Quinolino-pyrrolidin-2-one derivative and application thereof

Abstract

Disclosed are a series of quinolino-pyrrolidin-2-one compounds, and application thereof in preparation of drugs for ATM inhibitor-related diseases. The present disclosure specifically relates to a derivative compound represented by formula (I), tautomers thereof or pharmaceutically acceptable compositions thereof. ##STR00001##

Claims

1. A compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, ##STR00110## wherein, E is selected from —N(R.sub.5)—, —O— and —C(R.sub.6)(R.sub.7)—; R.sub.1 is selected from C.sub.1-3 alkyl, C.sub.1-3 alkoxy and C.sub.3-6 cycloalkyl, wherein the C.sub.1-3 alkyl, C.sub.1-3 alkoxy and C.sub.3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R.sub.a; R.sub.2 is selected from H, F, Cl, Br, I, OH and NH.sub.2; R.sub.3 is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, C.sub.1-3 alkyl and C.sub.1-3 alkoxy, wherein the C.sub.1-3 alkyl and C.sub.1-3 alkoxy are optionally substituted with 1, 2 or 3 R.sub.b; R.sub.4 is selected from C.sub.1-6 alkyl and N(R.sub.c)(R.sub.d); R.sub.5 is selected from H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-C═O—, C.sub.1-6 alkyl-O—C═O— and C.sub.3-6 cycloalkyl-C═O—, wherein the C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-C═O—, C.sub.1-6 alkyl-O—C═O— and C.sub.3-6 cycloalkyl-C═O— are optionally substituted with 1, 2 or 3 R.sub.e; R.sub.6 and R.sub.7 are each independently selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, C.sub.1-6 alkyl and C.sub.1-6 alkoxy, wherein the C.sub.1-6 alkyl or C.sub.1-6 alkoxy are optionally substituted with 1, 2 or 3 R.sub.f; L.sub.1 is selected from a single bond, —(CH.sub.2).sub.m— and —(CH.sub.2).sub.m—O—; m is selected from 1, 2, 3 and 4; ring B is selected from phenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5-to 6-membered heteroaryl are optionally substituted with 1, 2 or 3 R.sub.g; R.sub.a and R.sub.b are each independently selected from F, Cl, Br, I, OH and NH.sub.2; R.sub.c and R.sub.d are each independently selected from H, C.sub.1-3 alkyl and C.sub.3-6 cycloalkyl, wherein the C.sub.1-3 alkyl and C.sub.3-6 cycloalkyl are each independently selected from 1, 2 or 3 R; or, R.sub.c and R.sub.d together with the N atom to which they are attached form 4- to 6-membered heterocycloalkyl optionally substituted by 1, 2 or 3 R; R.sub.e, R.sub.f and R.sub.g are each independently selected from F, Cl, Br, I, OH and NH.sub.2; Each R is independently selected from F, Cl, Br, I, OH and NH.sub.2; and the 5- to 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl are each independently comprise 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from —NH—, —O—, —S— and N.

2. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.1 is selected from CH.sub.3, CH.sub.2CH.sub.3 and cyclopropyl, and the CH.sub.3, CH.sub.2CH.sub.3 and cyclopropyl are optionally substituted with 1, 2 or 3 R.sub.a.

3. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 2, wherein R.sub.1 is selected from CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3 and cyclopropyl.

4. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.3 is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, CH.sub.3, CH.sub.2CH.sub.3 and ##STR00111## and the CH.sub.3, CH.sub.2CH.sub.3 and ##STR00112## are optionally substituted with 1, 2 or 3 R.sub.b.

5. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 4, wherein R.sub.3 is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3 and ##STR00113##

6. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.c and R.sub.d are each independently selected from CH.sub.3, CH.sub.2CH.sub.3 and cyclopropyl.

7. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in a claim 1, wherein R.sub.c and R.sub.d together with the N atom to which they are attached form pyrrolidyl and piperidinyl, wherein the pyrrolidyl and piperidinyl are optionally substituted with 1, 2 or 3 R.

8. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 7, wherein R.sub.c and R.sub.d together with the N atom to which they are attached form ##STR00114##

9. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 8, wherein R.sub.4 is selected from CH.sub.3, CH.sub.2CH.sub.3, ##STR00115##

10. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.5 is selected from H, CH.sub.3, CH.sub.3CH.sub.2, CH(CH.sub.3).sub.2, cyclopropyl, CH.sub.3OC═O—, CH(CH.sub.3).sub.2OC═O—, CH.sub.3C═O—, and cyclopropyl-C═O—, and the CH.sub.3, CH.sub.3CH.sub.2, CH(CH.sub.3).sub.2, cyclopropyl, CH.sub.3OC═O—, CH(CH.sub.3).sub.2OC═O—, CH.sub.3C═O—, and cyclopropyl-C═O— are optionally substituted with 1, 2 or 3 R.sub.e.

11. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 10, wherein R.sub.5 is selected from H, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.3CH.sub.2, CH.sub.2FCH.sub.2, CHF.sub.2CH.sub.2, CF.sub.3CH.sub.2, CH(CH.sub.3).sub.2, cyclopropyl, CH.sub.3OC═O—, CH(CH.sub.3).sub.2OC═O—, CH.sub.3C═O—, and cyclopropyl-C═O—.

12. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.6 and R.sub.7 are each independently selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, CH.sub.3, CH.sub.3CH.sub.2, CH(CH.sub.3).sub.2 and ##STR00116## and the CH.sub.3, CH.sub.3CH.sub.2, CH(CH.sub.3).sub.2 and ##STR00117## are optionally substituted with 1, 2 or 3 R.sub.f.

13. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 12, wherein R.sub.6 and R.sub.7 are each independently selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, CH.sub.3CH.sub.2, CH(CH.sub.3).sub.2 and ##STR00118##

14. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 13, wherein E is selected from —O—, —CF.sub.2—, —N(CH.sub.3)—, —NH—, ##STR00119##

15. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein Li is selected from a single bond, —(CH.sub.2)—O— and —(CH.sub.2).sub.3—O—.

16. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring B is selected from phenyl, pyridyl, pyrazolyl, indazolyl and imidazolyl, and the phenyl, pyridyl, pyrazolyl, indazolyl and imidazolyl are optionally substituted with 1, 2 or 3 R.sub.g.

17. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 16, wherein ring B is selected from ##STR00120## and the ##STR00121## are optionally substituted with 1, 2 or 3 R.sub.g.

18. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 17, wherein ring B is selected from ##STR00122##

19. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 15, wherein R.sub.4-L.sub.1- is selected from CH.sub.3, CH.sub.3OCH.sub.2—, ##STR00123##

20. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 1, selected from ##STR00124## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and L.sub.1 are as defined in claim 1.

21. A compound represented by the following formulas, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##

22. The compound, isomer thereof or pharmaceutically acceptable salt thereof as defined in claim 21, selected from ##STR00131##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: relative weight change;

(2) FIG. 2: tumor growth curve.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(3) The present disclosure will be described in detail with the following examples, but not imply any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and the specific embodiments thereof are also disclosed therein. For a person skilled in the art, without departing from the spirit and scope of the present disclosure, all the variations and improvements made to the specific embodiments of the present disclosure would have been obvious.

Intermediate A

(4) ##STR00029##

Synthetic Route

(5) ##STR00030##

Step 1: Synthesis of Intermediate A

(6) DMF (95.00 mg, 1.30 mmol, 0.1 mL) was added to a solution of compound A-1 (34 g, 126.37 mmol) in SOCl.sub.2 (200 mL), and the reaction solution was stirred at 80° C. for 16 hours. After completion of the reaction, SOCl.sub.2 was removed under reduced pressure to obtain a crude A, which was directly used in the next step.

(7) MS m/z: 286.7[M+H].sup.+

(8) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 7.94 (dd, J=2.3, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H)

Intermediate B

(9) ##STR00031##

Synthetic Route

(10) ##STR00032##

Step 1: Synthesis of Compound B-2

(11) At 0° C. and under nitrogen protection, a solution of NBS (30.12 g, 169.22 mmol) in DMF (100 mL) was added to a solution of B-1 (25 g, 161.16 mmol) in DMF (100 mL), and the reaction system was stirred at 30° C. for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the reaction solvent, then slurried for 30 minutes with water (100 mL), and then washed with acetonitrile (10 mL) to obtain B-2.

(12) MS m/z: 233.8[M+H].sup.+

(13) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (br d, J=7.88 Hz, 1H), 6.69 (br d, J=11.38 Hz, 1H)

Step 2: Synthesis of Compound B-6

(14) In a round-bottom flask, nitromethane (18 g, 294.89 mmol, 15.93 mL) (B-3) was added slowly to a solution of NaOH (17.69 g, 442.33 mmol) in H.sub.2O (100 mL), and the internal temperature was kept at 30° C. Then the mixture was heated to 40° C. and stirred for 30 minutes, and cooled. Then another part of nitromethane (18.00 g, 294.89 mmol, 15.93 mL) was slowly added, the reaction system was heated to 45° C. and stirred for 30 minutes, and then raised to 50° C.-55° C. and stirred for 5 minutes to obtain a mixed solution of B-6, which was directly used in the next step.

Step 3: Synthesis of Compound B-4

(15) A mixed solution of B-6 was cooled to 30° C., and ice (80 g) and concentrated hydrochloric acid (15 mL) were added. The above-mentioned mixed solution was added to a solution of B-2 (34.3 g, 146.57 mmol) in HCl (12 M, 90 mL) and H.sub.2O (200 mL), and stirred at 30° C. for 12 h. A solid was precipitated, and filtered. The filter cake was collected, and then washed with acetonitrile (50 mL) to obtain compound B-4.

(16) MS m/z: 304.7[M+H].sup.+

(17) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.99 (br d, J=12.5 Hz, 1H), 8.23-8.13 (m, 1H), 8.08-7.96 (m, 1H), 7.88 (br d, J=10.5 Hz, 1H), 6.80 (br s, 1H)

Step 4: Synthesis of Compound B-5

(18) Under nitrogen protection, a solution of B-4 (44 g, 111.06 mmol) in acetic anhydride (397.79 g, 3.90 mol, 364.94 mL) was heated at 100° C. for 1 h, and then heating was discontinued. Sodium acetate (9.38 g, 114.39 mmol) was added, and refluxed at 150° C. for 15 minutes. Finally, another portion of sodium acetate (9.38 g, 114.39 mmol) was added, and the reaction system was refluxed at 150° C. for 1 h. After completion of the reaction, the solvent was removed by concentration. The residual solids were slurried with water (200 mL) for 1 h, then slurried with a mixed solution of EtOAc and methanol (55 mL, EtOAc:MeOH=10:1) for 1 h, and filtered to obtain compound B-5.

(19) MS m/z: 287.0[M+H].sup.+

(20) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 8.44 (d, J=7.5 Hz, 1H), 7.63 (br d, J=9.3 Hz, 1H)

Step 5: Synthesis of Intermediate B

(21) Except for using the corresponding raw materials, the intermediate B was prepared using the same method as in the preparation of compound A in Intermediate A.

(22) MS m/z: 304.7[M+H].sup.+

Intermediate C

(23) ##STR00033##

Synthetic Route

(24) ##STR00034##

Step 1: Synthesis of Compound C-2

(25) Except for using the corresponding raw materials, the compound C-2 was prepared using the same method as in the preparation of compound B-2 in Intermediate B.

(26) MS m/z: 249.8[M+H].sup.+

(27) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (br s, 1H), 7.01 (br s, 1H)

Step 2: Synthesis of Compound C-3

(28) Except for using the corresponding raw materials, the compound C-3 was prepared using the same method as in the preparation of compound B-4 in Intermediate B.

(29) MS m/z: 320.8[M+H].sup.+

(30) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.71-13.60 (m, 1H), 12.91 (br s, 1H), 8.26-8.01 (m, 3H), 6.80 (br s, 1H)

Step 3: Synthesis of Compound C-4

(31) Except for using the corresponding raw materials, the compound C-4 was prepared using the same method as in the preparation of compound B-5 in Intermediate B.

(32) MS m/z: 302.7[M+H].sup.+

(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.29 (br s, 1H), 8.46 (s, 1H), 7.94 (s, 1H)

Step 4: Synthesis of Intermediate C

(34) Except for using the corresponding raw materials, the intermediate C was prepared using the same method as in the preparation of compound A in Intermediate A.

(35) MS m/z: 320.7[M+H].sup.+

Example 1: Compound 1

(36) ##STR00035##

Synthetic Route

(37) ##STR00036##

Step 1: Synthesis of Compound 1-A

(38) n-BuLi (2.5 M, 765.23 μL) was slowly added dropwise to a solution of DIPA (193.58 mg, 1.91 mmol, 270.37 μL) in THF (1 mL) at −60° C., and stirred for 0.5 h. Then methyl tetrahydropyran-4-carboxylate (300.88 mg, 2.09 mmol, 278.59 μL) was added dropwise at −60° C. and stirred for 1 h, and a solution of intermediate A (500 mg, 1.74 mmol) in THF (4 mL) was added and stirred at −60° C. for 2 h. After completion of the reaction, the reaction was quenched by adding 20 mL of saturated NH.sub.4Cl solution at 0° C., and extracted with EtOAc (30 mL, 10 mL*3). The organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (0 to 10% THF/PE) to obtain compound 1-A.

(39) MS m/z: 394.9[M+H].sup.+

(40) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 7.88 (dd, J=2.0, 9.0 Hz, 1H), 4.00-3.89 (m, 4H), 3.69 (s, 3H), 2.52-2.46 (m, 2H), 2.43-2.31 (m, 2H)

Step 2: Synthesis of Compound 1-B

(41) Zn (330.92 mg, 5.06 mmol) and NH.sub.4Cl (270.70 mg, 5.06 mmol) were added to a solution of compound 1-A (200 mg, 506.07 μmol) in H.sub.2O (10 mL) and THF (10 mL). The reaction solution was stirred at 70° C. for 0.5 h. After completion of the reaction, the reaction solution was filtered through celite. The filtrate was extracted with EtOAc (90 mL, 30 mL*3). The organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (0 to 10% THF/DCM) to obtain compound 1-B.

(42) MS m/z: 332.8[M+H].sup.+

(43) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.74 (s, 1H), 8.23 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.69 (dd, J=2.0, 9.0 Hz, 1H), 4.48-4.40 (m, 2H), 4.01 (dd, J=5.1, 11.7 Hz, 2H), 2.68 (dt, J=5.1, 13.5 Hz, 2H), 1.75 (br d, J=14.3 Hz, 2H)

Step 3: Synthesis of Compound 1-C

(44) Mel (1.350 g, 9.51 mmol, 592.11 μL), TBAB (9.68 mg, 30.01 μmol) and NaOH (24.01 mg, 600.28 μmol) were added to a mixed solution of compound 1-B (100 mg, 300.14 μmol) in DCM (5 mL) and H.sub.2O (5 mL), and stirred at 25° C. for 21 h. After completion of the reaction, the reaction system was added with 10 mL of water at room temperature to quench the reaction, and extracted with DCM (30 mL, 10 mL*3). The organic phase was combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (0 to 10% THF/DCM) to obtain compound 1-C.

(45) MS m/z: 346.9[M+H].sup.+

(46) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.68 (dd, J=2.1, 9.1 Hz, 1H), 4.48 (dt, J=2.1, 12.2 Hz, 2H), 4.00 (dd, J=5.1, 11.6 Hz, 2H), 3.38 (s, 3H), 2.67 (dt, J=5.3, 13.4 Hz, 2H), 1.66 (br d, J=14.3 Hz, 2H)

Step 4: Synthesis of Compound 1-D

(47) Under nitrogen protection, 1,4-dioxane (3 mL) and H.sub.2O (3 mL) were added to a reaction system of compound 1-C (70 mg, 201.61 μmol), 2-fluoropyridine-5-boracic acid (42.61 mg, 302.41 μmol), Pd(PPh.sub.3).sub.4 (23.30 mg, 20.16 μmol) and Na.sub.2CO.sub.3 (64.11 mg, 604.83 mol), and stirred at 80° C. for 3 h. After completion of the reaction, the reaction system was added with H.sub.2O (20 mL) and EtOAc (30 mL), and filtered through celite. The organic phase was collected, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (0 to 30% THF/DCM) to obtain compound 1-D.

(48) MS m/z: 364.0[M+H].sup.+

(49) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.56 (d, J=2.1 Hz, 1H), 8.26 (d, J=8.9 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.11 (dt, J=2.5, 8.0 Hz, 1H), 7.79 (dd, J=1.8, 8.8 Hz, 1H), 7.12 (dd, J=3.0, 8.4 Hz, 1H), 4.50 (br t, J=11.3 Hz, 2H), 4.00 (dd, J=4.9, 11.7 Hz, 2H), 3.41 (s, 3H), 2.74 (dt, J=5.3, 13.4 Hz, 2H), 1.72 (br d, J=14.1 Hz, 2H)

Step 5: Synthesis of Compound 1

(50) At 0° C. and under nitrogen protection, a solution of compound 3-dimethylamino-1-propanol (34.39 mg, 333.34 μmol, 38.99 μL) in DMF (2 mL) was added with NaH (26.67 mg, 666.68 μmol, 60% purity), and then a solution of compound 1-D (61.45 mg, 166.67 μmol) in DMF (2 mL) was added, and stirred at 27° C. for 2.5 h. At 0° C., the reaction system was added with 50 mL of water to quench the reaction, and extracted with DCM/i-prOH (5/1) (10 mL*3). The organic phase was combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was subjected to column chromatography (0 to 10% MeOH/DCM (adding aqueous ammonia)) to obtain compound 1.

(51) MS m/z: 447.2[M+H].sup.+

(52) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.88 (dd, J=2.5, 8.6 Hz, 1H), 7.75 (dd, J=1.7, 8.8 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.49-4.34 (m, 4H), 3.94 (dd, J=4.9, 11.6 Hz, 2H), 3.35 (s, 3H), 2.71 (dt, J=5.1, 13.4 Hz, 2H), 2.50-2.43 (m, 2H), 2.25 (s, 6H), 2.02-1.94 (m, 2H), 1.65 (br d, J=14.0 Hz, 2H)

Example 2: Compound 2

(53) ##STR00037##

Synthetic Route

(54) ##STR00038##

Step 1: Synthesis of Compound 2

(55) Under nitrogen protection, 1,4-dioxane (3 mL) was added to a reaction system of compound 1-C (200 mg, 576.03 μmol), (1-methyl-1H-pyrazol)-4-boracic acid (179.78 mg, 864.04 μmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (47.04 mg, 57.60 μmol) and potassium acetate (169.59 mg, 1.73 mmol), and stirred at 80° C. for 18 h. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (0 to 10% THF/DCM) to obtain compound 2.

(56) MS m/z: 349.1[M+H].sup.+

(57) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 8.13 (d, J=8.9 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.75 (dd, J=1.8, 8.8 Hz, 1H), 4.51 (dt, J=2.1, 12.2 Hz, 2H), 4.04-3.98 (m, 5H), 3.38 (s, 3H), 2.81-2.70 (m, 2H), 1.69 (br d, J=14.3 Hz, 2H)

Example 3: Compound 3

(58) ##STR00039##

Synthetic Route

(59) ##STR00040##

Step 1: Synthesis of Compound 3-C

(60) Acetonitrile (10 mL) was added to a flask of 3-A (200 mg, 1.59 mmol), 3-B (225.80 mg, 1.62 mmol, 146.62 μL) and K.sub.2CO.sub.3 (660.37 mg, 4.78 mmol), and stirred at 80° C. for 12 h. The system was filtered by adding methanol (50 mL), and then the solvent was removed from the filtrate under reduced pressure. The residual solid was added to dichloromethane (50 mL), filtered, and concentrated under reduced pressure to obtain 3-C.

(61) MS m/z: 147.9[M+H].sup.+

(62) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 5.28-5.07 (m, 1H), 3.72-3.57 (m, 2H), 3.04-2.87 (m, 2H), 2.73-2.56 (m, 3H), 2.47-2.39 (m, 1H), 2.28-1.90 (m, 2H), 1.82-1.69 (m, 2H)

Step 2: Synthesis of Compound 3

(63) Except for using the corresponding raw materials, the compound 3 was prepared using the same method as in the preparation of compound 1 in Example 1.

(64) MS m/z: 491.2[M+H].sup.+

(65) ee: 100%, RT=1.955 min (column type: Chiralpak AD-3 50×3 mm I.D., 3 m; mobile phase: A: CO.sub.2, B: ethanol (0.05% diethylamine); gradient: the proportion of B in mobile phase rises from 5% to 40% within 2.5 minutes and keeps at 40% for 0.35 minutes, and then the proportion of mobile phase is reduced from 40% to 5% within 0.15 minutes; flow rate: 2.5 mL/min, column temperature: 40° C.)

(66) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.93 (dd, J=2.5, 8.5 Hz, 1H), 7.80 (dd, J=1.9, 8.9 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.28-5.09 (m, 1H), 4.53-4.42 (m, 4H), 3.99 (dd, J=4.8, 11.5 Hz, 2H), 3.40 (s, 3H), 2.98-2.85 (m, 2H), 2.84-2.77 (m, 1H), 2.75 (br d, J=5.0 Hz, 1H), 2.74-2.66 (m, 3H), 2.52-2.44 (m, 1H), 2.25-1.98 (m, 4H), 1.70 (br d, J=14.3 Hz, 2H)

Example 4: Compound 4

(67) ##STR00041##

Synthetic Route

(68) ##STR00042##

Step 1: Synthesis of Compound 4-C

(69) Except for using the corresponding raw materials, the compound 4-C was prepared using the same method as in the preparation of compound 3-C in Example 3.

(70) MS m/z: 147.9[M+H].sup.+

(71) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 5.30-5.08 (m, 1H), 3.64 (t, J=6.28 Hz, 2H), 3.04-2.89 (m, 2H), 2.62 (ddd, J=9.66, 5.52, 2.38 Hz, 3H), 2.42 (td, J=8.16, 7.03 Hz, 1H), 2.29-1.94 (m, 2H), 1.83-1.70 (m, 2H)

Step 2: Synthesis of Compound 4

(72) Except for using the corresponding raw materials, the compound 4 was prepared using the same method as in the preparation of compound 1 in Example 1.

(73) MS m/z: 491.3[M+H].sup.+

(74) ee: 100%, retention time=1.952 min (column type: Chiralpak AD-3 50×3 mm I.D., 3 m; mobile phase: A: CO.sub.2, B: ethanol (0.05% diethylamine); gradient: 5%-40% B, 2.5 minutes 40%-40% B, 0.35 minutes; 40%-5% B, 0.15 minutes; flow rate: 2.5 mL/min; column temperature: 40° C.)

(75) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 7.93 (dd, J=2.4, 8.7 Hz, 1H), 7.83-7.77 (m, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.28-5.08 (m, 1H), 4.54-4.42 (m, 4H), 3.99 (br dd, J=4.6, 11.7 Hz, 2H), 3.40 (s, 3H), 2.98-2.85 (m, 2H), 2.84-2.66 (m, 5H), 2.53-2.43 (m, 1H), 2.26-1.97 (m, 4H), 1.71 (br s, 2H)

Example 5: Compound 5

(76) ##STR00043##

Synthetic Route

(77) ##STR00044##

Step 1: Synthesis of Compound 5-C

(78) Except for using the corresponding raw materials, the compound 5-C was prepared using the same method as in the preparation of compound 3-C in Example 3.

(79) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.84-4.56 (m, 1H), 3.83-3.70 (m, 3H), 3.52 (t, J=6.5 Hz, 1H), 2.64-2.57 (m, 3H), 2.10-04 (m, 1H), 1.93-1.87 (m, 2H), 1.87-1.81 (m, 2H), 1.74-1.68 (m, 2H)

Step 2: Synthesis of Compound 5

(80) Except for using the corresponding raw materials, the compound 5 was prepared using the same method as in the preparation of compound 1 in Example 1.

(81) MS m/z: 505.3[M+H].sup.+

(82) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.93 (dd, J=2.5, 8.8 Hz, 1H), 7.80 (dd, J=1.8, 8.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.80-4.59 (m, 1H), 4.49 (br t, J=11.4 Hz, 2H), 4.43 (t, J=6.5 Hz, 2H), 3.99 (dd, J=4.9, 11.7 Hz, 2H), 3.40 (s, 3H), 2.76 (dt, J=5.1, 13.5 Hz, 2H), 2.63 (br s, 2H), 2.56 (br t, J=7.4 Hz, 2H), 2.42 (br s, 2H), 2.08-1.99 (m, 2H), 1.88 (br d, J=4.5 Hz, 4H), 1.70 (br d, J=14.1 Hz, 2H)

Example 6: Compound 6

(83) ##STR00045##

Synthetic Route

(84) ##STR00046##

Step 1: Synthesis of Compound 6-C

(85) Except for using the corresponding raw materials, the compound 6-C was prepared using the same method as in the preparation of compound 3-C in Example 3.

(86) MS m/z: 155.9 [M+H].sup.+

Step 2: Synthesis of Compound 6

(87) Except for using the corresponding raw materials, the compound 6 was prepared using the same method as in the preparation of compound 1 in Example 1.

(88) MS m/z: 499.3[M+H].sup.+

(89) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 7.93 (dd, J=2.5, 8.5 Hz, 1H), 7.80 (dd, J=1.9, 8.9 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.49 (br t, J=11.2 Hz, 2H), 4.39 (t, J=6.5 Hz, 2H), 3.99 (dd, J=4.8, 11.5 Hz, 2H), 3.40 (s, 3H), 2.94-2.88 (m, 2H), 2.76 (dt, J=5.0, 13.4 Hz, 2H), 2.18-2.10 (m, 2H), 1.94-1.87 (m, 2H), 1.70 (br d, J=14.3 Hz, 2H), 0.50-0.39 (m, 8H)

Example 7: Compound 7

(90) ##STR00047##

Synthetic Route

(91) ##STR00048##

Step 1: Synthesis of Compound 7-A

(92) Except for using the corresponding raw materials, the compound 7-A was prepared using the same method as in the preparation of compound 1-A in Example 1.

(93) MS m/z: 443.0[M+H].sup.+

(94) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.79 (s, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 7.88 (dd, J=1.9, 8.9 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 2.66-2.57 (m, 2H), 2.53-2.39 (m, 3H), 2.38-2.27 (m, 1H), 2.21-2.09 (m, 2H), 1.08 (t, J=7.2 Hz, 3H)

Step 2: Synthesis of Compound 7-B

(95) Except for using the corresponding raw materials, the compound 7-B was prepared using the same method as in the preparation of compound 1-B in Example 1.

(96) MS m/z: 366.8[M+H].sup.+

(97) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.78 (s, 1H), 8.05-8.02 (m, 2H), 7.70 (dd, J=2.0, 9.0 Hz, 1H), 2.92-2.80 (m, 1H), 2.78-2.65 (m, 3H), 2.17 (br s, 2H), 1.94 (br d, J=12.3 Hz, 2H)

Step 3: Synthesis of Compound 7-C

(98) Except for using the corresponding raw materials, the compound 7-C was prepared using the same method as in the preparation of compound 1-C in Example 1.

(99) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.68 (dd, J=1.8, 9.0 Hz, 1H), 3.38 (s, 3H), 2.94-2.75 (m, 2H), 2.74-2.63 (m, 2H), 2.15 (br s, 2H), 1.89-1.79 (m, 2H)

Step 4: Synthesis of Compound 7-D

(100) Except for using the corresponding raw materials, the compound 7-D was prepared using the same method as in the preparation of compound 1-D in Example 1.

(101) MS m/z: 398.0[M+H].sup.+

(102) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.10 (dt, J=2.5, 8.0 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.82 (dd, J=2.0, 8.8 Hz, 1H), 7.11 (dd, J=2.9, 8.4 Hz, 1H), 3.41 (s, 3H), 2.95-2.73 (m, 4H), 2.15 (br d, J=5.3 Hz, 2H), 1.90 (br d, J=11.5 Hz, 2H)

Step 5: Synthesis of Compound 7

(103) Except for using the corresponding raw materials, the compound 7 was prepared using the same method as in the preparation of compound 1 in Example 1.

(104) MS m/z: 481.2[M+H].sup.+

(105) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (s, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.91 (dd, J=2.6, 8.7 Hz, 1H), 7.81 (dd, J=1.9, 8.9 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 3.40 (s, 3H), 2.96-2.74 (m, 4H), 2.58 (br t, J=7.5 Hz, 2H), 2.35 (s, 6H), 2.20-2.11 (m, 2H), 2.10-2.01 (m, 2H), 1.88 (br d, J=9.8 Hz, 2H)

Example 8: Compound 8

(106) ##STR00049##

Synthetic Route

(107) ##STR00050## ##STR00051##

Step 1: Synthesis of Compound 8-A

(108) Except for using the corresponding raw materials, the compound 8-A was prepared using the same method as in the preparation of compound 1-A in Example 1.

(109) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.74 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.88 (dd, J=2.0, 9.0 Hz, 1H), 4.02 (br s, 2H), 3.66 (s, 3H), 3.36-3.22 (m, 2H), 2.53 (br s, 2H), 2.28-2.18 (m, 2H), 1.48 (s, 9H)

Step 2: Synthesis of Compound 8-B

(110) Except for using the corresponding raw materials, the compound 8-B was prepared using the same method as in the preparation of compound 1-B in Example 1.

(111) MS: m z: 432.0[M+H].sup.+

(112) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.73 (s, 1H), 8.07 (s, 1H), 8.02-7.98 (m, 2H), 7.68 (dd, J=2.0, 9.0 Hz, 1H), 4.30-4.01 (m, 2H), 3.78-3.72 (m, 2H), 2.49 (br s, 2H), 1.78 (br d, J=13.8 Hz, 2H), 1.62 (s, 9H)

Step 3: Synthesis of Compound 8-C

(113) Except for using the corresponding raw materials, the compound 8-C was prepared using the same method as in the preparation of compound 1-C in Example 1.

(114) MS m/z: 446.0[M+H].sup.+

(115) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.03-7.99 (m, 2H), 7.67 (dd, J=2.1, 9.2 Hz, 1H), 4.30-4.02 (m, 2H), 3.75 (br d, J=6.8 Hz, 2H), 3.38 (s, 3H), 2.48 (br s, 2H), 1.69 (br d, J=13.1 Hz, 2H), 1.57 (s, 9H)

Step 4: Synthesis of Compound 8-D

(116) Except for using the corresponding raw materials, the compound 8-D was prepared using the same method as in the preparation of compound 1-D in Example 1.

(117) MS m/z: 463.2[M+H].sup.+

(118) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.06 (dt, J=2.6, 8.0 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.78 (dd, J=1.8, 8.8 Hz, 1H), 7.06 (dd, J=3.0, 8.5 Hz, 1H), 4.29-4.02 (m, 2H), 3.90-3.72 (m, 2H), 3.41 (s, 3H), 2.55 (br s, 2H), 1.76 (br d, J=14.1 Hz, 2H), 1.50 (s, 9H)

Step 5: Synthesis of Compound 8-E

(119) Except for using the corresponding raw materials, the compound 8-E was prepared using the same method as in the preparation of compound 1 in Example 1.

(120) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (s, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.86 (dd, J=2.5, 8.5 Hz, 1H), 7.78 (dd, J=1.9, 8.9 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.41 (t, J=6.5 Hz, 2H), 3.81-3.77 (m, 2H), 3.39 (s, 3H), 2.57-2.52 (m, 2H), 2.50-2.45 (m, 2H), 2.28 (s, 6H), 2.03-1.96 (m, 2H), 1.74 (br d, J=13.6 Hz, 2H), 1.71-1.65 (m, 2H), 1.51 (s, 9H)

Step 6: Synthesis of Compound 8

(121) Trifluoroacetic acid (1 mL) was added to 8-E (100 mg, 183.26 μmol). The reaction solution was stirred at 20° C. for 1 h. Trifluoroacetic acid was removed under reduced pressure to obtain a crude, which was separated by preparative chromatography (acid, mobile phase: acetonitrile-water). Then ammonia water was added to adjust pH=8. The crude product was obtained by concentration under reduced pressure, and purified by column chromatography (0 to 10% MeOH/DCM) to obtain compound 8.

(122) MS m/z: 446.2[M+H].sup.+

(123) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.93 (dd, J=2.6, 8.6 Hz, 1H), 7.77 (dd, J=1.7, 8.8 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.42 (t, J=6.5 Hz, 2H), 3.74-3.65 (m, 2H), 3.38 (s, 3H), 3.04 (br dd, J=3.4, 12.3 Hz, 2H), 2.59 (dt, J=4.6, 13.3 Hz, 2H), 2.50-2.45 (m, 2H), 2.27 (s, 6H), 2.04-1.96 (m, 2H), 1.75 (br d, J=14.0 Hz, 2H)

Example 9: Compound 9

(124) ##STR00052##

Synthetic Route

(125) ##STR00053##

Step 1: Synthesis of Compound 9

(126) Aqueous formaldehyde solution (127.51 mg, 1.57 mmol, 116.98 μL, 37% purity) was added to a solution of compound 8 (70 mg, 157.11 μmol) in formic acid (3 mL), and the reaction solution was stirred at 60° C. for 23 h. After completion of the reaction, a crude product was obtained by concentration under reduced pressure. 20 ml of ammonia water was added, and a crude product was obtained by concentration under reduced pressure. The crude product was purified by column chromatography (0 to 6% MeOH/DCM) and then purified by preparative chromatography (neutral, mobile phase: acetonitrile-water) to obtain compound 9.

(127) MS m/z: 460.3[M+H].sup.+

(128) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67 (s, 1H), 8.52 (br s, 1H), 8.26 (br s, 1H), 8.19 (br d, J=8.8 Hz, 1H), 7.96 (br d, J=7.8 Hz, 1H), 7.76 (br d, J=8.5 Hz, 1H), 6.87 (br d, J=8.5 Hz, 1H), 4.41 (br t, J=6.1 Hz, 2H), 3.37 (s, 3H), 3.10-2.98 (m, 2H), 2.79 (br d, J=8.8 Hz, 4H), 2.51-2.45 (m, 2H), 2.27 (s, 9H), 2.05-1.94 (m, 2H), 1.76 (br d, J=12.8 Hz, 2H)

Example 10: Compound 10

(129) ##STR00054##

Synthetic Route

(130) ##STR00055##

Step 1: Synthesis of Compound 10-A

(131) Trifluoroacetic acid (3 mL) was added to compound 8-C (900 mg, 2.02 mmol), and the reaction solution was stirred at 20° C. for 0.5 h. After completion of the reaction, a crude product was obtained by concentration under reduced pressure. Ammonia water was added to adjust pH=9. Extraction with dichloromethane (90 mL, 30 mL*3) was performed, and the organic phase was concentrated under reduced pressure to obtain a crude product 10-A, which was directly used in the next step.

(132) MS m/z: 346.1[M+H].sup.+

(133) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.69 (dd, J=2.0, 9.0 Hz, 1H), 3.97-3.88 (m, 2H), 3.39 (s, 3H), 3.35 (br d, J=3.0 Hz, 2H), 2.94-2.86 (m, 2H), 1.84 (br d, J=14.6 Hz, 2H)

Step 2: Synthesis of Compound 10-B

(134) At 20° C. and under nitrogen protection, K.sub.2CO.sub.3 (1.20 g, 8.67 mmol) was added to a solution of compound 10-A (1 g, 2.89 mmol) and ethyl bromide (629.82 mg, 5.78 mmol, 431.38 μL) in acetonitrile (20 mL). The reaction solution was stirred at 60° C. for 1 h. The reaction was quenched by adding water (5 mL) at 20° C., then diluted with water (20 mL), extracted with EtOAc (90 mL, 30 mL*3). The organic phase was combined, washed with saturated sodium chloride (90 mL, 30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (0 to 5% MeOH/DCM) to obtain compound 10-B.

(135) MS m/z: 373.9[M+H].sup.+

(136) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.94 (s, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.76 (dd, J=2.3, 9.0 Hz, 1H), 3.30 (s, 3H), 2.92-2.75 (m, 4H), 2.56-2.53 (m, 1H), 2.48-2.39 (m, 3H), 1.80-1.64 (m, 2H), 1.14-1.08 (m, 3H)

Step 3: Synthesis of Compound 10-C

(137) Under nitrogen protection, an aqueous solution of compound 10-B (400 mg, 1.07 mmol), 2-fluoropyridine-5-boracic acid (301.19 mg, 2.14 mmol), Na.sub.2CO.sub.3 (226.55 mg, 2.14 mmol) and Pd(PPh.sub.3).sub.4 (123.50 mg, 106.87 μmol) in dioxane (18 mL) and H.sub.2O (2 mL) was stirred at 100° C. for 4 h. The reaction solvent was removed by concentration, and the crude product was subjected to column chromatography (0 to 5% MeOH/DCM) to obtain compound 10-C.

(138) MS m/z: 391.1[M+H].sup.+

Step 8: Synthesis of Compound 10

(139) At 20° C. and under nitrogen protection, compound 10-C (200 mg, 512.23 μmol) was added to a solution of 3-dimethylamino-1-propanol (105.69 mg, 1.02 mmol, 119.82 μL) and NaH (81.96 mg, 2.05 mmol, 60% purity) in DMF (10 mL), and the reaction solution was stirred for 2 h at 70° C. The reaction solution was quenched with water (2 mL) at 20° C., diluted by adding water (10 mL), and extracted with EtOAc (10 mL*3). The organic phase was combined, washed with saturated sodium chloride (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was subjected to column chromatography (0 to 5% MeOH/DCM) to obtain compound 10.

(140) MS m/z: 474.2[M+H].sup.+

(141) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.26-8.23 (m, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.98-7.89 (m, 1H), 7.80-7.71 (m, 1H), 6.88 (d, J=8.8 Hz, 1H), 4.42 (t, J=6.5 Hz, 2H), 3.37 (s, 3H), 3.03 (br s, 2H), 2.87 (br d, J=11.5 Hz, 2H), 2.76 (br s, 2H), 2.62 (q, J=7.1 Hz, 2H), 2.47 (s, 2H), 2.27 (s, 6H), 2.04-1.96 (m, 2H), 1.78 (br d, J=13.8 Hz, 2H), 1.17 (t, J=7.3 Hz, 3H)

Example 11: Compound 11

(142) ##STR00056##

Synthetic Route

(143) ##STR00057##

Step 1: Synthesis of Compound 11-C

(144) Except for using the corresponding raw materials, the compound 11-C was prepared using the same method as in the preparation of compound 3-C in Example 3.

(145) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.96-5.45 (m, 1H), 3.78-3.70 (m, 2H), 2.51 (t, J=5.6 Hz, 2H), 2.47-2.05 (m, 4H), 1.65 (quin, J=5.5 Hz, 2H), 1.52 (quin, J=5.5 Hz, 4H), 1.39 (br s, 2H)

Step 2: Synthesis of Compound 11

(146) Except for using the corresponding raw materials, the compound 11 was prepared using the same method as in the preparation of compound 10 in Example 10.

(147) MS m/z: 514.3[M+H].sup.+

(148) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67 (s, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.30 (d, J=1.3 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.97 (dd, J=2.5, 8.8 Hz, 1H), 7.77 (dd, J=1.8, 8.8 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.40 (t, J=6.5 Hz, 2H), 3.37 (s, 3H), 3.11-2.98 (m, 2H), 2.92-2.84 (m, 2H), 2.78 (br s, 2H), 2.62 (q, J=7.1 Hz, 2H), 2.54-2.33 (m, 8H), 2.08-1.95 (m, 2H), 1.77 (br d, J=13.8 Hz, 2H), 1.64-1.60 (m, 2H), 1.44 (br d, J=4.8 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H)

Example 12: Compound 12

(149) ##STR00058##

Synthetic Route

(150) ##STR00059##

Step 1: Synthesis of Compound 12-A

(151) Except for using the corresponding raw materials, the compound 12-A was prepared using the same method as in the preparation of compound 10-B in Example 10.

(152) MS m/z: 410.4 [M+H].sup.+

(153) 1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 7.67 (dd, J=2.0, 9.0 Hz, 1H), 6.21-5.85 (m, 1H), 3.36 (s, 3H), 3.33-3.25 (m, 2H), 3.00-2.87 (m, 4H), 2.65 (dt, J=4.6, 13.4 Hz, 2H), 1.73 (br d, J=14.6 Hz, 2H)

Step 2: Synthesis of Compound 12-B

(154) Except for using the corresponding raw materials, the compound 12-B was prepared using the same method as in the preparation of compound 10-C in Example 10.

(155) MS m/z: 427.2[M+H].sup.+

Step 3: Synthesis of Compound 12

(156) Except for using the corresponding raw materials, the compound 12 was prepared using the same method as in the preparation of compound 10 in Example 10.

(157) MS m/z: 510.4 [M+H].sup.+

(158) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.24-8.16 (m, 2H), 7.93 (dd, J=2.5, 8.5 Hz, 1H), 7.78 (dd, J=2.0, 8.8 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.20-5.81 (m, 1H), 4.43 (t, J=6.5 Hz, 2H), 3.38 (s, 3H), 3.31 (br t, J=11.0 Hz, 2H), 3.00-2.93 (m, 1H), 2.92-2.81 (m, 3H), 2.75 (dt, J=4.8, 13.3 Hz, 2H), 2.52-2.46 (m, 2H), 2.29 (s, 6H), 2.07-1.96 (m, 2H), 1.77 (br d, J=14.3 Hz, 2H).

Example 13: Compound 13

(159) ##STR00060##

Synthetic Route

(160) ##STR00061##

Step 1: Synthesis of Compound 13-A

(161) Except for using the corresponding raw materials, the compound 13-A was prepared using the same method as in the preparation of compound 10-B in Example 10.

(162) MS m/z: 428.1[M+H].sup.+

Step 2: Synthesis of Compound 13-B

(163) Except for using the corresponding raw materials, the compound 13-B was prepared using the same method as in the preparation of compound 10-C in Example 10.

(164) MS m/z: 445.2[M+H].sup.+

(165) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.73 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.27-8.22 (m, 2H), 8.13 (dt, J=2.6, 8.0 Hz, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 7.11 (dd, J=2.9, 8.4 Hz, 1H), 3.50-3.41 (m, 2H), 3.39 (s, 3H), 3.17 (q, J=9.5 Hz, 2H), 2.94 (br dd, J=3.9, 10.9 Hz, 2H), 2.76 (dt, J=4.8, 13.3 Hz, 2H), 1.80 (br s, 2H).

Step 3: Synthesis of Compound 13

(166) Except for using the corresponding raw materials, the compound 13 was prepared using the same method as in the preparation of compound 10 in Example 10.

(167) MS m/z: 528.3[M+H].sup.+

(168) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.23-8.18 (m, 2H), 7.94 (dd, J=2.5, 8.8 Hz, 1H), 7.79 (dd, J=1.6, 8.9 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 3.46 (br t, J=11.2 Hz, 2H), 3.38 (s, 3H), 3.17 (q, J=9.7 Hz, 2H), 2.92 (br d, J=11.0 Hz, 2H), 2.78 (dt, J=4.5, 13.3 Hz, 2H), 2.53-2.46 (m, 2H), 2.28 (s, 6H), 2.06-1.96 (m, 2H), 1.77 (br s, 2H)

Example 14: Compound 14

(169) ##STR00062##

Synthetic Route

(170) ##STR00063##

Step 1: Synthesis of Compound 14

(171) Except for using the corresponding raw materials, the compound 14 was prepared using the same method as in the preparation of compound 10 in Example 10.

(172) MS m/z: 568.3[M+H].sup.+

(173) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.24-8.18 (m, 2H), 7.94 (dd, J=2.5, 8.5 Hz, 1H), 7.79 (dd, J=1.6, 8.9 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.42 (t, J=6.4 Hz, 2H), 3.46 (br t, J=11.2 Hz, 2H), 3.38 (s, 3H), 3.17 (q, J=9.5 Hz, 2H), 2.92 (br d, J=11.3 Hz, 2H), 2.77 (dt, J=4.6, 13.4 Hz, 2H), 2.58-2.51 (m, 2H), 2.46 (br s, 2H), 2.10-2.00 (m, 2H), 1.77 (br d, J=14.1 Hz, 2H), 1.63 (br s, 6H), 1.46 (br s, 2H).

Example 15: Compound 15

(174) ##STR00064##

Synthetic Route

(175) ##STR00065##

Step 1: Synthesis of Compound 15-A

(176) Except for using the corresponding raw materials, the compound 15-A was prepared using the same method as in the preparation of compound 10-B in Example 10.

(177) MS m/z: 388.1[M+H].sup.+

(178) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.94 (s, 1H), 8.22-8.14 (m, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.76 (dd, J=2.0, 9.0 Hz, 1H), 3.30 (s, 3H), 3.19-3.04 (m, 2H), 2.92 (br d, J=8.3 Hz, 1H), 2.83-2.66 (m, 2H), 2.43 (br s, 2H), 1.82-1.68 (m, 2H), 1.11 (br d, J=4.8 Hz, 6H)

Step 2: Synthesis of Compound 15-B

(179) Except for using the corresponding raw materials, the compound 15-B was prepared using the same method as in the preparation of compound 10-C in Example 10.

(180) MS m/z: 405.0[M+H].sup.+

(181) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.39 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.70 (dd, J=1.8, 8.8 Hz, 1H), 6.98 (dd, J=2.8, 8.5 Hz, 1H), 3.31 (s, 3H), 3.28-3.17 (m, 2H), 2.87 (br s, 1H), 2.83-2.67 (m, 4H), 1.81-1.67 (m, 2H), 1.09 (br d, J=6.0 Hz, 6H)

Step 3: Synthesis of Compound 15

(182) Except for using the corresponding raw materials, the compound 15 was prepared using the same method as in the preparation of compound 10 in Example 10.

(183) MS m/z: 488.4[M+H].sup.+

(184) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.70 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.03 (br d, J=6.8 Hz, 1H), 7.85-7.76 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.44 (s, 2H), 3.39 (s, 3H), 3.37-3.26 (m, 2H), 2.97 (br s, 1H), 2.81 (br s, 4H), 2.49 (s, 2H), 2.29 (s, 6H), 2.07-1.98 (m, 2H), 1.87-1.75 (m, 2H), 1.19 (br d, J=6.5 Hz, 6H)

Example 16: Compound 16

(185) ##STR00066##

Synthetic Route

(186) ##STR00067##

Step 1: Synthesis of Compound 16

(187) Except for using the corresponding raw materials, the compound 16 was prepared using the same method as in the preparation of compound 10 in Example 10.

(188) MS m/z: 528.2[M+H].sup.+

(189) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.61 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.29 (br s, 1H), 8.13 (d, J=8.9 Hz, 1H), 7.94 (br s, 1H), 7.71 (br d, J=8.8 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.33 (s, 2H), 3.31 (s, 3H), 3.28-3.16 (m, 2H), 2.89 (br s, 1H), 2.73 (br s, 4H), 2.43 (br d, J=7.9 Hz, 2H), 2.36 (br s, 4H), 2.05 (br s, 2H), 1.99-1.93 (m, 2H), 1.72 (br d, J=12.8 Hz, 2H), 1.58-1.54 (m, 2H), 1.38 (br d, J=3.8 Hz, 2H), 1.11 (br d, J=6.1 Hz, 6H)

Example 17: Compound 17

(190) ##STR00068##

Synthetic Route

(191) ##STR00069##

Step 1: Synthesis of Compound 17-A

(192) Compound 10-A (150 mg, 433.25 μmol) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (111.99 mg, 866.50 μmol, 150.93 μL) was added, and acetylchloride (51.01 mg, 649.87 μmol, 46.38 μL) was added at 0° C. under a nitrogen atmosphere. The mixed system was warmed to 30° C., stirred for 2 h, and then concentrated to obtain a crude product, which was separated and purified by chromatography column (DCM/THF=1/0 to 4/1) to obtain compound 17-A.

(193) MS m/z: 388.1[M+H].sup.+

(194) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (s, 1H), 8.01 (d, J=9.3 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.68 (dd, J=2.0, 9.0 Hz, 1H), 4.74 (br dd, J=4.9, 13.7 Hz, 1H), 4.18 (dt, J=2.8, 13.3 Hz, 1H), 3.84 (br dd, J=4.6, 13.7 Hz, 1H), 3.60 (dt, J=2.9, 13.2 Hz, 1H), 3.39 (s, 3H), 2.56-2.40 (m, 2H), 2.26 (s, 3H), 1.87-1.74 (m, 2H)

Step 2: Synthesis of Compound 17-B

(195) Compound 17-A (85 mg, 218.93 μmol) was dissolved in anhydrous dioxane (10 mL) and water (2 mL), 2-fluoropyridine-5-boracic acid (46.27 mg, 328.39 μmol) and sodium carbonate (69.61 mg, 656.78 μmol) were added, and tetrakistriphenylphosphine palladium (37.95 mg, 32.84 μmol) was added under a nitrogen atmosphere. The mixed system was stirred at 80° C. for 4 h, and then extracted with dichloromethane (150 mL, 50 mL*3). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by chromatography column (DCM:THF=1/0 to 4/1) to obtain compound 17-B.

(196) MS m/z: 405.6[M+H].sup.+

(197) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.76 (s, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.09-8.01 (m, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.78 (dd, J=2.0, 8.8 Hz, 1H), 7.12 (dd, J=2.9, 8.4 Hz, 1H), 4.71 (br d, J=8.5 Hz, 1H), 4.20 (dt, J=2.9, 13.2 Hz, 1H), 3.84 (br d, J=9.3 Hz, 1H), 3.68-3.54 (m, 1H), 3.42 (s, 3H), 2.65-2.49 (m, 2H), 2.22 (s, 3H), 1.86 (br dd, J=14.9, 18.9 Hz, 2H)

Step 3: Synthesis of Compound 17

(198) Sodium hydride (24.07 mg, 601.71 μmol, purity: 60%) was dissolved in N, N dimethylformamide (10 mL), and 3-dimethylamino-1-propanol (23.28 mg, 225.64 μmol, 26.39 L) was added at 0° C. under a nitrogen atmosphere and stirred for 0.5 h, and then a solution of 17-B (70 mg, 150.43 μmol) in N, N dimethylformamide (5 mL) was added. The mixed system was raised to room temperature (25° C.) and stirred for 4 h, and then quenched by adding water (20 mL). The mixed system was dispersed into 100 mL of water, and extracted with dichloromethane (150 mL, 50 mL*3). The organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by preparative high performance liquid chromatography (neutral, mobile phase: acetonitrile-water) to obtain compound 17.

(199) MS m/z: 488.4[M+H].sup.+

(200) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.85 (dd, J=2.5, 8.5 Hz, 1H), 7.79 (dd, J=1.9, 8.9 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.71 (br d, J=10.0 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 4.24-4.13 (m, 1H), 3.83 (br d, J=13.8 Hz, 1H), 3.68-3.57 (m, 1H), 3.41 (s, 3H), 2.65-2.52 (m, 2H), 2.52-2.43 (m, 2H), 2.28 (s, 6H), 2.23 (s, 3H), 2.05-1.96 (m, 2H), 1.85 (br t, J=14.2 Hz, 2H)

Example 18: Compound 18

(201) ##STR00070##

Synthetic Route

(202) ##STR00071##

Step 1: Synthesis of Compound 18-A

(203) Except for using the corresponding raw materials, the compound 18-A was prepared using the same method as in the preparation of compound 17-A in Example 17.

(204) MS m/z: 414.1[M+H].sup.+

Step 2: Synthesis of Compound 18-B

(205) Except for using the corresponding raw materials, the compound 18-B was prepared using the same method as in the preparation of compound 17-B in Example 17.

(206) MS m/z: 431.2[M+H].sup.+

(207) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.76 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.05 (dt, J=2.6, 8.0 Hz, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.79 (dd, J=1.9, 8.9 Hz, 1H), 7.11 (dd, J=2.8, 8.5 Hz, 1H), 4.67 (br d, J=12.5 Hz, 1H), 4.26 (br d, J=7.5 Hz, 2H), 3.67 (br t, J=12.8 Hz, 1H), 3.42 (s, 3H), 2.59 (br d, J=12.3 Hz, 2H), 1.95-1.85 (m, 2H), 1.79 (br d, J=13.1 Hz, 1H), 1.12 (br s, 1H), 1.00 (br s, 1H), 0.83 (dd, J=3.6, 7.9 Hz, 2H)

Step 3: Synthesis of Compound 18

(208) Except for using the corresponding raw materials, the compound 18 was prepared using the same method as in the preparation of compound 17 in Example 17.

(209) MS m/z: 514.4[M+H].sup.+

(210) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (s, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.91 (d, J=1.8 Hz, 1H), 7.86 (dd, J=2.5, 8.5 Hz, 1H), 7.80 (dd, J=1.8, 8.8 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 4.67 (br d, J=11.0 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 4.25 (br d, J=8.3 Hz, 2H), 3.67 (br t, J=12.3 Hz, 1H), 3.41 (s, 3H), 2.71-2.52 (m, 4H), 2.34 (s, 6H), 2.09-2.05 (m, 1H), 2.04-2.00 (m, 1H), 1.95-1.83 (m, 3H), 1.16-1.01 (m, 2H), 0.89-0.79 (m, 2H)

Example 19: Compound 19

(211) ##STR00072##

Synthetic Route

(212) ##STR00073##

Step 1: Synthesis of Compound 19-A

(213) Except for using the corresponding raw materials, the compound 19-A was prepared using the same method as in the preparation of compound 17-A in Example 17.

(214) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.03-7.99 (m, 2H), 7.67 (dd, J=2.0, 9.0 Hz, 1H), 4.35-4.09 (m, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 2.57-2.44 (m, 2H), 1.74 (br d, J=14.1 Hz, 2H), 1.04 (br s, 2H)

Step 2: Synthesis of Compound 19-B

(215) Except for using the corresponding raw materials, the compound 19-B was prepared using the same method as in the preparation of compound 17-B in Example 17.

(216) MS m/z: 421.1[M+H].sup.+

(217) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.07 (dt, J=2.5, 7.9 Hz, 1H), 7.97 (s, 1H), 7.78 (dd, J=1.8, 8.8 Hz, 1H), 7.11 (dd, J=2.9, 8.4 Hz, 1H), 4.24 (br s, 2H), 3.83 (br s, 2H), 3.79 (s, 3H), 3.41 (s, 3H), 2.64-2.51 (m, 2H), 1.79 (br d, J=14.1 Hz, 2H)

Step 3: Synthesis of Compound 19

(218) Except for using the corresponding raw materials, the compound 19 was prepared using the same method as in the preparation of compound 17 in Example 17.

(219) MS m/z: 504.2[M+H].sup.+

(220) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.46 (d, J=2.3 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.88 (dd, J=2.5, 8.5 Hz, 1H), 7.78 (dd, J=1.9, 8.9 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 4.42 (t, J=6.4 Hz, 2H), 4.32-4.08 (m, 2H), 3.92-3.81 (m, 2H), 3.79 (s, 3H), 3.40 (s, 3H), 2.65-2.55 (m, 2H), 2.53-2.47 (m, 2H), 2.29 (s, 6H), 2.06-1.97 (m, 2H), 1.76 (br s, 2H)

Example 20: Compound 20

(221) ##STR00074##

Synthetic Route

(222) ##STR00075##

Step 1: Synthesis of Compound 20

(223) Except for using the corresponding raw materials, the compound 20 was prepared using the same method as in the preparation of compound 17 in Example 17.

(224) MS m/z: 544.3[M+H].sup.+

(225) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.46 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.87 (dd, J=2.1, 8.7 Hz, 1H), 7.78 (br d, J=9.0 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.41 (br t, J=6.4 Hz, 2H), 4.33-4.07 (m, 2H), 3.94-3.81 (m, 2H), 3.79 (s, 3H), 3.40 (s, 3H), 2.66-2.37 (m, 8H), 2.10-1.98 (m, 2H), 1.78 (br d, J=12.8 Hz, 6H), 1.45 (br s, 2H)

Example 21: Compound 21

(226) ##STR00076##

Synthetic Route

(227) ##STR00077##

Step 1: Synthesis of Compound 21-A

(228) Except for using the corresponding raw materials, the compound 21-A was prepared using the same method as in the preparation of compound 17-A in Example 17.

(229) MS m/z: 432.2[M+H].sup.+

Step 2: Synthesis of Compound 21-B

(230) Except for using the corresponding raw materials, the compound 21-B was prepared using the same method as in the preparation of compound 17-B in Example 17.

(231) MS m/z: 449.2[M+H].sup.+

(232) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.09-8.02 (m, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.78 (dd, J=2.0, 8.8 Hz, 1H), 7.08 (dd, J=2.9, 8.4 Hz, 1H), 5.02 (td, J=6.3, 12.4 Hz, 1H), 4.15 (br s, 2H), 3.83 (br s, 2H), 3.41 (s, 3H), 2.57 (br s, 2H), 1.77 (br d, J=14.1 Hz, 2H), 1.28 (d, J=6.3 Hz, 6H)

Step 3: Synthesis of Compound 21

(233) Except for using the corresponding raw materials, the compound 21 was prepared using the same method as in the preparation of compound 17 in Example 17.

(234) MS m/z: 532.3[M+H].sup.+

(235) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.77 (s, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.02 (dd, J=2.5, 8.8 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.85 (dd, J=1.8, 9.0 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 4.97 (td, J=6.2, 12.5 Hz, 1H), 4.44 (t, J=6.0 Hz, 2H), 4.12 (br dd, J=3.5, 13.3 Hz, 2H), 3.84-3.71 (m, 2H), 3.38 (s, 3H), 3.13-3.06 (m, 2H), 2.74 (s, 6H), 2.60-2.49 (m, 2H), 2.23-2.13 (m, 2H), 1.73 (br d, J=14.1 Hz, 2H), 1.27 (d, J=6.3 Hz, 6H)

Example 22: Compound 22

(236) ##STR00078##

Synthetic Route

(237) ##STR00079## ##STR00080##

Step 1: Synthesis of Compound 22-B

(238) 1,2-dichloroethane (100 mL) was added to methyl 4-piperidinecarboxylate (10 g, 69.84 mmol), cyclopropylboronic acid (12.00 g, 139.68 mmol), pyridine (5.52 g, 69.84 mmol, 5.64 mL) and sodium carbonate (14.80 g, 139.68 mmol, 2 eq), replaced three times with oxygen, and stirred for 16 h at 70° C. under oxygen atmosphere. After completion of the reaction, the reaction was cooled 0° C. and quenched by adding 200 mL of water. Then 100 mL of ammonia water was added, and extracted with dichloromethane (150 mL, 50 mL*3). The organic phase was combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (0 to 10% EtOAc/PE) to obtain compound 22-B.

(239) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.66 (s, 3H), 3.03-2.95 (m, 2H), 2.29 (tt, J=4.0, 11.2 Hz, 1H), 2.20 (dt, J=2.5, 11.5 Hz, 2H), 1.91-1.83 (m, 2H), 1.73-1.62 (m, 2H), 1.59-1.52 (m, 1H), 0.46-0.40 (m, 2H), 0.40-0.36 (m, 2H)

Step 2: Synthesis of Compound 22-C

(240) Except for using the corresponding raw materials, the compound 22-C was prepared using the same method as in the preparation of compound 1-A in Example 1.

(241) MS m/z: 434.0[M+H].sup.+

(242) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.68 (d, J=1.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.86 (dd, J=1.9, 8.9 Hz, 1H), 3.67 (s, 3H), 2.95 (br d, J=12.3 Hz, 2H), 2.81-2.70 (m, 2H), 2.55 (br d, J=13.1 Hz, 2H), 2.32-2.22 (m, 2H), 1.77-1.66 (m, 1H), 0.45 (br d, J=7.0 Hz, 2H), 0.42 (br d, J=4.3 Hz, 2H)

Step 3: Synthesis of Compound 22-D

(243) Compound 22-C (1.7 g, 3.91 mmol) was dissolved in THF (70 mL), a solution of NH.sub.4Cl (2.09 g, 39.14 mmol) in water (70 mL) was added, and then a zinc powder (2.56 g, 39.14 mmol) was added. The reaction solution was stirred at 70° C. for 24 h. After completion of the reaction, the zinc powder was removed, and the mixed solution was concentrated to obtain a crude product which was directly used in the next step.

(244) MS m/z: 371.9[M+H].sup.+

Step 4: Synthesis of Compound 22-E

(245) A solution of sodium hydroxide (322.36 mg, 8.06 mmol) and tetrabutylammonium bromide (64.95 mg, 201.47 μmol) in water (20 mL) was added to a solution of 22-D (1.5 g, 4.03 mmol) in dichloromethane (40 mL). Then iodomethane (3.660 g, 25.79 mmol, 1.61 mL) was added dropwise, and the reaction solution was stirred at 20° C. for 48 h. After completion of the reaction, the reaction system was added with 50 mL of water at room temperature to quench the reaction, and extracted with dichloromethane (90 mL, 30 mL*3). The organic phase was combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, a solvent was removed under reduced pressure to obtain a crude compound 22-E, which was directly used in the next step.

(246) MS m/z: 386.1[M+H].sup.+

Step 5: Synthesis of Compound 22-F

(247) Under nitrogen protection, 1,4-dioxane (20 mL) and H.sub.2O (20 mL) were added to a reaction system of compound 22-E (1 g, 2.53 mmol), 2-fluoropyridine-5-boracic acid (534.71 mg, 3.79 mmol), tetrakistriphenylphosphine palladium (292.34 mg, 252.98 μmol) and sodium carbonate (804.41 mg, 7.59 mmol), and stirred at 80° C. for 16 h. After completion of the reaction, a solvent was removed under reduced pressure to obtain a crude compound 22-F, which was directly used in the next step.

(248) MS m/z: 403.1[M+H].sup.+

Step 6: Synthesis of Compound 22

(249) Except for using the corresponding raw materials, the compound 22 was prepared using the same method as in the preparation of compound 1 in Example 1.

(250) MS m/z: 486.3[M+H].sup.+

(251) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.94 (dd, J=2.0, 8.5 Hz, 1H), 7.76 (br d, J=8.8 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.41 (t, J=6.4 Hz, 2H), 3.38 (s, 3H), 3.27 (br t, J=11.4 Hz, 2H), 2.97 (br d, J=9.5 Hz, 2H), 2.68 (dt, J=4.4, 13.2 Hz, 2H), 2.47 (br t, J=7.4 Hz, 2H), 2.27 (s, 6H), 1.98 (br s, 2H), 1.88 (br d, J=4.3 Hz, 1H), 1.75 (br d, J=13.8 Hz, 2H), 0.52 (br s, 4H)

Example 23: Compound 23

(252) ##STR00081##

Synthetic Route

(253) ##STR00082##

Step 1: Synthesis of Compound 23

(254) Except for using the corresponding raw materials, the compound 23 was prepared using the same method as in the preparation of compound 1 in Example 1.

(255) MS m/z: 526.3[M+H].sup.+

(256) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.94 (dd, J=2.5, 8.5 Hz, 1H), 7.76 (dd, J=1.8, 8.8 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.40 (t, J=6.5 Hz, 2H), 3.38 (s, 3H), 3.32-3.22 (m, 2H), 3.01-2.93 (m, 2H), 2.68 (dt, J=4.5, 13.3 Hz, 2H), 2.55-2.49 (m, 2H), 2.44 (br s, 2H), 2.08-1.97 (m, 6H), 1.91-1.86 (m, 1H), 1.75 (br d, J=13.8 Hz, 2H), 1.65-1.62 (m, 1H), 1.60-1.58 (m, 1H), 1.45 (br s, 2H), 0.55-0.49 (m, 4H)

Example 24: Compound 24

(257) ##STR00083##

Synthetic Route

(258) ##STR00084##

Step 1: Synthesis of Compound 24

(259) Sodium hydride (101.26 mg, 2.53 mmol, purity: 60%) was dissolved in N,N-dimethylformamide (10 mL), and a solution of compound 11-C (181.31 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) was added at 0° C. under a nitrogen atmosphere, and stirred for 0.5 h, and then a solution of 1-D (230 mg, 632.94 μmol) in N,N-dimethylformamide (5 mL) was added. The mixed system was raised to room temperature (25° C.), continuously stirred 2 h under a nitrogen atmosphere, then quenched by adding water (10 mL), and extracted with dichloromethane (150 mL, 50 mL*3). The organic phase was collected, and the organic phase was concentrated to obtain a crude product, which was separated and purified by preparative high performance liquid chromatography ([water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile B %: 28%-58%, 7 min) to obtain compound 24.

(260) MS m/z: 487.3[M+H].sup.+

(261) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.15 (s, 1H), 7.91 (dd, J=2.3, 8.5 Hz, 1H), 7.78 (br d, J=8.0 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.54-4.34 (m, 4H), 3.97 (br dd, J=4.8, 11.5 Hz, 2H), 3.38 (s, 3H), 2.74 (dt, J=4.9, 13.2 Hz, 2H), 2.54-2.46 (m, 2H), 2.42 (br s, 2H), 2.12 (br s, 2H), 2.02 (td, J=6.9, 14.3 Hz, 2H), 1.68 (br d, J=13.8 Hz, 2H), 1.62-1.53 (m, 4H), 1.43 (br s, 2H)

Example 25: Compound 25

(262) ##STR00085##

Synthetic Route

(263) ##STR00086## ##STR00087##

Step 1: Synthesis of Compound 25-A

(264) Except for using the corresponding raw materials, the compound 25-A was prepared using the same method as in the preparation of compound 1-A in Example 1.

(265) MS m/z: 465.0[M+H].sup.+

Step 2: Synthesis of Compound 25-B

(266) Except for using the corresponding raw materials, the compound 25-B was prepared using the same method as in the preparation of compound 1-B in Example 1.

(267) MS m/z: 389.4[M+H].sup.+

Step 3: Synthesis of Compound 25-C

(268) Compound 25-B (3.2 g, 8.22 mmol) was dissolved in tetrahydrofuran (10 mL), and trifluoroacetic acid (15.40 g, 135.06 mmol, 10.00 mL) and water (10.00 g, 555.08 mmol, 10 mL) were added. The mixed system was stirred at room temperature (25° C.) for 12 h, then adjusted to achieve pH=7 to 8 with sodium hydroxide (1 M), and extracted with EtOAc (200 mL, 100 mL*2). The organic phase was collected, and concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane/tetrahydrofuran=1/0 to 4/1) to obtain compound 25-C.

(269) MS m/z: 345.1[M+H].sup.+

Step 4: Synthesis of Compound 25-D

(270) Except for using the corresponding raw materials, the compound 25-D was prepared using the same method as in the preparation of compound 1-C in Example 1.

(271) MS m/z: 359.1[M+H].sup.+

Step 5: Synthesis of Compound 25-E

(272) Compound 25-D (0.367 g, 1.02 mmol) was dissolved in methanol (20 mL), and sodium borohydride (77.30 mg, 2.04 mmol) was added at 0° C. under a nitrogen atmosphere. The mixed system was raised to room temperature (20° C.), continuously stirred for 3 h, then quenched by adding water (20 mL), and extracted with dichloromethane/methanol=10/1 (50 mL). The organic phase was collected, and concentrated to obtain a crude product, which was separated and purified by chromatography column (DCM/THF=I/O to 4/1) to obtain compound 25-E.

(273) MS m/z: 360.9[M+H].sup.+

Step 6: Synthesis of Compound 25-F

(274) Sodium hydride (106.29 mg, 2.66 mmol, purity: 60%) was dissolved in tetrahydrofuran (10 mL), and a solution of 25-E (320 mg, 885.86 μmol) in tetrahydrofuran (10 mL) was added at 0° C. under a nitrogen atmosphere, and stirred at 0° C. for 0.5 h. Then iodomethane (502.95 mg, 3.54 mmol, 220.59 μL) was added under a nitrogen atmosphere. The mixed system was raised to room temperature (25° C.), and stirred for 2 h under a nitrogen atmosphere. The mixed solution was quenched by dispersing into 50 mL of water, extracted with dichloromethane (150 mL, 50 mL*3), and washed with saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and separated and purified by chromatography column (dichloromethane/tetrahydrofuran=1/0 to 10/1) to obtain compound 25-F.

(275) MS m/z 375.1[M+H].sup.+

Step 6: Synthesis of Compound 25-G

(276) Except for using the corresponding raw materials, the compound 25-G was prepared using the same method as in the preparation of compound 1-D in Example 1.

(277) MS m/z: 392.6[M+H].sup.+

Step 7: Synthesis of Compound 25

(278) Except for using the corresponding raw materials, the compound 25 was prepared using the same method as in the preparation of compound 1 in Example 1.

(279) MS m/z: 475.2[M+H].sup.+

(280) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.90 (dd, J=2.5, 8.5 Hz, 1H), 7.76 (dd, J=1.5, 8.8 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 3.48 (s, 3H), 3.38 (s, 3H), 2.53-2.44 (m, 4H), 2.41-2.35 (m, 2H), 2.28 (s, 6H), 2.10-1.97 (m, 4H), 1.91 (br d, J=13.8 Hz, 2H), 1.78 (br s, 2H)

Example 26: Compound 26

(281) ##STR00088##

Synthetic Route

(282) ##STR00089##

Step 1: Synthesis of Compound 26-A

(283) Compound 25-C (1.05 g, 3.04 mmol) was dissolved in methanol (20 mL), and sodium borohydride (172.62 mg, 4.56 mmol) was added at 0° C. under a nitrogen atmosphere. The mixed system was raised to room temperature (20° C.), continuously stirred for 3 h, then quenched by adding water (20 mL), and extracted with dichloromethane (100 mL, 50 mL*2). The organic phase was collected, and concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane/tetrahydrofuran=1/0 to 4/1) to obtain compound 26-A.

(284) MS m/z: 347.0[M+H].sup.+

Step 2: Synthesis of Compound 26-B

(285) Compound 26-A (840 mg, 2.42 mmol) was dissolved in dichloromethane (5 mL), a solution of sodium hydroxide (387.09 mg, 9.68 mmol) in water (5 mL), and tetrabutylammonium bromide (39.00 mg, 120.97 μmol) were added, and iodomethane (1.37 g, 9.68 mmol, 602.44 μL) was added at 0° C. under a nitrogen atmosphere. The mixed system was raised to room temperature (25° C.) and stirred for 3 h under a nitrogen atmosphere, and then the mixed solution was dispersed into 50 mL of water, and extracted with dichloromethane (100 mL, 50 mL*2). The organic phase was collected and concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane/tetrahydrofuran=1/0 to 5/1) to obtain 26-B.

(286) MS m/z: 361.1[M+H].sup.+

Step 3: Synthesis of Compound 26-C

(287) Compound 26-B (260 mg, 719.76 μmol) was dissolved in N,N dimethylformamide (10 mL), and pyridine (56.93 mg, 719.76 μmol, 58.09 μL) and TBSOTf (190.26 mg, 719.76 mol, 165.44 μL) were added, and stirred for 3 h at room temperature (25° C.), then washed by adding 300 mL (100 mL*3) of water, and extracted with 150 mL (50 mL*3) of dichloromethane. The organic phase was collected, and concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane/tetrahydrofuran=1/0 to 10/1) to obtain 26-C.

(288) MS m/z: 474.6[M+H].sup.+

Step 4: Synthesis of Compound 26-D

(289) Except for using the corresponding raw materials, the compound 26-D was prepared using the same method as in the preparation of compound 1-D in Example 1.

(290) MS m/z: 492.3[M+H].sup.+

(291) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.72 (s, 1H), 8.55 (d, J=2.3 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.12-8.05 (m, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.75 (dd, J=2.0, 8.8 Hz, 1H), 7.12 (dd, J=2.8, 8.5 Hz, 1H), 3.39 (s, 3H), 2.55-2.40 (m, 4H), 1.94-1.78 (m, 4H), 0.97-0.88 (m, 9H), 0.13 (s, 6H)

Step 5: Synthesis of Compound 26

(292) Except for using the corresponding raw materials, the compound 26 was prepared using the same method as in the preparation of compound 1 in Example 1.

(293) MS m/z: 461.3[M+H].sup.+

(294) 1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.89 (dd, J=2.6, 8.7 Hz, 1H), 7.77 (dd, J=1.8, 8.8 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.43 (t, J=6.5 Hz, 2H), 3.99-3.89 (m, 1H), 3.39 (s, 3H), 2.58-2.36 (m, 6H), 2.28 (s, 6H), 2.06-1.96 (m, 4H), 1.89 (br d, J=13.8 Hz, 2H)

Example 27: Compound 27

(295) ##STR00090##

Synthetic Route

(296) ##STR00091##

Step 1: Synthesis of Compound 27-A

(297) Compound 25-D (900 mg, 2.51 mmol) was dissolved in tetrahydrofuran (20 mL) at 0° C., and methyl magnesium bromide (4 M, 1.88 mL) was added dropwise under a nitrogen atmosphere. The mixed system was raised to 25° C., and stirred for 2 h under a nitrogen atmosphere, and then the reaction system was quenched with water (50 mL), and extracted with dichloromethane/isopropanol=10/1 (50 mL*3). The organic phase was collected, separated and purified by chromatography column (DCM/tetrahydrofuran=1/0 to 3/1) to obtain compound 27-A.

(298) MS m/z: 375.0[M+H].sup.+

Step 2: Synthesis of Compound 27-B

(299) Compound 27-A (380 mg, 1.01 mmol) was dissolved in dichloromethane (10 mL), and TBSOTf (401.52 mg, 1.52 mmol, 349.14 μL) and triethylamine (204.94 mg, 2.03 mmol, 281.89 μL) were added. The mixed system was stirred for 12 h at room temperature (25° C.), then washed by adding 300 mL (100 mL*3) of water, and extracted with dichloromethane (150 mL, 50 mL*3). The organic phase was collected, and concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane/tetrahydrofuran=1/0 to 10/1) to obtain 27-B.

(300) MS m/z: 489.3[M+H].sup.+

(301) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 7.66 (dd, J=2.3, 9.0 Hz, 1H), 3.36 (s, 3H), 2.71-2.54 (m, 2H), 2.41 (dt, J=3.8, 14.2 Hz, 2H), 1.80-1.65 (m, 4H), 1.56 (s, 3H), 0.91 (s, 9H), 0.22-0.13 (m, 6H)

Step 3: Synthesis of Compound 27-C

(302) Except for using the corresponding raw materials, the compound 27-C was prepared using the same method as in the preparation of compound 1-D in Example 1.

(303) MS m/z: 506.8[M+H].sup.+

Step 4: Synthesis of Compound 27-D

(304) Except for using the corresponding raw materials, the compound 27-D was prepared using the same method as in the preparation of compound 1 in Example 1.

(305) MS m/z: 589.6[M+H].sup.+

Step 5: Synthesis of Compound 27

(306) Compound 27-D (110 mg, 186.80 μmol) was dissolved in trifluoroacetic acid (21.30 mg, 186.80 μmol, 13.83 μL), stirred at 60° C. for 1 h, then adjusted with 1 M sodium hydroxide solution to pH=7 to 8, extracted with dichloromethane (150 mL, 50 mL*3), and washed with saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by preparative high performance liquid chromatography (neutral, mobile phase: acetonitrile-water) to obtain compound 27.

(307) MS m/z: 475.3[M+H].sup.+

(308) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.89 (dd, J=2.5, 8.5 Hz, 1H), 7.79 (dd, J=2.0, 8.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.42 (t, J=6.5 Hz, 2H), 3.39 (s, 3H), 2.57 (d, J=9.0 Hz, 4H), 2.51-2.45 (m, 2H), 2.28 (s, 6H), 2.04-1.96 (m, 2H), 1.87-1.75 (m, 4H), 1.58 (s, 3H)

Example 28: Compound 28

(309) ##STR00092##

Synthetic Route

(310) ##STR00093##

Step 1: Synthesis of Compound 28-A

(311) Except for using the corresponding raw materials, the compound 28-A was prepared using the same method as in the preparation of compound 1 in Example 1.

(312) MS m/z: 629.6[M+H].sup.+

Step 2: Synthesis of Compound 28

(313) Except for using the corresponding raw materials, the compound 28 was prepared using the same method as in the preparation of compound 27 in Example 27.

(314) MS m/z: 515.4[M+H].sup.+

(315) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.69 (s, 1H), 8.49 (d, J=2.8 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.05 (d, J=1.5 Hz, 1H), 7.89 (dd, J=2.5, 8.5 Hz, 1H), 7.79 (dd, J=2.0, 8.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.41 (t, J=6.5 Hz, 2H), 3.39 (s, 3H), 2.57 (d, J=9.3 Hz, 2H), 2.50 (br d, J=8.0 Hz, 2H), 2.43 (br s, 2H), 2.09-1.97 (m, 2H), 1.84 (br d, J=8.5 Hz, 2H), 1.78 (br d, J=7.8 Hz, 2H), 1.59 (br s, 8H), 1.57 (br s, 3H), 1.45 (br s, 2H)

Example 29: Compound 29

(316) ##STR00094##

Synthetic Route

(317) ##STR00095##

Step 1: Synthesis of Compound 29-A

(318) Compound 1-B (200 mg, 600.28 μmol) was dissolved in anhydrous toluene (15 mL), and cyclopropylboronic acid (103.12 mg, 1.20 mmol), sodium carbonate (127.25 mg, 1.20 mmol), copper acetate (109.03 mg, 600.28 μmol) and pyridine (94.96 mg, 1.20 mmol, 96.90 L) were added. The mixed system was stirred for 12 h at 70° C., and then filtered. The filtrate was collected, and concentrated to obtain a crude product, which was separated and purified by chromatography column (dichloromethane/tetrahydrofuran=1/0 to 10/1) to obtain compound 29-A.

(319) MS m/z: 373.0[M+H].sup.+

(320) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 1H), 8.22 (d, J=1.5 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.67 (dd, J=2.0, 9.0 Hz, 1H), 4.50-4.35 (m, 2H), 4.03-3.91 (m, 2H), 2.80 (tt, J=3.6, 7.0 Hz, 1H), 2.64 (dt, J=5.4, 13.5 Hz, 2H), 1.64 (s, 2H), 1.23-1.15 (m, 2H), 1.01-0.93 (m, 2H)

Step 2: Synthesis of Compound 29-B

(321) Except for using the corresponding raw materials, the compound 29-B was prepared using the same method as in the preparation of compound 1-D in Example 1.

(322) MS m/z: 390.1[M+H].sup.+

(323) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.99 (s, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.17 (d, J=1.0 Hz, 1H), 8.11 (dt, J=2.5, 7.9 Hz, 1H), 7.85-7.75 (m, 1H), 7.11 (dd, J=2.9, 8.4 Hz, 1H), 4.47 (br t, J=11.3 Hz, 2H), 3.98 (dd, J=5.0, 11.8 Hz, 2H), 2.83 (tt, J=3.7, 6.9 Hz, 1H), 2.71 (dt, J=5.3, 13.4 Hz, 2H), 1.70 (br s, 2H), 1.28-1.16 (m, 2H), 1.05-0.90 (m, 2H)

Step 3: Synthesis of Compound 29

(324) Except for using the corresponding raw materials, the compound 29 was prepared using the same method as in the preparation of compound 1 in Example 1.

(325) MS m/z: 473.3[M+H].sup.+

(326) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H), 7.92 (dd, J=2.5, 8.5 Hz, 1H), 7.79 (dd, J=1.8, 8.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.51-4.42 (m, 4H), 3.97 (dd, J=4.9, 11.7 Hz, 2H), 2.82 (td, J=3.3, 6.9 Hz, 1H), 2.73 (dt, J=5.3, 13.7 Hz, 2H), 2.64 (br s, 2H), 2.40 (s, 6H), 2.14-2.05 (m, 2H), 1.67 (br d, J=14.1 Hz, 2H), 1.21 (q, J=6.8 Hz, 2H), 1.02-0.96 (m, 2H)

Example 30: Compound 30

(327) ##STR00096##

Synthetic Route

(328) ##STR00097##

Step 1: Synthesis of Compound 30

(329) Except for using the corresponding raw materials, the compound 30 was prepared using the same method as in the preparation of compound 1 in Example 1.

(330) MS m/z: 513.2[M+H].sup.+

(331) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.92 (dd, J=2.6, 8.7 Hz, 1H), 7.79 (dd, J=1.9, 8.9 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.51-4.39 (m, 4H), 3.97 (dd, J=4.9, 11.7 Hz, 2H), 2.82 (tt, J=3.5, 7.0 Hz, 1H), 2.73 (dt, J=5.3, 13.4 Hz, 2H), 2.55-2.48 (m, 2H), 2.43 (br s, 2H), 2.12-1.98 (m, 2H), 1.68 (br s, 4H), 1.63-1.56 (m, 4H), 1.45 (br d, J=5.3 Hz, 2H), 1.26-1.14 (m, 2H), 1.08-0.90 (m, 2H)

Example 31: Compound 31

(332) ##STR00098##

Synthetic Route

(333) ##STR00099##

Step 1: Synthesis of Compound 31-B

(334) At 0° C. and under nitrogen protection, compound 31-A (5 g, 26.59 mmol) was added slowly to a solution of sodium hydride (1.60 g, 39.89 mmol, 60% purity) in THF (20 mL). The reaction solution was stirred at 25° C. for 0.5 h, and then a solution of iodomethane (5.66 g, 39.89 mmol, 2.48 mL) in THF (10 mL) was added slowly at 0° C. The reaction solution was stirred at 20° C. for 12 h. At 20° C., the reaction solution was quenched with water (20 mL), diluted by adding water (10 mL), and extracted with EtOAc (150 mL, 50 mL*3). The organic phase was combined, washed with saturated sodium chloride (150 mL, 50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, The residue was purified by column chromatography (0 to 10% EtOAc/PE) to obtain 31-B.

(335) MS m/z: 201.8[M+H].sup.+

(336) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.61 (d, J=2.0 Hz, 1H), 7.82 (dd, J=2.3, 8.5 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 4.53 (s, 2H), 3.47 (s, 3H)

Step 2: Synthesis of Compound 31-C

(337) Under nitrogen protection, a mixed solution of 31-B (4.8 g, 23.76 mmol), bis(pinacolato)diboron (6.64 g, 26.13 mmol), potassium acetate (6.99 g, 71.27 mmol) and Pd(dppf)Cl.sub.2 (1.74 g, 2.38 mmol) in dioxane (40 mL) and water (8 mL) was stirred at 100° C. for 12 h. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue, which was separated and purified by preparative thin-layer chromatography silica gel plate to obtain compound 31-C.

(338) MS m/z: 167.9[M+H].sup.+

(339) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.88 (s, 1H), 8.49 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 4.69 (s, 2H), 3.42 (s, 3H).

Step 3: Synthesis of Compound 31

(340) Except for using the corresponding raw materials, the compound 31 was prepared using the same method as in the preparation of compound 1-D in Example 1.

(341) MS m/z: 390.3[M+H].sup.+

(342) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.92 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 8.28-8.19 (m, 2H), 8.03 (dd, J=2.3, 8.0 Hz, 1H), 7.84 (dd, J=2.0, 8.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 4.69 (s, 2H), 4.56-4.41 (m, 2H), 3.99 (dd, J=4.9, 11.7 Hz, 2H), 3.54 (s, 3H), 3.40 (s, 3H), 2.75 (dt, J=5.3, 13.4 Hz, 2H), 1.71 (br d, J=14.1 Hz, 2H)

Example 32: Compound 32

(343) ##STR00100##

Synthetic Route

(344) ##STR00101##

Step 1: Synthesis of Compound 32-A

(345) At −60° C. and under nitrogen protection, n-BuLi (2.5 M, 3.93 mL) was added slowly to a solution of DIPA (993.72 mg, 9.82 mmol, 1.39 mL) in THF (10 mL), and the reaction system was stirred for 30 minutes at −30° C., and then a solution of methyl tetrahydropyran-4-carboxylate (1.49 g, 10.31 mmol, 1.38 mL) in THF (10 mL) was added slowly. The reaction system was stirred for 1 h at −65° C., and finally a solution of compound B (1.5 g, 4.91 mmol) in THF (10 mL) was added slowly. The reaction system was stirred at −65° C. for 2 h. After completion of the reaction, the reaction was quenched by adding water (5 mL), and then diluted by adding saturated brine (10 mL), and extracted with EtOAc (30 mL, 10 mL*3). The organic phase was combined, washed with saturated brine (30 mL, 10 mL*3), dried over anhydrous sodium sulfate, and concentrated to obtain residual solids, which were subjected to column chromatography (0 to 5% THF/PE) to obtain 32-A.

(346) MS m/z: 412.8[M+H].sup.+

Step 2: Synthesis of Compound 32-B

(347) Under nitrogen protection, a zinc powder (1.14 g, 17.43 mmol) was added to a solution of 32-A (720 mg, 1.74 mmol) and NH.sub.4Cl (932.10 mg, 17.43 mmol, 609.22 μL) in THF (10 mL) and H.sub.2O (10 mL), and the reaction system was stirred at 70° C. for 3 h. After completion of the reaction, the reaction system was filtered, and the filtrate was concentrated to obtain residual solids. The solids were slurried with water (20 mL) for 30 minutes to obtain 32-B.

(348) MS m/z: 350.9[M+H].sup.+

Step 3: Synthesis of Compound 32-C

(349) Under nitrogen protection, a solution of iodomethane (347.68 mg, 2.45 mmol, 152.49 L) in dichloromethane (10 mL) was added to a solution of 32-B (500 mg, 1.07 mmol), TBAB (34.33 mg, 106.50 μmol) and NaOH (63.90 mg, 1.60 mmol) in DCM (10 mL) and H.sub.2O (10 mL), and the reaction system was stirred at 30° C. for 1 h. After completion of the reaction, the reaction system was filtered, and the filtrate was concentrated to obtain residual solids. The residual solids were slurried with water (20 mL) for 30 minutes to obtain 32-C.

(350) MS m/z: 364.9[M+H].sup.+

Step 4: Synthesis of Compound 32-D

(351) Under nitrogen protection, a solution of 32-C (200 mg, 547.65 μmol), 2-fluoropyridine-5-boracic acid (154.34 mg, 1.10 mmol), Na.sub.2CO.sub.3 (116.09 mg, 1.10 mmol), Pd.sub.2(dba).sub.3 (50.15 mg, 54.77 μmol) and Xphos (50.15 mg, 54.77 μmol) in dioxane (18 mL) and water (2 mL) was stirred at 100° C. for 2 h. The reaction mixed solution was concentrated to obtain residual solids, and the solids were subjected to column chromatography (0 to 50% EtOAc/PE) to obtain compound 32-D.

(352) MS m/z: 382.0[M+H].sup.+

Step 5: Synthesis of Compound 32

(353) At 20° C. and under nitrogen protection, 32-D (100 mg, 262.21 μmol) was added to a solution of 1-piperidinepropanol (75.11 mg, 524.42 μmol, 28.71 μL) and NaH (41.95 mg, 1.05 mmol, 60% purity) in DMF (10 mL), and the reaction system was stirred at 70° C. for 2 h. After completion of the reaction, the reaction was quenched by adding water (2 mL), and concentrated to obtain the residual solids. The solids was separated by column chromatography (0 to 10% MeOH/DCM) and preparative HPLC (column: Boston Prime C18 150×30 mm 5 m; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile]; acetonitrile B %: 50%-80%, 8 min) to obtain compound 32.

(354) MS m/z: 505.3[M+H].sup.+

(355) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71 (s, 1H), 8.42 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93-7.84 (m, 2H), 6.89 (d, J=8.8 Hz, 1H), 4.56-4.34 (m, 4H), 3.97 (dd, J=4.8, 11.5 Hz, 2H), 3.39 (s, 3H), 2.78-2.60 (m, 2H), 2.52 (br s, 2H), 2.50-2.33 (m, 4H), 2.10-1.99 (m, 2H), 1.69 (br d, J=14.3 Hz, 2H), 1.60 (br s, 4H), 1.50-1.40 (m, 2H)

Example 33: Compound 33

(356) ##STR00102##

Synthetic Route

(357) ##STR00103##

Step 1: Synthesis of Compound 33

(358) Except for using the corresponding raw materials, the compound 33 was prepared using the same method as in the preparation of compound 1 in Example 1.

(359) MS m/z: 465.2[M+H].sup.+

(360) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 8.37-8.32 (m, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.85-7.77 (m, 2H), 6.82 (d, J=8.5 Hz, 1H), 4.45-4.35 (m, 4H), 3.90 (dd, J=4.9, 11.7 Hz, 2H), 3.32 (s, 3H), 2.69-2.54 (m, 4H), 2.34 (s, 6H), 2.11-1.97 (m, 2H), 1.63 (br d, J=14.1 Hz, 2H)

Example 34: Compound 34

(361) ##STR00104##

Synthetic Route

(362) ##STR00105##

Step 1: Synthesis of Compound 34-A

(363) Except for using the corresponding raw materials, the compound 34-A was prepared using the same method as in the preparation of compound 29-A in Example 29.

(364) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 1H), 8.31 (d, J=7.3 Hz, 1H), 7.84 (d, J=9.5 Hz, 1H), 4.50-4.37 (m, 2H), 3.98 (dd, J=5.0, 11.8 Hz, 2H), 2.84-2.72 (m, 1H), 2.66-2.52 (m, 2H), 1.62 (s, 2H), 0.98-0.94 (m, 2H), 0.90-0.86 (m, 2H)

Step 2: Synthesis of Compound 34-B

(365) Except for using the corresponding raw materials, the compound 34-B was prepared using the same method as in the preparation of compound 1-D in Example 1.

(366) MS m/z: 408.1[M+H].sup.+

(367) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.92 (s, 1H), 8.42 (s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.86 (d, J=11.4 Hz, 1H), 7.05 (dd, J=2.9, 8.4 Hz, 1H), 4.38 (dt, J=1.9, 12.1 Hz, 2H), 3.89 (dd, J=5.1, 11.7 Hz, 2H), 2.75 (s, 1H), 2.56 (br d, J=4.6 Hz, 2H), 1.63 (s, 1H), 1.61-1.59 (m, 1H), 1.17-1.11 (m, 2H), 0.96-0.89 (m, 2H)

Step 3: Synthesis of Compound 34

(368) Except for using the corresponding raw materials, the compound 34 was prepared using the same method as in the preparation of compound 1 in Example 1.

(369) MS m/z: 491.3[M+H].sup.+

(370) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.97 (s, 1H), 8.43 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.96-7.85 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.46 (br t, J=6.4 Hz, 4H), 4.03-3.92 (m, 2H), 2.90-2.79 (m, 1H), 2.72-2.62 (m, 2H), 2.56-2.49 (m, 2H), 2.31 (s, 6H), 2.07-2.01 (m, 2H), 1.71-1.66 (m, 2H), 1.26-1.20 (m, 2H), 1.05-0.97 (m, 2H)

Example 35: Compound 35

(371) ##STR00106##

Synthetic Route

(372) ##STR00107##

Step 1: Synthesis of Compound 35

(373) Except for using the corresponding raw materials, the compound 35 was prepared using the same method as in the preparation of compound 1 in Example 1.

(374) MS m/z: 531.4[M+H].sup.+

(375) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.97 (s, 1H), 8.43 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.95-7.85 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 4.45 (br d, J=6.8 Hz, 4H), 4.04-3.94 (m, 2H), 2.88-2.80 (m, 1H), 2.72-2.61 (m, 2H), 2.57-2.51 (m, 2H), 2.50-2.33 (m, 4H), 2.11-2.03 (m, 2H), 1.72-1.66 (m, 6H), 1.47 (br s, 2H), 1.26-1.20 (m, 2H), 1.05-0.98 (m, 2H)

Example 36: Compound 36

(376) ##STR00108##

Synthetic Route

(377) ##STR00109##

Step 1: Synthesis of Compound 36-A

(378) Except for using the corresponding raw materials, the compound 36-A was prepared using the same method as in the preparation of compound 1-A in Example 1.

(379) MS m/z: 429.0[M+H].sup.+

Step 2: Synthesis of Compound 36-B

(380) Except for using the corresponding raw materials, the compound 36-B was prepared using the same method as in the preparation of compound 1-B in Example 1.

(381) MS m/z: 366.9[M+H].sup.+

Step 3: Synthesis of Compound 36-C

(382) Except for using the corresponding raw materials, the compound 36-C was prepared using the same method as in the preparation of compound 1-C in Example 1.

(383) MS m/z: 381.0[M+H].sup.+

Step 4: Synthesis of Compound 36-D

(384) Except for using the corresponding raw materials, the compound 36-D was prepared using the same method as in the preparation of compound 1-D in Example 1.

(385) MS m/z: 398.0[M+H].sup.+

(386) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.76 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 8.00-7.94 (m, 1H), 7.10 (dd, J=2.8, 8.3 Hz, 1H), 4.50-4.39 (m, 2H), 3.95 (dd, J=5.0, 11.8 Hz, 2H), 3.40 (s, 3H), 2.61 (dt, J=5.3, 13.4 Hz, 2H), 1.68 (br d, J=14.6 Hz, 2H)

Step 5: Synthesis of Compound 36

(387) Except for using the corresponding raw materials, the compound 36 was prepared using the same method as in the preparation of compound 1 in Example 1.

(388) MS m/z: 481.3[M+H].sup.+

(389) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (s, 1H), 8.27-8.17 (m, 2H), 7.93 (s, 1H), 7.73 (dd, J=2.5, 8.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 4.45-4.33 (m, 4H), 3.88 (dd, J=4.9, 11.7 Hz, 2H), 3.33 (s, 3H), 2.75-2.65 (m, 2H), 2.57 (dt, J=5.3, 13.3 Hz, 2H), 2.43 (s, 6H), 2.16-2.06 (m, 2H), 1.61 (br d, J=13.8 Hz, 2H)

Biological Evaluation

Experimental Example 1: In Vitro Evaluation

(390) The compounds of the present disclosure used for experiments are all prepared in-house, and their chemical names and structural formulas are shown in the preparation examples of each compound. The experimental tests were carried out by a UK company Eurofins, and the experimental results were provided by the company. The following experimental processes were also provided by the company.

Experiment Process of ATM Enzyme Activity Test

(391) Human-derived ATM kinase was incubated in a buffer solution containing 30 nM of GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP was determined according to different needs. The reaction was initiated by adding a Mg/ATP complex. After incubating for about 30 minutes at room temperature, a stop solution containing EDTA was added to stop the reaction. Finally, for phosphorylated p53, a detection buffer containing a d2-labeled anti-GST monoclonal antibody and an europium-labeled phosphorylated Ser15 antibody was added. Then time-resolved fluorescence mode was used to read a detection disk, and a homogeneous time-resolved fluorescence (HTRF) signal was obtained by calculating formula HTRF=10000×(Em665 nm/Em620 nm).

Experiment Process of DNA-PK Enzyme Activity Test

(392) Human-derived DNA-PK kinase was incubated in a buffer solution containing 50 nM of GST-cMyc-p53 and Mg/ATP. The concentration of Mg/ATP was determined according to different needs. The reaction was initiated by adding a Mg/ATP complex. After incubating for about 30 minutes at room temperature, a stop solution containing EDTA was added to stop the reaction. Finally, for phosphorylated p53, a detection buffer containing a d2-labeled anti-GST monoclonal antibody and an europium-labeled phosphorylated Ser15 antibody was added. Then time-resolved fluorescence mode was used to read a detection disk, and a homogeneous time-resolved fluorescence (HTRF) signal was obtained by calculating formula HTRF=10000×(Em665 nm/Em620 nm).

(393) TABLE-US-00001 TABLE 1 In vitro cell activity determination results (IC.sub.50) of the compounds of the present disclosure ATM DNA-PK Compound No. (IC50 nM) (IC50 nM) AZD0156 1 58 Example 1 0.9 78 Example 2 288 73 Example 3 1 48 Example 4 1 62 Example 5 2 92 Example 6 2 800 Example 7 1 153 Example 8 3 99 Example 9 1 83 Example 10 2 80 Example 11 2 243 Example 12 2 26 Example 13 4 27 Example 14 3 46 Example 15 2 41 Example 16 4 204 Example 17 3 352 Example 18 2 343 Example 19 0.8 77 Example 20 2 129 Example 21 7 509 Example 22 1 14 Example 23 0.8 30 Example 24 2 80 Example 25 1 92 Example 26 1 76 Example 27 1 99 Example 28 2 334 Example 29 2 269 Example 30 2 475 Example 31 63 88 Example 32 2 561 Example 33 1 593 Example 34 5 >1000 Example 35 3 >1000 Example 36 12 >1000

(394) Conclusion: The compound of the present disclosure has a significant inhibitory effect on ATM kinase and has good selectivity for DNA-PK kinase.

Experimental Example 2

(395) In vivo pharmacodynamic studies of ATM inhibitors and etoposide that act synergistically in female BALB/c nude mouse model with human lung cancer H446 cell subcutaneous xenograft tumor

Experiment Object

(396) Evaluation of the in vivo efficacy of the test drug ATM inhibitor and etoposide in a BALB/c nude mouse model with human lung cancer H446 cell subcutaneous xenograft tumor via intraperitoneal or oral administration.

Experimental Design

(397) TABLE-US-00002 TABLE 2 Experimental animal grouping and dosage regimen for in vivo efficacy of ATM inhibitors and etoposide Number Number of Route of Frequency and of groups mice per Dosage admini- cycle of (G) group (N) Treatment (mg/kg) stration administration 1 6 Vehicle — PO QD × 4 W Control 2 6 etoposide 15 IP BIW × 4 W 3 6 Example 32 5 PO QD (PG-D0, 3D on, 4D off from PG-D1) × 4 W 4 6 etoposide + 15 + 5 IP + PO BIW + QD (PG- example 32 D0, 3D on, 4D off from PG-D1) × 4 W 5 6 etoposide + 15 + 5 IP + PO BIW + QD (PG- AZD0156 D0, 3D on, 4D off from PG-D1) × 4 W Note: IP: Intraperitoneal injection; PO: Oral administration; QD: Once a day; BIW: Twice a week; QD (PG-D0, 3D on, 4D off from PG-D1) × 4 W: administration from Tuesday to Thursday, once a day, weekly cycle, for four weeks; BIW + QD (PG-D0, 3D on, 4D off from GPG-D1) × 4 W: etoposide was administered on Monday, ATM inhibitor was administered from Tuesday to Thursday, once a day, weekly cycle, for four weeks.

(398) Note: IP: Intraperitoneal injection; P0: Oral administration; QD: Once a day; BIW: Twice a week; QD (PG-D0, 3D on, 4D off from PG-D31)×4W: administration from Tuesday to Thursday, once a day, weekly cycle, for four weeks; BIW+QD (PG-D0, 3D on, 4D off from PG-D1)×4 W: etoposide was administered on Monday, ATM inhibitor was administered from Tuesday to Thursday, once a day, weekly cycle, for four weeks.

Experimental Methods and Steps

(399) 1. Cell Culture

(400) Human lung cancer cells H446 (ATCC, Manassas, Va., HTB-171) were cultured in a monolayer in vitro. The culture conditions were: RPMI-1640 medium with 10% fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin, and 37° C. 5% CO.sub.2 culture. Conventional digestion treatment with pancreatin-EDTA for passage was carried out twice a week. When the cell saturation was 80% to 90%, the cells were collected, counted and inoculated.

(401) 2. Tumor Cell Inoculation

(402) 0.2 mL 5×10.sup.6 of H446 cells (1:1 plus matrigel) were subcutaneously inoculated on the right back of each nude mouse. The grouping and administration were started when the average tumor volume reached 125 mm.sup.3 (Table).

(403) 3. Preparation of Tested Samples

(404) TABLE-US-00003 TABLE 3 Preparation method of tested samples Compound Compound preparation Storage conditions Vehicle 1 45 g of Captisol was taken, 100 mL of water was Room temperature added, vortexed until clear, and finally water was added to adjust the volume to 150 mL. Vehicle 2 50 g of HP-β-CD was taken, 200 mL of water was Room temperature added, vortexed until clear, and finally water was added to adjust the volume to 500 mL, and PH was adjusted to 6. Etoposide 13.636 mg of etoposide was weighed, and a stirrer was 4° C. put. Firstly, 1.8 mL of PEG300 was added, and stirred at 50° C. until a clear solution, and then 0.9 mL of Solutol HS15 (thawing Solutol at 50° C.) was added and stirred at 50° C. until a clear solution. 6.3 mL of 20% HP-β-CD prepared with 50 mM of phosphate buffer (pH = 6.8) was added and stirred at room temperature until a clear solution. Example 32 5.4 mg of Example 32 was weighed, firstly 0.54 mL of 4° C. DMSO was added, and stirred until a clear solution, and then 4.86 mL of Vehicle 1 was added and stirred until a clear solution, and PH was adjusted to 4-6. AZD0156 2.735 mg of AZD0156 was weighed, firstly 0.54 mL of 4° C. DMSO was added, and stirred until a clear solution, and then 4.86 mL of Vehicle 1 was added and stirred until clear. PH was adjusted to 4-6. Note: Drugs needs to be mixed gently and thoroughly before administering to animals.

(405) Note: Drugs needs to be mixed gently and thoroughly before administering to animals.

Tumor Measurement and Experimental Index

(406) The experimental index was to investigate whether the tumor growth was inhibited, delayed or cured. Tumor diameter was measured twice a week with a vernier caliper. The calculation formula of tumor volume: V=0.5a×b.sup.2, wherein a and b represented the long and short diameters of the tumor, respectively.

(407) The tumor suppressive effect of the compounds uses TGI (0%). TGI (0%) reflected the tumor growth inhibition rate. Calculation of TGI (0%): TGI (0%)=[1−(average tumor volume at the end of administration in a treatment group−average tumor volume at the beginning of administration in this treatment group)/(average tumor volume at the end of administration in the solvent control group−average tumor volume at the beginning of administration in the solvent control group)]×10000.

(408) Tumor proliferation rate T/C (%): wherein T is the average tumor volume obtained from the last measurement (PG-D26) of the treatment group, and C is the average tumor volume obtained from the last measurement (PG-D26) of the control group.

Statistical Analysis

(409) Mean value and standard error (SEM) of the tumor volume of each group at each time point were included (specific data is shown in tables). The treatment group showed the best treatment effect on day 26 after the administration at the end of the test, so the statistical analysis was performed based on this data to evaluate the differences between the groups. The comparison between two groups was analyzed by T-test, and the comparison between three or more groups was analyzed by one-way ANOVA. If there was heterogeneity of variance, the Games-Howell test was applied. If there was homogeneity of variance, the Dunnet (2-sided) test was used for analysis. All data analysis was performed with SPSS 17.0. p<0.05 was considered significantly different.

Experimental Results

Mortality, Morbidity, and Weight Changes

(410) The body weight of experimental animals is used as a reference index for indirect determination of drug toxicity. In this model, none of the administration groups showed significant weight loss (FIG. 1). Mice with no. 42161 were found dead on day 15 after administration of the combination group of 15 mg/kg of etoposide and 5 mg/kg of AZD0156. In the treatment group where etoposide was used in combination with Example 32 and AZD0156, respectively, a part of animals lost more than 10% but not less than 15% in body weight. The effect of the test drug ATM inhibitor and etoposide on the body weight of the female BALB/c nude mouse model with H446 cell subcutaneous xenograft tumor was shown in FIG. 1. Relative weight change was calculated based on the weight of an animal at the beginning of administration. The data point represents the percent change in average weight within a group, and the error bar represents standard error (SEM).

Tumor volume

(411) The tumor volume changes in each group after the treatment by administrating the test drug ATM inhibitor and etoposide in female BALB/c nude mouse model with H446 cells subcutaneous xenograft tumor are shown in Table 4.

(412) TABLE-US-00004 TABLE 4 Tumor volume at different time points in each group Tumor volume (mm.sup.3).sup.a Etoposide + After Etoposide + AZD0156 administration Vehicle 1 + Etoposide Example 32 example 32 15 + 5 Days Vehicle 2 15 mg/kg 5 mg/kg 15 + 5 mg/kg mg/kg 0 125 ± 7  125 ± 8  125 ± 7  125 ± 7  124 ± 7  3 148 ± 10  132 ± 11  138 ± 6  119 ± 18  133 ± 8  7 275 ± 21  259 ± 37  229 ± 10  170 ± 29  197 ± 26  10 434 ± 40  364 ± 47  359 ± 36  245 ± 40  291 ± 29  14 751 ± 61  552 ± 66  644 ± 83  317 ± 59  417 ± 36  17 1128 ± 74  851 ± 84  974 ± 129 413 ± 64  590 ± 59  21 1798 ± 153  1021 ± 112  1240 ± 157  570 ± 88  759 ± 82  26 2782 ± 265  1667 ± 193  2054 ± 221  930 ± 142 1344 ± 146  Note: .sup.aMean ± SEM.

(413) Note: a. Mean±SEM.

Tumor Growth Curve

(414) Tumor growth curve of tumor-bearing mice model with H446 xenograft tumor after administering with the test drug ATM inhibitor and etoposide. Tumor growth curve is shown in FIG. 2. The data point represents mean tumor volume within a group, and the error bar represents standard error (SEM).

Anti-Tumor Efficacy Evaluation Index (Calculated Based on Tumor Volume on Day 26 after Administration)

(415) TABLE-US-00005 TABLE 5 Evaluation of tumor suppressive efficacy of test drug ATM inhibitor and etoposide on H446 xenograft tumor model Tumor volume (mm.sup.3).sup.a T/C.sup.b TGI.sup.b Groups (Day 26) (%) (%) p value.sup.c Vehicle 1 + Vehicle 2 2782 ± 265  — — — etoposide, 15 mg/kg 1667 ± 193  59.93 41.95 0.119 Example 32, 5 mg/kg 2054 ± 221  73.86 27.36 0.559 Etoposide + example 32, 930 ± 142 33.42 69.70 0.006 15 + 5 mg/kg Etoposide + AZD0156, 1344 ± 146  48.30 54.17 0.028 15 + 5 mg/kg Note: .sup.aMean ± SEM. The animal #42161 in group 5 was found dead on PG-D15, and its data is not counted in statistics. .sup.bTumor growth inhibition was calculated by T/C and TGI (TGI (%) = [1 − (T.sub.26 − T.sub.0)/(V.sub.26 − V.sub.0)] × 100). .sup.cThe p value was calculated based on the tumor volume.

(416) Note: a. Mean±SEM. The animal #42161 in group 5 was found dead on PG-D15, and its data is not counted in statistics.

(417) b. Tumor growth inhibition was calculated by T/C and TGI (TGI (%)=[1−(T.sub.26−T0)/(V.sub.26−V.sub.0)]×100).

(418) c. The p value was calculated based on the tumor volume.

Experiment Discussion

(419) In this experiment, we evaluated the in vivo efficacy of the test drug ATM inhibitor and etoposide in the human lung cancer H446 xenograft tumor model. The tumor volume of each group at different time points was shown in Table 4, Table 5 and FIG. 2. 26 days after administration, the tumor volume of tumor-bearing mice in the solvent control group reached 2,782 mm.sup.3, and for groups Etoposide+Example 32 (15 mg/kg+5 mg/kg) and Etoposide+AZD0156 (15 mg/kg+5 mg/kg), the average tumor volume was 930 mm.sup.3 and 1,344 mm.sup.3, respectively, the T/C was 33.42% and 48.30, respectively, the TGI was 69.70% and 54.11%, and the p value was 0.006 and 0.028 compared with the solvent control, respectively.

Experiment Conclusion

(420) In the in vivo efficacy experiment of the ATM inhibitor and etoposide in the human lung cancer H446 xenograft tumor model, the combination of Example 32 and etoposide showed a good synergistic effect, which was better than the efficacy of AZD0156 in combination with etoposide.