N-(BENZOYL)-PHENYLALANINE COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING SAME, AND USE THEREOF

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and relates to an N-(benzoyl)-phenylalanine compound used as an ?4?7 integrin antagonist, including the pharmaceutical composition and the use, and in particular to a compound represented by general formula (1). The compound exhibits good ?4?7 integrin binding inhibitory activity, can be used as a high-efficiency ?4?7 integrin antagonist, and used for preventing and/or treating ?4?7 integrin-related diseases such as autoimmune diseases and inflammatory diseases.

##STR00001##

Claims

1. A compound as shown in general formula (1) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof, ##STR00272## wherein: R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, C.sub.6-10 aryl, or 5-10 membered heteroaryl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl; each R.sub.4 is independently hydrogen or halogen; each X.sub.1 is independently hydrogen or halogen; X.sub.2 is hydrogen, halogen, hydroxyl, amino, aldehyde, carboxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylthio, C.sub.1-6 haloalkythio, C.sub.1-6 alkanoyl, C.sub.1-6 alkylamino, di (C.sub.1-6 alkyl) amino, C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkanoyloxy, C.sub.1-6 alkyl amido, aminoformyl, C.sub.1-6 alkyl aminoformyl, di (C.sub.1-6alkyl) carbamoyl, C.sub.1-6 alkoxy sulfonyl, C.sub.1-6 alkyl sulfonyloxy, C.sub.1-6 alkyl sulfonyl amino, amino sulfonyl, C.sub.1-6 alkyl amino sulfonyl, di (C.sub.1-6 alkyl) amino sulfonyl, C.sub.3-6 cycloalkyl, 3-7-membered heterocyclic alkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.6-10 aryloxy, 5-10 membered heteroaryloxy, C.sub.6-10 arylthio, 5-10 membered heteroaryl thio, C.sub.6-10 arylamino, 5-10 membered heteroarylamino, C.sub.6?10 arylcarbonyl, 5-10 membered heteroarylcarbonyl, C.sub.6?10 aryloxycarbonyl, 5?10 membered heteroaryloxycarbonyl, C.sub.6?10 arylformyloxy, 5?10 membered heteroarylformyloxy, C.sub.6?10 arylformamido, 5?10 membered heteroarylformamido, C.sub.6?10 arylaminoformyl, 5?10 membered heteroarylaminoformyl, C.sub.6?10 aryloxy sulfonyl, 5?10 membered heteroaryloxy sulfonyl, C.sub.6?10 arylsulfonyloxy, 5?10 membered heteroarylsulfonyloxy, C.sub.6?10 arylsulfonylamino, 5?10 membered heteroarylsulfonylamino, C.sub.6?10 arylaminosulfonyl, or 5?10 membered heteroarylaminosulfonyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1?6 alkyl, C.sub.3?6 cycloalkyl, 3?7 membered heterocyclic alkyl, C.sub.6?10 aryl, and 5?10 membered heteroaryl; each X.sub.3 is independently hydrogen or halogen; A is a group as shown in general formula (2-1), (2-2), or (2-3), ##STR00273## ring H is C.sub.3-6 sub-cyclic alkyl or 3-7 membered sub-heterocyclic alkyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl; Y is O or S; each Z is independently CR.sub.1 or N; if present, each R.sub.1 is independently hydrogen, halogen, hydroxyl, amino, aldehyde, carboxyl, cyano, nitro, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylthio, C.sub.1-6 haloalkythio, C.sub.1-6 alkanoyl, C.sub.1-6 alkylamino, di (C.sub.1-6 alkyl) amino, C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkanoyloxy, C.sub.1-6 alkyl amido, aminoformyl, C.sub.1-6 alkyl aminoformyl, di (C.sub.1-6 alkyl) carbamoyl, C.sub.1-6 alkoxy sulfonyl, C.sub.1-6 alkyl sulfonyloxy, C.sub.1-6 alkyl sulfonyl amino, amino sulfonyl, C.sub.1-6 alkyl amino sulfonyl, di (C.sub.1-6 alkyl) amino sulfonyl, C.sub.3-6 cycloalkyl, 3-7-membered heterocyclic alkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.6-10 aryloxy, 5-10 membered heteroaryloxy, C.sub.6-10 arylthio, 5-10 membered heteroaryl thio, C.sub.6-10 arylamino, 5-10 membered heteroarylamino, C.sub.6?10 arylcarbonyl, 5-10 membered heteroarylcarbonyl, C.sub.6?10 aryloxycarbonyl, 5?10 membered heteroaryloxycarbonyl, C.sub.6?10 arylformyloxy, 5?10 membered heteroarylformyloxy, C.sub.6?10 arylformamido, 5?10 membered heteroarylformamido, C.sub.6?10 arylaminoformyl, 5?10 membered heteroarylaminoformyl, C.sub.6?10 aryloxy sulfonyl, 5?10 membered heteroaryloxy sulfonyl, C.sub.6?10 arylsulfonyloxy, 5?10 membered heteroarylsulfonyloxy, C.sub.6?10 arylsulfonylamino, 5?10 membered heteroarylsulfonylamino, C.sub.6?10 arylaminosulfonyl, or 5?10 membered heteroarylaminosulfonyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1?6 alkyl, C.sub.3?6 cycloalkyl, 3?7 membered heterocyclic alkyl, C.sub.6?10 aryl, and 5?10 membered heteroaryl; if present, each R.sub.2 is independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkyl amido, aminoformyl, C.sub.1-6 alkylaminoformyl, di (C.sub.1-6 alkyl) aminoformyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.6-10 arylcarbonyl, 5-10 membered heteroarylcarbonyl, C.sub.6-10 aryloxycarbonyl, 5-10 membered heteroaryloxycarbonyl, C.sub.6?10 arylaminoformyl, or 5?10 membered heteroarylaminoformyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl.

2. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, 3-7-membered heterocyclic alkyl, C.sub.6-10 aryl, or 5-10 membered heterocyclic alkyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl.

3. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein each R.sub.4 is independently hydrogen, fluorine, chlorine, or bromine.

4. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein each X.sub.1 is independently fluorine, chlorine, or bromine.

5. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein X.sub.2 is hydrogen, halogen, C.sub.1-6 alkylamino, di (C.sub.1-6 alkyl) amino, C.sub.3-6 cycloalkyl, or 3-7 membered heterocyclic alkyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and 3-7 membered heterocyclic alkyl.

6. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein each X.sub.3 is independently hydrogen or fluorine.

7. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein: A is a group as shown in the general formula (2-1-1) or (2-1-1), ##STR00274## ring H is C.sub.3-6 cycloalkyl or 3-7-membered heterocyclic alkyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl; Y is O or S; when A is a group as shown in general formula (2-1-1), two of the four R.sub.1 are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and the rest are hydrogen; alternatively, one of the four R.sub.1 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and the rest are hydrogen; alternatively, all four R.sub.1 are hydrogen; when A is a group as shown in general formula (2-1-1), two of the three R.sub.1 are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and one is hydrogen; alternatively, one of the three R.sub.1 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and the rest are hydrogen; alternatively, all three R.sub.1 are hydrogen.

8. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein: A is a group as shown in general formula (2-2-1), ##STR00275## Y is O or S; two of the four R.sub.1 are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and the rest are hydrogen; alternatively, one of the four R.sub.1 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and the rest are hydrogen; R.sub.2 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, or 3-7-membered heterocyclic alkyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl.

9. The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1, wherein: A is a group as shown in general formula (2-3-1), ##STR00276## Y is O or S; one of the four R.sub.1 is halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or di (C.sub.1-6 alkyl) amino, and the rest are hydrogen; each R.sub.2 is independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, or 3-7-membered heterocyclic alkyl, which is optionally substituted by at least one of the following substituents: halogen, C.sub.1-6 alkyl, C.sub.3-6cycloalkyl, and 3-7-membered heterocyclic alkyl.

10. A compound or pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof having a structure selected from the group consisting of: ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283##

11. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1.

12. (canceled)

13. (canceled)

14. A method for preventing and/or treating diseases and/or symptoms mediated at least partially by ?4?7 integrin, comprising: administering the compounds or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 to a subject in need thereof.

15. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 10.

16. A method for preventing and/or treating diseases and/or symptoms mediated at least partially by ?4?7 integrin, comprising: administering the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 10 to a subject in need thereof.

17. A method for preventing and/or treating diseases and/or symptoms mediated at least partially by ?4?7 integrin, comprising: administering the pharmaceutical composition according to claim 11 to a subject in need thereof.

18. A method for preventing and/or treating diseases and/or symptoms mediated at least partially by ?4?7 integrin, comprising: administering the pharmaceutical composition according to claim 15 to a subject in need thereof.

Description

INTERMEDIATE PREPARATION EXAMPLE 1: SYNTHESIS OF 3-(4-IODOPHENYL)-2-(TRIPHENYLAMINO) METHYL PROPIONATE (P-1)

(Step 1) (S)-2-amino-3-(4-iodophenyl) methyl propionate

[0207] ##STR00048##

[0208] Dissolve 4-iodo-L-phenylalanine (29.1 g, 10 mmol) in anhydrous methanol (290 mL) and cool in an ice bath. Add thionyl chloride (17.9 g, 15 mmol) and N,N-Dimethylformamide (2.9 mL), react at 40? C. for 24 h. Concentrate the reaction solution with vacuum, a white solid is obtained, which is the title compound (29 g, 95%). ESI-QQQ-MS: m/z 306 [M+H].sup.+.

(Step 2) 3-(4-iodophenyl)-2-(triphenylamino) methyl propionate (P-1)

[0209] ##STR00049##

[0210] Dissolve (S)-2-amino-3-(4-iodophenyl) methyl propionate (24.4 g, 8 mmol) in dichloromethane (480 mL) and cool in an ice bath. Add triethylamine (12.1 g, 12 mmol) and 1.2 eq triphenylmethyl chloride (26.8 g, 9.6 mmol), react at room temperature for 8 h. After concentrating the reaction solution with vacuum, purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to obtain the title compound (30.7 g, 70%). ESI-QQQ-MS: m/z 548 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 2: SYNTHESIS OF SPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-2)

[0211] ##STR00050##

[0212] Dissolve indoline-2-ketone (0.27 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C. add LDA (2 mol/L, 0.4 mL, 8 mmol), stir for 30 min, heat to 0? C., add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.19 g, 60%). ESI-QQQ-MS: m/z 160 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 3: SYNTHESIS OF 7-FLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-3)

[0213] ##STR00051##

[0214] Dissolve 7-fluoroindolin-2-one (0.3 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C. add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C., add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.19 g, 54%). ESI-QQQ-MS: m/z 178 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 4: SYNTHESIS OF 6-FLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-4)

[0215] ##STR00052##

[0216] Dissolve 6-fluoroindolin-2-one (0.3 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C. add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C., add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.22 g, 62%). ESI-QQQ-MS: m/z 178 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 5: SYNTHESIS OF 5-FLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-5)

[0217] ##STR00053##

[0218] Dissolve 5-fluoroindolin-2-one (0.3 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 241. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (022 g, 61%). ESI-QQQ-MS: m/z 178 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 6: SYNTHESIS OF 7-CHLOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-6)

[0219] ##STR00054##

[0220] Dissolve 7-chloroindoline-2-one (0.33 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to 40? C. add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C., add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.2 g, 52%). ESI-QQQ-MS: m/z 194 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 7: SYNTHESIS OF 6-CHLOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-7)

[0221] ##STR00055##

[0222] Dissolve 6-chloroindoline-2-one (0.33 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.21 g, 54%). ESI-QQQ-MS: m/z 194 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 8: SYNTHESIS OF 5-CHLOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-8)

[0223] ##STR00056##

[0224] Dissolve 5-chloroindoline-2-one (0.33 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.19 g, 50%). ESI-QQQ-MS: m/z 194 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 9: SYNTHESIS OF 7-METHOXYSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-9)

[0225] ##STR00057##

[0226] Dissolve 7-methoxyspiro-2-one (0.33 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.2 g, 53%). ESI-QQQ-MS: m/z 190 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 10: SYNTHESIS OF 5,6-DIFLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-10)

[0227] ##STR00058##

[0228] Dissolve 5,6-difluorospiro-2-one (0.34 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.22 g, 57%). ESI-QQQ-MS: m/z 196 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 11: SYNTHESIS OF 6-CHLORO-5-FLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-11)

[0229] ##STR00059##

[0230] Dissolve 6-chloro-5-fluoroindolin-2-one (0.37 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.21 g, 50%). ESI-QQQ-MS: m/z 212 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 12: SYNTHESIS OF 6,7-DIFLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2NE (P-12)

(Step 1) (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino)acetamide

[0231] ##STR00060##

[0232] Add hydrochloric acid solution (0.6 mL) of 2,3-difluoroaniline (0.78 g, 6 mmol) to a mixed system of chloral hydrate (1.4 g, 8.4 mmol), sodium sulfate (4.74 g, 33.4 mmol) and water (6 mL), react at room temperature for 1 h, then add hydroxylamine hydrochloride (0.58 g, 8.4 mmol), heat to 60? C., and react for 2 h. Cool and filter the reaction solution, the filter cake is the title compound (crude product, 0.7 g), which is directly used for the next reaction. ESI-QQQ-MS: m/z 201 [M+H].sup.+.

(Step 2) 6,7-difluoroindoline-2,3-dione

[0233] ##STR00061##

[0234] Add (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino) acetamide (0.7 g, 3.5 mmol) to sulfuric acid (2.5 mL), heat to 80? C. and react for 3 h. After cooling the reaction system, pour ice water (20 mL), filter out the precipitate, and dry with vacuum to obtain the title compound (crude product, 0.35 g). ESI-QQQ-MS: m/z 184 [M+H].sup.+.

(Step 3) 6,7-difluoroindolin-2-one

[0235] ##STR00062##

[0236] Dissolve 6,7-difluoroindoline-2,3-dione (0.35 g, 1.9 mmol) in ethylene glycol (2 mL), add hydrazine hydrate (0.18 mL, 3.8 mmol), heat to 130? C. react for 4 h, then cool to 25? C., react for 16 h, add water (2 mL) and concentrated hydrochloric acid (0.2 mL), continue to heat to 45? C., react for 1 h. Cool the reaction system in an ice bath, filter out the precipitate, wash with water for 3 times, and dry with vacuum at 90? C. to obtain the title compound (0.26 g, 70%). ESI-QQQ-MS: m/z 170 [M+H].sup.+.

(Step 4) 6,7-difluoro[cyclopropane-1,3-dihydroindole]-2-one (P-12)

[0237] ##STR00063##

[0238] Dissolve 6,7-difluoroindoline-2-one (0.26 g, 1.54 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 3 mL, 6 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (0.87 g, 4.6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.16 g, 53%). ESI-QQQ-MS: m/z 1% [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 13: SYNTHESIS OF 7-CHLORO-3,3-DIMETHYLINDOLIN-2-ONE (P-13)

[0239] ##STR00064##

[0240] Dissolve 7-chloroindoline-2-one (0.34 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add iodomethane (0.85 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (024 g, 61%). ESI-QQQ-MS: m/z 196 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 14: SYNTHESIS OF 7-CHLORO-2,3,5,6-TETRAHYDROSPIRO[INDOLINE-3,4-PYRAN]-2-ONE (P-14)

[0241] ##STR00065##

[0242] Dissolve 7-chloroindoline-2-one (0.34 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C. add 1-iodo-2-(2-iodoethoxy)ethane (1.96 g, 6 mmol), and react at room temperature for 241. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.23 g, 49%). ESI-QQQ-MS: m/z 238 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 15: SYNTHESIS OF 5-(DIMETHYLAMINO) SPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-15)

(Step 1) 5-(dimethylamino) indoline-2-one

[0243] ##STR00066##

[0244] Dissolve 5-aminoindoline-2-one (0.30 g, 2 mmol) in glacial acetic acid (4 mL), add sodium cyanoborohydride (0.31 g, 5 mmol) and paraformaldehyde (0.48 g, 16 mmol) sequentially, and react at room temperature for 24 h. Concentrate the reaction system with vacuum and add water (20 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (dichloromethane/methanol=30:1) to obtain the title compound (0.24 g, 68%). ESI-QQQ-MS: m/z 177 [M+H].sup.+.

(Step 2) 5-(dimethylamino) spiro[cyclopropane-1,3-indoline]-2-one (P-15)

[0245] ##STR00067##

[0246] Dissolve 5-(dimethylamino) indoline-2-one (0.24 g, 1.35 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C. add LDA (2 mol/L, 2.7 mL, 5.4 mmol), stir for 30 min, heat to 0? C., add 1,2-dibromoethane (0.76 g, 4.05 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.11 g, 40%). ESI-QQQ-MS: m/z 203 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 16: SYNTHESIS OF 6-(DIMETHYLAMINO)-5-FLUOROSPIRO[CYCLOPROPANE-1,3-INDOLINE]-2-ONE (P-16)

(Step 1) 6-(dimethylamino)-5-fluoroindolin-2-one

[0247] ##STR00068##

[0248] Dissolve 6-amino-5-fluoroindolin-2-one (0.33 g, 2 mmol) in glacial acetic acid (4 mL), add sodium cyanoborohydride (0.31 g, 5 mmol) and paraformaldehyde (0.48 g, 16 mmol) sequentially, and react at room temperature for 24 h. Concentrate the reaction system with vacuum and add water (20 mL) and ethyl acetate (10 mL) to the reaction system, stand for layering, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (dichloromethane/methanol=30:1) to obtain the title compound (0.25 g, 65%). ESI-QQQ-MS: m/z 195 [M+H].sup.+.

(Step 2) 6-(dimethylamino)-5-fluorospiro[cyclopropane-1,3-indoline]-2-one (P-16)

[0249] ##STR00069##

[0250] Dissolve 6-(dimethylamino)-5-fluoroindolin-2-one (0.24 g, 1.3 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C. add LDA (2 mol/L, 2.6 mL, 5.2 mmol), stir for 30 min, heat to 0? C. add 1,2-dibromoethane (0.73 g, 3.9 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.12 g, 42%). ESI-QQQ-MS: m/z 221 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 17: SYNTHESIS OF SPIRO[CYCLOPROPANE-1,3-PYRROLO[2,3-B]PYRIDINE]-2(1H)-ONE (P-17)

[0251] ##STR00070##

[0252] Dissolve 1H-pyrrolo[2,3-b]pyridine-2(3H)-one (0.27 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to ?40? C., add LDA (2 mol/L, 4 mL, 8 mmol), stir for 30 min, heat to 0? C., add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate for three times (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to obtain the title compound (0.11 g, 34%). ESI-QQQ-MS: m/z 161 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 18: SYNTHESIS OF 4-CHLORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-18)

(Step 1) 3-chloro-N-methyl-2-nitroaniline

[0253] ##STR00071##

[0254] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.37 g, 98%). ESI-QQQ-MS: m/z 187 [M+H].sup.+.

(Step 2) 3-chloro-N.SUP.1.-methylbenzene-1,2-diamine

[0255] ##STR00072##

[0256] Dissolve 3-chloro-N-methyl-2-nitroaniline (0.3 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.24 g, 98%). ESI-QQQ-MS: m/z 157 [M+H].sup.+.

(Step 3) 4-chloro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-18)

[0257] ##STR00073##

[0258] Dissolve 3-chloro-N.sup.1-methylbenzene-1,2-diamine (0.2 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.19 g, 80%). ESI-QQQ-MS: m/z 183 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 19: SYNTHESIS OF 6-CHLORO-1-CYCLOPROPYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-19)

(Step 1) 5-chloro-N-cyclopropyl-2-nitroaniline

[0259] ##STR00074##

[0260] Dissolve 4-chloro-2-fluoro-1-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol), heat to reflux, and stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.35 g, 82%). ESI-QQQ-MS: m/z 213 [M+H].sup.+.

(Step 2) 5-chloro-N.SUP.1.-cyclopropylbenzene-1,2-diamine

[0261] ##STR00075##

[0262] Dissolve 5-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.27 g, 92%). ESI-QQQ-MS: m/z 183 [M+H].sup.+.

(Step 3) 6-chloro-1-cyclopropyl-1H-benzo[d]imidazole-2(3H)-one (P-19)

[0263] ##STR00076##

[0264] Dissolve 5-chloro-N1-cyclopropylbenzene-1,2-diamine (0.24 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.20 g, 74%). ESI-QQQ-MS: m/z 209 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 20: SYNTHESIS OF 5-CHLORO-1-CYCLOPROPYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-20)

(Step 1) 4-chloro-N-cyclopropyl-2-nitroaniline

[0265] ##STR00077##

[0266] Dissolve 4-chloro-1-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.35 g, 85%). ESI-QQQ-MS: m/z 213 [M+H].sup.+.

(Step 2) 4-chloro-N.SUP.1.-cyclopropylbenzene-1,2-diamine

[0267] ##STR00078##

[0268] Dissolve 4-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C., stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.26 g, 90%). ESI-QQQ-MS: m/z 183 [M+H].sup.+.

(Step 3) 5-chloro-1-cyclopropyl-1H-benzo[d]imidazole-2(3H)-one (P-20)

[0269] ##STR00079##

[0270] Dissolve 4-chloro-N.sup.1-cyclopropylbenzene-1,2-diamine (0.24 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, and react at rom temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.19 g, 70%). ESI-QQQ-MS: m/z 209 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 21: SYNTHESIS OF 4-CHLORO-1-CYCLOPROPYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-21)

(Step 1) 3-chloro-N-cyclopropyl-2-nitroaniline

[0271] ##STR00080##

[0272] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.37 g, 87%). ESI-QQQ-MS: m/z 213 [M+H].sup.+.

(Step 2) 3-chloro-N.SUP.1.-cyclopropylbenzene-1,2-diamine

[0273] ##STR00081##

[0274] Dissolve 3-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C. and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.27 g, 93%). ESI-QQQ-MS: m/z 183 [M+H].sup.+.

(Step 3) 4-chloro-1-cyclopropyl-1H-benzo[d]imidazole-2(3H)-one (P-21)

[0275] ##STR00082##

[0276] Dissolve 3-chloro-N1-cyclopropylbenzene-1,2-diamine (0.24 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.18 g, 66%). ESI-QQQ-MS: m/z 209 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 22: SYNTHESIS OF 4-CHLORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-THIONE (P-22)

[0277] ##STR00083##

[0278] Dissolve 3-chloro-N.sup.1-methylbenzene-1,2-diamine (0.24 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C. add triethylamine (0.16 g, 1.6 mmol), and slowly add sulfurphosgene/dichloromethane solution (0.18 g/1 mL) dropwise to the reaction system, react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.14 g, 54%). ESI-QQQ-MS: m/z 199 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 23: SYNTHESIS OF 4-CHLORO-1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-23)

(Step 1) N-(3-chloro-2-nitrophenyl) tetrahydro-2H-pyran-4-amine

[0279] ##STR00084##

[0280] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and tetrahydro-2H-pyran-4-amine (0.24 g, 2.4 mmol), heat to reflux, and stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.30 g, 59%). ESI-QQQ-MS: m/z 257 [M+H].sup.+.

(Step 2) 3-chloro-N.SUP.1.-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

[0281] ##STR00085##

[0282] Dissolve N-(3-chloro-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (0.28 g, 1.1 mmol) in anhydrous methanol (4 mL), add zinc powder (0.72 g, 1 mmol) and ammonium chloride (0.29 g, 5.5 mmol), heat to 50? C., and stir for 3 h. Perform suction filtration for reaction solution, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.22 g, 89%). ESI-QQQ-MS: m/z 227 [M+H].sup.+.

(Step 3) 4-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-2(3H)-one (P-23)

[0283] ##STR00086##

[0284] Dissolve 3-chloro-N.sup.1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (0.22 g, 0.97 mmol) in dichloromethane (2 mL), cool to ? C. add triethylamine (0.13 g, 1.3 mmol), and slowly add triphosgene/dichloromethane solution (0.12 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify, the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (0.12 g, 49%). ESI-QQQ-MS: m/z 253 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 24: SYNTHESIS OF 4-CHLORO-1-(1-METHYLPIPERIDINE-4-YL)-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-24)

(Step 1) N-(3-chloro-2-nitrophenyl)-1-methylpiperidine-4-amine

[0285] ##STR00087##

[0286] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 1-methylpiperidine-4-amine (0.27 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.28 g, 51%). ESI-QQQ-MS: m/z 270 [M+H].sup.+.

(Step 2) 3-chloro-N.SUP.1.-(1-methylpiperidine-4-yl) benzene-1,2-diamine

[0287] ##STR00088##

[0288] Dissolve N-(3-chloro-2-nitrophenyl)-1-methylpiperidine-4-amine (0.27 g, 1.0 mmol) in anhydrous methanol (4 mL), add zinc powder (0.65 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.22 g, 92%). ESI-QQQ-MS: m/z 240 [M+H].sup.+.

(Step 3) 4-chloro-1-(1-methylpiperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (P-24)

[0289] ##STR00089##

[0290] Dissolve 3-chloro-N.sup.1-(1-methylpiperidine-4-yl)benzene-1,2-diamine (0.22 g, 0.92 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.12 g, 1.2 mmol), and slowly add triphosgene/dichloromethane solution (0.11 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify, the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain the title compound (0.11 g, 45%). ESI-QQQ-MS: m/z 266 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 25: SYNTHESIS OF 4-FLUORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-25)

(Step 1) 3-fluoro-N-methyl-2-nitroaniline

[0291] ##STR00090##

[0292] Dissolve 1,3-difluoro-2-nitrobenzene (0.32 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.32 g, 95%). ESI-QQQ-MS: m/z 171 [M+H].sup.+.

(Step 2) 3-fluoro-N.SUP.1.-methylbenzene-1,2-diamine

[0293] ##STR00091##

[0294] Dissolve 3-fluoro-N-methyl-2-nitroaniline (0.27 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C. and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.22 g, 98%). ESI-QQQ-MS: m/z 141 [M+H].sup.+.

(Step 3) 4-fluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-25)

[0295] ##STR00092##

[0296] Dissolve 3-fluoro-N.sup.1-methylbenzene-1,2-diamine (0.18 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.17 g, 78%). ESI-QQQ-MS: m/z 167 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 26: SYNTHESIS OF 4,6-DIFLUORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-26)

(Step 1) 3,5-difluoro-N-methyl-2-nitroaniline

[0297] ##STR00093##

[0298] Dissolve 1,3,5-trifluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.26 g, 70%). ESI-QQQ-MS: m/z 189 [M+H].sup.+.

(Step 2) 3,5-difluoro-N.SUP.1.-methylbenzene-1,2-diamine

[0299] ##STR00094##

[0300] Dissolve 3,5-difluoro-N-methyl-2-nitroaniline (0.24 g, 1.3 mmol) in anhydrous methanol (4.5 mL), add zinc powder (0.85 g, 13 mmol) and ammonium chloride (0.35 g, 6.5 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.19 g, 92%). ESI-QQQ-MS: m/z 159 [M+H].sup.+.

(Step 3) 4,6-difluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-26)

[0301] ##STR00095##

[0302] Dissolve 3,5-difluoro-N.sup.1-methylbenzene-1,2-diamine (0.17 g, 1.1 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.14 g, 1.4 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.16 g, 80%). ESI-QQQ-MS: m/z 185 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 27: SYNTHESIS OF 5,6-DICHLORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-27)

(Step 1) 4,5-dichloro-N-methyl-2-nitroaniline

[0303] ##STR00096##

[0304] Dissolve 1,2-dichloro-4-fluoro-5-nitrobenzene (0.42 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.4 g, 90%). ESI-QQQ-MS: m/z 221 [M+H].sup.+.

(Step 2) 4,5-dichloro-N.SUP.1.-methylbenzene-1,2-diamine

[0305] ##STR00097##

[0306] Dissolve 4,5-dichloro-N-methyl-2-nitroaniline (0.35 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1.0 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.29 g, 95%). ESI-QQQ-MS: m/z 191 [M+H].sup.+.

(Step 3) 5,6-dichloro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-27)

[0307] ##STR00098##

[0308] Dissolve 4,5-dichloro-N.sup.1-methylbenzene-1,2-diamine (0.29 g, 1.5 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.14 g, 1.9 mmol), and slowly add triphosgene/dichloromethane solution (0.18 g/1 mL) dropwise to the reaction system and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.24 g, 74%). ESI-QQQ-MS: m/z 217 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 28: SYNTHESIS OF 1-CYCLOPROPYL-4-FLUORO-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-28)

(Step 1) N-cyclopropyl-3-fluoro-2-nitroaniline

[0309] ##STR00099##

[0310] Dissolve 1,3-difluoro-2-nitrobenzene (0.32 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.35 g, 90%). ESI-QQQ-MS: m/z 197 [M+H].sup.+.

(Step 2) N.SUP.1.-cyclopropyl 3-fluorobenzene-1,2-diamine

[0311] ##STR00100##

[0312] Dissolve N-cyclopropyl-3-fluoro-2-nitroaniline (0.31 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50? C. and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.26 g, 96%). ESI-QQQ-MS: m/z 167 [M+H].sup.+.

(Step 3) 1-cyclopropyl-4-fluoro-1H-benzo[d]imidazole-2(3H)-one (P-28)

[0313] ##STR00101##

[0314] Dissolve N.sup.1-cyclopropyl 3-fluorobenzene-1,2-diamine (0.22 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C. add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.19 g, 75%). ESI-QQQ-MS: m/z 193 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 29: SYNTHESIS OF 4,5-DIFLUORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-29)

(Step 1) 1,2,4-trifluoro-3-nitrobenzene

[0315] ##STR00102##

[0316] Mix 65% concentrated nitric acid (2 mL) and 98% concentrated sulfuric acid (4 mL), and slowly add 1,2,4-trifluorobenzene (1.32 g) dropwise, and react at 30? C. for 2 h. Stand for layering, wash the organic phase twice with saturated sodium carbonate solution and wash with saturated salt solution, concentrate with vacuum to obtain the title compound (1.7 g, 95%). ESI-QQQ-MS: m/z 178 [M+H].sup.+.

(Step 2) 3,4-difluoro-N-methyl-2-nitroaniline

[0317] ##STR00103##

[0318] Dissolve 1,2,4-trifluoro-3-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol) and heat to 50? C. for 12 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.2 g, 50%). ESI-QQQ-MS: m/z 189 [M+H].sup.+.

(Step 3) 3,4-difluoro-N.SUP.1.-methylbenzene-1,2-diamine

[0319] ##STR00104##

[0320] Dissolve 3,4-difluoro-N-methyl-2-nitroaniline (0.19 g, 1 mmol) in anhydrous methanol (3 mL), add zinc powder (0.66 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.14 g, 90%). ESI-QQQ-MS: m/z 159 [M+H].sup.+.

(Step 4) 4,5-difluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-29)

[0321] ##STR00105##

[0322] Dissolve 3,4-difluoro-N.sup.1-methylbenzene-1,2-diamine (0.14 g, 0.89 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.1 g, 1.2 mmol), and slowly add triphosgene/dichloromethane solution (0.1 g/1 mL) dropwise to the reaction system, react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.12 g, 74%). ESI-QQQ-MS: m/z 185 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 30: SYNTHESIS OF 6,7-DIFLUORO-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-30)

(Step 1) 2,3-difluoro-N-methyl-6-nitroaniline

[0323] ##STR00106##

[0324] Dissolve 1,2,3-trifluoro-4-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethanamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to 50? C. and react for 121. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.24 g, 60%). ESI-QQQ-MS: m/z 189 [M+H].sup.+.

(Step 3) 5,6-difluoro-N.SUP.1.-methylbenzene-1,2-diamine

[0325] ##STR00107##

[0326] Dissolve 3,4-difluoro-N-methyl-2-nitroaniline (0.19 g, 1 mmol) in anhydrous methanol (3 mL), add zinc powder (0.66 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.14 g, 88%). ESI-QQQ-MS: m/z 159 [M+H].sup.+.

(Step 4) 6,7-difluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-30)

[0327] ##STR00108##

[0328] Dissolve 3,4-difluoro-N.sup.1-methylbenzene-1,2-diamine (0.12 g, 0.76 mmol) in dichloromethane (2 mL), cool to 0? C. add triethylamine (0.1 g, 1.2 mmol), and slowly add triphosgene/dichloromethane solution (0.1 g/1 mL) dropwise to the reaction system, react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.13 g, 80%). ESI-QQQ-MS: m/z 185 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 31: SYNTHESIS OF 4-METHOXY-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-31)

(Step 1) 3-methoxy-N-methyl-2-nitroaniline

[0329] ##STR00109##

[0330] Dissolve 1-fluoro-3-methoxy-2-nitrobenzene (0.34 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to reflux, stir for 20 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.29 g, 80%). ESI-QQQ-MS: m/z 183 [M+H].sup.+.

(Step 2) 3-methoxy-N.SUP.1.-methylbenzene-1,2-diamine

[0331] ##STR00110##

[0332] Dissolve 3-methoxy-N-methyl-2-nitroaniline (0.27 g, 1.5 mmol) in anhydrous methanol (4.5 mL), add zinc powder (0.98 g, 15 mmol) and ammonium chloride (0.4 g, 7.5 mmol), heat to 50? C., stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.21 g, 92%). ESI-QQQ-MS: m/z 153 [M+H].sup.+.

(Step 3) 4-methoxy-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-31)

[0333] ##STR00111##

[0334] Dissolve 3-methoxy-N.sup.1-methylbenzene-1,2-diamine (0.2 g, 1.3 mmol) in dichloromethane (2 mL), cool to 0? C., add triethylamine (0.14 g, 1.7 mmol), and slowly add triphosgene/dichloromethane solution (0.15 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.16 g, 70%). ESI-QQQ-MS: m/z 179 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 32: SYNTHESIS OF 5-(DIMETHYLAMINO)-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-32)

(Step 1) N.SUP.1.-methyl-4-nitrobenzene-1,2-diamine

[0335] ##STR00112##

[0336] Dissolve 4-nitrobenzene-1,2-diamine (0.33 g, 2 mmol) in DMF (4 mL), add saturated sodium carbonate solution (0.5 mL) and iodomethane (0.24 g, 1.7 mmol) sequentially, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (0.2 g, 60%). ESI-QQQ-MS: m/z 168 [M+H].sup.+.

(Step 2) 1-methyl-5-nitro-1H-benzo[d]imidazole-2(3H)-one

[0337] ##STR00113##

[0338] Dissolve N.sup.1-methyl-4-nitrobenzene-1,2-diamine (0.2 g, 1.3 mmol) in dichloromethane (4 mL), cool to 0? C. add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene/dichloromethane solution (0.14 g/1 mL) dropwise to the reaction system, and react at rom temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (dichloromethane/methanol=20:1) to obtain the title compound (0.16 g, 68%). ESI-QQQ-MS: m/z 194 [M+H].sup.+.

(Step 3) 5-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one

[0339] ##STR00114##

[0340] Dissolve 1-methyl-5-nitro-1H-benzo[d]imidazole-2(3H)-one (0.16 g, 0.83 mmol) in anhydrous methanol (2.5 mL), add zinc powder (0.54 g, 8.3 mmol) and ammonium chloride (0.22, 4.2 mmol), heat to 50? C., and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (10 mL) to the concentrate, extract with dichloromethane for three times (5 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.12 g, 87%). ESI-QQQ-MS: m/z 164 [M+H].sup.+.

(Step 4) 5-(dimethylamino)-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-32)

[0341] ##STR00115##

[0342] Dissolve 5-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one (0.12 g, 0.73 mmol) in anhydrous DMF (3 mL), add sodium hydrogen (0.07 g, 2.9 mmol), stir for 0.5 h, then add iodomethane (0.26 g, 1.8 mmol), react at room temperature for 12 h. Concentrate the reaction system with vacuum and add water (10 mL) to the reaction system, extract with ethyl acetate twice (5 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (dichloromethane/methanol=10:1) to obtain the title compound (0.06 g, 40%). ESI-QQQ-MS: m/z 192 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 33: SYNTHESIS OF 6-(DIMETHYLAMINO)-1-METHYL-1H-BENZO[D]IMIDAZOLE-2(3H)-ONE (P-33)

(Step 1) 1-methyl-6-nitro-1H-benzo[d]imidazole-2(3H)-one

[0343] ##STR00116##

[0344] Dissolve N.sup.1-methyl-5-nitrobenzene-1,2-diamine (0.33 g, 2 mmol) in dichloromethane (4 mL), cool to 0? C., add triethylamine (0.14 g, 2.6 mmol), and slowly add triphosgene/dichloromethane solution (0.24 g/1 mL) dropwise to the reaction system, and react at room temperature for 1 h. Concentrate the reaction solution with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate with silica gel column chromatography (dichloromethane/methanol=20:1) to obtain the title compound (0.23 g, 60%). ESI-QQQ-MS: m/z 194 [M+H].sup.+.

(Step 2) 6-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one

[0345] ##STR00117##

[0346] Dissolve 1-methyl-6-nitro-1H-benzo[d]imidazole-2(3H)-one (0.23 g, 1.2 mmol) in anhydrous methanol (4.5 mL), add zinc powder (0.91 g, 12 mmol) and ammonium chloride (0.37 g, 6 mmol), heat to 50? C. and stir for 3 h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2 mL each time), combine the filtrate, and concentrate with vacuum, add water (20 mL) to the concentrate, extract with dichloromethane for three times (10 mL each time), combine the organic layer, wash once with water and saturated salt solution respectively, dry with anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (0.16 g, 81%). ESI-QQQ-MS: m/z 164 [M+H].sup.+.

(Step 3) 6-(dimethylamino)-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-33)

[0347] ##STR00118##

[0348] Dissolve 6-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one (0.16 g, 0.98 mmol) in anhydrous DMF (3 mL), add sodium hydrogen (0.1 g, 4 mmol), stir for 0.5 h, and add iodomethane (0.36 g, 2.5 mmol), react at room temperature for 12 h. Concentrate the reaction system with vacuum and add water (20 mL) to the reaction system, extract with ethyl acetate twice (10 mL each time), combine organic phase, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (dichloromethane/methanol=10:1) to obtain the title compound (0.08 g, 42%). ESI-QQQ-MS: m/z 192 [M+H].sup.+.

INTERMEDIATE PREPARATION EXAMPLE 34: SYNTHESIS OF 2,4,6-TRICHLOROBENZOYL CHLORIDE (P-34)

[0349] ##STR00119##

[0350] Dissolve 2,4,6-trichlorobenzoic acid (0.23 g, 1 mmol) in 5 mL of dichloromethane, add thionyl chloride (0.24 g, 2 mmol) and DMF (3 drops), and react at room temperature for 3 h. Concentrate the reaction solution with vacuum to obtain the title compound and directly use in the next reaction.

INTERMEDIATE PREPARATION EXAMPLE 35: SYNTHESIS OF 2,6-DICHLORO-4-(DIETHYLAMINO) BENZOYL CHLORIDE (P-35)

(Step 1) methyl 4-bromo-2,6-dichlorobenzoate

[0351] ##STR00120##

[0352] Dissolve 4-bromo-2,6-dichlorobenzoic acid (0.27 g, 1 mmol) in 5 mL of methanol, cool to 0? C., and add thionyl chloride (0.24 g, 2 mmol) to the reaction system and react at room temperature for 3 h. Concentrate the reaction solution with vacuum, add ethyl acetate (5 mL) and saturated sodium bicarbonate solution (10 mL), stand for layering, wash the organic layer with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (0.24 g, 85%). ESI-QQQ-MS: m/z 283 [M+H].sup.+.

(Step 2) methyl 2,6-dichloro-4-(diethylamino)benzoate

[0353] ##STR00121##

[0354] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), diethylamine (0.12 g, 1.7 mmol), palladium (II) acetate (10 mg, 5 mol %). (?)-2,2-bis-(diphenylphosphino)-1,1-binaphthyl (63 mg, 10 mol %), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL), displace nitrogen, and react in microwave at 120? C. for 2 h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10 mL), extract with ethyl acetate twice (5 mL each time), combine the organic layer, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (0.16 g, 70%). ESI-QQQ-MS: m/z 276 [M+H].sup.+.

(Step 3) 2,6-dichloro-4-(diethylamino)benzoyl chloride (P-35)

[0355] ##STR00122##

[0356] Dissolve methyl 2,6-dichloro-4-(diethylamino)benzoate (0.16 g, 0.58 mmol) in methanol (3 mL) and water (0.5 mL), and add 6N sodium hydroxide solution (0.15 mL, 0.87 mmol) and react at room temperature for 24 h. Adjust the reaction solution to 5-6 with 2N hydrochloric acid, filter and wash the filter cake 3 times, dry with vacuum, dissolve the dried solid in 3 mL of dichloromethane, add thionyl chloride (0.13 g, 1.1 mmol) and DMF (2 drops), and react at room temperature for 4 h. Concentrate the reaction solution with vacuum to obtain the title compound and directly use in the next reaction.

INTERMEDIATE PREPARATION EXAMPLE 36: SYNTHESIS OF 2,6-DICHLORO-4-MORPHOLINOBENZOYL CHLORIDE (P-36)

(Step 1) methyl 2,6-dichloro-4-morpholinobenzoate

[0357] ##STR00123##

[0358] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), morpholine (0.1 g, 1.2 mmol), palladium (II) acetate (10 mg, 5 mol %), (?)-2,2-bis-(diphenylphosphino)-1,1-binaphthyl (63 mg, 10 mol %), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL), displace nitrogen and react in microwave at 120? C. for 2 h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10 mL), extract with ethyl acetate twice (5 mL each time), combine the organic layer, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (0.18 g, 74%). ESI-QQQ-MS: m/z 290 [M+H].sup.+.

(Step 2) 2,6-dichloro-4-morpholinobenzoyl chloride (P-36)

[0359] ##STR00124##

[0360] Dissolve methyl 2,6-dichloro-4-morpholinobenzoate (0.18 g, 0.62 mmol) in methanol (3 mL) and water (0.5 mL), add 6N sodium hydroxide solution (0.16 mL, 0.93 mmol) and react at room temperature for 24 h. Adjust the reaction solution to 5-6 with 2N hydrochloric acid, filter and wash the filter cake 3 times, dry with vacuum, dissolve the dried solid in 3 mL of dichloromethane, add thionyl chloride (0.14 g, 1.2 mmol) and DMF (2 drops), and react at room temperature for 4 h. Concentrate the reaction solution with vacuum to obtain the title compound and directly use in the next reaction.

INTERMEDIATE PREPARATION EXAMPLE 37: SYNTHESIS OF 4-(2-OXA-5-AZADICYCLO[2.2.1]HEPTAN-5-YL)-2,6-DICHLOROBENZOYL CHLORIDE (P-37)

(Step 1) Methyl 4-(2-oxa-5-azadicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzoate

[0361] ##STR00125##

[0362] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), 2-oxa-5-azabicyclo[2.2.1]heptan (0.12 g, 1.2 mmol), palladium (II) acetate (10 mg, 5 mol %), (?)-2,2-bis-(diphenylphosphino)-1,1-binaphthyl (63 mg, 10 mol %), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL), displace nitrogen, and react in microwave at 120? C. for 2 h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10 mL), extract with ethyl acetate twice (5 mL each time), combine the organic layer, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (0.2 g, 78%). ESI-QQQ-MS: m/z 302 [M+H].sup.+.

(Step 2) 4-(2-oxa-5-azadicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzoyl chloride (P-37)

[0363] ##STR00126##

[0364] Dissolve methyl 4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzoate (0.2 g, 0.66 mmol) in methanol (3 mL) and water (0.5 mL), add 6N sodium hydroxide solution (0.17 mL, 0.99 mmol) and react at room temperature for 24 h. Adjust the reaction solution to 5-6 with 2N hydrochloric acid, filter and wash the filter cake 3 times, dry with vacuum, dissolve the dried solid in 3 mL of dichloromethane, add thionyl chloride (0.15 g, 1.3 mmol) and DMF (2 drops), and react at room temperature for 4 h. Concentrate the reaction solution with vacuum to obtain the title compound and directly use in the next reaction.

INTERMEDIATE PREPARATION EXAMPLE 38: SYNTHESIS OF 2,6-DICHLORO-4-(4-MORPHOLINOPIPERIDIN-1-YL)BENZOYL CHLORIDE (P-38)

(Step 1) Methyl 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoate

[0365] ##STR00127##

[0366] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), 4-(piperidin-4-yl)morpholine (0.2 g, 1.2 mmol), palladium (II) acetate (10 mg, 5 mol %), (?)-2,2-bis-(diphenylphosphino)-1,1-binaphthyl (63 mg, 10 mol %), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL), displace nitrogen, and react in microwave reaction at 120? C. for 2 h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10 mL), extract with ethyl acetate twice (5 mL each time), combine the organic layer, wash with saturated salt solution once, dry with anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (0.23 g, 72%). ESI-QQQ-MS: m/z 373 [M+H].sup.+.

(Step 2) 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoyl chloride (P-38)

[0367] ##STR00128##

[0368] Dissolve methyl 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoate (0.23 g, 0.62 mmol) in methanol (3 mL) and water (0.5 mL), add 6N sodium hydroxide solution (0.16 mL, 0.93 mmol) and react at room temperature for 241. Adjust the reaction solution to 5-6 with 2N hydrochloric acid, filter and wash the filter cake 3 times, dry with vacuum, dissolve the dried solid in 3 mL of dichloromethane, add thionyl chloride (0.14 g, 1.2 mmol) and DMF (2 drops), and react at room temperature for 4 h. Concentrate the reaction solution with vacuum to obtain the title compound and directly use in the next reaction.

EXAMPLE 1: SYNTHESIS OF COMPOUND 1

Step 1

(S)-3-(4-(5,6-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0369] ##STR00129##

[0370] Dissolve P-10 (98 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 361. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (215 mg, 70%). ESI-QQQ-MS: m/z 615 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5,6-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0371] ##STR00130##

[0372] Dissolve (S)-3-(4-(5,6-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (154 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhdrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (86 mg, 92%). ESI-QQQ-MS: m/z 373 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5,6-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-phenyl)methyl propionate

[0373] ##STR00131##

[0374] Dissolve (S)-2-amino-3-(4-(5,6-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (107 mg, 88%). ESI-QQQ-MS: m/z 529 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5,6-difluoro-2-oxospirino[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0375] ##STR00132##

[0376] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-phenyl)methyl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (57 mg, 65%). ESI-QQQ-MS: m/z 515 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.90 (brs, 1H), 9.16 (d, J=8.3 Hz, 1H), 7.50-7.42 (m, 3H), 7.39-7.28 (m, 4H), 7.24 (t, J=8.6 Hz, 1H), 6.74-6.70 (m, 1H), 4.77-4.72 (m, 1H), 3.25 (dd, J=14.0, 4.4 Hz, 1H), 3.00 (dd, J=13.9, 10.5 Hz, 1H), 1.79-1.77 (m, 2H), 1.66-1.63 (m, 2H).

EXAMPLE 2: SYNTHESIS OF COMPOUND 2

Step 1

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indolinyl]-1-yl)phenyl)-2-(tritylamino)methyl propionate

[0377] ##STR00133##

[0378] Dissolve P-6 (97 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 361. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (178 mg, 58%). ESI-QQQ-MS: m/z 613 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0379] ##STR00134##

[0380] Dissolve (S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate (153 mg, 0.25 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhdrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (83 mg, 90%). ESI-QQQ-MS: m/z 371 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide) methyl propionate

[0381] ##STR00135##

[0382] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (112 mg, 92%). ESI-QQQ-MS: m/z 527 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide) propionic acid

[0383] ##STR00136##

[0384] Dissolve (S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)methyl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (55 mg, 63%). ESI-QQQ-MS: m/z 513 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.84 (brs, 1H), 9.19 (d, J=8.1 Hz, 1H), 7.47-7.40 (m, 3H), 7.33-7.23 (m, 4H), 7.19-7.17 (m, 1H), 7.08-7.02 (m, 2H), 4.72-4.67 (m, 1H), 3.22 (dd, J=14.1, 4.3 Hz, 1H), 3.01 (dd, J=14.1, 10.3 Hz, 1H), 1.78-1.76 (m, 2H), 1.68-1.66 (m, 2H).

EXAMPLE 3: SYNTHESIS OF COMPOUND 4

Step 1

(S)-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0385] ##STR00137##

[0386] Dissolve P-9 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) to reaction system, under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (188 mg, 62%). ESI-QQQ-MS: m/z 609 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0387] ##STR00138##

[0388] Dissolve (S)-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (152 mg, 0.25 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (83 mg, 91%). ESI-QQQ-MS: m/z 367 [M+H].sup.+.

Step 3

(S)-2-(2,6-dichlorobenzamido)-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0389] ##STR00139##

[0390] Dissolve (S)-2-amino-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (109 mg, 88%). ESI-QQQ-MS: m/z 539 [M+H].sup.+.

Step 4

(S)-2-(2,6-dichlorobenzamido)-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0391] ##STR00140## ##STR00141##

[0392] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(7-methoxy-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (92 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 ml each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (52 mg, 59%). ESI-QQQ-MS: m/z 525 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.74 (brs, 1H), 9.15 (d, J=8.2 Hz, 1H), 7.46-7.32 (m, 5H), 7.19 (d, J=8.2 Hz, 2H), 7.02 (t, J=7.9 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.71 (d, J=7.4 Hz, 1H), 4.74-4.69 (m, 1H), 3.46 (s, 3H), 3.19 (dd, J=14.0, 4.7 Hz, 1H), 2.99 (dd, J=14.0, 9.8 Hz, 1H), 1.68-1.64 (m, 2H), 1.62-1.58 (m, 2H).

EXAMPLE 4: SYNTHESIS OF COMPOUND 6

Step 1

(S)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0393] ##STR00142##

[0394] Dissolve P4 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (202 mg, 68%). ESI-QQQ-MS: m/z 597 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0395] ##STR00143##

[0396] Dissolve (S)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (149 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (84 mg, 95%). ESI-QQQ-MS: m/z 355 [M+H].sup.+.

Step 3

(S)-2-(2,6-dichlorobenzamido)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0397] ##STR00144##

[0398] Dissolve methyl (S)-2-amino-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (108 mg, 89%). ESI-QQQ-MS: m/z 527 [M+H].sup.+.

Step 4

(S)-2-(2,6-dichlorobenzamido)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0399] ##STR00145##

[0400] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 ml each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m/z 513 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.75 (brs, 1H), 9.13 (d, J=8.4 Hz, 1H), 7.51-7.49 (m, 2H), 7.45-7.32 (m, 5H), 7.15-7.13 (m, 1H), 6.93-6.79 (m, 1H), 6.53-6.51 (m, 1H), 4.83-4.71 (m, 1H), 3.25 (dd, J=14.0, 4.3 Hz, 1H), 2.99 (dd, J=13.9, 10.7 Hz, 1H), 1.75-1.71 (m, 2H), 1.64-1.60 (m, 2H).

EXAMPLE 5: SYNTHESIS OF COMPOUND 7

(Step 1) (S)-3-(4-(7-fluoro-2-oxospiro [cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0401] ##STR00146##

[0402] Dissolve P-3 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (182 mg, 61%). ESI-QQQ-MS: m/z 597 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0403] ##STR00147##

[0404] Dissolve (S)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (149 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (85 mg, 96%). ESI-QQQ-MS: m/z 355 [M+H].sup.+.

Step 3

(S)-2-(2,6-dichlorobenzamido)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0405] ##STR00148##

[0406] Dissolve (S)-2-amino-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (109 mg, 90%). ESI-QQQ-MS: m/z 527 [M+H].sup.+.

Step 4

(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0407] ##STR00149##

[0408] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 ml each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 58%). ESI-QQQ-MS: m/z 513 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.79 (brs, 1H), 9.15 (d, J=8.3 Hz, 1H), 7.44-7.37 (m, 5H), 7.35-7.31 (m, 2H), 7.11-7.01 (m, 2H), 6.97-6.91 (m, 1H), 4.74-4.72 (m, 1H), 3.22 (dd, J=14.1, 4.3 Hz, 1H), 2.99 (dd, J=14.1, 10.4 Hz, 1H), 1.79-1.74 (m, 2H), 1.69-1.64 (m, 2H).

EXAMPLE 6: SYNTHESIS OF COMPOUND 8

Step 1

(S)-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0409] ##STR00150##

[0410] Dissolve P-2 (80 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (197 mg, 68%). ESI-QQQ-MS: m/z 579 [M+H].sup.+.

(Step 2) (S)-2-amino-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0411] ##STR00151##

[0412] Dissolve (S)-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (145 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (79 mg, 94%). ESI-QQQ-MS: m/z 337 [M+H].sup.+.

Step 3

(S)-2-(2,6-dichlorobenzamido)-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0413] ##STR00152##

[0414] Dissolve (S)-2-amino-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (77 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-4-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (111 mg, 95%). ESI-QQQ-MS: m/z 509 [M+H].sup.+.

Step 4

(S)-2-(2,6-dichlorobenzamido)-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0415] ##STR00153##

[0416] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (87 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 64%). ESI-QQQ-MS: m/z 495 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.85 (brs, 1H), 9.14 (d, J=8.4 Hz, 1H), 7.51-7.33 (m, 7H), 7.20-7.19 m, 1H), 7.13-7.03 (m, 2H), 6.76 (d, J=7.9 Hz, 1H), 4.78-4.76 (m, 1H), 3.25 (dd, J=14.0, 4.4 Hz, 1H), 3.00 (dd, J=14.0, 10.5 Hz, 1H), 1.73-1.69 (m, 2H), 1.65-1.61 (m, 2H).

EXAMPLE 7: SYNTHESIS OF COMPOUND 9

Step 1

(S)-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0417] ##STR00154##

[0418] Dissolve P-14 (119 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (180 mg, 55%). ESI-QQQ-MS: m/z 657 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-phenyl)methyl propionate

[0419] ##STR00155##

[0420] Dissolve (S)-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-yl)phenyl)methyl propionate (164 mg, 0.25 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (98 mg, 95%). ESI-QQQ-MS: m/z 415 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate

[0421] ##STR00156##

[0422] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-phenyl)methyl propionate (95 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., and add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol), react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (118 mg, 90%). ESI-QQQ-MS: m/z 571 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)propionic acid

[0423] ##STR00157##

[0424] Dissolve (S)-3-(4-(7-chloro-2-oxo-2,3,5,6-tetrahydrospiro[indoline-3,4-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino) methyl propionate (97 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 57%). ESI-QQQ-MS: m/z 557 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.87 (brs, 1H), 9.15 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.47-7.36 (m, 3H), 7.31-7.21 (m, 5H), 7.09 (d, J=7.8 Hz, 1H), 4.70-4.65 (m, 1H), 4.06 (t, J=10.6 Hz, 2H), 3.87-3.79 (m, 2H), 3.22 (dd, J=14.1, 4.3 Hz, 1H), 3.01 (dd, J=14.0, 10.1 Hz, 1H), 2.00-1.93 (m, 2H), 1.87-1.83 (m, 2H).

EXAMPLE 8: SYNTHESIS OF COMPOUND 10

Step 1

(S)-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0425] ##STR00158##

[0426] Dissolve P-11 (112 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (211 mg, 67%). ESI-QQQ-MS: m/z 631 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0427] ##STR00159##

[0428] Dissolve (S)-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (158 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (89 mg, 92%). ESI-QQQ-MS: m/z 389 [M+H].sup.+.

Step 3

(S)-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate

[0429] ##STR00160##

[0430] Dissolve (S)-2-amino-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (89 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (113 mg, 90%). ESI-QQQ-MS: m/z 545 [M+H].sup.+.

Step 4

(S)-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)propionic acid

[0431] ##STR00161##

[0432] Dissolve (S)-3-(4-(6-chloro-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)methyl propionate (93 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 60%/6). ESI-QQQ-MS: m/z 531 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.89 (brs, 1H), 9.13 (d, J=8.3 Hz, 1H), 7.51-7.42 (m, 3H), 7.38-7.34 (m, 3H), 7.30 (d, J=8.1 Hz, 1H), 7.24 (t, J=8.6 Hz, 1H), 6.77 (d, J=6.0 Hz, 1H), 4.77-4.73 (m, 1H), 3.26 (d, J=4.1 Hz, 1H), 2.99 (dd, J=13.8, 10.8 Hz, 1H), 1.86-1.81 (m, 2H), 1.72-1.64 (m, 2H).

EXAMPLE 9: SYNTHESIS OF COMPOUND 11

Step 1

(S)-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0433] ##STR00162##

[0434] Dissolve P-5 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (197 mg, 66%). ESI-QQQ-MS: m/z 597 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0435] ##STR00163##

[0436] Dissolve (S)-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (149 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (84 mg, 95%). ESI-QQQ-MS: m/z 355 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)methyl propionate

[0437] ##STR00164##

[0438] Dissolve (S)-2-amino-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (107 mg, 88%). ESI-QQQ-MS: m/z 511 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)propionic acid

[0439] ##STR00165##

[0440] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)methyl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (50 mg, 57%). ESI-QQQ-MS: m/z 497 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.86 (brs, 1H), 9.17 (d, J=8.3 Hz, 1H), 7.51-7.41 (m, 3H), 7.39-7.23 (m, 4H), 7.13-7.00 (m, 2H), 6.75-6.72 (m, 1H), 4.76-4.71 (m, 1H), 3.25 (dd. J=14.0, 4.5 Hz, 1H), 3.00 (dd, J=14.0, 10.4 Hz, 1H), 1.80-1.76 (m, 2H), 1.68-1.64 (m, 2H).

EXAMPLE 10: SYNTHESIS OF COMPOUND 12

Step 1

(S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0441] ##STR00166##

[0442] Dissolve P-13 (97 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (154 mg, 50%). ESI-QQQ-MS: m/z 615 [M+H].sup.+.

(Step 2) (S)-2-amino-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)methyl propionate

[0443] ##STR00167##

[0444] Dissolve (S)-3-(4-(3,3-dimethyl-2-oxoindoline-1-yl)phenyl)-2-(triphenylamino)methyl propionate (154 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (89 mg, 95%). ESI-QQQ-MS: m/z 373 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)methyl propionate

[0445] ##STR00168##

[0446] Dissolve (S)-2-amino-3-(4-(3,3-dimethyl-2-oxoindoline-1-yl)phenyl)methyl propionate (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (114 mg, 94%). ESI-QQQ-MS: m/z 529 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)propionic acid

[0447] ##STR00169##

[0448] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)meth yl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (49 mg, 54%). ESI-QQQ-MS: m/z 515 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.81 (brs, 1H), 9.18 (d, J=8.1 Hz, 1H), 7.47-7.39 (m, 4H), 7.34-7.23 (m, 4H), 7.21-7.19 (m, 1H), 7.11-7.04 (m, 1H), 4.70-4.68 (m, 1H), 3.22 (dd, J=14.1, 4.3 Hz, 1H), 3.00 (dd, J=14.1, 10.3 Hz, 1H), 1.40 (s, 6H).

EXAMPLE 11: SYNTHESIS OF COMPOUND 14

Step 1

(S)-3-(4-(6-(dimethylamino)-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0449] ##STR00170##

[0450] Dissolve P-16 (110 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (160 mg, 50%). ESI-QQQ-MS: m/z 640 [M+H].sup.+.

(Step 2) (S)-2-amino-3-(4-(6-(dimethylamino)-5-fluoro-2-oxospiro [cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0451] ##STR00171##

[0452] Dissolve (S)-3-(4-(6-dimethylamino-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (160 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (94 mg, 95%). ESI-QQQ-MS: m/z 398 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6-(dimethylamino)-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0453] ##STR00172##

[0454] Dissolve (S)-2-amino-3-(4-(6-(dimethylamino)-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (91 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (114 mg, 90%). ESI-QQQ-MS: m/z 554 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6-(dimethylamino)-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0455] ##STR00173##

[0456] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6-(dimethylamino)-5-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (94 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (38 mg, 42%). ESI-QQQ-MS: m/z 540 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.97 (brs, 1H), 9.13 (d, J=8.2 Hz, 1H), 7.51-7.18 (m, 7H), 7.01 (d, J=12.2 Hz, 1H), 6.37 (d, J=7.3 Hz, 1H), 4.82-4.68 (m, 1H), 3.25 (d, J=3.9 Hz, 1H), 2.99 (dd, J=13.8, 10.9 Hz, 1H), 2.66 (s, 6H), 1.68-1.64 (m, 2H), 1.58-1.53 (m, 2H).

EXAMPLE 12: SYNTHESIS OF COMPOUND 15

Step 1

(S)-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0457] ##STR00174##

[0458] Dissolve P-15 (101 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (162 mg, 52%). ESI-QQQ-MS: m/z 622 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0459] ##STR00175##

[0460] Dissolve (S)-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (155 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (89 mg, 94%). ESI-QQQ-MS: m/z 380 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0461] ##STR00176##

[0462] Dissolve (S)-2-amino-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (87 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (114 mg, 90%). ESI-QQQ-MS: m/z 536 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0463] ##STR00177##

[0464] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5-(dimethylamino)-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (94 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (34 mg, 38%). ESI-QQQ-MS: m/z 522 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 8.86 (d, J=6.7 Hz, 1H), 7.43 (t, J=8.0 Hz, 3H), 7.34-7.28 (m, 3H), 7.26-7.23 (m, 1H), 6.68 (d, J=8.5 Hz, 1H), 6.60-6.54 (m, 2H), 4.64-4.60 (m, 1H), 3.24 (dd, J=13.7, 3.8 Hz, 1H), 3.01 (dd, J=13.4, 9.6 Hz, 1H), 2.83 (s, 6H), 1.70-1.64 (m, 2H), 1.60-1.54 (m, 2H).

EXAMPLE 13: SYNTHESIS OF COMPOUND 16

(Step 1) (S)-3-(4-(6-fluoro-2-oxospiro [cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0465] ##STR00178##

[0466] Dissolve P4 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (210 mg, 70%). ESI-QQQ-MS: m/z 597 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0467] ##STR00179##

[0468] Dissolve (S)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (149 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (81 mg, 92%). ESI-QQQ-MS: m/z 355 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)methyl propionate

[0469] ##STR00180##

[0470] Dissolve (S)-2-amino-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (81 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (105 mg, 90%). ESI-QQQ-MS: m/z 511 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-4-fluorobenzamide)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)propionic acid

[0471] ##STR00181##

[0472] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)methyl propionate (87 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 ml each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 60%). ESI-QQQ-MS: m/z 497 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO): ? 12.89 (s, 1H), 9.15 (d, J=8.3 Hz, 1H), 7.51-7.42 (m, 3H), 7.38 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.1 Hz, 1H), 7.24 (t, J=8.6 Hz, 1H), 7.16-7.12 (m, 1H), 6.92-6.84 (m, 1H), 6.53 (dd, J=9.4, 2.3 Hz, 1H), 4.77-4.73 (m, 1H), 3.26 (dd, J=14.0, 4.4 Hz, 1H), 3.00 (dd, J=13.9, 10.5 Hz, 1H), 1.75-1.71 (m, 2H), 1.64-1.60 (m, 2H).

EXAMPLE 14: SYNTHESIS OF COMPOUND 17

(Step 1) (S)-3-(4-(7-fluoro-2-oxospiro [cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0473] ##STR00182##

[0474] Dissolve P-3 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (216 mg, 72%). ESI-QQQ-MS: m/z 597 [M+H].sup.+.

(Step 2) methyl (S)-2-amino-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionate

[0475] ##STR00183##

[0476] Dissolve (S)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (149 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (82 mg, 91%). ESI-QQQ-MS: m/z 355 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)methyl propionate

[0477] ##STR00184##

[0478] Dissolve (S)-2-amino-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (81 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (102 mg, 87%). ESI-QQQ-MS: m/z 511 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)propionic acid

[0479] ##STR00185##

[0480] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl) phenyl)methyl propionate (87 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (53 mg, 62%). ESI-QQQ-MS: m/z 497 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO): ? 12.85 (s, 1H), 9.18 (d, J=8.1 Hz, 1H), 7.48-7.21 (m, 7H), 7.09-7.05 (m, 2H), 6.98-6.94 (m, 1H), 4.72-4.68 (m, 1H), 3.22 (dd, J=14.1, 4.4 Hz, 1H), 3.00 (dd, J=14.1, 10.3 Hz, 1H), 1.78-1.74 (m, 2H), 1.69-1.65 (m, 2H).

EXAMPLE 15: SYNTHESIS OF COMPOUND 18

Step 1

(S)-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0481] ##STR00186##

[0482] Dissolve P-12 (98 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 361. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (206 mg, 67%). ESI-QQQ-MS: m/z 615 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0483] ##STR00187##

[0484] Dissolve (S)-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (154 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (87 mg, 94%). ESI-QQQ-MS: m/z 373 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0485] ##STR00188##

[0486] Dissolve (S)-2-amino-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (107 mg, 88%). ESI-QQQ-MS: m/z 529 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6,7-difluoro-2-oxospirino[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0487] ##STR00189##

[0488] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl))methyl propionate (90 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (49 mg, 56%). ESI-QQQ-MS: m/z 515 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.87 (brs, 1H), 9.18 (d, J=8.2 Hz, 1H), 7.47-7.36 (m, 5H), 7.33-7.20 (m, 2H), 7.11-7.06 (m, 11H), 6.97-6.94 (m, 1H), 4.73-4.68 (m, 1H), 3.23 (dd, J=14.1, 4.4 Hz, 1H), 3.01 (dd, J=14.1, 10.3 Hz, 1H), 1.78-1.74 (m, 2H), 1.68-1.64 (m, 2H).

EXAMPLE 16: SYNTHESIS OF COMPOUND 19

Step 1

(S)-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)-2-(triphenylamino)methyl propionate

[0489] ##STR00190##

[0490] Dissolve P-17 (80 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (145 mg, 50%). ESI-QQQ-MS: m/z 580 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)methyl propionate

[0491] ##STR00191##

[0492] Dissolve (S)-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)-2-(triphenylamino)methyl propionate (145 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (78 mg, 92%). ESI-QQQ-MS: m/z 338 [M+H].sup.+.

Step 3

(S)-2-(2,6-dichlorobenzamido)-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)methyl propionate

[0493] ##STR00192##

[0494] Dissolve (S)-2-amino-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)methyl propionate (78 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (100 mg, 85%). ESI-QQQ-MS: m/z 510 [M+H].sup.+.

Step 4

(S)-2-(2,6-dichlorobenzamido)-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)propionic acid

[0495] ##STR00193##

[0496] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(2-oxospiro[cyclopropane-1,3-pyrrolo[2,3-b]pyridine]-1(2H)-yl)phenyl)methyl propionate (87 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (33 mg, 40%). ESI-QQQ-MS: m/z 496 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 8.80 (s, 1H), 8.07 (d, J=4.4 Hz, 1H), 7.51 (d, J=7.0 Hz, 1H), 7.42-7.30 (m, 8H), 7.11-7.01 (m, 1H), 4.68-4.62 (m, 1H), 3.24 (d, J=4.1 Hz, 1H), 3.03 (dd, J=13.3, 9.1 Hz, 1H), 1.82-1.78 (m, 2H), 1.72-1.66 (m, 2H).

EXAMPLE 17: SYNTHESIS OF COMPOUND 20

Step 1

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,4,6-trichlorobenzoylamino)methyl propionate

[0497] ##STR00194##

[0498] Dissolve (S)-2-amino-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (85 mg, 0.23 mmol, the preparation process is detailed in Example 2) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add the intermediate P-34 (61 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (125 mg, 94%). ESI-QQQ-MS: m/z 577 [M+H].sup.+.

Step 2

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,4,6-trichlorobenzoylamino)propionic acid

[0499] ##STR00195##

[0500] Dissolve (S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,4,6-trichlorobenzoylamino)methyl propionate (98 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 56%). ESI-QQQ-MS: m/z 562 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.91 (brs, 1H), 9.18 (d, J=8.0 Hz, 1H), 7.67 (s, 2H), 7.44-7.15 (m, 5H), 7.10-7.01 (m, 2H), 4.73-4.69 (m, 1H), 3.26-3.19 (m, 1H), 3.04-2.92 (m, 1H), 1.78-1.74 (m, 2H), 1.68-1.64 (m, 2H).

EXAMPLE 18: SYNTHESIS OF COMPOUND 21

Step 1

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-(diethylamino)benzoylamino)methyl propionate

[0501] ##STR00196##

[0502] Dissolve (S)-2-amino-3-(4-(7-fluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (85 mg, 0.23 mmol, the preparation process is detailed in Example 2) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add the intermediate P-35 (70 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (125 mg, 94%). ESI-QQQ-MS: m/z 614 [M+H].sup.+.

Step 2

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-(diethylamino)benzoylamino)propionic acid

[0503] ##STR00197##

[0504] Dissolve (S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-(diethylamino)benzoylamino)methyl propionate (102 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 56%). ESI-QQQ-MS: m/z 600 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.67 (brs, 1H), 8.79 (d, J=7.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.26 (d, J=7.3 Hz, 2H), 7.20-7.15 (m, 1H), 7.09-7.01 (m, 2H), 6.57 (s, 2H), 4.64-4.60 (m, 1H), 3.33-3.20 (m, 4H), 3.17 (dd, J=14.1, 4.2 Hz, 1H), 3.00 (dd, J=14.0, 10.1 Hz, 1H), 1.78-1.74 (m, 2H), 1.68-1.64 (m, 2H), 1.05 (t, J=7.0 Hz, 6H).

EXAMPLE 19: SYNTHESIS OF COMPOUND 22

Step 1

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinoylbenzoylamino)methyl propionate

[0505] ##STR00198##

[0506] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (85 mg, 0.23 mmol, the preparation process is detailed in Example 2) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add the intermediate P-36 (74 mg, 0.25 mmol) dropwise to the reaction system, and the react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (123 mg, 85%). ESI-QQQ-MS: m/z 628 [M+H].sup.+.

Step 2

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzoylamino)propionic acid

[0507] ##STR00199##

[0508] Dissolve (S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzoylamino)methyl propionate (107 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 52%). ESI-QQQ-MS: m/z 614 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 8.54 (s, 1H), 7.40-7.38 (m, 2H), 7.24-7.17 (m, 3H), 7.09-7.02 (m, 2H), 6.93 (s, 2H), 4.59-4.52 (m, 1H), 3.72-3.66 (m, 4H), 3.21 (s, 1H), 3.21-3.17 (m, 4H), 3.04 (dd, J=13.4, 9.1 Hz, 1H), 1.78-1.74 (m, 2H), 1.68-1.64 (m, 2H).

EXAMPLE 20: SYNTHESIS OF COMPOUND 23

Step 1

(2S)-2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzamido)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate

[0509] ##STR00200##

[0510] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl) methyl propionate (85 mg, 0.23 mmol, the preparation process is detailed in Example 2) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add the intermediate P-37 hept-5-yl (77 mg, 0.25 mmol) dropwise to the reaction system, and the react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (109 mg, 74%). ESI-QQQ-MS: m/z 640 [M+H].sup.+.

Step 2

(2S)-2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzamido)-3-(47-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)propionic acid

[0511] ##STR00201##

[0512] Dissolve (2S)-methyl 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzamido)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)methyl propionate (109 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol), and react at room temperature reaction for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (52 mg, 49%). ESI-QQQ-MS: m/z 626 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.76 (brs, 1H), 8.81 (d, J=5.9 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.27-7.17 (m, 3H), 7.11-7.01 (m, 2H), 6.63 (s, 2H), 4.67 (s, 1H), 4.62 (s, 2H), 3.73 (d, J=7.3 Hz, 1H), 3.58 (d, J=7.5 Hz, 1H), 3.45 (d, J=9.4 Hz, 1H), 3.23-3.13 (m, 1H), 3.05-2.95 (m, 2H), 1.91-1.83 (m, 2H), 1.77-1.66 (m, 4H).

EXAMPLE 21: SYNTHESIS OF COMPOUND 24

Step 1

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoylamino)methyl propionate

[0513] ##STR00202##

[0514] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl) methyl propionate (85 mg, 0.23 mmol, the preparation process is detailed in Example 2) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add the intermediate P-38 (94 mg, 0.25 mmol) dropwise to the reaction system, and the react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (129 mg, 79%). ESI-QQQ-MS: m/z 711 [M+H].sup.+.

Step 2

(S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoylamino)propionic acid

[0515] ##STR00203##

[0516] Dissolve (S)-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoylamino)methyl propionate (121 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (59 mg, 50%). ESI-QQQ-MS: m/z 696 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.75 (brs, 1H), 8.87 (d, J=7.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.27-7.25 (m, 2H), 7.20-7.16 (m, 1H), 7.09-7.02 (m, 2H), 6.90 (s, 2H), 4.65-4.61 (m, 1H), 3.82 (d, J=12.9 Hz, 2H), 3.55 (s, 4H), 3.17 (dd, J=14.1, 4.3 Hz, 1H), 3.00 (dd, J=14.0, 10.2 Hz, 1H), 2.76 (t, J=11.9 Hz, 2H), 2.45 (s, 4H), 2.37-2.29 (m, 1H), 1.81-1.75 (m, 4H), 1.67-1.65 (m, 2H), 1.41-1.35 (m, 2H).

EXAMPLE 22: SYNTHESIS OF COMPOUND 25

Step 1

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0517] ##STR00204##

[0518] Dissolve P-18 (91 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (180 mg, (0%). ESI-QQQ-MS: m/z 602 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0519] ##STR00205##

[0520] Dissolve (S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (150 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (85 mg, 95%). ESI-QQQ-MS: m/z 360 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)methyl propionate

[0521] ##STR00206##

[0522] Dissolve (S)-2-amino-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (86 mg, 0.24 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (105 mg, 85%/6). ESI-QQQ-MS: m/z 516 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo-1H-imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)propionic acid

[0523] ##STR00207##

[0524] Dissolve (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo-1H-imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)methyl propionate (88 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated saline solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (60 mg, 70%). ESI-QQQ-MS: m/z 502 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.86 (brs, 1H), 9.19 (d, J=8.1 Hz, 1H), 7.48-7.38 (m, 3H), 7.33-7.22 (m, 5H), 7.12 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 4.73-4.68 (m, 1H), 3.39 (s, 3H), 3.23 (dd, J=14.1.4.1 Hz, 1H), 3.02 (dd, J=13.9, 10.5 Hz, 1H).

EXAMPLE 23: SYNTHESIS OF COMPOUND 26

Step 1

(S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0525] ##STR00208##

[0526] Dissolve P-19 (104 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) to reaction system, under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (198 mg, 63%). ESI-QQQ-MS: m/z 628 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate

[0527] ##STR00209##

[0528] Dissolve (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (157 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (88 mg, 91%). ESI-QQQ-MS: m/z 386 [M+H].sup.+.

Step 3

(S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)methyl propionate

[0529] ##STR00210##

[0530] Dissolve (S)-2-amino-3-(4-(5-chloro-3<cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (88 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2,6-dichlorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the water layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (112 mg, 87%). ESI-QQQ-MS: m/z 558 [M+H].sup.+.

Step 4

(S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)propionic acid

[0531] ##STR00211##

[0532] Dissolve (S)-3-(4-5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)methyl propionate (95 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated saline solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (57 mg, 62%). ESI-QQQ-MS: m/z 544 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.76 (brs, 1H), 9.13 (d, J=8.4 Hz, 1H), 7.51-7.31 (m, 8H), 7.12-7.10 (m, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.24 (dd, J=14.0, 4.5 Hz, 1H), 3.03-2.93 (m, 2H), 1.10-1.06 (m, 2H), 0.97-0.93 (m, 2H).

EXAMPLE 24: SYNTHESIS OF COMPOUND 27

Step 1

(S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0533] ##STR00212##

[0534] Dissolve P-20 (104 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (182 mg, 58%). ESI-QQQ-MS: m/z 628 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate

[0535] ##STR00213##

[0536] Dissolve (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate (157 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (91 mg, 94%). ESI-QQQ-MS: m/z 386 [M+H].sup.+.

Step 3

(S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)methyl propionate

[0537] ##STR00214##

[0538] Dissolve (S)-2-amino-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (89 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2,6-dichlorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (118 mg, 92%). ESI-QQQ-MS: m/z 558 [M+H].sup.+.

Step 4

(S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)propionic acid

[0539] ##STR00215##

[0540] Dissolve (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)methyl propionate (95 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (56 mg, 61%). ESI-QQQ-MS: m/z 544 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.85 (brs, 1H), 9.12 (d, J=8.4 Hz, 1H), 7.50-7.48 (m, 2H), 7.45-7.38 (m, 5H), 7.30 (d, J=8.3 Hz, 1H), 7.20-7.18 (m, 1H), 6.87 (d, J=1.8 Hz, 1H), 4.80-4.75 (m, 1H), 3.26 (dd, J=14.0, 4.4 Hz, 1H), 3.01-2.95 (m, 2H), 1.09-1.05 (m, 2H), 0.97-0.93 (m, 2H).

EXAMPLE 25: SYNTHESIS OF COMPOUND 28

Step 1

(S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0541] ##STR00216##

[0542] Dissolve P-21 (10.sup.4 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 361. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (157 mg, 50%). ESI-QQQ-MS: m/z 628 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate

[0543] ##STR00217##

[0544] Dissolve (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (157 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (92 mg, 95%). ESI-QQQ-MS: m/z 386 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)methyl propionate

[0545] ##STR00218##

[0546] Dissolve (S)-2-amino-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (89 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2,6-dichlorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (115 mg, 90%). ESI-QQQ-MS: m/z 558 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)propionic acid

[0547] ##STR00219##

[0548] Dissolve (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)methyl propionate (95 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (49 mg, 53%). ESI-QQQ-MS: m/z 544 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.84 (brs, 1H), 9.17 (d, J=8.2 Hz, 1H), 7.47-7.37 (m, 5H), 7.29 (t, J=7.8 Hz, 3H), 7.13 (t, J=8.0 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.75-4.70 (m, 1H), 3.22 (dd, J=14.1, 4.2 Hz, 1H), 3.06-2.93 (m, 2H), 1.09-1.05 (m, 2H), 0.97-0.92 (m, 2H).

EXAMPLE 26: SYNTHESIS OF COMPOUND 29

Step 1

(S)-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0549] ##STR00220##

[0550] Dissolve P-22 (99 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (173 mg, 56%). ESI-QQQ-MS: m/z 618 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0551] ##STR00221##

[0552] Dissolve (S)-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (155 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (86 mg, 92%). ESI-QQQ-MS: m/z 376 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-fluorobenzoylamino)methyl propionate

[0553] ##STR00222##

[0554] Dissolve (S)-2-amino-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (110 mg, 90%). ESI-QQQ-MS: m/z 532 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionic acid

[0555] ##STR00223##

[0556] Dissolve (S)-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate (91 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m/z 518 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.88 (brs, 1H), 9.08 (s, 1H), 7.57 (s, 1H), 7.44-7.12 (m, 9H), 4.65-4.63 (m, 1H), 3.76 (s, 3H), 3.16 (dd, J=14.1, 4.1 Hz, 1H), 2.92 (dd, J=13.9, 10.5 Hz, 1H).

EXAMPLE 27: SYNTHESIS OF COMPOUND 30

Step 1

(S)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0557] ##STR00224##

[0558] Dissolve P-28 (96 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (193 mg, 63%/6). ESI-QQQ-MS: m/z 612 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)m ethyl propionate

[0559] ##STR00225##

[0560] Dissolve (S)-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl)-2-(triphenylamino)methyl propionate (153 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (88 mg, 95%). ESI-QQQ-MS: m/z 370 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-1-yl)phenyl)methyl propionate

[0561] ##STR00226##

[0562] Dissolve (S)-2-amino-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl))methyl propionate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (109 mg, 90%). ESI-QQQ-MS: m/z 526 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-1-yl)phenyl)propionic acid

[0563] ##STR00227##

[0564] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6,7-difluoro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl))methyl propionate (89 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (47 mg, 54%). ESI-QQQ-MS: m/z 512 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.86 (brs, 1H), 9.18 (d, J=8.0 Hz, 1H), 7.48-7.22 (m, 7H), 7.17-7.10 (m, 2H), 6.99-6.82 (m, 1H), 4.71-4.68 (m, 1H), 3.22 (dd, J=14.1.4.2 Hz, 1H), 3.05-2.93 (m, 2H), 1.10-1.04 (m, 2H), 0.97-0.93 (m, 2H).

EXAMPLE 28: SYNTHESIS OF COMPOUND 31

Step 1

(S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-phenyl)-2-(triphenylamino)methyl propionate

[0565] ##STR00228##

[0566] Dissolve P-23 (126 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 361. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (175 mg, 0.52%). ESI-QQQ-MS: m/z 672 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0567] ##STR00229##

[0568] Dissolve (S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-phenyl)-2-(triphenylamino)methyl propionate (168 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (102 mg, 95%). ESI-QQQ-MS: m/z 430 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-H-benzo[d]imidazol-1-phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate

[0569] ##STR00230##

[0570] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl) phenyl)methyl propionate (99 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (119 mg, 88%). ESI-QQQ-MS: m/z 586 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionic acid

[0571] ##STR00231##

[0572] Dissolve (S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate (100 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (53 mg, 54%). ESI-QQQ-MS: m/z 572 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.81 (brs, 1H), 9.18 (d, J=7.9 Hz, 1H), 7.56-7.19 (m, 8H), 7.15-7.03 (m, 2H), 4.74-4.68 (m, 1H), 4.55-4.47 (m, 1H), 4.00 (d, J=8.0 Hz, 2H), 3.49 (t, J=11.6 Hz, 2H), 3.26-3.21 (m, 1H), 3.07-2.95 (m, 1H), 2.47-2.42 (m, 2H), 1.76-1.70 (m, 2H).

EXAMPLE 29: SYNTHESIS OF COMPOUND 32

Step 1

(S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate

[0573] ##STR00232##

[0574] Dissolve P-24 (133 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (151 mg, 44%). ESI-QQQ-MS: m/z 685 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0575] ##STR00233##

[0576] Dissolve (S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (171 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (104 mg, 94%). ESI-QQQ-MS: m/z 443 [M+H].sup.+.

Step 3

(S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate

[0577] ##STR00234##

[0578] Dissolve (S)-2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (102 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (117 mg, 85%). ESI-QQQ-MS: m/z 599 [M+H].sup.+.

Step 4

(S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionic acid

[0579] ##STR00235##

[0580] Dissolve (S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)methyl propionate (102 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (40 mg, 40%). ESI-QQQ-MS: m/z 585 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 9.01 (d, J=7.6 Hz, 1H), 7.48-7.37 (m, 4H), 7.34-7.19 (m, 4H), 7.12-7.00 (m, 2H), 4.70-4.64 (m, 1H), 4.43-4.34 (m, 1H), 3.32-2.95 (m, 6H), 2.60-2.53 (m, 2H), 2.43 (s, 3H), 1.84-1.80 (m, 2H).

EXAMPLE 30: SYNTHESIS OF COMPOUND 33

Step 1

(S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0581] ##STR00236##

[0582] Dissolve P-25 (83 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (187 mg, 64%). ESI-QQQ-MS: m/z 586 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0583] ##STR00237##

[0584] Dissolve (S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (146 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (81 mg, 94%). ESI-QQQ-MS: m/z 344 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0585] ##STR00238##

[0586] Dissolve (S)-2-amino-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (79 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (103 mg, 90%). ESI-QQQ-MS: m/z 500 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-4-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0587] ##STR00239##

[0588] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (85 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (56 mg, 68%). ESI-QQQ-MS: m/z 486 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.84 (brs, 1H), 9.18 (d, J=8.1 Hz, 1H), 7.47-7.36 (m, 5H), 7.33-7.23 (m, 2H), 7.14-7.10 (m, 2H), 6.96-6.88 (m, 1H), 4.73-4.65 (m, 1H), 3.40 (s, 3H), 3.25-3.18 (m, 1H), 3.01 (dd, J=13.9, 10.3 Hz, 1H).

EXAMPLE 31: SYNTHESIS OF COMPOUND 34

Step 1

(S)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0589] ##STR00240##

[0590] Dissolve P-26 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (166 mg, 55%). ESI-QQQ-MS: m/z 604 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0591] ##STR00241##

[0592] Dissolve (S)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (151 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (86 mg, 95%). ESI-QQQ-MS: m/z 362 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0593] ##STR00242##

[0594] Dissolve (S)-2-amino-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution one, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (105 mg, 88%). ESI-QQQ-MS: m/z 518 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0595] ##STR00243##

[0596] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,7-difluoro-3-methyl-2-exo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (88 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (50 mg, 59%). ESI-QQQ-MS: m/z 504 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6) 12.52 (brs, 1H), 9.15 (d, J=8.1 Hz, 1H), 7.46-7.16 (m, 8H), 6.99-6.92 (m, 1H), 4.72-4.68 (m, 1H), 3.40-3.36 (m, 4H), 3.25-3.21 (m, 2H), 3.03-2.96 (m, 1H).

EXAMPLE 32: SYNTHESIS OF COMPOUND 35

Step 1

(S)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0597] ##STR00244##

[0598] Dissolve P-27 (109 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 361. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (207 mg, 65%). ESI-QQQ-MS: m/z 636 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0599] ##STR00245##

[0600] Dissolve (S)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (159 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (94 mg, 95%). ESI-QQQ-MS: m/z 394 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0601] ##STR00246##

[0602] Dissolve (S)-2-amino-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (91 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (110 mg, 87%). ESI-QQQ-MS m/z 550 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0603] ##STR00247##

[0604] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (94 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 59%). ESI-QQQ-MS: m/z 536 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.87 (s, 1H), 9.14 (d, J=8.3 Hz, 1H), 7.63 (s, 1H), 7.52-7.42 (m, 5H), 7.33-7.21 (m, 2H), 7.05 (s, 1H), 4.77-4.72 (m, 1H), 3.40 (s, 3H), 3.27 (dd, J=14.0, 4.5 Hz, 1H), 3.00 (dd, J=13.9, 10.5 Hz, 1H).

EXAMPLE 33: SYNTHESIS OF COMPOUND 36

Step 1

(S)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0605] ##STR00248##

[0606] Dissolve P-29 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (196 mg, 65%). ESI-QQQ-MS: m/z 604 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0607] ##STR00249##

[0608] Dissolve (S)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (151 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (85 mg, 94%). ESI-QQQ-MS: m/z 362 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6,7-difluoro-3-methyl-2-exo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0609] ##STR00250##

[0610] Dissolve (S)-2-amino-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (104 mg, 87%). ESI-QQQ-MS: m/z 518 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6,7-difluoro-3-methyl-2-exo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0611] ##STR00251##

[0612] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (88 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (45 mg, 52%). ESI-QQQ-MS: m/z 504 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.89 (brs, 1H), 9.17 (d, J=8.1 Hz, 1H), 7.47-7.40 (m, 5H), 7.31 (d, J=8.1 Hz, 1H), 7.28-7.15 (m, 2H), 7.09-7.07 (m, 1H), 4.744.69 (m, 1H), 3.39 (s, 3H), 3.24 (dd, J=14.1, 4.5 Hz, 1H), 3.01 (dd, J=14.1, 10.3 Hz, 1H).

EXAMPLE 34: SYNTHESIS OF COMPOUND 37

Step 1

(S)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0613] ##STR00252##

[0614] Dissolve P-30 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (205 mg, 68%). ESI-QQQ-MS: m/z 604 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0615] ##STR00253##

[0616] Dissolve (S)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (151 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (86 mg, 95%). ESI-QQQ-MS: m/z 362 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0617] ##STR00254##

[0618] Dissolve (S)-2-amino-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (102 mg, 85%). ESI-QQQ-MS: m/z 518 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0619] ##STR00255##

[0620] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (88 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m/z 504 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO): ? 12.89 (s, 1H), 9.16 (d, J=7.5 Hz, 1H), 7.56-7.37 (m, 5H), 7.32-7.24 (n, 2H), 7.14-7.06 (m, 1H), 6.71 (d, J=6.1 Hz, 1H), 4.76-4.68 (m, 1H), 3.55 (s, 3H), 3.28-3.22 (m, 1H), 3.04-2.96 (m, 1H).

EXAMPLE 35: SYNTHESIS OF COMPOUND 38

Step 1

(S)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenyl methylamino)methyl propionate

[0621] ##STR00256##

[0622] Dissolve P-31 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain the title compound (155 mg, 52%). ESI-QQQ-MS: m/z 598 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazo-1-yl)phenyl)methyl propionate

[0623] ##STR00257##

[0624] Dissolve (S)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenyl amino)methyl propionate (149 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (85 mg, 96%). ESI-QQQ-MS: m/z 356 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0625] ##STR00258##

[0626] Dissolve (S)-2-amino-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (82 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (104 mg, 88%). ESI-QQQ-MS: m/z 512 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0627] ##STR00259##

[0628] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (87 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (42 mg, 50%). ESI-QQQ-MS: m/z 498 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.84 (brs, 1H), 9.19 (d, J=8.1 Hz, 1H), 7.47-7.42 (m, 1H), 7.36-7.31 (m, 3H), 7.27-7.25 (m, 3H), 7.11-7.09 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 4.72-4.68 (m, 1H), 3.56 (s, 3H), 3.36 (s, 3H), 3.21 (dd, J=14.1, 4.5 Hz, 1H), 3.01 (dd, J=14.0, 10.0 Hz, 1H).

EXAMPLE 36: SYNTHESIS OF COMPOUND 39

Step 1

(S)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0629] ##STR00260##

[0630] Dissolve P-32 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (147 mg, 48%). ESI-QQQ-MS: m/z 611 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0631] ##STR00261##

[0632] Dissolve (S)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (153 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (86 mg, 94%). ESI-QQQ-MS: m/z 369 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0633] ##STR00262##

[0634] Dissolve (S)-2-amino-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (111 mg, 92%). ESI-QQQ-MS: m/z 525 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0635] ##STR00263##

[0636] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (89 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify, the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (37 mg, 42%). ESI-QQQ-MS: m/z 511 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.91 (brs, 1H), 9.18 (d, J=8.3 Hz, 1H), 7.52-7.39 (m, 5H), 7.33-7.09 (m, 3H), 7.02-6.21 (m, 2H), 4.77-4.73 (m, 1H), 3.26 (dd. J=14.1, 4.3 Hz, 1H), 3.00 (dd, J=14.0, 10.6 Hz, 1H), 2.89 (s, 6H), 2.54 (s, 3H).

EXAMPLE 37: SYNTHESIS OF COMPOUND 40

Step 1

(S)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)methyl propionate

[0637] ##STR00264##

[0638] Dissolve P-33 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), then add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol), under nitrogen protection, heat to 100? C., and react for 36 h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether/ethyl acetate=2:1) to obtain the title compound (153 mg, 50%). ESI-QQQ-MS: m/z 611 [M+H].sup.+.

Step 2

(S)-2-amino-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0639] ##STR00265##

[0640] Dissolve (S)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylamino)methyl propionate (153 mg, 0.25 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (228 mg, 2 mmol) to the reaction system, and react at room temperature for 1 h. Concentrate with vacuum, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8-9 with saturated sodium bicarbonate solution, stand for layering, extract the aqueous layer twice with dichloromethane, combine the organic layers, and wash the organic layer once with water and saturated salt solution respectively, dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (87 mg, 95%). ESI-QQQ-MS: m/z 369 [M+H].sup.+.

Step 3

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate

[0641] ##STR00266##

[0642] Dissolve (S)-2-amino-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (109 mg, 90%). ESI-QQQ-MS: m/z 525 [M+H].sup.+.

Step 4

(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

[0643] ##STR00267##

[0644] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methyl propionate (89 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.6 mL, 0.29 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (35 mg, 40%). ESI-QQQ-MS: m/z 511 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.93 (brs, 1H), 9.13 (d, J=8.2 Hz, 1H), 7.50-7.36 (m, 5H), 7.35-7.20 (m, 2H), 6.87 (d, J=8.6 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.47 (dd, J=8.7, 2.3 Hz, 1H), 4.74-4.69 (m, 1H), 3.36 (s, 3H), 3.23 (dd, J=14.0, 4.6 Hz, 1H), 3.00 (dd, J=13.9, 10.2 Hz, 1H), 2.89 (s, 6H).

EXAMPLE 38: SYNTHESIS OF COMPOUND 41

Step 1

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,4,6-trichlorobenzamido)methyl propionate

[0645] ##STR00268##

[0646] Dissolve (S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (83 mg, 0.23 mmol, the preparation process is detailed in Example 22) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add intermediate P-34 (61 mg, 0.25 mmol) dropwise to the reaction system, react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (124 mg, 95%). ESI-QQQ-MS: m/z 566 [M+H].sup.+.

Step 2

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,4,6-trichlorobenzamido)propionic acid

[0647] ##STR00269##

[0648] Dissolve (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,4,6-trichlorobenzamido)methyl propionate (96 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 54%). ESI-QQQ-MS: m/z 552 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 9.05 (d, J=7.8 Hz, 1H), 7.66 (s, 2H), 7.35 (dd, J=58.9, 8.0 Hz, 4H), 7.23 (d, J=7.8 Hz, 1H), 7.15-6.99 (m, 2H), 4.70-4.64 (m, 1H), 3.39 (s, 3H), 3.24 (dd, J=13.9, 3.8 Hz, 1H), 3.01 (dd, J=13.8, 10.0 Hz, 1H).

EXAMPLE 39: SYNTHESIS OF COMPOUND 42

Step 1

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinylbenzoylamino)methyl propionate

[0649] ##STR00270##

[0650] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxospiro[cyclopropane-1,3-indoline]-1-yl)phenyl) methyl propionate (83 mg, 0.23 mmol, the preparation process is detailed in Example 22) and triethylamine (30 mg, 0.3 mmol) in dichloromethane (2 mL), cool to 0? C., add the intermediate P-36 (74 mg, 0.25 mmol) dropwise to the reaction system, and the react at room temperature for 1 h. Add water (5 mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, and dry over anhydrous sodium sulfate, filter and concentrate with vacuum to obtain the title compound (113 mg, 80%). ESI-QQQ-MS: m/z 617 [M+H].sup.+.

Step 2

(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinylbenzylamino)propionic acid

[0651] ##STR00271##

[0652] Dissolve (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinylbenzoylamino)methyl propionate (105 mg, 0.17 mmol) in tetrahydrofuran (2 mL), then add 0.5 mol/L sodium hydroxide solution (0.4 mL, 0.2 mmol) to the reaction system, and react at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol/L dilute hydrochloric acid, extract three times with dichloromethane (2 mL each time), combine the organic layers, wash the organic layers with water and saturated salt solution once, dry over anhydrous sodium sulfate, filter and concentrate with vacuum, and purify the concentrate by RP-HPLC (H.sub.2O/CH.sub.3CN system containing 0.1% formic acid) to obtain the title compound (45 mg, 44%). ESI-QQQ-MS: m/z 603 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d6): ? 12.77 (brs, 1H), 8.91 (d, J=7.5 Hz, 1H), 7.43-7.41 (m, 2H), 7.31-7.22 (m, 3H), 7.16-7.01 (m, 2H), 6.93 (s, 2H), 4.68-4.64 (m, 1H), 3.70-3.68 (m, 4H), 3.39 (s, 3H), 3.21 (s, 1H), 3.19-3.17 (m, 4H), 3.04-2.99 (m, 1H).

EXAMPLE: MADCAM-1/?4?7 INTEGRIN BINDING INHIBITION ACTIVITY EVALUATION TEST (?4?7-MADCAM-1 ELISA)

[0653] Coat the 96-well microplate (Costar) with 50 ?L of recombinant human MAdCAM-1 (R&D Systems) solution per well, and incubate overnight (12-18 hours) at 4? C. Wash three times with 150 ?L of TBS buffer per well. Block plate with 150 ?L per well with blocking buffer for 1 h at 37? C. Wash three times with 150 ?L of TBS buffer per well. Dilute the recombinant human integrin ?4?7 (R&D Systems) with TBS buffer containing 0.1% bovine serum albumin (BSA), then add to the 96 well plate with 50 ?L per well. Add 1 ?L of test compound or DMSO, cover, incubate at room temperature for 2 h, wash three times with 150 ?L of TBS buffer per well. Dilute the anti-?7 antibody (R&D Systems) with 0.1% BSA TBS buffer, then add to the 96 well plate with 50 ?L per well, cover, incubate at room temperature for 1 h, wash three times with 150 ?L of TBS buffer per well. Add 50 ?L of streptavidin-HRP (R&D Systems) per well, incubate at room temperature for 20 min, wash three times with 150 ?L of TBS buffer per well. Add 50 ?L of TMB substrate solution (Sigma) per well, incubate at room temperature for 5-30 min, and add 25 ?L of stop solution per well to stop the reaction. Finally, measure absorbance at 450 nm with microplate reader (SpectraMax 340PC. Molecular Devices). Repeat the test to find the binding rate of cells at each concentration when the absorbance of the well without the test substance is used as 100%, and calculate the concentration IC.sub.50 that causes 50% binding inhibition and summarize the results in Table 1.

[0654] It should be stated that, as a test compound, the free form of the compound synthesized in the above examples is used.

TABLE-US-00001 TABLE 1 Results of MAdCAM-1/?4?7 Integrin Binding Inhibition Activity IC.sub.50 (nM) Compound No. ?4?7 Example 1 14.29 Example 2 2.57 Example 3 5.48 Example 4 2.54 Example 5 2.87 Example 6 5.81 Example 7 16.11 Example 8 17.59 Example 9 95.48 Example 10 38.84 Example 11 3.05 Example 12 4.15 Example 13 8.02 Example 14 6.21 Example 15 5.62 Example 16 0.75 Example 17 64.21 Example 19 11.41 Example 20 4.15 Example 21 23.75 Example 22 1.19 Example 23 143.4 Example 24 5.67 Example 25 7.50 Example 26 160.1 Example 27 8.81 Example 28 10.89 Example 29 18.14 Example 30 1.83 Example 31 5.34 Example 32 4.19 Example 33 2.70 Example 34 10.46 Example 35 0.45 Example 36 1.51 Example 37 5.09 Example 38 27.91 Example 39 3.65

[0655] As described above, the novel N-(benzoyl)-phenylalanine compounds of the present invention have excellent ?4?7 integrin binding inhibitory activity. Therefore, the novel N-(benzoyl)-phenylalanine compounds of the present invention can provide therapeutic agents or prophylactic agents for ?4?7-dependent autoimmune diseases and inflammatory bowel diseases (Crohn's disease and ulcerative colitis).

[0656] The compounds of the present invention have a high blood concentration or bioavailability when administered orally, and are useful as oral administration formulations.

[0657] In addition, the compounds of the present invention have good stability in acidic and alkaline solutions and can be used for the development of various dosage forms.

[0658] In addition to those examples described herein, according to the foregoing description, a variety of modifications of the present invention will be obvious to those skilled in the art. Such modification intentions also fall within the scope of the attached claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.