PYRIMIDOIMIDAZOLE COMPOUNDS USED AS DNA-PK INHIBITORS

Abstract

A class of DNA-PK inhibitors, in particular a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, and an application thereof in the preparation of a drug relating to a DNA-PK inhibitor.

##STR00001##

Claims

1. A compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, ##STR00098## wherein, the structural moiety ##STR00099## is selected from ##STR00100## E.sub.1 is selected from a single bond, —O— and —C(R.sub.6R.sub.7)—; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R′ and R″ are each independently selected from H, F and Cl; or R.sub.1 and R.sub.2 are connected together such that the structural moiety ##STR00101## is selected from ##STR00102## or R.sub.3 and R.sub.4 are connected together such that the structural moiety ##STR00103## is selected from ##STR00104## or R.sub.1 and R.sub.4 are connected together such that the structural moiety ##STR00105## is selected from ##STR00106## or R.sub.2 and R″ connected together with the carbon atoms to which they are attached form a C.sub.3-5 cycloalkyl; R.sub.5 is selected from F, Cl, Br, I, cyclopropyl and C.sub.1-3 alkyl, and the C.sub.1-3 alkyl is optionally substituted with OH or 1, 2 or 3 R.sub.a; R.sub.6 and R.sub.7 are each independently selected from H, F, Cl, Br, I and CN; or R.sub.6 and R.sub.7 connected together with the carbon atoms to which they are attached form a cyclopropyl or a 4-membered oxetanyl; ring A is selected from C.sub.3-5 cycloalkyl; Y.sub.1 is selected from cyclopropyl and C.sub.1-3 alkyl, and the C.sub.1-3 alkyl is optionally substituted with 1, 2, 3, 4 or 5 F; R.sub.a is selected from H, F, Cl, Br and I.

2. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IV) or the pharmaceutically acceptable salt thereof is selected from a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, ##STR00107## wherein, W, E.sub.1, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R′ and R″ are as defined above.

3. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound is selected from ##STR00108## ##STR00109## ##STR00110## wherein, ring B is selected from C.sub.3-5 cycloalkyl; ring C is cyclopropyl or 4-membered oxetanyl; n is selected from 0 and 1; ring A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined above.

4. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are connected together such that the structural moiety ##STR00111## is selected from ##STR00112##

5. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.3 and R.sub.4 are connected together such that the structural moiety ##STR00113## is selected from ##STR00114##

6. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.4 are connected together such that the structural moiety ##STR00115## is selected from ##STR00116##

7. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein ring A is selected from ##STR00117##

8. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.6 and R.sub.7 connected together with the carbon atoms to which they are attached form ##STR00118##

9. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.2 and R″ connected together with the carbon atoms to which they are attached form ##STR00119##

10. The compound as claimed in claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.5 is selected from F, Cl, CH.sub.2OH, CF.sub.3 and CH.sub.3.

11. A compound represented by following formula or a pharmaceutically acceptable salt thereof ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##

12. A method for inhibiting DNA-PK in a subject in need thereof, comprising: administering the compound as defined in claim 1 or the pharmaceutically acceptable salt thereof to the subject.

13. The method as claimed in claim 12, wherein the compound or the pharmaceutically acceptable salt thereof plays a therapeutic effect as a single medicament in tumors with defects in other DNA repair pathways.

14. The method as claimed in claim 12, wherein the compound or the pharmaceutically acceptable salt thereof is used in combination with a chemoradiotherapy medicament to enhance the inhibitory effect on solid tumors and hematological tumors.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0117] FIG. 1. Tumor photographs of day 21 of an in vivo pharmacodynamic study of human NCI-H1703 non-small cell lung cancer.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0118] The present disclosure will be specifically described below by way of embodiments, but the scope of the present disclosure is not limited thereto. The present disclosure has been described in detail herein, wherein specific embodiments thereof are also disclosed, for those skilled in the art, it is obvious that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

Embodiment 1

[0119] ##STR00063##

Step 1

[0120] At 0° C., compound 1b (1.84 g, 18.0 mmol, 1.2 eq) was added to a solution of compound 1a (2.91 g, 15.0 mmol, 1 eq) in 1,4-dioxane (50 mL), and after the addition was completed, the reaction was carried out at 0° C. for 8 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:3) to obtain compound 1c. MS: m/z. 259.8 [M+H].sup.+.

[0121] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.08 (s, 1H), 9.06 (s, 1H), 3.84-4.06 (m, 4H), 2.93-3.11 (m, 4H).

Step 2

[0122] Iron powder (1.18 g, 21.18 mmol, 5 eq) and ammonium chloride (1.13 g, 21.18 mmol, 5 eq) were added sequentially to a mixed solution of compound 1c (1.1 g, 4.24 mmol, 1 eq) in ethanol (10 mL) and water (10 mL), and after the addition was completed, the reaction was carried out at 80° C. for 1 hour. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was diluted with water (50 mL), extracted with ethyl acetate (50 mL*2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 1d. MS: m/z. 229.9 [M+H].sup.+.

Step 3

[0123] N,N′-Carbonyldiimidazole (0.97 g, 6.0 mmol, 1.22 mL, 2 eq) was added to a solution of compound 1d (0.69 g, 3.0 mmol, 1 eq) in acetonitrile (15 mL), and after the addition was completed, the reaction was carried out at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-4:1) to obtain compound 1e. MS: m/z 255.9 [M+H].sup.+.

[0124] .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.09 (s, 1H), 3.86-3.97 (m, 4H), 3.45-3.65 (m, 4H).

Step 4

[0125] Cesium carbonate (3.5 g, 10.76 mmol, 5 eq) and iodomethane (1.06 g, 7.45 mmol, 465 μL, 3 eq) were added sequentially to a solution of compound 1e (1.1 g, 2.15 mmol, 1 eq) in N,N-dimethylformamide (50 mL), and after the addition was completed, the reaction was carried out at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 1f. MS: m/z 269.8 [M+H].sup.+.

Step 5

[0126] A solution of compound if (0.13 g, 500 μmol, 1 eq), compound 1g (188.9 mg, 600.00 μmol, 1.2 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (90.6 mg, 100.00 μmol, 0.2 eq) and cesium carbonate (325.8 mg, 1.00 mmol, 2 eq) in dioxane (5 mL) and water (0.5 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was filtered with celite, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile) %: 8%-38%, 8 minutes) to obtain compound 1. MS: m/z 382.2 [M+H].

[0127] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.81 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.58 (s, 1H), 6.80 (s, 1H), 3.96 (t, J=4.6 Hz, 4H), 3.47-3.55 (m, 4H), 3.42 (s, 3H), 2.53 (s, 3H).

Embodiment 2

[0128] ##STR00064##

Step 1

[0129] N,N-Dimethylformamide dimethyl acetal (14.30 g, 120 mmol, 15.94 mL, 3 eq) was added to a solution of compound 2a (10.18 g, 40 mmol, 1 eq) in toluene (80 mL), and after the addition was completed, the reaction solution was reacted at 110° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 2b. MS: m/z 309.8 [M+H].sup.+.

Step 2

[0130] Hydroxylamine hydrochloride (5.56 g, 80 mmol, 2 eq) was added to a solution of compound 2b (12.38 g, 40 mmol, 1 eq) in methanol (100 mL), and after the addition was completed, the reaction solution was reacted at 70° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 2c. MS: m/z 297.7 [M+H].sup.+.

Step 3

[0131] At 0° C., trifluoroacetic anhydride (12.60 g, 60 mmol, 8.35 mL, 1.5 eq) was added to a solution of compound 2c (11.90 g, 40 mmol, 1 eq) in tetrahydrofuran (100 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The concentrated reaction solution was diluted with water (100 mL), extracted with 300 mL of ethyl acetate (100 mL*3), washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 2d. MS: m/z 279.7 [M+H].sup.+.

[0132] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.55 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H).

Step 4

[0133] Compound 2d (3.91 g, 14 mmol, 1 eq), compound 2e (2.79 g, 15.40 mmol, 1.1 eq), tris(dibenzylideneacetone)dipalladium (641 mg, 700 μmol, 0.05 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (810.1 mg, 1.4 mmol, 0.1 eq) and cesium carbonate (9.12 g, 28 mmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, and then anhydrous N,N-dimethylformamide (30 mL) was added to the mixture and the reaction was carried out at 80° C. for 6 hours. After the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in tetrahydrofuran (100 mL), and 3 N hydrochloric acid (20 mL) was added thereto, and the mixture was stirred at 20° C. for 0.5 hours. After the reaction was completed, water (100 mL) was added to the reaction solution. The reaction solution was extracted with ethyl acetate (100 mL*3), and the organic phase was discarded; ammonium hydroxide (30 mL) was added to the aqueous phase to adjust the pH to basic, and the aqueous phase was extracted with ethyl acetate (100 mL*3) again. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:0) to obtain compound 2f. MS: m/z 168.8 [M+H].sup.+.

[0134] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.28 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 5.35-5.43 (m, 2H).

Step 5

[0135] Compound 2f (67.4 mg, 400 μmol, 1 eq), compound if (107.8 mg, 400 μmol, 1 eq), tris(dibenzylideneacetone)dipalladium (36.6 mg, 40 μmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.3 mg, 80 μmol, 0.2 eq) and cesium carbonate (195.5 mg, 600 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, and then anhydrous dioxane (8 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer preparative chromatography (dichloromethane:methanol=10:1) to obtain compound 2. MS: m/z 401.9 [M+H].sup.+.

[0136] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 10.24 (s, 1H), 8.31 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.47 (s, 1H), 3.96 (t, J=4.69 Hz, 4H), 3.51-3.57 (m, 4H), 3.43 (s, 3H).

Embodiment 3

[0137] ##STR00065##

Step 1

[0138] N,N-Dimethylformamide dimethyl acetal (12.54 g, 105.25 mmol, 3 eq) was added to a solution of compound 3a (6.7 g, 35.08 mmol, 1 eq) in toluene (100 mL), and after the addition was completed, the reaction was carried out at 110° C. for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 3b.

Step 2

[0139] Hydroxylamine hydrochloride (4.69 g, 67.46 mmol, 2 eq) was added to a solution of compound 3b (8.3 g, 33.73 mmol, 1 eq) in methanol (100 mL), and the reaction was carried out at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 3c. MS: m/z 233.8 [M+H].sup.+.

Step 3

[0140] At 0° C., trifluoroacetic anhydride (15.33 mL, 100.24 mmol, 2 eq) was added to a solution of compound 3c (12.9 g, 55.12 mmol, 1 eq) in tetrahydrofuran (100 mL), and after the addition was completed, the reaction was carried out at 21° C. for 21 hours. After the reaction was completed, the crude product obtained by concentrating the reaction solution under reduced pressure was purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:2) to obtain compound 3d. MS: m/z 217.8 [M+H].sup.+.

Step 4

[0141] 1,1′-Binaphthyl-2,2′-diphemyl phosphine (288.3 mg, 462.94 μmol, 0.1 eq), compound 2e (922.9 mg, 5.09 mmol, 1.1 eq), tris(dibenzylideneacetone)dipalladium (211.9 mg, 231.47 μmol, 0.05 eq) and potassium tert-butoxide (1.04 g, 9.26 mmol, 2 eq) were added sequentially to a solution of compound 3d (1 g, 4.63 mmol, 1 eq) in toluene (50 mL), and after the addition was completed, the reaction was carried out at 110° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the concentrated reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL*2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Then, the crude product was dissolved in ethanol (20 mL), and 1 N hydrochloric acid (12 mL) was added thereto and stirred for half an hour. After the reaction was completed, the pH was adjusted to basic by adding ammonium hydroxide, and the mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (methanol:dichloromethane=0:1-1:6) to obtain compound 3f.

Step 5

[0142] Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (21.7 mg, 20.93 μmol, 0.05 eq) and cesium carbonate (311.5 mg, 956.13 μmol, 2 eq) were added sequentially to a solution of compound 3f (132 mg, 489.46 μmol, 1.02 eq) and compound 1f (80 mg, 525.87 μmol, 1.1 eq) in dioxane (20 mL), and after the addition was completed, the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the crude product obtained by concentrating the reaction solution under reduced pressure was purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 3. MS: m/z 386.0 [M+H].sup.+.

[0143] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 10.15 (br d, J=7.03 Hz, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.47 (br d, J=9.54 Hz, 1H), 3.96 (br s, 4H), 3.53 (br s, 4H), 3.43 (s, 3H).

Embodiment 4

[0144] ##STR00066## ##STR00067##

Step 1

[0145] At 0° C., a solution of sodium nitrite (1.52 g, 22 mmol, 1.1 eq) in water (3 mL) was slowly added to a mixed solution of compound 4a (2.99 g, 20 mmol, 1 eq, hydrochloride) in acetic acid (30 mL) and water (9 mL), and after the addition was completed, the reaction was carried out at 20° C. for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with 300 mL of ethyl acetate (100 mL*3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 4b.

[0146] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 5.08 (br d, J=7.03 Hz, 1H), 4.89 (br d, J=6.27 Hz, 1H), 3.77-3.93 (m, 2H), 3.54-3.68 (m, 2H), 2.05-2.22 (m, 3H), 1.78-1.94 (m, 1H).

Step 2

[0147] At 0° C., zinc powder (4.71 g, 72 mmol, 4 eq) and acetic acid (20 mL) were added sequentially to a solution of compound 4b (2.56 g, 18 mmol, 1 eq) in methanol (20 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 4 hours. After the reaction was completed, the reaction solution was filtered through celite and washed with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 4c.

Step 3

[0148] At 0° C., compound 4c (3.01 g, 16 mmol, 1 eq, acetate) and triethylamine (8.10 g, 80 mmol, 5 eq, 11.14 mL) were added sequentially to a solution of compound 1a (6.21 g, 32 mmol, 2 eq) in dioxane (150 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 5 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with 300 mL of ethyl acetate (100 mL*3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 4e. MS: m/z 285.9 [M+H].sup.+.

[0149] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.29 (br s, 1H), 9.04 (s, 1H), 4.02 (d, J=11.13 Hz, 2H), 3.64 (dd, J=11.32, 1.94 Hz, 2H), 3.48 (br d, J=2.88 Hz, 2H), 2.07-2.21 (m, 4H).

Step 4

[0150] Iron powder (1.79 g, 32 mmol, 5 eq) and ammonium chloride (1.71 g, 32 mmol, 5 eq) were added sequentially to a mixed solution of compound 4e (2.03 g, 6.4 mmol, 1 eq) in ethanol (16 mL) and water (4 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with ethyl acetate (300 mL), filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 4f. MS: m/z 256.0 [M+H].sup.+.

Step 5

[0151] N,N′-Carbonyldiimidazole (1.62 g, 10 mmol, 2 eq) was added to a solution of compound 4f (1.28 g, 5 mmol, 1 eq) in acetonitrile (20 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 2 hours. After the reaction was completed, the crude product obtained by concentrating the reaction solution under reduced pressure was purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:0) and slurrying (methanol/dichloromethane: 2 mL/10 mL, 25° C., 15 minutes) to obtain compound 4g. MS: m/z 281.2 [M+H].sup.+.

[0152] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.63 (br s, 1H), 8.09 (s, 1H), 3.76-3.86 (m, 4H), 3.59 (br d, J=8.63 Hz, 2H), 2.27-2.36 (m, 2H), 1.90-1.99 (m, 2H).

Step 6

[0153] Cesium carbonate (0.489 g, 1.5 mmol, 1.5 eq) and iodomethane (0.177 g, 1.25 mmol, 1.25 eq) were added sequentially to a solution of compound 4g (0.282 g, 1 mmol, 1 eq) in N,N-dimethylformamide (10 mL), and after the addition was completed, the reaction solution was reacted at 21° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with 90 mL of ethyl acetate (30 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-4:1) to obtain compound 4h. MS: m/z 295.9 [M+H].sup.+.

[0154] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.99 (s, 1H), 4.10 (d, J=10.51 Hz, 2H), 3.83-3.91 (m, 2H), 3.68 (dd, J=10.63, 2.00 Hz, 2H), 3.42 (s, 3H), 2.39-2.47 (m, 2H), 2.12-2.20 (m, 2H).

Step 7

[0155] Compound 4h (221.8 mg, 0.75 mmol, 1 eq), compound 1g (88.9 mg, 0.6 mmol, 0.8 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (136 mg, 150 μmol, 0.2 eq) and cesium carbonate (366.6 mg, 1.13 mmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (20 mL) was added to the mixture, and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product, then the crude product was purified by column chromatography (methanol:dichloromethane=0:1-1:9) and slurrying (dichloromethane/ethyl acetate: 3 mL/3 mL, 25° C., 15 minutes) to obtain compound 4. MS: m/z 408.2 [M+H].sup.+.

[0156] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.77 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 6.72 (s, 1H), 4.15 (d, J=10.54 Hz, 2H), 3.84-3.90 (m, 2H), 3.71 (br d, J=10.54 Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 2.37-2.46 (m, 2H), 2.09-2.18 (m, 2H).

Embodiment 5

[0157] ##STR00068## ##STR00069##

Step 1

[0158] At 0° C., a solution of sodium nitrite (2.28 g, 33 mmol, 1.1 eq) in water (4.5 mL) was slowly added to a mixed solution of compound 5a (4.49 g, 30 mmol, 1 eq, hydrochloride) in acetic acid (50 mL) and water (18 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with 150 mL of ethyl acetate (50 mL*3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 5b. MS: m/z. 143.0 [M+H].sup.+.

Step 2

[0159] At 0° C., zinc powder (6.80 g, 104 mmol, 4 eq) and acetic acid (20 mL) were added sequentially to a solution of compound 5b (3.70 g, 26 mmol, 1 eq) in methanol (20 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 4 hours. After the reaction was completed, the reaction solution was filtered through celite and washed with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 5c.

Step 3

[0160] At 0° C., compound 5c (4.89 g, 26 mmol, 1 eq) and triethylamine (13.15 g, 130 mmol, 5 eq, 18.09 mL) were added sequentially to a solution of compound 1a (10.09 g, 52 mmol, 2 eq) in dioxane (150 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 5 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with 300 mL of ethyl acetate (100 mL*3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 5e. MS: m/z 285.9 [M+H].sup.+.

[0161] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.05 (s, 1H), 8.97 (br s, 1H), 4.43 (br dd, J=4.44, 2.06 Hz, 2H), 2.94-3.06 (m, 4H), 2.19-2.28 (m, 2H), 1.90-2.03 (m, 2H).

Step 4

[0162] Iron powder (2.37 g, 42.5 mmol, 5 eq) and ammonium chloride (2.27 g, 42.5 mmol, 5 eq) were added sequentially to a mixed solution of compound 5e (2.43 g, 8.5 mmol, 1 eq) in ethanol (120 mL) and water (30 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with ethyl acetate (200 mL), filtered through celite and concentrated under reduced pressure to obtain a crude product of compound 5f. MS: m/z 256.0 [M+H].sup.+.

Step 5

[0163] N,N′-Carbonyldiimidazole (2.76 g, 17 mmol, 2 eq) was added to a solution of compound 5f (2.17 g, 8.5 mmol, 1 eq) in acetonitrile (30 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:0) to obtain compound 5g. MS: m/z 281.9 [M+H].sup.+.

[0164] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 11.61 (br s, 1H), 8.12 (s, 1H), 4.38 (br d, J=2.01 Hz, 2H), 3.73 (dd, J=9.91, 1.63 Hz, 2H), 2.81 (d, J=9.54 Hz, 2H), 1.99-2.09 (m, 2H), 1.78-1.87 (m, 2H).

Step 6

[0165] Cesium carbonate (2.15 g, 6.6 mmol, 1.5 eq) and iodomethane (780 mg, 5.5 mmol, 1.25 eq) were added sequentially to a solution of compound 5g (1.24 g, 4.4 mmol, 1 eq) in N,N-dimethylformamide (40 mL), and after the addition was completed, the reaction solution was reacted at 21° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with 180 mL of ethyl acetate (60 mL*3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-4:1) to obtain compound 5h. MS: m/z 295.9 [M+H].sup.+.

[0166] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.98-8.05 (m, 1H), 4.45 (br d, J=2.25 Hz, 2H), 3.99 (dd, J=9.69, 1.81 Hz, 2H), 3.41 (s, 3H), 2.80 (br d, J=9.51 Hz, 2H), 2.23-2.31 (m, 2H), 1.94-2.04 (m, 2H).

Step 7

[0167] Compound 5h (502.7 mg, 1.7 mmol, 1 eq), compound 1g (201.5 mg, 1.36 mmol, 0.8 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (231.2 mg, 255 μmol, 0.15 eq) and cesium carbonate (830.8 mg, 2.55 mmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (30 mL) was added to the mixture and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product, then the crude product was purified by column chromatography (methanol/dichloromethane: 0-10%) and slurrying (dichloromethane/ethyl acetate: 1.5 mL/3 mL, 25° C., 15 min) to obtain compound 5. MS: m/z 408.2 [M+H].sup.+.

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.87 (s, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.57 (s, 1H), 6.76 (s, 1H), 4.48 (br d, J=2.25 Hz, 2H), 4.04 (dd, J=9.76, 1.88 Hz, 2H), 3.40 (s, 3H), 2.85 (d, J=9.51 Hz, 2H), 2.53 (s, 3H) 2.29-2.37 (m, 2H), 2.00-2.10 (m, 2H).

Embodiment 6

[0169] ##STR00070## ##STR00071##

Step 1

[0170] At 0° C., a solution of sodium nitrite (97.90 mg, 1.42 mmol, 1.1 eq) in water (1 mL) was slowly added to a mixed solution of compound 6a (350 mg, 1.29 mmol, 1 eq, p-toluenesulfonate) in acetic acid (5 mL) and water (1 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 3 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with 60 mL of ethyl acetate (20 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 6b.

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.79-4.87 (m, 1H), 4.68-4.76 (m, 2H), 4.59-4.66 (m, 1H), 4.20 (d, J=15.26 Hz, 1H), 3.61-3.73 (m, 1H), 3.29-3.40 (m, 1H), 1.79 (d, J=9.51 Hz, 1H).

Step 2

[0172] At 0° C., zinc powder (1.28 g, 19.51 mmol, 4 eq) and acetic acid (7 mL) were added sequentially to a solution of compound 6b (625 mg, 4.88 mmol, 1 eq) in methanol (7 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 4 hours. After the reaction was completed, the reaction solution was filtered through celite and washed with ethyl acetate (100 mL), and the filtrate was concentrated under reduced pressure to obtain compound 6c.

Step 3

[0173] At 0° C., compound 6c (1.92 g, 3.56 mmol, 1 eq, acetate) was added to a solution of compound 1a (1.72 g, 8.89 mmol, 2.5 eq) in dioxane (35 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL*3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 6e. MS: m/z 271.9 [M+H].sup.+.

Step 4

[0174] Iron powder (234.35 mg, 4.2 mmol, 5 eq) and ammonium chloride (224.47 mg, 4.2 mmol, 5 eq) were added sequentially to a solution of compound 6e (228 mg, 839.28 μmol, 1 eq) in ethanol (5 mL) and water (5 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and washed with ethanol (20 mL), and the washing solution was concentrated under reduced pressure to obtain a crude product, and the crude product was dissolved in a solution of dichloromethane/methanol (20 mL: 2 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6f.

Step 5

[0175] N,N′-Carbonyldiimidazole (207.99 mg, 1.28 mmol, 2 eq) was added to a solution of compound 6f (155 mg, 641.35 μmol, 1 eq) in acetonitrile (6 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 6g. MS: m/z 267.9 [M+H].sup.+.

[0176] .sup.1H NMR (400 MHz, CD.sub.3OD) δ ppm 9.00 (s, 1H), 5.38 (d, J=6.13 Hz, 2H), 4.76 (d, J=10.13 Hz, 2H), 4.04-4.13 (m, 2H), 3.80-3.91 (m, 1H), 3.21 (d, J=8.38 Hz, 1H).

Step 6

[0177] Cesium carbonate (255.62 mg, 784.54 μmol, 2 eq) and iodomethane (0.58 g, 4.09 mmol, 1.2 eq) were added sequentially to a solution of compound 6g (105 mg, 392.27 μmol, 1 eq) in N,N-dimethylformamide (6 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 6h. MS: m/z 281.8 [M+H].sup.+

[0178] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.38 (s, 1H), 4.54 (d, J=6.13 Hz, 2H), 3.90 (d, J=10.13 Hz, 2H), 3.35 (s, 3H), 3.23-3.28 (m, 2H), 2.96-3.03 (m, 1H), 2.37 (d, J=8.38 Hz, 1H).

Step 7

[0179] Compound 6h (95 mg, 337.24 μmol, 1 eq), compound 1g (44.97 mg, 303.52 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (61.14 mg, 67.45 μmol, 0.2 eq) and cesium carbonate (219.76 mg, 674.48 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (7 mL) was added to the mixture and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by preparative high performance liquid chromatography (Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water 0.225% formic acid)-acetonitrile]; B (acetonitrile) %: 6%-36%, 8 minutes) to obtain compound 6.

[0180] MS: m/z 394.0 [M+H].sup.+.

[0181] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.85 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 6.80 (s, 1H), 4.68 (d, J=6.53 Hz, 2H), 4.23 (d, J=9.79 Hz, 2H), 3.45-3.48 (m, 1H), 3.44 (s, 3H), 3.42-3.44 (m, 1H), 3.19-3.31 (m, 1H), 2.71 (d, J=8.53 Hz, 1H), 2.52 (s, 3H).

Embodiment 7

[0182] ##STR00072## ##STR00073##

Step 1

[0183] At 0° C., a solution of sodium nitrite (1.31 g, 18.99 mmol, 1 eq) in water (2.4 mL) was slowly added to a mixed solution of compound 7a (2.3 g, 18.99 mmol, 1 eq) in acetic acid (24 mL) and water (8 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1.5 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:3) to obtain compound 7b.

[0184] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.32-4.36 (m, 2H), 3.84-3.89 (m, 2H), 2.17 (tt, J=12.89, 6.31 Hz, 2H), 1.90 (tt, J=13.05, 6.40 Hz, 2H).

Step 2

[0185] At 0° C., zinc powder (3.12 g, 47.69 mmol, 4 eq) was added to a mixed solution of compound 7b (1.79 g, 11.92 mmol, 1 eq) in acetic acid (10 mL) and methanol (10 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 0.5 hours. After the reaction was completed, ethyl acetate (40 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 7c.

Step 3

[0186] At 0° C., a solution of compound 7c (3.8 g, 19.37 mmol, 1 eq, acetate) in dioxane (80 mL) and triethylamine (7.84 g, 77.47 mmol, 4 eq, 10.78 mL) were added sequentially to a solution of compound 1a (7.51 g, 38.74 mmol, 2 eq) in dioxane (100 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, the reaction was diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:4) to obtain compound 7e. MS: m/z 293.8 [M+H].sup.+;

[0187] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.12 (s, 1H), 9.08 (s, 1H), 3.13 (t, J=5.65 Hz, 4H), 2.20-2.30 (m, 4H).

Step 4

[0188] Iron powder (475.47 mg, 8.51 mmol, 5 eq) and ammonium chloride (455.38 mg, 8.51 mmol, 5 eq) were added sequentially to a mixed solution of compound 7e (0.5 g, 1.70 mmol, 1 eq) in ethanol (20 mL) and water (5 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (20 mL: 2 mL), stirred for 15 minutes, filtered. The filtrate was concentrated under reduced pressure to obtain compound 7f. MS: m/z 263.8 [M+H].sup.+.

Step 5

[0189] N,N′-Carbonyldiimidazole (848.64 mg, 5.23 mmol, 3 eq) was added to a solution of compound 7f (460 mg, 1.74 mmol, 1 eq) in acetonitrile (10 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 7g. MS: m/z 289.7 [M+H].sup.+;

[0190] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.32 (br s, 1H), 7.99 (s, 1H), 3.53 (br t, J=5.52 Hz, 4H), 2.13-2.25 (m, 4H).

Step 6

[0191] Cesium carbonate (2.43 g, 7.44 mmol, 4 eq) and iodomethane (792.34 mg, 5.58 mmol, 3 eq) were added sequentially to a solution of compound 7g (539 mg, 1.86 mmol, 1 eq) in N,N-dimethylformamide (6 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, water (6 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, then diluted with water (6 mL), extracted with ethyl acetate (10 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 7h. MS: m/z 303.8 [M+H].sup.+;

[0192] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.06 (s, 1H), 3.59 (br t, J=5.52 Hz, 4H), 3.46 (s, 3H), 2.24-2.34 (m, 4H).

Step 7

[0193] Compound 7h (218 mg, 717.82 μmol, 1 eq), compound 1g (95.72 mg, 646.04 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (130.14 mg, 143.56 μmol, 0.2 eq) and cesium carbonate (350.82 mg, 1.08 mmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (6 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 7. MS: m/z 416.1 [M+H].sup.+;

[0194] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.75 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 6.79 (s, 1H), 3.56-3.66 (m, 4H), 3.43 (s, 3H), 2.54 (s, 3H), 2.30 (s, 4H).

Embodiments 8 and 9

[0195] ##STR00074## ##STR00075##

Step 1

[0196] At 0° C., a solution of sodium nitrite (2.54 g, 36.88 mmol, 1 eq) in water (5 mL) was slowly added to a mixed solution of compound 8a (5 g, 36.88 mmol, 1 eq, hydrochloride) in acetic acid (50 mL) and water (17 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 18 hours. After the reaction was completed, the reaction solution was diluted with water (40 mL), extracted with ethyl acetate (50 mL*8), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-2:1) to obtain compound 8b.

[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 5.47 (s, 1H), 4.79 (s, 1H), 4.02 (s, 2H), 3.46-3.62 (m, 2H), 2.12 (d, J=10.29 Hz, 1H), 1.96 (dd, J=10.29, 2.26 Hz, 1H).

Step 2

[0198] At 0° C., zinc powder (3.94 g, 60.25 mmol, 4 eq) was added to a mixed solution of compound 8b (1.93 g, 15.06 mmol, 1 eq) in acetic acid (10 mL) and methanol (10 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 8c.

Step 3

[0199] At 0° C., a solution of compound 8c (4.4 g, 25.26 mmol, 1 eq, acetate) in dioxane (80 mL) and triethylamine (12.78 g, 126.29 mmol, 5 eq, 17.58 mL) were added sequentially to a solution of compound 1a (9.80 g, 50.52 mmol, 2 eq) in dioxane (140 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, the reaction was diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:2) to obtain compound 8e. MS: m/z 272.0 [M+H].sup.+.

[0200] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.37 (br s, 1H), 8.99 (s, 1H), 4.48 (s, 1H), 4.11 (d, J=9.29 Hz, 1H), 3.95 (s, 1H), 3.72 (dd, J=9.16, 1.63 Hz, 1H), 3.39-3.48 (m, 1H), 2.90-2.97 (m, 1H), 2.11 (d, J=10.29 Hz, 1H), 1.81-2.02 (m, 1H).

Step 4

[0201] Iron powder (513.97 mg, 9.20 mmol, 5 eq) and ammonium chloride (492.25 mg, 9.20 mmol, 5 eq) were added sequentially to a mixed solution of compound 8e (0.5 g, 1.84 mmol, 1 eq) in ethanol (5 mL) and water (5 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 0.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (10 mL: 1 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8f. MS: m/z 242.0 [M+H].sup.+.

Step 5

[0202] N,N′-Carbonyldiimidazole (509.91 mg, 3.14 mmol, 2 eq) was added to a solution of compound 8f (380 mg, 1.57 mmol, 1 eq) in acetonitrile (8 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:0) to obtain compound 8g. MS: m/z 267.8 [M+H].sup.+;

[0203] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.00 (s, 1H), 4.63 (s, 1H), 4.21 (d, J=7.53 Hz, 1H), 3.76-3.83 (m, 2H), 3.71 (dd, J=7.78, 1.76 Hz, 1H), 3.60 (d, J=10.04 Hz, 1H), 2.73 (d, J=10.04 Hz, 1H), 1.87 (d, J=10.79 Hz, 1H).

Step 6

[0204] Cesium carbonate (2.53 g, 7.77 mmol, 4 eq) and methyl iodide (827.22 mg, 5.83 mmol, 3 eq) were added sequentially to a solution of compound 8g (520 mg, 1.94 mmol, 1 eq) in N,N-dimethylformamide (6 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, water (5 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, then diluted with water (5 mL), extracted with ethyl acetate (10 mL*6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-4:1) to obtain compound 8h. MS: m/z 281.8 [M+H].sup.+;

[0205] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.05 (s, 1H), 4.71 (s, 1H), 4.28 (d, J=7.78 Hz, 1H), 3.82-3.88 (m, 2H), 3.79 (dd, J=7.78, 1.76 Hz, 1H), 3.66 (d, J=9.29 Hz, 1H), 3.47 (s, 3H), 2.81 (d, J=8.53 Hz, 1H), 1.95 (d, J=11.04 Hz, 1H).

Step 7

[0206] Compound 8h (160 mg, 567.98 μmol, 1 eq), compound 1g (75.74 mg, 511.18 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (102.98 mg, 113.60 μmol, 0.2 eq) and cesium carbonate (277.59 mg, 851.97 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (5 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain a racemate, then the racemate was purified by supercritical fluid chromatography (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); Mobile Phase: [0.1% ammonium hydroxide-isopropanol]; —B (0.1% ammonium hydroxide/isopropanol) %: 55%-55%) to obtain compound 8 and compound 9.

[0207] Compound 8: (retention time 9.25 min) MS: m/z 394.1 [M+H].sup.+;

[0208] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.86 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 6.85 (s, 1H), 4.77 (s, 1H), 4.32 (d, J=8.03 Hz, 1H), 3.99 (d, J=9.79 Hz, 1H), 3.91 (s, 1H), 3.83 (dd, J=7.78, 1.51 Hz, 1H), 3.70 (d, J=8.78 Hz, 1H), 3.44 (s, 3H), 2.75 (d, J=10.29 Hz, 1H), 2.54 (s, 3H), 1.97 (d, J=10.04 Hz, 1H).

[0209] Compound 9: (retention time 11.75 min) MS: m/z 394.1 [M+H].sup.+;

[0210] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.86 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 6.84 (s, 1H), 4.77 (s, 1H), 4.32 (d, J=7.78 Hz, 1H), 3.99 (d, J=9.79 Hz, 1H), 3.91 (s, 1H), 3.83 (dd, J=7.78, 1.76 Hz, 1H), 3.70 (d, J=9.79 Hz, 1H) 3.45 (s, 3H), 2.75 (d, J=8.53 Hz, 1H), 2.54 (s, 3H) 1.97 (d, J=10.04 Hz, 1H).

Embodiment 10

[0211] ##STR00076## ##STR00077##

Step 1

[0212] At 0° C., a solution of sodium nitrite (507.3 mg, 7.35 mmol, 1.1 eq) in water (1 mL) was slowly added to a mixed solution of compound 10a (1 g, 1.29 mmol, 1 eq, hydrochloride) in acetic acid (12 mL) and water (4 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 10b.

Step 2

[0213] At 0° C., zinc powder (1.58 g, 24.2 mmol, 4 eq) and acetic acid (5 mL) were added sequentially to a solution of compound 10b (860 mg, 6.05 mmol, 1 eq) in methanol (5 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (100 mL), filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 10c.

Step 3

[0214] At 0° C., compound 10c (1.41 g, 4.5 mmol, 1 eq, acetate) and triethylamine (910.7 mg, 9 mmol, 2 eq) were added to a solution of compound 1a (1.75 g, 9 mmol, 2 eq) in dioxane (60 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 5 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 10e. MS: m/z 285.9 [M+H].sup.+;

[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.32 (br s, 1H), 9.07 (s, 1H), 3.90-3.99 (m, 2H), 3.12-3.22 (m, 2H), 3.03 (s, 2H), 0.89-0.97 (m, 2H), 0.64-0.75 (m, 2H).

Step 4

[0216] Iron powder (156.38 mg, 2.8 mmol, 5 eq) and ammonium chloride (149.79 mg, 2.8 mmol, 5 eq) were added sequentially to a mixed solution of compound 10e (160 mg, 560.05 μmol, 1 eq) in ethanol (8 mL) and water (2 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and washed with ethanol (100 mL), and the washing solution was concentrated under reduced pressure to obtain a crude product 10f.

Step 5

[0217] N,N′-Carbonyldiimidazole (190.24 mg, 1.17 mmol, 2 eq) was added to a solution of compound 10f (150 mg, 586.62 μmol, 1 eq) in acetonitrile (4 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:0) to obtain compound 10g. MS: m/z 281.8 [M+H].sup.+.

Step 6

[0218] Cesium carbonate (242.89 mg, 745.48 μmol, 1.5 eq) and iodomethane (88.18 mg, 624.23 μmol, 1.25 eq) were added sequentially to a solution of compound 10g (140 mg, 496.99 μmol, 1 eq) in N,N-dimethylformamide (6 mL), and after the addition was completed, the reaction solution was reacted at 21° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:0) to obtain compound 10h. MS: m/z 296.0 [M+H].sup.+;

[0219] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.02 (s, 1H), 3.92-4.00 (m, 2H), 3.52-3.64 (m, 2H), 3.39-3.46 (m, 5H), 0.84-0.97 (m, 2H), 0.64-0.71 (m, 2H).

Step 7

[0220] Compound 10h (59.14 mg, 200 μmol, 1 eq), compound 1g (26.67 mg, 180 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (36.26 mg, 40 μmol, 0.2 eq) and cesium carbonate (97.75 mg, 300 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (5 mL) was added to the mixture and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product, and the crude product was first purified by column chromatography (methanol:dichloromethane=0:1-1:9), and then purified by supercritical fluid chromatography (DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonium hydroxide/ethanol]; —B (0.1% ammonium hydroxide/ethanol) %: 30%-30%) to obtain compound 10 (retention time 1.59 minutes). MS: m/z 430.0 [M+Na].sup.+;

[0221] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.83 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.57 (s, 1H), 6.77 (s, 1H), 3.96-4.04 (m, 2H), 3.60-3.69 (m, 2H), 3.44-3.50 (m, 2H), 3.41 (s, 3H), 2.53 (s, 3H), 0.91-1.03 (m, 2H), 0.62-0.76 (m, 2H).

Embodiment 11

[0222] ##STR00078## ##STR00079##

Step 1

[0223] At 0° C., a solution of sodium nitrite (501.83 mg, 7.27 mmol, 1 eq) in water (1.5 mL) was slowly added to a mixed solution of compound 11a (1.25 g, 7.27 mmol, 1 eq, hemioxalate) in acetic acid (15 mL) and water (5 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 2 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL*6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0: 1-2:1) to obtain compound 11b.

[0224] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.53 (q, J=6.00 Hz, 4H), 4.17-4.22 (m, 2H), 3.74-3.79 (m, 2H), 2.09-2.16 (m, 2H), 1.83-1.90 (m, 2H).

Step 2

[0225] At 0° C., zinc powder (574.43 mg, 8.78 mmol, 4 eq) was added to a mixed solution of compound 11b (343 mg, 2.20 mmol, 1 eq) in acetic acid (2 mL) and methanol (2 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 6 hours. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 11c.

Step 3

[0226] At 0° C., a solution of compound 11c (755 mg, 1.87 mmol, 1 eq, acetate) in dioxane (5 mL) and triethylamine (755.48 mg, 7.47 mmol, 5 eq, 1.04 mL) were added sequentially to a solution of compound 1a (724.11 mg, 3.73 mmol, 2 eq) in dioxane (30 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0: 1-1:1) to obtain compound 11e. MS: m/z 299.8 [M+H].sup.+;

[0227] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.06 (s, 1H), 9.01 (br s, 1H), 4.48 (s, 4H), 2.89 (t, J=5.14 Hz, 4H), 2.11 (t, J=5.52 Hz, 4H).

Step 4

[0228] Iron powder (93.17 mg, 1.67 mmol, 5 eq) and ammonium chloride (89.24 mg, 1.67 mmol, 5 eq) were added sequentially to a mixed solution of compound 11e (0.1 g, 333.65 μmol, 1 eq) in ethanol (2 mL) and water (2 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (10 mL: 1 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11f.

Step 5

[0229] N,N′-Carbonyldiimidazole (120.83 mg, 745.19 μmol, 3 eq) was added to a solution of compound 11f (67 mg, 248.40 μmol, 1 eq) in acetonitrile (2 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (ethyl acetate:petroleum ether=1:0) to obtain compound 11g. MS: m/z 295.8 [M+H].sup.+.

Step 6

[0230] Cesium carbonate (282.05 mg, 865.67 μmol, 4 eq) and iodomethane (92.16 mg, 649.25 μmol, 3 eq) were added sequentially to a solution of compound 11g (64 mg, 216.42 μmol, 1 eq) in N,N-dimethylformamide (2 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, water (3 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, then diluted with water (3 mL), extracted with ethyl acetate (10 mL*6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11h.

Step 7

[0231] Compound 11h (21 mg, 67.80 μmol, 1 eq), compound 1g (9.04 mg, 61.02 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (12.29 mg, 13.56 μmol, 0.2 eq) and cesium carbonate (33.13 mg, 101.69 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (3 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by thin-layer preparative chromatography (methanol:dichloromethane=1:20) to obtain compound 11. MS: m/z 422.4 [M+H].sup.+;

[0232] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.69 (s, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.57 (s, 1H), 6.75 (s, 1H), 4.52 (s, 4H), 3.39 (s, 7H) 2.50 (s, 3H), 2.13 (t, J=4.64 Hz, 4H).

Embodiment 12

[0233] ##STR00080## ##STR00081##

Step 1

[0234] At 0° C., a solution of sodium nitrite (834.47 mg, 12.09 mmol, 1 eq) in water (3.5 mL) was slowly added to a mixed solution of compound 12a (3.55 g, 12.09 mmol, 1 eq, hemioxalate) in acetic acid (35 mL) and water (12 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 16 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, then diluted with water (15 mL), extracted with ethyl acetate (50 mL*6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 12b.

[0235] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.52-4.69 (m, 2H), 4.40-4.50 (m, 2H), 4.09-4.17 (m, 1H), 3.25-3.34 (m, 1H), 2.43-2.54 (m, 2H), 2.24-2.33 (m, 1H), 2.02-2.11 (m, 1H), 1.88-1.99 (m, 1H), 1.61-1.70 (m, 1H).

Step 2

[0236] At 0° C., zinc powder (1.59 g, 24.33 mmol, 4 eq) was added to a mixed solution of compound 12b (0.95 g, 6.08 mmol, 1 eq) in acetic acid (5 mL) and methanol (5 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 2 hours. After the reaction was completed, ethyl acetate (50 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 12c.

Step 3

[0237] At 0° C., a solution of compound 12c (2.7 g, 6.67 mmol, 1 eq, acetate) in dioxane (35 mL) and triethylamine (2.70 g, 26.70 mmol, 4 eq, 3.72 mL) were added sequentially to a solution of compound 1a (2.59 g, 13.35 mmol, 2 eq) in dioxane (100 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, water (50 mL) was added to quench the reaction, and the reaction solution was diluted with water (25 mL), extracted with ethyl acetate (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 12e. MS: m/z 299.8 [M+H].sup.+;

[0238] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.05 (s, 2H), 4.55 (t, J=7.78 Hz, 2H), 2.90-3.07 (m, 4H), 2.46 (t, J=7.78 Hz, 2H), 2.13-2.22 (m, 2H), 2.04-2.11 (m, 2H).

Step 4

[0239] Iron powder (234.79 mg, 4.20 mmol, 5 eq) and ammonium chloride (224.87 mg, 4.20 mmol, 5 eq) were added sequentially to a mixed solution of compound 12e (252 mg, 840.80 μmol, 1 eq) in ethanol (12 mL) and water (4 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (10 mL: 1 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12f.

Step 5

[0240] N,N′-Carbonyldiimidazole (180.35 mg, 1.11 mmol, 3 eq) was added to a solution of compound 12f (100 mg, 370.74 μmol, 1 eq) in acetonitrile (3 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (ethyl acetate:petroleum ether=1:0) to obtain compound 12g. MS: m/z 296.0 [M+H].sup.+.

Step 6

[0241] Cesium carbonate (581.73 mg, 1.79 mmol, 4 eq) and iodomethane (190.07 mg, 1.34 mmol, 3 eq) were added sequentially to a solution of compound 12g (132 mg, 446.36 μmol, 1 eq) in N,N-dimethylformamide (4 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, water (5 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, then diluted with water (5 mL), extracted with ethyl acetate (10 mL*6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 12h.

Step 7

[0242] Compound 12h (55 mg, 177.56 μmol, 1 eq), compound 1g (23.68 mg, 159.81 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (32.19 mg, 35.51 μmol, 0.2 eq) and cesium carbonate (86.78 mg, 266.34 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (3 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by thin-layer preparative chromatography (methanol:dichloromethane=1:20) to obtain compound 12. MS: m/z 422.2 [M+H].sup.+;

[0243] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.70 (s, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 6.85 (s, 1H), 4.57 (t, J=7.69 Hz, 2H), 3.58 (br s, 2H), 3.39 (s, 3H), 3.36 (br s, 2H), 2.50 (s, 3H), 2.45-2.49 (m, 2H), 2.07-2.23 (m, 4H).

Embodiment 13

[0244] ##STR00082## ##STR00083##

Step 1

[0245] At 0° C., sodium nitrite (477.39 mg, 6.92 mmol, 1.1 eq) was slowly added to a mixed solution of compound 13a (800 mg, 6.29 mmol, 1 eq) in acetic acid (8 mL) and water (3.2 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 13b.

[0246] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.18-4.23 (m, 2H), 3.86 (s, 1H), 3.78-3.83 (m, 2H), 3.53-3.59 (m, 1H), 2.0-2.12 (m, 3H), 1.63-1.95 (m, 3H)

Step 2

[0247] At 0° C., zinc powder (1.5 g, 22.92 mmol, 4 eq) was added to a mixed solution of compound 13b (895 mg, 5.73 mmol, 1 eq) in acetic acid (5 mL) and methanol (5 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, ethyl acetate (100 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 13c.

Step 3

[0248] At 0° C., compound 13c (813.37 mg, 5.72 mmol, 1 eq, acetate) was added sequentially to a solution of compound 1a (2.22 g, 11.44 mmol, 2 eq) in dioxane (50 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 13e. MS: m/z 299.9 [M+H].sup.+

[0249] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.07 (s, 1H), 9.03 (s, 1H), 3.80-3.83 (m, 2H), 2.93-2.98 (m, 4H), 2.08-2.22 (m, 4H), 1.83-1.94 (m, 1H), 1.61-1.74 (m, 1H).

Step 4

[0250] Iron powder (130.43 mg, 2.34 mmol, 5 eq) and ammonium chloride (124.93 mg, 2.34 mmol, 5 eq) were added sequentially to a mixed solution of compound 13e (140 mg, 467.11 μmol, 1 eq) in ethanol (3 mL) and water (3 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and washed with ethanol (20 mL), and the washing solution was concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (10 mL: 1 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13f.

Step 5

[0251] N,N′-Carbonyldiimidazole (174.33 mg, 1.08 mmol, 2 eq) was added to a solution of compound 13f (145 mg, 537.57 μmol, 1 eq) in acetonitrile (4 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:10) to obtain compound 13g. MS: m/z 295.8 [M+H].sup.+.

Step 6

[0252] Cesium carbonate (275.44 mg, 845.38 μmol, 2 eq) and iodomethane (71.9 mg, 507.22 μmol, 1.2 eq) were added sequentially to a solution of compound 13g (125 mg, 422.69 μmol, 1 eq) in N,N-dimethylformamide (2 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, water (10 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:10) to obtain compound 13h. MS: m/z 309.9 [M+H].sup.+;

[0253] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.02 (s, 1H), 3.83-3.84 (m, 2H), 3.40-3.44 (m, 7H), 2.10-2.24 (m, 4H), 1.81-1.90 (m, 1H), 1.56-1.63 (m, 1H).

Step 7

[0254] Compound 13h (45 mg, 145.28 μmol, 1 eq), compound 1g (19.37 mg, 130.75 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (26.34 mg, 29.06 μmol, 0.2 eq) and cesium carbonate (94.67 mg, 290.56 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:10) to obtain compound 13. MS: m/z 422.0 [M+H].sup.+;

[0255] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.84 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.57 (s, 1H), 6.74 (s, 1H), 3.83-3.88 (m, 2H), 3.43-3.51 (m, 4H), 3.41 (s, 3H), 2.53 (s, 3H), 2.18-2.29 (m, 3H), 2.10-2.16 (m, 1H), 1.79-1.94 (m, 1H), 1.59-1.69 (m, 1H).

Embodiment 14

[0256] ##STR00084## ##STR00085##

Step 1

[0257] At 0° C., sodium nitrite (688.97 mg, 9.99 mmol, 1.1 eq) was added to a mixed solution of compound 14a (1 g, 9.08 mmol, 1 eq) in acetic acid (10 mL) and water (4 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 14b.

[0258] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.31-4.46 (m, 2H), 3.97-4.10 (m, 1H), 3.73-3.85 (m, 1H), 2.99-3.11 (m, 1H), 2.05-2.18 (m, 2H), 1.77-1.91 (m, 2H).

Step 2

[0259] At 0° C., zinc powder (1.88 g, 28.69 mmol, 4 eq) was added to a mixed solution of compound 14b (998 mg, 7.17 mmol, 1 eq) in acetic acid (8 mL) and methanol (8 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 14c.

Step 3

[0260] At 0° C., compound 14c (897.48 mg, 7.17 mmol, 1 eq, acetate) was added sequentially to a solution of compound 1a (2.78 g, 14.34 mmol, 2 eq) in dioxane (26 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 14e. MS: m/z 282.9 [M+H].sup.+;

[0261] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.11 (s, 1H), 9.08 (s, 1H), 3.10-3.19 (m, 2H), 3.01-3.09 (m, 2H), 2.77-2.86 (m, 1H), 2.09-2.20 (m, 4H).

Step 4

[0262] Iron powder (96.80 mg, 1.73 mmol, 5 eq) and ammonium chloride (92.72 mg, 1.73 mmol, 5 eq) were added sequentially to a mixed solution of compound 14e (98 mg, 346.67 μmol, 1 eq) in ethanol (2 mL) and water (2 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and washed with ethanol (20 mL), and the washing solution was concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (10 mL: 1 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14f.

Step 5

[0263] N,N′-Carbonyldiimidazole (93.68 mg, 577.75 μmol, 2 eq) was added to a solution of compound 14f (73 mg, 288.88 μmol, 1 eq) in acetonitrile (2 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:10) to obtain compound 14g. MS: m/z 278.9 [M+H].sup.+.

Step 6

[0264] Cesium carbonate (135.61 mg, 416.22 μmol, 2 eq) and iodomethane (35.45 mg, 249.73 μmol, 1.2 eq) were added sequentially to a solution of compound 14g (58 mg, 208.11 μmol, 1 eq) in N,N-dimethylformamide (2 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, water (10 mL) was added to quench the reaction, and the reaction solution was extracted with 30 mL of ethyl acetate (10 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:10) to obtain compound 14h. MS: m/z 292.9 [M+H].sup.+;

[0265] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.03 (s, 1H), 3.51-3.59 (m, 2H), 3.44-3.50 (m, 2H), 3.43 (s, 3H), 2.61-2.93 (m, 1H), 2.13-2.24 (m, 4H).

Step 7

[0266] Compound 14h (38 mg, 129.82 μmol, 1 eq), compound 1g (17.31 mg, 116.83 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (23.54 mg, 25.96 μmol, 0.2 eq) and cesium carbonate (84.59 mg, 259.63 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (methanol:dichloromethane=1:10) to obtain compound 14. MS: m/z 405.0 [M+H].sup.+;

[0267] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.75 (s, 1H), 8.27 (s, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 6.81 (s, 1H), 3.52-3.62 (m, 4H), 3.41 (s, 3H), 2.75-2.87 (m, 1H), 2.51 (s, 3H), 2.16-2.24 (m, 4H).

Embodiment 15

[0268] ##STR00086## ##STR00087##

Step 1

[0269] At 0° C., a solution of sodium nitrite (1.40 g, 20.32 mmol, 1 eq) in water (3 mL) was slowly added to a mixed solution of compound 15a (3 g, 20.32 mmol, 1 eq, hydrochloride) in acetic acid (30 mL) and water (10 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 16 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, diluted with water (30 mL), extracted with ethyl acetate (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:2) to obtain compound 15b.

[0270] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.43 (dd, J=12.69, 7.82 Hz, 1H), 4.10 (dd, J=12.63, 4.50 Hz, 1H), 3.79 (dd, J=15.20, 8.69 Hz, 1H), 3.42 (dd, J=15.32, 4.69 Hz, 1H), 2.69-2.89 (m, 2H), 1.85-2.00 (m, 2H), 1.61-1.82 (m, 2H), 1.41-1.56 (m, 2H).

Step 2

[0271] At 0° C., zinc powder (1.51 g, 23.11 mmol, 4 eq) was added to a mixed solution of compound 15b (0.81 g, 5.78 mmol, 1 eq) in acetic acid (5 mL) and methanol (5 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 2 hours. After the reaction was completed, ethyl acetate (100 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 15c.

Step 3

[0272] At 0° C., a solution of compound 15c (2.6 g, 6.98 mmol, 1 eq, acetate) in dioxane (3 mL) and triethylamine (2.83 g, 27.92 mmol, 4 eq, 3.89 mL) were added sequentially to a solution of compound 1a (2.71 g, 13.96 mmol, 2 eq) in dioxane (100 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, water (30 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (60 mL*4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:6) to obtain compound 15e. MS: m/z 284.0 [M+H].sup.+.

[0273] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.04 (s, 1H), 8.99 (br s, 1H), 3.37 (br t, J=7.94 Hz, 2H), 2.76 (br s, 2H), 2.50-2.59 (m, 2H), 1.65-1.77 (m, 4H), 1.25 (br s, 2H).

Step 4

[0274] Iron powder (113.19 mg, 2.03 mmol, 5 eq) and ammonium chloride (108.41 mg, 2.03 mmol, 5 eq) were added sequentially to a mixed solution of compound 15e (115 mg, 405.34 μmol, 1 eq) in ethanol (2 mL) and water (2 mL), and after the addition was completed, the reaction solution was reacted at 75° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (10 mL: 1 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15f.

Step 5

[0275] N,N′-Carbonyldiimidazole (230.06 mg, 1.42 mmol, 3 eq) was added to a solution of compound 15f (120 mg, 472.94 μmol, 1 eq) in acetonitrile (4 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (ethyl acetate:petroleum ether=1:0) to obtain compound 15g. MS: m/z 280.0 [M+H].sup.+.

Step 6

[0276] Cesium carbonate (172.39 mg, 529.09 μmol, 4 eq) and iodomethane (56.32 mg, 396.82 μmol, 3 eq) were added sequentially to a solution of compound 15g (37 mg, 132.27 μmol, 1 eq) in N,N-dimethylformamide (1.5 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 1 hour. After the reaction was completed, water (3 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure, then diluted with water (3 mL), extracted with ethyl acetate (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 15h.

Step 7

[0277] Compound 15h (26.5 mg, 90.21 μmol, 1 eq), compound 1g (12.03 mg, 81.19 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (16.36 mg, 18.04 μmol, 0.2 eq) and cesium carbonate (44.09 mg, 135.32 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by thin-layer preparative chromatography (methanol:dichloromethane=1:20) to obtain compound 15. MS: m/z 406.2 [M+H].sup.+;

[0278] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.70 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.55 (s, 1H), 6.80 (s, 1H), 3.58 (s, 2H), 3.39 (s, 3H), 3.29 (s, 2H), 2.79 (s, 2H), 2.48 (s, 3H), 1.62-1.89 (m, 6H).

Embodiment 16

[0279] ##STR00088## ##STR00089##

Step 1

[0280] At 0° C., a solution of sodium nitrite (634.66 mg, 9.20 mmol, 1.1 eq) in water (1 mL) was slowly added to a mixed solution of compound 16a (1 g, 8.36 mmol, 1 eq, hydrochloride) in acetic acid (10 mL) and water (3.5 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 3 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (200 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:4) to obtain compound 16b.

[0281] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 4.51 (d, J=12.05 Hz, 1H), 4.31 (dd, J=11.92, 4.14 Hz, 1H), 4.08 (d, J=14.4 Hz, 1H), 3.38 (ddd, J=14.31, 4.64, 1.13 Hz, 1H), 1.57-1.73 (m, 2H), 0.83-0.95 (m, 1H), 0.08-0.20 (m, 1H).

Step 2

[0282] At 0° C., zinc powder (1.70 g, 26.04 mmol, 4 eq) was added to a mixed solution of compound 16b (0.73 g, 6.51 mmol, 1 eq) in acetic acid (3 mL) and methanol (3 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 1 hour. After the reaction was completed, ethyl acetate (50 mL) was added to dilute the reaction solution, and the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 16c.

Step 3

[0283] At 0° C., compound 16c (2.2 g, 22.42 mmol, 1 eq) and diisopropylethylamine (14.49 g, 112.08 mmol, 5 eq, 19.52 mL) were added sequentially to a solution of compound 1a (4.35 g, 22.42 mmol, 1 eq) in ethanol (30 mL), and after the addition was completed, the reaction solution was reacted at 0° C. for 1 hour. After the reaction was completed, water (100 mL) was added to quench the reaction, and the reaction solution was extracted with dichloromethane (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:9) to obtain compound 16e. MS: m/z 255.7 [M+H].sup.+;

[0284] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.03 (s, 1H), 8.99 (br s, 1H), 3.37 (d, J=8.25 Hz, 2H), 3.09 (br d, J=7.88 Hz, 2H), 1.55-1.58 (m, 2H), 0.87 (q, J=4.17 Hz, 1H), 0.58-0.68 (m, 1H).

Step 4

[0285] Iron powder (87.37 mg, 1.56 mmol, 4 eq) and ammonium chloride (83.69 mg, 1.56 mmol, 4 eq) were added sequentially to a solution of compound 16e (100 mg, 391.14 μmol, 1 eq) in ethanol (2 mL) and water (2 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite and washed with ethanol (50 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was dissolved in a solution of dichloromethane/methanol (50 mL: 10 mL), stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16f.

Step 5

[0286] N,N′-Carbonyldiimidazole (71.85 mg, 443.11 μmol, 1 eq) was added to a solution of compound 16f (100 mg, 443.11 μmol, 1 eq) in acetonitrile (2 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL*2), washed with water (20 mL*2), and purified by thin-layer preparative chromatography (ethyl acetate:petroleum ether=1:2) to obtain compound 16g. MS: m/z 252.0 [M+H].sup.+;

[0287] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.12 (s, 1H), 3.73 (d, J=7.03 Hz, 2H), 3.11 (d, J=7.78 Hz, 2H), 1.55-1.61 (m, 2H), 0.73-0.77 (m, 1H), 0.57-0.65 (m, 1H).

Step 6

[0288] Cesium carbonate (51.78 mg, 158.94 μmol, 2 eq) and iodomethane (11.28 mg, 79.47 μmol, 1 eq) were added sequentially to a solution of compound 16g (20 mg, 79.47 μmol, 1 eq) in N,N-dimethylformamide (3 mL), and after the addition was completed, the reaction solution was reacted at 25° C. for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (20 mL*2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 16h.

Step 7

[0289] Compound 16h (28 mg, 105.38 μmol, 1 eq), compound 1g (14.05 mg, 94.84 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (19.11 mg, 21.08 μmol, 0.2 eq) and cesium carbonate (51.50 mg, 158.07 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (3 mL) was added to the mixture and the reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the reaction solution was filtered and washed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure, then purified by thin-layer preparative chromatography (methanol:dichloromethane=1:20) to obtain compound 16. MS: m/z 378.3 [M+H].sup.+;

[0290] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.16 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 3.76 (br d, J=7.03 Hz, 2H), 3.27 (s, 3H), 3.11 (br d, J=7.78 Hz, 2H), 2.39 (s, 3H), 1.52-1.61 (m, 2H), 0.70-0.76 (m, 1H), 0.53-0.62 (m, 1H).

Embodiment 17

[0291] ##STR00090##

Step 1

[0292] At 15° C., hydrazine monohydrate (4.61 g, 120.0 mmol, 4 eq) was added to a solution of compound 17a (5.18 g, 30.0 mmol, 1 eq) in 1,4-dioxane (30 mL), and after the addition was completed, the reaction was carried out at 15° C. for 8 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with water (50 mL) and dried under reduced pressure to obtain compound 17b. MS: m/z. 168.9 [M+H].sup.+.

Step 2

[0293] At 25° C., trimethyl orthoformate (12.73 g, 120 mmol, 4 eq) and trifluoroacetic acid (0.684 g, 6 mmol, 0.2 eq) were added sequentially to a solution of compound 17b (5.04 g, 30 mmol, 1 eq) in dichloromethane (60 mL), and after the addition was completed, the reaction was carried out at 25° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 17c. MS: m/z. 178.9 [M+H].sup.+.

[0294] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.70 (s, 1H), 9.35 (s, 1H), 7.84 (s, 1H), 2.59 (s, 3H).

Step 3

[0295] Iron powder (6.14 g, 110 mmol, 5 eq) and ammonium chloride (5.88 g, 110 mmol, 5 eq) were added sequentially to a mixed solution of compound 17c (3.92 g, 22 mmol, 1 eq) in ethanol (80 mL) and water (20 mL), and after the addition was completed, the reaction was carried out at 70° C. for 3 hours. After the reaction was completed, the reaction solution was filtered and washed with ethanol (20 mL), and the filtrate was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 17d. MS: m/z 148.8 [M+H].sup.+.

[0296] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.11 (s, 1H), 8.07 (s, 1H), 7.46 (s, 1H), 5.01 (s, 2H), 2.25 (d, J=0.88 Hz, 3H).

Step 4

[0297] A solution of compound 17d (29.63 mg, 200 μmol, 1 eq), compound 5h (59.14 mg, 200.00 μmol, 1 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (27.19 mg, 30.00 μmol, 0.15 eq) and cesium carbonate (97.75 mg, 300 μmol, 1.5 eq) in dioxane (2.5 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 2 hours under nitrogen protection. After the reaction was completed, the filtrate was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer preparative chromatography (methanol:dichloromethane=1:12) to obtain compound 17. MS: m/z 408.2 [M+H].sup.+.

[0298] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.88 (s, 1H), 8.28 (s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 6.93 (s, 1H), 4.46-4.54 (m, 2H), 4.05 (dd, J=9.88, 2.13 Hz, 2H), 3.41 (s, 3H), 2.86 (d, J=9.63 Hz, 2H), 2.55 (s, 3H), 2.29-2.36 (m, 2H), 2.01-2.09 (m, 2H).

Embodiment 18

[0299] ##STR00091##

[0300] A solution of compound 17d (29.63 mg, 200 μmol, 1 eq), compound 4h (59.14 mg, 200.00 μmol, 1 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (27.19 mg, 30.00 μmol, 0.15 eq) and cesium carbonate (97.75 mg, 300 μmol, 1.5 eq) in dioxane (2.5 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered through celite, concentrated under reduced pressure to obtain a crude product, and the crude product was purified by thin-layer preparative chromatography (methanol:dichloromethane=1:12) to obtain compound 18. MS: m/z 408.1 [M+H].sup.+.

[0301] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.77 (s, 1H), 8.27 (s, 1H), 7.90 (s, 1H), 7.59 (s, 1H), 6.77 (s, 1H), 4.13-4.22 (m, 2H), 3.85-3.94 (m, 2H), 3.69-3.75 (m, 2H), 3.40 (s, 3H), 2.52 (s, 3H), 2.37-2.46 (m, 2H), 2.09-2.18 (m, 2H).

Embodiment 19

[0302] ##STR00092##

Step 1

[0303] Chloroacetaldehyde (1.92 g, 9.80 mmol, 1.58 mL, 40% purity, 1.5 eq) was added to a solution of compound 19a (1 g, 6.53 mmol, 1 eq) in ethanol (10 mL), and after the addition was completed, the reaction solution was reacted at 70° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 19b.

[0304] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 9.95 (s, 1H), 8.34 (d, J=1.50 Hz, 1H), 8.15 (d, J=1.88 Hz, 1H), 7.93 (s, 1H), 2.71 (s, 3H).

Step 2

[0305] Iron powder (1.51 g, 27.09 mmol, 4 eq) and ammonium chloride (1.45 g, 27.09 mmol, 4 eq) were added sequentially to a mixed solution of compound 19b (1.2 g, 6.77 mmol, 1 eq) in ethanol (6 mL) and water (6 mL), and after the addition was completed, the reaction solution was reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. At 25° C., the crude product was treated with sonication in dichloromethane:methanol=30 mL: 3 mL for 5 minutes, filtered, and the filtrate was concentrated to obtain compound 19c. MS: m/z 147.9 [M+H].sup.+.

Step 3

[0306] Compound 5h (50 mg, 169.08 μmol, 1 eq), compound 19c (22.40 mg, 152.17 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (30.65 mg, 33.82 μmol, 0.2 eq) and cesium carbonate (82.63 mg, 253.61 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture, and after the addition was completed, the reaction solution was reacted at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was first purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain a crude product, and then purified by preparative high performance liquid chromatography (neutral conditions: chromatographic column: Phenomenex Gemini-NX 80*30 mm*3 μm; mobile phase: [Water (10 mM ammonium bicarbonate)-acetonitrile]; % acetonitrile: 16%-46%, 9 minutes) to obtain compound 19. MS: m/z 407.3 [M+H].sup.+.

[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.46 (s, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 6.77 (s, 1H), 4.47-4.56 (m, 2H), 4.07-4.15 (m, 2H), 3.39 (s, 3H), 2.82-2.93 (m, 2H), 2.46 (s, 3H), 2.26-2.35 (m, 2H), 2.01-2.11 (m, 2H).

Embodiment 20

[0308] ##STR00093##

Step 1

[0309] Compound 4h (50 mg, 169.08 μmol, 1 eq), compound 19c (22.40 mg, 152.17 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (30.65 mg, 33.82 μmol, 0.2 eq) and cesium carbonate (82.63 mg, 253.61 μmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture, and after the addition was completed, the reaction solution was reacted at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and first purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain a crude product, then purified by preparative high performance liquid chromatography (neutral condition: chromatographic column: Phenomenex Gemini-NX 80*30 mm*3 μm; mobile phase: [Water (10 mM ammonium bicarbonate)-acetonitrile]; % acetonitrile: 13%-43%, 9 minutes) to obtain compound 20. MS: m/z 407.3 [M+H].sup.+.

[0310] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.20 (s, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.47 (s, 1H), 6.65 (s, 1H), 4.07-4.16 (m, 2H), 3.79-3.88 (m, 2H), 3.66-3.75 (m, 2H), 3.38 (s, 3H), 2.35-2.47 (m, 5H), 2.05-2.15 (m, 2H).

Embodiment 21

[0311] ##STR00094##

Step 1

[0312] 2,2-Dimethoxybenzylamine (6.35 g, 37.97 mmol, 5.72 mL, 3 eq) and N,N-diisopropylethylamine (4.91 g, 37.97 mmol, 6.61 mL, 3 eq) were added to a solution of compound 21a (3 g, 12.66 mmol, 1 eq) in dioxane (20 mL), and after the addition was completed, the reaction solution was reacted at 110° C. for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:3) to obtain compound 21b. MS: m/z 385.0 [M+H].sup.+.

[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.84 (s, 1H), 7.16-7.20 (m, 1H), 6.95 (s, 1H), 6.40-6.48 (m, 2H), 4.78 (s, 1H), 4.31-4.37 (m, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.22 (s, 3H).

Step 2

[0314] Trifluoroacetic acid (6.93 g, 60.78 mmol, 4.5 mL, 27 eq) was added to a solution of compound 21b (865 g, 2.25 mmol, 1 eq) in dichloromethane (9 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate (20 mL) was added to adjust the pH to 8-9, then the reaction solution was extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 21c. MS: m/z 234.9 [M+H].sup.+.

Step 3

[0315] N,N-Dimethylformamide dimethyl acetal (572.80 mg, 4.81 mmol, 638.58 μL, 3 eq) was added to a solution of compound 21c (375 mg, 1.6 mmol, 1 eq) in toluene (4 mL), and after the addition was completed, the reaction solution was reacted at 110° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 21d.

Step 4

[0316] Hydroxylamine hydrochloride (298.04 mg, 4.29 mmol, 2 eq) was added to a solution of compound 21d (620 mg, 2.14 mmol, 1 eq) in methanol (6 mL), and after the addition was completed, the reaction solution was reacted at 70° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 21e.

Step 5

[0317] At 0° C., trifluoroacetic anhydride (1.30 g, 6.17 mmol, 858.47 μL, 1.5 eq) was added to a solution of compound 21e (1.14 g, 4.11 mmol, 1 eq) in tetrahydrofuran (12 mL), and after the addition was completed, the reaction solution was reacted at 20° C. for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 21f. MS: m/z 259.9 [M+H].sup.+.

Step 6

[0318] Compound 21f (175 mg, 675.55 μmol, 1 eq), benzophenoneimine (134.68 mg, 743.11 μmol, 124.70 μL, 1.1 eq), tris(dibenzylideneacetone)dipalladium (12.37 mg, 13.51 μmol), 0.02 eq), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (11.74 mg, 20.29 μmol, 0.03 eq) and sodium tert-butoxide (97.38 mg, 1.01 mmol, 1.5 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous toluene (3 mL) was added to the mixture, and after the addition was completed, the reaction solution was reacted at 90° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then tetrahydrofuran (10 mL) and 3 mol/L hydrochloric acid solution (3 mL) were added, and the mixture was stirred at 20° C. for 0.5 hours, and then diluted with water (20 mL), extracted with ethyl acetate (15 mL*2), and the organic phase was discarded. The pH of aqueous phase was adjusted to 9-11 by adding an appropriate amount of aqueous ammonium hydroxide solution, then the aqueous phase was extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 21g. MS: m/z 148.9 [M+H].sup.+.

[0319] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.20 (s, 1H), 8.08 (s, 1H), 6.78 (s, 1H), 4.17 (s, 2H), 2.20-2.24 (m, 3H).

Step 7

[0320] Compound 21g (22.55 mg, 152.17 μmol, 0.9 eq), compound 5h (50 mg, 169.08 μmol, 1 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (30.65 mg, 33.82 μmol, 0.2 eq) and cesium carbonate (110.18 mg, 338.15 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (methanol:dichloromethane=1:10) to obtain compound 21. MS: m/z 408.1 [M+H].sup.+.

[0321] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.03 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.11 (s, 1H), 4.46-4.54 (m, 2H), 4.01-4.11 (m, 2H), 3.42 (s, 3H), 2.80-2.91 (m, 2H), 2.45 (s, 3H), 2.30-2.39 (m, 2H), 2.01-2.08 (m, 2H).

Embodiment 22

[0322] ##STR00095##

Step 1

[0323] Compound 4h (50 mg, 169.08 μmol, 1 eq), compound 21g (22.55 mg, 152.17 μmol, 0.9 eq), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (30.65 mg, 33.82 μmol, 0.2 eq) and cesium carbonate (110.18 mg, 338.15 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (3 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (methanol:dichloromethane=1:10) to obtain compound 22. MS: m/z 430.1 [M+Na].sup.+.

[0324] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.97 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.10 (s, 1H), 4.13-4.19 (m, 2H), 3.87-3.93 (m, 2H), 3.70-3.76 (m, 2H), 3.41 (s, 3H), 2.41-2.49 (m, 5H), 2.14-2.20 (m, 2H).

Embodiment 23

[0325] ##STR00096##

Step 1

[0326] Chloroacetaldehyde (5.26 g, 26.80 mmol, 670.12 μL, 40% purity, 1.2 eq) was added to a mixed solution of compound 23a (4.2 g, 22.34 mmol, 1 eq) in ethanol (42 mL) and water (17.5 mL), and after the addition was completed, the reaction solution was reacted at 100° C. for 16 hours. After the reaction was completed, the reaction solution was diluted with saturated sodium bicarbonate solution (60 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=0:1-1:1) to obtain compound 23b. MS: m/z 213.8 [M+H+2].sup.+.

[0327] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.57 (s, 1H), 7.84-7.86 (m, 1H), 7.48-7.50 (m, 1H), 2.79 (s, 3H).

Step 2

[0328] Compound 23b (1 g, 4.72 mmol, 1 eq), benzophenoneimine (940.15 mg, 5.19 mmol, 870.51 μL, 1.1 eq), tris(dibenzylideneacetone)dipalladium (431.85 mg, 471.59 μmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (545.75 mg, 943.19 μmol, 0.2 eq) and cesium carbonate (3.07 g, 9.43 mmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (30 mL) was added to the mixture and the reaction was carried out at 120° C. for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, then tetrahydrofuran (10 mL) and 3 mol/L hydrochloric acid solution (12 mL) were added, and the reaction solution was stirred at 20° C. for half an hour, then diluted with water (20 mL), extracted with ethyl acetate (20 mL*3), and the organic phase was discarded. An appropriate amount of ammonium hydroxide solution was added to the aqueous phase to adjust the pH to 9-11, then the aqueous phase was directly concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane=0:1-1:9) to obtain compound 23c. MS: m/z 148.8 [M+H].sup.+.

Step 3

[0329] Compound 23c (40.08 mg, 270.52 μmol, 2 eq), compound 5h (40 mg, 135.26 μmol, 1 eq), tris(dibenzylideneacetone)dipalladium (12.39 mg, 13.53 μmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.65 mg, 27.05 μmol, 0.2 eq) and cesium carbonate (88.14 mg, 270.52 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, then anhydrous dioxane (2 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (methanol:dichloromethane=1:10) to obtain compound 23. MS: m/z 408.2 [M+H].sup.+.

[0330] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.74 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 6.83 (s, 1H), 4.48-4.54 (m, 2H), 4.03-4.10 (m, 2H), 3.41 (s, 3H), 2.84-2.90 (m, 2H), 2.74 (s, 3H), 2.25-2.32 (m, 2H), 2.03-2.11 (m, 2H).

Embodiment 24

[0331] ##STR00097##

Step 1

[0332] Compound 4h (40 mg, 135.26 μmol, 1 eq), compound 23c (40.08 mg, 270.52 μmol, 2 eq), tris(dibenzylideneacetone)dipalladium (12.39 mg, 13.53 μmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.65 mg, 27.05 μmol, 0.2 eq) and cesium carbonate (88.14 mg, 270.52 μmol, 2 eq) were placed in a reaction flask, and the reaction flask was vacuumized and replaced with nitrogen three times, and then anhydrous dioxane (2 mL) was added to the mixture and the reaction was carried out at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by thin-layer preparative chromatography (methanol:dichloromethane=1:10) to obtain compound 24. MS: m/z 408.1 [M+H].sup.+.

[0333] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.60 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.43-7.50 (m, 1H), 6.76 (s, 1H), 4.06-4.14 (m, 2H), 3.79-3.86 (m, 2H), 3.67-3.75 (m, 2H), 3.39 (s, 3H), 2.72 (s, 3H), 2.39-2.47 (m, 2H), 2.09-2.18 (m, 2H).

[0334] Biological Test Data:

Experimental Embodiment 1: DNA-Dependent Protein Kinase (DNA-PK) Inhibitory Activity Screening Experiment

[0335] This experiment was tested in the Eurofins

[0336] Experimental Materials and Methods:

[0337] Human DNA-PK; Mg/ATP; GST-cMyc-p53; EDTA; Ser15 antibody; ATP: 10 μM.

[0338] Experimental Method (Eurofins Pharma Discovery Service):

[0339] DNA-PK (h) was incubated in assay buffer containing 50 nM GST-cMyc-p53 and Mg/ATP (according to the required concentration). The reaction was initiated by adding Mg/ATP mixture. After 30 minutes of incubation at room temperature, the reaction was stopped by adding a stop solution containing EDTA. Finally, detection buffer (containing labeled anti-GST monoclonal antibody and europium-labeled anti-Ser15 antibody against phosphorylated p53) was added. The plate was then read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined according to the formula HTRF=10000×(Em665 nm/Em620 nm).

[0340] Test Results:

TABLE-US-00001 TABLE 1 DNA-PK kinase activity test results Testing sample DNA-PK kinase inhibition IC.sub.50 (nM) Compound 1 2 Compound 4 1 Compound 5 1 Compound 6 1 Compound 7 2 Compound 8 7 Compound 9 3 Compound 10 2.5 Compound 11 5 Compound 12 4 Compound 13 2 Compound 14 5 Compound 15 1 Compound 16 0.5 Compound 17 0.5 Compound 18 0.9 Compound 19 0.6 Compound 20 0.9 Compound 21 0.5 Compound 22 0.4 Compound 23 10 Compound 24 68

[0341] Conclusion: The compounds of the present disclosure have significant DNA-PK kinase inhibitory activity.

Experimental Embodiment 2: Pharmacokinetic Evaluation (1)

[0342] 1. Experimental Method

[0343] Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water (compounds 1, 4, 10, 17) or 20% N,N-dimethylacetamide/80% water (compound 5), vortexed and sonicated to prepare a nearly clear solution of 0.08 mg/mL (compounds 1, 4, 10, 17) or 0.50 mg/mL (compound 5), then filtered through a microporous membrane for next step. Balb/c male mice of 18 to 20 grams were selected and administered intravenously with the candidate compound solution at a dose of 0.4 (compounds 1, 4, 10, 17) or 1 mg/kg (compound 5). Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water (compounds 1, 4, 10, 17) or 20%-hydroxypropyl-β-cyclodextrin (compound 5), vortexed and sonicated to prepare a nearly clear solution of 0.2 mg/mL (compounds 1, 4, 10, 17) or 1 mg/mL (compound 5), then filtered through a microporous membrane for next step. Balb/c male mice of 18 to 20 grams were selected and orally administered with the candidate compound solution at a dose of 2 (compounds 1, 4, 10, 17) or 5 mg/kg (compound 5). Whole blood was collected for a certain period of time, and plasma was prepared, then drug concentration was detected by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).

Definition of Each Parameter

[0344] IV: intravenous injection; PO: oral; C.sub.0: instantaneous required concentration after intravenous injection; C.sub.max: highest plasma concentration after administration; T.sub.max: time required to reach peak of drug concentration after administration; T.sub.1/2: time required for the plasma drug concentration to decrease by half, V.sub.dss: apparent volume of distribution, refers to the proportional constant of the drug dose in vivo and the blood drug concentration when the drug reaches a dynamic equilibrium in vivo. Cl: clearance rate, refers to the apparent volume of distribution of the drug cleared from the body per unit time; T.sub.last: time at the last detection point; AUC.sub.0-last: area under the drug-time curve, refers to the area covered by the plasma concentration curve and the time axis; F: a measure of the speed and degree of drug absorption into the blood circulation, which is an important indicator for evaluating the degree of drug absorption.

[0345] Test Results:

[0346] The experimental results are shown in Table 2.

TABLE-US-00002 TABLE 2 Cassette PK test results of compounds in plasma V.sub.dss Cl AUC.sub.0-last C.sub.0 C.sub.max T.sub.max T.sub.1/2 (L/ (mL/min/ T.sub.last (nM .Math. F Parameter (nM) (nM) (h) (h) kg) kg) (h) h) (%) Com- IV(0.4 959 — — 0.598 1.51 37.7 4 426 — pound 1 mg/kg) PO(2 — 1425 0.5 0.841 — — 8 2497 96.4 mg/kg) Com- IV(0.4 919 — — 0.24 1.08 57 2 286 — pound 4 mg/kg) PO(2 — 1595 0.25 0.609 — — 4 1736 123 mg/kg) Com- IV(1 3604 — — 1.28 1.49 24.7 ND 1657 — pound 5 mg/kg) PO(5 — 2170 0.25 3.85 — — 10 3489 44.5 mg/kg) Com- IV(0.4 1121 — — 0.591 0.883 25.4 4 640 — pound mg/kg) 10 PO(2 — 2065 0.5 1.22 — — 8 3832 120 mg/kg) Com- IV(0.4 748 — — 0.559 1.39 34.7 4 470 — pound mg/kg) 17 PO(2 — 1545 1.0 0.81 — — 8 3397 144 mg/kg) ND: Not detected “—” means that not tested or no data was obtained.

[0347] Conclusion: The compounds of the present disclosure exhibit longer half-life, lower clearance rate and higher drug exposure, and have good pharmacokinetic properties in vivo.

Experimental Embodiment 3: Pharmacokinetic Evaluation in Mice (2)

Experimental Method

[0348] Test compounds were mixed with 10 dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 0.4 mg/mL (compound 5), then filtered through a microporous membrane for next step. Balb/c male mice of 18 to 20 grams were selected and administered intravenously with the candidate compound solution at a dose of 2 mg/kg. Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 1 mg/mL, then filtered with a microporous membrane for next step. Balb/c male mice of 18 to 20 grams were selected and orally administered with the candidate compound solution at a dose of 10 mg/kg. Whole blood was collected for a certain period of time, and plasma was prepared, then drug concentration was detected by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).

[0349] Test Results:

[0350] The experimental results are shown in Table 3.

TABLE-US-00003 TABLE 3 PK test results of compound in plasma V.sub.dss Cl AUC.sub.0-last C.sub.0 C.sub.max T.sub.max T.sub.1/2 (L/ (mL/min/ T.sub.last (nM .Math. F Parameter (nM) (nM) (h) (h) kg) kg) (h) h) (%) Com- IV (2 4742 — — 0.733 1.07 23.7 8 3454 — pound mpk) 5 PO (10 — 11433 0.50 0.850 — — 10 23184 134 mpk) “—” means that not tested or no data was obtained.

[0351] Conclusion: The compounds of the present disclosure exhibit longer half-life, lower clearance rate and higher drug exposure, and have good pharmacokinetic properties in vivo.

Experimental Embodiment 4: Pharmacokinetic and Brain Exposure Evaluation in Rats

Experimental Method

[0352] Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 0.5 mg/mL (compound 5) or 1 mg/mL (compound 17), then filtered through a microporous membrane for next step. SD male rats were selected and administered intravenously with the candidate compound solution at a dose of 1 mg/kg (compound 5) or 2 mg/kg (compound 17). Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a homogeneous suspension of 4 mg/mL (compound 5) or a nearly clear solution of 1 mg/mL (compound 17). SD male rats were selected and orally administered with the candidate compound solution at a dose of 40 mg/kg (compound 5) or 10 mg/kg (compound 17). Whole blood, cerebrospinal fluid, brain tissue were collected for a certain period of time and plasma was prepared, and the drug concentration was detected by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).

[0353] Test Results:

[0354] The experimental results are shown in Table 4.

TABLE-US-00004 TABLE 4 PK test results of compounds in plasma, cerebrospinal fluid, and brain tissue V.sub.dss Cl AUC.sub.0-last C.sub.0 C.sub.max T.sub.max T.sub.1/2 (L/ (mL/min/ T.sub.last (nM .Math. Parameter (nM) (nM) (h) (h) kg) kg) (h) h) Com- IV (1 mpk) 3043 — — 1.45 1.41 17.0 8  2382 pound PO Plasma — 10223 2 ND — — 8 59896 5 (40 mpk) Cerebro- —  1260 2 ND — — 8  7740 spinal fluid Brain —  1019.sup.a 4 ND — — 8  6369.sup.b tissue Com- IV (2 mpk) 5303 — — 1.16 1.40 16.9 8  4861 pound PO (10 mpk) —  6245 2 2.29 — — 8 32535 17 ND: Not detected “—” means that not tested or no data was obtained. .sup.aunit nmol/kg; .sup.bunit h*nmol/kg.

[0355] Conclusion: The compounds of the present disclosure exhibit longer half-life, lower clearance rate and higher drug exposure, and have good pharmacokinetic properties in vivo.

[0356] At the same time, the compound has a good brain exposure.

Experimental Embodiment 5: Pharmacokinetic Evaluation in Beagle Dogs

Experimental Method

[0357] Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 1 mg/mL, then filtered through a microporous membrane for next step. Male Beagle dogs were selected and administered intravenously with the candidate compound solution at a dose of 1 mg/kg. Test compounds were mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 1 mg/mL, then filtered with a microporous membrane for next step. Male Beagle dogs were selected and orally administered with the candidate compound solution at a dose of 5 mg/kg. Whole blood was collected for a certain period of time, and plasma was prepared, then drug concentration was detected by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).

[0358] Test Results:

[0359] The experimental results are shown in Table 5.

TABLE-US-00005 TABLE 5 PK test results of compounds in plasma V.sub.dss Cl AUC.sub.0-last C.sub.0 C.sub.max T.sub.max T.sub.1/2 (L/ (mL/min/ T.sub.last (nM .Math. F Parameter (nM) (nM) (h) (h) kg) kg) (h) h) (%) Com- IV (1 1450 — — 5.04 1.58 5.89 24 6817 — pound mpk) 17 PO (5 — 4935 1.50 4.27 — — 24 31535 92.3 mpk) Com- IV (1 1820 — — 4.04 1.87 8.26 24 4957 — pound mpk) 5 PO (5 — 9270 1.67 4.27 — — 24 68263 279 mpk) “—” means that not tested or no data was obtained.

[0360] Conclusion: The compounds of the present disclosure exhibit longer half-life, lower clearance rate and higher drug exposure, and have good pharmacokinetic properties in vivo.

Experimental Embodiment 6: Pharmacokinetic Evaluation in Cynomolgus Monkeys

Experimental Method

[0361] Test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 1 mg/mL, then filtered through a microporous membrane for next step. Male cynomolgus monkeys were selected and administered intravenously with the candidate compound solution at a dose of 1 mg/kg. Test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a nearly clear solution of 1 mg/mL, then filtered with a microporous membrane for next step. Male cynomolgus monkeys were selected and orally administered with the candidate compound solution at a dose of 5 mg/kg. Whole blood was collected for a certain period of time, and plasma was prepared, then drug concentration was detected by LC-MS/MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).

[0362] Test Results:

[0363] The experimental results are shown in Table 6.

TABLE-US-00006 TABLE 6 PK test results of compound in plasma V.sub.dss Cl AUC.sub.0-last C.sub.0 C.sub.max T.sub.max T.sub.1/2 (L/ (mL/min/ T.sub.last (nM .Math. F Parameter (nM) (nM) (h) (h) kg) kg) (h) h) (%) Com- IV (1 2291 — — 3.60 1.52 16.8 ND 2440 — pound mpk) 5 PO (5 — 4503 1.17 1.35 — — 12 14024 115 mpk) ND: Not detected “—” means that not tested or no data was obtained.

[0364] Conclusion: The compounds of the present disclosure exhibit longer half-life, lower clearance rate and higher drug exposure, and have good pharmacokinetic properties in vivo.

Experimental Embodiment 7: In Vivo Pharmacodynamics Study of BALB/c Nude Mice Model with Human Non-Small Cell Lung Cancer NCI-H1703 Cell Subcutaneous Xenograft Tumor

[0365] Experimental purpose: To study the in vivo pharmacodynamics of the test compounds in BALB/c nude mice model with human non-small cell lung cancer NCI-H1703 cell subcutaneous xenograft tumor

[0366] Experimental animals: Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams; supplier: Shanghai Sippe-Bk Lab Animal Co., Ltd.

Experimental Methods and Steps

[0367] 7.1 Cell Culture

[0368] Human non-small cell lung cancer NCI-H1703 cells were cultured in vitro in RPMI1640 medium with 10% fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin at 37° C. in a 5% CO.sub.2 incubator. Conventional digestion with trypsin-EDTA was performed twice a week for passage. When the cell saturation was 80%-90% and the number reached the requirement, the cells were collected, counted, and seeded.

[0369] 7.2 Tumor Cell Seeding (Tumor Seeding)

[0370] 0.2 mL (5×10.sup.6 cells) NCI-H1703 cells (added with matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached about 130 mm.sup.3.

[0371] 7.3 Preparation of Test Sample:

[0372] Compound 5 was prepared into 3 mg/mL, 6 mg/mL, 9 mg/mL suspension solutions, and compound 17 was prepared into 9 mg/mL suspensions, and the solvent was 0.5% HPMC+1% Tween 80.

[0373] 7.4 Tumor Measurements and Experimental Indicators

[0374] Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5a×b.sup.2, wherein a and b represent the long and short diameters of the tumor, respectively.

[0375] The antitumor efficacy of the compounds 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: means RTV in the treatment group; C.sub.RTV: means RTV in the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement. The calculation formula is RTV=V.sub.t/V.sub.0, wherein V.sub.0 is the tumor volume measured at the time of group administration (i.e., day 0), and V.sub.t is the tumor volume at one measurement. Data of the same day was taken for T.sub.RTV and C.sub.RTV.

[0376] TGI (%), reflecting tumor growth inhibition rate. TGI (%)=[1−(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-average volume at the beginning of treatment in the solvent control group tumor volume)]×100%. After the experiment, the tumor weight was detected, and the T/weight percentage was calculated. T weight and C weight represent the tumor weight of the administration group and the solvent control group, respectively.

[0377] 7.5 Statistical Analysis

[0378] Statistical analysis was performed using SPSS software based on RTV data at the end of the experiment. The treatment group showed the best treatment effect on the 21st day after dosing at the end of the experiment, therefore statistical analysis was performed based on this data to evaluate the difference between groups. T-test was used to analyze the comparison between two groups, and one-way ANOVA was used to analyze the comparison between three or more groups. If the variance was homogeneous (F value had no significant difference), Tukey's method was used for analysis. If the variance was not homogeneous (F value had significant difference), the Games-Howell method was used to test. p<0.05 was considered a significant difference.

[0379] 7.6 Experimental Conclusions and Discussion

[0380] In this experiment, compound 5 at doses of 60 mg/kg and 90 mg/kg (dosed twice a day), and compound 17 at a dose of 90 mg/kg (dosed twice a day), compared with the blank control have a significant inhibitory effect. Compound 5 has a certain tumor inhibitory effect at a dose of 30 mg/kg (administered twice a day). The therapeutic effects of compound 5 are all dose-dependent, and the experimental results are shown in Table 7. Results of tumor weights and tumor photographs on day 21 are shown in Table 8 and FIG. 1.

TABLE-US-00007 TABLE 7 Tumor inhibitory effect of compounds on human lung cancer NCI-H1703 xenograft tumor model Tumor Tumor volume volume RTV T/C (mm.sup.3).sup.a (mm.sup.3).sup.a (Day TGI (%).sup.b (%).sup.b Group (Day 0) (Day 21) 21) (Day 21) (Day 21) p.sup.c Blank control group 131 ± 11 1200 ± 54  9.55 ± 0.69 — — — Compound 5 131 ± 10 979 ± 86 7.57 ± 0.53 20.6 79.3 0.202 (30 mg/kg) Compound 5 131 ± 10 427 ± 64 3.31 ± 0.51 72.3 34.7 <0.001 (60 mg/kg) Compound 5 130 ± 10 351 ± 64 2.64 ± 0.45 79.4 27.7 <0.001 (90 mg/kg) Compound 17 130 ± 13 435 ± 94 3.19 ± 0.46 71.6 33.4 <0.001 (90 mg/kg) Notes: .sup.aMean ± SEM, n = 9 (compound 5) or n = 6 (compound 17). .sup.bTumor growth inhibition was calculated from T/C and TGI (TGI (%) = [1-(T.sub.21-T.sub.0)/(V.sub.21-V.sub.0)] x 100). .sup.cp-value was obtained by analyzing relative tumor volume (RTV) using one-way ANOVA.

TABLE-US-00008 TABLE 8 Tumor weights and photographs in each experimental group Tumor weight (g).sup.a T/C.sub.weight.sup.b Corresponding Group (PG-D21) (%) p-value .sup.c photographs Blank control group 1.296 ± 0.060 — — First row Compound 5 (30 mg/kg) 1.031 ± 0.095 79.6 0.301 Second row Compound 5 (60 mg/kg) 0.467 ± 0.078 36.0 <0.001 Third row Compound 5 (90 mg/kg) 0.379 ± 0.069 29.2 <0.001 Fourth row Compound 17 (90 mg/kg) 0.466 ± 0.103 35.9 <0.001 Fifth row Note: .sup.aMean ± SEM, n = 9 (compound 5) or n = 6 (compound 17). .sup.bTumor growth inhibition was calculated from T/C.sub.weight = TW.sub.treatment/TW.sub.solvent. .sup.c The p value was analyzed by one-way ANOVA and solvent treatment group, if there was a significant difference in the F value, Games-Howell method should be used to analyze.

[0381] Conclusion: In this experiment, compound 5 at the dose of 60 mg/kg and 90 mg/kg, and compound 17 at the dose of 90 mg/kg, have a significant tumor inhibitory effect compared with the control group, and the curative effect of compound 5 is dose-dependent. In this experiment, the tumor-bearing mice show good tolerance to the compounds, and there is no significant weight loss in all treatment groups.