, J=7.1 Hz, 2H) 3.65 (s, 2H), 1.61 (s, 6H), 1.25 (t, J=7.2 Hz, 3H)

Step 4: Compound 83-e

[1034] Compound 83-d (6.86 g, 25.57 mmol, 1.00 eq), Compound 44-f (10.91 g, 25.57 mmol, 1.00 eq) was added into a dried reaction flask, and then tetrahydrofuran (100.00 mL) was added. The mixture was stirred at 50 C. for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 83-e.

[1035] MS m/z (ESI): 417.1 [M+1].

[1036] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.85-7.72 (m, 2H), 7.29-7.16 (m, 3H), 7.08-6.94 (m, 1H), 6.76 (d, J=15.3 Hz, 1H), 6.57-6.47 (m, 2H), 4.19-4.14 (m, 2H), 3.82-3.77 (m, 1H), 3.50 (d, J=6.5 Hz, 1H), 2.46-2.43 (m, 3H), 1.54-1.51 (m, 6H), 1.21-1.16 (m, 3H).

Step 5: Compound 83-f

[1037] Compound 83-e (3.69 g, 8.86 mmol, 1.00 eq) was added into a dried reaction flask, and then 1,4-dioxane (150.00 mL) was added. Next, trifluoroacetic acid (50.51 mg, 443.00 mol, 0.05 eq) was added into the reaction system, and then N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (6.31 g, 26.58 mmol, 3.00 eq) dissolved in 1,4-dioxane (30.00 mL) was added into the mixed solution at a rate of 1 drop per two seconds. The mixed solution was stirred at 100 C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 83-f.

[1038] MS m/z (ESI): 550.1 [M+1].

[1039] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.65 (d, J=8.5 Hz, 2H), 7.25 (br d, J=2.0 Hz, 2H), 7.19-7.11 (m, 5H), 6.93-6.84 (m, 1H), 6.41-6.35 (m, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.61-3.52 (m, 3H), 3.04-2.95 (m, 2H), 2.71-2.59 (m, 3H), 2.55-2.46 (m, 2H), 2.43 (s, 3H), 1.44 (d, J=4.0 Hz, 6H), 1.20-1.17 (m, 3H).

Step 6: Compound 83-g

[1040] Compound 83-f (1.85 g, 3.37 mmol, 1.00 eq) and chloroform (30.00 mL) was added into a dried reaction flask. Then, phenyl chloroformate (2.64 g, 16.85 mmol, 2.11 mL, 5.00 eq) was slowly added. The mixed solution was stirred at 70 C. for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-85:15) to give Compound 83-g.

[1041] MS m/z (ESI): 580.2 [M+1].

[1042] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.68 (t, J=7.8 Hz, 2H), 7.39-7.33 (m, 2H), 7.25-7.13 (m, 5H), 7.04 (t, J=8.8 Hz, 1H), 6.61-6.53 (m, 2H), 4.24 (dq, J=2.0, 7.1 Hz, 2H), 3.99-3.90 (m, 1H), 3.85-3.61 (m, 3H), 3.51-3.36 (m, 1H), 3.01-2.86 (m, 1H), 2.79 (br d, J=5.8 Hz, 2H), 2.53 (s, 3H), 1.60 (d, J=4.3 Hz, 6H), 1.26 (s, 3H)

Step 7: Compound 83-h

[1043] Compound 83-g (328.00 mg, 565.83 mol, 1.00 eq) was added into a dried reaction flask, and then ethanol (15.00 mL) was added. Next, lithium hydroxide (135.52 mg, 5.66 mmol, 10.00 eq) and water (5.00 mL) were added into the reaction system, and the mixed solution was stirred at 20 C. for 16 h. A saturated aqueous solution of potassium bisulfate was added dropwise into the reaction system to pH=6. The reaction mixture was extracted with ethyl acetate (20 mL) and water (20 mL). After phase separation, the organic phases were collected, and the aqueous phase was extracted with ethyl acetate (310 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-60:40) to give Compound 83-h.

[1044] MS m/z (ESI): 552.1 [M+1].

Step 8: Compound 83

[1045] Compound 83-h (195.00 mg, 353.50 mol, 1.00 eq) was isolated by chiral supercritical chromatography to give Compound 83.

[1046] MS m/z (ESI): 552.1 [M+1].

[1047] .sup.1H MR (400 MHz, CDCl.sub.3) ppm 7.66 (br dd, J=5.4, 8.2 Hz, 2H), 7.39-7.32 (m, 2H), 7.25-7.18 (m, 3H), 7.13 (br d, J=7.8 Hz, 2H), 7.08-7.00 (m, 1H), 6.63 (br s, 2H), 4.00-3.62 (m, 4H), 3.51-3.32 (m, 1H), 2.97-2.86 (m, 1H), 2.81-2.69 (m, 2H), 2.51 (s, 3H), 1.57 (br s, 6H)

[1048] Conditions of the chiral resolution: chiral column: AD (250 mm30 mm, 10 m); mobile phase: 40% of methanol (0.05% DEA) in CO.sub.2; flow rate: 80 mL/min; column temperature: 40 C.

[1049] Retention time of Compound 83: 0.546 min (peak 1).

Experimental Example 1: In Vitro Evaluation

[1050] In Vitro Testing Principles of PPAR Agonist Activity

[1051] Cell Nuclear Hormon Receptor (NHR) Test

[1052] PathHunter's NHR protein interaction and nuclear translocation test is used to detect the activation ability of a cell nuclear hormone receptor in uniform, non-imaging experiments. This technology is called Enzyme Fragmentation Complementation (ETC), and developed by DiscoverX.

[1053] NHR protein test is based on the detection of protein-protein interaction between a standard-length of NHR protein in an activated state, and a nuclear fusion protein containing a steroid receptor co-activation peptide (SRCP) region and one or more standard LXXLL acting sequence(s).

[1054] NHR is labeled on the ProLink component of the EFC test system, meanwhile the SRCP region and the enzyme acceptor (EA) component are fused and expressed in a nucleus. When bound with a ligand, NHR will be translocated to the nucleus and obtain the SRCP region, in which a complementatory effect would be produced, resulting in one equivalent of actived galactosidase (-Gal), accompanied with chemiluminescent signals. The benefits associated with this pathway include reduced incubation time of compounds, direct test of NHR targets, use of a standard length of human NHR sequences, and selection of some novel types of compounds based on disrupting protein-protein interaction.

[1055] NHR NT test detects the translocation of NHR between cytoplasm and nuclear compartments. The receptor is labeled on the ProLink component of the EFC test system, meanwhile EA is fused with nuclear sequences, thereby limiting the expression of EA in nuclei. The translocation of NHR to nuclei results in the complementation with EA, which produces one equivalent of actived galactosidase, accompanied with the generation of chemiluminescent signals.

[1056] Treatment of Cells: [1057] 1. A PathHunter NHR cell strain was expanded from a frozen stock in accordance with a standard procedure. [1058] 2. Cells were seeded in a white 384-well plate at 20 L/well, and incubated at 37 C. for a proper period of time followed by the test. The culture medium contained activated Charcoal/Dextran in which serum was filtered and removed to decrease the level of hormone expression.

[1059] Agonist Experiment Procedure: [1060] 1. For testing the agonist activity, the cells were required to be incubated with a compound to induce a response. [1061] 2. The compound was formulated with a buffer solution to obtain a stock solution, which would be diluted 5. [1062] 3. 5 L of 5-diluted solution of the compound was added to the cells, and then the cells were incubated at 37 C. (or room temperature) for 3-16 h. The final medium concentration should be ensured to be 1%.

[1063] Inhibitor Experiment Procedure: [1064] 1. For testing the inhibitor activity, cells were required to be pre-incubated with an antagonist, and then challenged with an agonist at the EC.sub.80 concentration. [1065] 2. The compound was formulated with a buffer solution to obtain a stock solution, which would be diluted 5. [1066] 3. 5 L of 5-diluted solution of the compound was added to the cells, and then the cells were incubated at 37 C. (or room temperature) for 60 min. The final medium concentration should be ensured to be 1%. [1067] 4. 5 L of EC.sub.80 agonist, which was 6 diluted with a buffer solution, was added to the cells, and incubated at 37 C. (or room temperature) for 3-16 h.

[1068] Test of Signals: [1069] 1. Experimental signals were generated by 12.5 L or 15 L of (50% v/v) a PathHunter test reagent mixture which was added at one time and subsequently incubated at room temperature for 1 h. [1070] 2. The chemiluminescent signals generated in the microplate was detected by a PerkinElmer Envision Instrument.

[1071] Data Analysis:

[1072] 1. The activity of compounds is analyzed by CIBS Data Analysis Software (ChemInnovation, CA).

[1073] 2. With respect to the experiments of the agonist procedure, the percent activity is calculated in accordance with the following equation:

% Activity=100%(RLU mean of the tested compoundBackground RLU mean of medium)/(Maximum control mean of the ligandBackground RLU mean of the medium)

[1074] 3. For the experiments of antagonist procedure, the percent activity is calculated in accordance with the following equation:

% Inhibition=100%(1(RLU mean of the tested compoundBackground RLU mean of the medium)/(RLU mean of EC.sub.80 control compoundBackground RLU mean of medium))

[1075] 4. It should be noted that the response of the ligand will cause a reduced activity of the receptor (inverse agonists having a continuously active target). The activity of these inverse agonists is calculated in accordance with the following equation:

% inverse agonist activity=100%((Background RLU mean of the mediumRLU mean of the tested compound)/(Background RLU mean of the mediumMaximum control RLU mean of the ligand))

[1076] The experimental results are shown in Table 1:

TABLE-US-00001 TABLE 1 Results of in vitro screening experiments of the compounds of the present invention PPAR Alpha PPAR Delta PPAR Gamma Maximum Maximum Maximum Activation Activation Activation Compounds EC.sub.50 nM Response % EC.sub.50 nM Response % EC.sub.50 nM Response % GW7647 A 100% / / / / L-165,041 / / A 100% / / Troglitazone / / / / E 100% GFT-505 E I C II E II (Elafibranor) Compound 1 E III / / / / (rac-) Compound 2 E III / / / / (rac-) Compound 3 E III / / / / (rac-) Compound 4 (*) E III / / / / Compound 5 (*) E I B II E III Compound 6 (*) E II / / / / Compound 7 (*) E II E II / / Compound 8 (*) E II / / / / Compound 9 (*) E I / / / / Compound 10 (*) E III / / / / Compound 11 (*) D I C II E I Compound 12 C I E II (rac-) Compound 13 (*) A II A II E I Compound 14 (*) A II A II E I Compound 15 C I D II / / (rac-) Compound 16 (*) E I / / / / Compound 17 (*) E I / / / / Compound 18 (*) D I E II / / Compound 19 (*) D I E II / / Compound 20 (*) D II E II / / Compound 21 (*) E I E II / / Compound 22 (*) E III / / / / Compound 23 (*) E III / / / / Compound 24 (*) E I E I / / Compound 25 (*) A I A II E I Compound 26 (*) A I A II E I Compound 27 (*) A I A II / / Compound 28 (*) A I A II / / Compound 29 (*) A I A I / / Compound 30 (*) A I A I / / Compound 31 (*) C I E I / / Compound 32 (*) A I E II / / Compound 33 (*) D I E II / / Compound 34 (*) A I E III E I Compound 35 (*) D I C II / / Compound 36 A I E II / / (rac-) Compound 37 A I D II / / (rac-) Compound 38 (*) A I C II / / Compound 39 (*) A I B I / / Compound 40 (*) A I B I / / Compound 41 (*) A I A I / / Compound 42 (*) A I A I / / Compound 43 (*) A I A I / / Compound 44 (*) A I D III E I Compound 45 (*) A I C II E I Compound 46 (*) A I A I E I Compound 47 (*) A I A I C I Compound 48 A II B II / / (rac-) Compound 49 (*) C II B II D II Compound 50 (*) C III C II / / Compound 51 (*) A I A I D I Compound 52 (*) A I A I C I Compound 53 B I B II E I (rac-) Compound 54 A I B I D I (rac-) Compound 55 E III D II E III (rac-) Compound 56 E III D II E III (rac-) Compound 57 (*) A I A II D II Compound 58 (*) B I A II D II Compound 59 (*) D II D II / / Compound 60 (*) D II D II / / Compound 61 (*) E III E III / / Compound 62 (*) B I B I / / Compound 63 (*) A I A I D I Compound 64 (*) A I A I D I Compound 65 (*) A I A I D I Compound 66 (*) A I A I C I Compound 67 E I E I E I (rac-) Compound 68 E I E I E I (rac-) Compound 69 (*) A I A I C I Compound 70 (*) A I A I C I Compound 71 D I C I / / (rac-) Compound 72 A I B I / / (rac-) Compound 73 D I E I / / (rac-) Compound 74 (*) A I B I / / Compound 75 (*) E I D I / / Compound 76 (*) B I B I E I Compound 77 (*) C I C I E I Compound 78 (*) B I B I E I Compound 79 (*) B I C I D I Compound 80 (*) A I C I E I Compound 81 (*) A I B I D I Compound 82 (*) A I B I D I Compound 83 (*) B I D I / / Note 1: The maximum activation response values, determined in in vitro platform, of a known PPAR agonist GW7647, PPAR agonist L-165,041 and PPAR agonist Troglitazone are indicated to be 100%. The maximum response values of other compound are compared with the maximum activation responses of the known agonists, to obtain the corresponding maximum activation response values. In general, a compound having a maximum activation response value of greater than 80% is considered to be a full agonist, a compound having a maximum activation response value of greater than 50% and less than 80% is considered to be a partial agonist, and a compound having a maximum activation response value of less than 50% is considered to be an agonist with insufficient effect. Note 2: A 100 nM; 100 nM < B 150 nM; 150 nM < C 200 nM; 200 nM < D 250 nM; E > 250 nM. Note 3: 100% I 80%; 80% II 50%; III < 50%. Note 4: * refers to be optically pure compounds. Note 5: rac- refers to be trans-racemic compounds. Conclusion: the compounds of the present invention activate significantly PPAR Alpha and Delta receptors, and activate selectively PPAR Gamma receptor.