N-(benzoyl)-phenylalanine compound, pharmaceutical composition containing same, and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and relates to an N-(benzoyl)-phenylalanine compound used as an α4β7 integrin antagonist, a pharmaceutical composition containing same, and a use thereof, and in particular to a compound represented by general formula (1). The compound exhibits good α4β7 integrin binding inhibitory activity, can be used as a high-efficiency α4β7 integrin antagonist, and used for preventing and / or treating α4β7 integrin-related diseases such as autoimmune diseases and inflammatory diseases.

Description

N-(BENZOYL)-PHENYLALANINE COMPOUND, A PHARMACEUTICAL COMPOSITION CONTAINING SAME, AND A USE THEREOF The present invention claims the priority of an invention patent application filed in China on January 20, 2021, titled "N-(benzoyl)-phenylalanine compound, a pharmaceutical composition containing same, and a use thereof", with application number 202110075764.7. Technical Field The present invention relates to the field of pharmaceutical chemistry, and relates to a N-(benzoyl)-phenylalanine compound used as an <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin antagonist, a pharmaceutical composition containing same as an active ingredient, and their uses for prevention and / or treatment of <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin related diseases (such as autoimmune and inflammatory diseases). Technology Background Integrin is a member of integral protein family. It is a kind of heterodimer cell surface protein that generally exists on the surface of vertebrate cells and depends on Ca2+or Mg2+. It is used to mediate the mutual recognition and adhesion between cells and between cells and extracellular matrixes, and plays the role of connecting the external effects and the internal structure of cells. Integrin is a transmembrane heterodimer composed of two non-covalently bound transmembrane subunits (i.e. <semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and <semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>). The extracellular head can combine with extracellular matrix protein, and the intracellular tail can connect with actin. Both subunits of the integrin are glycosylated and bound together by a non-covalent bond. Currently, there are a total of 18 known <semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> subunits and 8 known <semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics> subunits. Among them, the <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin is expressed on the surface of lymphocytes and recognizes the mucosal address in cell adhesion molecule-1 (MAdCAM-1) of the extracellular ligand, which is expressed in the high endothelial venules (HEV) of the intestinal mucosal venules and the gut-associated lymphoid tissues (GALT). α4β7 integrin control the transfer of lymphocytes to intestinal tissues and their retention in the intestine through their interaction with MAdCAM-1. Someone has proposed that inhibiting the interaction between integrin and its ligand is an effective method for treating various autoimmune and inflammatory diseases, and blocking the <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics>-MAdCAM-1 interaction has shown therapeutic effects on inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC). Therefore, there is an urgent need to develop <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin antagonists for the prevention and / or treatment of autoimmune and inflammatory diseases (especially inflammatory bowel diseases). Summary of the Invention The purpose of the present invention is to provide a N-(benzoyl)-phenylalanine compound with a novel structure, which has high selectivity and inhibitory activity on <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin, and can be administered orally. In addition, the purpose of the present invention is to provide a pharmaceutical composition containing the aforementioned compound as an active ingredient for the drug. In addition, the purpose of the present invention is to provide the intended use of aforementioned compound or pharmaceutical composition for the prevention and / or treatment of <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin related diseases (such as autoimmune and inflammatory diseases). Specifically, the aforementioned purposes of the present invention are achieved through the following solutions: [1] Compounds as shown in general formula (1) or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers, or prodrugs thereof, [Image disponible dans le document PDF, Image available in the PDF document] (1) Where, R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, or 5-10 membered heteroaryl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, and 5-10 membered heteroaryl; Each R4 is independently hydrogen or halogen; Each <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is independently hydrogen or halogen; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is hydrogen, halogen, hydroxyl, amino, aldehyde, carboxyl, cyano, nitro, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> haloalkyl, <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkenyl, <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkynyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> haloalkoxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylthio, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> haloalkythio, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylamino, di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxycarbonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyloxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl amido, aminoformyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl aminoformyl, di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) carbamoyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy sulfonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl sulfonyloxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl sulfonyl amino, amino sulfonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl amino sulfonyl, di (C1-6 alkyl) amino sulfonyl, C3-6 cycloalkyl, 3-7-membered heterocyclic alkyl, C6-10 aryl, 5-10 membered heteroaryl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryloxy, 5-10 membered heteroaryloxy, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylthio, 5-10 membered heteroaryl thio, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylamino, 5-10 membered heteroarylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylcarbonyl, 5-10 membered heteroarylcarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxycarbonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxycarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformamido, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformamido, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminoformyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylaminoformyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxy sulfonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxy sulfonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonylamino, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminosulfonyl or 5~10 membered heteroarylaminosulfonyl, which is optionally substituted by at least one of the following substituents: halogen, <semantics>C1∼6<annotation encoding="application / x-tex">C_{1\sim6}< / annotation>< / semantics> alkyl, <semantics>C3∼6<annotation encoding="application / x-tex">C_{3\sim6}< / annotation>< / semantics> cycloalkyl, <semantics>3∼7<annotation encoding="application / x-tex">3\sim7< / annotation>< / semantics> membered heterocyclic alkyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryl and <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryl; Each X3 is independently hydrogen or halogen; A is a group as shown in general formula <semantics>(2−1)<annotation encoding="application / x-tex">(2-1)< / annotation>< / semantics>, <semantics>(2−2)<annotation encoding="application / x-tex">(2-2)< / annotation>< / semantics>, or <semantics>(2−3)<annotation encoding="application / x-tex">(2-3)< / annotation>< / semantics>, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1)<annotation encoding="application / x-tex">(2-1)< / annotation>< / semantics> <semantics>(2−2)<annotation encoding="application / x-tex">(2-2)< / annotation>< / semantics> <semantics>(2−3)<annotation encoding="application / x-tex">(2-3)< / annotation>< / semantics> The ring H is a <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> sub-cyclic alkyl or a 3-7 membered sub-heterocyclic alkyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, and 5-10 membered heteroaryl; Y is either O or S; Each Z is independently <semantics>CR1<annotation encoding="application / x-tex">CR_1< / annotation>< / semantics> or N; If it is present, each R1 is independently hydrogen, halogen, hydroxyl, amino, aldehyde, carboxyl, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 alkanoyl, C1-6 alkylamino, di (C1-6 alkyl) amino, C1-6 alkoxycarbonyl, C1-6 alkanoyloxy, C1-6 alkyl amido, aminoformyl, C1-6 alkyl aminoformyl, di <semantics>(C1−6 alkyl)<annotation encoding="application / x-tex">(C_{1-6} \text{ alkyl})< / annotation>< / semantics> carbamoyl, <semantics>C1−6 alkoxy sulfonyl<annotation encoding="application / x-tex">C_{1-6} \text{ alkoxy sulfonyl}< / annotation>< / semantics>, <semantics>C1−6 alkyl sulfonyloxy<annotation encoding="application / x-tex">C_{1-6} \text{ alkyl sulfonyloxy}< / annotation>< / semantics>, <semantics>C1−6 alkyl sulfonyl<annotation encoding="application / x-tex">C_{1-6} \text{ alkyl sulfonyl}< / annotation>< / semantics> amino, amino sulfonyl, C1-6 alkyl amino sulfonyl, di (C1-6 alkyl) amino sulfonyl, C3-6 cycloalkyl, 3-7-membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, 5-10 membered heteroaryl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryloxy, 5-10 membered heteroaryloxy, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylthio, 5-10 membered heteroaryl thio, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylamino, 5-10 membered heteroarylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylcarbonyl, 5-10 membered heteroarylcarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxycarbonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxycarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformamido, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformamido, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminoformyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylaminoformyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxy sulfonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxy sulfonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonylamino, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminosulfonyl or 5~10 membered heteroarylaminosulfonyl, which is optionally substituted by at least one of the following substituents: halogen, <semantics>C1∼6<annotation encoding="application / x-tex">C_{1\sim6}< / annotation>< / semantics> alkyl, <semantics>C3∼6<annotation encoding="application / x-tex">C_{3\sim6}< / annotation>< / semantics> cycloalkyl, <semantics>3∼7<annotation encoding="application / x-tex">3\sim7< / annotation>< / semantics> membered heterocyclic alkyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryl and 5~10 membered heteroaryl; If it is present, each R2 is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkyl amido, aminoformyl, C1-6 alkylaminoformyl, di (C1-6 alkyl) aminoformyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, 5-10 membered heteroaryl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylcarbonyl, 5-10 membered heteroarylcarbonyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryloxycarbonyl, 5-10 membered heteroaryloxycarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminoformyl or <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaylaminoformyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl. [2] The following compounds or their pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers, or prodrugs, including: (1)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'- indoline]-1'-yl)phenyl)propionic acid; (2)(S)-3-(4-(7'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2- (2-chloro-6-fluorobenzoylamino)propionic acid; (3)(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(5',6'-difluoro-2'-oxospiro [cyclopropane-1,3'- indoline]-1'-yl) phenyl) propionic acid; (4)(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin e]-1'-yl) phenyl) propionic acid; (5)(S)-3-(4-(6'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2- (2,6-dichlorobenzoylamino) propionic acid; (6)(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(6'-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (7)(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]- 1'-yl) phenyl) propionic acid; (8)(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (9)(S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro [indoline-3,4'-pyran]-1-yl) phenyl)-2-(2-chloro-6-fluorobenzoylamino) propionic acid; (10)(S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl)-2- (2-chloro-6-fluorobenzoylamino) propionic acid; (11)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5'-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (12)(S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoyl amino) propionic acid; (13)(S)-3-(4-(5'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl)-2- (2-chloro-6-fluorobenzoylamino) propionic acid; (14) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (15)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5'-(dimethylamino)-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (16)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4- (6 '-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (17)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4- (7'-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (18)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6',7'-difluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (19)(S)-2-(2,6-dichlorobenzoylamino)-3-(4-(2'-oxospiro [cyclopropane-1,3'-pyrrolo [2,3-b] pyridine]-1'(2'H)-yl) phenyl) propionic acid; (20)(S)-3-(4-(7'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl)-2- (2,4,6-trichlorobenzoylamino) propionic acid; (21)(S)-3-(4-(7'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl)-2- (2,6-dichloro-4-(diethylamino) benzoylamino) propionic acid; (22)(S)-3-(4-(7'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl)-2- (2,6-dichloro-4-morpholinylbenzoylamino) propionic acid; (23) (2S)-2-(4-(2-oxa-5-azabicyclo [2.2.1] hept-5-yl)-2,6-dichlorobenzoylamino)-3-(4-(7'- chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl) propionic acid; (24)(S)-3-(4-(7'-chloro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl) phenyl)-2- (2,6-dichloro-4-(4-morpholinylpiperidin-1-yl) benzoylamino) propionic acid; (25) (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-1-yl) phenyl)-2- (2-chloro-6-fluorobenzoylamino) propionic acid; (26)(S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-1-yl) phenyl) -2- (2,6-dichlorobenzoylamino) propionic acid; (27) (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d] imidazol-1-yl) phenyl) -2-(2,6-dichlorobenzoylamino) propionic acid; (28) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d] imidazol-1-yl) phenyl) -2-(2,6-dichlorobenzoylamino) propionic acid; (29) (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; (30)(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; (31) (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; (32)(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; (33)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-b enzo [d] imidazol-1-yl) phenyl) propionic acid; (34)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1 H-benzo [d] imidazol-1-yl) phenyl) propionic acid; (35)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1 H-benzo [d] imidazol-1-yl) phenyl) propionic acid; (36)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1 H-benzo [d] imidazol-1-yl) phenyl) propionic acid; (37)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1 H-benzo [d] imidazol-1-yl) phenyl) propionic acid; (38)(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; (39)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dih ydro-1H-benzo [d] imidazol-1-yl) phenyl) propionic acid; (40)(S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dih ydro-1H-benzo [d] imidazol-1-yl) phenyl) propionic acid; (41) (S)-3-(4- (7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-1-yl) phenyl) -2- (2,4,6-trichlorobenzoylamino) propionic acid; and (42) (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) propionic acid. [3] A pharmaceutical composition comprising the aforementioned compounds or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers, or prodrugs thereof. [4] The use of the aforementioned compounds or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs thereof, or pharmaceutical compositions thereof, used for preparation of drugs for prevention and / or treatment of diseases and / or symptoms at least partially mediated by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin. [5] The aforementioned compounds or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs thereof, or pharmaceutical compositions thereof, used for prevention and / or treatment of diseases and / or symptoms at least partially mediated by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin. [6] A method for preventing and / or treating diseases and / or symptoms mediated at least partially by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin, which includes the following steps: administrating the aforementioned compounds or their pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs thereof, or the aforementioned drug compositions thereof, to individuals in need. The novel N-(benzoyl)-phenylalanine compound of the present invention has excellent <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin binding inhibitory activity, therefore, the novel N-(benzoyl)-phenylalanine compound of the present invention can provide <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> dependent therapeutic or preventive agents for autoimmune diseases and inflammatory bowel diseases (Krohn's disease and ulcerative colitis). The compound of the present invention has a high blood drug concentration or bioavailability when administered orally, making it very useful as an oral administration drug. In addition, the compound of the present invention has good stability in acidic and alkaline solutions and can be used for the development of various dosage forms. Specific Implementation Methods Definition of terms Unless otherwise defined, the meanings of the terms used in this article are the same as those commonly understood by those skilled in the field. The technical intent used in this article refers to the commonly understood techniques in the field, including changes or equivalent replacements that are obvious to those skilled in the field. Although the following terms are easy to understand for those skilled in the field, they are still elaborated as follows to better explain the present invention. The terms "including", "comprising", "having", or "involving" and their other variant forms in this article refer to inclusive or open set concepts, and do not exclude other elements or methods / steps that are not enumerated. Technicians in this field should understand that the aforementioned terms, such as "including", cover the meaning of "being...composed of". The term "one or more" or similar expression "at least one" refers to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. When the lower and upper limits of a numerical range are disclosed, any numerical value or any sub-range that falls within that range indicates specific disclosure. Specifically, each numerical range of the parameters disclosed in this article (for example, in the form of "approximate a-b", or equivalent "approximate a-b", or equivalent "approximate a-b") should be understood to cover each numerical value and sub-range within it. For example, "C1-6" refers to any sub-range and each point value that are covered in it, such as C2-5, C3-4, C1-2, C1-3, C1-4, C1-5, etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, '3-6 membered' should be understood as covering any sub-range and each point value, such as 3-4 membered, 3-5 membered, 3-6 membered, 4-5 membered, 4-6 membered, 5-6 membered, etc., as well as 3, 4, 5, 6 membered, etc. The term "pharmaceutically acceptable salts" refers to the salts of the compound of the present invention, which is basically non-toxic to organisms, and generally includes (but is not limited to) the salts generated by the reaction of the compound of the present invention with pharmaceutically acceptable inorganic acid / organic acid / acidic amino acid or inorganic base / organic base / basic amino acid. Such salts are also called acid addition salts or base addition salts. Suitable salts can be found in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley VCH, 2002). The pharmaceutically acceptable salts of the compound of the present invention include (but are not limited to) metal salts (such as sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, zinc salts, and aluminum salts, etc.), organic amine salts (such as dimethylamine salts, trimethylamine salts, diethylamine salts, trimethylamine salts, and diisopropylethylamine salts, etc.), and basic amino acids (such as lysine salts, and arginine salts, etc.) formed by acidic groups (such as carboxyl); inorganic salts (e.g., hydrochlorides, sulfates, and phosphates, etc.) and organic salts (e.g., maleates, tartrates, succinates, citrates, and acetates, etc.) formed by basic groups (e.g., amino). The term "esters" refers to the esters of the compound of the present invention, which is basically non-toxic to organisms, and generally includes (but is not limited to) the esters generated by the reaction of the hydroxyl of the compound of the present invention with pharmaceutically acceptable inorganic acid / organic acid / acidic amino acid or the reaction of the carboxyl with other pharmaceutically acceptable alcohols / phenols / compounds with hydroxyl. The term "solvates" refers to complexes generated by the interaction of the compound of the present invention with pharmaceutically acceptable solvents, with specific spatial arrangements and solute / solvent molecular molar ratios. It typically includes (but is not limited to) solvates generated by the compound of the present invention with polar protic solvents / polar aprotic solvents / non-polar solvents, such as hydrates and alcohols, etc. The term "optical isomers" refers to a plurality of isomers with different optical rotations due to the fact that the compound of the invention has chiral elements (such as chiral centers, chiral axes, and chiral planes, etc.), which generally include (but are not limited to) the enantiomer and non-enantiomer of the compound of the present invention. The term 'tautomers' refers to multiple isomers with different structural formulas resulting from the tautomerism of the compound of the present invention, typically including (but not limited to) ketone-enol tautomerism, and amide-iminol tautomerism, etc. The term "isotope markers" refers to compounds formed by replacing at least one atom in the compound of the present invention with its isotope atom, typically including (but not limited to) deuterium substituted compounds in which hydrogen atoms are substituted with deuterium atoms. The term 'prodrugs' refers to derivative compounds of the compound of the present invention that can be directly or indirectly obtained after the drug is administrated to an individual (for example, the drug is converted into the compound of the present invention through the oxidation, reduction, and hydrolysis, etc. of enzymes or gastric acid under physiological conditions within the body). Specifically, derived compounds or prodrugs are compounds that can enhance the bioavailability (such as those that are more easily absorbed into the bloodstream) of the compound of the present invention when administrated to individuals, or compounds that promote the delivery of the parent compound to the site of action (such as the lymphatic system). For suitable prodrugs, see T Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. In addition, the present invention also covers the compound of the present invention containing protective groups. In any process of preparing the compound of the present invention, protecting sensitive or reactive groups on any relevant molecule may be necessary and / or desirable, thereby a form of chemical protection for the compound of the present invention is generated. For example, when the compound of the present invention has a carboxyl, the corresponding prodrugs can be prepared through esterification or amidation; when the compound of the present invention has an amino, the corresponding prodrugs can be prepared by amidation, phosphorylation, or alkylation; when the compound of the present invention has a hydroxyl, corresponding prodrugs can be prepared by esterification, phosphorylation, or alkylation. For suitable protective groups, see T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. By using methods known in this field, these protective groups can be removed at appropriate subsequent stages. Unless otherwise specified, the term "halogen" used in this article refers to fluorine (F), chlorine (Cl), bromine (Br), and / or iodine (I). Unless otherwise specified, the term "hydroxyl" used in this article refers to -OH. Unless otherwise specified, the term "amino" used in this article refers to -NH2, and the term "substituted amino" refers to the mono-substituted form of the amino-NHR or bi-substituted form -NRR'. Unless otherwise specified, the term "aldehyde group" used in this article refers to -CH (=O). Unless otherwise specified, the term "carboxyl" used in this article refers to -C (=O) OH. Unless otherwise specified, the term "cyano" used in this article refers to -CN. Unless otherwise specified, the term 'nitro' used in this article refers to <semantics>−N<annotation encoding="application / x-tex">-N< / annotation>< / semantics> (=O)2. Unless otherwise specified, the term "alkyl" used in this article refers to linear or branched saturated aliphatic hydrocarbonyl. For example, the term "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl" used in this article refers to linear or branched alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert butyl, n-amyl, isopentyl, neopentyl, and n-hexyl, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). When it is optionally substituted by one or more (such as 1 to 3) substituents described in this article (for example, when it is substituted by halogens, the group is "C1-6 haloalkyl", such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, and -CH2CH2F3, etc.). Unless otherwise specified, the term "alkenyl" used in this article refers to aliphatic hydrocarbonly with one or more (such as 1 to 3) linear or branched carbon-carbon double bonds. For example, the term "<semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkenyl" used in this article refers to alkenyls with 2 to 6 carbon atoms and one, two, or three carbon-carbon double bonds (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl, etc.), which can be optionally substituted by one or more (such as 1-3) substituents described in this article. Unless otherwise specified, the term "alkoxy" used in this article refers to the aforementioned alkyl, namely -O-alkyl, which is connected to the parent molecule through oxygen atoms. For example, the term "C1-6 alkoxy" used in this article refers to alkoxy (such as methoxy, ethoxy, isopropoxy, and tert butoxy, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms), which can be optionally substituted by one or more (such as 1-3) substituents described in this article (for example, when it is substituted by halogen, the group is "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> halogenated alkoxy", such as <semantics>−OCF3<annotation encoding="application / x-tex">-OCF_3< / annotation>< / semantics>, <semantics>−OC2F5<annotation encoding="application / x-tex">-OC_2F_5< / annotation>< / semantics>, <semantics>−OCHF2<annotation encoding="application / x-tex">-OCHF_2< / annotation>< / semantics>, and <semantics>−OCH2Cl<annotation encoding="application / x-tex">-OCH_2Cl< / annotation>< / semantics>, etc.). Unless otherwise specified, the term "alkylthio" used in this article refers to the aforementioned alkyl, i.e. -S-alkyl, which is connected to the parent molecule through sulfur atoms. For example, the term "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylthio" used in this article refers to an alkylthio group (such as methylthio, ethylthio, isopropyl thio, and tert butylthio, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms), which is optionally substituted by one or more (such as 1-3) substituents described in this article (for example, when it is substituted by halogen, the group is "C1-6 haloalkythio", such as -SCF3, -SC2F5, -SCHF2, and -SCH2Cl, etc.). Unless otherwise specified, the term "alkanoyl" used in this article refers to the aforementioned alkyl, namely -C(=O)-alkyl, which is connected to the parent molecule through carbonyl. For example, the term "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyl" used in this article refers to alkanoyl (such as acetyl, and isobutyryl, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "(di) alkylamino" used in this article refers to the aforementioned alkyl, namely -NH alkyl or -N (alkyl)2, which are connected to the parent molecular through nitrogen atoms. For example, the term "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylamino" used in this article refers to alkylamino (such as ethylamino and isopropylamino, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms), while the term "di (C1-6 alkyl) amino" used in this article refers to dialkylamino (such as dimethylamino and diethylamino, etc.) with two groups of 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "alkoxycarbonyl" used in this article refers to the aforementioned alkyl, namely <semantics>−C(=O)<annotation encoding="application / x-tex">-C(=O)< / annotation>< / semantics>-O-alkyl, which is sequentially connected to the parent molecule through oxygen atoms and carbonyl. For example, the term "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxycarbonyl" used in this article refers to alkoxycarbonyl (such as ethoxycarbonyl, isopropoxycarbonyl, and tert butoxycarbonyl, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "alkanoyloxy" used in this article refers to the aforementioned alkyl, namely -O-C(=O)-alkyl, which is sequentially connected to the parent molecular through carbonyl and oxygen atoms. For example, the term "C1-6 alkanoyloxy" as used in this article refers to alkanoyloxy (such as acetoxy, isobutyryloxy, and pivaloyloxy, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "alkyl amido" used in this article refers to the aforementioned alkyl, namely-NH-C(=O)-alkyl, which is sequentially connected to the parent molecular through carbonyl and nitrogen atoms. For example, the term "C1-6 alkyl amido" used in this article refers to alkyl amido (such as acetylamino, isobutyrylamino, and pivaloylamino, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "aminoformyl" used in this article refers to -C (=O)-NH2, and "(di) alkyl aminoformyl" refers to the aforementioned alkyl, namely -C(=O)-NH alkyl or -C (=O)-N (alkyl)2, which are sequentially connected to the parent molecule through amino and carbonyl. For example, the term "C1-6 alkyl aminoformyl" used in this article refers to alkyl aminoformyl (such as ethylaminoformyl, isopropylaminoformyl, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms), and the term "di (C1-6 alkyl) aminoformyl" used in this article refers to dialkyl aminoformyl (such as diethylaminoformyl, diisopropylaminoformyl, etc.) with two groups of 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "alkoxy sulfonyl" used in this article refers to the aforementioned alkyl, namely-<semantics>S(=O)2<annotation encoding="application / x-tex">S (=O)_2< / annotation>< / semantics>-O-alkyl, which is sequentially connected to the parent molecular through oxygen atoms and sulfonyl. For example, the term "C1-6 alkoxy sulfonyl" used in this article refers to the alkoxy sulfonyl (such as ethoxy sulfonyl, isopropoxy sulfonyl, and tert butoxy sulfonyl, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "alkyl sulfonyloxy" used in this article refers to the aforementioned alkyl, namely -O-S (=O)2-alkyl, which is sequentially connected to the parent molecular part through sulfone groups and oxygen atoms. For example, the term <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl sulfonyloxy" used in this article refers to alkyl sulfonyloxy (such as ethylsulfonyloxy, isopropylsulfonyloxy, and tert butylsulfonyloxy, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "alkyl sulfonyl amide" used in this article refers to the aforementioned alkyl group, namely-NH-S (=O)2-alkyl, which is sequentially connected to the parent molecular through sulfone groups and nitrogen atoms. For example, the term "C1-6" alkylsulfonamide" used in this article refers to alkylsulfonamide groups (such as ethylsulfonamide, isopropylsulfonamide, and tert butylsulfonylamino, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "amino sulfonyl" used in this article refers to -S(=O)2-NH2, and the term "(di) alkyl amino sulfonyl" refers to the aforementioned alkyl, namely -S(=O)2-NH-alkyl or -S(=O)2-N (alkyl)2, which is sequentially connected to the parent molecular by nitrogen atoms and sulfonyl. For example, the term "<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylamino sulfonyl" used in this article refers to an alkylamino sulfonyl (such as ethylamino sulfonyl, isopropylamino sulfonyl, etc.) with 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5, or 6 carbon atoms), and the term "di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino sulfonyl" used in this article refers to dialkylamino sulfonyl (such as diethylamino sulfonyl, diisopropylamino sulfonyl, etc.) with two groups of 1-6 carbon atoms (such as 1, 2, 3, 4, 5 or 6 carbon atoms). Unless otherwise specified, the term "cycloalkyl" used in this article refers to cyclic saturated aliphatic hydrocarbonly. For example, the term "C3-6 cycloalkyl" used in this article refers to cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, etc.) with 3 to 6 cyclic carbon atoms (such as 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "cyclopropylene" used in this article refers to a cyclic saturated aliphatic hydrocarbonly that connects two other segments simultaneously. For example, the term "C3-6 cycloalkylene" used in this article refers to a cycloalkylene group (such as a cyclopropylene group) with 3 to 6 cyclic carbon atoms (such as 3, 4, 5, or 6 carbon atoms). Unless otherwise specified, the term "heterocyclic alkyl" used in this article refers to saturated aliphatic hydrocarbonly with one or more carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more segments (such as 1, 2, 3, or 4) independently selected from <semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>-, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>-, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>(<semantics>=O<annotation encoding="application / x-tex">=O< / annotation>< / semantics>)-, -S(=O)2-, and -NR- (R represents hydrogen atoms or substituents, such as alkyl or cycloalkyl). For example, the term "3-7-membered heterocyclic alkyl" used in this article refers to heterocyclic alkyl (such as epoxyethanyl (oxocyclopropyl), cyclothioethanyl (thiocyclopropyl), cyclonitroethanyl (nitrocyclopropyl), nitrocyclobutyl, oxocynobutyl, thiocycloputyl, tetrahydrofuranyl, 1,3-dioxcyclopentanyl, tetrahydrothienyl, pyrrolidine, pyrrolidone, imidazolidinyl, pyrazolidine, tetrahydropyran, tetrahydropyran, piperidine, azapyran, morpholine, thiomorpholine, 1,4-thiaxalkyl, 1,4-dioxane, 1,4-dithialkyl, piperazine, 1,3,5-trioxalkyl, 1,3,5-triathialkyl, and 1,4-thiazinyl, etc.) with 3 to 7 cyclic atoms (such as 3, 4, 5, 6, or 7 atoms). Unless otherwise specified, the term "sub-heterocyclic alkyl" used in this article refers to saturated aliphatic hydrocarbonly with one or more carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more segments (such as 1, 2, 3, or 4) independently selected from -O-, -S-, -S(=O)-, -S(=O)2-, and -NR- (R represents hydrogen atoms or substituents, such as alkyl or cycloalkyl). For example, the term "3-7-membered sub-heterocyclic alkyl" used in this article refers to the sub-heterocyclic alkyl (such as tetrahydro-2H-pyran-4-yl, etc.) with 3 to 7 cyclic atoms (such as 3, 4, 5, 6, or 7 atoms). Unless otherwise specified, the term "aryl" used in this article refers to aromatic hydrocarbonly with conjugated <semantics>π<annotation encoding="application / x-tex">\pi< / annotation>< / semantics> -electron systems that are single or fused rings. For example, the term "<semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl" used in this article refers to aryl (such as phenyl, naphthyl, etc.) with 6 to 10 (such as 6, 7, 8, 9, or 10) cyclic carbon atoms, which is optionally substituted by one or more substituents described in this article (such as methylphenyl substituted by C1-6 alkyl, and the chlorophenyl substituted by halogen, etc.). Unless otherwise specified, the term "heteroaryl" used in this article refers to aromatic groups with conjugated <semantics>π<annotation encoding="application / x-tex">\pi< / annotation>< / semantics> -electron systems that are single or fused ring containing one or more (such as 1, 2, 3, or 4) carbon atoms and one or more (such as 1, 2, 3, or 4) segments independently selected from -O-, -S-, -S(=O)-, -S(=O)2-, -N=, and -NR-(R represents hydrogen atoms or substituents, such as alkyl or cycloalkyl). As used in this article, the "5-10 membered heteroaryl" refers to the heteroaryl (such as thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazole, oxadiazolyl, triazolyl, tetrazolyl, etc., or such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or its benzo derivatives, such as indazolyl, indolyl, isoindolyl, quinolinyl, isoquinoline, etc., or pyrazopyridinyl, pyrrolopyrimidinyl, pyrrolo Pyridinyl, pyrazole pyrimidine, etc.), which can be optionally substituted by one or more substituents described in this article (such as a methylpyridinyl substituted by C1-C6 alkyl, and a chloropyridinyl substituted by halogen, etc.). If the valence bond requirement is met, the heteroaryl can be connected to the parent molecular through any cyclic atom. If the valence bond requirement is met, the heteroaryl can be connected to other groups (or segments) through any carbon atom or heteroatom (such as N atom) in the ring. Moreover, the heteroaryl can be optionally fused on the aryl, heterocycloalkyl and cycloalkyl, wherein the ring connected with the parent structure is a heteroaryl. Unless otherwise specified, the terms "aryloxy" and "heteroaryloxy" used in this article refer to the aforementioned aryl or heteroaryl, namely -O-aryl (such as phenoxy, naphthalene-1-methoxy, etc.) and -O-heteroaryl (such as furan-2-methoxy, pyridine-4-methoxy, etc.), which are connected to the parent molecular through oxygen atoms. Unless otherwise specified, the terms "arylthio" and "heteroaryl thio" used in this article refer to the aforementioned aryl or hetero aryl, namely -S-aryl (such as phenylthio, naphthalene-1-ylthio, etc.) and -S-heteroaryl (such as furan-2-ylthio, pyridine-4-ylthio, etc.), which are connected to the parent molecular through sulfur atoms. Unless otherwise specified, the terms "arylcarbonyl" and "heteroarylcarbonyl" used in this article refer to the aforementioned aryl or heteroaryl, namely -C (=O)-aryl (such as benzoyl, 1-naphthoyl, etc.) and -C(=O)-heteroaryl (such as furoyl, nicotinyl, etc.), which are connected to the parent molecule through carbonyl. Unless otherwise specified, the terms "arylamino" and "heteroarylamino" used in this article refer to the aforementioned aryl or heteroaryl, namely –NH-aryl (such as phenylamino, naphthalen-1-ylamino, etc.) and –NH-heteroaryl (such as furan-2-methoxy, pyridine-4-methoxy, etc.), which are connected to the parent molecular through nitrogen atoms. Unless otherwise specified, the terms "aryloxyacyl" and "heteroaryloxyacyl" used in this article refer to the aforementioned aryl or heteroaryl, namely -C(=O)-O-aryl (such as phenoxyformyl) and -C (=O)-O-heteroaryl (such as furan-2-methoxyformyl), which are sequentially connected to the parent molecule through oxygen atoms and carbonyl. Unless otherwise specified, the terms "arylformyloxy" and "heteroarylformyloxy" used in this article refer to the aforementioned aryl or heteroaryl, namely -O-C (=O)-aryl (such as benzoyloxy) and -O-C(=O)-heteroaryl (such as furoyloxy), which are sequentially connected to the parent molecule through carbonyl and oxygen atoms. Unless otherwise specified, the terms " arylformamido" and " heteroarylformamido" used in this article refer to the aforementioned aryl or heteroaryl, namely -NH-C(=O)-aryl (such as benzoylamino) and -NH-C(=O)-heteroaryl (such as furoylamino), which are sequentially connected to the parent molecule through carbonyl and nitrogen atoms. Unless otherwise specified, the terms "arylaminoformyl" and "heteroaylaminoformyl" used in this article refer to the aforementioned aryl or heteroaryl, namely <semantics>−C(=O)−NH<annotation encoding="application / x-tex">-C(=O)-NH< / annotation>< / semantics>-aryl (such as phenylaminoformyl) and -C(=O)-NH-heteroaryl (such as furan-2-ylaminoformyl), which are sequentially connected to the parent molecular through nitrogen atoms and carbonyl. Unless otherwise specified, the terms "aryloxy sulfonyl" and "heteroaryloxy sulfonyl" used in this article refer to the aforementioned aryl or heteroaryl, namely <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics> (=O)2-O-aryl (such as phenoxy sulfonyl) and <semantics>−S(=O)2<annotation encoding="application / x-tex">-S(=O)_2< / annotation>< / semantics>-O-heteroaryl (such as furan-2-yloxy sulfonyl), which are sequentially connected to the parent molecular by oxygen atoms and sulfonyl. Unless otherwise specified, the terms " arylsulfonyloxy " and "heteroarylsulfonyloxy" used in this article refer to the aforementioned aryl or heteroaryl, namely -O-S(=O)2-aryl (such as benzenesulfonyloxy) and -O-S(=O)2-heteroaryl (such as furan-2-sulfoyloxy), which are sequentially connected to the parent molecular through sulfones and oxygen atoms. Unless otherwise specified, the terms "arylsulfonylamino" and "heteroarylsulfonylamino" used in this article refer to the aforementioned aryl or heteroaryl, namely -NH-S (=O)2-aryl (such as benzenesulfonylamino) and -NH-S(=O)2-heteroaryl (such as furan-2-sulfonylamino), which are sequentially connected to the parent molecule through sulfones and nitrogen atoms. Unless otherwise specified, the terms "arylaminosulfonyl" and "heteroarylaminosulfonyl" used in this article refer to the aforementioned aryl or heteroaryl, namely -S (=O)2-NH-aryl (such as phenylaminosulfonyl) and <semantics>−S(=O)2<annotation encoding="application / x-tex">-S(=O)_2< / annotation>< / semantics>-NH-heteroaryl (such as furan-2-ylaminosulfonyl), which are sequentially connected to the parent molecular through nitrogen atoms and sulfonyl. Unless otherwise specified, the term "independently" used in this article refers to at least two functional groups (or segments) with the same or similar value range that exist in the structure and can have the same or different meanings in specific situations. For example, if R1 and R2 are independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when R1 is hydrogen, R2 can be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl; similarly, when R2 is hydrogen, R1 can be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. Unless otherwise specified, the term "substitution" and its variant forms used in this article mean that one or more (such as 1, 2, 3 or 4) atoms or atomic clusters (such as hydrogen atoms) on the designated atoms are substituted by other equivalents, provided that the normal valence of the designated atoms or atomic clusters in the current situation is not exceeded and stable compounds can be formed. Unless otherwise specified, the connecting site of the substituent in this article can be any suitable position of the substituent. Compounds of the general formula The present invention provides a compound as shown in general formula (1) or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers, or prodrugs thereof, [Image disponible dans le document PDF, Image available in the PDF document] (1) Where, R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, C6-10 aryl, or 5-10 membered heteroaryl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, and 5-10 membered heteroaryl; Each R4 is independently hydrogen or halogen; Each <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is independently hydrogen or halogen; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is hydrogen, halogen, hydroxyl, amino, aldehyde, carboxyl, cyano, nitro, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylamino, di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxycarbonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyloxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl amido, aminoformyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl aminoformyl, di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) carbamoyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy sulfonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl sulfonyloxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl sulfonyl amino, amino sulfonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl amino sulfonyl, di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino sulfonyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkyl, 3-7-membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, 5-10 membered heteroaryl, C6-10 aryloxy, 5-10 membered heteroaryloxy, C6-10 arylthio, 5-10 membered heteroaryl thio, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylamino, 5-10 membered heteroarylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylcarbonyl, 5-10 membered heteroarylcarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxycarbonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxycarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformamido, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformamido, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminoformyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylaminoformyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxy sulfonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxy sulfonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonylamino, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminosulfonyl or 5~10 membered heteroarylaminosulfonyl, which is optionally substituted by at least one of the following substituents: halogen, <semantics>C1∼6<annotation encoding="application / x-tex">C_{1\sim6}< / annotation>< / semantics> alkyl, <semantics>C3∼6<annotation encoding="application / x-tex">C_{3\sim6}< / annotation>< / semantics> cycloalkyl, <semantics>3∼7<annotation encoding="application / x-tex">3\sim7< / annotation>< / semantics> membered heterocyclic alkyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryl and <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryl; Each X3 is independently hydrogen or halogen; A is a group as shown in general formula <semantics>(2−1)<annotation encoding="application / x-tex">(2-1)< / annotation>< / semantics>, <semantics>(2−2)<annotation encoding="application / x-tex">(2-2)< / annotation>< / semantics>, or <semantics>(2−3)<annotation encoding="application / x-tex">(2-3)< / annotation>< / semantics>, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1)<annotation encoding="application / x-tex">(2-1)< / annotation>< / semantics> <semantics>(2−2)<annotation encoding="application / x-tex">(2-2)< / annotation>< / semantics> <semantics>(2−3)<annotation encoding="application / x-tex">(2-3)< / annotation>< / semantics> The ring H is a <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> sub-cyclic alkyl or a 3-7 membered sub-heterocyclic alkyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, and 5-10 membered heteroaryl; Y is either O or S; Each Z is independently CR1 or N; If it is present, each R1 is independently hydrogen, halogen, hydroxyl, amino, aldehyde, carboxyl, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylthio, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> haloalkythio, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkylamino, di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxycarbonyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkanoyloxy, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl amido, aminoformyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl aminoformyl, di <semantics>(C1−6 alkyl)<annotation encoding="application / x-tex">(C_{1-6} \text{ alkyl})< / annotation>< / semantics> carbamoyl, <semantics>C1−6 alkoxy sulfonyl<annotation encoding="application / x-tex">C_{1-6} \text{ alkoxy sulfonyl}< / annotation>< / semantics>, <semantics>C1−6 alkyl sulfonyloxy<annotation encoding="application / x-tex">C_{1-6} \text{ alkyl sulfonyloxy}< / annotation>< / semantics>, <semantics>C1−6 alkyl sulfonyl<annotation encoding="application / x-tex">C_{1-6} \text{ alkyl sulfonyl}< / annotation>< / semantics> amino, amino sulfonyl, C1-6 alkyl amino sulfonyl, di (C1-6 alkyl) amino sulfonyl, C3-6 cycloalkyl, 3-7-membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, 5-10 membered heteroaryl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryloxy, 5-10 membered heteroaryloxy, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylthio, 5-10 membered heteroaryl thio, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylamino, 5-10 membered heteroarylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylcarbonyl, 5-10 membered heteroarylcarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryloxycarbonyl, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryloxycarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylformamido, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylformamido, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminoformyl, 5~10 membered heteroarylaminoformyl, C6~10 aryloxy sulfonyl, 5~10 membered heteroaryloxy sulfonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonyloxy, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonyloxy, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylsulfonylamino, <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroarylsulfonylamino, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminosulfonyl or 5~10 membered heteroarylaminosulfonyl, which is optionally substituted by at least one of the following substituents: halogen, <semantics>C1∼6<annotation encoding="application / x-tex">C_{1\sim6}< / annotation>< / semantics> alkyl, <semantics>C3∼6<annotation encoding="application / x-tex">C_{3\sim6}< / annotation>< / semantics> cycloalkyl, <semantics>3∼7<annotation encoding="application / x-tex">3\sim7< / annotation>< / semantics> membered heterocyclic alkyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> aryl and <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaryl; If it is present, each <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is independently hydrogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> haloalkyl, <semantics>C2−6<annotation encoding="application / x-tex">C_{2-6}< / annotation>< / semantics> alkenyl, C2-6 alkynyl, C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkyl amido, aminoformyl, C1-6 alkylaminoformyl, di (C1-6 alkyl) aminoformyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl, 5-10 membered heteroaryl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> arylcarbonyl, 5-10 membered heteroarylcarbonyl, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryloxycarbonyl, 5-10 membered heteroaryloxycarbonyl, <semantics>C6∼10<annotation encoding="application / x-tex">C_{6\sim10}< / annotation>< / semantics> arylaminoformyl or <semantics>5∼10<annotation encoding="application / x-tex">5\sim10< / annotation>< / semantics> membered heteroaylaminoformyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-10 aryl, and 5-10 membered heteroaryl. In an embodiment of the present invention, R3 in the compound shown in general formula (1) is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 3-7 membered heterocyclic alkyl, C6-10 aryl or 5-10 membered heteroaryl, and the aforementioned groups can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocyclic alkyl; Preferably, R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or 3-7-membered heterocyclic alkyl, and the aforementioned groups can be optionally substituted by at least one of the following substituents: halogen and <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl; more preferably, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics> is hydrogen or methyl; further preferably, R3 is hydrogen. In an embodiment of the present invention, each R4 in the compound shown in general formula (1) is independently hydrogen, fluorine, chlorine, or bromine; preferably, each R4 is independently hydrogen, fluorine, or chlorine; more preferably, R4 is hydrogen. In an embodiment of the present invention, each <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> in the compound shown in general formula (1) is independently fluorine, chlorine, or bromine; preferably, each <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is independently fluorine or chlorine. In an embodiment of the present invention, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> in the compound shown in general formula (1) is hydrogen, halogen, C1-6 alkylamino, di (C1-6 alkyl) amino, C3-6 cycloalkyl, or 3-7 membered heterocyclic alkyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocyclic alkyl; preferably, X2 is hydrogen, halogen, di (C1-6 alkyl) amino, or 3-7-membered heterocyclic alkyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl; more preferably, X2 is hydrogen, chlorine, <semantics>∼∼<annotation encoding="application / x-tex">\sim\sim< / annotation>< / semantics> <semantics>∼∼∼<annotation encoding="application / x-tex">\sim\sim\sim< / annotation>< / semantics> diethylamino, morpholinyl ( O ), 2-oxa-5-azabicyclic [2.2.1] hept-5-yl ( O ) or [Image disponible dans le document PDF, Image available in the PDF document] 4-morpholinyl piperidin-1-yl In an embodiment of the present invention, each <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> in the compound shown in general formula (1) is independently hydrogen or fluorine; preferably, X3 is hydrogen. [Image disponible dans le document PDF, Image available in the PDF document] In a preferred embodiment of the present invention, the of the compound shown in general formula (1) is selected from the following structural segments: [Image disponible dans le document PDF, Image available in the PDF document] , In a more preferred embodiment of the present invention, the <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> of the compound shown in general formula (1) is selected from the following structural segments: [Image disponible dans le document PDF, Image available in the PDF document] ~~~~ In a further preferred embodiment of the present invention, the of the compound shown in general formula (1) is selected from the following structural segments: [Image disponible dans le document PDF, Image available in the PDF document] In an embodiment of the present invention, A in the compound shown in general formula (1) is a group shown in general formula (2-1-1) or (2-1-1'), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1−1)<annotation encoding="application / x-tex">(2-1-1)< / annotation>< / semantics> <semantics>(2−1−1′)<annotation encoding="application / x-tex">(2-1-1')< / annotation>< / semantics> Where, The ring H is a <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkyl or a 3-7-membered heterocyclic alkyl, and the aforementioned groups can be optionally substituted by at least one of the following substituents: halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, C3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl; preferably, the ring H is a [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] sub-cyclopropyl or a tetrahydro-2H-pyran-4-yl Y is O or S; preferably, Y is O; When A is a group as shown in the general formula <semantics>(2−1−1)<annotation encoding="application / x-tex">(2-1-1)< / annotation>< / semantics>, two of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, while the rest are hydrogen; alternatively, one of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; alternatively, all the four R1 are hydrogen; preferably, two of the four R1 are independently halogen or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, while the rest are hydrogen; alternatively, one of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; alternatively, all the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are hydrogen; more preferably, two of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently fluorine, chlorine, or dimethylamino, while the rest are hydrogen; alternatively, one of the four R1 is fluorine, chlorine, methoxy or dimethylamino, and the rest are hydrogen; alternatively, all four R1 are hydrogen; When A is a group as shown in the general formula <semantics>(2−1−1′)<annotation encoding="application / x-tex">(2-1-1')< / annotation>< / semantics>, two of the three <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, while the rest is hydrogen; alternatively, one of the three R1 is halogen, C1-6 alkyl, C1-6 alkoxy or di (C1-6 alkyl) amino, and the rest are hydrogen; alternatively, all the three R1 are hydrogen; preferably, two of the three R1 are independently halogen or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, while the rest is hydrogen; alternatively, one of the three <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; alternatively, all three <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are hydrogen; more preferably, all the three <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are hydrogen. In a preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-1-2), [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1−2)<annotation encoding="application / x-tex">(2-1-2)< / annotation>< / semantics> Where, ring H, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In a more preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-1-3), [Image disponible dans le document PDF, Image available in the PDF document] (2-1-0) Where, ring H, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In a preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-1-2'), [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1−2′)<annotation encoding="application / x-tex">(2-1-2')< / annotation>< / semantics> Where, ring H, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In a more preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-1-3'), [Image disponible dans le document PDF, Image available in the PDF document] ·- · - / Where, ring H, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In an embodiment of the present invention, A in the compound shown in general formula (1) is a functional group shown in general formula (2-2-1), Y is O or S; preferably, Y is O; Two of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; alternatively, one of the four R1 is halogen, C1-6 alkyl, C1-6 alkoxy, or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; preferably, two of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently halogen, and the rest are hydrogen; alternatively, one of the four R1 is halogen, C1-6 alkoxy or di <semantics>(C1−6 alkyl)<annotation encoding="application / x-tex">(C_{1-6} \text{ alkyl})< / annotation>< / semantics> amino, and the rest are hydrogen; more preferably, two of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently fluorine or chlorine, and the rest are hydrogen; alternatively, one of the four R1 is fluorine, chlorine, methoxy or dimethylamino, and the rest are hydrogen; R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or 3-7-membered heterocyclic alkyl, and the aforementioned groups can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl; preferably, <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkyl, or a 3-7-membered heterocyclic alkyl, and the aforementioned groups can be optionally substituted by the <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl; more preferably, <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is methyl, cyclopropyl, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] tetrahydro-2H-pyran-4-yl( O ) or 1-methylpiperidin-4-yl( ). In a preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-2-2), [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−2−2)<annotation encoding="application / x-tex">(2-2-2)< / annotation>< / semantics> Where, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In a more preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-2-3), [Image disponible dans le document PDF, Image available in the PDF document] (2-2-3) Where, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In an embodiment of the present invention, A in the compound shown in general formula (1) is a functional group shown in general formula (2-3-1), [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−3−1)<annotation encoding="application / x-tex">(2-3-1)< / annotation>< / semantics> Y is O or S; preferably, Y is O; One of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; preferably, one of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is chlorine, and the rest are hydrogen; Each R2 is independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or 3-7-membered heterocyclic alkyl, which can be optionally substituted by at least one of the following substituents: halogen, C1-6 alkyl, C3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl; preferably, each <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is independently <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl; more preferably, all <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> are methyl. In a preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-3-2), [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−3−2)<annotation encoding="application / x-tex">(2-3-2)< / annotation>< / semantics> Where, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. In a more preferred embodiment of the present invention, the compound shown in general formula (1) is a compound shown in general formula (2-3-3), [Image disponible dans le document PDF, Image available in the PDF document] \- - -, Where, Y, <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> are defined as those in the present invention. [Image disponible dans le document PDF, Image available in the PDF document] In a preferred embodiment of the present invention, the of the compound as shown in general formula (2-1-1), (2-1-2), (2-1-3), (2-2-1), (2-2-2), (2-2-3), (2-3-1), (2-3-2) or (2-3-3) is selected from the following structural segments: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a more preferred embodiment of the present invention, the of the compound as shown in general formula (2-1-1), (2-1-2), (2-1-3), (2-2-1), (2-2-2), (2-2-3), (2-3-1), (2-3-2) or (2-3-3) are selected from the following structural segments: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a further preferred embodiment of the present invention, the of the compound as shown in general formula (2-1-1), (2-1-2), (2-1-3), (2-2-1), (2-2-2), (2-2-3), (2-3-1), (2-3-2) or (2-3-3) are selected from the following structural segments: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a preferred embodiment of the present invention, the of the compound as [Image disponible dans le document PDF, Image available in the PDF document] shown in general formula (2-1-1'), (2-1-2'), or (2-1-3') is The present invention also provides the following compounds or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers, or prodrugs thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] Preparation method of general formula compound The compound shown in general formula (1) of the present invention (such as having a carboxyl at the end, i.e. R3 is hydrogen) can be prepared by the following method. [Image disponible dans le document PDF, Image available in the PDF document] Where, R4, X1, X2, X3, and A are defined as those in general formula (1); W1 is bromine or iodine, W2 is hydroxyl or chlorine, and R is an amino protecting group. First, intermediate P1 and intermediate H-A undergo coupling reaction to obtain intermediate M1; preferably, the coupling reaction is carried out in the presence of metal catalysts (such as cuprous iodide, etc.), ligands (such as N, N-dimethylglycine or its hydrochloride, etc.), bases (such as cesium carbonate, etc.) and organic solvents (such as acetonitrile, 1,4-dioxane, etc.) that may not have adverse effects on the reaction. Secondly, intermediate M1 undergoes deprotection reaction to obtain intermediate M2; preferably, the deprotection reaction is carried out in the presence of acids (such as trifluoroacetic acid, etc.) and organic solvents (such as dichloromethane) that may not have adverse effects on the reaction. Furthermore, intermediate M2 and intermediate P2 undergo condensation reaction to obtain intermediate M3; preferably, the condensation reaction is carried out in the presence of bases (such as N, N-diisopropylethylamine, triethylamine, etc.) and organic solvents (such as dichloromethane) that may not have an adverse effect on the reaction. Finally, the intermediate M3 is hydrolyzed to obtain the target product; preferably, the hydrolysis reaction is carried out in the presence of bases (such as sodium hydroxide, etc.) and mixed solvents (such as tetrahydrofuran / water, etc.) that may not have adverse effects on the reaction. The compound shown in general formula (1) of the present invention (for example, having an ester group at the end, i.e. R3 is as defined in general formula (1), but is not hydrogen) can be prepared by the following method. Option 1: [Image disponible dans le document PDF, Image available in the PDF document] Where, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>, and A are defined as those in general formula (1). According to the preparation method of compounds with carboxyl (i.e. R3 is hydrogen) at the end, the intermediate M4 is obtained, and then the target product is obtained through esterification reaction with R3-OH; preferably, the esterification reaction is carried out in the presence of condensation aids (such as 1-hydroxybenzotriazole(HOBt), 1,3-dicyclohexylcarbodiimide (DCC), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), etc.), bases (such as N,N-diisopropylethylamine, triethylamine, and pyridine, etc.), and organic solvents (such as dichloromethane, tetrahydrofuran, and acetonitrile, etc.) that may not have adverse effects on the reaction. Option 2: [Image disponible dans le document PDF, Image available in the PDF document] Where, <semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>, <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>, <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>, and A are defined as those in general equation (1); W1 is bromine or iodine, and W2 is hydroxyl or chlorine. First, intermediate P3 and intermediate H-A undergo coupling reaction to obtain intermediate M5; preferably, the coupling reaction is carried out in the presence of metal catalysts (such as cuprous iodide, etc.), ligands (such as N, N-dimethylglycine or its hydrochloride, etc.), bases (such as cesium carbonate, etc.) and organic solvents (such as acetonitrile, 1,4-dioxane, etc.) that may not have adverse effects on the reaction. Secondly, the intermediate M5 undergoes deprotection reaction to obtain the intermediate M6; preferably, the deprotection reaction is carried out in the presence of acids (such as trifluoroacetic acid, etc.) and organic solvents (such as dichloromethane, etc.) that may not have adverse effects on the reaction. Furthermore, intermediate M6 and intermediate P2 undergo condensation reaction to obtain the target product; preferably, the condensation reaction is carried out in the presence of bases (such as N,N-diisopropylethylamine, triethylamine, etc.) and organic solvents (such as dichloromethane) that may not have adverse effects on the reaction. Pharmaceutical composition The present invention provides a pharmaceutical composition comprising the compound of the present invention or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs thereof. In an embodiment of the present invention, the pharmaceutical composition comprises not only the compound of the present invention as the active ingredient of the drug or its pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs, but also at least one pharmaceutically acceptable excipient, including (but not limited to) the following components: diluent, adhesive, lubricant, flow aid, surfactant, flavoring, smelling agent, pH regulators, aromatic, and sweetener, etc. In an embodiment of the present invention, the compound of the present invention as the active ingredient of the drug or its pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs, but also at least one other pharmaceutical active ingredient that can enhance and / or reduce toxicity after combination. In an embodiment of the present invention, the pharmaceutical composition exists in a specific form, including (but not limited to) the following dosage forms: tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension, injectable solution, elixir, and syrup, etc. In an embodiment of the present invention, a pharmaceutical composition of a unit of measurement or unit of drug comprising 0.01-1000 mg of the compound as shown in general formula (1) or equivalent pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers, or prodrugs. Medical uses related to <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin Pharmacological experiments have shown that the compound of the present invention has certain inhibitory activity for <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin and can therefore be used for prevention and / or treatment at least partially by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin mediated diseases and / or symptoms. The present invention also provides the uses of the compound of the present invention or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs thereof, or pharmaceutical compositions of the present invention, in the production of drugs for prevention and / or treatment at least partially by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin mediated diseases and / or symptoms. In addition, the present invention also provides a method for preventing and / or treating at least partially by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin mediated diseases and / or symptoms, which includes the following steps: administrating the aforementioned compounds or their pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope markers or prodrugs thereof, or the aforementioned drug compositions thereof, to individuals in need. In an embodiment of the present invention, at least partially by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin mediated diseases and / or symptoms include (but are not limited to) autoimmune diseases, inflammatory diseases, and tumor cell proliferation and metastasis. In an embodiment of the present invention, autoimmune diseases include (but are not limited to) rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). In an embodiment of the present invention, inflammatory diseases include (but are not limited to) inflammatory bowel disease (IBD); preferably, inflammatory bowel diseases include (but are not limited to) ulcerative colitis (UC) and Krohn's disease (CD). The present invention will be elaborated in detail through embodiments. These embodiments are only preferred embodiments of the present invention and should not be regarded as limitations on the invention. Further, unless otherwise indicated, the instruments, drugs, reagents, consumables, etc. used in the following embodiments may be obtained by conventional commercial means. It should be noted that intermediate preparation example 1 shows an example of synthesis of intermediate P-1 as shown in general formula P1, intermediate preparation examples 2 to 33 show an example of synthesis of intermediate P-2 to P-33 as shown in general formula H-A, intermediate preparation examples 34 to 38 show an example of synthesis of intermediate P-34 to P-38 as shown in general formula P2, and examples 1 to 39 show an example of synthesis of compounds of the present invention. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-iodo-L-phenylalanine (29.1g, 10mmol) in anhydrous methanol (290mL) and cool in an ice bath. Add thionyl chloride (17.9g, 15mmol) and N,N-Dimethylformamide (2.9mL), react at 40°C for 24h. Concentrate the reaction solution with vacuum, a white solid is obtained, which is the title compound (29g, 95%). ESI-QQQ-MS: m / z 306 [M+H]+. (Step 2) 3-(4-iodophenyl)-2-(triphenylamino) methyl propionate (P-1) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-iodophenyl) methyl propionate (24.4g, 8mmol) in dichloromethane (480mL) and cool in an ice bath. Add triethylamine (12.1g, 12mmol) and 1.2eq triphenylmethyl chloride (26.8g, 9.6mmol), react at room temperature for 8h. 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 (30.7g, 70%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 548 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. Intermediate preparation example 2: Synthesis of spiro[cyclopropane-1,3'-indoline]-2'-one <semantics>(P−2).<annotation encoding="application / x-tex">(P-2).< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] Dissolve indoline-2-ketone (0.27g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 0.4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.19g, 60%). ESI-QQQ-MS: m / z 160 [M+H]+. Intermediate preparation example 3: Synthesis of 7'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-3). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 7-fluoroindolin-2-one (0.3g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.19g, 54%). ESI-QQQ-MS: m / z 178 [M+H]+. Intermediate preparation example 4: Synthesis of 6'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-4). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6-fluoroindolin-2-one (0.3g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.22g, 62%). ESI-QQQ-MS: m / z 178 [M+H]+. Intermediate preparation example 5: Synthesis of 5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-5). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-fluoroindolin-2-one (0.3g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 (022g, 61%). ESI-QQQ-MS: m / z 178 [M+H]+. Intermediate preparation example 6: Synthesis of 7'-chlorospiro[cyclopropane-1,3'-indoline]-2'-one (P-6). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 7-chloroindoline-2-one (0.33g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.2g, 52%). ESI-QQQ-MS: m / z 194 [M+H]+. Intermediate preparation example 7: Synthesis of 6'-chlorospiro[cyclopropane-1,3'-indoline]-2'-one (P-7). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6-chloroindoline-2-one (0.33g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.21g, 54%). ESI-QQQ-MS: m / z 194 [M+H]+. Intermediate preparation example 8: Synthesis of 5'-chlorospiro[cyclopropane-1,3'-indoline]-2'-one (P-8). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-chloroindoline-2-one (0.33g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.19g, 50%). ESI-QQQ-MS: m / z 194 [M+H]+. Intermediate preparation example 9: Synthesis of 7'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (P-9). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 7-methoxyspiro-2-one (0.33g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.2g, 53%). ESI-QQQ-MS: m / z 190 [M+H]+. Intermediate preparation example 10: Synthesis of 5',6'-difluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-10). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5,6-difluorospiro-2-one (0.34g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL) 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.22g, 57%). ESI-QQQ-MS: m / z 196 [M+H]+. Intermediate preparation example 11: Synthesis of 6'-chloro-5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-11). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6-chloro-5-fluoroindolin-2-one (0.37g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 (0.21g, 50%). ESI-QQQ-MS: m / z 212 [M+H]+. Intermediate preparation example 12: Synthesis of 6',7'-difluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-12). (Step 1) (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino)acetamide [Image disponible dans le document PDF, Image available in the PDF document] Add hydrochloric acid solution (0.6mL) of 2,3-difluoroaniline (0.78g, 6mmol) to a mixed system of chloral hydrate (1.4g, 8.4mmol), sodium sulfate (4.74g, 33.4mmol) and water (6mL), react at room temperature for 1h, then add hydroxylamine hydrochloride (0.58g, 8.4mmol), heat to 60°C, and react for 2h. Cool and filter the reaction solution, the filter cake is the title compound (crude product, 0.7g), which is directly used for the next reaction. ESI-QQQ-MS: m / z 201 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 2) 6,7-difluoroindoline-2,3-dione [Image disponible dans le document PDF, Image available in the PDF document] Add (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino) acetamide (0.7g, 3.5mmol) to sulfuric acid (2.5mL), heat to 80°C, and react for 3h. After cooling the reaction system, pour ice water (20mL), filter out the precipitate, and dry with vacuum to obtain the title compound (crude product, 0.35g). ESI-QQQ-MS: m / z 184 [M+H]+. (Step 3) 6,7-difluoroindolin-2-one [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6,7-difluoroindoline-2,3-dione (0.35g, 1.9mmol) in ethylene glycol (2mL), add hydrazine hydrate (0.18mL, 3.8mmol), heat to 130°C, react for 4h, then cool to 25°C, react for 16h, add water (2mL) and concentrated hydrochloric acid (0.2mL), continue to heat to 45°C, react for 1h. 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 (0.26g, 70%). ESI-QQQ-MS: <semantics>m / z170[M+H]+<annotation encoding="application / x-tex">m / z 170 [M+H]^+< / annotation>< / semantics>. (Step 4) 6',7'-difluoro[cyclopropane-1,3'-dihydroindole]-2'-one(P-12) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6,7-difluoroindoline-2-one (0.26g, 1.54mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 3mL, 6mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (0.87g, 4.6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 (0.16g, 53%). ESI-QQQ-MS: m / z 196 [M+H]+. Intermediate preparation example 13: Synthesis of 7-chloro-3,3-dimethylindolin-2-one <semantics>(P−13)<annotation encoding="application / x-tex">(P-13)< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 7-chloroindoline-2-one (0.34g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add iodomethane (0.85g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (024g, 61%). ESI-QQQ-MS: m / z 196 [M+H]+. Intermediate preparation example 14: Synthesis of 7-chloro-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (P-14). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 7-chloroindoline-2-one (0.34g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1-iodo-2-(2-iodoethoxy)ethane (1.96g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.23g, 49%). ESI-QQQ-MS: m / z 238 [M+H]+. Intermediate preparation example 15: Synthesis of 5'-(dimethylamino) spiro[cyclopropane-1,3'-indoline]-2'-one (P-15). (Step 1) 5-(dimethylamino) indoline-2-one [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-aminoindoline-2-one (0.30g, 2mmol) in glacial acetic acid (4mL), add sodium cyanoborohydride (0.31g, 5mmol) and paraformaldehyde (0.48g, 16mmol) sequentially, and react at room temperature for 24h. Concentrate the reaction system with vacuum and add water (20mL) to the reaction system, extract with ethyl acetate twice (10mL 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 (0.24g, 68%). ESI-QQQ-MS: m / z <semantics>177[M+H]+<annotation encoding="application / x-tex">177 [M+H]^{+}< / annotation>< / semantics>. (Step 2) 5'-(dimethylamino) spiro[cyclopropane-1,3'-indoline]-2'-one (P-15) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-(dimethylamino) indoline-2-one (0.24g, 1.35mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 2.7mL, 5.4mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (0.76g, 4.05mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 (0.11g, 40%). ESI-QQQ-MS: m / z 203 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6-amino-5-fluoroindolin-2-one (0.33g, 2mmol) in glacial acetic acid (4mL), add sodium cyanoborohydride (0.31g, 5mmol) and paraformaldehyde (0.48g, 16mmol) sequentially, and react at room temperature for 24h. Concentrate the reaction system with vacuum and add water (20mL) and ethyl acetate (10mL) to the reaction system, stand for layering, extract with ethyl acetate twice (10mL 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 (0.25g, 65%). ESI-QQQ-MS: m / z 195 [M+H]+. (Step 2) 6'-(dimethylamino)-5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-16) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6-(dimethylamino)-5-fluoroindolin-2-one (0.24g, 1.3mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 2.6mL, 5.2mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (0.73g, 3.9mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate twice (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.12g, 42%). ESI-QQQ-MS: m / z 221 [M+H]+. Intermediate preparation example 17: Synthesis of spiro[cyclopropane-1,3'-pyrrolo[2,3-b] pyridine]-2'(1'H)-one (P-17) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1H-pyrrolo[2,3-b]pyridine-2(3H)-one (0.27g, 2mmol) in anhydrous tetrahydrofuran (3mL), cool to -40°C, add LDA (2mol / L, 4mL, 8mmol), stir for 30min, heat to 0°C, add 1,2-dibromoethane (1.14g, 6mmol), and react at room temperature for 24h. Add saturated ammonium chloride solution (5mL) and water (15mL) to the reaction system, extract with ethyl acetate for three times (10mL 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 (0.11g, 34%). ESI-QQQ-MS: m / z 161 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethylamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.37g, 98%). ESI-QQQ-MS: m / z 187 [M+H]+. (Step 2) 3-chloro-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N-methyl-2-nitroaniline (0.3g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.24g, 98%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 157 [M+H]+. (Step 3) 4-chloro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-18) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N¹-methylbenzene-1,2-diamine(0.2g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.19g, 80%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 183 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-chloro-2-fluoro-1-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and cyclopropylamine (0.14g, 2.4mmol), heat to reflux, and stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.35g, 82%). ESI-QQQ-MS: m / z 213 [M+H]+. (Step 2) 5-chloro-N¹-cyclopropylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-chloro-N-cyclopropyl-2-nitroaniline (0.34g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.27g, 92%). ESI-QQQ-MS: m / z 183 [M+H]+. (Step 3) 6-chloro-1-cyclopropyl-1H-benzo[d]imidazole-2(3H)-one (P-19) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-chloro-N1-cyclopropylbenzene-1,2-diamine (0.24g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.20g, 74%). ESI-QQQ-MS: m / z 209 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-chloro-1-fluoro-2-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and cyclopropylamine (0.14g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.35g, 85%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 213 [M+H]+. (Step 2) 4-chloro-N¹-cyclopropylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-chloro-N-cyclopropyl-2-nitroaniline (0.34g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50°C, stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.26g, 90%). ESI-QQQ-MS: m / z 183 [M+H]+. (Step 3) 5-chloro-1-cyclopropyl-1H-benzo[d]imidazole-2(3H)-one (P-20) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-chloro-N¹-cyclopropylbenzene-1,2-diamine (0.24g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.19g, 70%). ESI-QQQ-MS: m / z 209 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and cyclopropylamine (0.14g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.37g, 87%). ESI-QQQ-MS: <semantics>m / z213[M+H]+<annotation encoding="application / x-tex">m / z 213 [M+H]^+< / annotation>< / semantics>. (Step 2) 3-chloro-N¹-cyclopropylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N-cyclopropyl-2-nitroaniline (0.34g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50 °C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.27g, 93%). ESI-QQQ-MS: m / z 183 [M+H]+. (Step 3) 4-chloro-1-cyclopropyl-1H-benzo[d]imidazole-2(3H)-one(P-21) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N1-cyclopropylbenzene-1,2-diamine (0.24g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.18g, 66%). ESI-QQQ-MS: m / z 209 [M+H]+. Intermediate preparation example 22: Synthesis of 4-chloro-1-methyl-1H-benzo[d]imidazole-2(3H)-thione (P-22) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N¹-methylbenzene-1,2-diamine (0.24g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add sulfurphosgene / dichloromethane solution (0.18g / 1mL) dropwise to the reaction system, react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.14g, 54%). ESI-QQQ-MS: m / z 199 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and tetrahydro-2H-pyran-4-amine (0.24g, 2.4mmol), heat to reflux, and stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.30g, 59%). ESI-QQQ-MS: <semantics>m / z257[M+H]+<annotation encoding="application / x-tex">m / z 257 [M+H]^+< / annotation>< / semantics>. (Step 2) 3-chloro-N¹-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve N-(3-chloro-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (0.28g, 1.1mmol) in anhydrous methanol (4mL), add zinc powder (0.72g, 11mmol) and ammonium chloride (0.29g, 5.5mmol), heat to 50°C, and stir for 3h. Perform suction filtration for reaction solution, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL) 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 (0.22g, 89%). ESI-QQQ-MS: m / z 227 [M+H]+. (Step 3) 4-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-2(3H)-one (P-23) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N¹-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (0.22g, 0.97mmol) in dichloromethane (2mL), cool to 0 °C, add triethylamine (0.13g, 1.3mmol), and slowly add triphosgene / dichloromethane solution (0.12g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=2:1<annotation encoding="application / x-tex">= 2:1< / annotation>< / semantics>) to obtain the title compound (0.12g, 49%). ESI-QQQ-MS: m / z 253 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethylamine (0.34g, 2.6mmol) and 1-methylpiperidine-4-amine (0.27g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.28g, 51%). ESI-QQQ-MS: m / z 270 [M+H]+. (Step 2) 3-chloro-N¹-(1-methylpiperidine-4-yl) benzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve N-(3-chloro-2-nitrophenyl)-1-methylpiperidine-4-amine (0.27g, 1.0mmol) in anhydrous methanol (4mL), add zinc powder (0.65g, 10mmol) and ammonium chloride (0.27g, 5mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.22g, 92%). ESI-QQQ-MS: m / z 240 [M+H]+. (Step 3) 4-chloro-1-(1-methylpiperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one(P-24) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-chloro-N¹-(1-methylpiperidine-4-yl)benzene-1,2-diamine (0.22g, 0.92mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.12g, 1.2mmol), and slowly add triphosgene / dichloromethane solution (0.11g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=1:1<annotation encoding="application / x-tex">= 1:1< / annotation>< / semantics>) to obtain the title compound (0.11g, 45%). ESI-QQQ-MS: m / z 266 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1,3-difluoro-2-nitrobenzene (0.32g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethylamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.32g, 95%). ESI-QQQ-MS: m / z 171 [M+H]+. (Step 2) 3-fluoro-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-fluoro-N-methyl-2-nitroaniline (0.27g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.22g, 98%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 141 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 3) 4-fluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-25) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-fluoro-N¹-methylbenzene-1,2-diamine (0.18g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.17g, 78%). ESI-QQQ-MS: m / z 167 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1,3,5-trifluoro-2-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.26g, 70%). ESI-QQQ-MS: m / z 189 [M+H]+. (Step 2) 3,5-difluoro-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3,5-difluoro-N-methyl-2-nitroaniline (0.24g, 1.3mmol) in anhydrous methanol (4.5mL), add zinc powder (0.85g, 13mmol) and ammonium chloride (0.35g, 6.5mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.19g, 92%). ESI-QQQ-MS: m / z 159 [M+H]+. (Step 3) 4,6-difluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-26) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3,5-difluoro-N¹-methylbenzene-1,2-diamine (0.17g, 1.1mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.14g, 1.4mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.16g, 80%). ESI-QQQ-MS: m / z 185 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1,2-dichloro-4-fluoro-5-nitrobenzene (0.42g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.4g, 90%). ESI-QQQ-MS: m / z 221 [M+H]+. (Step 2) 4,5-dichloro-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4,5-dichloro-N-methyl-2-nitroaniline (0.35g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1.0g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50 °C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.29g, 95%). ESI-QQQ-MS: m / z 191 [M+H]+. (Step 3) 5,6-dichloro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-27) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4,5-dichloro-N¹-methylbenzene-1,2-diamine (0.29g, 1.5mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.14g, 1.9mmol), and slowly add triphosgene / dichloromethane solution (0.18g / 1mL) dropwise to the reaction system and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.24g, 74%). ESI-QQQ-MS: m / z 217 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1,3-difluoro-2-nitrobenzene (0.32g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and cyclopropylamine (0.14g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.35g, 90%). ESI-QQQ-MS: m / z 197 [M+H]+. (Step 2) N¹-cyclopropyl 3-fluorobenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve N-cyclopropyl-3-fluoro-2-nitroaniline (0.31g, 1.6mmol) in anhydrous methanol (4.5mL), add zinc powder (1g, 16mmol) and ammonium chloride (0.43g, 8mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.26g, 96%). ESI-QQQ-MS: m / z 167 [M+H]+. (Step 3) 1-cyclopropyl-4-fluoro-1H-benzo[d]imidazole-2(3H)-one (P-28) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve N¹-cyclopropyl 3-fluorobenzene-1,2-diamine (0.22g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.19g, 75%). ESI-QQQ-MS: m / z 193 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Mix 65% concentrated nitric acid (2mL) and 98% concentrated sulfuric acid (4mL), and slowly add 1,2,4-trifluorobenzene (1.32g) dropwise, and react at 30°C for 2h. 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 (1.7g, 95%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 178 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 2) 3,4-difluoro-N-methyl-2-nitroaniline [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1,2,4-trifluoro-3-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol) and heat to 50°C for 12h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.2g, 50%). ESI-QQQ-MS: m / z 189 [M+H]+. (Step 3) 3,4-difluoro-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3,4-difluoro-N-methyl-2-nitroaniline (0.19g, 1mmol) in anhydrous methanol (3mL), add zinc powder (0.66g, 10mmol) and ammonium chloride (0.27g, 5mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.14g, 90%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 159 [M+H]+. (Step 4) 4,5-difluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-29) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3,4-difluoro-N¹-methylbenzene-1,2-diamine (0.14g, 0.89mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.1g, 1.2mmol), and slowly add triphosgene / dichloromethane solution (0.1g / 1mL) dropwise to the reaction system, react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.12g, 74%). <semantics>ESI−QQQ−MS:m / z185[M+H]+<annotation encoding="application / x-tex">ESI-QQQ-MS: m / z 185 [M+H]^+< / annotation>< / semantics>. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1,2,3-trifluoro-4-nitrobenzene (0.35g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethanamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol), heat to 50°C and react for 12h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.24g, 60%). ESI-QQQ-MS: m / z 189 [M+H]+. (Step 3) 5,6-difluoro-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3,4-difluoro-N-methyl-2-nitroaniline (0.19g, 1mmol) in anhydrous methanol (3mL), add zinc powder (0.66g, 10mmol) and ammonium chloride (0.27g, 5mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.14g, 88%). ESI-QQQ-MS: m / z 159 [M+H]+. (Step 4) 6,7-difluoro-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-30) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3,4-difluoro-N¹-methylbenzene-1,2-diamine (0.12g, 0.76mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.1g, 1.2mmol), and slowly add triphosgene / dichloromethane solution (0.1g / 1mL) dropwise to the reaction system, react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.13g, 80%). ESI-QQQ-MS: m / z 185 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-fluoro-3-methoxy-2-nitrobenzene (0.34g, 2mmol) in absolute ethanol (4mL), add N,N-diisopropylethylamine (0.34g, 2.6mmol) and 33% methylamine ethanol solution (0.23g, 2.4mmol), heat to reflux, stir for 20h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.29g, 80%). ESI-QQQ-MS: m / z 183 [M+H]+. (Step 2) 3-methoxy-N¹-methylbenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-methoxy-N-methyl-2-nitroaniline (0.27g, 1.5mmol) in anhydrous methanol (4.5mL), add zinc powder (0.98g, 15mmol) and ammonium chloride (0.4g, 7.5mmol), heat to 50°C, stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.21g, 92%). ESI-QQQ-MS: m / z 153 [M+H]+. (Step 3) 4-methoxy-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-31) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 3-methoxy-N¹-methylbenzene-1,2-diamine (0.2g, 1.3mmol) in dichloromethane (2mL), cool to 0°C, add triethylamine (0.14g, 1.7mmol), and slowly add triphosgene / dichloromethane solution (0.15g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.16g, 70%). ESI-QQQ-MS: m / z 179 [M+H]+. Intermediate preparation example 32: Synthesis of 5-(dimethylamino)-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-32). (Step 1) N¹-methyl-4-nitrobenzene-1,2-diamine [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-nitrobenzene-1,2-diamine (0.33g, 2mmol) in DMF (4mL), add saturated sodium carbonate solution (0.5mL) and iodomethane (0.24g, 1.7mmol) sequentially, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (0.2g, 60%). ESI-QQQ-MS: m / z 168 [M+H]+. (Step 2) 1-methyl-5-nitro-1H-benzo[d]imidazole-2(3H)-one [Image disponible dans le document PDF, Image available in the PDF document] Dissolve N¹-methyl-4-nitrobenzene-1,2-diamine (0.2g, 1.3mmol) in dichloromethane (4mL), cool to 0°C, add triethylamine (0.16g, 1.6mmol), and slowly add triphosgene / dichloromethane solution (0.14g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.16g, 68%). ESI-QQQ-MS: m / z <semantics>194[M+H]+<annotation encoding="application / x-tex">194 [M+H]^+< / annotation>< / semantics>. (Step 3) 5-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-methyl-5-nitro-1H-benzo[d]imidazole-2(3H)-one (0.16g, 0.83mmol) in anhydrous methanol (2.5mL), add zinc powder (0.54g, 8.3mmol) and ammonium chloride (0.22, 4.2mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (10mL) to the concentrate, extract with dichloromethane for three times (5mL 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 (0.12g, 87%). ESI-QQQ-MS: m / z 164 [M+H]+. (Step 4) 5-(dimethylamino)-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-32) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 5-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one (0.12g, 0.73mmol) in anhydrous DMF (3mL), add sodium hydrogen (0.07g, 2.9mmol), stir for 0.5h, then add iodomethane (0.26g, 1.8mmol), react at room temperature for 12h. Concentrate the reaction system with vacuum and add water (10mL) to the reaction system, extract with ethyl acetate twice (5mL 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 <semantics>(0.06g,40%)<annotation encoding="application / x-tex">(0.06g, 40\%)< / annotation>< / semantics>. ESI-QQQ-MS: m / z 192 [M+H]+. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve N¹-methyl-5-nitrobenzene-1,2-diamine (0.33g, 2mmol) in dichloromethane (4mL), cool to 0°C, add triethylamine (0.14g, 2.6mmol), and slowly add triphosgene / dichloromethane solution (0.24g / 1mL) dropwise to the reaction system, and react at room temperature for 1h. Concentrate the reaction solution with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.23g, 60%). ESI-QQQ-MS: m / z <semantics>194[M+H]+<annotation encoding="application / x-tex">194 [M+H]^+< / annotation>< / semantics>. (Step 2) 6-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 1-methyl-6-nitro-1H-benzo[d]imidazole-2(3H)-one (0.23g, 1.2mmol) in anhydrous methanol (4.5mL), add zinc powder (0.91g, 12mmol) and ammonium chloride (0.37g, 6mmol), heat to 50°C, and stir for 3h. Filter the reaction solution with vacuum, rinse the filter cake twice with absolute ethanol (2mL each time), combine the filtrate, and concentrate with vacuum, add water (20mL) to the concentrate, extract with dichloromethane for three times (10mL 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 (0.16g, 81%). ESI-QQQ-MS: m / z 164 [M+H]+. (Step 3) 6-(dimethylamino)-1-methyl-1H-benzo[d]imidazole-2(3H)-one (P-33) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 6-amino-1-methyl-1H-benzo[d]imidazole-2(3H)-one (0.16g, 0.98mmol) in anhydrous DMF (3mL), add sodium hydrogen (0.1g, 4mmol), stir for 0.5h, and add iodomethane (0.36g, 2.5mmol), react at room temperature for 12h. Concentrate the reaction system with vacuum and add water (20mL) to the reaction system, extract with ethyl acetate twice (10mL 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 = <semantics>10:1<annotation encoding="application / x-tex">10:1< / annotation>< / semantics>) to obtain the title compound (<semantics>0.08g,42%<annotation encoding="application / x-tex">0.08g, 42\%< / annotation>< / semantics>). ESI-QQQ-MS: m / z 192 [M+H]+. Intermediate preparation example 34: Synthesis of 2,4,6-trichlorobenzoyl chloride (P-34). [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 2,4,6-trichlorobenzoic acid (0.23g, 1mmol) in 5mL of dichloromethane, add thionyl chloride (0.24g, 2mmol) and DMF (3 drops), and react at room temperature for 3h. 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve 4-bromo-2,6-dichlorobenzoic acid (0.27g, 1mmol) in 5mL of methanol, cool to 0°C, and add thionyl chloride (0.24g, 2mmol) to the reaction system and react at room temperature for 3h. Concentrate the reaction solution with vacuum, add ethyl acetate (5mL) and saturated sodium bicarbonate solution (10mL), 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 (0.24g, 85%). ESI-QQQ-MS: m / z 283 [M+H]+. (Step 2) methyl 2,6-dichloro-4-(diethylamino)benzoate [Image disponible dans le document PDF, Image available in the PDF document] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24g, 0.85 mmol), diethylamine (0.12g, 1.7mmol), palladium (II) acetate (10mg, 5mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63mg, 10mol%), cesium carbonate (0.3g, 0.92mmol) and anhydrous dioxane (6mL), displace nitrogen, and react in microwave at 120°C for 2h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10mL), extract with ethyl acetate twice (5mL 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 (0.16g, 70%). ESI-QQQ-MS: m / z 276 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 3) 2,6-dichloro-4-(diethylamino)benzoyl chloride (P-35) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve methyl 2,6-dichloro-4-(diethylamino)benzoate (0.16g, 0.58mmol) in methanol (3mL) and water (0.5mL), and add 6N sodium hydroxide solution (0.15mL, 0.87mmol) and react at room temperature for 24h. 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 3mL of dichloromethane, add thionyl chloride (0.13g, 1.1mmol) and DMF (2 drops), and react at room temperature for 4h. 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 [Image disponible dans le document PDF, Image available in the PDF document] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24g, 0.85mmol), morpholine (0.1g, 1.2mmol), palladium (II) acetate (10mg, 5mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63mg, 10mol%), cesium carbonate(0.3g, 0.92mmol) and anhydrous dioxane (6mL), displace nitrogen and react in microwave at 120°C for 2h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10mL), extract with ethyl acetate twice (5mL) 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 <semantics>=2:1<annotation encoding="application / x-tex">= 2:1< / annotation>< / semantics>) to obtain the title compound (0.18g, 74%). ESI-QQQ-MS: m / z 290 [M+H]+. (Step 2) 2,6-dichloro-4-morpholinobenzoyl chloride (P-36) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve methyl 2,6-dichloro-4-morpholinobenzoate (0.18g, 0.62mmol) in methanol (3mL) and water (0.5mL), add 6N sodium hydroxide solution (0.16mL, 0.93mmol) and react at room temperature for 24h. 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 3mL of dichloromethane, add thionyl chloride (0.14g, 1.2mmol) and DMF (2 drops), and react at room temperature for 4h. 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 [Image disponible dans le document PDF, Image available in the PDF document] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24g, 0.85mmol), 2-oxa-5-azabicyclo[2.2.1]heptan (0.12g, 1.2mmol), palladium (II) acetate (10mg, 5mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63mg, 10mol%), cesium carbonate (0.3g, 0.92mmol) and anhydrous dioxane (6mL), displace nitrogen, and react in microwave at 120°C for 2h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10mL), extract with ethyl acetate twice (5mL 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 (0.2g, 78%). ESI-QQQ-MS: m / z 302 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 2) 4-(2-oxa-5-azadicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzoyl chloride (P-37) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve methyl 4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzoate (0.2g, 0.66mmol) in methanol (3mL) and water (0.5mL), add 6N sodium hydroxide solution (0.17mL, 0.99mmol) and react at room temperature for 24h. 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 3mL of dichloromethane, add thionyl chloride (0.15g, 1.3mmol) and DMF (2 drops), and react at room temperature for 4h. 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 [Image disponible dans le document PDF, Image available in the PDF document] Mix methyl 4-bromo-2,6-dichlorobenzoate (0.24g, 0.85mmol), 4-(piperidin-4-yl)morpholine (0.2g, 1.2mmol), palladium (II) acetate (10mg, 5mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63mg, 10mol%), cesium carbonate (0.3g, 0.92mmol) and anhydrous dioxane (6mL), displace nitrogen, and react in microwave reaction at 120°C for 2h. Filter the reaction solution with purified siliceous earths, concentrate the filtrate with vacuum, add water (10mL), extract with ethyl acetate twice (5mL 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 = <semantics>2:1<annotation encoding="application / x-tex">2:1< / annotation>< / semantics>) to obtain the title compound (<semantics>0.23g<annotation encoding="application / x-tex">0.23g< / annotation>< / semantics>, <semantics>72%<annotation encoding="application / x-tex">72\%< / annotation>< / semantics>). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 373 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 2) 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoyl chloride (P-38) [Image disponible dans le document PDF, Image available in the PDF document] Dissolve methyl 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoate (0.23g, 0.62mmol) in methanol (3mL) and water (0.5mL), add 6N sodium hydroxide solution (0.16mL, 0.93mmol) and react at room temperature for 24h. 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 3mL of dichloromethane, add thionyl chloride (0.14g, 1.2mmol) and DMF (2 drops), and react at room temperature for 4h. 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'-oxosiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)me thyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-10 (98mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (215mg, 70%). ESI-QQQ-MS: m / z 615 [M+H]+. (Step 2) (S)-2-amino-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)m ethyl propionate (154mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (86mg, 92%). ESI-QQQ-MS: m / z 373 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1' -phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (86mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (107mg, 88%). ESI-QQQ-MS: m / z 529 [M+H]+. (Step 4) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5',6'-difluoro-2'-oxospirino[cyclopropane-1,3'-indoline] -1'-yl)phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline ]-1'-phenyl)methyl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (57mg, 65%). ESI-QQQ-MS: m / z 515 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.90 (brs, 1H), 9.16 (d, J = 8.3 Hz, 1H), 7.50-7.42 <semantics>(m,3H),7.39−7.28(m,4H),7.24(t,J=8.6Hz,1H),6.74−6.70(m,1H),4.77−4.72(m,1H),3.25<annotation encoding="application / x-tex">(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< / annotation>< / semantics> <semantics>(dd,J=14.0,4.4Hz,1H),3.00(dd,J=13.9,10.5Hz,1H),1.79−1.77(m,2H),1.66−1.63(m,2H).<annotation encoding="application / x-tex">(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).< / annotation>< / semantics> 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-6 (97mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (178mg, 58%). ESI-QQQ-MS: m / z 613 [M+H]+. (Step 2) (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylmethylamin o)methyl propionate (153mg, 0.25mmol) in dichloromethane (2mL), add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (83mg, 90%). ESI-QQQ-MS: m / z 371 [M+H]+. (Step 3) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluoroben zamide) methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (85mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (112mg, 92%). ESI-QQQ-MS: m / z 527 [M+H]+. (Step 4) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluoroben zamide) propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluoroben zamide)methyl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (55mg, 63%). ESI-QQQ-MS: m / z 513 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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 <semantics>=14.1,4.3 Hz,1H<annotation encoding="application / x-tex">= 14.1, 4.3 \text{ Hz}, 1\text{H}< / annotation>< / semantics>), <semantics>3.01 (dd, J=14.1,10.3 Hz,1H)<annotation encoding="application / x-tex">3.01 \text{ (dd, J} = 14.1, 10.3 \text{ Hz}, 1\text{H})< / annotation>< / semantics>, <semantics>1.78−1.76 (m, 2H)<annotation encoding="application / x-tex">1.78-1.76 \text{ (m, 2H)}< / annotation>< / semantics>, <semantics>1.68−1.66 (m, 2H)<annotation encoding="application / x-tex">1.68-1.66 \text{ (m, 2H)}< / annotation>< / semantics>. Example 3: Synthesis of compound 4 (Step 1) (S)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)me thyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-9 (95mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol) to reaction system, under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL each time), combine the filtrate, concentrate with vacuum, and purify the concentrate by silica gel column chromatography (petroleum ether / ethyl acetate <semantics>=4:1<annotation encoding="application / x-tex">= 4:1< / annotation>< / semantics>) to obtain the title compound (188mg, 62%). ESI-QQQ-MS: m / z 609 [M+H]+. (Step 2) (S)-2-amino-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)me thyl propionate (152mg, 0.25mmol) in dichloromethane (2mL), add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (83mg, 91%). ESI-QQQ-MS: m / z 367 [M+H]+. (Step 3) (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ph enyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (83mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (109mg, 88%). ESI-QQQ-MS: m / z 539 [M+H]+. (Step 4) (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ph enyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ph enyl)methyl propionate (92mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2ml 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (52mg, 59%). ESI-QQQ-MS: m / z 525 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.74 (brs, 1H), 9.15 (d, J = 8.2 Hz, 1H), 7.46-7.32 <semantics>(m,5H),7.19(d,J=8.2Hz,2H),7.02(t,J=7.9Hz,1H),6.91(d,J=8.2Hz,1H),6.71(d,J=7.4Hz,1H),6.91(d,J=8.2Hz,1H),6.71(d,J=7.4Hz,1H),6.91(d,J=8.2Hz,1H),6.71(d,J=7.4Hz,1H),6.9<annotation encoding="application / x-tex">(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), 6.91 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.9< / annotation>< / semantics> Hz, 1H), <semantics>4.74−4.69<annotation encoding="application / x-tex">4.74-4.69< / annotation>< / semantics> (m, 1H), <semantics>3.46<annotation encoding="application / x-tex">3.46< / annotation>< / semantics> (s, 3H), <semantics>3.19<annotation encoding="application / x-tex">3.19< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>4.7<annotation encoding="application / x-tex">4.7< / annotation>< / semantics> Hz, 1H), <semantics>2.99<annotation encoding="application / x-tex">2.99< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>9.8<annotation encoding="application / x-tex">9.8< / annotation>< / semantics> 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)methy 1 propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-4 (89mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (202mg, 68%). ESI-QQQ-MS: m / z 597 [M+H]+. (Step 2) (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)methy 1 propionate (149mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (84mg, 95%). ESI-QQQ-MS: m / z 355 [M+H]+. (Step 3) (S)-2-(2,6-dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phen yl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve methyl (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate (84mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (108mg, 89%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 527 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 4) (S)-2-(2,6-dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phen yl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phen yl)methyl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2ml 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (48mg, 55%). ESI-QQQ-MS: m / z 513 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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 <semantics>(m,1H),3.25(dd,J=14.0,4.3Hz,1H),2.99(dd,J=13.9,10.7Hz,1H),1.75−1.71(m,2H),<annotation encoding="application / x-tex">(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),< / annotation>< / semantics> 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-3 (89mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (182mg, 61%). ESI-QQQ-MS: m / z 597 [M+H]+. (Step 2) (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)methy 1 propionate (149mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (85mg, 96%). ESI-QQQ-MS: m / z 355 [M+H]+. (Step 3) (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phen yl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (84mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (109mg, 90%). ESI-QQQ-MS: m / z 527 [M+H]+. (Step 4) (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)ph enyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phen yl)methyl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2ml 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (51mg, 58%). ESI-QQQ-MS: m / z 513 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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 <semantics>=14.1,4.3 Hz,1H<annotation encoding="application / x-tex">= 14.1, 4.3 \text{ Hz}, 1\text{H}< / annotation>< / semantics>), 2.99 (dd, <semantics>J=14.1,10.4 Hz,1H<annotation encoding="application / x-tex">J = 14.1, 10.4 \text{ Hz}, 1\text{H}< / annotation>< / semantics>), 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-2 (80mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (197mg, 68%). ESI-QQQ-MS: m / z 579 [M+H]+. (Step 2) (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)methyl propionate (145mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (79mg, 94%). ESI-QQQ-MS: m / z 337 [M+H]+. (Step 3) (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (77mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (111mg, 95%). ESI-QQQ-MS: m / z 509 [M+H]+. (Step 4) (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propio nic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (87mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54mg, 64%). ESI-QQQ-MS: m / z 495 [M+H]+. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.85 (brs, 1H), 9.14 (d, J = 8.4 Hz, 1H), 7.51-7.33 (m, 7H), 7.20-7.19 m, 1H), <semantics>7.13−7.03<annotation encoding="application / x-tex">7.13-7.03< / annotation>< / semantics> (m, 2H), <semantics>6.76<annotation encoding="application / x-tex">6.76< / annotation>< / semantics> (d, <semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics> Hz, 1H), <semantics>4.78−4.76<annotation encoding="application / x-tex">4.78-4.76< / annotation>< / semantics> (m, 1H), <semantics>3.25<annotation encoding="application / x-tex">3.25< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>4.4<annotation encoding="application / x-tex">4.4< / annotation>< / semantics> Hz, 1H), <semantics>3.00<annotation encoding="application / x-tex">3.00< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>10.5<annotation encoding="application / x-tex">10.5< / annotation>< / semantics> Hz, 1H), <semantics>1.73−1.69<annotation encoding="application / x-tex">1.73-1.69< / annotation>< / semantics> (m, 2H), <semantics>1.65−1.61<annotation encoding="application / x-tex">1.65-1.61< / annotation>< / semantics> (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-(triphenyla mino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-14 (119mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (180mg, 55%). ESI-QQQ-MS: m / z 657 [M+H]+. (Step 2) (S)-2-amino-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)methyl propionate (164mg, 0.25mmol) in dichloromethane (2mL), add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (98mg, 95%). ESI-QQQ-MS: m / z 415 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-phenyl)methyl propionate (95mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, and add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol), react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (118mg, 90%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 571 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (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 [Image disponible dans le document PDF, Image available in the PDF document] 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 (97mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54mg, 57%). ESI-QQQ-MS: m / z 557 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.87 (brs, 1H), 9.15 (d, J = 8.0 Hz, 1H), 7.55 (d, J = <semantics>7.4 Hz<annotation encoding="application / x-tex">7.4 \text{ Hz}< / annotation>< / semantics>, <semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>), <semantics>7.47−7.36<annotation encoding="application / x-tex">7.47-7.36< / annotation>< / semantics> (m, <semantics>3H<annotation encoding="application / x-tex">3\text{H}< / annotation>< / semantics>), <semantics>7.31−7.21<annotation encoding="application / x-tex">7.31-7.21< / annotation>< / semantics> (m, <semantics>5H<annotation encoding="application / x-tex">5\text{H}< / annotation>< / semantics>), <semantics>7.09<annotation encoding="application / x-tex">7.09< / annotation>< / semantics> (d, <semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics> Hz, <semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>), <semantics>4.70−4.65<annotation encoding="application / x-tex">4.70-4.65< / annotation>< / semantics> (m, <semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>), <semantics>4.06<annotation encoding="application / x-tex">4.06< / annotation>< / semantics> (t, <semantics>J=10.6<annotation encoding="application / x-tex">J = 10.6< / annotation>< / semantics> Hz, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>3.87−3.79<annotation encoding="application / x-tex">3.87-3.79< / annotation>< / semantics> (m, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>3.22<annotation encoding="application / x-tex">3.22< / annotation>< / semantics> (dd, <semantics>J=14.1<annotation encoding="application / x-tex">J = 14.1< / annotation>< / semantics>, <semantics>4.3<annotation encoding="application / x-tex">4.3< / annotation>< / semantics> Hz, <semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>), <semantics>3.01<annotation encoding="application / x-tex">3.01< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, 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-(triphenylam ino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-11 (112mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (211mg, 67%). ESI-QQQ-MS: m / z 631 [M+H]+. (Step 2) (S)-2-amino-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylam ino)methyl propionate (158mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (89mg, 92%). ESI-QQQ-MS: m / z 389 [M+H]+. (Step 3) (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-f luorobenzoylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (89mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (113mg, 90%). ESI-QQQ-MS: m / z 545 [M+H]+. (Step 4) (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-f luorobenzamide)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-f luorobenzamide)methyl propionate (93mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54mg, 60%). ESI-QQQ-MS: m / z 531 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.89 (brs, 1H), 9.13 (d, J = 8.3 Hz, 1H), 7.51-7.42 <semantics>(m,3H),7.38−7.34(m,3H),7.30(d,J=8.1Hz,1H),7.24(t,J=8.6Hz,1H),6.77(d,J=6.0Hz,1H)<annotation encoding="application / x-tex">(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)< / annotation>< / semantics> 1H), <semantics>4.77−4.73<annotation encoding="application / x-tex">4.77-4.73< / annotation>< / semantics> (m, 1H), <semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics> (d, <semantics>J=4.1<annotation encoding="application / x-tex">J = 4.1< / annotation>< / semantics> Hz, 1H), <semantics>2.99<annotation encoding="application / x-tex">2.99< / annotation>< / semantics> (dd, <semantics>J=13.8<annotation encoding="application / x-tex">J = 13.8< / annotation>< / semantics>, <semantics>10.8<annotation encoding="application / x-tex">10.8< / annotation>< / semantics> Hz, 1H), <semantics>1.86−1.81<annotation encoding="application / x-tex">1.86-1.81< / annotation>< / semantics> (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)methy 1 propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-5 (89mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (197mg, 66%). ESI-QQQ-MS: m / z 597 [M+H]+. (Step 2) (S)-2-amino-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)methy 1 propionate (149mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (84mg, 95%). ESI-QQQ-MS: m / z 355 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (84mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (107mg, 88%). ESI-QQQ-MS: m / z 511 [M+H]+. (Step 4) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)methyl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (50mg, 57%). ESI-QQQ-MS: m / z 497 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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 <semantics>=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).<annotation encoding="application / x-tex">= 14.0, 4.5 \text{ Hz}, 1\text{H}), 3.00 \text{ (dd, J} = 14.0, 10.4 \text{ Hz}, 1\text{H}), 1.80-1.76 \text{ (m, 2H)}, 1.68-1.64 \text{ (m, 2H)}.< / annotation>< / semantics> 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-13 (97mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (154mg, 50%). ESI-QQQ-MS: m / z 615 [M+H]+. (Step 2) (S)-2-amino-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(3,3-dimethyl-2-oxoindoline-1-yl)phenyl)-2-(triphenylamino)methyl propionate (154mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (89mg, 95%). ESI-QQQ-MS: m / z 373 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)meth yl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(3,3-dimethyl-2-oxoindoline-1-yl)phenyl)methyl propionate (86mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (114mg, 94%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 529 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 4) (S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamide)propi onic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindoline-1-yl)phenyl)meth yl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (49mg, 54%). ESI-QQQ-MS: m / z 515 [M+H]+. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.81 (brs, 1H), 9.18 (d, J = 8.1 Hz, 1H), 7.47-7.39 (m, 4H), 7.34-7.23 (m, 4H), <semantics>7.21−7.19<annotation encoding="application / x-tex">7.21-7.19< / annotation>< / semantics> (m, 1H), <semantics>7.11−7.04<annotation encoding="application / x-tex">7.11-7.04< / annotation>< / semantics> (m, 1H), <semantics>4.70−4.68<annotation encoding="application / x-tex">4.70-4.68< / annotation>< / semantics> (m, 1H), <semantics>3.22<annotation encoding="application / x-tex">3.22< / annotation>< / semantics> (dd, <semantics>J=14.1<annotation encoding="application / x-tex">J = 14.1< / annotation>< / semantics>, <semantics>4.3<annotation encoding="application / x-tex">4.3< / annotation>< / semantics> Hz, 1H), <semantics>3.00 (dd, J=14.1,10.3 Hz, 1H),1.40 (s, 6H).<annotation encoding="application / x-tex">3.00 \text{ (dd, J} = 14.1, 10.3 \text{ Hz, 1H)}, 1.40 \text{ (s, 6H)}.< / annotation>< / semantics> 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-(tr iphenylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-16 (110mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (160mg, 50%). ESI-QQQ-MS: m / z 640 [M+H]+. (Step 2) (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro [cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6'-dimethylamino-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(trip henylamino)methyl propionate (160mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (94mg, 95%). ESI-QQQ-MS: m / z 398 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phe nyl)methyl propionate (91mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (114mg, 90%). ESI-QQQ-MS: m / z 554 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indoline]-1'-yl)phenyl)methyl propionate (94mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (38mg, 42%). ESI-QQQ-MS: m / z 540 [M+H]+. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.97 (brs, 1H), 9.13 (d, J = 8.2 Hz, 1H), 7.51-7.18 (m, 7H), 7.01 (d, <semantics>J=12.2<annotation encoding="application / x-tex">J = 12.2< / annotation>< / semantics> Hz, 1H), 6.37 (d, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), 4.82-4.68 (m, 1H), <semantics>3.25<annotation encoding="application / x-tex">3.25< / annotation>< / semantics> (d, <semantics>J=3.9<annotation encoding="application / x-tex">J = 3.9< / annotation>< / semantics> Hz, 1H), <semantics>2.99<annotation encoding="application / x-tex">2.99< / annotation>< / semantics> (dd, <semantics>J=13.8<annotation encoding="application / x-tex">J = 13.8< / annotation>< / semantics>, <semantics>10.9<annotation encoding="application / x-tex">10.9< / annotation>< / semantics> Hz, 1H), <semantics>2.66<annotation encoding="application / x-tex">2.66< / annotation>< / semantics> (s, <semantics>6<annotation encoding="application / x-tex">6< / annotation>< / semantics>H), <semantics>1.68−1.64<annotation encoding="application / x-tex">1.68-1.64< / annotation>< / semantics> (m, <semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>H), 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-(triphenyla mino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-15 (101mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (162mg, 52%). ESI-QQQ-MS: m / z 622 [M+H]+. (Step 2) (S)-2-amino-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methy 1 propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenyla mino)methyl propionate (155mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (89mg, 94%). ESI-QQQ-MS: m / z 380 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indol ine]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methy 1 propionate (87mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (114mg, 90%). ESI-QQQ-MS: m / z 536 [M+H]+. (Step 4) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indol ine]-1'-yl)phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indol ine]-1'-yl)phenyl)methyl propionate (94mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (34mg, 38%). ESI-QQQ-MS: m / z 522 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.86 (d, J = 6.7 Hz, 1H), 7.43 (t, J = 8.0 Hz, 3H), <semantics>7.34−7.28<annotation encoding="application / x-tex">7.34-7.28< / annotation>< / semantics> (m, 3H), <semantics>7.26−7.23<annotation encoding="application / x-tex">7.26-7.23< / annotation>< / semantics> (m, 1H), <semantics>6.68<annotation encoding="application / x-tex">6.68< / annotation>< / semantics> (d, <semantics>J=8.5<annotation encoding="application / x-tex">J = 8.5< / annotation>< / semantics> Hz, 1H), <semantics>6.60−6.54<annotation encoding="application / x-tex">6.60-6.54< / annotation>< / semantics> (m, 2H), <semantics>4.64−4.60<annotation encoding="application / x-tex">4.64-4.60< / annotation>< / semantics> (m, 1H), <semantics>3.24<annotation encoding="application / x-tex">3.24< / annotation>< / semantics> (dd, <semantics>J=13.7<annotation encoding="application / x-tex">J = 13.7< / annotation>< / semantics>, <semantics>3.8<annotation encoding="application / x-tex">3.8< / annotation>< / semantics> Hz, 1H), <semantics>3.01<annotation encoding="application / x-tex">3.01< / annotation>< / semantics> (dd, <semantics>J=13.4<annotation encoding="application / x-tex">J = 13.4< / annotation>< / semantics>, <semantics>9.6<annotation encoding="application / x-tex">9.6< / annotation>< / semantics> Hz, 1H), <semantics>2.83<annotation encoding="application / x-tex">2.83< / annotation>< / semantics> (s, 6H), <semantics>1.70−1.64<annotation encoding="application / x-tex">1.70-1.64< / annotation>< / semantics> (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-4 (89mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (210mg, 70%). ESI-QQQ-MS: m / z 597 [M+H]+. (Step 2) (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)methy 1 propionate (149mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (81mg, 92%). ESI-QQQ-MS: m / z 355 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (81mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (105mg, 90%). ESI-QQQ-MS: m / z 511 [M+H]+. (Step 4) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Ξ Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)methyl propionate (87mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2ml 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (51mg, 60%). ESI-QQQ-MS: m / z 497 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.89 (s, 1H), 9.15 (d, J = 8.3 Hz, 1H), 7.51-7.42 (m, 3H), <semantics>7.38<annotation encoding="application / x-tex">7.38< / annotation>< / semantics> (d, <semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics> Hz, 2H), <semantics>7.30<annotation encoding="application / x-tex">7.30< / annotation>< / semantics> (d, <semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics> Hz, 1H), <semantics>7.24<annotation encoding="application / x-tex">7.24< / annotation>< / semantics> (t, <semantics>J=8.6<annotation encoding="application / x-tex">J = 8.6< / annotation>< / semantics> Hz, 1H), <semantics>7.16−7.12<annotation encoding="application / x-tex">7.16-7.12< / annotation>< / semantics> (m, 1H), <semantics>6.92−6.84<annotation encoding="application / x-tex">6.92-6.84< / annotation>< / semantics> (m, 1H), <semantics>6.53<annotation encoding="application / x-tex">6.53< / annotation>< / semantics> (dd, <semantics>J=9.4<annotation encoding="application / x-tex">J = 9.4< / annotation>< / semantics>, <semantics>2.3<annotation encoding="application / x-tex">2.3< / annotation>< / semantics> Hz, 1H), <semantics>4.77−4.73<annotation encoding="application / x-tex">4.77-4.73< / annotation>< / semantics> (m, 1H), <semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>4.4<annotation encoding="application / x-tex">4.4< / annotation>< / semantics> Hz, 1H), <semantics>3.00 (dd, J=13.9,10.5 Hz,1H),1.75−1.71 (m, 2H),1.64−1.60 (m, 2H).<annotation encoding="application / x-tex">3.00 \text{ (dd, J} = 13.9, 10.5 \text{ Hz}, 1\text{H}), 1.75-1.71 \text{ (m, 2H)}, 1.64-1.60 \text{ (m, 2H)}.< / annotation>< / semantics> 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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-3 (89mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (216mg, 72%). ESI-QQQ-MS: m / z 597 [M+H]+. (Step 2) methyl (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)methy 1 propionate (149mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (82mg, 91%). ESI-QQQ-MS: m / z 355 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (81mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (102mg, 87%). ESI-QQQ-MS: m / z 511 [M+H]+. (Step 4) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl) phenyl)methyl propionate (87mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (53mg, 62%). ESI-QQQ-MS: m / z 497 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.85 (s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 7.48-7.21 (m, 7H), <semantics>7.09−7.05<annotation encoding="application / x-tex">7.09-7.05< / annotation>< / semantics> (m, 2H), <semantics>6.98−6.94<annotation encoding="application / x-tex">6.98-6.94< / annotation>< / semantics> (m, 1H), <semantics>4.72−4.68<annotation encoding="application / x-tex">4.72-4.68< / annotation>< / semantics> (m, 1H), <semantics>3.22<annotation encoding="application / x-tex">3.22< / annotation>< / semantics> (dd, <semantics>J=14.1<annotation encoding="application / x-tex">J = 14.1< / annotation>< / semantics>, <semantics>4.4<annotation encoding="application / x-tex">4.4< / annotation>< / semantics> Hz, 1H), <semantics>3.00 (dd, J=14.1,10.3 Hz,1H),1.78−1.74 (m, 2H),1.69−1.65 (m, 2H).<annotation encoding="application / x-tex">3.00 \text{ (dd, J} = 14.1, 10.3 \text{ Hz}, 1\text{H}), 1.78-1.74 \text{ (m, 2H)}, 1.69-1.65 \text{ (m, 2H)}.< / annotation>< / semantics> 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)m ethyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-12 (98mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (206mg, 67%). ESI-QQQ-MS: m / z 615 [M+H]+. (Step 2) (S)-2-amino-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylamino)m ethyl propionate (154mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (87mg, 94%). ESI-QQQ-MS: m / z 373 [M+H]+. (Step 3) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1' -yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (86mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (107mg, 88%). ESI-QQQ-MS: m / z 529 [M+H]+. (Step 4) (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6',7'-difluoro-2'-oxospirino[cyclopropane-1,3'-indoline] -1'-yl)phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1' -yl)phenyl))methyl propionate (90mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (49mg, 56%). ESI-QQQ-MS: m / z 515 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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, 1H), 6.97-6.94 (m, 1H), 4.73-4.68 (m, 1H), 3.23 (dd, J <semantics>=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).<annotation encoding="application / x-tex">= 14.1, 4.4 \text{ Hz}, 1\text{H}), 3.01 \text{ (dd, J} = 14.1, 10.3 \text{ Hz}, 1\text{H}), 1.78-1.74 \text{ (m, 2H)}, 1.68-1.64 \text{ (m, 2H)}.< / annotation>< / semantics> Example 16: Synthesis of compound 19 (Step 1) (S)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)-2-(triphenylam ino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-17 (80mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (145mg, 50%). ESI-QQQ-MS: m / z 580 [M+H]+. (Step 2) (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)methy 1 propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)-2-(triphenylam ino)methyl propionate (145mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (78mg, 92%). ESI-QQQ-MS: m / z 338 [M+H]+. (Step 3) (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H )-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)methy 1 propionate (78mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (100mg, 85%). ESI-QQQ-MS: m / z 510 [M+H]+. (Step 4) (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H )-yl)phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H )-yl)phenyl)methyl propionate (87mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (33mg, 40%). ESI-QQQ-MS: m / z 496 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 8.80 (s, 1H), 8.07 (d, J = 4.4 Hz, 1H), 7.51 (d, J = 7.0) Hz, 1H), <semantics>7.42−7.30<annotation encoding="application / x-tex">7.42-7.30< / annotation>< / semantics> (m, 8H), <semantics>7.11−7.01<annotation encoding="application / x-tex">7.11-7.01< / annotation>< / semantics> (m, 1H), <semantics>4.68−4.62<annotation encoding="application / x-tex">4.68-4.62< / annotation>< / semantics> (m, 1H), <semantics>3.24<annotation encoding="application / x-tex">3.24< / annotation>< / semantics> (d, <semantics>J=4.1<annotation encoding="application / x-tex">J = 4.1< / annotation>< / semantics> Hz, 1H), <semantics>3.03<annotation encoding="application / x-tex">3.03< / annotation>< / semantics> <semantics>(dd,J=13.3,9.1Hz,1H),1.82−1.78(m,2H),1.72−1.66(m,2H).<annotation encoding="application / x-tex">(dd, J = 13.3, 9.1 Hz, 1H), 1.82-1.78 (m, 2H), 1.72-1.66 (m, 2H).< / annotation>< / semantics> 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-trichlorobenzoy lamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (85mg, 0.23mmol, the preparation process is detailed in Example 2) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add the intermediate P-34 (61mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (125mg, 94%). ESI-QQQ-MS: m / z 577 [M+H]+. (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,4,6-trichlorobenzoy lamino)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,4,6-trichlorobenzoy lamino)methyl propionate (98mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54mg, 56%). ESI-QQQ-MS: m / z 562 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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-(dieth ylamino)benzoylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (85mg, 0.23mmol, the preparation process is detailed in Example 2) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add the intermediate P-35 (70mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (125mg, 94%). ESI-QQQ-MS: m / z 614 [M+H]+. (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(dieth ylamino)benzoylamino)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(dieth ylamino)benzoylamino)methyl propionate (102mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54mg, 56%). ESI-QQQ-MS: m / z 600 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^{+}< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.67 (brs, 1H), 8.79 (d, J = 7.7 Hz, 1H), 7.40 (d, J = <semantics>8.4 Hz,2H<annotation encoding="application / x-tex">8.4 \text{ Hz}, 2H< / annotation>< / semantics>), <semantics>7.26 (d, J=7.3 Hz,2H<annotation encoding="application / x-tex">7.26 \text{ (d, J} = 7.3 \text{ Hz}, 2H< / annotation>< / semantics>), <semantics>7.20−7.15 (m, 1H)<annotation encoding="application / x-tex">7.20-7.15 \text{ (m, 1H)}< / annotation>< / semantics>, <semantics>7.09−7.01 (m, 2H)<annotation encoding="application / x-tex">7.09-7.01 \text{ (m, 2H)}< / annotation>< / semantics>, <semantics>6.57 (s, 2H)<annotation encoding="application / x-tex">6.57 \text{ (s, 2H)}< / annotation>< / semantics>, <semantics>4.64−4.60<annotation encoding="application / x-tex">4.64-4.60< / annotation>< / semantics> (m, 1H), <semantics>3.33−3.20<annotation encoding="application / x-tex">3.33-3.20< / annotation>< / semantics> (m, 4H), <semantics>3.17<annotation encoding="application / x-tex">3.17< / annotation>< / semantics> (dd, <semantics>J=14.1<annotation encoding="application / x-tex">J = 14.1< / annotation>< / semantics>, <semantics>4.2<annotation encoding="application / x-tex">4.2< / annotation>< / semantics> Hz, 1H), <semantics>3.00<annotation encoding="application / x-tex">3.00< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>10.1<annotation encoding="application / x-tex">10.1< / annotation>< / semantics> Hz, 1H), <semantics>1.78−1.74<annotation encoding="application / x-tex">1.78-1.74< / annotation>< / semantics> (m, 2H), <semantics>1.68−1.64<annotation encoding="application / x-tex">1.68-1.64< / annotation>< / semantics> (m, 2H), <semantics>1.05<annotation encoding="application / x-tex">1.05< / annotation>< / semantics> (t, <semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics> 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-morph olinoylbenzoylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (85mg, 0.23mmol, the preparation process is detailed in Example 2) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add the intermediate P-36 (74mg, 0.25mmol) dropwise to the reaction system, and the react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (123mg, 85%). ESI-QQQ-MS: m / z 628 [M+H]+. (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-morph olinobenzoylamino)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-morph olinobenzoylamino)methyl propionate (107mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54mg, 52%). ESI-QQQ-MS: m / z 614 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 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), <semantics>3.04<annotation encoding="application / x-tex">3.04< / annotation>< / semantics> (dd, <semantics>J=13.4<annotation encoding="application / x-tex">J = 13.4< / annotation>< / semantics>, <semantics>9.1<annotation encoding="application / x-tex">9.1< / annotation>< / semantics> Hz, <semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>), <semantics>1.78−1.74<annotation encoding="application / x-tex">1.78-1.74< / annotation>< / semantics> (m, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>1.68−1.64<annotation encoding="application / x-tex">1.68-1.64< / annotation>< / semantics> (m, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>). 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'-oxos piro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl) methyl propionate (85mg, 0.23mmol, the preparation process is detailed in Example 2) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add the intermediate P-37 hept-5-yl (77mg, 0.25mmol) dropwise to the reaction system, and the react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (109mg, 74%). ESI-QQQ-MS: m / z 640 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. (Step 2) (2S)-2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzamido)-3-(4-(7'-chloro-2'-oxos piro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (2S)-methyl 2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzamido)-3-(4-(7'-chloro-2'-oxospiro[c yclopropane-1,3'-indoline]-1'-yl)phenyl)methyl propionate (109mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol), and react at room temperature reaction for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (52mg, 49%). ESI-QQQ-MS: m / z 626 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 12.76 (brs, 1H), 8.81 (d, J = <semantics>5.9 Hz<annotation encoding="application / x-tex">5.9 \text{ Hz}< / annotation>< / semantics>, <semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>), <semantics>7.40 (d, J=8.0 Hz<annotation encoding="application / x-tex">7.40 \text{ (d, J} = 8.0 \text{ Hz}< / annotation>< / semantics>, <semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>), <semantics>7.27−7.17 (m, 3H)<annotation encoding="application / x-tex">7.27-7.17 \text{ (m, 3H)}< / annotation>< / semantics>, <semantics>7.11−7.01 (m, 2H)<annotation encoding="application / x-tex">7.11-7.01 \text{ (m, 2H)}< / annotation>< / semantics>, <semantics>6.63 (s, 2H)<annotation encoding="application / x-tex">6.63 \text{ (s, 2H)}< / annotation>< / semantics>, <semantics>4.67 (s, 2H)<annotation encoding="application / x-tex">4.67 \text{ (s, 2H)}< / annotation>< / semantics> 1H), <semantics>4.62<annotation encoding="application / x-tex">4.62< / annotation>< / semantics> (s, 2H), <semantics>3.73<annotation encoding="application / x-tex">3.73< / annotation>< / semantics> (d, <semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics> Hz, 1H), <semantics>3.58<annotation encoding="application / x-tex">3.58< / annotation>< / semantics> (d, <semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics> Hz, 1H), <semantics>3.45<annotation encoding="application / x-tex">3.45< / annotation>< / semantics> (d, <semantics>J=9.4<annotation encoding="application / x-tex">J = 9.4< / annotation>< / semantics> 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-mo rpholinopiperidin-1-yl)benzoylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl) methyl propionate (85mg, 0.23mmol, the preparation process is detailed in Example 2) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add the intermediate P-38 (94mg, 0.25mmol) dropwise to the reaction system, and the react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (129mg, 79%). ESI-QQQ-MS: m / z 711 [M+H]+. (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(4-mo rpholinopiperidin-1-yl)benzoylamino)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(4-mo rpholinopiperidin-1-yl)benzoylamino)methyl propionate (121mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (59mg, 50%). ESI-QQQ-MS: m / z 696 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 12.75 (brs, 1H), 8.87 <semantics>(d,J=7.7Hz,1H),7.40(d,J=8.4Hz,2H),7.27−7.25(m,2H),7.20−7.16(m,1H),7.09−7.02(m,2H),7.20−7.16(m,2H),7.09−7.02(m,2H),7.20−7.16(m,2H),7.09−7.02(m,2H),7.20−7.16(m,2H),7.09−7.02(m,2H),7.<annotation encoding="application / x-tex">(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), 7.20-7.16 (m, 2H), 7.09-7.02 (m, 2H), 7.20-7.16 (m, 2H), 7.09-7.02 (m, 2H), 7.20-7.16 (m, 2H), 7.09-7.02 (m, 2H), 7.< / annotation>< / semantics> 2H), <semantics>6.90<annotation encoding="application / x-tex">6.90< / annotation>< / semantics> (s, 2H), <semantics>4.65−4.61<annotation encoding="application / x-tex">4.65-4.61< / annotation>< / semantics> (m, 1H), <semantics>3.82<annotation encoding="application / x-tex">3.82< / annotation>< / semantics> (d, <semantics>J=12.9<annotation encoding="application / x-tex">J = 12.9< / annotation>< / semantics> Hz, 2H), <semantics>3.55<annotation encoding="application / x-tex">3.55< / annotation>< / semantics> (s, 4H), <semantics>3.17<annotation encoding="application / x-tex">3.17< / annotation>< / semantics> (dd, <semantics>J=14.1<annotation encoding="application / x-tex">J = 14.1< / annotation>< / semantics>, 4.3 Hz, 1H), <semantics>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, J)<annotation encoding="application / x-tex">3.00 \text{ (dd, J} = 14.0, 10.2 \text{ Hz}, 1\text{H}), 2.76 \text{ (t, J} = 11.9 \text{ Hz}, 2\text{H}), 2.45 \text{ (s, 4H)}, 2.37-2.29 \text{ (m, J)}< / annotation>< / semantics> 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-(triphenylme thylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-18 (91mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (180mg, 60%). ESI-QQQ-MS: m / z 602 [M+H]+. (step 2) (S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)methy 1 propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylam ino)methyl propionate (150mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (85mg, 95%). ESI-QQQ-MS: m / z 360 [M+H]+. (Step 3) <semantics>(S)−3−(4−(7−chloro−3−methyl−2−oxo−2,3−dihydro−1H−benzo[d]imidazol−1−yl)phenyl)−2−(2−chloro−6−finaldistributionofthecontextofthecontextofthecontextofthecontextofthecontextofthecontextofthecontextof<annotation encoding="application / x-tex">(S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-final distribution of the context of the context of the context of the context of the context of the context of the context of< / annotation>< / semantics> luorobenzamide)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (86mg, 0.24mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2-chloro-6-fluorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (105mg, 85%). ESI-QQQ-MS: m / z 516 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] 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 (88mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.4mL, 0.2mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (60mg, 70%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 502 [M+H]+. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.86 (brs, 1H), 9.19 (d, J = 8.1 Hz, 1H), <semantics>7.48−7.38<annotation encoding="application / x-tex">7.48-7.38< / annotation>< / semantics> (m, 3H), <semantics>7.33−7.22<annotation encoding="application / x-tex">7.33-7.22< / annotation>< / semantics> (m, 5H), <semantics>7.12<annotation encoding="application / x-tex">7.12< / annotation>< / semantics> (t, <semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics> Hz, 1H), <semantics>7.03<annotation encoding="application / x-tex">7.03< / annotation>< / semantics> (d, <semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics> Hz, 1H), <semantics>4.73−4.68<annotation encoding="application / x-tex">4.73-4.68< / annotation>< / semantics> <semantics>(m,1H),3.39(s,3H),3.23(dd,J=14.1,4.1Hz,1H),3.02(dd,J=13.9,10.5Hz,1H).<annotation encoding="application / x-tex">(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).< / annotation>< / semantics> 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-(triphen ylmethylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-19 (104mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol) to reaction system, under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (198mg, 63%). ESI-QQQ-MS: m / z 628 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphen ylamino)methyl propionate (157mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (88mg, 91%). ESI-QQQ-MS: m / z 386 [M+H]+. (Step 3) (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (88mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2,6-dichlorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the water layer twice with dichloromethane (2mL 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 (112mg, 87%). ESI-QQQ-MS: m / z 558 [M+H]+. (Step 4) <semantics>(S)−3−(4−(5−chloro−3−cyclopropyl−2−oxo−2,3−dihydro−1H−benzo[d]imidazol−1−yl)phenyl)−2−(2,6−dical−1−yl)phenyl)<annotation encoding="application / x-tex">(S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dical-1-yl)phenyl)< / annotation>< / semantics> hlorobenzamido)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)methyl propionate (95mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.6mL, 0.29mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (57mg, 62%). ESI-QQQ-MS: <semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics> 544 [M+H]+. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.76 (brs, 1H), 9.13 (d, J = 8.4 Hz, 1H), <semantics>7.51−7.31<annotation encoding="application / x-tex">7.51-7.31< / annotation>< / semantics> (m, 8H), <semantics>7.12−7.10<annotation encoding="application / x-tex">7.12-7.10< / annotation>< / semantics> (m, 1H), <semantics>6.90<annotation encoding="application / x-tex">6.90< / annotation>< / semantics> (d, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 1H), <semantics>4.79−4.74<annotation encoding="application / x-tex">4.79-4.74< / annotation>< / semantics> (m, 1H), <semantics>3.24<annotation encoding="application / x-tex">3.24< / annotation>< / semantics> (dd, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 1H), <semantics>4.79−4.74<annotation encoding="application / x-tex">4.79-4.74< / annotation>< / semantics> (m, 1H), <semantics>3.24<annotation encoding="application / x-tex">3.24< / annotation>< / semantics> (dd, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz, 1H), <semantics>4.79−4.74<annotation encoding="application / x-tex">4.79-4.74< / annotation>< / semantics> (m, 1H), <semantics>3.24<annotation encoding="application / x-tex">3.24< / annotation>< / semantics> (dd, <semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics> Hz 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-(triphen ylmethylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-20 (104mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (182mg, 58%). ESI-QQQ-MS: m / z 628 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphen ylmethylamino)methyl propionate (157mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (91mg, 94%). ESI-QQQ-MS: m / z 386 [M+H]+. (Step 3) (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (89mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2,6-dichlorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (118mg, 92%). ESI-QQQ-MS: m / z 558 [M+H]+. (Step 4) (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)methyl propionate (95mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.6mL, 0.29mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (56mg, 61%). ESI-QQQ-MS: m / z 544 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics> 12.85 (brs, 1H), 9.12 (d, J = 8.4 Hz, 1H), 7.50-7.48 <semantics>(m,2H),7.45−7.38(m,5H),7.30(d,J=8.3Hz,1H),7.20−7.18(m,1H),6.87(d,J=1.8Hz,1H),<annotation encoding="application / x-tex">(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),< / annotation>< / semantics> <semantics>4.80−4.75<annotation encoding="application / x-tex">4.80-4.75< / annotation>< / semantics> (m, 1H), <semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics> (dd, <semantics>J=14.0<annotation encoding="application / x-tex">J = 14.0< / annotation>< / semantics>, <semantics>4.4<annotation encoding="application / x-tex">4.4< / annotation>< / semantics> Hz, 1H), <semantics>3.01−2.95<annotation encoding="application / x-tex">3.01-2.95< / annotation>< / semantics> (m, 2H), <semantics>1.09−1.05<annotation encoding="application / x-tex">1.09-1.05< / annotation>< / semantics> (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-(triphen ylmethylamino)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve P-21 (104mg, 0.5mmol) and P-1 (274mg, 0.5mmol) in anhydrous acetonitrile (3mL), then add N,N-dimethylglycine hydrochloride (52mg, 0.375mmol), cesium carbonate (489mg, 1.5mmol) and cuprous iodide (24mg, 0.125mmol), under nitrogen protection, heat to 100°C, and react for 36h. Cool, filter with purified siliceous earth, wash the filter cake twice with acetonitrile (1mL 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 (157mg, 50%). ESI-QQQ-MS: m / z 628 [M+H]+. (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 [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphen ylamino)methyl propionate (157mg, 0.25mmol) in dichloromethane (2mL), then add trifluoroacetic acid (228mg, 2mmol) to the reaction system, and react at room temperature for 1h. Concentrate with vacuum, add dichloromethane (3mL) 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 (92mg, 95%). ESI-QQQ-MS: m / z 386 [M+H]+. (Step 3) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)methyl propionate [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-2-amino-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl) methyl propionate (89mg, 0.23mmol) and triethylamine (30mg, 0.3mmol) in dichloromethane (2mL), cool to 0°C, add 2,6-dichlorobenzoyl chloride (48mg, 0.25mmol) dropwise to the reaction system, react at room temperature for 1h. Add water (5mL) to the reaction system, stand for layering, extract the aqueous layer twice with dichloromethane (2mL 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 (115mg, 90%). ESI-QQQ-MS: m / z 558 [M+H]+. (Step 4) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)propionic acid [Image disponible dans le document PDF, Image available in the PDF document] Dissolve (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dic hlorobenzamido)methyl propionate (95mg, 0.17mmol) in tetrahydrofuran (2mL), then add 0.5mol / L sodium hydroxide solution (0.6mL, 0.29mmol) to the reaction system, and react at room temperature for 2h. Adjust the pH of the reaction system to 1-2 with 2mol / L dilute hydrochloric acid, extract three times with dichloromethane (2mL 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 (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (49mg, 53%). ESI-QQQ-MS: m / z 544 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>. 1H NMR (500 MHz, DMSO-d6): <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>...

Claims

<pat:ClaimStatement>THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound as shown in general formula (1) or a pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof, [Image disponible dans le document PDF, Image available in the PDF document] (1) where, R3 is hydrogen, or methyl; each R4 is independently hydrogen; each <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is independently fluorine, chlorine, or bromine; X2 is hydrogen, halogen, di (C1-6 alkyl) amino, or 3-7 membered heterocycloalkyl, and the 3-7 membered heterocycloalkyl is unsubstituted or substituted by at least one 3-7 membered heterocycloalkyl; each X3 is independently hydrogen; A is a group as shown in general formula (2-1), (2-2), or (2-3), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1)<annotation encoding="application / x-tex">(2-1)< / annotation>< / semantics> <semantics>(2−2)<annotation encoding="application / x-tex">(2-2)< / annotation>< / semantics> <semantics>(2−3)<annotation encoding="application / x-tex">(2-3)< / annotation>< / semantics> the ring H is a <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkylene or a 3-7 membered heterocycloalkylene; Y is either O or S; each Z is independently CR1 or N; if it is present, each <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is independently hydrogen, halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino; if it is present, each <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is independently <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> cycloalkyl, 3-7 membered heterocycloalkyl, and the 3-7 membered heterocycloalkyl is optionally substituted by at least one <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl; the heterocycloalkyl comprises one or more segments independently selected from -O- and -NR-, wherein R represents hydrogen atom, alkyl or cycloalkyl; the heterocycloalkylene comprises one or more segments independently selected from -O- and -NR-, wherein R represents hydrogen atom, alkyl or cycloalkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to claim 1, where, R3 is hydrogen. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to claim 1 or 2, where, each <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is independently fluorine or chlorine. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1-3, where, [Image disponible dans le document PDF, Image available in the PDF document] X2 is hydrogen, chlorine, diethylamino, < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1 to 4, where, A is a group as shown in the general formula (2-1-1) or (2-1-1'), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−1−1)<annotation encoding="application / x-tex">(2-1-1)< / annotation>< / semantics> <semantics>(2−1−1′)<annotation encoding="application / x-tex">(2-1-1')< / annotation>< / semantics> the ring H is a C3-6 cycloalkylene or a 3-7 membered heterocycoalkylene; Y is O or S; when A is a group as shown in general formula (2-1-1), two of the four R1 are independently halogen, C1-6 alkoxy, or di (C1-6 alkyl) amino, and the rest are hydrogen; alternatively, one of the four R1 is halogen, C1-6 alkoxy, or di (C1-6 alkyl) amino, and the rest are hydrogen; alternatively, all four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are hydrogen; when A is a group as shown in general formula (2-1-1'), all three <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are hydrogen. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1 to 4, where, A is a group as shown in general formula (2-2-1), [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(2−2−1)<annotation encoding="application / x-tex">(2-2-1)< / annotation>< / semantics> Y is O or S; two of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> are independently halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, or di (<semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; alternatively, one of the four <semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics> is halogen, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkoxy, or di <semantics>(C1−6<annotation encoding="application / x-tex">(C_{1-6}< / annotation>< / semantics> alkyl) amino, and the rest are hydrogen; R2 is C1-6 alkyl, C3-6 cycloalkyl, or 3-7-membered heterocycloalkyl, and the 3-7-membered heterocycloalkyl is optionally substituted by one C1-6 alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1 to 4, where, A is a group as shown in general formula (2-3-1), [Image disponible dans le document PDF, Image available in the PDF document] (2-3-1) Y is O or S; one of the four R1 is halogen, C1-6 alkoxy, or di (C1-6 alkyl) amino, and the rest are hydrogen; each <semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics> is independently <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. A compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] <semantics>a¯<annotation encoding="application / x-tex">\overline{\phantom{a}}< / annotation>< / semantics> < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1-8 and at least one pharmaceutically acceptable excipient. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. Use of the compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, in the manufacture of a medicament for prevention and / or treatment of a disease and / or symptom at least partially mediated by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin, the disease and / or symptom at least partially mediated by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin is selected from the group consisting of autoimmune disease, inflammatory disease, and tumor cell proliferation and metastasis. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. The compound or the pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, for use in the prevention and / or treatment of a disease and / or symptom at least partially mediated by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin, the disease and / or symptom at least partially mediated by α4β7 integrin is selected from the group consisting of autoimmune disease, inflammatory disease, and tumor cell proliferation and metastasis. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. Use of the compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt, solvate, optical isomer, or tautomer thereof, or the pharmaceutical composition according to claim 9, for preventing or treating <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin mediated diseases and / or symptoms, the disease and / or symptom mediated by <semantics>α4β7<annotation encoding="application / x-tex">\alpha 4\beta 7< / annotation>< / semantics> integrin is selected from the group consisting of autoimmune disease, inflammatory disease, and tumor cell proliferation and metastasis. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>