Cyclopropylamine compound as LSD1 inhibitor and use thereof

Abstract

Provided is a cyclopropylamine compound as lysine-specific demethylase 1 (LSD1) inhibitor, and a use thereof in preparation of drug for treating diseases associated with LSD1. The cyclopropylamine compound is a compound represented by formula (I), an isomer thereof, and a pharmaceutically acceptable salt thereof. ##STR00001##

Claims

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ##STR00091## wherein, L.sub.1 is selected from —(CH.sub.2)g-, —C(═O)—NH—, —C(═O)— and —C(═O)—O—; R.sub.1 is selected from H, CI, F, Br, I, OH, NH.sub.2, CN, COOH, —C(═O)NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6alkoxyl, —C(═O)NH—C.sub.1-6 alkyl and 5-6 membered heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxyl, —C(═O)NH—C.sub.1-6 alkyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R.sub.a; ring A is selected from C.sub.6-10 aryl, 5-6 membered heteroaryl, C.sub.3-8 cycloalkyl and 3-6 membered heterocycloalkyl; R.sub.a is selected from F, Cl, Br, I, OH, NH.sub.2, CN, COOH and C.sub.1-3 alkyl; m is 1 or 2; n is 1; r is 1; q is 1; g is 0, 1, 2 or 3; each of the 5-6 membered heteroaryl and 3-6 membered heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from —NH—, —O—, —S— and N; the carbon atom marked with “*” is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer; the carbon atom marked with “#” is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.

2. The compound or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.a is selected from F, Cl, Br, I, OH, NH.sub.2, CN, COOH and —CH.sub.3.

3. The compound or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R.sub.1 is selected from H, CI, F, Br, I, OH, NH.sub.2, CN, COOH, —C(═O)NH.sub.2, C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, —C(═O)NH.sub.2—C.sub.1-3 alkyl and 5 membered heteroaryl, wherein the C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, —C(═O)NH.sub.2—C.sub.1-3 alkyl and 5 membered heteroaryl are optionally substituted by 1, 2 or 3 R.sub.a.

4. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 3, wherein R.sub.1 is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, COOH, —C(═O)NH.sub.2, —CH.sub.3, —OCH.sub.3 and tetrazolyl, wherein the —CH.sub.3, —OCH.sub.3 and tetrazolyl are optionally substituted by 1, 2 or 3 R.sub.a.

5. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as defined in claim 4, wherein R.sub.1 is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, COOH, —C(═O)NH.sub.2, —CF.sub.3, —OCH.sub.3, —CH.sub.2—COOH and ##STR00092##

6. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein L.sub.1 is selected from a single bond, —CH.sub.2-, —(CH.sub.2).sub.2-, —C(═O)—NH—, —C(═O)— and —C(═O)—O—.

7. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring A is selected from phenyl, naphthyl, tetrazolyl, pyridyl, pyrazinyl, cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[2.2.2]octyl and azetidinyl.

8. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 7, wherein ring A is selected from ##STR00093##

9. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the compound is ##STR00094## wherein, R.sub.1, L.sub.1 and ring A are as defined in claim 1.

10. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 9, wherein the compound is selected from ##STR00095## wherein, L.sub.2 is selected from a single bond, —CH.sub.2-, —(CH.sub.2).sub.2-, —(CH.sub.2).sub.3- and —NH.

11. A compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100##

12. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the salt is selected from hydrochloride.

13. A method for treating a disease associated with LSD1 in a subject in need thereof, comprising administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

14. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 11, wherein the salt is selected from hydrochloride.

15. A method for treating a disease associated with LSD1 in a subject in need thereof, comprising administering the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 11 to the subject.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

(1) The following examples further illustrate the present disclosure, but the present disclosure is not limited thereto. The present disclosure has been described in detail herein, and its specific embodiments have also been disclosed, for one skilled in the art, it is obvious to make various modifications and improvements to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

Embodiment 1

(2) ##STR00021##

(3) Synthetic Route:

(4) ##STR00022##

Step 1

(5) Sodium hydroxide (279 g, 6.99 mol) was dissolved in water (3 L), then the reaction mixture was cooled to 10° C. with an ice-water bath, compound 1-1 (997 g, 3.49 mol) was added to the reaction mixture in batches, and the reaction mixture was stirred at 10° C. for 2 hours. Ethyl acetate (2 L×1) was added to the reaction mixture for extraction, the mixture was extracted with ethyl acetate (1.6 L×1). The organic phases were combined, washed with water (1.5 L×1), and then washed with saturated brine (1.5 L×1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain the compound 1-2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.18-7.14 (m, 2H), 7.08-7.04 (m, 1H), 6.95-6.92 (m, 2H), 2.48-2.44 (m, 1H), 1.80-1.76 (m, 1H), 0.98-0.87 (m, 2H).

Step 2

(6) Compound 1-3 (1.00 g, 6.62 mmol) and compound 1-4 (1.50 g, 9.26 mmol) were dissolved in 1, 2-dichloroethane (10 mL). The reaction mixture was stirred at 50° C. for 12 hours. The reaction mixture was cooled to 0° C. and stirred for 1 hour, filtered, and the filter cake was washed with dichloromethane (10 mL×2) to obtain compound 1-5. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.43 (s, 1H), 8.02-7.99 (m, 2H), 7.82-7.80 (m, 2H), 7.11 (s, 1H), 7.04 (s, 1H), 3.85 (m, 3H).

Step 3

(7) Compound 1-6 (1.00 g, 3.92 mmol) and compound 1-2 (522 mg, 3.92 mmol) were dissolved in anhydrous dichloromethane (20 mL), and glacial acetic acid (706 mg, 11.8 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20° C. for 1 hour, sodium triacetoxyborohydride (2.49 g, 11.8 mmol) was added thereto, and the reaction mixture was stirred at 20° C. for 10 hours. The reaction mixture was diluted with dichloromethane (80 mL) and washed with saturated aqueous solution of sodium bicarbonate (100 mL×3), water (100 mL×2), and saturated brine (100 mL×1), and then dried over anhydrous sodium sulfate, filtered, and the resulting mother liquor was concentrated to obtain compound 1-7. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.18-7.16 (m, 2H), 7.11-7.17 (m, 1H), 6.96-6.94 (m, 2H), 3.92-3.89 (m, 1H), 3.61-3.55 (m, 1H), 3.52-3.48 (m, 3H), 3.27-3.23 (m, 2H), 2.24-2.21 (m, 1H), 1.99-1.94 (m, 1H), 1.85-1.79 (m, 1H), 1.55-1.47 (m, 6H), 1.38 (s, 9H), 1.01-0.90 (m, 2H). MS-ESI calculated value [M+H].sup.+ 373, measured value 373.

Step 4

(8) Compound 1-7 (1.10 g, 2.95 mmol) was dissolved in anhydrous dichloromethane (20 mL), triethylamine (448 mg, 4.43 mmol) and trifluoroacetic anhydride (930 mg, 4.43 mmol) were added thereto. The reaction mixture was stirred at 15° C. for 12 hours. Dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with hydrochloric acid (1M, 50 mL×1) and saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated, the crude product was purified by column chromatography (5/1 petroleum ether/ethyl acetate, R.sub.f=0.3) to obtain compound 1-8. MS-ESI calculated values [M−56+H].sup.+413, [M−Boc+H].sup.+369, measured values 413, 369.

Step 5

(9) Compound 1-8 (600 mg, 1.28 mmol) was dissolved in anhydrous dichloromethane (6 mL), and trifluoroacetic acid (4.62 g, 40.5 mmol) was added thereto at 20° C. The reaction mixture was stirred at 20° C. for 2 hours, concentrated under reduced pressure to remove the solvent, and the residue was dissolved in dichloromethane (6 mL), and then triethylamine (250 μL) was added thereto, and stirred at room temperature for half an hour. The solvent was removed by concentration under reduced pressure to obtain compound 1-9. MS-ESI calculated value [M+H].sup.+ 369, measured value 369.

Step 6

(10) Compound 1-9 (100 mg, 0.271 mmol) and compound 1-5 (69.9 mg, 0.285 mmol) were dissolved in 1, 2-dichloroethane (10 mL). The reaction mixture was stirred at 50° C. for 2 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane (50 mL), and the organic phase was washed with water (50 mL×1) and saturated brine (50 mL×1) in sequence, then dried over anhydrous sodium sulfate, filtered, and then the mother liquor was concentrated, the crude product was purified by thin layer chromatography (1/1 petroleum ether/ethyl acetate, R.sub.f=0.34) to obtain compound 1-10. MS-ESI calculated value [M+H].sup.+ 546, measured value 546.

Step 7

(11) Compound 1-10 (100 mg, 0.183 mmol) was dissolved in water (3 mL) and tetrahydrofuran (3 mL), and sodium hydroxide (22.0 mg, 0.549 mmol) was added thereto. The reaction mixture was stirred at 50° C. for 12 hours, concentrated under reduced pressure to remove tetrahydrofuran, and the residue was dissolved in water (3 mL), the pH value was adjusted to 4 with hydrochloric acid (1 mol/L), and the mixture was separated by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.92 (d, J=8.8, 2H), 7.47 (d, J=8.8, 2H), 7.34-7.30 (m, 2H), 7.26-7.22 (m, 1H), 7.20-7.18 (m, 2H), 4.16-4.06 (m, 3H), 3.86-3.79 (m, 2H), 3.42-3.38 (m, 2H), 3.02-3.01 (m, 1H), 2.53-2.38 (m, 2H), 1.93-1.79 (m, 4H), 1.56-1.53 (m, 2H), 1.46-1.43 (m, 1H). MS-ESI calculated value [M+H].sup.+ 436, measured value 436.

Embodiment 2

(12) ##STR00023##

(13) Synthetic Route:

(14) ##STR00024##

Step 1

(15) Compound 2-1 (194 mg, 0.856 mmol) and compound 1-2 (114 mg, 0.856 mmol) were dissolved in anhydrous dichloromethane (1 mL), glacial acetic acid (154 mg, 2.57 mmol) was added to the reaction mixture. The reaction mixture was stirred at 26° C. for 2 hours, sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added thereto, and the reaction mixture was stirred at 26° C. for 10 hours. Saturated sodium bicarbonate (30 mL) solution was added to the reaction mixture, extracted with dichloromethane (30 mL×3), the organic phases were combined and washed with saturated brine (30 mL×1), then dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated, the crude product was purified by thin layer chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.26) to obtain compound 2-2. MS-ESI calculated value [M+H].sup.+ 345, measured value 345.

Step 2

(16) Compound 2-2 (154 mg, 0.447 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (67.9 mg, 0.670 mmol) and trifluoroacetic anhydride (141 mg, 0.670 mmol) were added thereto. The reaction mixture was stirred at 25° C. for 12 hours. Dichloromethane (50 mL) was added to the reaction mixture, the organic phase was washed with hydrochloric acid (1M, 30 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated, the crude product was purified by thin layer chromatography (3/1 petroleum ether/ethyl acetate, R.sub.f=0.84) to obtain compound 2-3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.34-7.31 (m, 2H), 7.28-7.23 (m, 1H), 7.09-7.03 (m, 2H), 4.55-4.47 (m, 1H), 4.16-3.84 (m, 6H), 3.12-2.91 (m, 1H), 2.49-2.05 (m, 3H), 1.53-1.43 (m, 11H). MS-ESI calculated values [M−56+H].sup.+385, [M−Boc+H].sup.+341, measured values 385, 341.

Step 3

(17) Compound 2-3 (160 mg, 0.408 mmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1 mL, 13.5 μmol) was added dropwise at 0° C. The reaction mixture was stirred at 20° C. for 1 hour, and concentrated under reduced pressure to remove the solvent to obtain compound 2-4. MS-ESI calculated value [M+H].sup.+ 341, measured value 341.

Step 4

(18) Compound 2-4 (200 mg, 0.587 mmol), compound 2-5 (137 mg, 0.599 mmol) and triethylamine (178 mg, 1.76 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was stirred at 50° C. for 2 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane (50 mL), and the organic phase was washed with water (50 mL×1) and saturated brine (50 mL×1) in sequence, the mixture was dried over anhydrous sodium sulfate, filtered, the mother liquor was concentrated, and the crude product was purified by thin layer chromatography (1/1 petroleum ether/ethyl acetate, R.sub.f=0.34) to obtain compound 2-6. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.01-7.98 (m, 2H), 7.38-7.24 (m, 5H), 7.10-7.04 (m, 2H), 4.62-4.51 (m, 1H), 4.04-3.98 (m, 1H), 3.92-3.84 (m, 4H), 3.73-3.70 (m, 2H), 3.54-3.18 (m, 4H), 3.08-2.89 (m, 1H), 2.60-2.34 (m, 3H), 1.59-1.42 (m, 2H). MS-ESI calculated values [M+H].sup.+ 489, measured values 489.

Step 5

(19) Compound 2-6 (140 mg, 0.287 mmol) was dissolved in water (1 mL) and tetrahydrofuran (4 mL), and sodium hydroxide (34.4 mg, 0.859 mmol) was added thereto. The reaction mixture was stirred at 50° C. for 2 hours, concentrated under reduced pressure to remove tetrahydrofuran, and the residue was dissolved in water (3 mL), the pH value was adjusted to 4 with hydrochloric acid (1 mol/L), and the mixture was purified by high performance liquid chromatography (acid, hydrochloric acid system) to obtain the hydrochloride of compound 2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.12-8.10 (m, 2H), 7.61-7.59 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.17 (m, 3H), 4.65-4.45 (m, 3H), 4.36-4.08 (m, 6H), 3.03-2.99 (m, 1H), 2.90-2.80 (m, 1H), 2.60-2.53 (m, 2H), 1.61-1.55 (m, 1H), 1.45-1.40 (m, 1H). MS-ESI calculated values [M+H].sup.+ 379, measured values 379.

Embodiment 3

(20) ##STR00025##

(21) Synthetic Route:

(22) ##STR00026##

Step 1

(23) Compound 3-1 (89.1 mg, 0.543 mmol) and compound 1-9 (100 mg, 0.271 mmol) were dissolved in anhydrous dichloromethane (2 mL), and glacial acetic acid (48.9 mg, 0.814 mmol) was added thereto. The reaction mixture was stirred at 0-30° C. for 12 hours, sodium triacetoxyborohydride (173 mg, 0.814 mmol) was added thereto, and the reaction mixture was stirred at 30° C. for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane (10 mL×3), and the combined organic phase was washed with water (10 mL×1) and saturated brine (10 mL×1) in sequence, the mixture was then dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.86) to obtain compound 3-2. MS-ESI calculated value [M+H].sup.+ 517, measured value 517.

Step 2

(24) Compound 3-2 (30.0 mg, 0.580 mmol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and water (1 mL), and sodium hydroxide (6.97 mg, 0.174 mmol) was added to the reaction mixture. The reaction mixture was stirred for reaction at 60° C. for 3 hours, and concentrated under reduced pressure to remove the solvent. The residue was diluted with water, and the pH value was adjusted to about 4 with aqueous solution of hydrochloric acid (1 mol/L), and the mixture was purified by high performance liquid chromatography (hydrochloric acid system) to obtain the hydrochloride of compound 3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.23 (s, 1H), 8.18-8.16 (m, 1H), 7.85-7.83 (m, 1H), 7.64-7.62 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.19 (m, 3H), 4.54 (s, 2H), 4.44-4.14 (m, 3H), 3.42-3.37 (m, 2H), 3.31-3.28 (m, 2H), 3.03-3.02 (m, 1H), 2.62-2.58 (m, 1H), 2.45-2.40 (m, 1H), 2.16-2.05 (m, 4H), 1.95-1.88 (m, 1H), 1.64-1.59 (m, 1H), 1.46-1.42 (m, 1H). MS-ESI calculated values [M+H].sup.+ 407, measured values 407.

Embodiment 4

(25) ##STR00027##

(26) Synthetic Route:

(27) ##STR00028##

Step 1

(28) Compound 4-2 was obtained by referring to Step 1 of Embodiment 2. MS-ESI calculated value [M+H].sup.+ 359, measured value 359.

Step 2

(29) Compound 4-3 was obtained by referring to Step 2 of Embodiment 2. MS-ESI calculated values [M+Na].sup.+477, measured values 477.

Step 3

(30) Compound 4-4 was obtained by referring to Step 3 of Embodiment 2. MS-ESI calculated values [M+H].sup.+ 355, measured values 355.

Step 4

(31) Compound 4-6 was obtained by referring to Step 4 of Embodiment 2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92-7.90 (m, 2H), 7.28-7.26 (m, 4H), 7.25-7.22 (m, 2H), 7.16-7.01 (m, 1H), 4.32-4.27 (m, 2H), 4.14-4.02 (m, 1H), 3.84-3.74 (m, 1H), 3.66-3.63 (m, 2H), 3.40-3.37 (m, 2H), 3.15-3.08 (m, 1H), 3.03-2.95 (m, 3H), 2.15-2.10 (m, 4H), 1.65-1.55 (m, 1H), 1.39-1.29 (m, 5H). MS-ESI calculated values [M+H].sup.+ 517, measured values 517.

Step 5

(32) The hydrochloride of Compound 4 was obtained by referring to Step 5 of Embodiment 2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.11 (d, J=8.0, 2H), 7.63 (dd, J=8.0, 2.8, 2H), 7.31-7.29 (m, 2H), 7.23-7.19 (m, 3H), 4.55 (s, 2H), 4.36-4.34 (m, 3H), 4.23-4.02 (m, 2H), 3.64-3.62 (m, 2H), 3.02-2.99 (m, 1H), 2.79-2.71 (m, 1H), 2.55-2.49 (m, 1H), 2.12-2.07 (m, 1H), 1.85-1.73 (m, 2H), 1.60-1.56 (m, 1H), 1.46-1.44 (m, 1H). MS-ESI calculated values [M+H].sup.+ 393, measured values 393.

Embodiment 5

(33) ##STR00029##

(34) Synthetic Route:

(35) ##STR00030##

Step 1

(36) Compound 5-2 was obtained by referring to Step 1 of Embodiment 2. MS-ESI calculated values [M+H].sup.+ 359, measured values 359.

Step 2

(37) Compound 5-3 was obtained by referring to Step 2 of Embodiment 2. MS-ESI calculated values [M+H].sup.+ 455, measured values 455.

Step 3

(38) Compound 5-4 was obtained by referring to Step 3 of Embodiment 2. MS-ESI calculated values [M+H].sup.+ 355, measured values 355.

Step 4

(39) Compound 5-5 was obtained by referring to Step 4 of Embodiment 2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.96-7.94 (m, 2H), 7.36-7.29 (m, 4H), 7.22-7.20 (m, 1H), 7.02-6.95 (m, 2H), 4.63-4.52 (m, 2H), 4.32-4.26 (m, 2H), 3.52 (s, 2H), 3.11-3.02 (m, 1H), 2.65-2.63 (m, 2H), 2.29-2.14 (m, 3H), 1.93-1.79 (m, 2H), 1.54-1.49 (m, 4H), 1.33-1.26 (m, 4H). MS-ESI calculated values [M+H].sup.+ 517, measured values 517.

Step 5

(40) The hydrochloride of Compound 5 was obtained by referring to Step 5 of Embodiment 2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.13 (d, J=8.0, 2H), 7.68 (d, J=8.0, 2H), 7.31-7.28 (m, 2H), 7.24-7.15 (m, 3H), 4.70-4.64 (m, 1H), 4.45-4.37 (m, 3H), 3.53-3.34 (m, 2H), 3.27-3.21 (m, 2H), 2.91-2.88 (m, 1H), 2.60-2.20 (m, 6H), 1.63-1.58 (m, 1H), 1.38-1.32 (m, 1H). MS-ESI calculated values [M+H].sup.+ 393, measured values 393.

Embodiment 6

(41) ##STR00031##

(42) Synthetic Route:

(43) ##STR00032##

Step 1

(44) Compound 1-9 (345 mg, 0.936 mmol) and compound 6-1 (154 mg, 0.937 mmol) were dissolved in anhydrous dichloromethane (10 mL), and glacial acetic acid (5.62 mg, 93.6 μmol) was added to the reaction mixture. The reaction mixture was stirred at 20° C. for 10 hours, sodium triacetoxyborohydride (397 mg, 1.87 mmol) was added thereto, and the reaction mixture was stirred at 20° C. for 2 hours. After the reaction mixture was diluted with dichloromethane (50 mL), it was washed with saturated aqueous solution of sodium bicarbonate (50 mL×3), water (50 mL×2) and saturated brine (50 mL×1), and dried over anhydrous sodium sulfate, then filtered, the resulting mother liquor was concentrated, and the crude product was purified by thin layer chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.24) to obtain compound 6-2. MS-ESI calculated value [M+H]+ 517, measured value 517.

Step 2

(45) Compound 6-2 (280 mg, 0.542 mmol) was dissolved in tetrahydrofuran (3 mL), water (3 mL) and ethanol (3 mL), and sodium hydroxide (65.1 mg, 1.63 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 3 hours, concentrated under reduced pressure to remove tetrahydrofuran and ethanol, the residue was dissolved in water (10 mL), the pH value was adjusted to 4 with hydrochloric acid (1 M), and the mixture was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.13 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.34-7.30 (m, 2H), 7.26-7.19 (m, 3H), 4.43 (s, 2H), 4.22-4.19 (m, 1H), 4.7-4.11 (m, 2H), 3.53-3.37 (m, 2H), 3.32-3.24 (m, 2H), 3.03-3.00 (m, 1H), 2.64-2.60 (m, 1H), 2.45-2.40 (m, 1H), 2.24-2.05 (m, 4H), 2.00-1.93 (m, 1H), 1.64-1.61 (m, 1H), 1.45-1.40 (m, 1H). MS-ESI calculated value [M+H].sup.+ 407, measured value 407. The hydrochloride of compound 6 was dissolved in water (2 mL) and acetonitrile (2 mL), and the pH value was adjusted to neutral by adding saturated sodium bicarbonate solution. The mixture was purified by high performance liquid chromatography (neutral, ammonium bicarbonate system) to obtain compound 6.

Embodiment 7

(46) ##STR00033##

(47) Synthetic Route:

(48) ##STR00034##

Step 1

(49) Compound 7-2 was obtained by referring to Step 1 of Embodiment 6. MS-ESI calculated values [M+H].sup.+ 517, measured values 517.

Step 2

(50) The hydrochloride of Compound 7 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.25-8.23 (m, 1H), 7.74-7.65 (m, 3H), 7.34-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.61 (s, 2H), 4.23-4.21 (m, 3H), 3.52-3.37 (m, 4H), 3.03-3.00 (m, 1H), 2.67-2.63 (m, 1H), 2.44-2.40 (m, 1H), 2.16-2.09 (m, 4H), 1.96-1.87 (m, 1H), 1.69-1.66 (m, 1H), 1.45-1.39 (m, 1H). MS-ESI calculated value [M+H].sup.+ 407, measured value 407.

Embodiment 8

(51) ##STR00035##

(52) Synthetic Route:

(53) ##STR00036##

Step 1

(54) Compound 8-2 was obtained by referring to Step 1 of Embodiment 6. MS-ESI calculated values [M+H].sup.+ 489, measured values 489.

Step 2

(55) The hydrochloride of Compound 8 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.50 (d, J=8.8 Hz, 2H), 7.34-7.31 (m, 2H), 7.26-7.20 (m, 3H), 7.03 (d, J=8.8 Hz, 2H), 4.27 (s, 2H), 4.21-4.19 (m, 1H), 4.16-4.15 (m, 2H), 3.84 (s, 3H), 3.49-3.38 (m, 2H), 3.25-3.16 (m, 2H), 3.03-3.02 (m, 1H), 2.65-2.61 (m, 1H), 2.44-2.39 (m, 1H), 2.17-2.06 (m, 4H), 1.98-1.89 (m, 1H), 1.65-1.62 (m, 1H), 1.45-1.39 (m, 1H). MS-ESI calculated value [M+H].sup.+ 393, measured value 393.

Embodiment 9

(56) ##STR00037##

(57) Synthetic Route:

(58) ##STR00038##

Step 1

(59) Compound 9-1 (50.5 mg, 0.407 mmol) and compound 1-9 (100 mg, 0.271 mmol) were dissolved in anhydrous dichloromethane (6 mL), and glacial acetic acid (48.9 mg, 0.814 mmol) was added thereto. The reaction mixture was stirred at 0-30° C. for 12 hours, sodium triacetoxyborohydride (172 mg, 0.814 mmol) was added thereto, and the reaction mixture was stirred at 30° C. for 1 hour. Then saturated sodium bicarbonate (20 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane (10 mL×3), the organic phases were combined, and then washed with water (10 mL×1) and saturated brine (10 mL×1), dried over anhydrous sodium sulfate, filtered, then the mother liquor was concentrated, and the crude product was purified by thin layer chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.86) to obtain compound 9-2. MS-ESI calculated value [M+H].sup.+ 477, measured value 477.

Step 2

(60) Compound 9-2 (40.0 mg, 83.9 μmol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and water (1 mL), and sodium hydroxide (10.0 mg, 0.252 mmol) was added to the reaction mixture. The reaction mixture was stirred at 60° C. for 2.5 hours, concentrated under reduced pressure to remove the solvent, the residue was diluted with water, and the pH value was adjusted to about 4 with aqueous hydrochloric acid (1 mol/L). The hydrochloride of compound 9 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.66-7.63 (dd, J=7.7, 5.5, 2H), 7.33-7.31 (m, 2H), 7.26-7.20 (m, 5H), 4.35 (s, 2H), 4.22-4.15 (m, 3H), 3.43-3.36 (m, 2H), 3.26-3.20 (m, 2H), 3.03 (s, 1H), 2.63-2.62 (m, 1H), 2.45-2.40 (m, 1H), 2.19-2.08 (m, 4H), 1.98-1.95 (m, 1H), 1.65-1.62 (m, 1H), 1.43-1.42 (m, 1H). MS-ESI calculated value [M+H].sup.+ 381, measured value 381.

Embodiment 10

(61) ##STR00039##

(62) Synthetic Route:

(63) ##STR00040##

Step 1

(64) Compound 10-1 (70.9 mg, 0.407 mmol) and compound 1-9 (100 mg, 0.271 mmol) were dissolved in anhydrous dichloromethane (2 mL), and glacial acetic acid (48.9 mg, 0.814 mmol) was added to the reaction mixture. The reaction mixture was stirred at 30° C. for 12 hours, sodium triacetoxyborohydride (173 mg, 0.814 mmol) was added thereto, and the reaction mixture was stirred at 30° C. for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, extracted with dichloromethane (10 mL×3), the organic phases were combined and washed with water (10 mL×1) and saturated brine (10 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.86) to obtain compound 10-2. MS-ESI calculated value [M+H].sup.+ 527, measured value 527.

Step 2

(65) Compound 10-2 (40.0 mg, 76.0 umol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and water (1 mL), and sodium hydroxide (9.12 mg, 0.228 mmol) was added to the reaction mixture. The reaction mixture was stirred at 60° C. for 2.5 hours, concentrated under reduced pressure to remove the solvent, the residue was diluted with water, and the pH value was adjusted to about 4 with aqueous hydrochloric acid solution (1 mol/L). The hydrochloride of compound 10 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.84-7.80 (m, 4H), 7.35-7.31 (m, 2H), 7.27-7.26 (m, 1H), 7.22-7.19 (m, 2H), 4.46 (s, 2H), 4.23-4.12 (m, 3H), 3.45-3.42 (m, 2H), 3.29-3.25 (m, 2H), 3.04-3.02 (m, 1H), 2.61-2.57 (m, 1H), 2.46-2.41 (m, 1H), 2.20-2.04 (m, 4H), 1.97-1.94 (m, 1H), 1.61-1.59 (m, 1H), 1.47-1.41 (m, 1H). MS-ESI calculated value [M+H].sup.+ 431, measured value 431.

Embodiment 11

(66) ##STR00041##

(67) Synthetic Route:

(68) ##STR00042##

Step 1

(69) Compound 11-1 (87.6 mg, 0.407 mmol) and compound 1-9 (100 mg, 0.271 mmol) were dissolved in anhydrous dioxane (5 mL), and 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene (31.4 mg, 54.3 μmol), tris(dibenzylideneacetone) dipalladium (24.9 mg, 27.1 umol) and cesium carbonate (177 mg, 0.543 mmol) was added to the reaction mixture. The reaction mixture was stirred at 100° C. for 10 hours. Water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated. The crude product was purified by thin layer chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.40) to obtain compound 11-2. MS-ESI calculated value [M+H].sup.+ 503, measured value 503.

Step 2

(70) Compound 11-2 (35.0 mg, 55.5 μmol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and water (1 mL), and sodium hydroxide (6.66 mg, 0.166 mmol) was added to the reaction mixture. The reaction mixture was stirred for reaction at 60° C. for 3 hours, and concentrated under reduced pressure to remove the solvent. The residue was diluted with water, and the pH value was adjusted to about 4 with aqueous hydrochloric acid solution (1 mol/L). The hydrochloride of compound 11 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.15-8.13 (d, 2H), 7.64-7.61 (d, J=8.56, 2H), 7.36-7.33 (m, 2H), 7.28-7.22 (m, 3H), 4.25-4.18 (m, 3H), 3.81-3.62 (m, 4H), 3.10-3.06 (m, 1H), 2.63-2.59 (m, 1H), 2.55-2.50 (m, 1H), 2.33-2.32 (m, 1H), 2.20-2.09 (m, 4H), 1.65-1.60 (m, 1H), 1.49-1.45 (m, 1H). MS-ESI calculated value [M+H].sup.+ 393, measured value 393.

Embodiment 12

(71) ##STR00043##

(72) Synthetic Route:

(73) ##STR00044##

(74) Step 1

(75) Compound 12-1 (219 mg, 0.957 mmol) and compound 1-9 (235 mg, 0.638 mmol) were dissolved in anhydrous dioxane (4 mL), and cesium carbonate (520 mg, 1.59 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-tri-i-propyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (57.8 mg, 63.8 μmol) were added to the reaction mixture under nitrogen protection. The reaction mixture was stirred at 100° C. for 14 hours. Water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated. The crude product was purified by thin-layer chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.50) to obtain compound 12-2. MS-ESI calculated value [M+H].sup.+ 517, measured value 517.

Step 2

(76) Compound 12-2 (140 mg, 0.271 mmol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and water (1 mL), and sodium hydroxide (32.5 mg, 0.813 mmol) was added to the reaction mixture. The reaction mixture was stirred for reaction at 60° C. for 3 hours, and concentrated under reduced pressure to remove the solvent. The residue was diluted with water, and the pH value was adjusted to about 4 with aqueous hydrochloric acid solution (1 mol/L). The hydrochloride of compound 12 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.76-7.73 (d, 2H), 7.56-7.54 (d, J=8.31, 2H), 7.36-7.30 (m, 2H), 7.28-7.22 (m, 3H), 4.30-4.20 (m, 2H), 3.91-3.82 (m, 2H), 3.73 (s, 2H), 3.66-3.59 (m, 2H), 3.34-3.32 (m, 1H), 3.09-3.05 (m, 1H), 2.68-2.64 (m, 1H), 2.58-2.46 (m, 2H), 2.32-2.18 (m, 4H), 1.70-1.64 (m, 1H), 1.48-1.42 (m, 1H). MS-ESI calculated values [M+H].sup.+ 407, measured values 407.

Embodiment 13

(77) ##STR00045##

(78) Synthetic Route:

(79) ##STR00046##

Step 1

(80) Compound 1-9 (200 mg, 0.513 mmol) and compound 13-1 (114 mg, 0.814 mmol) were dissolved in anhydrous dichloromethane (5 mL), acetic acid (97.8 mg, 1.63 mmol) at 30° C. for 12 hours, sodium triacetoxyborohydride (345 mg, 1.63 mmol) was added thereto, and the reaction was carried out at 30° C. for 1 hour. The reaction mixture was diluted with dichloromethane (10 mL), and then washed with saturated sodium bicarbonate solution (15 mL×1), water (15 mL×1) and saturated brine (15 mL×1), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated. The product was purified by thin layer chromatography (1:2 petroleum ether/ethyl acetate, R.sub.f=0.25) to obtain compound 13-2. MS-ESI calculated values [M+H].sup.+ 493, measured values 493.

Step 2

(81) Compound 13-2 (67.0 mg, 0.136 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), ethanol (2 mL) and water (2 mL), and sodium hydroxide (16.3 mg, 0.408 mmol) was added thereto. The reaction was carried out at 50° C. for 2 hours. The organic phase was removed by concentration under reduced pressure. The residue was dissolved in water (3 mL), and the pH value was adjusted to 4 with hydrochloric acid (1 mol/L), the mixture was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to give the hydrochloride of compound 13. .sup.1H NMR (400 MHz, D.sub.2O) δ 7.48-7.46 (m, 2H), 7.41-7.39 (m, 2H), 7.35-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.16-7.14 (m, 2H), 4.30-4.17 (m, 3H), 4.12-4.03 (m, 2H), 3.52-3.33 (m, 2H), 3.18-3.00 (m, 2H), 2.89-3.00 (m, 1H), 2.54-2.48 (m, 1H), 2.42-2.38 (m, 1H), 2.07-1.93 (m, 4H), 1.84-1.70 (m, 1H), 1.55-1.46 (m, 1H), 1.45-1.38 (m, 1H). MS-ESI calculated values [M+H].sup.+ 397, measured values 397.

Embodiment 14

(82) ##STR00047##

(83) Synthetic Route:

(84) ##STR00048##

Step 1

(85) Compound 1-9 (200 mg, 0.543 mmol) and compound 14-1 (134 mg, 0.814 mmol) were dissolved in anhydrous dichloromethane (5 mL), acetic acid (97.8 mg, 1.63 mmol) was added thereto, the reaction was carried out at 30° C. for 12 hours, sodium triacetoxyborohydride (345 mg, 1.63 mmol) was added, and the reaction was carried out at 30° C. for 1 hour. The reaction mixture was diluted with dichloromethane (10 mL), and then washed with saturated sodium bicarbonate solution (15 mL×1), water (15 mL×1) and saturated brine (15 mL×1), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated. The crude product was purified by thin layer chromatography (1:2 petroleum ether/ethyl acetate, R.sub.f=0.25) to obtain compound 14-2. MS-ESI calculated value [M+H].sup.+ 518, measured value 518.

Step 2

(86) Compound 14-2 (109 mg, 0.210 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), ethanol (2 mL) and water (2 mL), and sodium hydroxide (25.3 mg, 0.632 mmol) was added thereto. The reaction was carried out at 50° C. for 2 hours. The mixture was concentrated under reduced pressure to remove the organic phase. The residue was dissolved in water (10 mL), the pH value was adjusted to 4 with hydrochloric acid (1 mol/L), and the mixture was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain hydrochloride of compound 14. .sup.1H NMR (400 MHz, D.sub.2O) δ 9.07 (s, 1H), 8.38 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.29-7.10 (m, 5H), 4.48 (s, 2H), 4.19-4.07 (m, 3H), 3.38-3.28 (m, 4H), 2.89-2.88 (m, 1H), 2.49-2.42 (m, 2H), 2.15-1.86 (m, 5H), 1.36-1.48 (m, 2H). MS-ESI calculated values [M+H].sup.+ 408, measured values 408.

Embodiment 15

(87) ##STR00049##

(88) Synthetic Route:

(89) ##STR00050##

Step 1

(90) Compounds 1-8 was separated by supercritical fluid extraction method [column: Chiralpak AD 250×25 mm I.D., 10 μm; mobile phase: A: carbon dioxide B: methanol (0.1% ammonia); isocratic: B 30%; flow: 60 g/min; column pressure: 100 bar] to obtain compound 15-1 (retention time=0.991 min) and compound 15-2 (retention time=1.248 min). Compound 15-1, calculated value MS-ESI [M+H].sup.+ 469, measured value 469; compound 15-2, MS-ESI calculated value [M+H].sup.+ 469, measured value 469.

Step 2

(91) Compound 15-1 (300 mg, 0.640 mmol) was dissolved in anhydrous dichloromethane (3 mL), cooled to 0° C. in an ice-water bath, and trifluoroacetic acid (1.54 g, 13.5 mmol, 1.0 mL) was added under an ice-water bath, the reaction mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to remove the solvent to obtain compound 15-3. MS-ESI calculated value [M+H].sup.+ 369, measured values 369.

Step 3

(92) Compound 15-3 (200 mg, 0.543 mmol) and triethylamine (164 mg, 1.63 mmol) were dissolved in acetonitrile (10 mL), compound 2-5 (186 mg, 0.814 mmol) was added thereto, and the reaction solution was allowed to react at 50° C. for 12 hours, the mixture was concentrated under reduced pressure to remove the solvent, the product was dissolved in dichloromethane (30 mL×1), and then washed with dilute hydrochloric acid (1 mol/L, 10 mL×2) and brine (10 mL×1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by thin layer chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.55) to obtain compound 15-4. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99-7.96 (m, 2H), 7.39-7.37 (m, 2H), 7.31-7.27 (m, 2H), 7.24-7.20 (m, 1H), 7.07-7.05 (m, 2H), 3.92-3.91 (m, 4H), 3.53 (s, 2H), 2.43-2.35 (m, 5H), 2.12-1.98 (m, 2H), 1.74-1.71 (m, 3H), 1.64-1.58 (m, 6H). MS-ESI calculated values [M+H].sup.+ 517, measured values 517.

Step 4

(93) The hydrochloride of Compound 15 was obtained by referring to Step 2 of Embodiment 14. .sup.1H NMR (400 MHz, D.sub.2O) δ ppm 8.04-8.00 (m, 2H), 7.55-7.53 (m, 2H), 7.33-7.27 (m, 2H), 7.26-7.23 (m, 1H), 7.14-7.12 (m, 2H), 4.37-4.32 (m, 3H), 4.07-4.06 (m, 2H), 3.51-3.33 (m, 2H), 3.19-3.09 (m, 2H), 2.92-2.88 (m, 1H), 2.49-2.34 (s, 2H), 2.03-1.95 (m, 4H), 1.76-1.69 (m, 1H), 1.47-1.37 (m, 2H). MS-ESI calculated values [M+H].sup.+ 407, measured values 407.

Embodiment 16

(94) ##STR00051##

(95) Synthetic Route:

(96) ##STR00052##

Step 1

(97) Compound 16-1 was obtained by referring to Step 2 of Embodiment 15. MS-ESI calculated values [M+H].sup.+ 369, measured values 369.

Step 2

(98) Compound 16-2 was obtained by referring to Step 3 of Embodiment 15. MS-ESI calculated values [M+H].sup.+ 517, measured values 517.

Step 3

(99) The hydrochloride of Compound 16 was obtained by referring to Step 2 of Embodiment 14. .sup.1H NMR (400 MHz, D.sub.2O) δ 8.04-8.02 (m, 2H), 7.55-7.53 (m, 2H), 7.32-7.23 (m, 3H), 7.14 (m, 2H), 4.37-4.32 (m, 2H), 4.19-4.03 (m, 3H), 3.49-3.33 (m, 2H), 3.22-3.04 (m, 2H), 2.90 (m, 1H), 2.48 (m, 1H), 2.40-2.34 (m, 1H), 2.03-1.92 (m, 4H), 1.77-1.70 (m, 1H), 1.50-1.37 (m, 2H). MS-ESI calculated values [M+H].sup.+ 407, measured values 407.

Embodiment 17

(100) ##STR00053##

(101) Synthetic Route:

(102) ##STR00054##

Step 1

(103) Compound 17-1 (100 mg, 0.462 mmol) and triethylamine (140 mg, 1.39 mmol) were dissolved in dichloromethane (5 mL), cooled to 0° C. in an ice-water bath, and compound 17-2 was added dropwise under nitrogen (106 mg, 0.925 mmol), the reaction was carried out at 20° C. for 12 hours, the reaction mixture was quenched by saturated sodium bicarbonate solution (10 mL), the organic phase was washed with saturated brine (10 mL×1), and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.53) to obtain compound 17-3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.60 (s, 1H), 8.10-8.07 (m, 1H), 7.97-7.95 (m, 1H), 7.88-7.86 (m, 2H), 7.59-7.56 (m, 1H), 4.76 (s, 2H), 3.99 (s, 3H), 1.59 (s, 3H).

Step 2

(104) Compound 17-4 was obtained by referring to Step 3 of Embodiment 15. MS-ESI calculated values [M+H].sup.+ 567, [M+Na].sup.+589, measured values 567, 589.

Step 3

(105) The hydrochloride of compound 17 was obtained by referring to Step 2 of Embodiment 14. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.20-8.16 (m, 3H), 8.08-8.05 (m, 1H), 7.77-7.74 (m, 1H), 7.37-7.27 (m, 2H), 8.71 (s, 1H), 7.29-7.27 (m, 1H), 7.22-7.20 (m, 2H), 4.58 (s, 2H), 4.23-4.11 (m, 3H), 3.52-3.36 (m, 4H), 3.05-3.01 (m, 1H), 2.57 (s, 1H), 2.47-2.42 (m, 1H), 2.14-2.11 (m, 4H), 1.97-1.92 (m, 1H), 1.60-1.58 (m, 1H), 1.48-1.43 (m, 1H). MS-ESI calculated values [M+H].sup.+ 457, measured values 457.

Embodiment 18

(106) ##STR00055##

(107) Synthetic Route:

(108) ##STR00056##

Step 1

(109) Compound 18-2 was obtained by referring to Step 3 of Embodiment 15. MS-ESI calculated values [M+H].sup.+ 519, [M+Na].sup.+541, measured values 519, 541.

Step 2

(110) The hydrochloride of compound 18 was obtained by referring to Step 2 of Embodiment 14. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.36 (s, 1H), 8.86 (s, 1H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.21-7.19 (m, 2H), 4.71 (s, 2H), 4.25-4.12 (m, 3H), 3.69-3.55 (m, 2H), 3.49-3.36 (m, 2H), 3.04-3.02 (m, 1H), 2.59-2.43 (m, 2H), 2.27-2.07 (m, 4H), 2.01-1.95 (m, 1H), 1.61-1.59 (m, 1H), 1.47-1.41 (m, 1H). MS-ESI calculated values [M+H].sup.+ 409, measured values 409.

Embodiment 19

(111) ##STR00057##

(112) Synthetic Route:

(113) ##STR00058##

Step 1

(114) Compound 19-2 was obtained by referring to Step 3 of Embodiment 15. MS-ESI calculated values [M+H].sup.+ 531, measured values 531.

Step 2

(115) The hydrochloride of compound 19 was obtained by referring to Step 2 of Embodiment 14. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.04-8.00 (m, 2H), 7.46-7.44 (m, 2H), 7.36-7.32 (m, 2H), 7.30-7.25 (m, 1H), 7.22-7.20 (m, 2H), 4.27-4.11 (m, 3H), 3.64-3.56 (m, 2H), 3.44-3.40 (m, 2H), 3.31-3.24 (m, 2H), 3.22-3.18 (m, 2H), 3.06-3.03 (m, 1H), 2.60-2.44 (m, 2H), 2.24-2.06 (m, 4H), 1.99-1.91 (m, 1H), 1.62-1.57 (m, 1H), 1.46 (m, 1H). MS-ESI calculated values [M+H].sup.+ 421, measured values 421.

Embodiment 20

(116) ##STR00059##

(117) Synthetic Route:

(118) ##STR00060##

Step 1

(119) Compound 20-2 was obtained by referring to Step 1 of Embodiment 6. MS-ESI calculated values [M+H].sup.+ 518, measured values 518.

Step 2

(120) The hydrochloride of compound 20 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.48-9.32 (m, 1H), 8.75-8.55 (m, 2H), 7.34-7.30 (m, 2H), 7.26-7.24 (m, 1H), 7.22-7.20 (m, 2H), 4.70 (brs, 2H), 4.25-4.18 (m, 3H), 3.42-3.37 (m, 4H), 3.05-3.03 (m, 1H), 2.64-2.62 (m, 1H), 2.45-2.43 (m, 1H), 2.36-2.24 (m, 1H), 2.12-2.06 (m, 4H), 1.65-1.61 (m, 1H), 1.43-1.40 (m, 1H). MS-ESI calculated values [M+H].sup.+ 408, measured values 408.

Embodiment 21

(121) ##STR00061##

(122) Synthetic Route:

(123) ##STR00062##

Step 1

(124) Compound 21-2 was obtained by referring to Step 1 of Embodiment 6. MS-ESI calculated values [M+H].sup.+ 484, measured values 484.

Step 2

(125) The hydrochloride of compound 21 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.89-7.87 (m, 2H), 7.82-7.80 (m, 2H), 7.35-7.31 (m, 2H), 7.27-7.25 (m, 1H), 7.23-7.20 (m, 2H), 4.45 (s, 2H), 4.22-4.19 (m, 1H), 4.17-4.15 (m, 2H), 3.50-3.33 (m, 3H), 3.28-3.25 (m, 1H), 3.04-3.02 (m, 1H), 2.63-2.59 (m, 1H), 2.46-2.40 (m, 1H), 2.25-2.17 (m, 1H), 2.14-2.06 (m, 3H), 2.00-1.94 (m, 1H), 1.63-1.61 (m, 1H), 1.47-1.40 (m, 1H). MS-ESI calculated values [M+H].sup.+ 388, measured values 388.

Embodiment 22

(126) ##STR00063##

(127) Synthetic Route:

(128) ##STR00064##

Step 1

(129) Compound 22-1 (102 mg, 0.567 mmol), O-(7-azabenzotriazol-1-yl)-N, N, N, N-tetramethyluronium hexafluorophosphate (294 mg, 0.773 mmol) and NN-diisopropylethylamine (133 mg, 1.03 mmol) were dissolved in N,N-dimethylformamide (8 mL), the reaction mixture was stirred at 27° C. for 0.5 hour, compound 1-9 (190 mg, 0.515 mmol) was added to the reaction mixture, and the new reaction mixture was stirred at 27° C. for 10 hours, then diluted with ethyl acetate (50 mL), and washed with water (50 mL×3) and saturated brine (50 mL×1) in sequence, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (1:2 petroleum ether/ethyl acetate, R.sub.f=0.6) to obtain compound 22-2. MS-ESI calculated value [M+H].sup.+ 531, measured value 531.

Step 2

(130) The hydrochloride of compound 22 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.12 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.35-7.29 (m, 2H), 7.26-7.25 (m, 1H), 7.23-7.20 (m, 2H), 4.24-4.18 (m, 2H), 4.13-4.09 (m, 2H), 3.47-3.44 (m, 3H), 3.03-3.02 (m, 1H), 2.59-2.56 (m, 1H), 2.42-2.38 (m, 1H), 2.05-1.99 (m, 1H), 1.93-1.89 (m, 2H), 1.81-1.73 (m, 2H), 1.62-1.58 (m, 1H), 1.46-1.41 (m, 1H). MS-ESI calculated value [M+H].sup.+ 421, measured value 421.

Embodiment 23

(131) ##STR00065##

(132) Synthetic Route:

(133) ##STR00066##

Step 1

(134) Compound 21-2 (100 mg, 0.207 mmol) was dissolved in dimethyl sulfoxide (2 mL), and anhydrous potassium carbonate (85.8 mg, 0.620 mmol) and hydrogen peroxide (30% aqueous solution, 70.3 mg, 0.620 mmol) were added to the reaction mixture and stirred for 12 hours under nitrogen protection at 25° C. The reaction mixture was quenched by adding saturated sodium thiosulfate solution (10 mL), and the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated sodium chloride solution (15 mL×2) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 23. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.98 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.33-7.28 (m, 2H), 7.25-7.17 (m, 3H), 4.40 (s, 2H), 4.22-4.08 (m, 3H), 3.43-3.36 (m, 2H), 3.28-3.14 (m, 2H), 3.02-2.99 (m, 1H), 2.61-2.54 (m, 1H), 2.44-2.22 (m, 1H), 2.20-2.01 (m, 4H), 1.96-1.87 (m, 1H), 1.63-1.56 (m, 1H), 1.47-1.39 (m, 1H). MS-ESI calculated values [M+H].sup.+ 406, measured values 406.

Embodiment 24

(135) ##STR00067##

(136) Synthetic Route:

(137) ##STR00068##

Step 1

(138) Compound 21-2 (90.0 mg, 0.160 mmol) was dissolved in dioxane (3 mL), and trimethylsilyl azide (73.7 mg, 0.640 mmol) and dibutyltin oxide (12.0 mg, 48.0 μmol)) were added to the reaction mixture, the reaction mixture was stirred at 120° C. for 12 hours. Water (10 mL) was added to the mixture at room temperature, then extracted with ethyl acetate (10 mL×3), the organic phases were combined, and washed with saturated sodium chloride solution (20 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 24-1. MS-ESI calculated values [M+H].sup.+ 527, measured values 527.

Step 2

(139) Compound 24-1 (101 mg, 0.172 mmol) was dissolved in tetrahydrofuran (2 mL) and absolute ethanol (2 mL), sodium hydroxide (20.6 mg, 0.515 mmol) was dissolved in water (2 mL) and added dropwise to the reaction mixture, the mixture was stirred for 2 hours at 50° C. The reaction mixture was concentrated under reduced pressure to remove the solvent, diluted with water (5 mL), the pH value was adjusted to 4 with hydrochloric acid (1 mol/L), and concentrated under reduced pressure, the crude product was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 24. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.19-8.17 (m, 2H), 7.80-7.75 (m, 2H), 7.32-7.17 (m, 5H), 4.40 (s, 2H), 4.20-4.11 (m, 3H), 3.49-3.40 (m, 4H), 3.07-2.94 (m, 1H), 2.68-2.47 (m, 1H), 2.45-2.29 (m, 1H), 2.20-1.99 (m, 4H), 1.94-1.82 (m, 1H), 1.67-1.50 (m, 1H), 1.48-1.33 (m, 1H). MS-ESI calculated value [M+H].sup.+ 431, measured value 431.

Embodiment 25

(140) ##STR00069##

(141) Synthetic Route:

(142) ##STR00070##

Step 1

(143) Compound 1-9 (150 mg, 0.407 mmol) was dissolved in acetonitrile (5 mL), compound 25-1 (96.1 mg, 0.448 mol) and triethylamine (124 mg, 1.22 mmol) were added to the reaction mixture, and the temperature of the system was raised to 50° C. and the mixture was stirred for 12 hours. After the solvent was removed by concentration under reduced pressure, the crude product was purified by thin layer chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.4) to obtain compound 25-2. MS-ESI calculated values [M+H].sup.+ 547, measured values 547.

Step 2

(144) Compound 25-2 (191 mg, 0.342 mmol) was dissolved in tetrahydrofuran (2 mL) and absolute ethanol (2 mL), and sodium hydroxide (68.4 mg, 1.71 mmol) was dissolved in water (2 mL) and added dropwise to the reaction mixture, the mixture was stirred at 50° C. for 2 hours. The pH value of the reaction solution was adjusted to 5 with hydrochloric acid (1 mol/L) and the mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 25. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.07-8.03 (m, 2H), 7.35-7.31 (m, 2H), 7.27-7.19 (m, 5H), 4.21-4.06 (m, 3H), 4.03-3.92 (m, 1H), 3.91-3.78 (m, 1H), 3.53-3.36 (m, 2H), 3.05-3.02 (m, 1H), 2.55-2.51 (m, 1H), 2.46-2.40 (m, 1H), 2.03-1.79 (m, 4H), 1.75-1.63 (m, 1H), 1.59-1.53 (m, 1H), 1.47-1.42 (m, 1H). MS-ESI calculated value [M+H].sup.+ 437, measured value 437.

Embodiment 26

(145) ##STR00071##

(146) Synthetic Route:

(147) ##STR00072## ##STR00073##

Step 1

(148) Compound 26-1 (50.0 g, 0.251 mol) was dissolved in anhydrous tetrahydrofuran (150 mL) and water (150 mL), and ammonium chloride (49.9 g, 0.934 mol) and zinc powder (49.2 g, 0.753 mol) were added to the reaction mixture at 0° C. Then compound 26-2 (91.1 g, 0.753 mol) was slowly added dropwise at 0° C. The reaction mixture was stirred at 20° C. for 12 hours. After filtration, the filtrate was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.47) to obtain compound 26-3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 5.88-5.80 (m, 1H), 5.18-5.10 (m, 2H), 3.95-3.64 (m, 2H), 3.28-3.02 (m, 2H), 2.23-2.21 (m, 2H), 1.58-1.48 (m, 4H), 1.45-1.44 (m, 9H).

Step 2

(149) Compound 26-3 (2.00 g, 8.29 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydrogen (60%, 0.994 mg, 24.9 mmol) was added to the reaction mixture at 0° C. under nitrogen protection, then compound 26-2 (3.01 g, 24.9 mmol) was added thereto under nitrogen protection. The reaction mixture was stirred at 25° C. for 2 hours. Saturated ammonium chloride solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.60) to obtain compound 26-4.

Step 3

(150) Compound 26-4 (2.15 g, 7.64 mmol) was dissolved in dichloromethane (20 mL), and (1,3-dimethylimidazolidin-2-yliene) (2-isopropyloxybenzylidene) ruthenium ruthenium (VI) chloride (0.479 g, 0.764 mmol). The reaction mixture was stirred at 25° C. for 3 hours. The reaction was quenched by adding water (100 mL), and extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, the crude product was purified by column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.51) to obtain compound 26-5. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 5.68-5.61 (m, 2H), 4.04-4.03 (m, 2H), 3.71-3.60 (m, 2H), 3.12-3.06 (m, 2H), 1.93-1.90 (m, 2H), 1.78-1.68 (m, 2H), 1.62-1.61 (m, 1H), 1.39 (s, 9H), 1.37-1.36 (m, 1H).

Step 4

(151) Compound 26-5 (1.87 g, 7.38 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane-tetrahydrofuran (1M, 22.1 mL) was added to the reaction mixture at 0° C. under nitrogen protection. The reaction mixture was stirred at 30° C. for 7 hours. Sodium hydroxide (3.54 g, 88.6 mmol), water (10 mL) and hydrogen peroxide (27.1 g, 0.295 mol) were added to the reaction mixture at 0° C. The reaction mixture was stirred for reaction at 30° C. for 1 hour. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined and washed with saturated brine (100 mL×1). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, the crude product was purified by column chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.20) to obtain compound 26-6. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 3.79-3.65 (m, 4H), 3.15-2.94 (m, 2H), 1.82-1.74 (m, 3H), 1.67-1.53 (m, 6H), 1.38 (s, 9H).

Step 5

(152) Compound 26-6 (1.65 g, 6.08 mmol) was dissolved in anhydrous dichloromethane (20 mL), and pyridinium dichromate (4.58 g, 12.2 mmol) was added to the reaction mixture at 0° C. under nitrogen protection. The reaction mixture was stirred for reaction at 30° C. for 12 hours. Then the mixture was filtered, the filtrate was extracted with dichloromethane (80 mL×1), the organic phases were combined, and washed with hydrochloric acid (1 mol/L, 50 mL) and saturated sodium chloride (100 mL×1). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated, the crude product was purified by column chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.59) to obtain compound 26-7. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 4.03-4.00 (m, 2H), 3.83-3.81 (m, 2H), 3.22-3.16 (m, 2H), 2.53-2.48 (m, 2H), 1.93-1.77 (m, 4H), 1.58-1.52 (m, 2H), 1.48-1.47 (m, 9H). MS-ESI calculated value [M−Boc+H].sup.+170, [M−56+H].sup.+214, measured value 170, 214.

Step 6

(153) Compound 26-7 (240 mg, 0.891 mmol) and compound 1-2 (142 mg, 1.07 mmol) were dissolved in dichloromethane (3 mL), glacial acetic acid (53.5 mg, 0.891 mol) was added to the reaction mixture, the reaction mixture was stirred and allowed to react at 25° C. for 10 hours, and then sodium triacetoxyborohydride (378 mg, 1.78 mmol) was added to the reaction mixture, and the reaction was carried out for another 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) at 25° C., and the mixture was extracted with dichloromethane (20 mL×3), the organic phase was washed with saturated sodium chloride solution (30 mL×1) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, the crude product was purified by thin layer chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.3) to obtain compound 26-8. MS-ESI calculated value [M+H].sup.+ 387, measured value 387.

Step 7

(154) Compound 26-8 (1.05 g, 2.72 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic anhydride (856 mg, 4.07 mmol) and N,N-diisopropylethylamine (527 mg, 4.07 mmol) were added thereto and stirred at 25° C. for 12 hours. Dichloromethane (50 mL) was added to the reaction mixture, the reaction mixture was then diluted, and the organic phase was washed with hydrochloric acid (1 mol/L 30 mL×1) and saturated sodium chloride solution (30.0 mL×1) respectively, and then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, the crude product was purified by thin layer chromatography (3:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain compound 26-9. 1H NMR (400 MHz, CDCl.sub.3) δ 7.34-7.30 (m, 2H), 7.27-7.23 (m, 1H), 7.15-7.02 (m, 2H), 4.48-4.19 (m, 1H), 3.90-3.62 (m, 4H), 3.22-3.18 (m, 1H), 3.10-2.96 (m, 1H), 2.41-2.26 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.94 (m, 1H), 1.83-1.69 (m, 3H), 1.52-1.45 (m, 12H), 1.41-1.37 (m, 1H), 1.31-1.26 (m, 1H). MS-ESI calculated values [M+Na].sup.+505, measured values 505.

Step 8

(155) Compound 26-9 (160 mg, 0.305 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (104 mg, 0.914 mmol) was added at 0° C., and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude compound 26-10. MS-ESI calculated value [M+H].sup.+ 383, measured value 383.

Step 9

(156) Compound 26-10 (200 mg, 0.403 mmol) was dissolved in acetonitrile (3 mL), triethylamine (122 mg, 1.21 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25° C. for 0.5 hour, then compound 2-5 (102 mg, 0.443 mol) was added to the reaction mixture, the system was heated to 50° C. and allowed to react under stirring for 12 hours. After concentration under reduced pressure to remove the solvent, the crude product was purified by thin layer chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain compound 26-11. MS-ESI calculated value [M+H].sup.+ 531, measured value 531.

Step 10

(157) Compound 26-11 (162 mg, 0.301 mmol) was dissolved in tetrahydrofuran (2 mL) and absolute ethanol (2 mL), and sodium hydroxide (36.1 mg, 0.902 mmol) was dissolved in water (2 mL) and added dropwise to the mixture, the mixture was stirred at 50° C. for 2 hours. The pH value of the reaction mixture was adjusted to 5 with hydrochloric acid (1 mol/L) and the reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 26. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.14-8.12 (m, 2H), 7.70-7.68 (m, 2H), 7.34-7.17 (m, 5H), 4.41 (s, 2H), 4.02-3.87 (m, 1H), 3.84-3.60 (m, 2H), 3.43-2.32 (m, 3H), 3.23-3.08 (m, 1H), 3.04-2.89 (m, 1H), 2.67-2.42 (m, 2H), 2.23-1.93 (m, 3H), 1.86-1.43 (m, 6H). MS-ESI calculated value [M+H].sup.+ 421, measured value 421.

Embodiment 27

(158) ##STR00074##

(159) Synthetic Route:

(160) ##STR00075##

Step 1

(161) Compound 27-1 (200 mg, 1.16 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) and cooled to 0° C., Dess-Martin periodinane (532 mg, 1.25 mmol) was added to the solution, and the reaction mixture was stirred at 29° C. for 3 hours. The reaction mixture was quenched by adding saturated sodium thiosulfate (30 mL) and extracted with ethyl acetate (30 mL×2). The organic phases were combined and washed with saturated sodium chloride solution (50 mL×1). 1)], then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product of compound 27-2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.56 (s, 1H), 3.61 (s, 3H), 2.24-2.14 (m, 2H), 2.05-1.98 (m, 4H), 1.48-1.39 (m, 2H), 1.28-1.21 (m, 2H).

Step 2

(162) Compound 27-3 was obtained by referring to Step 1 of Embodiment 6. MS-ESI calculated values [M+H].sup.+ 523, measured values 523.

Step 3

(163) The hydrochloride of compound 27 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, D.sub.2O) δ 7.34-7.30 (m, 2H), 7.26-7.23 (m, 1H), 7.16-7.14 (m, 2H), 4.20-4.19 (m, 1H), 4.13-4.04 (m, 2H), 3.53-3.38 (m, 2H), 3.07-2.98 (m, 3H), 2.92-2.90 (m, 2H), 2.58-2.51 (m, 1H), 2.43-2.37 (m, 1H), 2.30-2.23 (m, 1H), 2.11-2.08 (m, 1H), 2.03-1.92 (m, 5H), 1.84-1.75 (m, 4H), 1.49-1.46 (m, 1H), 1.42-1.30 (m, 3H), 1.06-0.97 (m, 2H). MS-ESI calculated value [M+H].sup.+ 413, measured value 413.

Embodiment 28

(164) ##STR00076##

(165) Synthetic Route:

(166) ##STR00077##

Step 1

(167) Compound 28-1 (2.00 g, 9.42 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), N,N-carbonyldiimidazole (1.53 g, 9.42 mmol) was added thereto, and the reaction mixture was stirred at 25° C. for 1 hour. After cooling the mixture to 0° C., sodium borohydride (357 mg, 9.42 mmol) was added thereto, and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched by adding saturated sodium bicarbonate (30 mL) and then extracted with ethyl acetate (30 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (1:2 petroleum ether/ethyl acetate, R.sub.f=0.68) to obtain compound 28-2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.62 (s, 3H), 3.26 (s, 2H), 1.79-1.75 (m, 6H), 1.45-1.41 (m, 6H).

Step 2

(168) Compound 28-3 was obtained by referring to Step 1 of Embodiment 27. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.39 (s, 1H), 3.59 (s, 3H), 1.80-1.76 (m, 6H), 1.63-1.59 (m, 6H).

Step 3

(169) Compound 28-4 was obtained by referring to Step 1 of Embodiment 6. MS-ESI calculated values [M+H].sup.+ 549, measured values 549.

Step 4

(170) The hydrochloride of compound 28 was obtained by referring to Step 2 of Embodiment 6. .sup.1H NMR (400 MHz, D.sub.2O) δ 7.36-7.32 (m, 2H), 7.28-7.25 (m, 1H), 7.17-7.15 (m, 2H), 4.22-4.18 (m, 1H), 4.12-4.05 (m, 2H), 3.51-3.42 (m, 2H), 3.23-3.08 (m, 2H), 3.03-2.92 (m, 3H), 2.53-2.38 (m, 2H), 2.21-2.06 (m, 1H), 1.96-1.85 (m, 4H), 1.78-1.75 (m, 6H), 1.57-1.54 (m, 6H), 1.51-1.47 (m, 1H), 1.44-1.39 (m, 1H). MS-ESI calculated values [M+H].sup.+ 439, measured values 439.

Embodiment 29

(171) ##STR00078##

(172) Synthetic Route:

(173) ##STR00079##

Step 1

(174) Compound 29-1 (100 mg, 0.694 mmol) was dissolved in dichloromethane (2 mL), after cooling to 0° C., methanesulfonyl chloride (79.5 mg, 0.694 mmol) and N,N-diisopropylethylamine (179 mg, 1.39 mmol) were added to the mixture, and the mixture was stirred for 2 hours at 25° C. under nitrogen protection. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated sodium chloride solution (20 mL×1) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of compound 29-2.

Step 2

(175) Compound 29-2 (70.0 mg, 0.315 mmol) and compound 1-9 (105 mg, 0.286 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (111 mg, 0.859 mmol) and potassium iodide (9.51 mg, 57.3 μmol) were added to the reaction mixture, and the system was heated to 50° C. and allowed to react under stirring for 12 hours. The reaction mixture was diluted with water (20 mL), and then extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated sodium chloride solution (15 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and then the crude product was purified by a thin layer chromatography (1:1 petroleum ether/ethyl acetate, R.sub.f=0.2) to obtain compound 29-3. MS-ESI calculated value [M+H].sup.+ 495, measured value 495.

Step 3

(176) Compound 29-3 (71.0 mg, 0.123 mmol) was dissolved in tetrahydrofuran (2 mL) and absolute ethanol (2 mL), sodium hydroxide (24.5 mg, 0.613 mmol) was dissolved in water (2 mL) and added dropwise to the mixture, then the mixture was stirred at 50° C. for 2 hours. The pH value of the reaction mixture was adjusted to 5 with hydrochloric acid (1 mol/L) and the mixture was concentrated under reduced pressure. The crude product was separated and purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 29. .sup.1H NMR (400 MHz, D.sub.2O) δ 7.41-7.37 (m, 2H), 7.34-7.30 (m, 1H), 7.22-7.20 (m, 2H), 4.29-4.23 (m, 1H), 4.20-4.09 (m, 2H), 3.55-3.33 (m, 2H), 3.28-2.96 (m, 6H), 2.90-2.68 (m, 1H), 2.63-2.54 (m, 1H), 2.50-2.42 (m, 3H), 2.22-1.99 (m, 6H), 1.90-1.77 (m, 1H), 1.59-1.44 (m, 2H). MS-ESI calculated value [M+H].sup.+ 385, measured value 385.

Embodiment 30

(177) ##STR00080##

(178) Synthetic Route:

(179) ##STR00081##

Step 1

(180) Compound 30-1 (1.00 g, 6.94 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), triethylamine (2.81 g, 27.8 mmol) was added thereto at 0° C., and the mixture was stirred for 15 minutes, benzyl bromide (4.15 g, 24.3 mmol) was added thereto, and the mixture was stirred at 0° C. for 15 minutes, then heated to 25° C. and stirred for 11.5 hours. The reaction solution was quenched by adding water (50 mL) and the mixture was extracted with ethyl acetate (50 mL×3), the organic phase was washed with saturated sodium bicarbonate solution (50 mL×1) and sodium chloride solution (50 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.78) to obtain compound 30-2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36-7.28 (m, 10H), 5.18 (s, 4H), 2.63-2.59 (m, 4H), 2.07-1.98 (m, 2H).

Step 2

(181) Compound 30-2 (6.00 g, 18.5 mmol) was dissolved in anhydrous dichloromethane (120 mL), and diisobutylaluminum hydride (1.5 M toluene solution, 24.7 mL, 36.9 mmol) was added dropwise at −78° C., the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched by adding hydrochloric acid (1 mol/L, 36.9 mL) and water (100 mL) at −78° C., the mixture was stirred at 25° C. for 30 minutes, and extracted with ethyl acetate (100 mL×3). The organic phase was washed with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, R.sub.f=0.5) to obtain compound 30-3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.81 (s, 1H), 7.40-7.34 (m, 5H), 5.23 (s, 2H), 2.52-2.48 (m, 4H), 2.05-1.88 (m, 2H).

Step 3

(182) Compound 1-9 (500 mg, 1.36 mmol) and compound 30-3 (594 mg, 2.72 mmol) were dissolved in anhydrous dichloromethane (10 mL), and glacial acetic acid (245 mg, 4.08 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20° C. for 10 hours, sodium triacetoxyborohydride (576 mg, 2.72 mmol) was added, and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL), then washed with saturated sodium bicarbonate aqueous solution (50 mL×3), water (50 mL×2), and saturated brine (50 mL×1) respectively, then dried over anhydrous sodium sulfate, filtered, and the mother liquor was then concentrated and dissolved in anhydrous dichloromethane (10 mL), compound 30-3 (297 mg, 1.36 mmol) and glacial acetic acid (8.17 mg, 0.136 mmol) were added thereto, the reaction mixture was stirred at 20° C. for 10 hours, and sodium triacetoxyborohydride (577 mg, 2.72 mmol) was added, the reaction mixture was stirred at 20° C. for 2 hours. After diluting with dichloromethane (50 mL), the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (50 mL×3) and water (50 mL×2) in sequence, and washed once with saturated brine (50 mL×1), then dried over anhydrous sodium sulfate, filtered, the resulting mother liquor was concentrated, and the crude product was purified by high performance liquid chromatography (neutral, ammonium bicarbonate system) to obtain compound 30-4. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42-7.31 (m, 7H), 7.28-7.24 (m, 1H), 7.15-7.09 (m, 2H), 5.19 (d, J=6.4 Hz, 2H), 4.65-4.61 (m, 1H), 4.09-4.01 (m, 1H), 3.94-3.87 (m, 1H), 3.00-2.97 (m, 1H), 2.73-7.71 (d, J=8.4 Hz, 2H), 2.51-2.34 (m, 7H), 2.04-1.88 (m, 6H), 1.71-1.67 (m, 1H), 1.64-1.61 (m, 2H), 1.50-1.41 (m, 3H) MS-ESI calculated value [M+H].sup.+571, measured value 571.

Step 4

(183) Compound 30-4 (220 mg, 0.385 mmol) was dissolved in tetrahydrofuran (2 mL), water (2 mL) and ethanol (2 mL), and sodium hydroxide (46.3 mg, 1.16 mmol) was added thereto. The reaction mixture was stirred at 60° C. for 2 hours, tetrahydrofuran and ethanol were removed by concentration under reduced pressure, the residue was dissolved in water (6 mL), and the pH value was adjusted to 4 with hydrochloric acid (1 mol/L), the mixture was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 30. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.34-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.24-4.21 (m, 1H), 4.19-4.13 (m, 2H), 3.67-3.59 (m, 2H), 3.47-3.35 (m, 2H), 3.30-3.27 (m, 1H), 3.04-3.02 (m, 1H), 2.71-2.67 (m, 1H), 2.59-2.52 (m, 2H), 2.46-2.39 (m, 1H), 2.30-2.21 (m, 3H), 2.20-1.95 (m, 6H), 1.71-1.65 (m, 2H), 1.44-1.40 (m, 1H). MS-ESI calculated value [M+H].sup.+ 385, measured value 385.

Embodiment 31

(184) ##STR00082##

(185) Synthetic Route:

(186) ##STR00083##

Step 1

(187) Compound 31-1 (10.0 g, 69.4 mmol) was dissolved in anhydrous dichloromethane (100 mL), and triethylamine (20.1 g, 0.208 mol) and methanesulfonyl chloride (15.9 g, 0.139 mol) were added to the reaction mixture at 0° C. under nitrogen protection. The reaction mixture was stirred at 25° C. for 2 hours. Saturated sodium bicarbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain compound 31-2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 4.27 (m, 2H), 4.12-4.09 (m, 2H), 3.02-3.01 (m, 3H), 1.38-1.36 (m, 2H), 1.21-1.18 (m, 3H), 0.99-0.96 (m, 2H).

Step 2

(188) Compound 31-2 (181 mg, 0.814 mmol) and compound 1-9 (150 mg, 0.407 mmol) were dissolved in anhydrous dioxane (3 mL), and triethylamine (124 mg, 1.22 mmol) was added to the reaction mixture under nitrogen protection. The reaction mixture was stirred at 50° C. for 3 hours. Water (10 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (10 mL×3), and the organic phases were combined and washed with saturated sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by thin layer chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.50) to obtain compound 31-3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.25-7.21 (m, 2H), 7.17-7.16 (m, 1H), 7.03-6.96 (m, 2H), 4.58-4.47 (m, 1H), 4.07-4.02 (m, 2H), 3.99-3.94 (m, 1H), 3.88-3.80 (m, 1H), 2.66 (s, 2H), 2.52-2.50 (m, 4H), 2.31-2.28 (m, 1H), 2.02-1.94 (m, 2H), 1.83-1.78 (m, 1H), 1.65-1.49 (m, 4H), 1.41-1.37 (m, 1H), 1.22-1.13 (m, 6H), 0.83 (m, 2H). MS-ESI calculated value [M+H].sup.+ 495, measured value 495.

Step 3

(189) Compound 31-3 (100 mg, 0.202 mmol) was dissolved in tetrahydrofuran (1 mL), ethanol (1 mL) and water (1 mL), and sodium hydroxide (24.3 mg, 0.607 mmol) was added to the reaction mixture. The reaction mixture was stirred and reacted at 60° C. for 3 hours, the solvent was removed by concentration under reduced pressure. The residue was diluted with water and the pH value was adjusted to about 4 with aqueous hydrochloric acid solution (1 mol/L). The mixture was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 31. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.35-7.31 (m, 2H), 7.27-7.21 (m, 3H), 4.23-4.14 (m, 3H), 3.64-3.57 (m, 2H), 3.44-3.30 (m, 4H), 3.04-3.02 (m, 1H), 2.69-2.65 (m, 1H), 2.47-2.41 (m, 1H), 2.24-2.00 (m, 5H), 1.68-1.64 (m, 1H), 1.52-1.51 (m, 2H), 1.45-1.40 (m, 1H), 1.28-1.25 (m, 2H). MS-ESI calculated value [M+H].sup.+ 371, measured value 371.

Embodiment 32

(190) ##STR00084##

(191) Synthetic Route:

(192) ##STR00085## ##STR00086##

Step 1

(193) Compound 32-2 (1.92 g, 7.59 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and potassium tert-butoxide (852 mg, 7.59 mmol) was added to the reaction mixture at 0° C. under nitrogen protection. The reaction mixture was stirred at 25° C. for 0.5 hour. Then a solution of compound 32-1 (1 g, 5.84 mmol) in tetrahydrofuran (20 mL) was added to the mixture at 0° C. under nitrogen protection. The reaction mixture was stirred at 25° C. for 11.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (5:1 petroleum ether/ethyl acetate, R.sub.f=0.80) to obtain compound 32-3. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 5.77-5.68 (m, 1H), 4.83-4.80 (m, 2H), 4.60-4.58 (m, 2H), 1.49 (s, 9H), 1.47 (s, 9H).

Step 2

(194) Compound 32-3 (450 mg, 1.67 mmol) and compound 1-9 (513 mg, 1.39 mmol) were dissolved in acetonitrile (20 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (106 mg, 0.696 mmol). The reaction mixture was stirred at 65° C. for 12 hours. Water (80 mL) was added to the reaction mixture and extracted with ethyl acetate (80 mL×3), the organic phases were combined and washed with saturated aqueous solution of sodium chloride (80 mL×1), dried over anhydrous sodium sulfate, filtered, the mother liquor was concentrated, and the crude product was purified by column chromatography (2:1 petroleum ether/ethyl acetate, R.sub.f=0.20) to obtain compound 32-4. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.35-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.09-7.07 (m, 2H), 4.66-4.62 (m, 1H), 3.96-3.92 (m, 3H), 3.80-3.76 (m, 2H), 2.57-2.50 (m, 4H), 2.40-2.34 (m, 3H), 2.07-2.04 (m, 3H), 1.85-1.83 (m, 1H), 1.76-1.74 (m, 3H), 1.51-1.44 (m, 21H). MS-ESI calculated values [M+H].sup.+ 638, measured values 638.

Step 3

(195) Compound 32-4 (420 mg, 0.659 mmol) was dissolved in tetrahydrofuran (4 mL), ethanol (4 mL) and water (4 mL), and sodium hydroxide (79.0 mg, 1.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at 60° C. for 3 hours, and then concentrated under reduced pressure to remove the solvent, the residue was diluted with water, and the pH value was adjusted to about 3 with aqueous solution of hydrochloric acid (1 mol/L). The mixture was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain compound 32-5. MS-ESI calculated value [M+H].sup.+ 486, measured value 486.

Step 4

(196) Compound 32-5 (280 mg, 0.577 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4M, 2.88 mL) was added to the reaction mixture. The reaction mixture was stirred at 30° C. for 3 hours, then concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (hydrochloric acid system) to obtain the hydrochloride of compound 32. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.37-7.33 (m, 2H), 7.29-7.26 (m, 1H), 7.18-7.16 (m, 2H), 4.68-4.67 (m, 1H), 4.47-4.41 (m, 3H), 4.22-4.10 (m, 3H), 3.17-3.06 (m, 6H), 2.94-2.93 (m, 1H), 2.52-2.43 (m, 2H), 2.05-1.89 (m, 5H), 1.51-1.50 (m, 1H), 1.45-1.40 (m, 1H). MS-ESI calculated value [M+H].sup.+ 386, measured value 386.

Embodiment 33

(197) ##STR00087##

(198) Synthetic Route:

(199) ##STR00088##

Step 1

(200) Compound 1-9 (300 mg, 0.622 mmol), compound 33-1 (125 mg, 0.933 mmol) and triethylamine (189 mg, 1.87 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was stirred at 50° C. for 10 hours, concentrated under reduced pressure to remove the solvent, and the residue was dissolved with dichloromethane (50 mL). The organic phase was washed with water (50 mL×1) and saturated brine (50 mL×1) in sequence, and dried over anhydrous sodium sulfate, filtered, the mother liquor was concentrated, and the crude product was purified by thin-layer chromatography (1:2 petroleum ether/ethyl acetate, R.sub.f=0.24) to obtain compound 33-2. MS-ESI calculated value [M+H].sup.+ 422, measured value 422.

Step 2

(201) Compound 33-2 (100 mg, 0.237 mmol) was dissolved in dioxane (3 mL), trimethylsilyl azide (109 mg, 0.949 mmol) and dibutyltin oxide (17.7 mg, 71.2 μmol)) were added to the reaction mixture, the reaction mixture was stirred at 120° C. for 10 hours. Water (10 mL) was added at room temperature, and then the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined and washed with saturated sodium chloride solution (20 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 33-3. MS-ESI calculated value [M+H].sup.+ 465, measured value 465.

Step 3

(202) Compound 33-3 (215 mg, 0.401 mmol) was dissolved in tetrahydrofuran (2 mL) and absolute ethanol (2 mL), sodium hydroxide (80.3 mg, 2.01 mmol) was dissolved in water (2 mL) and added dropwise to the solution, and the solution was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, the pH value was adjusted to 5 with hydrochloric acid (1 mol/L) and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain the hydrochloride of compound 33. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.33-7.28 (m, 2H), 7.25-7.19 (m, 3H), 4.24-4.16 (m, 3H), 3.66-3.52 (m, 6H), 3.02-3.30 (m, 2H), 3.01-3.00 (m, 1H), 2.70-2.55 (m, 1H), 2.49-2.35 (m, 1H), 2.78-2.06 (m, 4H), 2.05-1.93 (m, 1H), 1.71-1.56 (m, 1H), 1.47-1.37 (m, 1H). MS-ESI calculated value [M+H].sup.+ 369, measured value 369.

Embodiment 34

(203) ##STR00089##

(204) Synthetic Route:

(205) ##STR00090##

Step 1

(206) Lithium hydroxide monohydrate (830 mg, 19.8 mmol) was dissolved in water (3 mL), di-tert-butyl dicarbonate (2.37 g, 10.9 mmol) was added to a solution of compound 34-1 (1.00 g, 9.89 mmol) in tetrahydrofuran (12 mL), the reaction mixture was stirred at 15° C. for 12 hours. The pH value was adjusted to 6 with hydrochloric acid (1 N) aqueous solution, then diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3), the mixture was then washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product of compound 34-2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.56 (brs, 1H), 1.60-1.57 (m, 2H), 1.45 (s, 9H), 1.27-1.21 (m, 2H). MS-ESI calculated values [M+Na].sup.+224, measured values 224.

Step 2

(207) Compound 34-3 was obtained by referring to Step 1 of Embodiment 22. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.34-7.23 (m, 3H), 7.07-7.06 (m, 2H), 5.23-5.07 (m, 1H), 4.70-4.58 (m, 1H), 4.08-3.97 (m, 3H), 3.49-3.41 (m, 2H), 3.11-2.89 (m, 1H), 2.43-2.32 (m, 1H), 2.16-2.07 (m, 2H), 1.71-1.59 (m, 6H), 1.49-1.41 (m, 12H), 1.16-0.98 (m, 1H). MS-ESI calculated value [M+H].sup.+ 552, measured value 552.

Step 3

(208) Compound 34-4 was obtained by referring to Step 2 of Embodiment 6. MS-ESI calculated value [M+H].sup.+ 456, measured value 456.

Step 4

(209) The hydrochloride of the compound 34 was obtained by referring to Step 4 of Embodiment 32. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.33-7.29 (m, 2H), 7.24-7.18 (m, 3H), 4.18-3.93 (m, 5H), 3.48-3.39 (m, 2H), 3.28-3.21 (m, 1H), 3.02-3.00 (m, 1H), 2.65-2.56 (m, 1H), 2.47-2.37 (m, 1H), 2.05-1.92 (m, 4H), 1.66-1.53 (m, 2H), 1.39-1.30 (m, 4H). MS-ESI calculated values [M+H].sup.+ 356, measured values 356.

Biochemical Test: In Vitro Evaluation

Experiment 1: Evaluation of Enzyme Activity

(210) The purpose of this test was to detect the in vitro inhibitory activity of the compounds against LSD1. The enzyme used in this test was human LSD1, the standard substrate was histone H3K4me peptide (20 μM), the fluorescence coupling enzyme method was used to determine the activity of the compound by combining horseradish peroxidase (HRP) and fluorescent reagent Amplex Red to detect the H.sub.2O.sub.2 generation as a result of the reaction of LSD1. Compounds were tested in 10-dose IC50 mode with a 3-fold serial dilution starting at 10 μM. The enzyme and the substrate were co-incubated for 30 minutes before adding the compounds to the substrate to start the reaction. Fluorescence detector: Envision, excitation wavelength: Ex/Em=530/590 nM

(211) Testing the inhibitory activity of the compounds against LSD1, and the results are shown in Table 1.

(212) TABLE-US-00001 TABLE 1 In vitro enzyme activity screening test results of the compounds of the present disclosure Number of the compound IC.sub.50 (nM) Hydrochloride of 1689 the compound 1 Hydrochloride of 1578 the compound 2 Hydrochloride of 96.66 the compound 3 Hydrochloride of 939.7 the compound 4 Hydrochloride of 3854 the compound 5 Hydrochloride of 328.8 the compound 6 Hydrochloride of 45.07 the compound 7 Hydrochloride of 39.73 the compound 8 Hydrochloride of 37.76 the compound 9 Hydrochloride of 78.44 the compound 10 Hydrochloride of 2879 the compound 11 Hydrochloride of 1377 the compound 12 Hydrochloride of 46.59 the compound 13 Hydrochloride of 117.7 the compound 14 Hydrochloride of 352.8 the compound 15 Hydrochloride of 261.8 the compound 16 Hydrochloride of 70.63 the compound 17 Hydrochloride of 92.88 the compound 18 Hydrochloride of 208.3 the compound 19 Hydrochloride of 241.7 the compound 20 Hydrochloride of 92.19 the compound 21 Hydrochloride of 908.2 the compound 22 Hydrochloride of 64.62 the compound 23 Hydrochloride of 41.51 the compound 24 Hydrochloride of 1723 the compound 25 Hydrochloride of 271.4 the compound 26 Hydrochloride of 1776 the compound 27 Hydrochloride of 1456 the compound 28 Hydrochloride of 1672 the compound 29 Hydrochloride of 1137 the compound 30 Hydrochloride of 2123 the compound 31 Hydrochloride of 1162 the compound 32 Hydrochloride of 48.24 the compound 33 Hydrochloride of 38.4 the compound 34 Conclusion: the compounds of the present disclosure have obvious inhibitory activity against LSD1.

Experimental Example 2: Evaluation of Antiproliferation Activity of NCI-111417 Cells

(213) Experimental purpose: to detect the antiproliferation activity of the compounds on NCI-H1417 cells.

(214) Experimental materials: RPMI 1640 culture medium, fetal bovine serum, Promega CellTiter-Glo reagent. NCI-H1417 cell line purchased from ATCC. Envision multi-label reader (PerkinElmer).

(215) Experimental method: the compounds were dissolved to 10 mM, then the compounds were diluted 5 times with DMSO in a compound plate, the compounds were diluted 3-fold with Bravo from a starting concentration of 2 mM to the 10th concentration, 250 nL of the solutions were transferred to the upper and lower duplicate wells on a blank 384 cell plate by Echo transfer plate, cell suspension of per well/1000 cells/50 μL was added to the transferred 250 nL DMSO/compound, the compounds were diluted 200-fold, i.e., the initial action concentration was 10 μM. The cell plate was placed in a carbon dioxide incubator and incubated for 10 days. 25 μL of Promega CellTiter-Glo reagent was added to each well on the cell plate and was shaken at room temperature for 10 minutes to stabilize the luminescence signal. Readings were performed by PerkinElmer Envision multi-label analyzer.

(216) Data analysis: the equation (Max-Ratio)/(Max-Min)*100% was used to convert the original data into the inhibition rate, the value of IC.sub.50 can be obtained by curve fitting of four-parameters (the 205 mode in XLFITS, iDBS).

(217) Testing the antiproliferation activity of the compounds against NCI-H1417 cells, and the results are shown in Table 2.

(218) TABLE-US-00002 TABLE 2 test results of the antiproliferation activity of the compounds of the present disclosureon NCI-H1417 cells: Number of the compound IC.sub.50 (nM) Hydrochloride of 9.11 the compound 6 Hydrochloride of 13.10 the compound 15 Hydrochloride of 12.10 the compound 16 Hydrochloride of 0.65 the compound 17 Hydrochloride of 6.95 the compound 19 Hydrochloride of 3.99 the compound 20 Hydrochloride of 1.12 the compound 21 Hydrochloride of 1.68 the compound 23 Hydrochloride of 91.36 the compound 30 Hydrochloride of 3.97 the compound 32 Hydrochloride of 4.38 the compound 34 Conclusion: The compounds of the present disclosure have obvious antiproliferation activity on NCI-H1417 cells.

Experimental Example 3: Evaluation of Antiproliferation Activity on HL60 Cells

(219) Experimental purpose: to detect the antiproliferation activity of the compound to be tested on HL60 cells.

(220) Experimental materials: RPMI-1640 culture medium, fetal bovine serum, penicillin/streptomycin antibiotics purchased from Wisent. CellTiter-Glo (chemiluminescent cell viability assay reagent) reagents purchased from Promega. HL60 cell line purchased from Nanjing Cobioer Co., Ltd. Nivo multi-label reader (PerkinElmer).

(221) Experimental method: HL60 cells were planted in a white 384-well plate, 40 μL of cell suspension per well, 600 HL60 cells were contained therein. The cell plate was placed in a carbon dioxide incubator for overnight culture. The compounds to be tested were diluted 5-fold with a pipet until the 10th concentration, i.e., diluted from 2 mM to 1.024 nM, double duplicate well experiment was set. 78 μL of the culture medium was added to an intermediate plate, and then 2 μL per well of the serially diluted compounds were transferred to the corresponding positions on the intermediate plate, after mixing, 10 μL per well was transferred to the cell plate. The cell plate was incubated in a carbon dioxide incubator for 6 days. Another cell plate was prepared and the signal value on the day of dosing was read as the maximum value (Max value in the equation below) to participate in the data analysis. 20 μL of chemiluminescent cell viability assay reagent was added to each well of this cell plate, which was incubated at room temperature for 10 minutes to stabilize the luminescence signal. The multi-label reader was used for reading.

(222) Data analysis: the equation (Sample-Min)/(Max-Min)*100% was used to convert the original data into the inhibition rate, the IC.sub.50 value can be obtained by curve fitting of four-parameters (“log(inhibitor) vs. response—Variable slope” mode in GraphPad Prism)).

(223) The antiproliferation activity of the compounds on HL60 cells were tested, and the results are shown in Table 3.

(224) TABLE-US-00003 TABLE 3 Test results of antiproliferation activity of the compounds of the present disclosure on HL60 cells Number of the compound IC.sub.50 (nM) Hydrochloride of 14.74 the compound 6 Hydrochloride of 13.8 the compound 15 Hydrochloride of 8.46 the compound 16 Hydrochloride of 0.78 the compound 17 Hydrochloride of 20.44 the compound 18 Hydrochloride of 1.46 the compound 19 Hydrochloride of 8.99 the compound 20 Hydrochloride of 1.17 the compound 21 Hydrochloride of 39.1 the compound 24 Hydrochloride of 337.2 the compound 30 Hydrochloride of 0.55 the compound 32 Hydrochloride of 1.92 the compound 34 Conclusion: The compounds of the present disclosure have obvious antiproliferation activity on HL60 cells.

Experimental Example 4: Evaluation of Inhibitory Activity Against Proliferation of MV-4-11 Cells

(225) Experimental purpose: to detect the antiproliferation activity of the compound to be tested on MV-4-11 cells.

(226) Experimental materials: IMDM culture medium, fetal bovine serum, penicillin/streptomycin antibiotics purchased from Wisent. CellTiter-Glo (chemiluminescent cell viability assay reagent) reagents purchased from Promega. MV-4-11 cell line was purchased from Nanjing Cobioer Co., Ltd. Nivo Multi-Marker Analyzer (PerkinElmer).

(227) Experimental method: MV-4-11 cells were planted in a white 96-well plate, 80 μL of cell suspension per well, which contained 6000 MV-4-11 cells. The cell plate was placed in a carbon dioxide incubator for overnight culture.

(228) The compounds to be tested were diluted 5-fold with a pipet until the 8th concentration, i.e., diluted from 2 mM to 25.6 nM, double duplicate well experiment was set. 78 μL of the culture medium was added to an intermediate plate, and then 2 μL per well of the serially diluted compounds were transferred to the corresponding positions on the intermediate plate, after mixing, 20 μL per well was transferred to the cell plate. The cell plate was incubated in a carbon dioxide incubator for 6 days. Another cell plate was prepared and the signal value on the day of dosing was read as the maximum value (Max value in the equation below) to participate in the data analysis. 25 μL of the chemiluminescent cell viability assay reagent was added to each well of this cell plate, which was incubated at room temperature for 10 minutes to stabilize the luminescence signal. The multi-label analyzer was used for reading.

(229) Data analysis: the equation (Sample-Min)/(Max-Min)*100% was used to convert the original data into the inhibition rate, the IC.sub.50 value can be obtained by curve fitting of four-parameters (“log(inhibitor) vs. response—Variable slope” mode in GraphPad Prism)).

(230) The antiproliferation activity of the compounds on MV-4-11 cells were tested, and the results are shown in Table 4.

(231) TABLE-US-00004 TABLE 4 Test results of antiproliferation activity of the compounds of the present disclosure on MV-4-11 cells. Number of the compound IC.sub.50 (nM) Hydrochloride of 3.21 the compound 6 Hydrochloride of 13.16 the compound 15 Hydrochloride of 13.70 the compound 16 Hydrochloride of 2.86 the compound 17 Hydrochloride of 16.03 the compound 18 Hydrochloride of 4.41 the compound 19 Hydrochloride of 9.56 the compound 20 Hydrochloride of 0.46 the compound 21 Hydrochloride of 38.32 the compound 24 Hydrochloride of 33.15 the compound 30 Hydrochloride of 1.9 the compound 32 Hydrochloride of 1.37 the compound 34 Conclusion: the compounds of the present disclosure have obvious antiproliferation activity on MV-4-11 cells.

Experimental Example 5: Pharmacokinetic Evaluation of the Compounds

Experimental Purpose: To Test the In Vivo Pharmacokinetics of the Compounds in CD-1 Mice

Experimental Materials

(232) CD-1 mice (male, 7-9 weeks old, Shanghai Slac)

Experimental Operation

(233) The rodent pharmacokinetic characteristics after intravenous injection and oral administration of the compounds were tested by standard protocols, in the experiment, the candidate compounds were formulated into clear solutions and administrated to mice via a single intravenous injection and oral administration. The vehicle for intravenous injection and oral administration was a mixed solution of 10% of dimethyl sulfoxide and 90% of 10% hydroxypropyl β cyclodextrin. This project used four male CD-1 mice, two mice were administered intravenously, with a dose of 1 mg/kg, and plasma samples were collected at 0 hour (before administration) and 0.0833, 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration. The other two mice were orally administered by gavage, with a dose of 2 mg/kg, plasma samples were collected at 0 hour (before administration) and 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration, whole blood samples were collected within 24 hours, which were centrifuged at 3000 g for 15 minutes, and the supernatants were separated to obtain plasma samples, 4 times volume of acetonitrile solutions containing internal standard were added to precipitate the protein, the mixtures were centrifuged to obtain the supernatants, the supernatants were added with water of equal volume and centrifuged again to take the supernatant for injection, and the blood drug concentration was quantitatively analyzed by the LC-MS/MS analysis method, and pharmacokinetic parameters were calculated, such as max concentration (Cmax), clearance (CL), half-life (T.sub.1/2), volumes of distribution (Vdss), the area under the plasma concentration-time curve (AUC.sub.0-last), bioavailability (F) etc.

(234) The experimental results are shown in Table 5:

(235) TABLE-US-00005 TABLE 5 Pharmacokinetic test results The area under the plasma Max Clearance Volumes of concentration- concentration CL distribution Half-life time curve Bioavailability C.sub.max (mL/min/ Vdss T.sub.1/2 AUC.sub.0-last PO F Compound (nM) kg) (L/kg) (IV, h) (nM .Math. hr) (%) Hydrochloride 718 40.2 1.19 1.54 691 33.2 of the compound 6 Hydrochloride 629 16.9 0.551 0.874 1376 28.7 of the compound 14 Hydrochloride 919 41.8 0.835 0.49 765 39.1 of the compound 15 Hydrochloride 860 33.8 0.88 0.579 891 36.9 of the compound 16 Hydrochloride 714 19.7 0.752 0.905 1342 29 of the compound 20 Hydrochloride 144 68.7 18.6 4.32 360 37.2 of the compound 23 Hydrochloride 1150 25.3 2.09 1.39 2141 58.3 of the compound 34 Conclusion: The compounds of the present disclosure have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance, etc.

Experimental Example 6: Inhibition Test for hERG Potassium Ion Channel

(236) Experimental purpose: to detect the effect of the embodiments to be tested on the potassium ion channel of hERG by using the fully automatic patch-clamp method.

Experimental Method

(237) 6.1. Cell Culture

(238) 6.1.1 CHO-hERG cells were cultured in a 175 cm.sup.2 culture flask, after the cell density was increased to 60-80%, the culture medium was removed, the cells were washed once with 7 mL PBS (Phosphate Buffered Saline), and then 3 mL digestive fluid was added for digestion.

(239) 6.1.2 After the digestion was complete, 7 mL of culture medium was added for neutralization, then the mixture was centrifuged, the supernatant was aspirated, and then 5 mL of culture medium was added for resuspention to ensure that the cell density was 2-5×10.sup.6/mL.

(240) 6.2 Solution Preparation

(241) TABLE-US-00006 TABLE 6.1 Composition of intracellular fluid and extracellular fluid Extracellular fluid Intracellular fluid Reagent (mM) (mM) CaCl.sub.2 2 5.374 MgCl.sub.2 1 1.75 KCl 4 120 NaCl 145 — Glucose 10 — 4-(2- 10 10 Hydroxyethyl)piperazine- 1-ethanesulfonic acid Ethylene glycol bis(2- — 5 aminoethyl ether) tetraacetic acid Na.sub.2ATP — 4 pH the pH value was the pH value was adjusted to 7.4 with adjusted to 7.4 with NaOH KOH Note: “—” means no such reagent.

(242) 6.3 Electrophysiological Recording Process

(243) The single-cell high-impedance sealing and the whole-cell mode formation process were all automatically completed by the Qpatch instrument of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. After the whole-cell recording mode was obtained, the cells were clamped at −80 millivolts. The cells first underwent a pre-voltage of −50 millivolts for 50 milliseconds, then underwent depolarization stimulation at +40 millivolts for 5 seconds, then underwent repolarization at −50 millivolts for 5 seconds, and then the voltage returned to −80 millivolts. This voltage stimulation was applied every 15 seconds. The data were recorded for 2 minutes, then extracellular fluid was administrated, and then the data were recorded for 5 minutes. Then, the administration process begun. The concentration of the test compound started from the lowest concentration, each test concentration was administrated for 2.5 minutes. After all the concentrations were administered continuously, 3 μM of Cisapride was administrated as the positive control compound. At least three cells (n≥3) were tested at each concentration.

(244) 6.4 Compound Preparation

(245) 6.4.1 20 mM Compound mother liquor was diluted with extracellular fluid, 5 μL of 20 mM compound mother liquor was added with 2495 μL of extracellular fluid to undergo 500-fold dilution to 40 μM. Then the solution was subjected to a 3-fold serial dilution with extracellular fluid containing 0.2% DMSO to obtain a required final concentration.

(246) 6.4.2 The highest test concentration was 40 μM, the concentrations were 40, 13.33, 4.44, 1.48, 0.49, 0.16 μM respectively, a total of 6 concentrations.

(247) 6.5 Data Analysis

(248) The experimental data were analyzed by XLFit software.

(249) 6.6 Test Results

(250) The hERG IC.sub.50 results of the embodiment compound are shown in Table 6.2.

(251) TABLE-US-00007 TABLE 6.2 hERG IC.sub.50 value of the embodiment compound Test sample hERG IC.sub.50 (μM) Number of testing Hydrochloride of the >40 N = 2 compound 6 Conclusion: the compounds of the present disclosure have no inhibitory effect on hERG potassium ion channels.

Experimental Example 7: In Vivo Pharmacodynamic Study of the Compounds of the Present Disclosure on MC38 Mouse Colon Cancer Transplanted Tumor Model

7.1 Experiment Purpose

(252) The purpose of this experiment was to evaluate the in vivo efficacy of the compounds of the present disclosure on MC38 mouse colon cancer transplanted tumor model.

7.2 Experimental Animals

(253) Species: Mice

(254) Line: C.sub.57BL/6 mice

(255) Week age and weight: 7 weeks old, weighing 18-23 grams

(256) Gender: female

(257) Supplier: Shanghai Slack Laboratory Animal Co., Ltd.

7.3 Experimental Methods and Procedures

(258) 7.3.1 Cell Culture

(259) Name: MC38 (Mouse Colon Cancer Cell)

(260) Source: Obio Biotechnology (Shanghai) Co., Ltd. The conservation of species and the maintenance of passage were performed by HD Biosciences (Shanghai) Co., Ltd.

(261) Cell culture: 1640 medium containing 10% fetal bovine serum was used as culture medium, and the culture condition was 37° C., 5% carbon dioxide. The passage ratio was 1:2 to 1:3, the passage was performed 2-3 times per week.

(262) 7.3.2 Tumor Cell Inoculation

(263) 0.1 mL (2×10.sup.5 cells) of cells were subcutaneously inoculated into the right back of each mouse. On the same day, the animals were randomly grouped according to their body weight.

(264) 7.3.3 Preparation of Test Compounds

(265) The vehicle used in the experiment was 0.5% methyl cellulose solution, the preparation method was: 5 g methyl cellulose was weighed and dissolved in 800 mL ultrapure water, stirred evenly and made up to 1000 mL with ultrapure water. The test substances were dissolved in solvent and prepared into a uniform solution with a certain concentration, and stored at 4° C.

(266) 7.3.4 Tumor Measurement and Experimental Indicators

(267) The experimental indicator is to investigate whether the tumor growth was inhibited, delayed or cured. Tumor diameters were measured with a vernier caliper twice a week. The tumor volume was calculated by the formula: V=0.5a×b.sup.2, a and b respectively represent the long and short diameters of the tumor.

(268) The efficacy of the compound was evaluated by relative tumor growth rate T/C (%). Relative tumor growth rate T/C (%): the calculation formula was as follows: T/C %=T.sub.RTV/C.sub.RTV×100% (T.sub.RTv: therapy group RTV; C.sub.RTV: Negative control group RTV). The relative tumor volume (RTV) was calculated based on the results of tumor measurement, the calculation formula was: RTV=V.sub.t/V.sub.0, wherein V.sub.0 was the average tumor volume measured at the time of grouping administration (i.e., do), V.sub.t is the average tumor volume measured at a single time, T.sub.RTV and C.sub.RTV were calculated from the data on the same day.

7.4 Experimental Result

(269) TABLE-US-00008 TABLE 7 Evaluation of anti-tumor efficacy of the test compounds on MC38 mouse colon cancer transplanted tumor model (Based on the calculation of tumor volume on the 28th day after administration) Tumor volume (mm.sup.3) T/C Group (28.sup.th day) (%) Vehicle (0.5% methylcellulose 1759 ± 978  / solution) Hydrochloride of the compound 6 1653 ± 893  92 (1.5 mg/kg, oral administration once a day) PD-1 monoclonal antibody 1022 ± 925  58 (5 mg/kg, intraperitoneal injection twice a week) PD-1 monoclonal antibody + 211 ± 269 12 hydrochloride of the compound 6 (5 mg/kg, intraperitoneal injection twice a week + 1.5 mg/kg, oral administration once a day) Note: PD-1 monoclonal antibody source: BioXcell. PD-1 monoclonal antibodies were administrated from the 7th day after grouping, and compound 6 was administered from the day of grouping. Conclusion: The combination of the compound of the present disclosure and PD-1 monoclonal antibody has an excellent anti-tumor effect on MC38 mouse colon cancer transplantated tumor model.

Embodiment 8: In Vivo Pharmacodynamic Study of the Compounds of the Present Disclosure on Human Small Cell Lung Cancer NCI-111417 Cell Subcutaneous Xenograft Tumor in CB-17 SCID Mouse Model

8.1 Experimental Purpose

(270) The purpose of the experiment was to evaluate the in vivo efficacy of the compounds of the present disclosure on subcutaneous xenograft tumor of human small cell lung cancer NCI-H1417 cells in a CB-17 SCID mouse model.

8.2 Experimental Animals

(271) Species: Mice

(272) Line: CB-17 SCID mice

(273) Week age and weight: 6-8 weeks old, weighing 16-21 grams

(274) Gender: female

(275) Supplier: Shanghai Lingchang Biotech Co., Ltd.

8.3 Experimental Methods and Procedures

(276) 8.3.1 Cell Culture

(277) Human small cell lung cancer NCI-H1417 cells (ATCC) were cultured in vitro in a single layer, the culture conditions were RPMI-1640 culture medium supplemented with 10% fetal bovine serum, 37° C. 5% CO.sub.2. When the cell saturation reached 80%-90%, the cells were collected, counted, and inoculated.

(278) 8.3.2 Tumor Cell Inoculation

(279) 0.2 mL of 10×10.sup.6 NCI-H1417 cells were subcutaneously inoculated into the right back of each mouse (PBS: Matrigel=1:1). Group administration was started when the average volume reached 100-150 mm.sup.3.

(280) 8.3.3 Preparation of Test Compounds

(281) The vehicle used in the experiment was 0.5% methylcellulose solution, the preparation method was: 5 g of methylcellulose was weighed and dissolved in 800 mL ultrapure water, stirred evenly and made up to 1000 mL with ultrapure water. The test substance was dissolved in a solvent and prepared into a uniform solution of a certain concentration, and stored at 4° C.

(282) Cisplatin (Cisplatin, manufacturer Qilu Pharmaceutical Co., Ltd., 10 mg/bottle freeze-dried powder for injection, lot number 7D011A8) was added to 10 mL 0.9% NaCl to make a 1 mg/mL mother liquor, and stored at room temperature and protected from light. The mother liquor was aliquoted into 0.63 mL and stored at room temperature. 5.67 mL 0.9% NaCl was added to one of the 0.63 mL mother liquor to make a 0.1 mg/mL solution.

(283) 8.3.4 Tumor Measurement and Experimental Indicators

(284) The experimental indicator is to investigate whether tumor growth was inhibited, delayed, or cured. Tumor diameters were measured with a vernier caliper twice a week. The tumor volume was calculated by the calculation formula: V=0.5a×b.sup.2, a and b respectively represent the long and short diameters of the tumor.

(285) The anti-tumor effect of the compounds was evaluated by TGI (%). TGI (%) can reflect the tumor growth inhibition rate. TGI (%) calculation: TGI (%)=[1-(the average tumor volume at the end of the administration in a treatment group—the average tumor volume at the beginning of the administration in the treatment group)/(the average tumor volume at the end of the treatment of the solvent control group—the average tumor volume at the beginning of the treatment of the solvent control group)]×100%.

8.4 Experimental Results

(286) TABLE-US-00009 TABLE 8 Evaluation of anti-tumor effect of the compound on human small cell lung cancer NCI-H1417 xenograft tumor model (Based on the calculation of tumor volume on the 28th day after administration) Tumor volume mean ± SEM TGI Group (mm.sup.3) (28.sup.th day) (%) Vehicle (0.5% methyl cellulose 446 ± 36  / solution) Cisplatin (1 mg/kg, intraperitoneal 165 ± 22  85.9% injection, twice a week) Hydrochloride of the compound 6 187 ± 14  79.2% (1.5 mg/kg, oral administration once a day) Cisplatin (1 mg/kg, intraperitoneal 33 ± 13  126% injection, twice a week) + hydrochloride of the compound 6 (1.5 mg/kg, oral administration once a day) Conclusion: The compounds of the present disclosure alone or in combination with the chemotherapy drug cisplatin have an excellent anti-tumor effect on the human small cell lung cancer NCI-H1417 xenograft tumor model.