1. Patent Search
  2. Details

BIARYL COMPOUND AS PAN-RAF KINASE INHIBITOR

20230046018 · 2023-02-16

    Inventors

    Cpc classification

    International classification

    Abstract

    Disclosed is a biarylamide compound as a Pan-RAF kinase inhibitor, and specifically disclosed are a compound as shown in formula (III) and a pharmaceutically acceptable salt thereof.

    ##STR00001##

    Claims

    1. A compound as shown in formula (III) or a pharmaceutically acceptable salt thereof, ##STR00071## wherein, X and Y are each independently selected from CH and N; L is selected from —O—, —S—, —S(═O)— and —S(═O).sub.2—; L.sub.1 is selected from —CH.sub.2— and a single bond; Z.sub.1 and Z.sub.2 are each independently selected from CH and N; R.sub.1 and R.sub.2 are each independently selected from H, F and C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 R.sub.a; R.sub.3 is selected from ##STR00072## R.sub.4 is selected from H and C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 R.sub.b; R.sub.5 is selected from H and C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 R.sub.c; R.sub.6 is selected from H and F; R.sub.7 is selected from H and CN; R.sub.8 is selected from H and CH.sub.3; R.sub.9 is selected from H, F and CH.sub.3; each R.sub.a is independently selected from F, Cl, Br and I; each R.sub.b is independently selected from F, Cl, Br, I and CH.sub.3; each R.sub.c is independently selected from F, Cl, Br and I.

    2. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound is selected from formula (I′), ##STR00073## wherein, X and Y are each independently selected from CH and N; L is selected from —O—, —S—, —S(═O)— and —S(═O).sub.2—; Z.sub.1 and Z.sub.2 are each independently selected from CH and N; R.sub.1 and R.sub.2 are each independently selected from H, F and C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 R.sub.a; R.sub.3 is selected from ##STR00074## R.sub.4 is selected from H and C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 R.sub.b; R.sub.5 is selected from H and C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 R.sub.c; R.sub.6 is selected from H and F; R.sub.7 is selected from H and CN; R.sub.8 is selected from H and CH.sub.3; R.sub.9 is selected from H, F and CH.sub.3; each R.sub.a is independently selected from F, Cl, Br and I; each R.sub.b is independently selected from F, Cl, Br, I and CH.sub.3; each R.sub.c is independently selected from F, Cl, Br and I.

    3. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.1 and R.sub.2 are each independently selected from H and F.

    4. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.3 is selected from ##STR00075##

    5. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.4 is selected from H, CH.sub.3 and CH.sub.2CH.sub.3.

    6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, R.sub.5 is selected from CH.sub.3.

    7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the moiety ##STR00076## is selected from ##STR00077##

    8. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the moiety ##STR00078## is selected from ##STR00079##

    9. The compound or the pharmaceutically acceptable salt thereof according to claim 8, wherein, the moiety ##STR00080## is selected from ##STR00081##

    10. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the moiety ##STR00082## is selected from ##STR00083##

    11. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the moiety ##STR00084## is selected from ##STR00085##

    12. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, moiety ##STR00086## is selected from ##STR00087##

    13. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound is selected from ##STR00088## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.9, Z.sub.1 and Z.sub.2 are as defined above.

    14. The compound or the pharmaceutically acceptable salt thereof according to claim 13, wherein, the compound is selected from ##STR00089## wherein, R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as defined above.

    15. A compound or a pharmaceutically acceptable salt thereof, A compound or a pharmaceutically acceptable salt thereof wherein, the compound is selected from ##STR00090## ##STR00091## ##STR00092##

    16. The compound or the pharmaceutically acceptable salt thereof according to claim 15, wherein, the compound is selected from ##STR00093## ##STR00094##

    17. A compound as shown in formula (IV-1), (IV-2), (IV-3) or (IV-4), or a pharmaceutically acceptable salt thereof, ##STR00095## wherein, X.sub.1 is selected from halogen, —SO.sub.2Me, —OMs, OTf, OTs, ##STR00096## X.sub.2 is selected from halogen, OH, —SO.sub.2Me, —OMs, OTf, OTs and H; R.sub.1, R.sub.2, R.sub.5, R.sub.6, R.sub.7, R.sub.9, X, Y, Z.sub.1 and Z.sub.2 are as defined in claim 1.

    18. A compound as shown in formula (V) or a pharmaceutically acceptable salt thereof, ##STR00097## wherein, X.sub.1 is selected from halogen, —SO.sub.2Me, —OMs, OTf, OTs, ##STR00098##

    19. A method for inhibiting RAF kinase activity in a subject in need thereof, comprising administrating to the subject a medicament comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1.

    20. A method for treating cancers in a subject in need thereof, comprising administrating to the subject the compound or the pharmaceutically acceptable salt thereof according to claim 1.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0114] FIG. 1 shows the tumor growth curves of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models after administration of compound 1.

    [0115] FIG. 2 shows the body weight of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models in the process of administration of compound 1.

    [0116] FIG. 3 shows the tumor growth curves of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models after administration of compound 16B.

    [0117] FIG. 4 shows the body weight of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models in the process of administration of compound 16B.

    DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

    [0118] The present disclosure will be described in detail with the following examples, but not imply any adverse limitation to the present disclosure. The compounds of the present disclosure can be prepared by various synthetic methods well known to a person skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods, and equivalent alternative embodiments well known to a person skilled in the art, wherein the preferred embodiments include but are not limited to the examples of the present disclosure. For a person skilled in the art, without departing from the spirit and scope of the present disclosure, all the variations and improvements made to the specific embodiments of the present disclosure would have been obvious.

    [0119] Synthesis of Intermediate 1A-5:

    ##STR00042##

    Compound 1A-3

    [0120] At 0° C., sodium hydride (43.81 mg, 1.10 mmol, 60% purity) was added to a solution of 1A-2 (192.15 mg, 1.31 mmol) in THF (1 mL), and the mixture was warmed to 25° C. and stirred for 30 minutes. At 0° C., 1A-1 (300 mg, 1.10 mmol) was added to the mixed solution; and the mixture was warmed to 25° C. and stirred for 2 hours. A saturated ammonium chloride solution (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL×3); the combined extract was concentrated; and the residue was separated by column chromatography (PE/EA=20/1, V/V) to obtain 1A-3.

    Compound 1A-5

    [0121] 1A-3 (200 mg, 521.36 μmol), 1A-4 (232.96 mg, 573.50 μmol), Pd(dppf)Cl.sub.2 (38.15 mg, 52.14 μmol) and sodium carbonate (110.52 mg, 1.04 mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10×2 mL). The combined organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by preparative silica gel plate (PE/EA=5/1, V/V) to obtain 1A-5. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.00 (d, J=5.0 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=4.8 Hz, 1H), 7.77 (dd, J=2.2, 8.2 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.12 (d, J=1.0 Hz, 1H), 6.86 (d, J=1.0 Hz, 1H), 4.68-4.64 (m, 1H), 4.52-4.40 (m, 2H), 3.82-3.71 (m, 2H), 3.48-3.41 (m, 2H), 2.26 (s, 3H), 1.75-1.58 (m, 2H), 1.53-1.40 (m, 4H).

    [0122] Synthesis of Intermediate 1A-6:

    ##STR00043##

    Compound 1A-6

    [0123] 1A-1 (1.0 g, 3.65 mmol), 1A-4 (1.67 g, 4.11 mmol), Pd(dppf)Cl.sub.2 (300 mg, 367.36 μmol) and sodium carbonate (774 mg, 7.30 mmol) were dissolved in a mixed solvent of dioxane (10 mL) and water (2.5 mL). Under nitrogen protection, the reaction mixture was heated to 70° C. and stirred for 4 hours. The reaction solution was filtered and extracted with ethyl acetate (10×3 mL). The combined organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=30/1 to 3/1, V/V) to obtain 1A-6. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.98-8.91 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.97-7.92 (d, J=5.0 Hz, 1H), 7.61-7.56 (m, 2H), 7.39-7.30 (d, J=9.0 Hz, 1H), 7.28-7.26 (m, 2H), 2.37-2.22 (m, 3H).

    [0124] Synthesis of Intermediate 1A-8:

    ##STR00044##

    Compound 1A-8

    [0125] 1A-1 (785 mg, 2.87 mmol), 1A-7 (1.11 g, 2.72 mmol), Pd(dppf)Cl.sub.2 (210 mg, 287.0 μmol) and sodium carbonate (609 mg, 5.75 mmol) were dissolved in a mixed solvent of DME (10 mL) and water (2.5 mL). Under nitrogen protection, the reaction mixture was heated to 90° C. and stirred for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was then filtered and washed with water (50×2 mL) and saturated brine (80×1 mL). The combined organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=20/1 to 3/1, V/V) to obtain 1A-8. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.65 (d, J=2.51 Hz, 1H), 8.26 (d, J=2.51 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J=7.91 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J=7.78 Hz, 1H), 7.69 (t, J=7.78 Hz, 1H), 7.31 (s, 2H), 2.53 (s, 3H).

    [0126] Synthesis of Intermediate 2-1:

    ##STR00045##

    Compound 2-1A

    [0127] DMSO (4 mL) was added to a mixture of sodium hydride (163.18 mg, 4.08 mmol, 60%) and 11-2A-1 (897.89 mg, 4.08 mmol). Under nitrogen protection, the reaction mixture was stirred at 20° C. for 0.5 hours. A solution of 11-2 (200 mg, 1.02 mmol) in DMSO (4 mL) was added to the reaction solution; and the reaction mixture was heated to 80° C. and stirred for 2.5 hours. Water (2 mL) and ethyl acetate (40 mL) were added to the reaction mixture, and the resulting mixture was washed with water (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by preparative silica gel plate (PE/EA=5/1, V/V) to obtain compound 2-1A. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.65-7.47 (m, 1H), 7.21-7.02 (m, 2H), 4.11-3.91 (m, 2H), 3.74-3.57 (m, 1H), 3.56-3.37 (m, 1H), 2.55-2.42 (m, 1H), 2.20-2.05 (m, 1H), 1.85-1.71 (m, 1H), 1.39-1.28 (m, 1H), 1.16-1.04 (m, 1H).

    Compound 2-1B

    [0128] 2-1A-1 (395.45 mg, 1.56 mmol), [Ir(COD)OMe].sub.2 (23.71 mg, 35.77 μmol), tmphen (16.91 mg, 71.54 μmol) and potassium acetate (11.5 g, 117.18 mmol) were dissolved in MTBE (8 mL). Under nitrogen protection, the reaction mixture was heated to 80° C. and stirred for 5 minutes. A solution of 2-1A (300 mg, 1.43 mmol) in MTBE (2 mL) was then added, and the mixture was warmed to 80° C. and stirred for 16 hours. The reaction solution was filtered and concentrated to obtain compound 2-1B as a crude. MS (ESI): m/z 254.1 [M+H−82].sup.+.

    Compound 2-1C

    [0129] 2-1B (480 mg, 1.43 mmol), 2-1B-1 (320 mg, 1.72 mmol), Pd(dppf)Cl.sub.2 (117 mg, 143 μmol) and sodium carbonate (454.74 mg, 4.29 mmol) were dissolved in a mixed solvent of DME (10 mL) and water (2 mL). Under nitrogen protection, the reaction mixture was heated to 80° C. and stirred for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was then filtered; the filtrate was washed with water (20×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=20/1 to 10/1) to obtain compound 2-1C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.09-7.06 (m, 2H), 7.05 (d, J=1.0 Hz, 1H), 6.70-6.64 (m, 1H), 6.53 (d, J=2.6 Hz, 1H), 4.07-4.00 (m, 1H), 3.99-3.93 (m, 1H), 3.70-3.59 (m, 3H), 3.52-3.42 (m, 1H), 2.56-2.47 (m, 1H), 2.16-2.14 (m, 3H), 2.14 (br s, 1H), 1.75-1.60 (m, 1H), 1.40-1.33 (m, 1H), 1.11 (dd, J=4.2, 6.4 Hz, 1H).

    Compound 2-1

    [0130] HATU (181.17 mg, 476.48 μmol) and DIPEA (123.16 mg, 952.96 μmol) were added to 2-1C (100 mg, 317.65 μmol) and 2-1C-1 (60.71 mg, 317.65 μmol) in DMF (3 mL), and the mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10×3 mL); the organic phase was combined, dried over anhydrous sodium sulfate and concentrated; and the residue was purified by preparative silica gel plate (PE/EA=2/1, V/V) to obtain compound 2-1. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.94 (d, J=5.0 Hz, 1H), 8.16-8.06 (m, 1H), 8.00-7.85 (m, 2H), 7.61-7.56 (m, 1H), 7.55-7.51 (m, 1H), 7.36-7.31 (m, 1H), 7.11-7.06 (m, 2H), 4.07-4.01 (m, 1H), 3.99-3.93 (m, 1H), 3.68-3.59 (m, 1H), 3.53-3.43 (m, 1H), 2.57-2.47 (m, 1H), 2.30-2.25 (m, 3H), 2.18-2.08 (m, 1H), 1.88-1.79 (m, 1H), 1.41-1.35 (m, 1H), 1.20-1.10 (dd, J=4.2, 6.4 Hz, 1H). MS (ESI) m/z: 488.1 [M+H].sup.+.

    [0131] Synthesis of Intermediate 14-2A:

    ##STR00046##

    Compound 14-2A-2

    [0132] Hydroxylamine hydrochloride (4.77 g, 68.71 mmol) and triethylamine (16.69 g, 164.90 mmol) were added to a solution of 14-2A-1 (10.5 g, 54.97 mmol) in DMF (100 mL), and the mixture was stirred at 20° C. for 1 hour. T.sub.3P (34.98 g, 54.97 mmol, 50% DMF solution) was added to the reaction solution, and the mixture was stirred at 20° C. for 4 hours. A saturated sodium bicarbonate solution (200 mL) was added to the reaction mixture; the resulting mixture was extracted with EtOAc (50 mL×3); and the combined extract was dried over anhydrous sodium sulfate and then concentrated to obtain 14-2A-2 as a crude. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.24-8.56 (m, 1H), 8.08 (s, 1H), 4.35-4.28 (t, J=2.2 Hz, 2H), 3.85-3.76 (t, J=5.6 Hz, 2H), 2.70-2.62 (m, 2H).

    Compound 14-2A

    [0133] Thionyl chloride (15.67 g, 131.74 mmol) was added to a solution of 14-2A-2 (9.5 g, 46.11 mmol) in DCM (100 mL), and the mixture was stirred at 20° C. for 1 hour. At 0° C., a saturated sodium bicarbonate solution (100 mL) was slowly added dropwise to the reaction mixture; the resulting mixture was extracted with DCM (100 mL×2); and the combined extract was dried over anhydrous sodium sulfate and then concentrated to obtain 14-2A as a crude. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 4.30-4.20 (t, J=2.6 Hz, 2H), 3.92-3.85 (t, J=5.4 Hz, 2H), 2.75-2.64 (tt, J=2.6, 5.4 Hz, 2H).

    EXAMPLE 1

    [0134] ##STR00047## ##STR00048##

    Compound 1-1

    [0135] 1A-5 (100 mg, 186.59 μmol), 1-1A (77 mg, 377.38 μmol), Pd(dppf)Cl.sub.2 (14 mg, 19.13 μmol) and sodium carbonate (40 mg, 377.40 μmol) were dissolved in a mixed solvent of DME (2 mL) and water (0.2 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 16 hours. The reaction solution was filtered; the filtrate was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=5/1, V/V) to obtain a crude, which was then separated by chromatographic column (silica gel) (HCOOH-MeCN—H.sub.2O) to obtain compound 1-1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.99-8.90 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.96-7.89 (m, 2H), 7.67-7.58 (dd, J=2.0, 8.6 Hz, 1H), 7.49-7.40 (d, J=1.8 Hz, 1H), 7.36-7.29 (d, J=8.4 Hz, 1H), 6.76 (s, 1H), 6.55-6.49 (d, J=0.8 Hz, 1H), 4.74-4.68 (t, J=3.6 Hz, 1H), 4.60-4.45 (m, 2H), 4.09-4.02 (m, 2H), 3.98-3.88 (m, 2H), 3.89-3.76 (ddd, J=4.0, 6.4, 11.2 Hz, 1H), 3.66-3.58 (m, 1H), 3.57-3.44 (m, 2H), 2.58-2.45 (td, J=5.2, 13.8 Hz, 1H), 2.27 (s, 3H), 2.14-2.07 (m, 1H), 1.89-1.81 (m, 2H), 1.77-1.71 (m, 1H), 1.68-1.61 (m, 2H), 1.45-1.36 (dd, J=4.0, 9.2 Hz, 1H), 1.10-1.02 (dd, J=4.0, 6.4 Hz, 1H), 0.99-0.73 (m, 2H).

    Compound 1

    [0136] Trifluoroacetic acid (616 mg, 5.4 mmol) was added to 1-1 (54 mg, 90.36 μmol) in dichloromethane (2 mL), and the reaction solution was stirred at 25° C. for 0.5 hours. The reaction solution was diluted with dichloromethane (20 mL) and adjusted to neutral with a saturated sodium bicarbonate aqueous solution. The organic phase was washed with saturated brine (15×1 mL), dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/1, V/V) to obtain compound 1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.99-8.90 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.96-7.85 (m, 2H), 7.67-7.59 (dd, J=1.8, 8.0 Hz, 1H), 7.51 (s, 1H), 7.37-7.28 (d, J=8.6 Hz, 1H), 6.84-6.78 (d, J=1.0 Hz, 1H), 6.57-6.52 (d, J=1.0 Hz, 1H), 4.53-4.46 (m, 2H), 4.08-4.03 (m, 1H), 4.00-3.94 (m, 3H), 3.69-3.58 (m, 1H), 3.54-3.36 (ddd, J=5.2, 8.6, 11.6 Hz, 1H), 2.53-2.46 (td, J=5.0, 14.0 Hz, 1H), 2.28 (s, 3H), 2.18-2.09 (ddd, J=5.4, 8.4, 13.8 Hz, 1H), 1.79-1.72 (m, 1H), 1.39-1.28 (dd, J=4.2, 8.8 Hz, 1H), 1.11-1.03 (m, 1H). MS (ESI) m/z: 514.2 [M+H].sup.+.

    Compound 1-2

    [0137] TBSC1 (10 mg, 48.68 μmol) was added to a solution of compound 1 (25 mg, 48.68 μmol) and imidazole (8 mg, 117.51 μmol) in dichloromethane (3 mL). The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water (30×1 mL) and saturated brine (20×1 mL); the organic phase was dried over anhydrous sodium sulfate; the filtrate was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=2/1, V/V) to obtain compound 1-2. MS (ESI) m/z: 628.3 [M+H].sup.+.

    Compound 1-2A and Compound 1-2B

    [0138] Compound 1-2 was subjected to SFC chiral separation (chiral column: REGIS (s,s) WHELK-O1 (250 mm*50 mm, 10 μm), mobile phase A: isopropanol (containing 0.05% DIEA); mobile phase B: carbon dioxide) to obtain compound 1-2A (retention time: 3.846 min) and compound 1-2B (retention time: 3.966 min). Compound 1-2A: MS (ESI) m/z: 628.3 [M+H].sup.+, 99.4% (ee %); Compound 1-2B: MS (ESI) m/z: 628.3 [M+H].sup.+, 94.3% (ee %).

    Compound 1A

    [0139] TBAF (1 M, 0.048 mL) was added to 1-2A (15 mg, 23.89 μmol) in THF (2 mL), and the reaction solution was stirred at 20° C. for 0.5 hours. The reaction solution was respectively diluted with ethyl acetate (30 mL) and washed with water (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/2, V/V) to obtain compound 1A. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.96-8.90 (d, J=5.0 Hz, 1H), 8.15-8.11 (m, 1H), 8.08 (s, 1H), 7.98-7.94 (m, 1H), 7.65-7.58 (m, 1H), 7.55-7.48 (d, J=2.0 Hz, 1H), 7.36-7.25 (d, J=8.2 Hz, 1H), 6.80 (s, 1H), 6.58-6.50 (d, J=1.0 Hz, 1H), 4.54-4.48 (m, 2H), 4.09-4.01 (m, 1H), 4.00-3.94 (m, 3H), 3.67-3.62 (m, 1H), 3.52-3.40(ddd, J=5.0, 8.4, 11.6 Hz, 1H), 2.50-2.40 (td, J=4.8, 14.2 Hz, 1H), 2.28 (s, 3H), 2.20-2.10 (ddd, J=5.6, 8.4, 13.8 Hz, 1H), 1.79-1.70 (m, 1H), 1.37-1.34 (m, 1H), 1.10-1.02 (dd, J=4.2, 6.0 Hz, 1H). MS (ESI) m/z: 514.2 [M+H].sup.+.

    Compound 1B

    [0140] TBAF (1 M, 0.035 mL) was added to 1-2B (11 mg, 17.52 μmol) in THF (2 mL), and the reaction solution was stirred at 20° C. for 0.5 hours. The reaction solution was respectively diluted with ethyl acetate (30 mL) and washed with water (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/2, V/V) to obtain compound 1B. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.96-8.90 (d, J=5.0 Hz, 1H), 8.15-8.11 (m, 1H), 7.97-7.89 (m, 2H), 7.64-7.55 (dd, J=1.6, 7.0 Hz, 1H), 7.54-7.48 (br d, J=0.8 Hz, 1H), 7.38-7.26(d, J=8.6 Hz, 1H), 6.84-6.78 (d, J=0.8 Hz, 1H), 6.58-6.50 (d, J=1.2 Hz, 1H), 4.54-4.47 (m, 2H), 4.07-4.02 (m, 1H), 4.00-3.93 (m, 3H), 3.68-3.58 (m, 1H), 3.53-3.44 (m, 1H), 2.50-2.40 (td, J=5.3, 13.6 Hz, 1H), 2.28 (s, 3H), 2.16-2.06 (ddd, J=5.6, 8.7, 14.1 Hz, 1H), 1.78-1.71 (m, 1H), 1.37-1.34 (m, 1H), 1.12-1.05 (m, 1H). MS (ESI) m/z: 514.2 [M+H].sup.+.

    EXAMPLE 2

    [0141] ##STR00049##

    Compound 2-1

    [0142] 1A-6 (1.0 g, 2.35 mmol), 1-1A (480 mg, 2.35 mmol), Pd(dppf)Cl.sub.2 (250 mg, 341.67 μmol) and cesium carbonate (1.6 g, 4.90 mmol) were dissolved in a mixed solvent of dioxane (30 mL) and water (5 mL). Under nitrogen protection, the reaction mixture was heated to 110° C. and stirred for 16 hours. The reaction solution was diluted with ethyl acetate (30 mL) and then filtered; the filtrate was washed with water (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=20/1 to 5/1, V/V) to obtain a crude, which was then separated by chromatographic column (silica gel) (HCOOH-MeCN—H.sub.2O) to obtain compound 2-1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.99-8.92 (d, J=5.0 Hz, 1H), 8.10 (s, 1H), 7.98-7.91 (d, J=4.4 Hz, 1H), 7.89 (s, 1H), 7.60-7.52 (br d, J=8.2 Hz, 1H), 7.54 (s, 1H), 7.38-7.30 (d, J=8.2 Hz, 1H), 7.14-7.06 (d, J=3.8 Hz, 2H), 4.09-4.01 (m, 1H), 3.99-3.92 (m, 1H), 3.69-3.58 (td, J=5.4, 11.4 Hz, 1H), 3.52-3.45 (ddd, J=5.4, 8.6, 11.4 Hz, 1H), 2.56-2.48 (td, J=5.0, 13.8 Hz, 1H), 2.28 (s, 3H), 2.22-2.10 (ddd, J=5.4, 8.6, 14.0 Hz, 1H), 1.88-1.79 (m, 1H), 1.45-1.36 (dd, J=4.2, 9.2 Hz, 1H), 1.18-1.10 (dd, J=4.2, 6.4 Hz, 1H), 0.87-0.82 (m, 1H).

    Compound 2-2

    [0143] Pd.sub.2dba.sub.3 (37.54 mg, 40.99 μmol), Ruphos (38.26 mg, 81.98 μmol) and cesium carbonate (248.99 mg, 764.19 μmol) were added to a solution of 2-1 (200 mg, 409.92 μmol) and 2-1A-2 (200 mg, 1.06 mmol) in toluene (5 mL). Under nitrogen protection, the reaction mixture was heated to 120° C. and stirred for 4 hours. The reaction mixture was filtered; the filtrate was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=2/1, V/V) to obtain compound 2-2. MS (ESI) m/z: 641.3 [M+H].sup.+.

    Compound 2

    [0144] TBAF (1 M, 0.25 mL) was added to 2-2 (80 mg, 124.84 μmol) in THF (5 mL), and the reaction solution was stirred at 20° C. for 0.5 hours. The reaction solution was filtered; the filtrate was washed with a citric acid solution (1 M, 20×2 mL) and saturated brine (15×1 mL) respectively; the organic phase was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/3, V/V) to obtain compound 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.67 (s, 1H), 9.07-9.96 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 8.24-8.16 (d, J=4.4 Hz, 1H), 7.78-7.70 (dd, J=2.2, 8.4 Hz, 1H), 7.66-7.58 (d, J=2.2 Hz, 1H), 7.36-7.25 (d, J=8.4 Hz, 1H), 6.44 (s, 1H), 6.29 (s, 1H), 4.68-4.62 (m, 1H), 3.98-3.88 (dd, J=4.8, 11.4 Hz, 1H), 3.85-3.74 (d, J=11.4 Hz, 1H), 3.60-3.53 (m, 3H), 3.52-3.45 (m, 1H), 3.40-3.36 (m, 1H), 3.30 (s, 2H), 3.04 (s, 3H), 2.23 (s, 3H), 1.98-1.89 (m, 1H), 1.76-1.68 (m, 1H), 1.30-1.21 (dd, J=3.2, 9.2 Hz, 1H), 0.99-0.90 (dd, J=3.6, 5.8 Hz, 1H). MS (ESI) m/z: 527.2 [M+H].sup.+.

    EXAMPLE 3

    [0145] ##STR00050##

    Compound 3-1

    [0146] Pd.sub.2dba.sub.3 (30.15 mg, 32.93 μmol), Ruphos (30.73 mg, 65.85 μmol) and cesium carbonate (200 mg, 613.84 μmol) were added to a solution of 2-1 (160 mg, 329.27 μmol) and 3-1A (150 mg, 855.46 μmol) in toluene (5 mL). Under nitrogen protection, the reaction mixture was heated to 120° C. and stirred for 4 hours. The reaction mixture was filtered; the filtrate was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=2/1, V/V) to obtain compound 3-1. MS (ESI) m/z: 627.2 [M+H].sup.+.

    Compound 3

    [0147] TBAF (1 M, 0.16 mL) was added to 3-1 (50 mg, 79.77 μmol) in THF (5 mL), and the reaction solution was stirred at 20° C. for 0.5 hours. The reaction solution was filtered; the filtrate was washed with a citric acid solution (1 M, 15×2 mL) and saturated brine (15×1 mL) respectively; the organic phase was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/5, V/V) to obtain compound 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.66 (s, 1H), 9.05-9.95 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 8.24-8.16 (d, J=4.8 Hz, 1H), 7.80-7.68 (dd, J=2.2, 8.4 Hz, 1H), 7.65-7.59 (d, J=2.2 Hz, 1H), 7.36-7.27 (d, J=8.4 Hz, 1H), 6.52-6.46 (t, J=5.6 Hz, 1H), 6.38 (s, 1H), 6.25-6.18 (d, J=0.6 Hz, 1H), 4.73-4.65 (t, J=5.4 Hz, 1H), 3.98-3.90 (dd, J=5.0, 11.4 Hz, 1H), 3.86-3.74 (d, J=11.4 Hz, 1H), 3.58-3.50 (q, J=5.8 Hz, 2H), 3.50-3.43 (m, 1H), 3.40-3.36 (m, 1H), 3.30 (s, 2H), 2.47-2.42 (m, 1H), 2.22 (s, 3H), 1.99-1.86 (ddd, J=5.0, 8.2, 13.6 Hz, 1H), 1.74-1.67 (m, 1H), 1.30-1.21 (dd, J=3.2, 9.2 Hz, 1H), 0.99-0.90 (dd, J=3.6, 6.2 Hz, 1H). MS (ESI) m/z: 513.2 [M+H].sup.+.

    EXAMPLE 4

    [0148] ##STR00051##

    Compound 4-1

    [0149] 1A-8 (460 mg, 1.08 mmol), 1-1A (405 mg, 1.19 mmol), Pd(dppf)Cl.sub.2 (79 mg, 107.97 μmol) and cesium carbonate (706 mg, 2.17 mmol) were dissolved in a mixed solvent of DME (8 mL) and water (2 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 24 hours. The reaction solution was diluted with ethyl acetate (20 mL) and then filtered; the filtrate was washed with water (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=5/1 to 2/1, V/V) to obtain compound 4-1. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.65 (d, J=2.6 Hz, 1H), 8.20 (d, J=2.6 Hz, 1H), 8.16 (s, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.12 (d, J=2.0 Hz, 2H), 4.08-3.95 (m, 2H), 3.69-3.62 (m, 1H), 3.49 (ddd, J=11.6, 8. 8, 5.2 Hz, 1H), 2.51 (s, 3H), 2.21-2.12 (m, 1H), 1.90-1.82 (m, 1H), 1.40 (dd, J=9.2, 4.0 Hz, 1H), 1.15 (dd, J=4.4, 2.0 Hz, 1H), 0.92 (dd, J=12.6, 5.6 Hz, 1H).

    Compound 4-2

    [0150] Pd.sub.2dba.sub.3 (53 mg, 57.88 μmol), Brettphos (31 mg, 57.75 μmol) and cesium carbonate (374 mg, 1.15 mmol) were added to a solution of 4-1 (280 mg, 573.89 μmol) and 1A-2 (126 mg, 861.93 μmol) in toluene (5 mL). The reaction solution was diluted with ethyl acetate (10 mL) and then filtered; the filtrate was washed with water (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=40/1 to 5/1, V/V) to obtain compound 4-2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ, 8.66 (d, J=2.6 Hz, 1H), 8.16 (s, 2H), 8.10 (d, J=2.6 Hz, 1H), 7.91 (s, 1H), 7.86 (br d, J=7.6 Hz, 1H), 7.66-7.70 (m, 1H), 6.79 (d, J=1.0 Hz, 1H), 6.55 (d, J=1.0 Hz, 1H), 4.72 (d, J=3.8 Hz, 1H), 4.60-4.54 (m, 2H), 4.04-4.09 (m, 2H), 3.93-3.97 (m, 2H), 3.82 (s, 1H), 3.76 (s, 1H), 3.58-3.52 (m, 2H), 2.80 (br d, J=6.4 Hz, 1H), 2.51 (s, 3H), 2.14-2.08 (m, 1H), 1.90-1.80 (m, 4H), 1.80-1.74 (m, 2H), 1.62 (br d, J=4.2 Hz, 1H), 1.39 (d, J=3.8 Hz, 1H), 1.07 (dd, J=6.2, 4.0 Hz, 1H).

    Compound 4

    [0151] HCl (2 M, 2.2 mL) was added to 4-2 (220 mg, 638.13 μmol) in DMF (2 mL), and the reaction solution was stirred at 15° C. for 0.5 hours. The reaction solution was adjusted to pH=8 by adding a saturated NaHCO.sub.3 solution, diluted with water (20 mL) and then extracted with ethyl acetate (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by preparative silica gel plate (DCM/MeOH=20/1, V/V) to obtain compound 4. .sup.1H NMR (400 MHz, MeOD) δ 8.88-8.80 (d, J=2.4 Hz, 1H), 8.30 (s, 1H), 8.26-8.19 (d, J=7.6 Hz, 1H), 8.15-8.09 (d, J=2.4 Hz, 1H), 7.99-7.91 (d, J=7.4 Hz, 1H), 7.72-7.78 (m, 1H), 6.96-6.89 (d, J=1.0 Hz, 1H), 6.65-6.60 (d, J=1.0 Hz, 1H), 4.40-4.44 (m, 2H), 4.10-4.02 (dd, J=11.4, 4.6 Hz, 1H), 3.97-3.90 (d, J=11.4 Hz, 1H), 3.91-3.88 (m, 2H), 3.68-3.60 (m, 1H), 3.54-3.46 (m, 2H), 2.60-2.51 (br d, J=14.0 Hz, 1H), 2.47 (s, 3H), 2.10 (s, 1H), 1.88-1.80 (m, 1H), 1.46-1.40 (dd, J=9.0, 4.2 Hz, 1H), 1.34-1.28 (br s, 1H), 1.10-1.01 (dd, J=6.4, 4.0 Hz, 1H). MS (ESI) m/z: 514.2 [M+H].sup.+.

    EXAMPLE 5

    [0152] ##STR00052## ##STR00053##

    Compound 5-1

    [0153] 1A-3 (2 g, 5.21 mmol), 5-1A (1.51 g, 5.74 mmol), Pd(dppf)Cl.sub.2 (190.74 mg, 260.68 μmol) and sodium carbonate (1.38 g, 13.03 mmol) were dissolved in a mixed solvent of dioxane (20 mL) and water (4 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 1.5 hours. The reaction solution was diluted with ethyl acetate (30 mL) and then filtered; the filtrate was washed with water (20×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=100/1 to 50/1, V/V) to obtain compound 5-1. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.17 (dd, J=2.6 8.4 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 6.88 (d, J=1.2 Hz, 1H), 6.67 (d, J=1.2 Hz, 1H), 4.74-4.69 (m, 1H), 4.57 (ddd, J=3.4, 6.0, 9.2 Hz, 2H), 4.08 (ddd, J=3.4, 5.8, 11.4 Hz, 1H), 3.96-3.78 (m, 2H), 3.60-3.50 (m, 1H), 2.38 (s, 3H), 1.94-1.80 (m, 1H), 1.79-1.70 (m, 1H), 1.69-1.53 (m, 4H).

    Compound 5-2

    [0154] 5-1 (200 mg, 509.12 μmol), 1-1A (190 mg, 558.72 μmol), Pd(dppf)Cl.sub.2 (38 mg, 51.93 μmol) and cesium carbonate (333 mg, 1.02 mmol) were dissolved in a mixed solvent of DME (4 mL) and water (1 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL) and then filtered; the filtrate was washed with water (10×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=3/1, V/V) to obtain compound 5-2. MS (ESI) m/z: 455.2 [M+H].sup.+.

    Compound 5-3

    [0155] Pd/C (10%, 15 mg) was added to a solution of 5-2 (120 mg, 264.02 μmol) in methanol (4 mL); under hydrogen gas (15 psi), the mixture was stirred at 25° C. for 1 hour. The reaction solution was filtered and then concentrated to obtain compound 5-3 as a crude. MS (ESI): m/z 447.2 [M+Na+H].sup.+.

    Compound 5-4

    [0156] HATU (120 mg, 315.59 μmol) and DIPEA (92 mg, 711.83 μmol) were added to 5-2A (60 mg, 346.59 μmol) and 5-3 (120 mg, 282.66 μmol) in DCM (5 mL), and the mixture was stirred at 20° C. for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20×2 mL); the organic phase was combined, then dried over anhydrous sodium sulfate and concentrated; the residue was purified by preparative silica gel plate (PE/EA=2/1, V/V) to obtain compound 5-4. .sup.1HNMR (400 MHz, CDCl.sub.3) δ, 8.89-8.80 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.82-7.76 (br d, J=5.4 Hz, 1H), 7.59-7.64 (m, 1H), 7.50-7.42 (d, J=1.8 Hz, 1H), 7.38-7.29 (d, J=8.2 Hz, 1H), 6.58-6.88 (m, 2H), 6.56-6.50 (d, J=0.8 Hz, 1H), 4.71 (t, J=3.6 Hz, 1H), 4.45-4.58 (m, 2H), 4.01-4.15 (m, 2H), 3.88-3.99 (m, 2H), 3.82 (ddd, J=11.0, 6.8, 3.8 Hz, 1H), 3.58-3.67 (m, 1H), 3.43-3.56 (m, 2H), 2.55 (dt, J=13.8, 5.2 Hz, 1H), 2.03-2.14 (m, 1H), 2.27 (s, 3H), 1.79-1.90 (m, 2H), 1.70-1.77 (m, 1H), 1.60-1.69 (m, 2H), 1.53 (br d, J=9.2 Hz, 2H), 1.39 (dd, J=9.0, 3.6 Hz, 1H), 1.05 (dd, J=6.2, 4.0 Hz, 1H).

    Compound 5

    [0157] HCl (4 M, 2 mL) was added to 5-4 (100 mg, 172.52 μmol) in DMF (2 mL), and the reaction solution was stirred at 15° C. for 0.5 hours. The reaction solution was adjusted to pH=8 by adding a saturated NaHCO.sub.3 solution, diluted with water (20 mL) and then extracted with ethyl acetate (20×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound 5. .sup.1HNMR (400 MHz, MeOD) δ 8.89-8.80 (d, J=5.0 Hz, 1H), 8.18 (s, 1H), 8.06-7.95 (d, J=4.6 Hz, 1H), 7.69-7.60 (dd, J=8.4, 2.2 Hz, 1H), 7.65-7.58 (d, J=2.2 Hz, 1H), 7.38-7.30 (d, J=8.4 Hz, 1H), 6.66-7.00 (m, 2H), 6.58-6.50 (d, J=1.0 Hz, 1H), 4.36-4.44 (m, 2H), 4.08-4.01 (dd, J=11.4, 4.6 Hz, 1H), 3.96-3.91 (d, J=1.2 Hz, 1H), 3.86-3.91 (m, 2H), 3.57-3.65 (m, 1H), 3.52-3.46 (ddd, J=11.60, 8.4, 5.2 Hz, 2H), 2.26 (s, 3H), 2.51-2.62 (m, 1H), 2.03-2.15 (m, 1H), 1.76-1.90 (m, 1H), 1.45-1.38 (dd, J=9.2, 3.8 Hz, 1H), 1.10-1.01 (dd, J=6.2, 4.0 Hz, 1H). MS (ESI) m/z: 496.1 [M+H].sup.+.

    EXAMPLE 6

    [0158] ##STR00054## ##STR00055##

    Compound 6-2

    [0159] HATU (610 mg, 1.60 mmol) and DIPEA (208 mg, 1.61 mmol) were added to 6-1 (250 mg, 1.34 mmol) and 6-1A (274 mg, 1.47 mmol) in DCM (5 mL); and the mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (15×2 mL); the organic phase was combined, then dried over anhydrous sodium sulfate and concentrated; the residue was purified by preparative silica gel plate (PE/EA=2/1, V/V) to obtain compound 6-2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.83 (d, J=5.0 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.87-7.79 (m, 2H), 7.49 (dd, J=2.0, 8.2 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 2.40 (s, 3H), 2.07 (t, J=18.8 Hz, 3H).

    Compound 6-3

    [0160] 6-2 (370 mg, 1.04 mmol), 2-1A-1 (317 mg, 1.25 mmol), Pd(dppf)Cl.sub.2 (39 mg, 53.30 μmol) and potassium acetate (205 mg, 2.09 mmol) were dissolved in DME (6 mL). Under nitrogen protection, the reaction mixture was heated to 90° C. and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (20 mL); the organic phase was washed with water (20×1 mL) and saturated brine (20×1 mL) and concentrated to obtain compound 6-3. MS (ESI): m/z 403.2 [M+H].sup.+.

    Compound 6-4

    [0161] 6-3 (600 mg, 1.49 mmol), 1-1A (450 mg, 1.64 mmol), Pd(dppf)Cl.sub.2 (55 mg, 75.17 μmol) and sodium carbonate (317 mg, 2.99 mmol) were dissolved in DME (8 mL) and H.sub.2O (2 mL). Under nitrogen protection, the reaction mixture was heated to 85° C. and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL); the organic phase was washed with water (30×1 mL) and saturated brine (30×1 mL) and concentrated to obtain compound 6-4. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.86-8.81 (d, J=5.0 Hz, 1H), 8.13-7.99 (m, 2H), 7.87-7.79 (d, J=5.0 Hz, 1H), 7.65-7.42 (m, 3H), 7.41-7.38 (d, J=8.2 Hz, 1H), 2.29 (s, 3H), 2.07-1.98 (m, 3H).

    Compound 6-5

    [0162] 6-4 (360 mg, 852.57 μmol), 1-1A (319 mg, 938.06 μmol), Pd(dppf)Cl.sub.2 (63 mg, 86.10 μmol) and cesium carbonate (556 mg, 1.71 mmol) were dissolved in a mixed solvent of DME (6 mL) and water (1 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 14 hours. The reaction solution was diluted with ethyl acetate (50 mL) and then filtered; the filtrate was washed with water (30×1 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/1, V/V) to obtain compound 6-5. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.84 (d, J=5.0 Hz, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.83 (d, J=4.4 Hz, 1H), 7.62-7.53 (m, 2H), 7.33 (d, J=8.2 Hz, 1H), 7.09 (d, J=3.6 Hz, 2H), 4.08-4.00 (m, 1H), 4.00-3.89 (m, 1H), 3.70-3.61 (m, 1H), 3.48 (ddd, J=5.2, 8.8, 11.8 Hz, 1H), 2.52 (td, J=4.8, 13.8 Hz, 1H), 2.27 (s, 3H), 2.18-2.13 (m, 1H), 2.07-2.02 (m, 3H), 1.87-1.79 (m, 1H), 1.38 (dd, J=4.2, 9.2 Hz, 1H), 1.13 (dd, J=4.2, 6.4 Hz, 1H).

    Compound 6-6

    [0163] Pd.sub.2dba.sub.3 (31 mg, 33.85 μmol), Brettphos (36 mg, 67.07 μmol) and cesium carbonate (216 mg, 662.94 μmol) were added to a solution of 6-5 (160 mg, 330.62 μmol) and 1A-2 (73 mg, 499.37 μmol) in toluene (4 mL). Under nitrogen protection, the reaction mixture was heated to 110° C. and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (30 mL) and then filtered; the filtrate was washed with water (20×1 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=2/1, V/V) to obtain compound 6-6. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.83 (d, J=4.6 Hz, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.83 (d, J=4.6 Hz, 1H), 7.62 (dd, J=2.0, 8.2 Hz, 1H), 7.49-7.45 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.76 (d, J=1.0 Hz, 1H), 6.51 (d, J=1.0 Hz, 1H), 4.75-4.68 (m, 1H), 4.59-4.47 (m, 2H), 4.09-4.01 (m, 2H), 3.99-3.88 (m, 2H), 3.82 (ddd, J=4.0, 6.6, 11.0 Hz, 1H), 3.65-3.59 (m, 1H), 3.57-3.44 (m, 2H), 2.55 (td, J=5.0, 14.2 Hz, 1H), 2.27 (s, 3H), 2.07-2.02 (m, 3H), 1.89-1.71 (m, 3H), 1.68-1.60 (m, 2H), 1.58-1.47 (m, 3H), 1.39 (dd, J=4.0, 9.0 Hz, 1H), 1.05 (dd, J=4.0, 6.2 Hz, 1H).

    Compound 6

    [0164] HCl (4 M, 0.5 mL) was added to 6-6 (150 mg, 252.67 μmol) in DMF (2 mL); and the reaction solution was stirred at 20° C. for 2 hours. The reaction solution was adjusted to pH=8 by adding a saturated NaHCO.sub.3 solution and extracted with ethyl acetate (20×1 mL); the organic phase was concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/2, V/V) to obtain compound 6. .sup.1HNMR (400 MHz, MeOD) δ 8.85-8.79 (d, J=5.0 Hz, 1H), 8.17 (s, 1H), 7.98-7.90 (d, J=4.6 Hz, 1H), 7.69-7.60 (dd, J=2.4, 8.2 Hz, 1H), 7.60-7.54 (d, J=2.2 Hz, 1H), 7.35-7.28 (d, J=8.2 Hz, 1H), 6.89-6.84 (m, 1H), 6.58-6.51 (d, J=1.0 Hz, 1H), 4.44-4.35 (m, 2H), 4.08-3.99 (dd, J=4.6, 11.2 Hz, 1H), 3.95-3.85 (m, 3H), 3.65-3.57 (m, 1H), 3.54-3.44 (m, 1H), 2.61-2.51 (m, 1H), 2.25 (s, 3H), 2.09-1.97 (m, 4H), 1.84-1.76 (m, 1H), 1.40-1.32 (dd, J=3.4, 9.2 Hz, 1H), 1.06-1.01 (dd, J=3.8, 6.2 Hz, 1H). MS (ESI) m/z: 510.3 [M+H].sup.+.

    Compound 6-7

    [0165] TBSC1 (67 mg, 444.53 μmol) was added to a solution of compound 6 (150 mg, 294.38 μmol) and imidazole (41 mg, 602.23 μmol) in DMF (3 mL). The reaction mixture was stirred at 35° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (15×1 mL) and saturated brine (15×3 mL); the organic phase was concentrated; and the residue was separated by preparative silica gel plate (PE/EA=3/1, V/V) to obtain compound 6-7. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.83 (d, J=5.0 Hz, 1H), 8.03 (s, 1H), 7.90 (s, 1H),7.83 (d, J=5.0 Hz, 1H), 7.62 (dd, J=2.0, 8.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.76 (s, 1H), 6.48 (s,1H), 4.41 (t, J=5.4 Hz, 2H), 4.08-4.02 (m, 1H), 3.99-3.97 (m, 2H), 3.78-3.74 (m, 1H), 3.62 (td, J=5.4, 11.2 Hz, 1H), 3.48(ddd, J=5.2, 8.4, 11.6 Hz, 1H), 2.55 (td, J=5.2, 14.0 Hz, 1H), 2.27 (s, 3H), 2.08-2.02 (m, 3H), 1.89-1.82 (m, 2H), 1.38 (dd, J=3.8, 9.0 Hz, 1H), 1.05 (dd, J=3.8, 6.0 Hz, 1H), 0.91 (s, 9H), 0.09 (s, 6H).

    Compound 6-7A and Compound 6-7B

    [0166] Compound 6-7 was subjected to SFC chiral separation (chiral column: REGIS (R,R)WHELK-O1 (250 mm*25 mm, 10 μm), mobile phase A: isopropanol (containing 0.05% DIEA); mobile phase B: carbon dioxide) to obtain compound 6-7A (retention time: 2.263 min) and compound 6-7B (retention time: 2.325 min).

    Compound 6A

    [0167] HCl (3 M, 0.78 mL) was added to 6-7A (55 mg, 88.17 μmol) in THF (2 mL); and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was neutralized with saturated NaHCO.sub.3 and then extracted with ethyl acetate (15×2 mL); the organic phase was washed with saturated brine (30×1 mL) and concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/1, V/V) to obtain compound 6A. .sup.1HNMR (400 MHz, MeOD) δ 8.85-8.79 (d, J=5.0 Hz, 1H), 8.17 (s, 1H), 7.98-7.90 (d, J=4.6 Hz, 1H), 7.69-7.60 (dd, J=2.4, 8.2 Hz, 1H), 7.60-7.54 (d, J=2.2 Hz, 1H), 7.35-7.28 (d, J=8.2 Hz, 1H), 6.89-6.84 (m, 1H), 6.58-6.51 (d, J=1.0 Hz, 1H), 4.44-4.35 (m, 2H), 4.08-3.99 (dd, J=4.6, 11.2 Hz, 1H), 3.95-3.85 (m, 3H), 3.65-3.57 (m, 1H), 3.54-3.44 (m, 1H), 2.61-2.51 (m, 1H), 2.25 (s, 3H), 2.09-1.97 (m, 4H), 1.84-1.76 (m, 1H), 1.40-1.32 (dd, J=3.4, 9.2 Hz, 1H), 1.06-1.01 (dd, J=3.8, 6.2 Hz, 1H). MS (ESI) m/z: 510.3 [M+H].sup.+, 100% (ee %).

    Compound 6B

    [0168] HCl (3 M, 0.74 mL) was added to 6-7B (52 mg, 83.36 μmol) in THF (2 mL); and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was neutralized with saturated NaHCO.sub.3 and then extracted with ethyl acetate (10×2 mL); the organic phase was washed with saturated brine (20×1 mL) and concentrated; and the residue was separated by preparative silica gel plate (PE/EA=1/1, V/V) to obtain compound 6B. .sup.1HNMR (400 MHz, MeOD) δ 8.85-8.79 (d, J=5.0 Hz, 1H), 8.17 (s, 1H), 7.98-7.90 (d, J=4.6 Hz, 1H), 7.69-7.60 (dd, J=2.4, 8.2 Hz, 1H), 7.60-7.54 (d, J=2.2 Hz, 1H), 7.35-7.28 (d, J=8.2 Hz, 1H), 6.89-6.84 (m, 1H), 6.58-6.51 (d, J=1.0 Hz, 1H), 4.44-4.35 (m, 2H), 4.08-3.99 (dd, J=4.6, 11.2 Hz, 1H), 3.95-3.85 (m, 3H), 3.65-3.57 (m, 1H), 3.54-3.44 (m, 1H), 2.61-2.51 (m, 1H), 2.25 (s, 3H), 2.09-1.97 (m, 4H), 1.84-1.76 (m, 1H), 1.40-1.32 (dd, J=3.4, 9.2 Hz, 1H), 1.06-1.01 (dd, J=3.8, 6.2 Hz, 1H). MS (ESI) m/z: 510.3 [M+H].sup.+, 100% (ee %).

    EXAMPLE 7

    [0169] ##STR00056##

    Compound 7-1

    [0170] Pd.sub.2dba.sub.3 (16 mg, 17.47 μmol), Brettphos (10 mg, 17.28 μmol) and DIPEA (44 mg, 340.45 μmol) were added to a solution of 2-1 (80 mg, 163.97 μmol) and 7-1A (25 mg, 208.04 μmol) in dioxane (2 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 12 hours. The reaction solution was concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/1, V/V) to obtain compound 7-1. MS (ESI) m/z: 572.3 [M+H].sup.+.

    Compound 7

    [0171] Lithium aluminium hydride (9 mg, 237.13 μmol) was added to 7-1 (85 mg, 148.70 μmol) in THF (3 mL), and the reaction solution was stirred at 0° C. for 15 minutes. At 0° C., water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15×2 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by column chromatography (HCOOH-MeCN—H.sub.2O) to obtain compound 7. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.94-8.90 (br d, J=4.8 Hz, 1H), 8.25 (br s, 1H), 8.13 (s, 1H), 7.98-7.91 (br d, J=4.0 Hz, 1H), 7.64-7.60 (br d, J=7.8 Hz, 1H), 7.48 (br s, 1H), 7.34-7.27 (br d, J=8.2 Hz, 1H), 7.04 (s, 1H), 6.91 (s, 1H), 4.58-4.28 (m, 1H), 4.11-3.88 (m, 4H), 3.71-3.57 (m, 1H), 3.55-3.30 (m, 3H), 2.44-2.34 (m, 1H), 2.26 (s, 3H), 2.19-2.06 (m, 1H), 1.74-1.69 (br d, J=4.4 Hz, 1H), 1.37-1.24 (m, 1H), 1.10-1.01 (br t, J=5.0 Hz, 1H). MS (ESI) m/z: 530.0 [M+H].sup.+.

    EXAMPLE 8

    [0172] ##STR00057##

    Compound 8-1

    [0173] 1A-3 (500 mg, 1.30 mmol), 1-1A (450 mg, 1.32 mmol), Pd(dppf)Cl.sub.2 (200 mg, 273.33 μmol) and cesium carbonate (860 mg, 2.64 mmol) were dissolved in DME (12 mL) and H.sub.2O (2 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and water (15×1 mL), and extracted with ethyl acetate (20×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by column chromatography (silica gel) (HCOOH-MeCN—H.sub.2O) to obtain compound 8-1. .sup.1HMMR (400 MHz, CDCl.sub.3) δ 6.68 (d, J=1.2 Hz, 1H), 6.47 (d, J=1.2 Hz, 1H), 4.62 (t, J=3.6 Hz, 1H), 4.40 (ddq, J=3.4, 6.2, 11.6 Hz, 2H), 3.99-3.78 (m, 5H), 3.71 (ddd, J=3.4, 6.2, 11.6 Hz, 1H), 3.54 (td, J=5.2, 11.6 Hz, 1H), 3.45 (td, J=5.2, 11.0 Hz, 1H), 3.33 (ddd, J=5.8, 8.4, 11.6 Hz, 1H), 2.05-1.97 (m, 2H), 1.82-1.61 (m, 2H), 1.60-1.50 (m, 2H), 1.45 (br d, J=5.4 Hz, 1H), 1.32-1.23 (m, 1H), 1.04-0.92 (m, 2H).

    Compound 8-2

    [0174] 8-1 (50 mg, 141.31 μmol), 1A-4 (80 mg, 196.94 μmol), Pd(dppf)Cl.sub.2 (15 mg, 20.50 μmol) and sodium carbonate (30 mg, 283.05 μmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (10 mL) and water (15 mL) and then filtered; the filtrate was extracted with ethyl acetate (10×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/1, V/V) to obtain compound 8-2. MS (ESI) m/z: 598.4 [M+H].sup.+.

    Compound 8

    [0175] HCl (4 M, 1 mL) was added to 8-2 (50 mg, 83.66 μmol) in DMF (2 mL); and the reaction solution was stirred at 15° C. for 0.5 hours. The reaction solution was diluted with ethyl acetate (10 mL) and water (15 mL), then adjusted to pH=8 with a saturated NaHCO.sub.3 solution and extracted with ethyl acetate (10×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/1, V/V) to obtain compound 8. .sup.1HNMR (400 MHz, MeOD) δ 8.97-8.92 (d, J=5.0 Hz, 1H), 8.33 (s, 1H), 8.18-8.11 (d, J=4.0 Hz, 1H), 7.83-7.75 (m, 1H), 7.73-7.68 (dd, J=2.2, 8.2 Hz, 1H), 7.36-7.29 (d, J=8.2 Hz, 1H), 7.05-6.95 (d, J=1.4 Hz, 1H), 6.75-6.70 (d, J=1.4 Hz, 1H), 4.43-4.38 (m, 2H), 4.10-4.02 (dd, J=4.6, 11.4 Hz, 1H), 3.97-3.90 (d, J=11.4 Hz, 1H), 3.91-3.86 (m, 2H), 3.67-3.59 (m, 1H), 3.56-3.49 (ddd, J=5.6, 8.2, 11.6 Hz, 1H), 2.39 (s, 3H), 2.25-2.14 (m, 2H), 1.56-1.51 (td, J=4.6, 9.2 Hz, 1H), 1.22-1.15 (m, 1H), 1.10-1.05 (m, 1H), 1.10-1.05 (m, 1H). MS (ESI) m/z: 514.3 [M+H].sup.+.

    EXAMPLE 9

    [0176] ##STR00058##

    Compound 9-1

    [0177] Pd.sub.2dba.sub.3 (28 mg, 30.58 μmol), Brettphos (33 mg, 61.48 μmol) and cesium carbonate (201 mg, 616.91 μmol) were added to a solution of 2-1 (150 mg, 307.44 μmol) and 9-1A (82 mg, 620.47 μmol) in toluene (4 mL). Under nitrogen protection, the reaction mixture was heated to 110° C. and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (20 mL) and washed with water (20×1 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=2/1, V/V) to obtain compound 9-1. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.93 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.94-7.85 (m, 2H), 7.59 (dd, J=2.0, 8.4 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 6.52 (d, J=1.0 Hz, 1H), 4.56-4.47 (m, 1H), 4.45-4.32 (m, 2H), 4.20-4.16 (m, 1H), 4.08-4.02 (m, 1H), 3.99-3.93 (m, 1H), 3.89 (ddd, J=1.2, 6.2, 8.4 Hz, 1H), 3.62 (td, J=5.4, 11.2 Hz, 1H), 3.48 (ddd, J=5.2, 8.4, 11.6 Hz, 1H), 2.54 (td, J=5.2, 12.4 Hz, 1H), 2.27 (s, 3H), 2.15-2.06 (m, 1H), 1.87-1.77 (m, 1H), 1.49 (s, 3H), 1.42 (s, 3H), 1.40-1.35 (m, 1H), 1.07 (dd, J=3.8, 6.2 Hz, 1H).

    Compound 9

    [0178] HCl (3 M, 0.2 mL) was added to 9-1 (140 mg, 239.89 μmol) in methanol (3 mL), and the reaction solution was stirred at 30° C. for 1 hour. The reaction solution was diluted with water (20 mL), then adjusted to pH=8 with a saturated NaHCO.sub.3 solution and extracted with ethyl acetate (20×1 mL); the organic phase was concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/1, V/V) to obtain compound 9. .sup.1HNMR (400 MHz, MeOD) δ 8.96-8.89 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 8.16-8.11 (dd, J=1.4, 5.0 Hz, 1H), 7.71-7.65 (dd, J=2.4, 8.2 Hz, 1H), 7.65-7.59 (d, J=2.4 Hz, 1H), 7.36-7.30 (d, J=8.2 Hz, 1H), 6.91-6.87 (d, J=1.0 Hz, 1H), 6.60-6.54 (d, J=1.0 Hz, 1H), 4.49-4.40 (m, 1H), 4.38-4.30 (m, 1H), 4.10-3.99 (m, 2H), 3.96-3.90 (dd, J=1.2, 11.2 Hz, 1H), 3.69-3.56 (m, 3H), 3.54-3.38 (ddd, J=5.2, 8.4, 11.6 Hz, 1H), 2.60-2.53 (td, J=5.2, 14.0 Hz, 1H), 2.27 (s, 3H), 2.15-2.04 (m, 1H), 1.90-1.76 (m, 1H), 1.48-1.36 (m, 1H), 1.09-1.01 (dd, J=4.0, 6.4 Hz, 1H). MS (ESI) m/z: 544.2 [M+H].sup.+.

    EXAMPLE 10

    [0179] ##STR00059##

    Compound 10

    [0180] Pd.sub.2dba.sub.3 (27 mg, 29.48 μmol), Brettphos (31 mg, 57.75 μmol) and cesium carbonate (187 mg, 573.94 μmol) were added to a solution of 2-1 (140 mg, 286.94 μmol) and 10-1A (46 mg, 433.47 μmol) in toluene (4 mL). Under nitrogen protection, the reaction mixture was heated to 110° C. and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (20 mL) and then washed with water (20×1 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=2/1, V/V) to obtain compound 10. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.69 (s, 1H), 9.01-8.97 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 8.23-8.18 (dd, J=1.0, 5.0 Hz, 1H), 7.77-7.73 (dd, J=2.4, 8.2 Hz, 1H), 7.69-7.65 (d, J=2.2 Hz, 1H), 7.37-7.32 (d, J=8.6 Hz, 1H), 6.89-6.85 (d, J=1.0 Hz, 1H), 6.55-6.51 (d, J=1.0 Hz, 1H), 5.08-5.01 (d, J=5.4 Hz, 1H), 4.32-4.23 (m, 1H), 4.22-4.14 (m, 1H), 4.00-3.92 (m, 2H), 3.83-3.77 (dd, J=1.2, 11.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.45-3.35 (m, 3H), 3.28 (s, 3H), 2.55-2.51 (br d, J=2.0 Hz, 1H), 2.24 (s, 3H), 2.06-1.93 (m, 1H), 1.84-1.73 (m, 1H), 1.36-1.30 (td, J=3.0, 9.0 Hz, 1H), 1.05-0.98 (dd, J=3.6, 6.2 Hz, 1H). MS (ESI) m/z: 558.0 [M+H].sup.+.

    EXAMPLE 11

    [0181] ##STR00060## ##STR00061##

    Compound 11-2

    [0182] 11-1 (7.5 g, 50.68 mmol), 11-1A (10.1 g, 48.15 mmol), Pd(dppf)Cl.sub.2 (4.1 g, 5.07 mmol) and sodium carbonate (10.7 g, 101.36 mmol) were dissolved in a mixed solvent of DME (225 mL) and water (50 mL). Under nitrogen protection, the reaction mixture was heated to 90° C. and stirred for 12 hours. The reaction solution was concentrated; and the residue was separated by silica gel column chromatography (PE/EA=1/0 to 0/1, V/V) to obtain compound 11-2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.56-7.52 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.03 (m, 1H), 6.72-6.70 (m, 1H), 4.31-4.29 (m, 2H), 3.87-3.85 (m, 2H), 2.54-2.51 (m, 2H).

    Compound 11-3

    [0183] 11-2 (1.8 g, 9.20 mmol), 11-2A (4.6 g, 32.11 mmol) and sodium iodide (450 mg, 3.00 mmol) were dissolved in THF (42 mL) solvent. Under nitrogen protection, the reaction mixture was heated to 80° C. and stirred for 12 hours. Dichloromethane (20 mL) and water (20 mL) were added to the reaction solution, and the mixture was subjected to liquid separation; the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound 11-3. MS (ESI) m/z:246.2[M+H].sup.+.

    Compound 11-4

    [0184] To 11-3 (2 g, 8.14 mmol) in dichloromethane (20 mL) solvent, m-chloroperoxybenzoic acid (4.1 g, 20.27 mmol, 85%) was added. The reaction mixture was heated to 65° C. and stirred for 12 hours. Sodium thiosulfate (20 g), water (200 mL) and dichloromethane (200 mL) were added to the reaction solution, and the mixture was stirred for 30 minutes. Sodium carbonate (15 g) was added, and the mixture was stirred for 20 minutes and subjected to liquid separation; the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (DCM/MeOH=1/0 to 1/1, V/V) to obtain compound 11-4. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.51-7.49 (m, 1H), 7.35-7.33 (m, 1H), 7.20-7.16 (m, 1H), 4.23-4.21 (m, 1H), 4.13-4.08 (m, 1H), 3.82-3.80 (m, 2H), 2.30-2.25 (m, 1H), 1.77-1.67 (m, 2H).

    Compound 11-5

    [0185] 11-4 (100 mg, 382.19 μmol) was dissolved in phosphorus oxychloride (2 mL), and the mixture was heated to 90° C. and stirred for 12 hours. A saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20×1 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound 11-5. MS (ESI) m/z: 280.1 [M+H].sup.+.

    Compound 11-6

    [0186] Potassium tert-butoxide (1.8 mL, 1 M) was added to 11-5 (100 mg, 357.02 μmol) and 11-3A (125.9 mg, 714.04 μmol) in THF (1 mL) solvent. The reaction mixture was stirred at 25° C. for 3 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and the mixture was subjected to liquid separation; the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=5/1, V/V) to obtain compound 11-6. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 6.89 (d, J=1.4 Hz, 1H), 6.67 (d, J=1.4 Hz, 1H), 4.38 (t, J=5.2 Hz, 2H), 4.18-4.01 (m, 2H), 3.94 (t, J=5.2 Hz, 2H), 3.67-3.47 (m, 2H), 2.57-2.48 (m, 1H), 2.41-2.27 (m, 1H), 2.21-2.09 (m, 1H), 0.93-0.88 (m, 1H), 0.91 (s, 8H), 0.15-0.05 (m, 6H).

    Compound 11-7

    [0187] 11-6 (100 mg, 238.12 μmol), 1A-4 (116 mg, 285.74 μmol), Pd(dppf)Cl2 (38.9 mg, 47.62 μmol) and sodium carbonate (50.5 mg, 476.23 μmol) were dissolved in a mixed solvent of dioxane (1 mL) and water (0.2 mL). Under nitrogen protection, the reaction mixture was heated to 90° C. and stirred for 3 hours. The reaction solution was concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=3/1, V/V) and then separated by chromatographic column (silica gel) (NH4HCO3-MeCN—H2O) to obtain compound 11-7. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.94 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.93 (d, J=4.6 Hz, 1H), 7.83 (s, 1H), 7.63 (br d, J=8.6 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.84 (s, 1H), 6.62 (d, J=1.0 Hz, 1H), 4.45 (t, J=5.2 Hz, 2H), 4.20-4.04 (m, 2H), 3.99 (t, J=5.2 Hz, 2H), 3.68-3.49 (m, 2H), 2.59 (ddd, J=3.2, 6.4, 9.8 Hz, 1H), 2.43-2.32 (m, 1H), 2.27 (s, 3H), 2.26-2.17 (m, 1H), 1.56 (s, 4H), 0.91 (s, 9H), 0.10 (s, 6H).

    Compound 11

    [0188] HCl (12 M, 0.03 mL) was added to 11-7 (120 mg, 180.79 μmol) in THF (3 mL), and the reaction solution was stirred at 20° C. for 3 hours. The reaction solution was diluted with water (10 mL), adjusted to pH=8 with a saturated NaHCO.sub.3 solution and extracted with ethyl acetate (10×1 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound 11. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.97-8.92 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.95-7.90 (br d, J=4.8 Hz, 1H), 7.88 (s, 1H), 7.64-7.58(br d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.36-7.30 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.68 (s, 1H), 4.59-4.50 (m, 2H), 4.17-3.97 (m, 4H), 3.67-3.49 (m, 2H), 3.27-3.23 (t, J=5.8 Hz, 1H), 2.53-2.42 (m, 1H), 2.41-2.30 (m, 1H), 2.28 (s, 3H), 2.23-2.11 (m, 1H). MS (ESI) m/z: 550.3 [M+H].sup.+.

    Compound 11A and Compound 11B

    [0189] Compound 11 was subjected to SFC separation (chiral column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm), mobile phase A: ethanol (containing 0.05% DIEA); mobile phase B: carbon dioxide) to obtain compound 11A (retention time: 1.325 min) and compound 11B (retention time: 1.422 min). Compound 11A: .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.97-8.92 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.95-7.90 (br d, J=4.8 Hz, 1H), 7.88 (s, 1H), 7.64-7.58(br d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.36-7.30 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.68 (s, 1H), 4.59-4.50 (m, 2H), 4.17-3.97 (m, 4H), 3.67-3.49 (m, 2H), 3.27-3.23 (t, J=5.8 Hz, 1H), 2.53-2.42 (m, 1H), 2.41-2.30 (m, 1H), 2.28 (s, 3H), 2.23-2.11 (m, 1H). MS (ESI) m/z: 550.0 [M+H].sup.+, 100% (ee %). Compound 11B: .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.97-8.92 (d, J=4.8 Hz, 1H), 8.11 (s, 1H), 7.95-7.90 (br d, J=4.8 Hz, 1H), 7.88 (s, 1H), 7.64-7.58(br d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.36-7.30 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.68 (s, 1H), 4.59-4.50 (m, 2H), 4.17-3.97 (m, 4H), 3.67-3.49 (m, 2H), 3.27-3.23 (t, J=5.8 Hz, 1H), 2.53-2.42 (m, 1H), 2.41-2.30 (m, 1H), 2.28 (s, 3H), 2.23-2.11 (m, 1H). MS (ESI) m/z: 550.0 [M+H].sup.+, 97.5% (ee %).

    EXAMPLE 12

    [0190] ##STR00062##

    Compound 12-2

    [0191] 12-1 (480 mg, 2.46 mmol), 1A-4 (1 g, 2.46 mmol), Pd(dppf)Cl.sub.2 (400 mg, 489.81 μmol) and sodium carbonate (520 mg, 4.91 mmol) were dissolved in a mixed solvent of dioxane (20 mL) and water (4 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 2 hours. The reaction solution was filtered; the filtrate was concentrated; and the residue was separated by silica gel column chromatography (PE/EA=10/1 to 5/1, V/V) to obtain compound 12-2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.92 (d, J=5.0 Hz, 1H), 8.11 (s, 2H), 7.93 (d, J=4.2 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.66 (dd, J=2.2, 8.2 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.14 (s, 1H), 2.61 (s, 3H), 2.44 (s, 3H).

    Compound 12-3

    [0192] 12-2 (300 mg, 683.60 μmol), 1-1A (156 mg, 764.56 μmol), Pd(dppf)Cl.sub.2 (120 mg, 146.94 μmol) and cesium carbonate (450 mg, 1.38 mmol) were dissolved in DME (10 mL) and H.sub.2O (2 mL). Under nitrogen protection, the reaction mixture was heated to 110° C. and stirred for 16 hours. The reaction solution was filtered; the filtrate was concentrated; and the residue was separated by silica gel column chromatography (PE/EA=10/1 to 5/1, V/V) to obtain compound 12-2. MS (ESI) m/z: 501.2 [M+H].sup.+.

    Compound 12-4

    [0193] To 12-3 (80 mg, 159.83 μmol) in dichloromethane (2 mL) solvent, m-chloroperoxybenzoic acid (65 mg, 320.17 μmol, 85%) was added. The reaction mixture was stirred at 15° C. for 1 hour. Water (2 mL) and dichloromethane (3 mL) were added to the reaction solution, and the mixture was subjected to liquid separation; the organic phase was washed with saturated sodium sulfite (1 mL); the organic phase was concentrated to obtain compound 12-4. MS (ESI) m/z: 533.3 [M+H].sup.+.

    Compound 12-5

    [0194] Sodium hydride (16 mg, 400.04 60%) was added to a solution of 1A-2 (16 mg, 109.45 μmol) in dioxane (2 mL). 12-4 (55 mg, 103.28 μmol) was added to the above-mentioned mixture, and the resulting mixture was stirred at 15° C. for 1 hour. A saturated ammonium chloride solution (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound 12-5. MS (ESI) m/z: 599.4 [M+H].sup.+.

    Compound 12

    [0195] HCl (2 M, 0.15 mL) was added to 12-5 (50 mg, 83.53 μmol) in DMF (2 mL), and the reaction solution was stirred at 15° C. for 1 hour. A saturated NaHCO.sub.3 solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by chromatographic column (silica gel) (HCOOH-MeCN—H.sub.2O) to obtain compound 12. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.80 (s, 1H), 9.02-8.97 (d, J=5.0 Hz, 1H), 8.39 (s, 1H), 8.24-8.20 (d, J=4.4 Hz, 1H), 7.89-7.86 (d, J=2.0 Hz, 1H), 7.87-7.83 (dd, J=2.2, 8.4 Hz, 1H), 7.39-7.34 (d, J=8.4 Hz, 1H), 7.17 (s, 1H), 4.91 (br s, 1H), 4.36-4.31 (t, J=5.2 Hz, 2H), 3.96-3.88 (m, 1H), 3.87-3.81 (m, 1H), 3.75-3.70 (br t, J=4.8 Hz, 2H), 3.60-3.52 (m, 1H), 2.64-2.58 (td, J=4.8, 14.0 Hz, 1H), 2.38 (s, 3H), 1.99-1.89 (ddd, J=5.8, 8.6, 14.2 Hz, 1H), 1.88-1.80 (m, 1H), 1.49-1.40 (dd, J=3.8, 9.2 Hz, 1H), 1.16-1.10 (dd, J=3.8, 6.4 Hz, 1H). MS (ESI) m/z: 515.1 [M+H].sup.+.

    EXAMPLE 13

    [0196] ##STR00063##

    Compound 13-1

    [0197] Pd.sub.2dba.sub.3 (30 mg, 32.76 μmol), Ruphos (30 mg, 64.29 μmol) and cesium carbonate (150 mg, 460.38 μmol) were added to a solution of 2-1 (100 mg, 204.96 μmol) and 13-1A (100 mg, 533.75 μmol) in toluene (4 mL). Under nitrogen protection, the reaction mixture was heated to 120° C. and stirred for 4 hours. The reaction solution was filtered; the filtrate was concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=3/1, V/V) to obtain compound 13-1. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.93 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.92 (br d, J=4.6 Hz, 1H), 7.85 (s, 1H), 7.62 (br d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.51 (s, 1H), 6.03 (s, 1H), 4.76 (quin, J=5.6 Hz, 1H), 4.22 (t, J=7.6 Hz, 2H), 4.06-3.99 (m, 1H), 3.98-3.93 (m, 1H), 3.84-3.77 (m, 2H), 3.62 (td, J=5.4, 11.2 Hz, 1H), 3.45 (ddd, J=5.4, 8.8, 11.2 Hz, 1H), 2.57 (td, J=4.8, 14.0 Hz, 1H), 2.10-2.03 (m, 1H), 1.81 (td, J=4.6, 9.2 Hz, 1H), 1.37 (dd, J=3.8, 9.2 Hz, 1H), 0.99 (dd, J=3.8, 6.4 Hz, 2H), 0.93-0.90 (m, 9H), 0.11-0.07 (m, 6H).

    Compound 13

    [0198] TFA (1 mL) was added to 13-1 (80 mg, 125.24 μmol) in dichloromethane (4 mL), and the reaction solution was stirred at 15° C. for 13 hours. The reaction solution was diluted with dichloromethane (10 mL), then adjusted to pH=8 with a saturated NaHCO.sub.3 solution and extracted with dichloromethane (10×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by chromatographic column (silica gel) (HCOOH-MeCN—H.sub.2O) to obtain compound 13. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.69 (s, 1H), 9.02-8.97 (d, J=5.0 Hz, 1H), 8.37 (s, 1H), 8.22-8.18 (d, J=5.0 Hz, 1H), 7.77-7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.64-7.61 (d, J=2.0 Hz, 1H), 7.35-7.30 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 6.12 (br s, 1H), 5.77-5.36 (m, 1H), 4.64-4.50 (m, 1H), 4.18-4.14 (br t, J=7.2 Hz, 2H), 3.96-3.92 (dd, J=4.6, 11.2 Hz, 1H), 3.83-3.79 (d, J=10.2 Hz, 1H), 3.75-3.61 (m, 2H), 3.51-3.47 (td, J=5.6, 11.4 Hz, 1H), 3.42-3.37 (m, 2H), 2.23 (s, 3H), 1.98-1.94 (ddd, J=5.6, 8.2, 13.8 Hz, 1H), 1.77-1.70 (m, 1H), 1.29-1.27 (dd, J=3.6, 9.0 Hz, 1H), 0.95-0.90 (dd, J=3.6, 6.0 Hz, 1H). MS (ESI) m/z: 525.2 [M+H].sup.+.

    EXAMPLE 14

    [0199] ##STR00064## ##STR00065##

    Compound 14-1

    [0200] At 0° C., sodium hydride (5.41 g, 135.14 mmol, 60% purity) was added to a solution of 1A-2 (11.8 g, 80.72 mmol) in THF (100 mL), and the mixture was warmed to 20° C. and stirred for 30 minutes. At 0° C., 11-1 (10 g, 67.57 mmol) was added to the mixed solution, and the mixture was warmed to 20° C. and stirred for 4 hours. A saturated ammonium chloride solution (30 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL×2); the combined extract was concentrated; and the residue was separated by column chromatography (PE/EA=100/0 to 80/1, V/V) to obtain 14-1. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.55-7.49 (m, 1H), 6.90 (d, J=7.4 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 4.71 (t, J=3.6 Hz, 1H), 4.58-4.43 (m, 2H), 4.05 (ddd, J=3.6, 5.8, 11.6 Hz, 1H), 3.90 (ddd, J=3.2, 8.0, 11.4 Hz, 1H), 3.81 (ddd, J=3.6, 6.4, 11.4 Hz, 1H), 3.58-3.49 (m, 1H), 1.91-1.80 (m, 1H), 1.79-1.70 (m, 1H), 1.68-1.50 (m, 4H).

    Compound 14-2

    [0201] 14-1 (10 g, 38.80 mmol), 2-1A-1 (20 g, 78.76 mmol), Pd(dppf)Cl.sub.2 (2.75 g, 3.76 mmol) and potassium acetate (11.5 g, 117.18 mmol) were dissolved in DMF (200 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 8 hours. The reaction solution was filtered to obtain compound 14-2 solution. MS (ESI): m/z 268.2 [M+H].sup.+.

    Compound 14-3

    [0202] 14-2 (9.6 g, 35.94 mmol), 14-2A (6 g, 31.91 mmol), Pd(dppf)Cl.sub.2 (2.4 g, 3.28 mmol) and sodium carbonate (7.2 g, 67.93 mmol) were dissolved in a mixed solvent of DMF (240 mL) and water (48 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 3 hours. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200×2 mL); the organic phase was washed with saturated brine (100×2 mL), dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=16/1 to 10/1, V/V) to obtain compound 14-3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.65 (dd, J=7.4, 8.2 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 4.74-4.71 (m, 1H), 4.70-4.59 (m, 2H), 4.43 (t, J=2.6 Hz, 2H), 4.10 (ddd, 5.8, 11.6 Hz, 1H), 3.97 (t, J=5.4 Hz, 2H), 3.94-3.77 (m, 2H), 3.57-3.49 (m, 1H), 2.77 (tt, J=2.8, 5.6 Hz, 2H), 1.91-1.82 (m, 1H), 1.80-1.71 (m, 1H), 1.70-1.62 (m, 2H), 1.58-1.52 (m, 2H).

    Compound 14-4

    [0203] At 0° C., a solution of tert-butyl alcohol lithium (1.45 g, 18.16 mmol) in NMP (20 mL) was added dropwise to a solution of 14-3 (2 g, 6.05 mmol) and chloroiodomethane (2 g, 18.16 mmol) in NMP (20 mL), and the mixture was warmed to 20° C. and stirred for 12 hours. A saturated ammonium chloride solution (50 mL) and water (50 mL) were added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL×2); the combined extract was concentrated; and the residue was separated by column chromatography (PE/EA=20/0 to 8/1) to obtain 14-4. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.66-7.53 (m, 1H), 7.04 (d, J=7.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.44 (d, J=6.2 Hz, 1H), 5.57 (d, J=6.2 Hz, 1H), 4.74-4.67 (m, 1H), 4.62 (ddd, J=3.8, 6.2, 11.6 Hz, 1H), 4.55 (t, J=5.0 Hz, 1H), 4.47 (ddd, J=3.8, 6.4, 11.7 Hz, 1H), 4.29 (d, J=10.8 Hz, 1H), 4.11-4.02 (m, 1H), 3.98 (d, J=10.8 Hz, 1H), 3.91 (ddd, J=3.2, 8.0, 11.2 Hz, 1H), 3.87-3.77 (m, 1H), 3.57-3.48 (m, 1H), 2.78 (ddd, J=0.8, 4.6, 7.2 Hz, 1H), 1.89-1.81 (m, 1H), 1.77 (d, J=4.0 Hz, 1H), 1.76-1.70 (m, 1H), 1.68-1.57 (m, 2H), 1.57-1.49 (m, 2H).

    Compound 14-5

    [0204] Pd/C (10%, 400 mg) was added to a solution of 14-4 (1.5 g, 4.38 mmol) in methanol (20 mL); under hydrogen gas (15 psi), the mixture was stirred at 20° C. for 1 hour. The reaction solution was filtered and then concentrated to obtain compound 14-5 as a crude. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.62-7.56 (m, 1H), 6.93 (dd, J=4.2, 7.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 4.73 (t, J=3.6 Hz, 1H), 4.65-4.49 (m, 2H), 4.19-4.13 (m, 1H), 4.09 (dddd, 3.8, 5.6, 11.2 Hz, 1H), 4.05-4.01 (m, 1H), 3.93 (ddd, J=3.2, 8.0, 11.2 Hz, 1H), 3.89-3.79 (m, 2H), 3.58-3.48 (m, 2H), 2.59-2.49 (m, 1H), 2.28 (dd, J=5.0, 12.4 Hz, 1H), 2.12-2.00 (m, 1H), 1.94-1.83 (m, 1H), 1.82-1.72 (m, 1H), 1.71-1.64 (m, 1H), 1.62 (s, 1H), 1.59-1.54 (m, 2H), 1.49 (d, J=5.0 Hz, 1H).

    Compound 14-6

    [0205] 2-1A-1 (884.79 mg, 3.48 mmol), [Ir(COD)OMe].sub.2 (200 mg, 301.72 μmol) and dtbpy (162.10 mg, 603.94 μmol) were dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, the reaction mixture was heated to 80° C. and stirred for 5 minutes. A solution of 14-5 (800 mg, 2.32 mmol) in tetrahydrofuran (10 mL) was then added, and the mixture was stirred at 80° C. for 4 hours. The reaction solution was filtered and then concentrated to obtain compound 14-6 as a crude. MS (ESI): m/z 305.1 [M+H-THP].sup.+.

    Compound 14-7

    [0206] 14-6 (500 mg, 1.39 mmol), 14-5A (600 mg, 1.28 mmol), Pd(dppf)Cl.sub.2 (93.66 mg, 128.00 μmol) and sodium carbonate (271.33 mg, 2.56 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Under nitrogen protection, the reaction mixture was heated to 80° C. and stirred for 2 hours. The reaction mixture was filtered; the filtrate was concentrated; ethyl acetate (30 mL) was then added; the mixture was washed with saturated brine (20 mL×2) and then concentrated; and the residue was separated by column chromatography (PE/EA=20/1 to 5/1) to obtain 14-7. MS (ESI): m/z 623.3 [M+H].sup.+.

    Compound 14

    [0207] TFA (0.5 mL) was added to 14-7 (50 mg, 80.30 μmol) in dichloromethane (1 mL), and the reaction solution was stirred at 20° C. for 0.5 hours. The reaction solution was adjusted to pH=8 with a saturated sodium bicarbonate solution and extracted with dichloromethane (20×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/2, V/V) to obtain compound 14. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 9.02-8.95 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.21-8.18 (d, J=4.8 Hz, 1H), 7.82-7.74 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.60 (d, J=2.2 Hz, 1H), 7.39-7.30 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 6.69 (s, 1H), 4.89-4.83 (t, J=5.6 Hz, 1H), 4.39-4.32 (t, J=5.0 Hz, 2H), 4.10-4.05 (d, J=11.2 Hz, 1H), 3.98-4.86 (d, J=11.4 Hz, 1H), 3.82-3.68 (m, 3H), 3.55-3.49 (m, 1H), 2.61-2.55 (m, 1H), 2.46-2.38 (d, J=5.4 Hz, 1H), 2.23 (s, 3H), 2.02-1.93 (m, 1H), 1.54-1.47 (d, J=5.4 Hz, 1H). MS (ESI): m/z 539.2 [M+H].sup.+.

    Compound 14A and 14B

    [0208] Compound 14 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm), mobile phase A: isopropanol (containing 0.05% DIEA); mobile phase B: carbon dioxide) to obtain compound 14A (retention time: 1.702 min) and compound 14B (retention time: 1.815 min). Compound 14A: .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 9.02-8.95 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.21-8.18 (d, J=4.8 Hz, 1H), 7.82-7.74 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.60 (d, J=2.2 Hz, 1H), 7.39-7.30 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 6.69 (s, 1H), 4.89-4.83 (t, J=5.6 Hz, 1H), 4.39-4.32 (t, J=5.0 Hz, 2H), 4.10-4.05 (d, J=11.2 Hz, 1H), 3.98-4.86 (d, J=11.4 Hz, 1H), 3.82-3.68 (m, 3H), 3.55-3.49 (m, 1H), 2.61-2.55 (m, 1H), 2.46-2.38 (d, J=5.4 Hz, 1H), 2.23 (s, 3H), 2.02-1.93 (m, 1H), 1.54-1.47 (d, J=5.4 Hz, 1H). MS (ESI): m/z 539.2 [M+H].sup.+, 100% (ee %). Compound 14B: .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 9.02-8.95 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 8.21-8.18 (d, J=4.8 Hz, 1H), 7.82-7.74 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.60 (d, J=2.2 Hz, 1H), 7.39-7.30 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 6.69 (s, 1H), 4.89-4.83 (t, J=5.6 Hz, 1H), 4.39-4.32 (t, J=5.0 Hz, 2H), 4.10-4.05 (d, J=11.2 Hz, 1H), 3.98-4.86 (d, J=11.4 Hz, 1H), 3.82-3.68 (m, 3H), 3.55-3.49 (m, 1H), 2.61-2.55 (m, 1H), 2.46-2.38 (d, J=5.4 Hz, 1H), 2.23 (s, 3H), 2.02-1.93 (m, 1H), 1.54-1.47 (d, J=5.4 Hz, 1H). MS (ESI): m/z 539.2 [M+H].sup.+, 100% (ee %).

    EXAMPLE 15

    [0209] ##STR00066##

    Compound 15

    [0210] Pd.sub.2dba.sub.3 (37.54 mg, 40.99 μmol), Brettphos (44.01 mg, 81.98 μmol) and cesium carbonate (267.12 mg, 819.84 μmol) were added to a solution of 2-1 (200 mg, 409.92 μmol) and 15-1A (84.97 mg, 942.81 μmol) in toluene (5 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (10 mL) and then filtered; the filtrate was concentrated; and the residue was separated by chromatographic column (silica gel) (HCOOH-MeCN—H.sub.2O) to obtain compound 15. .sup.1HNMR (400 MHz, CD.sub.3OD) δ 8.94-8.92 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 8.16-8.12 (dd, J=1.0, 5.0 Hz, 1H), 7.72-7.66 (dd, J=2.4, 8.2 Hz, 1H), 7.66-7.63 (d, J=2.2 Hz, 1H), 7.37-7.32 (d, J=8.6 Hz, 1H), 6.90-6.87 (d, J=1.0 Hz, 1H), 6.60-6.58 (d, J=1.0 Hz, 1H), 4.60 (s, 2H), 4.20 (s, 2H), 4.10-4.05 (m, 1H), 3.98-3.92 (m, 1H), 3.64-3.61 (m, 1H), 3.54-3.46 (m, 1H), 2.60-2.58 (m, 1H), 2.29 (s, 3H), 2.06-1.98 (m, 1H), 1.85-1.76 (m, 1H), 1.43-1.38 (m, 1H), 1.33 (s, 6H), 1.06-1.04 (m, 1H). MS (ESI) m/z: 542.1 [M+H].sup.+.

    EXAMPLE 16

    [0211] ##STR00067## ##STR00068##

    Compound 16-2

    [0212] At −78° C., n-butyllithium (23 mL, 2.5 M) was added to a solution of 16-1 (10 g, 51.96 mmol) in dichloromethane (100 mL), and the mixture was stirred for 30 minutes. At −78° C., 16-1A (4.92 g, 57.16 mmol) was added to the mixed solution, and the mixture was warmed to 25° C. and stirred for 0.5 hours. A saturated ammonium chloride solution (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (40 mL×2); the combined extract was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by column chromatography (PE/EA=10/1 to 5/1, V/V) to obtain compound 16-2. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.72 (t, J=7.8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 4.35 (s, 1H), 4.24-4.14 (m, 2H), 4.05-4.00 (m, 1H), 3.96-3.92 (m, 1H), 2.45 (td, J=8.8, 13.0 Hz, 1H), 2.32-2.22 (m, 1H).

    Compound 16-3

    [0213] To a solution of 16-2 (6 g, 30.06 mmol) in toluene (80 mL), p-toluenesulfonic acid (11.5 g, 60.46 mmol) was added; and the mixture was warmed to 110° C. and stirred for 16 hours. A saturated sodium bicarbonate solution (40 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the resulting mixture was subjected to liquid separation; the organic phase was washed with a saturated sodium bicarbonate solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=50/1 to 20/1, V/V) to obtain compound 16-3. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.64 (t, J=7.8 Hz, 1H), 7.23 (dd, J=5.2, 7.8 Hz, 2H), 6.68 (quin, J=2.0 Hz, 1H), 5.08 (dt, 5.0 Hz, 2H), 4.91 (dt, 5.0 Hz, 2H).

    Compound 16-4

    [0214] DMSO (50 mL) was added to a mixture of potassium tert-butoxide (3.71 g, 33.04 mmol) and 11-2A-1 (7.3 g, 33.17 mmol). Under nitrogen protection, the reaction mixture was stirred at 25° C. for 1 hour. A solution of 16-3 (1 g, 5.51 mmol) in DMSO (5 mL) was added to the reaction solution, and the reaction mixture was heated to 70° C. and stirred for 6 hours. Water (180 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=20/1, V/V) to obtain compound 16-4. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.46 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 4.11-4.04 (m, 2H), 3.89-3.78 (m, 2H), 2.08 (ddd, J=2.8, 5.2, 8.0 Hz, 1H), 1.32 (dd, J=4.4, 8.0 Hz, 1H), 1.07 (t, J=4.6 Hz, 1H).

    Compound 16-5

    [0215] 2-1A-1 (1.08 g, 4.25 mmol), [Ir(COD)OMe].sub.2 (70 mg, 105.60 μmol) and tmphen (50 mg, 211.59 μmol) were dissolved in methyl tertiary butyl ether (20 mL). Under nitrogen protection, 16-4 (770 mg, 3.94 mmol) was added to the reaction mixture, and the resulting mixture was heated to 80° C. and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 16-5 as a crude. MS (ESI): m/z 240.3 [M−84+2H].sup.+.

    Compound 16-6

    [0216] 16-5 (1.2 g, 3.73 mmol), 14-5A (1.4 g, 3.90 mmol), Pd(dppf)Cl.sub.2.DCM (300 mg, 367.36 μmol) and sodium carbonate (800 mg, 7.55 mmol) were dissolved in dioxane (50 mL) and water (10 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 3 hours. The reaction mixture was filtered; the filtrate was concentrated; ethyl acetate (20 mL) and water (10 mL) were then added; the mixture was subjected to liquid separation; the aqueous phase was extracted with ethyl acetate (10 mL×3); the combined organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=10/1 to 5/1) to obtain 16-6. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.92 (d, J=5.0 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.94 (d, J=5.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.10 (d, J=1.2 Hz, 1H), 6.90 (d, J=1.2 Hz, 1H), 4.19-4.14 (m, 2H), 3.95-3.87 (m, 2H), 2.27 (s, 3H), 2.24-2.17 (m, 1H), 1.48-1.41 (m, 1H), 1.20-1.15 (m, 1H).

    Compound 16-7

    [0217] Pd.sub.2dba.sub.3 (180 mg, 196.57 μmol), Brettphos (200 mg, 372.60 μmol) and cesium carbonate (1.26 g, 3.87 mmol) were added to a solution of 16-6 (900 mg, 1.90 mmol) and 11-3A (400 mg, 2.27 mmol) in toluene (30 mL). Under nitrogen protection, the reaction mixture was heated to 110° C. and stirred for 4 hours. The reaction solution was filtered; the filtrate was concentrated; and the residue was separated by silica gel column chromatography (PE/EA=20/1 to 6/1) to obtain compound 16-7. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.65 (s, 1H), 8.95 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 8.14 (d, J=4.6 Hz, 1H), 7.70 (dd, J=2.0, 8.2 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.68 (s, 1H), 6.49 (s, 1H), 4.31 (br d, J=2.8 Hz, 1H), 4.07-3.97 (m, 2H), 3.90-3.86 (m, 2H), 3.79-3.69 (m, 2H), 2.17 (s, 3H), 2.15-2.09 (m, 1H), 1.33 (dd, J=3.8, 7.8 Hz, 1H), 1.13 (t, J=7.2 Hz, 1H), 0.96-0.91 (m, 1H), 0.80 (s, 9H), 0.00 (s, 6H).

    Compound 16

    [0218] Hydrochloric acid (1 mL, 4 M) was added to 16-7 (300 mg, 488.81 μmol) in tetrahydrofuran (10 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was diluted with ethyl acetate (20 mL), then adjusted to pH=8 with a saturated NaHCO.sub.3 solution and extracted with ethyl acetate (10×3 mL); the organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by thin-layer silica gel plate (PE/EA=1/1, V/V) to obtain compound 16. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 9.06-8.95 (d, J=5.0 Hz, 1H), 8.37 (s, 1H), 8.23-8.18 (d, J=4.2 Hz, 1H), 7.77-7.71 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.64 (d, J=2.2 Hz, 1H), 7.39-7.31 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 6.59-6.54 (d, J=1.0 Hz, 1H), 4.86-4.81 (t, J=5.2 Hz, 1H), 4.35-4.30 (t, J=5.2 Hz, 2H), 4.13-4.03 (m, 2H), 3.83-3.70 (m, 4H), 2.24 (s, 3H), 2.22-2.08 (ddd, J=2.4, 5.0, 7.8 Hz, 1H), 1.40-1.32 (dd, J=3.6, 7.8 Hz, 1H), 1.02-0.96 (t, J=4.4 Hz, 1H). MS (ESI) m/z: 500.4 [M+H].sup.+.

    Compound 16A and 16B

    [0219] Compound 16 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm), mobile phase A: ethanol (containing 0.05% DIEA); mobile phase B: carbon dioxide) to obtain compound 16A (retention time: 1.487 min) and compound 16B (retention time: 1.590 min).

    [0220] Compound 16A: .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 9.06-8.95 (d, J=5.0 Hz, 1H), 8.37 (s, 1H), 8.23-8.18 (d, J=4.2 Hz, 1H), 7.77-7.71 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.64 (d, J=2.2 Hz, 1H), 7.39-7.31 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 6.59-6.54 (d, J=1.0 Hz, 1H), 4.86-4.81 (t, J=5.2 Hz, 1H), 4.35-4.30 (t, J=5.2 Hz, 2H), 4.13-4.03 (m, 2H), 3.83-3.70 (m, 4H), 2.24 (s, 3H), 2.22-2.08 (ddd, 5.0, 7.8 Hz, 1H), 1.40-1.32 (dd, J=3.6, 7.8 Hz, 1H), 1.02-0.96 (t, J=4.4 Hz, 1H). MS (ESI) m/z: 500.4 [M+H].sup.+, 100% (ee %).

    [0221] Compound 16B: .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 9.06-8.95 (d, J=5.0 Hz, 1H), 8.37 (s, 1H), 8.23-8.18 (d, J=4.2 Hz, 1H), 7.77-7.71 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.64 (d, J=2.2 Hz, 1H), 7.39-7.31 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 6.59-6.54 (d, J=1.0 Hz, 1H), 4.86-4.81 (t, J=5.2 Hz, 1H), 4.35-4.30 (t, J=5.2 Hz, 2H), 4.13-4.03 (m, 2H), 3.83-3.70 (m, 4H), 2.24 (s, 3H), 2.22-2.08 (ddd, 5.0, 7.8 Hz, 1H), 1.40-1.32 (dd, J=3.6, 7.8 Hz, 1H), 1.02-0.96 (t, J=4.4 Hz, 1H). MS (ESI) m/z: 500.4 [M+H].sup.+, 99.7% (ee %).

    Compound 16B

    [0222] ##STR00069## ##STR00070##

    Compound 16B-1

    [0223] At −70° C., n-butyllithium (500 mL, 2.5 M) was added to a solution of acetonitrile (54.60 g, 1.33 mol) in tetrahydrofuran (500 mL), and the reaction mixture was stirred for 1 hour. At −70° C., a solution of 11-1 (65 g, 439.22 mmol) in tetrahydrofuran (200 mL) was added to the mixed solution, and the mixture was stirred for 1 hour and then warmed to 25° C. and stirred for another 1 hour. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×2); the combined extract was dried over anhydrous sodium sulfate and then concentrated to obtain compound 16B-1 as a crude. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.74 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 3.94 (s, 2H).

    Compound 16B-3

    [0224] At −30° C., LiHMDS (940.79 mL, 1 M) was added dropwise to a solution of 16B-1 (130 g, 852.01 mmol) and 16B-2 (80.5 g, 870.04 mmol) in methyl tertiary butyl ether (1.2 L), and the mixture was warmed to −10° C.-0° C. and stirred for 2 hours. At −30° C., NaHMDS (855.26 mL, 1 M) was added dropwise to the mixed solution, and the mixture was warmed to 25° C. and stirred for 16 hours. Water (40 mL) was added to the reaction mixture, and the reaction solution was concentrated to obtain compound 16B-3 as a crude.

    Compound 16B-4

    [0225] Potassium hydroxide (900 mL, 2 M) was added dropwise to a solution of 16B-3 (180 g, 862.71 mmol) in ethanol (1 L), and the mixture was warmed to 80° C. and stirred for 4 hours to obtain a mixed solution of compound 16B-4.

    Compound 16B-5

    [0226] At 50° C., hydrochloric acid (740 mL, 6 M) was added dropwise to a mixed solution 16B-4, and the mixture was warmed to 60° C. and stirred for 1 hour. The reaction mixture was concentrated to remove ethanol; the aqueous phase was extracted with ethyl acetate (800 mL×3); the combined organic phase was washed with saturated brine (500 mL×1), dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=20/1 to 10/1) to obtain compound 16B-5. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.06 (dd, J=0.8, 7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.16 (dd, J=0.8, 7.8 Hz, 1H), 4.41 (dd, J=4.6, 9.2 Hz, 1H), 4.29 (d, J=9.2 Hz, 1H), 3.02-2.84 (m, 1H), 2.12 (dd, J=4.2, 7.8 Hz, 1H), 1.54-1.38 (m, 1H).

    Compound 16B-6

    [0227] At −5° C., lithium borohydride (100 mL, 4 M) was added to a solution of 16B-5 (44 g, 209.89 mmol) in tetrahydrofuran (400 mL), and the mixture was warmed 20° C. and stirred for 2 hours. A saturated ammonium chloride aqueous solution (100 mL) was slowly added to the reaction mixture, and the mixture was filtered; the filtrate was washed with water (60 mL×2); the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain a crude, which was slurried with PE/EA (10:1, 80 mL) to obtain compound 16B-6. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.50 (t, J=7.8 Hz, 1H), 7.07 (dd, J=0.6, 7.8 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 4.66-4.53 (m, 1H), 4.32 (dd, J=4.6, 8.3 Hz, 1H), 4.10 (ddd, J=5.2, 9.2, 12.4 Hz, 1H), 3.54-3.46 (m, 1H), 3.43-3.34 (m, 1H), 3.43-3.34 (m, 1H), 1.76-1.59 (m, 1H), 1.41 (dd, J=5.6, 8.8 Hz, 1H), 0.85 (t, J=5.6 Hz, 1H).

    Compound 16B-7

    [0228] At 0° C., DEAD (45.03 g, 258.53 mmol) was added dropwise to a solution of triphenylphosphine (58 g, 221.13 mmol) in tetrahydrofuran (500 mL), and the mixture was stirred at 0° C. for 30 minutes. At 0° C., 16B-6 (40 g, 187.21 mmol) in tetrahydrofuran (200 mL) was added dropwise to the mixed solution, and the mixture was warmed to 25° C. and stirred for 1 hour. Water (100 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the resulting mixture was subjected to liquid separation; the organic phase was washed with water (100 mL×2), dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by column chromatography (PE/EA=100/1 to 20/1, V/V) to obtain 16B-7. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.54 (t, J=7.8 Hz, 1H), 7.12 (dd, J=0.6, 7.8 Hz, 1H), 6.95 (dd, J=0.6, 7.8 Hz, 1H), 4.18-4.13 (m, 2H), 3.95-3.85 (m, 2H), 2.16 (ddd, 5.2, 8.0 Hz, 1H), 1.40 (dd, J=4.4, 8.0 Hz, 1H), 1.15 (t, J=4.6 Hz, 1H).

    Compound 16B-8

    [0229] At 110° C., 16B-7 (26.7 g, 136.47 mmol) was added to a solution of potassium tert-butoxide (30.6 g, 272.70 mmol) and 1A-2 (24 g, 164.18 mmol) in dioxane (200 mL), and the mixture was stirred at 110° C. for 1 hour. The reaction solution was filtered; the filtrate was concentrated; and then water (100 mL) and ethyl acetate (200 mL) were added. The mixture was subjected to liquid separation; the organic phase was washed with water (100 mL×2), dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by column chromatography (PE/EA=50/1 to 20/1, V/V) to obtain 16B-8. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.50-7.42 (m, 1H), 6.59 (t, J=8.0 Hz, 2H), 4.70 (t, J=3.6 Hz, 1H), 4.53-4.39 (m, 2H), 4.20-4.16 (m, 1H), 4.13-4.09 (m, 1H), 4.04 (ddd, J=4.0, 5.8, 11.2 Hz, 1H), 3.92-3.84 (m, 3H), 3.80 (ddd, J=4.0, 6.8, 11.2 Hz, 1H), 3.57-3.48 (m, 1H), 2.12-2.07 (m, 1H), 1.89-1.81 (m, 1H), 1.79-1.71 (m, 1H), 1.68-1.60 (m, 2H), 1.58-1.48 (m, 2H), 1.39 (dd, J=4.2, 8.0 Hz, 1H), 1.06 (t, J=4.4 Hz, 1H).

    Compound 16B-9

    [0230] 2-1A-1 (36 g, 141.77 mmol), [Ir(COD)OMe].sub.2 (2 g, 3.02 mmol) and tmphen (1.6 g, 6.77 mmol) were dissolved in methyl tertiary butyl ether (400 mL), and 16B-8 (40 g, 130.99 mmol) was added. Under nitrogen protection, the reaction mixture was heated to 80° C. and stirred for 4 hours. The reaction solution was concentrated to obtain compound 16B-9 as a crude. MS (ESI): m/z 350.4 [M-84+2H].sup.+.

    Compound 16B-10

    [0231] 16B-9 (52 g, 120.56 mmol), 14-5A (48.53 g, 135.14 mmol), Pd(dppf)Cl.sub.2.DCM (10.4 g, 12.74 mmol) and sodium carbonate (26 g, 245.31 mmol) were dissolved in dioxane (500 mL) and water (100 mL). Under nitrogen protection, the reaction mixture was heated to 100° C. and stirred for 3 hours. The reaction mixture was filtered; the filtrate was concentrated; ethyl acetate (400 mL) and water (300 mL) were then added; the mixture was subjected to liquid separation; the aqueous phase was extracted with ethyl acetate (100 mL×3); the combined organic phase was dried over anhydrous sodium sulfate and then concentrated; and the residue was separated by silica gel column chromatography (PE/EA=7/1 to 3/1) to obtain compound 16B-10. .sup.1HNMR (400 MHz, CDCl.sub.3) δ 8.83 (d, J=5.0 Hz, 1H), 8.11 (br s, 1H), 8.05 (s, 1H), 7.86 (br d, J=4.6 Hz, 1H), 7.53 (br d, J=8.2 Hz, 1H), 7.40-7.32 (m, 1H), 7.19 (s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 4.62 (t, J=3.6 Hz, 1H), 4.51-4.35 (m, 2H), 4.13-4.06 (m, 1H), 4.05-3.97 (m, 2H), 3.86-3.71 (m, 4H), 3.51-3.40 (m, 1H), 2.18 (s, 3H), 2.05 (ddd, J=2.6, 5.0, 7.8 Hz, 1H), 1.82-1.63 (m, 2H), 1.57-1.39 (m, 4H), 1.37-1.30 (m, 1H), 1.01 (t, J=4.4 Hz, 1H).

    Compound 16B

    [0232] Hydrochloric acid (128.51 mL, 4 M) was added to 16B-10 (60 g, 102.81 mmol) in DMF (60 mL), and the reaction solution was stirred at 40° C. for 2 hours. Water (2.5 L) was added to the reaction solution, and the resulting mixed solution was filtered; the filter cake was dried and then dissolved in dichloromethane; the mixture was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (PE/EA=3/1 to 0/1) to obtain compound 16B as a crude, which was dissolved in a mixed solution of PE/EA (4:1, 150 mL), stirred and filtered to obtain compound 16B. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 9.06-8.95 (d, J=5.0 Hz, 1H), 8.37 (s, 1H), 8.23-8.18 (d, J=4.2 Hz, 1H), 7.77-7.71 (dd, J=2.2, 8.4 Hz, 1H), 7.68-7.64 (d, J=2.2 Hz, 1H), 7.39-7.31 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 6.59-6.54 (d, J=1.0 Hz, 1H), 4.86-4.81 (t, J=5.2 Hz, 1H), 4.35-4.30 (t, J=5.2 Hz, 2H), 4.13-4.03 (m, 2H), 3.83-3.70 (m, 4H), 2.24 (s, 3H), 2.22-2.08 (ddd, 5.0, 7.8 Hz, 1H), 1.40-1.32 (dd, J=3.6, 7.8 Hz, 1H), 1.02-0.96 (t, J=4.4 Hz, 1H). MS (ESI) m/z: 500.4 [M+H].sup.+, 100% ee (chiral column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm), mobile phase A: ethanol (containing 0.05% DIEA); mobile phase B: carbon dioxide) retention time: 1.592 min).

    EXPERIMENTAL EXAMPLE 1

    Experiments for c-RAF Enzyme Inhibitory Activity

    [0233] Experimental Materials:

    TABLE-US-00001 Experimental material Brand Catalog No cRAF protein Creative BioMart-RAF1-416H MEK1 protein Invitrogen-PR3984A ADP-Glo kinase detection kit Promega-V9102 Tris-HCl, pH 7.4 Sigma-T2663-1L MgCl.sub.2 Sigma-63020-1L NaCl Sigma-S5150 DTT Invitrogen-P2325 Triton X-100 Sigma-X100 H.sub.2O Gibco-15230-162 384 intermediate plate Greiner-781280 384 experimental plate PerkinElmer-6007299

    [0234] Experimental Steps:

    [0235] (1) Compound Preparation:

    [0236] the compounds to be tested and reference compounds were diluted to 100 μM with DMSO, and the compounds were further subjected to a 3-fold gradient dilution using Echo to obtain target plates with 11 concentration gradients.

    [0237] (2) Experimental Process:

    [0238] 1) buffer formulation: 50 mM Tris-HCl (pH 7.4), 3.5 mM MgCl.sub.2, 150 mM NaCl, 1 mM DTT, 0.02% Triton X-100, H.sub.2O;

    [0239] 2) a mixed solution of MEK1 and ATP was formulated with a buffer, and 5 μL of the substrate mixed solution was added to the 384 intermediate plate;

    [0240] 3) the cRAF enzyme was diluted with a buffer, and 5 μL was added to the 384 intermediate plate;

    [0241] 4) 5 μL of the mixed reaction solution was transferred to the 384 experimental plate using Bravo, and the plate was centrifuged for 15 seconds and then incubated in a 23° C. incubator;

    [0242] 5) after 1 hour, 5 μL of ADP-Glo was added to the 384 experimental plate, and the plate was shaken, centrifuged for 15 seconds and then incubated in a 23° C. incubator;

    [0243] 6) after 40 minutes, 10 μL of the kinase detection reagent was added to the 384 experimental plate, and the plate was shaken, centrifuged for 15 seconds and then incubated in a 23° C. incubator;

    [0244] 7) after 1 hour, the plate was read on Envision.

    [0245] Experimental Results:

    TABLE-US-00002 c-RAF IC.sub.50 c-RAF IC.sub.50 Compound (μM) Compound (μM) Compound 1A 0.0025 Compound 1B 0.0020 Compound 2 0.0027 Compound 3 0.0017 Compound 5 0.0010 Compound 6 0.0009 Compound 7 0.0025 Compound 8 0.0011 Compound 9 0.0012 Compound 10 0.0025 Compound 11 0.0028 Compound 16 0.0008 Compound 16B 0.0006 / /

    [0246] Experimental conclusion: the compounds of the present disclosure have a better c-RAF enzyme inhibitory activity.

    EXPERIMENTAL EXAMPLE 2

    Experiments for Ca1u-6 (Kras.SUP.Q61K.) Antiproliferative Activity

    [0247] Experimental Materials:

    [0248] 1) Experimental reagents and consumables

    TABLE-US-00003 Name Brand Catalog No EMEM medium Vicente-320-005-CL Fetal bovine serum Biosera-FB-1058/500 0.25% trypsin Basalmedia-S310KJ Double antibodies (penicillin and streptomycin) Procell-PB180120 CellTiter Glo Promega-G7573 Cell plate Corning-3610

    [0249] 2) Experimental instruments

    TABLE-US-00004 Name Brand Catalog No Cell counting plate Qukin Victor Nivo PerkinElmer

    [0250] Experimental Steps:

    [0251] Cell Inoculation:

    [0252] (1) cell medium: 89% EMEM, 10% fetal bovine serum and 1% penicillin-streptomycin;

    [0253] (2) the original medium in the cell culture flask was removed; the cells were digested with trypsin and then counted; and the cell suspension was diluted with the medium to a cell density of 3.75×10.sup.4 cells per milliliter required for plating;

    [0254] (3) 100 μL of the medium was added to the outermost circle of wells of the cell plate; 80 μL of the cell suspension was added to other wells; and the plate was cultured overnight in a 37° C. incubator with 5% CO.sub.2.

    [0255] Compound Supplementation:

    [0256] the compounds were subjected to a gradient dilution and then supplemented using Echo; and the cell plate was put back into the incubator for three days.

    [0257] Plate Read and Data Analysis:

    [0258] adding CTG and reading the plate involve adding 20 μL of CellTiterGlo to each well of the cell plate, shaking the plate for 10 min in the dark, and reading the plate on Victor Nivo.

    [0259] Experimental Results:

    TABLE-US-00005 Calu-6 anti- Calu-6 anti- proliferative proliferative activity activity Compound IC.sub.50 (μM) Compound IC.sub.50 (μM) Compound 1A 1.2 Compound 1B 0.96 Compound 2 1.1 Compound 3 1.4 Compound 5 4.6 Compound 6 1.0 Compound 6A 1.2 Compound 6B 1.3 Compound 8 1.0 Compound 9 6.4 Compound 10 7.1 Compound 11 1.1 Compound 11A 3.1 Compound 11B 1.1 Compound 13 0.2 Compound 14 3.5 Compound 14A 3.7 Compound 14B 4.6 Compound 15 4.7 Compound 16 1.3 Compound 16A 1.3 Compound 16B 0.6

    [0260] Experimental conclusion: the compounds of the present disclosure have a Ca1u-6 antiproliferative activity.

    EXPERIMENTAL EXAMPLE 3

    Experiments for HCT-116(Kras.SUP.G13D.) Antiproliferative Activity

    [0261] Experimental Materials:

    [0262] 1) Experimental reagents and consumables

    TABLE-US-00006 Name Brand Catalog No Mc’Coy 5A medium BI-01-075-1ACS Fetal bovine serum Biosera-FB-1058/500 0.25% trypsin Basalmedia-S310KJ Double antibodies (penicillin and Procell-PB180120 streptomycin) CellTiter Glo Promega-G7573 Cell plate Corning-3610

    [0263] 2) Experimental instruments

    TABLE-US-00007 Name Brand Catalog No Cell counting plate Qukin Victor Nivo PerkinElmer

    [0264] Experimental Steps:

    [0265] Cell Inoculation:

    [0266] (1) cell medium: 89% Mc'Coy 5A, 10% fetal bovine serum and 1% penicillin-streptomycin;

    [0267] (2) the original medium in the cell culture flask was removed; the cells were digested with trypsin and then counted; and the cell suspension was diluted with the medium to a cell density of 2.5×10.sup.4 cells per milliliter required for plating;

    [0268] (3) 100 μL of the medium was added to the outermost circle of wells of the cell plate; 80 μL of the cell suspension was added to other wells; and the plate was cultured overnight in a 37° C. incubator with 5% CO.sub.2.

    [0269] Compound Supplementation:

    [0270] the compounds were subjected to a gradient dilution and then supplemented; and the cell plate was put back into the incubator for three days.

    [0271] Plate Read and Data Analysis:

    [0272] adding CTG and reading the plate involve adding 20 μL of CellTiterGlo to each well of the cell plate, shaking the plate for 10 min in the dark, and reading the plate on Victor Nivo.

    [0273] Experimental Results:

    TABLE-US-00008 HCT-116 HCT-116 antiproliferative antiproliferative Compound activity IC.sub.50 (μM) Compound activity IC.sub.50 (μM) Compound 1A 0.6 Compound 1B 0.6 Compound 2 2.3 Compound 3 2.3 Compound 5 2.6 Compound 6 0.6 Compound 6A 1.4 Compound 6B 1.5 Compound 8 1.1 Compound 9 0.8 Compound 10 5.3 Compound 11 0.8 Compound 11A 3.6 Compound 11B 1.4 Compound 13 0.2 Compound 14 0.4 Compound 14A 2.1 Compound 14B 2.3 Compound 15 0.9 Compound 16 2.2 Compound 16A 2.3 Compound 16B 1.1

    [0274] Experimental conclusion: the compounds of the present disclosure have an HCT-116(Kras.sup.G13D) antiproliferative activity.

    EXPERIMENTAL EXAMPLE 4

    Experiments for HCT116(Kras.SUP.G13D.) ERK Phosphorylation Inhibition

    [0275] Experimental Materials:

    [0276] 1. Reagents and consumables

    TABLE-US-00009 Reagent Brand Catalog No Highly sensitive detection kit for Cisbi 0-64AERPEH human ERK phosphorylated protein RPMI1640 medium Gibco-22400089 Fetal bovine serum Hyclone-SV30087.03 96 HTRF microwell plate Cisbio-66PL96025 96 microwell plate COSTAR-3599 DMSO Sigma-D2650-100 mL 0.05% Trypsin-EDTA Gibco-25300-062

    [0277] 2. Main instruments

    TABLE-US-00010 Instrument Manufacturer Model number Biosafety cabinet AIRTECH BSC-1304IIA2 Carbon dioxide incubator Thermo 311 Cell counter BECKMAN Vi-cellXR Microplate reader PerkinElmer Envision Centrifuge Eppendorf Centrifuge 5810R

    [0278] 3. Cell information

    TABLE-US-00011 TABLE 1 Cell information Cell name Source Catalog No. HCT116 ATCC ATCC-HTB-132

    [0279] Experimental Steps and Methods:

    [0280] 1) cells were resuscitated, cultured to a logarithmic growth phase, then digested with trypsin and seeded in a 96-well plate, and the plate was incubated overnight in an incubator;

    [0281] 2) serial gradients of compounds dissolved in DMSO were added to the 96-well plate, which was then put back into the incubator for 1 hour;

    [0282] 3) the cell plate was taken out; the supernatant was removed; and the cells were incubated and lysed by adding cell lysates (containing 1% blocking peptide) for 30 minutes at room temperature;

    [0283] 4) 16 μL of cell lysates per well was transferred to the HTRF plate, and then 4 μL of the mixed antibody solution formulated thereby was added;

    [0284] 5) after overnight incubation, the plate was read on Envision; the fitted curves were obtained according to ratio (the ratio of Ex665/Ex615 fluorescence intensity); and EC.sub.50 was calculated with the four-parameter fitting formula, i.e., Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogEC50−X)*Hill Slope)) on Graphpad.

    [0285] Experimental Results:

    TABLE-US-00012 HCT-116 ERK HCT-116 ERK phosphorylation phosphorylation inhibitory activity inhibitory activity Compound IC.sub.50 (μM) Compound IC.sub.50 (μM) Compound 1 0.12 Compound 1A 0.14 Compound 1B 0.22 Compound 2 0.21 Compound 3 0.19 Compound 6A 0.16 Compound 6B 0.19 Compound 11A 0.38 Compound 11B 0.31 Compound 16 0.16 Compound 16A 0.23 Compound 16B 0.18

    [0286] Experimental conclusion: the present disclosure compounds have an HCT-116 ERK phosphorylation inhibitory activity.

    EXPERIMENTAL EXAMPLE 5

    Experiments for Ca1u-6(Kras.SUP.Q61K.) ERK Phosphorylation Inhibition

    [0287] Experimental Materials:

    [0288] Reagents and consumables

    TABLE-US-00013 Reagent Brand Catalog No Highly sensitive detection kit for Cisbi 0-64 AERPEH human ERK phosphorylated protein RPMI1640 medium Gibco-22400089 Fetal bovine serum Hyclone-SV30087.03 96 HTRF microwell plate Cisbio-66PL96025 96 microwell plate COSTAR-3599 DMSO Sigma-D2650-100 mL 0.05% Trypsin-EDTA Gibco-25300-062

    [0289] Main instruments

    TABLE-US-00014 Instrument Manufacturer Model number Biosafety cabinet AIRTECH BSC-1304IIA2 Carbon dioxide incubator Thermo 311 Cell counter BECKMAN Vi-cellXR Microplate reader PerkinElmer Envision Centrifuge Eppendorf Centrifuge 5810R

    [0290] Cell information:

    TABLE-US-00015 Cell name Source Catalog No. Calu6 ATCC ATCC-HTB-56

    [0291] Experimental Steps and Methods:

    [0292] 1) cells were resuscitated, cultured to a logarithmic growth phase, then digested with trypsin and seeded in a 96-well plate, and the plate was incubated overnight in an incubator;

    [0293] 2) serial gradients of compounds dissolved in DMSO were added to the 96-well plate, which was then put back into the incubator for 1 hour;

    [0294] 3) the cell plate was taken out; and the cells were incubated and lysed by adding cell lysates (containing 1% blocking peptide) for 30 minutes at room temperature;

    [0295] 4) 16 μL of cell lysates per well was transferred to the HTRF plate, and then 4 μL of the mixed antibody solution formulated thereby was added;

    [0296] 5) after overnight incubation, the plate was read on Envision; the fitted curves were obtained according to ratio (the ratio of Ex665/Ex615 fluorescence intensity); and EC.sub.50 was calculated with the four-parameter fitting formula, i.e., Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogEC50−X)*Hill Slope)) on Graphpad.

    [0297] Experimental Results:

    TABLE-US-00016 Calu-6 ERK Calu-6 ERK phosphorylation phosphorylation inhibitory activity inhibitory activity Compound IC.sub.50 (μM) Compound IC.sub.50 (μM) Compound 1A 0.22 Compound 1B 0.25 Compound 5 0.17 Compound 6 0.22 Compound 8 0.35 Compound 9 0.18 Compound 11 0.43 Compound 13 0.39 Compound 14A 0.35 Compound 14B 0.25 Compound 14 0.33 Compound 15 0.33 Compound 16A 0.63 Compound 16B 0.49

    [0298] Experimental conclusion: the present disclosure compounds have a Ca1u-6 ERK phosphorylation inhibitory activity.

    EXPERIMENTAL EXAMPLE 6

    Experiments for In Vivo Pharmacodynamics of Human Lung Cancer Ca1u-6 Subcutaneous Xenograft Tumor BALB/c Nude Mouse Model

    [0299] Experimental Materials:

    [0300] 1.1 Experimental Animals and Feeding Environment

    [0301] 1.1.1 Experimental Animals

    [0302] Specie: Mice

    [0303] Strain BALB/c nude mice

    [0304] Week old upon arrival: 6-8 weeks old

    [0305] Gender: female

    [0306] 1.1.2 Feeding Environment

    [0307] Mice are fed in SPF-level animal rooms in IVC (individual ventilated cages; constant temperature and humidity) (3-5 per cage)

    [0308] Temperature: 20° C.-26° C.

    [0309] Humidity: 40%-70%

    [0310] 1.2 Compound Information

    TABLE-US-00017 Molecular Content Storage Name weight Purity (%) (mg) condition Compound 1 518.49 99.21 380.0 RT Compound 16B 499.48 99.44 655.0 RT

    [0311] 1.3 Tumor Tissue or Cell Information

    [0312] Cells: human lung cancer Ca1u-6 cells, which were cultured in vitro in EMEM medium containing 0.2 units/mL bovine insulin and 10% fetal bovine serum in a 37° C. incubator with 5% CO.sub.2. Conventional digestion treatment with trypsin-EDTA for passage was carried out twice a week. When the cell saturation was 80% to 90%, and the number reached the requirement, the cells were collected, counted and inoculated.

    [0313] 1.4 Additional Reagent Information

    TABLE-US-00018 Name Manufacturer Catalog No. Storage condition Fetal bovine serum Hyclone SV30087.03 −20° C. Trypsin Gibco 25200-072 −20° C. EMEM medium ATCC ATCC30-2003 2-8° C.

    [0314] 1.5 Instrument Information

    TABLE-US-00019 Name Manufacturer Model number Carbon dioxide incubator Thermo Fisher Heracell240i Cryogenic high-speed Eppendorf 5810R centrifuge Analytical balance Sartorius SECURA225D- 1CN General balance Changzhou Tianzhiping EL-2KJ Instrument Equipment Co., Ltd. Digital vernier caliper Mitutoyo 0-150 mm

    [0315] Experimental Methods and Steps:

    [0316] 2.1 Tumor Cell Inoculation

    [0317] Cell inoculation: 0.2 mL of Ca1u-6 cells (at 1:1 ratio with Matrigel) were subcutaneously inoculated on the right back of each mouse, and when the average tumor volume reached 173 mm.sup.3, mice were grouped and administrated.

    [0318] 2.2 Grouping

    TABLE-US-00020 TABLE 2 Grouping and administrating schedule for experimental animals Administration volume Compound Dose parameters Route of Frequency of Groups N.sup.1 treatment (mg/kg) (μL/g).sup.2 administration administration 1 6 Solvent control — 10 PO QD × 21 days group.sup.3 2 6 Compound 1 100 10 PO QD × 21 days 3 6 Compound 16B 100 10 PO QD × 21 days Note: .sup.1Number of mice per group .sup.2Administration volume parameters based on mouse body weight (10 μL/g). If the body weight decreases by more than 15%, the administration is stopped until the body weight returns to within 10% of the original body weight; .sup.30.5% MC (methyl cellulose).

    [0319] 2.3 Formulation of Test Substances

    TABLE-US-00021 TABLE 3 Formulation method of test substances Concentration Storage Compound Package Formulation method.sup.1 (mg/mL) condition Solvent   80% (5% solutol aqueous solution) + 20% — 4° C. control PEG 400 group Compound 255.0 18.06 mg of compound 1 was weighed, and 10 4° C. 1 mg/bottle 1.44 ml of 5% solutol was added; vortex or sonication is performed until same is fully dissolved; and then 0.36 ml of 20% PEG-400 was added and fully dissolve to obtain a 10 mg/mL solution. Compound 580 18.10 mg of compound 16B was weighed, 10 4° C. 16B mg/bottle and 1.44 ml of 5% solutol was added; vortex or sonication is performed until same is fully dissolved; and then 0.36 ml of 20% PEG-400 was added and fully dissolve to obtain a 10 mg/mL solution. Note: 1. before administration to mice, the compounds to be administrated needs to be mixed gently and thoroughly, wherein solutol is polyethylene glycol-15-hydroxystearate.

    [0320] 2.4 Tumor Measurement and Experimental Index

    [0321] Tumor diameter was measured twice a week with a vernier caliper. The calculation formula of tumor volume was V=0.5a×b.sup.2, wherein a and b represent the long and short diameters of the tumor, respectively.

    [0322] The anti-tumor efficacy of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C(%)=T.sub.RTV/C.sub.RTV×100% (T.sub.RTV: mean RTV of the treatment group; C.sub.RTV: mean RTV of the negative control group). The relative tumor volume (RTV) was calculated according to the results of the tumor measurement. The calculation formula was RTV=V.sub.t/V.sub.0, wherein V.sub.0 was the tumor volume measured at the beginning of the grouping and administration (i.e., D0), and V.sub.t was the tumor volume in a certain measurement. T.sub.RTV and C.sub.RTV were obtained from the data on the same day.

    [0323] TGI (%) reflected the tumor growth inhibition rate. TGI(%)=[1−(average tumor volume at the end of administration in a certain treatment group−average tumor volume at the beginning of administration in the treatment group)/(average tumor volume at the end of administration in the solvent control group−average tumor volume at the beginning of administration in the solvent control group)]×100%.

    [0324] 2.5 Statistical Analysis

    [0325] statistical analysis was performed using SPSS software on the basis of RTV data at the end of the experiment. The comparison between groups was analyzed by one-way ANOVA. If there was heterogeneity of variance (F value was significantly different), the Games-Howell test was applied. p<0.05 was considered significantly different.

    [0326] 3. Experimental Results

    [0327] 3.1 Inhibitory Effect of Test Substances on the Growth of Subcutaneously Transplanted Tumors in Human Lung Cancer-Bearing Nude Mice

    [0328] In this experiment, the efficacy of the test substances in human lung cancer xenograft tumor models was evaluated, and the solvent control group was used as a reference. The tumor volumes for each group at different time points were as shown in FIGS. 1 and 3. The group with administration of compound 1 (100 mg/kg) had a T/C of 18.5% and a TGI of 100.9%, indicating a significant tumor inhibitory effect (P<0.01). The tumor growth curves of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models after administration of compounds were shown in FIG. 1. The group with administration of compound 16B (100 mg/kg) had a T/C of 11.4%, and a TGI of 99.1%, indicating a significant tumor inhibitory effect (P<0.01). The tumor growth curves of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models after administration of the compounds were shown in FIG. 3.

    [0329] 3.2 Body Weight Changes

    [0330] No abnormality was observed in the weight and state of mice. The effects of test substances on the body weight of mice are shown in FIGS. 2 and 4.

    [0331] Experimental Conclusion:

    [0332] The compounds of the present disclosure have a significant inhibitory effect on the tumor growth of tumor-bearing mice as human lung cancer Ca1u-6 subcutaneous xenograft tumor models.

    EXPERIMENTAL EXAMPLE 7

    Experiments for In Vivo Pharmacokinetics in Mice

    [0333] Experimental Objective

    [0334] In vivo pharmacokinetic parameters of the compounds of the present disclosure in mice were detected.

    [0335] Experimental Scheme

    [0336] 1) Experimental drug: Compound 16B;

    [0337] 2) Experimental animals: 4 female CD-1 mice, which were divided into 2 groups, 2 mice in each group;

    [0338] 3) Drug formulation: An appropriate amount of the drug was weighed and dissolved in an aqueous solution of solutol (5% by volume), DMSO (5% by volume) and PEG-300 (25% by volume) for injection administration. An appropriate amount of the drug was weighed and dispersed in a 5% solutol aqueous solution (80% by volume), and then PEG-400 (20% by volume) was added; the mixture was mixed well and used for intragastric administration. Solutol is polyethylene glycol-15-hydroxystearate.

    [0339] Experimental Operations

    [0340] The animals in the first group were administered the compound at a dose of 2 mg/kg at a concentration of 1 mg/mL by intravenous administration. Plasma samples were collected from the animals at 0.117, 0.333, 1, 2, 4, 7 and 24 hours after administration. The animals in the second group were administered the compound at a dose of 100 mg/kg at a concentration of 10 mg/mL by intragastric administration. Plasma samples were collected from the animals at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. The drug concentration at each point was determined by the LC-MS/MS method, and kinetic parameters of the tested drug were as follows:

    TABLE-US-00022 Compound Intravenous Clearance Initial Distribution Half-life Curve area 16B administration rate concentration volume group Cl C.sub.0 Vd T.sub.1/2 AUC (mL/min/kg) (nM) (L/kg) (h) (nM .Math. h) 25.8 2011   2.75 1.43 2614 Intragastric Maximum Maximum Curve Bioavailability — administration concentration concentration area group time C.sub.max T.sub.max AUC F — (nM) (h) (nM .Math. h) (%) 25000 1 177513 131 — Note: — means absence

    [0341] Experimental Conclusion

    [0342] The compounds of the present disclosure have good in vivo pharmacokinetic properties in mice.