N-(benzoyl)-phenylalanine compounds, pharmaceutical compositions comprising the same, and uses thereof

Abstract

The application belongs to the field of medicinal chemistry, and relates to N-(benzoyl)-phenylalanine compounds as alpha4beta7 integrin antagonists, pharmaceutical compositions containing the same and uses thereof. Specifically, the application relates to a compound as shown in general formula (1), which exhibits good alpha4beta7 integrin binding inhibition activity, can be used as an efficient alpha4beta7 integrin antagonist, and is used for preventing and / or treating autoimmune diseases and inflammatory diseases related to alpha4beta7 integrin and the like.

Description

[0001] Cross-references to related applications

[0002] This invention claims priority to Chinese Patent Application No. 202110075764.7, filed on January 20, 2021, entitled “N-(benzoyl)-phenylalanine compounds, pharmaceutical compositions comprising the same, and uses thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry and relates to N-(benzoyl)-phenylalanine compounds as α4β7 integrin antagonists, pharmaceutical compositions containing such compounds as pharmaceutical active ingredients, and their use for the prevention and / or treatment of diseases related to α4β7 integrin (such as autoimmune diseases and inflammatory diseases). Background Technology

[0004] Integrins, also known as integrins, belong to the integral protein family. They are a class of proteins that are ubiquitous on the surface of vertebrate cells and depend on calcium. 2+ or Mg 2+ These are heterodimeric cell surface proteins that mediate cell-cell and extracellular matrix recognition and adhesion, thus linking external cell functions with internal cell structures.

[0005] Integrins are transmembrane heterodimers composed of two non-covalently linked transmembrane subunits (α and β subunits). The extracellular head binds to extracellular matrix proteins, while the intracellular tail is attached to actin. Both integrin subunits are glycosylated and linked together non-covalently.

[0006] Currently, there are 18 known α subunits and 8 known β subunits. Among them, α4β7 integrin is expressed on the surface of lymphocytes and recognizes an extracellular ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed in intestinal mucosal venules and high endothelial venules (HEV) of gut-associated lymphoid tissue (GALT). α4β7 integrin controls the transfer of lymphocytes to intestinal tissues and their retention in the intestine through interaction with MAdCAM-1. It has been suggested that inhibition of the interaction of integrin with its ligand is an effective method for treating various autoimmune and inflammatory diseases, and blocking α4β7-MAdCAM-1 interaction has shown therapeutic effects on inflammatory bowel disease, such as Crohn's disease (CD) and ulcerative colitis (UC).

[0007] Therefore, there is an urgent need to develop an α4β7 integrin antagonist for preventing and / or treating autoimmune diseases and inflammatory diseases, particularly inflammatory bowel disease. SUMMARY

[0008] The present application aims to provide N-(benzoyl)-phenylalanine compounds having a novel structure, which have high selectivity and inhibitory activity against α4β7 integrin and can be orally administered.

[0009] In addition, the present application also aims to provide a pharmaceutical composition comprising the above-mentioned compound as an active pharmaceutical ingredient.

[0010] In addition, the present application also aims to provide the use of the above-mentioned compound or pharmaceutical composition for preventing and / or treating diseases associated with α4β7 integrin, such as autoimmune diseases and inflammatory diseases.

[0011] Specifically, the above-mentioned objects of the present application will be achieved by the following solutions:

[0012] [1] a compound represented by the following general formula (1) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound, or prodrug thereof,

[0013]

[0014] wherein,

[0015] R3 is hydrogen, C 1～6 alkyl, C1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl or 5- to 10-membered heteroaryl, which is optionally substituted by at least one of halogen, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0016] each R4 is independently hydrogen or halogen;

[0017] each X1 is independently hydrogen or halogen;

[0018] X2 is hydrogen, halogen, hydroxy, amino, aldehyde, carboxyl, cyano, nitro, C 1～6 alkyl, C 1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 alkoxy, C 1～6 haloalkoxy, C 1～6 alkylthio, C 1～6 haloalkylthio, C 1～6 alkanoyl, C 1～6 alkylamino, di(C 1～6 alkyl)amino, C 1～6 alkoxycarbonyl, C 1～6 alkanoyloxy, C 1～6 alkanoylamino, carbamoyl, C 1～6 alkylcarbamoyl, di(C 1～6 alkyl)carbamoyl, C 1～6 alkoxysulfonyl, C 1～6 alkylsulfonyloxy, C 1～6 alkylsulfonylamino, aminosulfonyl, C 1～6 alkylaminosulfonyl, di(C 1～6 alkyl)sulfonyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, C 6～10 aryloxy, 5- to 10-membered heteroaryloxy, C 6～10 arylthio, 5- to 10-membered heteroarylthio, C 6～10 arylamino, 5- to 10-membered heteroarylamino, C 6～10 arylcarbonyl, 5- to 10-membered heteroarylcarbonyl, C 6～10 aryloxycarbonyl, 5- to 10-membered heteroaryloxycarbonyl, C 6～10 arylformyloxy, 5- to 10-membered heteroarylformyloxy, C6～10 arylcarbonylamino, 5- to 10-membered heteroarylcarbonylamino, C 6～10 aroylcarbamoyl, 5- to 10-membered heteroaroylcarbamoyl, C 6～10 aryloxysulfonyl, 5- to 10-membered heteroaryloxysulfonyl, C 6～10 arylsulfonyloxy, 5- to 10-membered heteroarylsulfonyloxy, C 6～10 arylsulfonamido, 5- to 10-membered heteroarylsulfonamido, C 6～10 aroyl, 5- to 10-membered heteroaroyl, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0019] each X3is independently hydrogen or halogen;

[0020] A is a group as shown in general formula (2-1), (2-2) or (2-3),

[0021]

[0022] cycloalkyl, 3- to 7-membered heterocycloalkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0023] Y is O or S;

[0024] each Z is independently CR1or N;

[0025] each R1, if present, is independently hydrogen, halogen, hydroxy, amino, aldehyde, carboxyl, cyano, nitro, C 1～6 alkyl, C 1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 alkoxy, C 1～6 haloalkoxy, C 1～6 alkylthio, C 1～6 haloalkylthio, C 1～6 alkanoyl, C 1～6 alkylamino, di(C 1～6 alkyl)amino, C 1～6 alkoxycarbonyl, C 1～6 alkanoyloxy, C 1～6 alkanoylamino, carbamoyl, C 1～6Alkyl carbamoyl, di(C 1～6 alkyl) carbamoyl, C 1～6 Alkoxysulfonyl, C 1～6 Alkylsulfonyloxy, C 1～6 Alkylsulfonylamino, aminosulfonyl, C 1～6 alkylaminosulfonyl, di(C 1～6 alkyl)aminosulfonyl, C 3～6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 6～10 Aryl, 5-10 quinone heteroaryl, C 6～10 Aryloxy groups, 5-10 heteroaryloxy groups, C 6～10 Arylthio, 5-10 heteroarylthio, C 6～10 Aromatic amino groups, 5-10 membered heteroaromatic amino groups, C 6～10 aryl carbonyl, 5-10 membered heteroaryl carbonyl, C 6～10 Aryloxycarbonyl, 5-10 member heteroaryloxycarbonyl, C 6～10 arylformyloxy, 5-10 heteroarylformyloxy, C 6～10 Arylformamide, 5-10 heteroarylformamide, C 6～10 Aryl carbamoyl, 5-10 member heteroaryl carbamoyl, C 6～10 Aryloxysulfonyl, 5-10 member heteroaryloxysulfonyl, C 6～10 arylsulfonyloxy, 5-10 member heteroarylsulfonyloxy, C 6～10 Arylsulfonamide, 5-10 heteroarylsulfonamide, C 6～10 Aromatic aminosulfonyl or 5- to 10-membered heteroaromatic aminosulfonyl, wherein the above group is optionally substituted by at least one of the following substituents: halogen, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 6～10 Aryl and 5-10 heteroaryl groups;

[0026] If they exist, each R2 is independently hydrogen or C. 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl group, C 1～6 Alkyl group, C 1～6 alkoxycarbonyl, C 1～6 Alkylamino, carbamoyl, C 1～6 Alkyl carbamoyl, di(C 1～6 alkyl) carbamoyl, C 3～6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 6～10 Aryl, 5-10 quinone heteroaryl, C 6～10 aryl carbonyl, 5-10 membered heteroaryl carbonyl, C 6～10aryloxy, 5- to 10-membered heteroaryloxy, C 6～10 arylcarbonylamino or 5- to 10-membered heteroarylcarbonylamino, the above groups being optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl.

[0027] [2] The following compounds or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotopically labeled forms or prodrugs thereof, including:

[0028] (1) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid;

[0029] (2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2-chloro-6- fluorobenzamido)propanoic acid;

[0030] (3) (S)-2-(2,6-dichlorobenzamido)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid;

[0031] (4) (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid;

[0032] (5) (S)-3-(4-(6'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichlorobenzamido)propanoic acid;

[0033] (6) (S)-2-(2,6-dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid;

[0034] (7) (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid;

[0035] (8) (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid;

[0036] (9) (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]- 1-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid;

[0037] (10) (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid;

[0038] (11) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-1'-yl)phenyl)propanoic acid;

[0039] (12) (S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindolin-1-yl)phenyl)-2-(2-chloro-6- fluorobenzamido)propanoic acid;

[0040] (13) (S)-3-(4-(5'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2- chloro-6-fluorobenzamido)propanoic acid;

[0041] (14) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'- oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid;

[0042] (15) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-(dimethylamino)-2'- oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid;

[0043] (16) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-1'-yl)phenyl)propanoic acid;

[0044] (17) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-1'-yl)phenyl)propanoic acid;

[0045] (18) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6',7'-difluoro-2'- oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid;

[0046] (19) (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-l,3'- pyrrolo[2,3-b]pyridine]-l'(2'H)-yl)phenyl)propanoic acid;

[0047] (20) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,4,6- trichlorobenzamido)propanoic acid;

[0048] (21) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(diethylamino)benzamido)propanoic acid;

[0049] (22) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-morpholinobenzamido)propanoic acid;

[0050] (23) (2S)-2-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzamido)-3-(4-(7'- chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid;

[0051] (24) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(4-morpholinopiperidin-l-yl)benzamido)propanoic acid;

[0052] (25) (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)-2- (2-chloro-6-fluorobenzamido)propanoic acid;

[0053] (26) (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)- 2-(2,6-dichlorobenzamido)propanoic acid;

[0054] (27) (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)- 2-(2,6-dichlorobenzamido)propanoic acid;

[0055] (28) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)- 2-(2,6-dichlorobenzamido)propanoic acid;

[0056] (29) (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid;

[0057] (30) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid;

[0058] (31) (S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid;

[0059] (32) (S)-3-(4-(7-chloro-3-(l-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid;

[0060] (33) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid;

[0061] (34) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid;

[0062] (35) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid;

[0063] (36) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid;

[0064] (37) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid;

[0065] (38) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid;

[0066] (39) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid;

[0067] (40) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid;

[0068] (41) (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2- (2,4,6-trichlorobenzamido)propanoic acid; and

[0069] (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-morpholinobenzamido)propanoic acid.

[0070] [3] A pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version, or prodrug thereof.

[0071] [4] Use of the above-mentioned compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version, or prodrug thereof, or the above-mentioned pharmaceutical composition, for the manufacture of a medicament for the prevention and / or treatment of a disease and / or disorder mediated at least in part by α4β7 integrin.

[0072] [5] The above-mentioned compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version, or prodrug thereof, or the above-mentioned pharmaceutical composition, for use in the prevention and / or treatment of a disease and / or disorder mediated at least in part by α4β7 integrin.

[0073] [6] A method for the prevention and / or treatment of a disease and / or disorder mediated at least in part by α4β7 integrin, comprising the step of administering to an individual in need thereof the above-mentioned compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version, or prodrug thereof, or the above-mentioned pharmaceutical composition.

[0074] The novel N-(benzoyl)-phenylalanine compound of the present application has excellent α4β7 integrin binding inhibitory activity, and thus, the novel N-(benzoyl)-phenylalanine compound of the present application can provide a therapeutic or prophylactic agent for α4β7-dependent autoimmune diseases and inflammatory bowel diseases (Crohn's disease and ulcerative colitis). The compound of the present application is useful as an oral administration preparation because of high blood concentration or bioavailability upon oral administration. In addition, the compound of the present application is stable in acidic and basic solutions, and thus, can be used for development of various dosage forms. DETAILED DESCRIPTION

[0075] Definitions of terms

[0076] Unless otherwise defined, the terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be apparent to those skilled in the art that various modifications and variations can be made to the techniques described herein. Other aspects of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. It is intended that the specification and examples be considered as exemplary only.

[0077] The terms "comprises", "comprising", "includes", "including", "has", "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus. Terms such as "consisting of" are intended to be construed as "including but not limited to".

[0078] The terms "a" or "an", as used herein, mean "one or more" when applied to any element. Thus, "a" or "an" means one or more of something. For example, "an element" means one or more element.

[0079] When a range of values is disclosed, any value or subrange within that range is included in the disclosure. In particular, each numerical range of values disclosed herein (for example, in the form "about a to b", or equivalently "approximately a to b", or equivalently "about a-b") is to be construed as encompassing each individual numerical value and subrange within that range. For example, "C 1～6 " encompasses any subrange within that range as well as each individual point value, such as C 2～5 , C 3～4 , C 1～2 , C 1～3 , C 1～4 , C 1～5 , etc., as well as C1, C2, C3, C4, C5, C6, etc. Also for example, "3-6 membered" is to be construed as encompassing any subrange within that range as well as each individual 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.

[0080] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application that is substantially non-toxic to the organism, typically including, but not limited to, a salt of a compound of the present application formed by reaction with a pharmaceutically acceptable inorganic / organic acid / acidic amino acid or inorganic base / organic base / alkaline amino acid, such a salt being also referred to as an acid addition salt or a base addition salt. Suitable salts are described in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Pharmaceutically acceptable salts of a compound of the present application include, but are not limited to, metal salts (e.g., sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, zinc salt, aluminum salt, etc.) of an acidic group (e.g., carboxyl group), organic amine salts (e.g., dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, diisopropylethylamine salt, etc.), basic amino acids (e.g., lysine salt, arginine salt, etc.); inorganic acid salts (e.g., hydrochloride, sulfate, phosphate, etc.) of a basic group (e.g., amino group), organic acid salts (e.g., maleate, tartrate, succinate, citrate, acetate, etc.).

[0081] The term "ester" refers to an ester of a compound of the present application that is substantially non-toxic to the organism, typically including, but not limited to, an ester of a compound of the present application formed by reaction of its hydroxyl group with a pharmaceutically acceptable inorganic / organic acid / acidic amino acid or by reaction of its carboxyl group with a pharmaceutically acceptable alcohol / phenol / other compound having a hydroxyl group.

[0082] The term "solvate" refers to a complex formed by the interaction of a compound of the present application and a pharmaceutically acceptable solvent, having a specific spatial arrangement and solute / solvent molar ratio, typically including, but not limited to, a solvate of a compound of the present application with a polar protic solvent / polar aprotic solvent / non-polar solvent, such as a hydrate, alcoholate, etc.

[0083] The term "optical isomer" refers to a plurality of isomers having different optical rotations resulting from a chiral element (e.g., chiral center, chiral axis, chiral plane, etc.) of a compound of the present application, typically including, but not limited to, an enantiomer and a diastereomer of a compound of the present application.

[0084] The term "tautomers" refers to a plurality of isomers having different structural formulas resulting from a tautomerism phenomenon of a compound of the present application, typically including, but not limited to, a keto-enol tautomer, an amide-imine alcohol tautomer, etc.

[0085] The term "isotopically-labeled" refers to compounds of the present application in which at least one atom is replaced by an isotope of that atom, typically including but not limited to deuterium-substituted compounds in which a hydrogen atom is replaced by a deuterium atom.

[0086] The term "prodrug" refers to a derivative compound that, upon administration to a subject, is capable of providing (directly or indirectly) a compound of the present application (e.g., by being oxidized, reduced, hydrolyzed, etc. by enzymes or gastric acid under physiological conditions within the body). Particularly preferred are derivatives or prodrugs that increase the bioavailability of a compound of the present application when administered to a subject (e.g., are more readily absorbed into the blood), or that facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Suitable prodrugs are described in T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. In addition, the present application also encompasses compounds of the present application containing protecting groups. During any of the processes for preparation of the compounds of the present application, protecting groups may be necessary and / or desirable for protecting sensitive or reactive groups on any of the molecules concerned. For example, when a compound of the present application has a carboxyl group, the corresponding prodrug can be prepared by esterification or amidation; when a compound of the present application has an amino group, the corresponding prodrug can be prepared by amidation, phosphorylation, or alkylation; when a compound of the present application has a hydroxyl group, the corresponding prodrug can be prepared by esterification, phosphorylation, or alkylation. Suitable protecting groups are described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at a suitable subsequent stage using methods known in the art.

[0087] Unless otherwise indicated, the term "halogen" as used herein means fluorine (F), chlorine (CI), bromine (Br), and / or iodine (I).

[0088] Unless otherwise indicated, the term "hydroxyl" as used herein means -OH.

[0089] Unless otherwise indicated, the term "amino" as used herein means -NH2, and the term "substituted amino" means the mono-substituted form -NHR or the di-substituted form -NRR ’ .

[0090] Unless otherwise indicated, the term "aldehyde" as used herein means -CH(=0).

[0091] The term "carboxyl," as used herein, unless otherwise indicated by context, refers to -C(=0)OH.

[0092] The term "cyano," as used herein, unless otherwise indicated by context, refers to -CN.

[0093] The term "nitro," as used herein, unless otherwise indicated by context, refers to -N(=0)2.

[0094] The term "alkyl," as used herein, unless otherwise indicated by context, refers to straight or branched chain saturated aliphatic hydrocarbon groups. For example, the term "C 1～6 alkyl," as used herein, refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with a halogen, the group is a "C 1～6 haloalkyl," such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2C1, -CH2CH2CF3, and the like).

[0095] The term "alkenyl," as used herein, unless otherwise indicated by context, refers to straight or branched chain aliphatic hydrocarbon groups having one or more (e.g., 1 to 3) carbon-carbon double bonds. For example, the term "C 2～6 alkenyl," as used herein, refers to alkenyl groups having 2 to 6 carbon atoms and one, two, or three carbon-carbon double bonds (e.g., ethenyl, 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, 4-methyl-3-pentenyl, and the like), optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

[0096] The term "alkynyl," as used herein, unless otherwise indicated by context, refers to straight or branched chain aliphatic hydrocarbon groups having one or more (e.g., 1 to 3) carbon-carbon triple bonds. For example, the term "C 2～6 alkynyl," as used herein, refers to alkynyl groups having 2 to 6 carbon atoms and one, two, or three carbon-carbon triple bonds (e.g., ethynyl, 1 -propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like), optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

[0097] Unless otherwise stated, the term "alkoxy" as used herein refers to the aforementioned alkyl group that is attached to the parent molecule moiety via an oxygen atom, i.e., -O-alkyl. For example, the term "C" as used herein... 1～6 "Alkoxy" refers to an alkoxy group (such as methoxy, ethoxy, isopropoxy, tert-butoxy, etc.) having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), which is optionally substituted by one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with a halogen, the group is "C"). 1～6 "Haloalkoxy groups", such as -OCF3, -OC2F5, -OCHF2, -OCH2Cl, etc.

[0098] Unless otherwise stated, the term "alkathioyl" as used herein refers to the aforementioned alkyl group that is attached to the parent molecule via a sulfur atom, i.e., -S-alkyl. For example, the term "C" as used herein... 1～6 "Alkylthio" refers to an alkylthio group (such as methylthio, ethylthio, isopropylthio, tert-butylthio, etc.) having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), which is optionally substituted by one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with a halogen, the group is "C"). 1～6 "Haloalkylthio groups", such as -SCF3, -SC2F5, -SCHF2, -SCH2Cl, etc.

[0099] Unless otherwise stated, the term "alkanoyl" as used herein refers to the aforementioned alkyl group attached to the parent molecule moiety via a carbonyl group, i.e., -C(=O)-alkyl. For example, the term "C" as used herein... 1～6 "Alkyl" refers to an alkanoyl group (such as acetyl, isobutyryl, etc.) having 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5 or 6 carbon atoms).

[0100] Unless otherwise stated, the term "(ii)alkylamino" as used herein refers to the aforementioned alkyl group that is attached to the parent molecule moiety via a nitrogen atom, namely -NH-alkyl or -N(alkyl)2. For example, the term "C" as used herein... 1～6 "Alkylamino" refers to alkylamino groups (such as ethylamino, isopropylamino, etc.) having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). The term "di(C)" as used herein... 1～6 "Alkyl)amino" refers to dialkylamino (such as dimethylamino, diethylamino, etc.) having two groups of 1 to 6 carbon atoms (such as 1, 2, 3, 4, 5 or 6 carbon atoms).

[0101] Unless otherwise stated, the term "alkoxycarbonyl" as used herein refers to the aforementioned alkyl group, i.e., -C(=O)-O-alkyl, which is sequentially attached to the parent molecule moiety via an oxygen atom and a carbonyl group. For example, the term "C" as used herein...1～6 "Alkoxycarbonyl" means an alkoxyl group as previously defined having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms) attached through a carbonyl group, e.g., ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and the like.

[0102] The term "alkanoyloxy," as used herein unless otherwise indicated, refers to the above- defined alkyl group attached to the parent molecular moiety through a carbonyl and oxygen atom in sequence, i.e., -O-C(=O)-alkyl. For example, the term "C 1～6 "Alkanoyloxy" means an alkanoyl group as previously defined having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms) attached through an oxygen atom, e.g., acetoxy, isobutyryloxy, neopentanoyloxy, and the like.

[0103] The term "alkanoylamino," as used herein unless otherwise indicated, refers to the above- defined alkyl group attached to the parent molecular moiety through a carbonyl and nitrogen atom in sequence, i.e., -NH-C(=O)-alkyl. For example, the term "C 1～6 "Alkanoylamino" means an alkanoyl group as previously defined having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms) attached through a nitrogen atom, e.g., acetylamino, isobutyrylamino, neopentanoylamino, and the like.

[0104] The term "carbamoyl," as used herein unless otherwise indicated, refers to -C(=O)-NH2, and "(dialkyl)carbamoyl" refers to the above-defined alkyl group attached to the parent molecular moiety through an amino and carbonyl group in sequence, i.e., -C(=O)-NH-alkyl or -C(=O)-N(alkyl)2. For example, the term "C 1～6 "Alkylcarbamoyl" means an alkylcarbamoyl group having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), e.g., ethylcarbamoyl, isopropylcarbamoyl, and the like, and the term "di(C 1～6 "Alkylcarbamoyl" means an alkylcarbamoyl group having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), e.g., ethylcarbamoyl, isopropylcarbamoyl, and the like, and the term "di(C

[0105] The term "alkoxysulfonyl," as used herein unless otherwise indicated, refers to the above- defined alkyl group attached to the parent molecular moiety through an oxygen atom and a sulfonyl group in sequence, i.e., -S(=O)2-O-alkyl. For example, the term "C 1～6 "Alkoxysulfonyl" means an alkoxyl group as previously defined having from one to six carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms) attached through a sulfonyl group, e.g., ethoxysulfonyl, isopropoxysulfonyl, t-butoxysulfonyl, and the like.

[0106] The term "alkylsulfonyloxy," as used herein unless otherwise indicated, refers to an alkyl group, as previously defined, attached to the parent molecular moiety through a sulfonyl and then an oxygen atom, i.e., -O-S(=O)2-alkyl. For example, the term "C 1～6 alkylsulfonyloxy," as used herein unless otherwise indicated, refers to an alkyl group, as previously defined, attached to the parent molecular moiety through a sulfonyl and then an oxygen atom, i.e., -O-S(=O)2-alkyl. For example, the term "C

[0107] The term "alkylsulfonamido," as used herein unless otherwise indicated, refers to an alkyl group, as previously defined, attached to the parent molecular moiety through a sulfonyl and then a nitrogen atom, i.e., -NH-S(=O)2-alkyl. For example, the term "C 1～6 alkylsulfonamido," as used herein unless otherwise indicated, refers to an alkyl group, as previously defined, attached to the parent molecular moiety through a sulfonyl and then a nitrogen atom, i.e., -NH-S(=O)2-alkyl. For example, the term "C

[0108] The term "aminosulfonyl," as used herein unless otherwise indicated, refers to -S(=O)2-NH2, and the term "(di)alkylaminosulfonyl," as used herein unless otherwise indicated, refers to an alkyl group, as previously defined, attached to the parent molecular moiety through a nitrogen atom and then a sulfonyl, i.e., -S(=O)2-NH-alkyl or -S(=O)2-N(alkyl)2. For example, the term "C 1～6 alkylaminosulfonyl," as used herein unless otherwise indicated, refers to an alkyl group, as previously defined, having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), and the term "di(C 1～6 alkyl)aminosulfonyl," as used herein unless otherwise indicated, refers to a dialkyl group, as previously defined, having two sets of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms).

[0109] The term "cycloalkyl," as used herein unless otherwise indicated, refers to a cyclic, saturated aliphatic hydrocarbon radical. For example, the term "C 3～6 cycloalkyl," as used herein unless otherwise indicated, refers to a cyclic, saturated aliphatic hydrocarbon radical having 3 to 6 ring-forming carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). The term "cycloalkylene," as used herein unless otherwise indicated, refers to a cyclic, saturated aliphatic hydrocarbon radical that simultaneously connects two other fragments. For example, the term "C 3～6 cycloalkylene," as used herein unless otherwise indicated, refers to a cyclic, saturated aliphatic hydrocarbon radical that simultaneously connects two other fragments. For example, the term "C

[0110] The term "heterocycloalkyl" as used herein, unless otherwise indicated, means a saturated aliphatic hydrocarbon radical having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) fragments each independently selected from -0-, -S-, -S(=0)-, -S(=0)2-, and -NR- (R represents a hydrogen atom or a substituent such as an alkyl group or a cycloalkyl group). For example, the term "3- to 7-membered heterocycloalkyl" as used herein means a heterocycloalkyl group having 3 to 7 ring-forming atoms (e.g., 3, 4, 5, 6, or 7 atoms) (e.g., oxiranyl (oxiranyl), thiranyl (thiiranyl), aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, 1,4-thioxanyl, 1,4-dioxanyl, 1,4-dithianyl, piperazinyl, 1,3,5-trioxanyl, 1,3,5-trithianyl, 1,4-thiazinanyl, and the like). The term "heterocycloalkylene" as used herein, unless otherwise indicated, means a saturated aliphatic hydrocarbon radical having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) fragments each independently selected from -0-, -S-, -S(=0)-, -S(=0)2-, and -NR- (R represents a hydrogen atom or a substituent such as an alkyl group or a cycloalkyl group), and simultaneously linking two other fragments. For example, the term "3- to 7-membered heterocycloalkylene" as used herein means a heterocycloalkylene group having 3 to 7 ring-forming atoms (e.g., 3, 4, 5, 6, or 7 atoms) (e.g., tetrahydro-2H-pyranyl-4-ylidene, and the like).

[0111] The term "aryl" as used herein, unless otherwise indicated, means a monocyclic or fused ring aromatic hydrocarbon radical having a conjugated pi-electron system. For example, the term "C 6～10 aryl" as used herein means an aryl group having 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring-forming carbon atoms (e.g., phenyl, naphthyl, and the like), which is optionally substituted with one or more substituents described herein (e.g., substituted with a C 1～6 alkyl group, a tolyl group substituted with a halo group, and the like).

[0112] ​The term "heteroaryl" as used herein, unless otherwise indicated, refers to a monocyclic or fused ring aromatic group having a conjugated pi electron system with one or more (e.g., 1, 2, 3, or 4) carbon atoms and one or more (e.g., 1, 2, 3, or 4) fragments each independently selected from -0-, -S-, -S(=0)-, -S(=0)2-, -N=, and -NR- (R represents a hydrogen atom or a substituent such as alkyl or cycloalkyl). As used herein, "5-10 membered heteroaryl" is a heteroaryl (e.g., thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, and the like, or e.g., pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, or a benzo derivative thereof such as indazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, and the like, or e.g., pyrazolo pyridyl, pyrrolo pyrimidinyl, pyrrolo pyridyl, pyrazolo pyrimidinyl, and the like) having 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring-forming atoms, which is optionally substituted with one or more substituents described herein (e.g., methylpyridyl substituted with C1-C6 alkyl, chloropyridyl substituted with halogen, and the like). The heteroaryl group can be attached to the parent molecular moiety through any one of the ring-forming atoms if valence requirements are satisfied. The heteroaryl group can be attached to other groups (or fragments) through any one of the carbon atoms or heteroatoms (e.g., N atom) in the ring if valence requirements are satisfied. Also, the heteroaryl group can be optionally fused to aryl, heterocycloalkyl, cycloalkyl, wherein the ring attached to the parent structure is heteroaryl.

[0113] The terms "aryloxy" and "heteroaryloxy" as used herein, unless otherwise indicated, refer to the above-described aryl or heteroaryl groups attached to the parent molecular moiety through an oxygen atom, i.e., -O-aryl (e.g., phenoxy, naphthalen-1-yloxy, and the like) and -O-heteroaryl (e.g., furan-2-yloxy, pyridin-4-yloxy, and the like).

[0114] The terms "arylthio" and "heteroarylthio" as used herein, unless otherwise indicated, refer to the above-described aryl or heteroaryl groups attached to the parent molecular moiety through a sulfur atom, i.e., -S-aryl (e.g., phenylthio, naphthalen-1-ylthio, and the like) and -S-heteroaryl (e.g., furan-2-ylthio, pyridin-4-ylthio, and the like).

[0115] The terms "arylcarbonyl" and "heteroarylcarbonyl" as used herein, unless otherwise indicated, refer to the above-described aryl or heteroaryl groups attached to the parent molecular moiety through a carbonyl group, i.e., -C(=O)-aryl (e.g., benzoyl, 1-naphthoyl, and the like) and -C(=O)-heteroaryl (e.g., furancarbonyl, nicotinoyl, and the like).

[0116] The terms "arylaminocarbonyl" and "heteroarylaminocarbonyl," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through a nitrogen atom and a carbonyl group, i.e., -C(=O)-NH-aryl (such as phenylaminocarbonyl) and -C(=O)-NH-heteroaryl (such as furan-2- ylaminocarbonyl), respectively, unless otherwise indicated.

[0117] The terms "aryloxyacyl" and "heteroaryloxyacyl," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through an oxygen atom and a carbonyl group, i.e., -C(=O)-O-aryl (such as phenyloxyformyl) and -C(=O)-O-heteroaryl (such as furan-2- yloxyformyl), respectively, unless otherwise indicated.

[0118] The terms "arylcarbonyloxy" and "heteroarylcarbonyloxy," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through a carbonyl group and an oxygen atom, i.e., -O-C(=O)-aryl (such as benzoyloxy) and -O-C(=O)-heteroaryl (such as furfuryloxy), respectively, unless otherwise indicated.

[0119] The terms "arylcarbonylamino" and "heteroarylcarbonylamino," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through a carbonyl group and a nitrogen atom, i.e., -NH-C(=O)-aryl (such as benzoylamino) and -NH-C(=O)-heteroaryl (such as furfurylamino), respectively, unless otherwise indicated.

[0120] The terms "arylaminocarbonyl" and "heteroarylaminocarbonyl," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through a nitrogen atom and a carbonyl group, i.e., -C(=O)-NH-aryl (such as phenylaminocarbonyl) and -C(=O)-NH-heteroaryl (such as furan-2- ylaminocarbonyl), respectively, unless otherwise indicated.

[0121] The terms "aryloxyacyl" and "heteroaryloxyacyl," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through an oxygen atom and a carbonyl group, i.e., -C(=O)-O-aryl (such as phenyloxyformyl) and -C(=O)-O-heteroaryl (such as furan-2- yloxyformyl), respectively, unless otherwise indicated.

[0122] The terms "aryloxyacyl" and "heteroaryloxyacyl," as used herein, mean the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through an oxygen atom and a carbonyl group, i.e., -C(=O)-O-aryl (such as phenyloxyformyl) and -C(=O)-O-heteroaryl (such as furan-2- yloxyformyl), respectively, unless otherwise indicated.

[0123] The terms "arylaminosulfonyl" and "heteroarylamino- sulfonyl" as used herein, unless otherwise indicated, denote the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through a nitrogen atom and a sulfonyl group, i.e., -S(=O)2-NH-aryl (such as phenylaminosulfonyl) and -S(=O)2-NH-heteroaryl (such as furan-2- ylamino-sulfonyl), respectively.

[0124] The terms "arylaminosulfonyl" and "heteroarylamino- sulfonyl" as used herein, unless otherwise indicated, denote the above-mentioned aryl or heteroaryl groups attached to the parent molecular moiety through a nitrogen atom and a sulfonyl group, i.e., -S(=O)2-NH-aryl (such as phenylaminosulfonyl) and -S(=O)2-NH-heteroaryl (such as furan-2- ylamino-sulfonyl), respectively.

[0125] The term "independently" as used herein, unless otherwise indicated, means that at least two groups (or moieties) present in a structure have the same or similar range of values and can have the same or different meaning in a particular instance. For example, R1and R2are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when R1is hydrogen, R2may be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; and similarly, when R2is hydrogen, R1may be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0126] The term "substituted" and its variants as used herein, unless otherwise indicated, means that one or more (such as 1, 2, 3, or 4) atoms or moieties (such as hydrogen atoms) of the designated atom or moiety are replaced with other equivalents, provided that the designated atom or moiety does not exceed the normal valency for the atom or moiety in the current context and that a stable compound is formed. Unless otherwise indicated, the point of attachment of a substituent can be from any suitable position of the substituent.

[0127] Compounds of general formula

[0128] The present application provides a compound as shown in general formula (1) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled, or prodrug thereof,

[0129]

[0130] wherein,

[0131] R3 is hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10aryl or 5- to 10-membered heteroaryl, the above groups being optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0132] each R4 is independently hydrogen or halogen;

[0133] each X1 is independently hydrogen or halogen;

[0134] X2 is hydrogen, halogen, hydroxy, amino, aldehyde, carboxyl, cyano, nitro, C 1～6 alkyl, C 1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 alkoxy, C 1～6 haloalkoxy, C 1～6 alkylthio, C 1～6 haloalkylthio, C 1～6 alkanoyl, C 1～6 alkylamino, di(C 1～6 alkyl)amino, C 1～6 alkoxycarbonyl, C 1～6 alkanoyloxy, C 1～6 alkanoylamino, carbamoyl, C 1～6 alkylcarbamoyl, di(C 1～6 alkyl)carbamoyl, C 1～6 alkoxysulfonyl, C 1～6 alkylsulfonyloxy, C 1～6 alkylsulfonylamino, sulfamoyl, C 1～6 alkylsulfamoyl, di(C 1～6 alkyl)sulfamoyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, C 6～10 aryloxy, 5- to 10-membered heteroaryloxy, C 6～10 arylthio, 5- to 10-membered heteroarylthio, C 6～10 arylamino, 5- to 10-membered heteroarylamino, C 6～10 arylcarbonyl, 5- to 10-membered heteroarylcarbonyl, C 6～10 aryloxycarbonyl, 5- to 10-membered heteroaryloxycarbonyl, C 6～10 arylformyloxy, 5- to 10-membered heteroarylformyloxy, C 6～10 arylformylamino, 5- to 10-membered heteroarylformylamino, C 6～10 arycarbamoyl, 5- to 10-membered heteroarycarbamoyl, C 6～10aryloxy, 5- to 10-membered heteroaryloxy, C 6～10 arylsulfonyloxy, 5- to 10-membered heteroarylsulfonyloxy, C 6～10 arylsulfonamido, 5- to 10-membered heteroarylsulfonamido, C 6～10 aromatic aminosulfonyl or 5- to 10-membered heteroaromatic aminosulfonyl, each of which is optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0135] each X3is independently hydrogen or halogen;

[0136] A is a group represented by formula (2-1), (2-2) or (2-3),

[0137]

[0138] ring H is C 3～6 cycloalkylene or 3- to 7-membered heterocycloalkylene, each of which is optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0139] Y is O or S;

[0140] each Z is independently CR1or N;

[0141] each R1, if present, is independently hydrogen, halogen, hydroxy, amino, aldehyde, carboxyl, cyano, nitro, C 1～6 alkyl, C 1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 alkoxy, C 1～6 haloalkoxy, C 1～6 alkylthio, C 1～6 haloalkylthio, C 1～6 alkanoyl, C 1～6 alkylamino, di(C 1～6 alkyl)amino, C 1～6 alkoxycarbonyl, C 1～6 alkanoyloxy, C 1～6 alkanoylamino, carbamoyl, C 1～6 alkylcarbamoyl, di(C 1～6 alkyl)carbamoyl, C 1～6 alkoxysulfonyl, C 1～6 alkylsulfonyloxy, C1～6 alkylsulfonylamino, aminosulfonyl, C 1～6 alkylaminosulfonyl, di(C 1～6 alkyl)sulfonyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, C 6～10 aryloxy, 5- to 10-membered heteroaryloxy, C 6～10 arylthio, 5- to 10-membered heteroarylthio, C 6～10 arylamino, 5- to 10-membered heteroarylamino, C 6～10 arylcarbonyl, 5- to 10-membered heteroarylcarbonyl, C 6～10 aryloxycarbonyl, 5- to 10-membered heteroaryloxycarbonyl, C 6～10 aryformyloxy, 5- to 10-membered heteroaryformyloxy, C 6～10 arylformylamino, 5- to 10-membered heteroarylformylamino, C 6～10 arycarbamoyl, 5- to 10-membered heteroarycarbamoyl, C 6～10 aryloxysulfonyl, 5- to 10-membered heteroaryloxysulfonyl, C 6～10 arylsulfonyloxy, 5- to 10-membered heteroarylsulfonyloxy, C 6～10 arylsulfonylamino, 5- to 10-membered heteroarylsulfonylamino, C 6～10 arylamino sulfonyl or 5- to 10-membered heteroarylamino sulfonyl, which are optionally substituted by at least one of halogen, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl;

[0142] each R2, if present, is independently hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 alkanoyl, C 1～6 alkoxycarbonyl, C 1～6 alkanoylamino, carbamoyl, C 1～6 alkylcarbamoyl, di(C 1～6 alkyl)carbamoyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, C 6～10 arylcarbonyl, 5- to 10-membered heteroarylcarbonyl, C 6～10 aryloxycarbonyl, 5- to 10-membered heteroaryloxycarbonyl, C 6～10 arycarbamoyl or 5- to 10-membered heteroarycarbamoyl, which are optionally substituted by at least one of halogen, C1～6 alkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl and 5- to 10-membered heteroaryl.

[0143] In one embodiment of the application, R3in the compound according to formula (1) is hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 3～6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6～10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl and 3- to 7-membered heterocycloalkyl; preferably, R3is hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 3～6 cycloalkyl or 3- to 7-membered heterocycloalkyl, which are optionally substituted by at least one substituent selected from the group consisting of halogen and C 1～6 alkyl; more preferably, R3is hydrogen or methyl; further preferably, R3is hydrogen.

[0144] In one embodiment of the application, each R4in the compound according to formula (1) is independently hydrogen, fluorine, chlorine or bromine; preferably, each R4is independently hydrogen, fluorine or chlorine; more preferably, R4is hydrogen.

[0145] In one embodiment of the application, each X1in the compound according to formula (1) is independently fluorine, chlorine or bromine; preferably, each X1is independently fluorine or chlorine.

[0146] In one embodiment of the application, X2in the compound according to formula (1) is hydrogen, halogen, C 1～6 alkylamino, di(C 1～6 alkyl)amino, C 3～6 cycloalkyl or 3- to 7-membered heterocycloalkyl, which are optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl and 3- to 7-membered heterocycloalkyl; preferably, X2is hydrogen, halogen, di(C 1～6 alkyl)amino or 3- to 7-membered heterocycloalkyl, which are optionally substituted by at least one substituent selected from the group consisting of halogen, C 1～6 alkyl, C 3～6 cycloalkyl and 3- to 7-membered heterocycloalkyl; more preferably, X2is hydrogen, chlorine, diethylamino, morpholinyl 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl or 4-morpholinopiperidin-1-yl

[0147] In one embodiment of the invention, each X3 in the compound represented by general formula (1) is independently hydrogen or fluorine; preferably, all X3 are hydrogen.

[0148] In a preferred embodiment of the invention, the compound as shown in general formula (1) Selected from the following structural fragments:

[0149]

[0150] In a more preferred embodiment of the invention, the compound as shown in general formula (1) Selected from the following structural fragments:

[0151]

[0152] In a further preferred embodiment of the invention, the compound as shown in general formula (1) Selected from the following structural fragments:

[0153]

[0154] In one embodiment of the invention, A in the compound represented by general formula (1) is a group represented by general formula (2-1-1) or (2-1-1').

[0155]

[0156] in,

[0157] Ring H is C 3～6 Cycloalkylene or 3- to 7-membered heterocycloalkylene, wherein the above groups are optionally substituted by at least one of the following substituents: halogen, C 1～6 Alkyl, C 3～6 Cycloalkyl and 3- to 7-membered heterocyclic alkyl groups; preferably, the ring H is a cyclopropyl group. or tetrahydro-2H-pyran-4-yl

[0158] Y is either O or S; preferably, Y is O.

[0159] When A is a group as shown in general formula (2-1-1), two of the four R1s are independently halogens and C. 1～6 Alkyl, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the rest being hydrogen; or, one of the four R1 groups is a halogen, C 1～6 Alkyl, C 1～6 Alkoxy or di(C) 1～6Alkyl)amino, the remainder being hydrogen; or, all four R1s are hydrogen; preferably, two of the four R1s are each independently halogen or bis(C)amino. 1～6 Alkyl)amino, the rest being hydrogen; or, one of the four R1 groups is a halogen, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the remainder being hydrogen; or, all four R1s are hydrogen; more preferably, two of the four R1s are independently fluorine, chlorine or dimethylamino, the remainder being hydrogen; or, one of the four R1s is fluorine, chlorine, methoxy or dimethylamino, the remainder being hydrogen; or, all four R1s are hydrogen.

[0160] When A is a group as shown in general formula (2-1-1'), two of the three R1s are independently halogens and C. 1～6 Alkyl, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the remainder being hydrogen; or, one of the three R1 groups is a halogen, C 1～6 Alkyl, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the remainder being hydrogen; or, all three R1s are hydrogen; preferably, two of the three R1s are each independently halogen or bis(C)amino. 1～6 Alkyl)amino, the remainder being hydrogen; or, one of the three R1 groups is a halogen, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the remainder being hydrogen; or, all three R1s are hydrogen; more preferably, all three R1s are hydrogen.

[0161] In a preferred embodiment of the present invention, the compound represented by general formula (1) is a compound represented by general formula (2-1-2).

[0162]

[0163] Among them, rings H, Y, R1, R3, R4, X1, X2 and X3 are as defined in this invention.

[0164] In a more preferred embodiment of the present invention, the compound represented by general formula (1) is a compound represented by general formula (2-1-3).

[0165]

[0166] Among them, rings H, Y, R1, R3, R4, X1, X2 and X3 are as defined in this invention.

[0167] In a preferred embodiment of the present invention, the compound represented by general formula (1) is a compound represented by general formula (2-1-2').

[0168]

[0169] Among them, rings H, Y, R1, R3, R4, X1, X2 and X3 are as defined in this invention.

[0170] In a more preferred embodiment of the present invention, the compound represented by general formula (1) is a compound represented by general formula (2-1-3').

[0171]

[0172] Among them, rings H, Y, R1, R3, R4, X1, X2 and X3 are as defined in this invention.

[0173] In one embodiment of the present invention, A in the compound represented by general formula (1) is a group represented by general formula (2-2-1).

[0174]

[0175] Y is either O or S; preferably, Y is O.

[0176] Two of the four R1s are independently halogens and C. 1～6 Alkyl, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the rest being hydrogen; or, one of the four R1 groups is a halogen, C 1～6 Alkyl, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the remainder being hydrogen; preferably, two of the four R1s are each independently halogenated, the remainder being hydrogen; or, one of the four R1s is halogenated, C 1～6 Alkoxy or di(C) 1～6 Alkyl)amino, the remainder being hydrogen; more preferably, two of the four R1s are each independently fluorine or chlorine, the remainder being hydrogen; or, one of the four R1s is fluorine, chlorine, methoxy or dimethylamino, the remainder being hydrogen;

[0177] R2 is hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl or 3- to 7-membered heterocycloalkyl groups, wherein the above groups are optionally substituted by at least one of the following substituents: halogen, C 1～6 Alkyl, C 3～6 Cycloalkyl and 3- to 7-membered heterocyclic alkyl; preferably, R2 is C 1～6 Alkyl, C 3～6 Cycloalkyl or 3- to 7-membered heterocycloalkyl groups, wherein the above groups are optionally C-shaped. 1～6 Alkyl substitution; more preferably, R2 is methyl, cyclopropyl, or tetrahydro-2H-pyran-4-yl. or 1 -methylpiperidin-4-yl

[0178] In a preferred embodiment of the present application, the compound of formula (1) is a compound of formula (2-2-2),

[0179]

[0180] wherein Y, R1, R2, R3, R4, X1, X2and X3are as defined in the present application.

[0181] In a more preferred embodiment of the present application, the compound of formula (1) is a compound of formula (2-2-3),

[0182]

[0183] wherein Y, R1, R2, R3, R4, X1, X2and X3are as defined in the present application.

[0184] In an embodiment of the present application, A in the compound of formula (1) is a group of formula (2-3-1),

[0185]

[0186] Y is O or S; preferably, Y is O;

[0187] one of the four R1is halogen, C 1～6 alkyl, C 1～6 alkoxy or di(C 1～6 alkyl)amino, and the others are hydrogen; preferably, one of the four R1is chlorine, and the others are hydrogen;

[0188] each R2is independently of the others hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 3～6 cycloalkyl or 3- to 7-membered heterocycloalkyl, which groups are optionally substituted by at least one halogen, C 1～6 alkyl, C 3～6 cycloalkyl and 3- to 7-membered heterocycloalkyl; preferably, each R2is independently of the others C 1～6 alkyl; more preferably, R2is methyl.

[0189] In a preferred embodiment of the present application, the compound of formula (1) is a compound of formula (2-3-2),

[0190]

[0191] wherein Y, R1, R2, R3, R4, X1, X2and X3are as defined in the present application.

[0192] In a more preferred embodiment of the present application, the compound according to formula (1) is a compound according to formula (2-3-3),

[0193]

[0194] wherein Y, R1, R2, R3, R4, X1, X2and X3are as defined in the present application.

[0195] In a preferred embodiment of the present application, R1in the compound according to 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 fragments:

[0196]

[0197]

[0198] In a more preferred embodiment of the present application, R1in the compound according to 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 fragments:

[0199]

[0200] In a further preferred embodiment of the present application, R1in the compound according to 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 fragments:

[0201]

[0202] In a preferred embodiment of the present application, R1in the compound according to formula (2-1-1'), (2-1-2') or (2-1-3') is

[0203] The present application also provides the following compounds or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled form or prodrug thereof, ​

[0204]

[0205] Process for the preparation of compounds of general formula

[0206] The compound as shown in the general formula (1) (for example, the terminal has a carboxyl group, that is, R3 is hydrogen) in the present application can be prepared by the following method.

[0207]

[0208] wherein, R4, X1, X2, X3 and A are as defined in the general formula (1); W1 is bromine or iodine, W2 is hydroxyl or chlorine, and R is an amino protecting group.

[0209] Firstly, the intermediate P1 is coupled with the intermediate H-A to obtain the intermediate M1; preferably, the coupling reaction is carried out in the presence of a metal catalyst (for example, cuprous iodide, etc.), a ligand (for example, N,N-dimethylglycine or its hydrochloride, etc.), a base (for example, cesium carbonate, etc.) and an organic solvent (for example, acetonitrile, 1,4-dioxane, etc.) which will not adversely affect the reaction.

[0210] Secondly, the intermediate M1 is subjected to a deprotection reaction to obtain the intermediate M2; preferably, the deprotection reaction is carried out in the presence of an acid (for example, trifluoroacetic acid, etc.) and an organic solvent (for example, dichloromethane, etc.) which will not adversely affect the reaction.

[0211] Thirdly, the intermediate M2 is subjected to a condensation reaction with the intermediate P2 to obtain the intermediate M3; preferably, the condensation reaction is carried out in the presence of a base (for example, N,N-diisopropylethylamine, triethylamine, etc.) and an organic solvent (for example, dichloromethane) which will not adversely affect the reaction.

[0212] Finally, the intermediate M3 is subjected to a hydrolysis reaction to obtain the target product; preferably, the hydrolysis reaction is carried out in the presence of a base (for example, sodium hydroxide, etc.) and a mixed solvent (for example, tetrahydrofuran / water, etc.) which will not adversely affect the reaction.

[0213] The compound as shown in the general formula (1) (for example, the terminal has an ester group, that is, R3 is as defined in the general formula (1), but is not hydrogen) in the present application can be prepared by the following method.

[0214] Scheme 1:

[0215]

[0216] wherein, R4, X1, X2, X3 and A are as defined in the general formula (1).

[0217] According to the preparation method of the compound of general formula (1) with a carboxyl group at the end (i.e., R3 is hydrogen), an intermediate M4 is obtained, and then the target product is obtained by esterification with R3-OH; preferably, the esterification is carried out in the presence of a condensation aid (such as 1-hydroxybenzotriazole (HOBt), 1,3-dicyclohexyl carbodiimide (DCC), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc.), a base (such as N,N-diisopropyl ethylamine, triethylamine, pyridine, etc.), and an organic solvent (such as dichloromethane, tetrahydrofuran, acetonitrile, etc.) that does not adversely affect the reaction.

[0218] Scheme 2:

[0219]

[0220] wherein R4, X1, X2, X3 and A are as defined in general formula (1); W1 is bromine or iodine, and W2 is hydroxyl or chlorine.

[0221] First, the intermediate P3 is coupled with the intermediate H-A to obtain the intermediate M5; preferably, the coupling is carried out in the presence of a metal catalyst (such as cuprous iodide, etc.), a ligand (such as N,N-dimethyl glycine or its hydrochloride, etc.), a base (such as cesium carbonate, etc.), and an organic solvent (such as acetonitrile, 1,4-dioxane, etc.) that does not adversely affect the reaction.

[0222] Second, the intermediate M5 is subjected to a deprotection reaction to obtain the intermediate M6; preferably, the deprotection is carried out in the presence of an acid (such as trifluoroacetic acid, etc.) and an organic solvent (such as dichloromethane, etc.) that does not adversely affect the reaction.

[0223] Third, the intermediate M6 is subjected to a condensation reaction with the intermediate P2 to obtain the target product; preferably, the condensation is carried out in the presence of a base (such as N,N-diisopropyl ethylamine, triethylamine, etc.) and an organic solvent (such as dichloromethane) that does not adversely affect the reaction.

[0224] Pharmaceutical compositions

[0225] The present application provides a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled, or prodrug thereof.

[0226] In an embodiment of the present application, the pharmaceutical composition comprises, as a pharmaceutically active ingredient, a compound of the present application or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version or prodrug thereof, and at least one pharmaceutically acceptable excipient, including but not limited to, diluents, binders, lubricants, glidants, surfactants, flavoring agents, odorants, pH adjusting agents, aromatics, sweeteners, and the like.

[0227] In an embodiment of the present application, the pharmaceutical composition comprises, as a pharmaceutically active ingredient, a compound of the present application or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version or prodrug thereof, and at least one other pharmaceutically active ingredient that is capable of synergistic potentiation and / or attenuation upon combination.

[0228] In an embodiment of the present application, the pharmaceutical composition is in a specific form, including but not limited to, the following dosage forms: tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.

[0229] In an embodiment of the present application, the pharmaceutical composition comprises 0.01 to 1000 mg of a compound of the present application or an equivalent amount of a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version or prodrug thereof, per unit dose or unit formulation.

[0230] Medical use related to alpha4beta7 integrin

[0231] The compounds of the present application have been shown to have inhibitory activity against α4β7 integrin by pharmacological experiments, and thus can be used for the prevention and / or treatment of diseases and / or conditions mediated at least in part by α4β7 integrin. The present application also provides the use of a compound of the present application or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version or prodrug thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for the prevention and / or treatment of diseases and / or conditions mediated at least in part by α4β7 integrin.

[0232] In addition, the present application also provides a method for the prevention and / or treatment of diseases and / or conditions mediated at least in part by α4β7 integrin, comprising the step of administering a compound of the present application or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled version or prodrug thereof, or a pharmaceutical composition of the present application, to an individual in need thereof.

[0233] In an embodiment of the present application, the diseases and / or disorders mediated at least in part by α4β7 integrin include, but are not limited to, autoimmune diseases, inflammatory diseases, and tumor cell proliferation and metastasis.

[0234] In an embodiment of the present application, the autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS).

[0235] In an embodiment of the present application, the inflammatory diseases include, but are not limited to, inflammatory bowel disease (IBD); preferably, the inflammatory bowel disease includes, but is not limited to, ulcerative colitis (UC) and Crohn's disease (CD).

[0236] The present application will be described in detail below by way of Examples. These Examples are merely preferred embodiments of the present application, and should not be considered as limiting the present application. In addition, unless otherwise specified, the instruments, drugs, reagents, materials, etc. used in the following Examples can be obtained by conventional commercial means.

[0237] It should be noted that Intermediate Preparation Example 1 shows a synthesis example of the intermediate P-1 as shown in General Formula P1, Intermediate Preparation Examples 2 to 33 show synthesis examples of the intermediates P-2 to P-33 as shown in General Formula H-A, Intermediate Preparation Examples 34 to 38 show synthesis examples of the intermediates P-34 to P-38 as shown in General Formula P2, and Examples 1 to 39 show synthesis examples of the compounds of the present application.

[0238] Intermediate Preparation Example 1: Synthesis of methyl 3-(4-iodophenyl)-2- (tritylamino)propanoate (P-1)

[0239] (Step 1) methyl (S)-2-amino-3-(4-iodophenyl)propanoate

[0240]

[0241] Dissolve 4-iodo-L-phenylalanine (29.1 g, 10 mmol) in anhydrous methanol (290 mL) and cool in an ice bath. Add dichlorosulfoxide (17.9 g, 15 mmol) and N,N-dimethylformamide (2.9 mL) and react at 40°C for 24 h. Concentrate the reaction solution under reduced pressure to obtain a white solid, which is the title compound (29 g, 95%). ESI-QQQ-MS: m / z 306 [M+H] + .

[0242] (Step 2) 3-(4-iodophenyl)-2-(tritylamino)propionic acid methyl ester (P-1)

[0243]

[0244] (S)-2-amino-3-(4-iodophenyl)propionic acid methyl ester (24.4 g, 8 mmol) was dissolved in dichloromethane (480 mL) and cooled in an ice bath. Triethylamine (12.1 g, 12 mmol) and 1.2 eq of trityl chloride (26.8 g, 9.6 mmol) were added, and the reaction was allowed to proceed at room temperature for 8 h. The reaction was concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the title compound (30.7 g, 70%). ESI-QQQ-MS: m / z 548 [M+H] + .

[0245] Intermediate Preparation Example 2: Synthesis of spiro[cyclopropane-1,3'-indolin]-2'-one (P-2)

[0246]

[0247] Indolin-2-one (0.27 g, 2 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to -40 °C. LDA (2 mol / L, 0.4 mL, 8 mmol) was added, and the mixture was stirred for 30 min and warmed to 0 °C. 1,2-dibromoethane (1.14 g, 6 mmol) was added, and the reaction was allowed to proceed at room temperature for 24 h. Saturated aqueous ammonium chloride solution (5 mL) and water (15 mL) were added to the reaction, and the mixture was extracted twice with ethyl acetate (10 mL each time). The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.19 g, 60%). ESI-QQQ-MS: m / z 160 [M+H] + .

[0248] Intermediate Preparation Example 3: Synthesis of 7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (P-3)

[0249]

[0250] Intermediate Preparation Example 4: Synthesis of 6'-fluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-4) + .

[0251] Intermediate Preparation Example 4: Synthesis of 6'-fluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-4)

[0252]

[0253] Intermediate Preparation Example 4: Synthesis of 6'-fluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-4) + .

[0254] Intermediate Preparation Example 4: Synthesis of 6'-fluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-4)

[0255]

[0256] 5-Fluoroindoline-2-one (0.3 g, 2 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), cooled to -40 °C, and LDA (2 mol / L, 4 mL, 8 mmol) was added. The mixture was stirred for 30 min, heated to 0 °C, and 1,2-dibromoethane (1.14 g, 6 mmol) was added. The reaction mixture was allowed to react at room temperature for 24 h. A saturated ammonium chloride aqueous solution (5 mL) and water (15 mL) were added to the reaction mixture. The mixture was extracted twice with ethyl acetate (10 mL each time). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.22 g, 61%). ESI-QQQ-MS: m / z 178 [M+H] + .

[0257] Intermediate Preparation Example 6: Synthesis of 7'-chlorospiro[cyclopropane-1,3'-indoline]-2'-one (P-6)

[0258]

[0259] 7-Chloroindoline-2-one (0.33 g, 2 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), cooled to -40 °C, and LDA (2 mol / L, 4 mL, 8 mmol) was added. The mixture was stirred for 30 min, heated to 0 °C, and 1,2-dibromoethane (1.14 g, 6 mmol) was added. The reaction mixture was allowed to react at room temperature for 24 h. A saturated ammonium chloride aqueous solution (5 mL) and water (15 mL) were added to the reaction mixture. The mixture was extracted twice with ethyl acetate (10 mL each time). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.2 g, 52%). ESI-QQQ-MS: m / z 194 [M+H] + .

[0260] Intermediate Preparation Example 7: Synthesis of 6'-chlorospiro[cyclopropane-1,3'-indoline]-2'-one (P-7)

[0261]

[0262] To a solution of 6-chloroindolin-2-one (0.33 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled to -40 °C, then LDA (2 mol / L, 4 mL, 8 mmol) was added. The mixture was stirred for 30 min, then warmed to 0 °C, 1,2-dibromoethane (1.14 g, 6 mmol) was added, and the mixture was stirred at room temperature for 24 h. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 mL) and water (15 mL), and the mixture was extracted with ethyl acetate twice (10 mL each time). The combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.21 g, 54%). ESI-QQQ-MS: m / z 194 [M+H] + .

[0263] Intermediate Preparation Example 8: Synthesis of 5'-chlorospiro[cyclopropane-1,3'- indolin]-2'-one (P-8)

[0264]

[0265] To a solution of 6-chloroindolin-2-one (0.33 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled to -40 °C, then LDA (2 mol / L, 4 mL, 8 mmol) was added. The mixture was stirred for 30 min, then warmed to 0 °C, 1,2-dibromoethane (1.14 g, 6 mmol) was added, and the mixture was stirred at room temperature for 24 h. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 mL) and water (15 mL), and the mixture was extracted with ethyl acetate twice (10 mL each time). The combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.21 g, 54%). ESI-QQQ-MS: m / z 194 [M+H] + .

[0266] Intermediate Preparation Example 9: Synthesis of 7'-methoxyspiro[cyclopropane-1,3'- indolin]-2'-one (P-9)

[0267]

[0268] Intermediate Preparation Example 10: Synthesis of 5',6'-difluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-10) + .

[0269] Intermediate Preparation Example 10: Synthesis of 5',6'-difluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-10)

[0270]

[0271] Intermediate Preparation Example 10: Synthesis of 5',6'-difluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-10) + .

[0272] Intermediate Preparation Example 10: Synthesis of 5',6'-difluorospiro[cyclopropane-l,3'- indolin]-2'-one (P-10)

[0273]

[0274] To a solution of 6-chloro-5-fluoroindolin-2-one (0.37 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL) was added LDA (2 mol / L, 4 mL, 8 mmol) at -40 °C. The mixture was stirred for 30 min and then warmed to 0 °C. 1,2-Dibromoethane (1.14 g, 6 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (5 mL) and water (15 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.21 g, 50%). ESI-QQQ-MS: m / z 212 [M+H] + .

[0275] Intermediate Preparation Example 12: Synthesis of 6',7'-difluorospiro[cyclopropane-1,3'- indolin]-2'-one (P-12)

[0276] (Step 1) (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino)acetamide

[0277]

[0278] To a mixture of chloral hydrate (1.4 g, 8.4 mmol), sodium sulfate (4.74 g, 33.4 mmol) and water (6 mL) was added a solution of 2,3-difluoroaniline (0.78 g, 6 mmol) in hydrochloric acid (0.6 mL) at room temperature. The mixture was stirred for 1 h and then hydroxylamine hydrochloride (0.58 g, 8.4 mmol) was added. The mixture was heated to 60 °C and stirred for 2 h. After cooling, the mixture was filtered to give the title compound (crude, 0.7 g) which was used directly in the next step. ESI-QQQ-MS: m / z 201 [M+H] + .

[0279] (Step 2) 6,7-difluoroindoline-2,3-dione

[0280]

[0281] To a solution of (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino)acetamide (0.7 g, 3.5 mmol) in sulfuric acid (2.5 mL) was heated to 80 °C and stirred for 3 h. After cooling, the mixture was poured into ice water (20 mL) and the precipitate was filtered and dried under reduced pressure to give the title compound (crude, 0.35 g). ESI-QQQ-MS: m / z 184 [M+H] + .

[0282] (Step 3) 6,7-difluoroindolin-2-one

[0283]

[0284] To a solution of 6,7-difluoroindoline-2,3-dione (0.35 g, 1.9 mmol) in ethylene glycol (2 mL) was added hydrazine hydrate (0.18 mL, 3.8 mmol) and heated to 130 °C for 4 h, then cooled to 25 °C for 16 h. Water (2 mL) and concentrated hydrochloric acid (0.2 mL) were added and heated to 45 °C for 1 h. The reaction mixture was cooled with ice bath and the precipitate was filtered and washed with water for 3 times. The precipitate was dried under reduced pressure at 90 °C to give the title compound (0.26 g, 70 %). ESI-QQQ-MS: m / z 170 [M+H] + .

[0285] (Step 4) 6',7'-difluoro[cyclopropane-l,3'-dihydroindol]-2'-one (P-12)

[0286]

[0287] To a solution of 6,7-difluoroindoline-2-one (0.26 g, 1.54 mmol) in anhydrous tetrahydrofuran (3 mL) was added LDA (2 mol / L, 3 mL, 6 mmol) at -40 °C and stirred for 30 min. The reaction mixture was warmed to 0 °C and 1,2-dibromoethane (0.87 g, 4.6 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. Saturated aqueous ammonium chloride solution (5 mL) and water (15 mL) were added to the reaction mixture. The organic phase was extracted with ethyl acetate (10 mL x 2), combined and washed with saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4: 1) to give the title compound (0.16 g, 53 %). ESI-QQQ-MS: m / z 196 [M+H] + .

[0288] Intermediate Preparation Example 13: Synthesis of 7-chloro-3,3-dimethylindolin-2-one (P-13)

[0289]

[0290] To a solution of 7-chloroindolin-2-one (0.34 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled to -40 °C, then LDA (2 mol / L, 4 mL, 8 mmol) was added. After stirring for 30 min, the reaction mixture was warmed to 0 °C, and iodomethane (0.85 g, 6 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 mL) and water (15 mL), and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.24 g, 61%). ESI-QQQ-MS: m / z 196 [M+H] + .

[0291] Intermediate Preparation Example 14: Synthesis of 7-chloro-2',3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one (P-14)

[0292]

[0293] To a solution of 7-chloroindolin-2-one (0.34 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL) was cooled to -40 °C, then LDA (2 mol / L, 4 mL, 8 mmol) was added. After stirring for 30 min, the reaction mixture was warmed to 0 °C, and iodomethane (0.85 g, 6 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 mL) and water (15 mL), and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine solution once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.24 g, 61%). ESI-QQQ-MS: m / z 196 [M+H] + .

[0294] Intermediate Preparation Example 15: Synthesis of 5'-(dimethylamino)spiro[cyclopropane-1,3'-indolin]-2'-one (P-15)

[0295] (Step 1) 5-(dimethylamino)indolin-2-one

[0296]

[0297] To a solution of 5-aminoindolin-2-one (0.30 g, 2 mmol) in glacial acetic acid (4 mL) was added sodium cyanoborohydride (0.31 g, 5 mmol) and paraformaldehyde (0.48 g, 16 mmol) successively. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. To the reaction mixture was added water (20 mL), and the mixture was extracted with ethyl acetate twice (10 mL each time). The combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 30:1) to give the title compound (0.24 g, 68%). ESI-QQQ-MS: m / z 177 [M+H] + .

[0298] (Step 2) 5'-(Dimethylamino)spiro[cyclopropane-1,3'-indolin]-2'-one (P-15)

[0299]

[0300] To a solution of 5-(dimethylamino)indolin-2-one (0.24 g, 1.35 mmol) in anhydrous tetrahydrofuran (3 mL) was added LDA (2 mol / L, 2.7 mL, 5.4 mmol) at -40 °C. The mixture was stirred for 30 min, and then 1,2-dibromoethane (0.76 g, 4.05 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 24 h. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 mL) and water (15 mL), and the mixture was extracted with ethyl acetate twice (10 mL each time). The combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.11 g, 40%). ESI-QQQ-MS: m / z 203 [M+H] + .

[0301] Intermediate Preparation Example 16: Synthesis of 6'-(dimethylamino)-5'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (P-16)

[0302] (Step 1) 6-(dimethylamino)-5-fluoroindolin-2-one

[0303]

[0304] To a solution of 6-amino-5-fluoroindolin-2-one (0.33 g, 2 mmol) in glacial acetic acid (4 mL) was added sodium cyanoborohydride (0.31 g, 5 mmol) and paraformaldehyde (0.48 g, 16 mmol) successively. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. Water (20 mL) and ethyl acetate (10 mL) were added to the reaction mixture. The mixture was allowed to stand to separate into layers. The ethyl acetate layer was extracted twice more. The organic layers were combined and washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (dichloromethane / methanol = 30:1) to give the title compound (0.25 g, 65%). ESI-QQQ-MS: m / z 195 [M+H] + .

[0305] (Step 2) 6'-(Dimethylamino)-5'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (P-16)

[0306]

[0307] To a solution of 6-(dimethylamino)-5-fluoroindolin-2-one (0.24 g, 1.3 mmol) in anhydrous tetrahydrofuran (3 mL) was added LDA (2 mol / L, 2.6 mL, 5.2 mmol) dropwise at -40 °C. The mixture was stirred for 30 min and then warmed to 0 °C. 1,2-Dibromoethane (0.73 g, 3.9 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. Saturated aqueous ammonium chloride solution (5 mL) and water (15 mL) were added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL) twice. The organic layers were combined and washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.12 g, 42%). ESI-QQQ-MS: m / z 221 [M+H] + .

[0308] Intermediate Preparation Example 17: Synthesis of spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one (P-17)

[0309]

[0310] Intermediate Preparation Example 18: Synthesis of 4-chloro-l-methyl-lH- benzo[d]imidazol-2(3H)-one (P-18) + .

[0311] Intermediate Preparation Example 18: Synthesis of 4-chloro-l-methyl-lH- benzo[d]imidazol-2(3H)-one (P-18)

[0312] (Step 1) 3-chloro-N-methyl-2-nitroaniline

[0313]

[0314] Intermediate Preparation Example 18: Synthesis of 4-chloro-l-methyl-lH- benzo[d]imidazol-2(3H)-one (P-18) + .

[0315] (Step 2) 3-chloro-N 1 -methylbenzene-l,2-diamine

[0316]

[0317] 3-Chloro-N-methyl-2-nitroaniline (0.3 g, 1.6 mmol) was dissolved in anhydrous methanol (4.5 mL), and zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol) were added. The mixture was heated to 50 °C and stirred for 3 h. The reaction solution was filtered, and the filter cake was washed twice with anhydrous ethanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted three times with dichloromethane (10 mL each time). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.24 g, 98%). ESI-QQQ-MS: m / z 157 [M+H] + .

[0318] (Step 3) 4-Chloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-18)

[0319]

[0320] 3-chloro-N 1 1,2-methylbenzene-1,2-diamine (0.2 g, 1.3 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and triethylamine (0.16 g, 1.6 mmol) was added. Triphosgene / dichloromethane solution (0.15 g / 1 mL) was slowly added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the concentrate. The mixture was extracted three times with dichloromethane (10 mL each time). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.19 g, 80%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0321] Intermediate Preparation Example 19: Synthesis of 6-chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-19)

[0322] (Step 1) 5-Chloro-N-cyclopropyl-2-nitroaniline

[0323]

[0324] To a solution of 4-chloro-2-fluoro-1-nitrobenzene (0.35 g, 2 mmol) in anhydrous ethanol (4 mL) was added N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol), and the reaction mixture was heated to reflux and stirred for 20 h. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water and saturated brine (each once), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.35 g, 82%). ESI-QQQ-MS: m / z 213 [M+H] + .

[0325] (Step 2) 5-Chloro-N 1 -cyclopropylbenzene-1,2-diamine

[0326]

[0327] To a solution of 5-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), and the reaction mixture was heated to 50 °C and stirred for 3 h. The reaction mixture was suction filtered, the filter cake was rinsed with anhydrous ethanol (2 mL x 2), the filtrates were combined, and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water and saturated brine (each once), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.27 g, 92%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0328] (Step 3) 6-chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-19)

[0329]

[0330] To a solution of 5-chloro-N-cyclopropylbenzene-1,2-diamine (0.24 g, 1.3 mmol) in dichloromethane (2 mL) was added triethylamine (0.16 g, 1.6 mmol), and the reaction mixture was cooled to 0 °C. To the reaction mixture was slowly added a solution of triphosgene in dichloromethane (0.15 g in 1 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water and saturated brine (each once), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.20 g, 74%). ESI-QQQ-MS: m / z 209 [M+H]+ .

[0331] Intermediate Preparation Example 20: Synthesis of 5-chloro-l-cyclopropyl-lH- benzo[d]imidazol-2(3H)-one (P-20)

[0332] (Step 1) 4-chloro-N-cyclopropyl-2-nitroaniline

[0333]

[0334] To a solution of 4-chloro-l-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in anhydrous ethanol (4 mL) was added N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol), and the reaction was heated to reflux and stirred for 20 h. The reaction was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The organic layers were combined, washed with water and saturated brine (each once), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.35 g, 85%). ESI-QQQ-MS: m / z 213 [M+H] + .

[0335] (Step 2) 4-chloro-N 1 -cyclopropylbenzene-l,2-diamine

[0336]

[0337] To a solution of 4-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), and the reaction was heated to 50 °C and stirred for 3 h. The reaction was filtered under suction, the filter cake was rinsed with anhydrous ethanol (2 mL x 2), the filtrates were combined, and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The organic layers were combined, washed with water and saturated brine (each once), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.26 g, 90%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0338] (Step 3) 5-chloro-l-cyclopropyl-lH-benzo[d]imidazol-2(3H)-one (P-20)

[0339]

[0340] To a solution of 4-chloro-N 1Cyclopropylbenzene-1,2-diamine (0.24 g, 1.3 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, triethylamine (0.16 g, 1.6 mmol) was added, and a solution of triphosgene in dichloromethane (0.15 g / 1 mL) was added slowly dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1 ) to give the title compound (0.19 g, 70%). ESI-QQQ-MS: m / z 209 [M+H] + .

[0341] Intermediate Preparation Example 21 : Synthesis of 4-chloro-1 - cyclopropyl-1 H-benzo[d]imidazol-2(3H)-one (P-21 )

[0342] (Step 1 ) 3-chloro-N-cyclopropyl-2-nitroaniline

[0343]

[0344] 1 -chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) was dissolved in anhydrous ethanol (4 mL), N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and cyclopropylamine (0.14 g, 2.4 mmol) were added, and the reaction was allowed to proceed at reflux for 20 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.37 g, 87%). ESI-QQQ-MS: m / z 213 [M+H] + .

[0345] (Step 2) 3-chloro-N 1 -cyclopropylbenzene-1,2-diamine

[0346]

[0347] To a solution of 3-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol) and the reaction mixture was warmed to 50 °C and stirred for 3 h. The reaction mixture was suction filtered, the filter cake was rinsed twice with anhydrous ethanol (2 mL each), the filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate and the mixture was extracted with dichloromethane (10 mL each, 3 times). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.27 g, 93%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0348] (Step 3) 4-Chloro-l-cyclopropyl-lH-benzo[d]imidazol-2(3H)-one (P-21)

[0349]

[0350] To a solution of 3-chloro-N-cyclopropylbenzene-l,2-diamine (0.24 g, 1.3 mmol) in dichloromethane (2 mL) was added triethylamine (0.16 g, 1.6 mmol) and the reaction mixture was cooled to 0 °C. To the reaction mixture was added a solution of triphosgene in dichloromethane (0.15 g in 1 mL) dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added to the concentrate. The mixture was extracted with dichloromethane (10 mL each, 3 times) and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4: 1) to give the title compound (0.18 g, 66%). ESI-QQQ-MS: m / z 209 [M+H] + .

[0351] Intermediate Preparation Example 22: Synthesis of 4-chloro-l-methyl-lH- benzo[d]imidazol-2(3H)-thione (P-22)

[0352]

[0353] To a solution of 3-chloro-N 1Methylbenzene-1,2-diamine (0.24 g, 1.3 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, triethylamine (0.16 g, 1.6 mmol) was added, and thionyl chloride / dichloromethane solution (0.18 g / 1 mL) was added slowly dropwise into the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, dichloromethane was extracted 3 times (10 mL each time), the organic layers were combined, washed with water and saturated brine once respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.14 g, 54%). ESI-QQQ-MS: m / z 199 [M+H] + .

[0354] Intermediate Preparation Example 23: Synthesis of 4-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-23)

[0355] (Step 1) N-(3-chloro-2-nitrophenyl)tetrahydro-2H-pyran-4-amine

[0356]

[0357] 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) was dissolved in anhydrous ethanol (4 mL), N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and tetrahydro-2H-pyran-4-amine (0.24 g, 2.4 mmol) were added, and the reaction was allowed to proceed at reflux with stirring for 20 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, dichloromethane was extracted 3 times (10 mL each time), the organic layers were combined, washed with water and saturated brine once respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.30 g, 59%). ESI-QQQ-MS: m / z 257 [M+H] + .

[0358] (Step 2) 3-chloro-N 1 -(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

[0359]

[0360] N-(3-chloro-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (0.28 g, 1.1 mmol) was dissolved in anhydrous methanol (4 mL), zinc powder (0.72 g, 11 mmol) and ammonium chloride (0.29 g, 5.5 mmol) were added, and the temperature was raised to 50 °C, and stirred for 3 h. The reaction solution was suction filtered, the filter cake was rinsed twice with anhydrous ethanol (2 mL each time), the filtrates were combined, concentrated under reduced pressure, water (20 mL) was added to the concentrate, extracted with dichloromethane three times (10 mL each time), the organic layers were combined, washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.22 g, 89%). ESI-QQQ-MS: m / z 227 [M+H] + .

[0361] (Step 3) 4-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-23)

[0362]

[0363] 3-chloro-N 1 -(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (0.22 g, 0.97 mmol) was dissolved in dichloromethane (2 mL), the temperature was lowered to 0 °C, triethylamine (0.13 g, 1.3 mmol) was added, and a solution of triphosgene in dichloromethane (0.12 g / 1 mL) was slowly added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, extracted with dichloromethane three times (10 mL each time), the organic layers were combined, washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound (0.12 g, 49%). ESI-QQQ-MS: m / z 253 [M+H] + .

[0364] Intermediate Preparation Example 24: Synthesis of 4-chloro-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-24)

[0365] (Step 1) N-(3-chloro-2-nitrophenyl)-1-methylpiperidin-4-amine

[0366]

[0367] To a solution of 3-chloro-2-nitrobenzonitrile (0.50 g, 2.6 mmol) in anhydrous ethanol (4 mL) was added N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 1-methylpiperidin-4-amine (0.27 g, 2.4 mmol) and the reaction mixture was heated to reflux and stirred for 20 h. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added to the concentrate. The mixture was extracted with dichloromethane (10 mL) three times and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.28 g, 51%). ESI-QQQ-MS: m / z 270 [M+H] + .

[0368] (Step 2) 3-Chloro-N 1 -(1-methylpiperidin-4-yl)benzene-1,2-diamine

[0369]

[0370] To a solution of N-(3-chloro-2-nitrophenyl)-1-methylpiperidin-4-amine (0.27 g, 1.0 mmol) in anhydrous methanol (4 mL) was added zinc powder (0.65 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol) and the reaction mixture was heated to 50 °C and stirred for 3 h. The reaction mixture was suction filtered and the filter cake was rinsed with anhydrous ethanol (2 mL) twice. The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate and the mixture was extracted with dichloromethane (10 mL) three times. The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.22 g, 92%). ESI-QQQ-MS: m / z 240 [M+H] + .

[0371] (Step 3) 4-Chloro-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-24)

[0372]

[0373] To a solution of 3-chloro-N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine (0.22 g, 0.92 mmol) in dichloromethane (2 mL) was added triethylamine (0.12 g, 1.2 mmol) at 0 °C, and then a solution of triphosgene in dichloromethane (0.11 g / 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic layers were washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to give the title compound (0.11 g, 45%). ESI-QQQ-MS: m / z 266 [M+H] + .

[0374] Intermediate Preparation Example 25: Synthesis of 4-fluoro-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-25)

[0375] (Step 1) 3-Fluoro-N-methyl-2-nitroaniline

[0376]

[0377] To a solution of 3-chloro-N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine (0.22 g, 0.92 mmol) in dichloromethane (2 mL) was added triethylamine (0.12 g, 1.2 mmol) at 0 °C, and then a solution of triphosgene in dichloromethane (0.11 g / 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic layers were washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to give the title compound (0.11 g, 45%). ESI-QQQ-MS: m / z 266 [M+H] + .

[0378] (Step 2) 3-Fluoro-N 1 -methylbenzene-1,2-diamine

[0379]

[0380] 3-Fluoro-N-methyl-2-nitroaniline (0.27 g, 1.6 mmol) was dissolved in anhydrous methanol (4.5 mL), and zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol) were added. The mixture was heated to 50 °C and stirred for 3 h. The reaction solution was filtered, and the filter cake was washed twice with anhydrous ethanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted three times with dichloromethane (10 mL each time). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.22 g, 98%). ESI-QQQ-MS: m / z 141 [M+H] + .

[0381] (Step 3) 4-Fluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-25)

[0382]

[0383] 3-fluoro-N 1 1,2-methylbenzene-1,2-diamine (0.18 g, 1.3 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and triethylamine (0.16 g, 1.6 mmol) was added. Triphosgene / dichloromethane solution (0.15 g / 1 mL) was slowly added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the concentrate. The mixture was extracted three times with dichloromethane (10 mL each time). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.17 g, 78%). ESI-QQQ-MS: m / z 167 [M+H] + .

[0384] Intermediate Preparation Example 26: Synthesis of 4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-26)

[0385] (Step 1) 3,5-Difluoro-N-methyl-2-nitroaniline

[0386]

[0387] To a solution of 3,5-difluoro-2-nitroaniline (0.24 g, 1.3 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (0.85 g, 13 mmol) and ammonium chloride (0.35 g, 6.5 mmol) and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was filtered under suction and the filter cake was rinsed twice with anhydrous methanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate and the mixture was extracted with dichloromethane (10 mL each time, 3 times). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.19 g, 92%). ESI-QQQ-MS: m / z 159 [M+H] + .

[0388] (Step 2) 3,5-Difluoro-N 1 -methylbenzene-1,2-diamine

[0389]

[0390] To a solution of 3,5-difluoro-2-nitroaniline (0.24 g, 1.3 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (0.85 g, 13 mmol) and ammonium chloride (0.35 g, 6.5 mmol) and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was filtered under suction and the filter cake was rinsed twice with anhydrous methanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate and the mixture was extracted with dichloromethane (10 mL each time, 3 times). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.19 g, 92%). ESI-QQQ-MS: m / z 159 [M+H] + .

[0391] (Step 3) 4,6-Difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-26)

[0392]

[0393] To a solution of 3,5-difluoro-2-nitroaniline (0.24 g, 1.3 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (0.85 g, 13 mmol) and ammonium chloride (0.35 g, 6.5 mmol) and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was filtered under suction and the filter cake was rinsed twice with anhydrous methanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate and the mixture was extracted with dichloromethane (10 mL each time, 3 times). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.19 g, 92%). ESI-QQQ-MS: m / z 159 [M+H] 1Methylbenzene-1, 2-diamine (0.17 g, 1.1 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, triethylamine (0.14 g, 1.4 mmol) was added, and a solution of triphosgene in dichloromethane (0.15 g / 1 mL) was slowly added dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.16 g, 80%). ESI-QQQ-MS: m / z 185 [M+H] + .

[0394] Intermediate Preparation Example 27: Synthesis of 5,6-dichloro-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-27)

[0395] (Step 1) 4,5-dichloro-N-methyl-2-nitroaniline

[0396]

[0397] 1,2-dichloro-4-fluoro-5-nitrobenzene (0.42 g, 2 mmol) was dissolved in anhydrous ethanol (4 mL), N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol) were added, and the reaction was allowed to proceed at reflux for 20 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.4 g, 90%). ESI-QQQ-MS: m / z 221 [M+H] + .

[0398] (Step 2) 4,5-dichloro-N 1 -methylbenzene-1, 2-diamine

[0399]

[0400] To a solution of 4,5-dichloro-N-methyl-2-nitroaniline (0.35 g, 1.6 mmol) in anhydrous methanol (4.5 mL), zinc powder (1.0 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol) were added, and the reaction mixture was warmed to 50 °C and stirred for 3 h. The reaction mixture was suction filtered, and the filter cake was rinsed twice with anhydrous ethanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL each time, 3 times). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.29 g, 95%). ESI-QQQ-MS: m / z 191 [M+H] + .

[0401] (Step 3) 5,6-Dichloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-27)

[0402]

[0403] To a solution of 4,5-dichloro-N 1 -methylbenzene-1,2-diamine (0.29 g, 1.5 mmol) in dichloromethane (2 mL), triethylamine (0.14 g, 1.9 mmol) was added, and the reaction mixture was cooled to 0 °C. Triflic anhydride (0.18 g in 1 mL of dichloromethane) was slowly added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL each time, 3 times). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.24 g, 74%). ESI-QQQ-MS: m / z 217 [M+H] + .

[0404] Intermediate Preparation Example 28: Synthesis of 1-cyclopropyl-4-fluoro-1H- benzo[d]imidazol-2(3H)-one (P-28)

[0405] (Step 1) N-cyclopropyl-3-fluoro-2-nitroaniline

[0406]

[0407] To a solution of 3-fluoro-2-nitroaniline (0.50 g, 3.2 mmol) in anhydrous ethanol (5 mL) was added N,N-diisopropylethylamine (0.68 g, 5.2 mmol) and cyclopropylamine (0.28 g, 4.8 mmol) at room temperature. The reaction mixture was stirred at reflux for 20 h. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water and saturated brine solution once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.35 g, 90%). ESI-QQQ-MS: m / z 197 [M+H] + .

[0408] (Step 2) N 1 -cyclopropyl 3-fluoro-benzene-1,2-diamine

[0409]

[0410] To a solution of N-cyclopropyl-3-fluoro-2-nitroaniline (0.31 g, 1.6 mmol) in anhydrous methanol (4.5 mL) was added zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol) at 50 °C. The reaction mixture was stirred for 3 h. The reaction mixture was suction filtered, the filter cake was rinsed with anhydrous ethanol (2 mL x 2), the filtrates were combined, and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with water and saturated brine solution once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.26 g, 96%). ESI-QQQ-MS: m / z 167 [M+H] + .

[0411] (Step 3) 1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-2(3H)-one (P-28)

[0412]

[0413] To a solution of N 1Cyclopropyl 3-fluoro-benzene-1,2-diamine (0.22 g, 1.3 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, triethylamine (0.16 g, 1.6 mmol) was added, and a solution of triphosgene in dichloromethane (0.15 g / 1 mL) was added dropwise to the reaction system slowly. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.19 g, 75%). ESI-QQQ-MS: m / z 193 [M+H] + .

[0414] Intermediate Preparation Example 29: Synthesis of 4,5-difluoro-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-29)

[0415] Step 1) 1,2,4-trifluoro-3-nitrobenzene

[0416]

[0417] A mixture of 65% concentrated nitric acid (2 mL) and 98% concentrated sulfuric acid (4 mL) was prepared, and 1,2,4-trifluorobenzene (1.32 g) was added dropwise slowly. The reaction was allowed to proceed at 30 °C for 2 h. The layers were separated after standing, and the organic phase was washed with saturated sodium carbonate solution twice, saturated brine, and concentrated under reduced pressure to give the title compound (1.7 g, 95%). ESI-QQQ-MS: m / z 178 [M+H] + .

[0418] Step 2) 3,4-difluoro-N-methyl-2-nitroaniline

[0419]

[0420] 1,2,4-trifluoro-3-nitrobenzene (0.35 g, 2 mmol) was dissolved in anhydrous ethanol (4 mL), and N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol) were added. The reaction was allowed to proceed at 50 °C for 12 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.2 g, 50%). ESI-QQQ-MS: m / z 189 [M+H] + .

[0421] Step 3) 3,4-difluoro-N1 - methylbenzene-1, 2-diamine

[0422]

[0423] To a solution of 3, 4-difluoro-N-methyl-2-nitroaniline (0.19 g, 1 mmol) in anhydrous methanol (3 mL), zinc powder (0.66 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol) were added, and the reaction was warmed to 50 °C and stirred for 3 h. The reaction was filtered under suction, and the filter cake was rinsed twice with anhydrous ethanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.14 g, 90%). ESI-QQQ-MS: m / z 159 [M+H] + .

[0424] (Step 4) 4, 5-difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-29)

[0425]

[0426] To a solution of 3, 4-difluoro-N 1 methylbenzene-1, 2-diamine (0.14 g, 0.89 mmol) in dichloromethane (2 mL), triethylamine (0.1 g, 1.2 mmol) was added, and the reaction was slowly added with a solution of triphosgene in dichloromethane (0.1 g / 1 mL) at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and water (20 mL) was added to the concentrate. The mixture was extracted with dichloromethane three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.12 g, 74%). ESI-QQQ-MS: m / z 185 [M+H] + .

[0427] Intermediate Preparation Example 30: Synthesis of 6, 7-difluoro-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-30)

[0428] (Step 1) 2, 3-difluoro-N-methyl-6-nitroaniline

[0429]

[0430] To a solution of 3,4-difluoro-2-nitroaniline (0.19 g, 1 mmol) in anhydrous methanol (3 mL) was added zinc powder (0.66 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol) at 50 °C and stirred for 3 h. The reaction was filtered off and the filter cake was washed with anhydrous methanol twice (2 mL each). The filtrate was combined and concentrated under reduced pressure. To the concentrate was added water (20 mL) and extracted with dichloromethane three times (10 mL each). The organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.14 g, 88%). ESI-QQQ-MS: m / z 159 [M+H] + .

[0431] (Step 3) 5,6-Difluoro-N 1 -methylbenzene-1,2-diamine

[0432]

[0433] To a solution of 3,4-difluoro-2-nitroaniline (0.19 g, 1 mmol) in anhydrous methanol (3 mL) was added zinc powder (0.66 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol) at 50 °C and stirred for 3 h. The reaction was filtered off and the filter cake was washed with anhydrous methanol twice (2 mL each). The filtrate was combined and concentrated under reduced pressure. To the concentrate was added water (20 mL) and extracted with dichloromethane three times (10 mL each). The organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.14 g, 88%). ESI-QQQ-MS: m / z 159 [M+H] + .

[0434] (Step 4) 6,7-Difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-30)

[0435]

[0436] To a solution of 3,4-difluoro-2-nitroaniline (0.19 g, 1 mmol) in anhydrous methanol (3 mL) was added zinc powder (0.66 g, 10 mmol) and ammonium chloride (0.27 g, 5 mmol) at 50 °C and stirred for 3 h. The reaction was filtered off and the filter cake was washed with anhydrous methanol twice (2 mL each). The filtrate was combined and concentrated under reduced pressure. To the concentrate was added water (20 mL) and extracted with dichloromethane three times (10 mL each). The organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.14 g, 88%). ESI-QQQ-MS: m / z 159 [M+H] 1Methylbenzene-1, 2-diamine (0.12 g, 0.76 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, triethylamine (0.1 g, 1.2 mmol) was added, and a solution of triphosgene in dichloromethane (0.1 g / 1 mL) was slowly added dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.13 g, 80%). ESI-QQQ-MS: m / z 185 [M+H] + .

[0437] Intermediate Preparation Example 31: Synthesis of 4-methoxy-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-31)

[0438] (Step 1) 3-methoxy-N-methyl-2-nitroaniline

[0439]

[0440] 1-fluoro-3-methoxy-2-nitrobenzene (0.34 g, 2 mmol) was dissolved in anhydrous ethanol (4 mL), N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol) were added, and the reaction was allowed to proceed at reflux for 20 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.29 g, 80%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0441] (Step 2) 3-methoxy-N 1 -methylbenzene-1, 2-diamine

[0442]

[0443] To a solution of 3-methoxy-N-methyl-2-nitroaniline (0.27 g, 1.5 mmol) in anhydrous methanol (4.5 mL), zinc powder (0.98 g, 15 mmol) and ammonium chloride (0.4 g, 7.5 mmol) were added, and the reaction mixture was warmed to 50 °C and stirred for 3 h. The reaction mixture was suction filtered, and the filter cake was rinsed twice with anhydrous ethanol (2 mL each time). The filtrates were combined and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and the mixture was extracted with dichloromethane (10 mL each time, three times). The organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.21 g, 92%). ESI-QQQ-MS: m / z 153 [M+H] + .

[0444] (Step 3) 4-Methoxy-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-31)

[0445]

[0446] To a solution of 3-methoxy-N 1 -methylbenzene-1,2-diamine (0.2 g, 1.3 mmol) in dichloromethane (2 mL), triethylamine (0.14 g, 1.7 mmol) was added, and the reaction mixture was cooled to 0 °C. Triflic anhydride (0.15 g in 1 mL of dichloromethane) was slowly added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the concentrate. The mixture was extracted with dichloromethane (10 mL each time, three times). The organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.16 g, 70%). ESI-QQQ-MS: m / z 179 [M+H] + .

[0447] Intermediate Preparation Example 32: Synthesis of 5-(dimethylamino)-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-32)

[0448] (Step 1) N 1 -methyl-4-nitrobenzene-1,2-diamine

[0449]

[0450] To a solution of 4-nitrobenzene-1,2-diamine (0.33 g, 2 mmol) in DMF (4 mL) was added saturated aqueous sodium carbonate solution (0.5 mL) and iodomethane (0.24 g, 1.7 mmol) successively, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue. The mixture was extracted with dichloromethane (10 mL) three times, and the combined organic layer was washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.2 g, 60%). ESI-QQQ-MS: m / z 168 [M+H] + .

[0451] (Step 2) 1-Methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0452]

[0453] To a solution of N 1 To a solution of 4-nitrobenzene-1,2-diamine (0.33 g, 2 mmol) in DMF (4 mL) was added saturated aqueous sodium carbonate solution (0.5 mL) and iodomethane (0.24 g, 1.7 mmol) successively, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue. The mixture was extracted with dichloromethane (10 mL) three times, and the combined organic layer was washed with water and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give the title compound (0.2 g, 60%). ESI-QQQ-MS: m / z 168 [M+H] + .

[0454] (Step 3) 5-Amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[0455]

[0456] To a solution of 5-amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one (0.12 g, 0.73 mmol) in dry DMF (3 mL) was added sodium hydride (0.07 g, 2.9 mmol) and stirred for 0.5 h. Then iodomethane (0.26 g, 1.8 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate twice (5 mL each time). The organic phase was combined and washed with saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10:1) to give the title compound (0.06 g, 40%). ESI-QQQ-MS: m / z 192 [M+H] + .

[0457] (Step 4) 5-(Dimethylamino)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-32)

[0458]

[0459] To a solution of 5-amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one (0.12 g, 0.73 mmol) in dry DMF (3 mL) was added sodium hydride (0.07 g, 2.9 mmol) and stirred for 0.5 h. Then iodomethane (0.26 g, 1.8 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate twice (5 mL each time). The organic phase was combined and washed with saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10:1) to give the title compound (0.06 g, 40%). ESI-QQQ-MS: m / z 192 [M+H] + .

[0460] Intermediate Preparation Example 33: Synthesis of 6-(dimethylamino)-1-methyl-1H- benzo[d]imidazol-2(3H)-one (P-33)

[0461] (Step 1) 1-methyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0462]

[0463] To a solution of 5-amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one (0.12 g, 0.73 mmol) in dry DMF (3 mL) was added sodium hydride (0.07 g, 2.9 mmol) and stirred for 0.5 h. Then iodomethane (0.26 g, 1.8 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate twice (5 mL each time). The organic phase was combined and washed with saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10:1) to give the title compound (0.06 g, 40%). ESI-QQQ-MS: m / z 192 [M+H] 1Methyl-5-nitrobenzene-1,2-diamine (0.33 g, 2 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 °C, triethylamine (0.14 g, 2.6 mmol) was added, and a solution of triphosgene in dichloromethane (0.24 g / 1 mL) was slowly added dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound (0.23 g, 60%). ESI-QQQ-MS: m / z 194 [M+H] + .

[0464] (Step 2) 6-Amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[0465]

[0466] 1-Methyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one (0.23 g, 1.2 mmol) was dissolved in anhydrous methanol (4.5 mL), and zinc powder (0.91 g, 12 mmol) and ammonium chloride (0.37 g, 6 mmol) were added. The reaction was allowed to proceed at 50 °C for 3 h. The reaction solution was suction filtered, the filter cake was rinsed twice with anhydrous ethanol (2 mL each time), the filtrates were combined, and concentrated under reduced pressure. Water (20 mL) was added to the concentrate, and dichloromethane was extracted three times (10 mL each time). The organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.16 g, 81%). ESI-QQQ-MS: m / z 164 [M+H] + .

[0467] (Step 3) 6-(Dimethylamino)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-33)

[0468]

[0469] Dissolve 6-amino-l-methyl-lH-benzo[d]imidazol-2(3H)-one (0.16 g, 0.98 mmol) in anhydrous DMF (3 mL), add sodium hydride (0.1 g, 4 mmol), stir for 0.5 h, then add iodomethane (0.36 g, 2.5 mmol), and react at room temperature for 12 h. Concentrate the reaction mixture under reduced pressure, add water (20 mL) to the reaction mixture, extract twice with ethyl acetate (10 mL each time), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the concentrate by column chromatography on silica gel (dichloromethane / methanol = 10:1) to obtain the title compound (0.08 g, 42%). ESI-QQQ-MS: m / z 192 [M+H] + .

[0470] Intermediate Preparation Example 34: Synthesis of 2,4,6-trichlorobenzoyl chloride (P-34)

[0471]

[0472] Dissolve 2,4,6-trichlorobenzoic acid (0.23 g, 1 mmol) in 5 mL of dichloromethane, add dichlorosulfoxide (0.24 g, 2 mmol) and DMF (3 drops), and react at room temperature for 3 h. Concentrate the reaction mixture to dryness under reduced pressure to obtain the title compound, which is used directly in the next reaction.

[0473] Intermediate Preparation Example 35: Synthesis of 2,6-dichloro-4-(diethylamino)benzoyl chloride (P-35)

[0474] (Step 1) Methyl 4-bromo-2,6-dichlorobenzoate

[0475]

[0476] Dissolve 4-bromo-2,6-dichlorobenzoic acid (0.27 g, 1 mmol) in 5 mL of methanol, cool to 0°C, add dichlorosulfoxide (0.24 g, 2 mmol) to the reaction mixture, and react at room temperature for 3 h. Concentrate the reaction mixture under reduced pressure, add ethyl acetate (5 mL) and saturated aqueous sodium bicarbonate solution (10 mL), separate the layers by standing, wash the organic layer once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the concentrate by column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (0.24 g, 85%). ESI-QQQ-MS: m / z 283 [M+H] + .

[0477] (Step 2) Methyl 2,6-dichloro-4-(diethylamino)benzoate

[0478]

[0479] A mixture of 4-bromo-2,6-dichlorobenzoic acid methyl ester (0.24 g, 0.85 mmol), diethylamine (0.12 g, 1.7 mmol), palladium acetate (10 mg, 5 mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63 mg, 10 mol%), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL) was purged with nitrogen and subjected to microwave irradiation at 120 °C for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water (10 mL) was added and the mixture was extracted twice with ethyl acetate (5 mL each time). The combined organic layers were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2:1) to give the title compound (0.16 g, 70%). ESI-QQQ-MS: m / z 276 [M+H] + .

[0480] (Step 3) 2,6-Dichloro-4-(diethylamino)benzoyl chloride (P-35)

[0481]

[0482] A mixture of 2,6-dichloro-4-(diethylamino)benzoic acid methyl ester (0.16 g, 0.58 mmol) in methanol (3 mL) and water (0.5 mL) was treated with 6 N sodium hydroxide solution (0.15 mL, 0.87 mmol) and stirred at room temperature for 24 h. The reaction mixture was adjusted to pH 5-6 with 2 N hydrochloric acid, filtered and the filter cake was washed with water three times and dried under reduced pressure. The dried solid was dissolved in dichloromethane (3 mL), treated with dichloromethane sulfoxide (0.13 g, 1.1 mmol) and DMF (2 drops) and stirred at room temperature for 4 h. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound, which was used directly in the next step.

[0483] Intermediate Preparation Example 36: Synthesis of 2,6-dichloro-4-morpholinobenzoyl chloride (P-36)

[0484] (Step 1) 2,6-Dichloro-4-morpholinobenzoic acid methyl ester

[0485]

[0486] Methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), morpholine (0.1 g, 1.2 mmol), palladium acetate (10 mg, 5 mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63 mg, 10 mol%), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL) were mixed, purged with nitrogen, and subjected to microwave reaction at 120 °C for 2 h. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, water solution (10 mL) was added, and the mixture was extracted with ethyl acetate twice (5 mL each time). The combined organic layer was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (0.18 g, 74%). ESI-QQQ-MS: m / z 290 [M+H] + .

[0487] (Step 2) 2,6-Dichloro-4-morpholinobenzoyl chloride (P-36)

[0488]

[0489] Methyl 2,6-dichloro-4-morpholinobenzoate (0.18 g, 0.62 mmol) was dissolved in methanol (3 mL) and water (0.5 mL), and 6 N sodium hydroxide solution (0.16 mL, 0.93 mmol) was added. The mixture was stirred at room temperature for 24 h. The reaction solution was adjusted to 5-6 with 2 N hydrochloric acid, filtered, and the filter cake was washed with water three times and dried under reduced pressure. The dried solid was dissolved in 3 mL of dichloromethane, and dichlorosulfoxide (0.14 g, 1.2 mmol) and DMF (2 drops) were added. The mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give the title compound, which was used directly in the next reaction.

[0490] Intermediate Preparation Example 37: Synthesis of 4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzoyl chloride (P-37)

[0491] (Step 1) Methyl 4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2,6-dichlorobenzoate

[0492]

[0493] Methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), 2-oxa-5- azabicyclo[2.2.1]heptane (0.12 g, 1.2 mmol), palladium acetate (10 mg, 5 mol%), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (63 mg, 10 mol%), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL) were mixed, purged with nitrogen, and subjected to microwave reaction at 120 °C for 2 h. The reaction was filtered through celite, the filtrate was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted twice with ethyl acetate (5 mL each time). The combined organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (0.2 g, 78%). ESI-QQQ-MS: m / z 302 [M+H] + .

[0494] (Step 2) 4-(2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzoyl chloride (P-37)

[0495]

[0496] Methyl 4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzoate (0.2 g, 0.66 mmol) was dissolved in methanol (3 mL) and water (0.5 mL), and 6N sodium hydroxide solution (0.17 mL, 0.99 mmol) was added. The mixture was stirred at room temperature for 24 h. The reaction was adjusted to 5-6 with 2N hydrochloric acid, filtered, and the filter cake was washed with water three times and dried under reduced pressure. The dried solid was dissolved in 3 mL of dichloromethane, and thionyl chloride (0.15 g, 1.3 mmol) and DMF (2 drops) were added. The mixture was stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure to give the title compound, which was used directly in the next reaction.

[0497] Intermediate Preparation Example 38: Synthesis of 2,6-dichloro-4-(4- morpholinopiperidin-1-yl)benzoyl chloride (P-38)

[0498] (Step 1) Methyl 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoate

[0499]

[0500] Methyl 4-bromo-2,6-dichlorobenzoate (0.24 g, 0.85 mmol), 4-(piperidin-4- yl)morpholine (0.2 g, 1.2 mmol), palladium acetate (10 mg, 5 mol%), (±)-2,2'- bis-(diphenylphosphino)-1,1 '-binaphthyl (63 mg, 10 mol%), cesium carbonate (0.3 g, 0.92 mmol) and anhydrous dioxane (6 mL) were mixed, purged with nitrogen and subjected to microwave reaction at 120 °C for 2 h. The reaction was filtered through celite, the filtrate was concentrated under reduced pressure, water (10 mL) was added, the mixture was extracted twice with ethyl acetate (5 mL each time), the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (0.23 g, 72%). ESI-QQQ-MS: m / z 373 [M+H] + .

[0501] (Step 2) Methyl 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoate (P-38)

[0502]

[0503] Methyl 2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoate (0.23 g, 0.62 mmol) was dissolved in methanol (3 mL) and water (0.5 mL), 6 N sodium hydroxide solution (0.16 mL, 0.93 mmol) was added and the mixture was allowed to react at room temperature for 24 h. The reaction was adjusted to 5-6 with 2 N hydrochloric acid, filtered, the filter cake was washed with water three times and dried under reduced pressure. The dried solid was dissolved in 3 mL of dichloromethane, thionyl chloride (0.14 g, 1.2 mmol) and DMF (2 drops) were added and the mixture was allowed to react at room temperature for 4 h. The reaction was concentrated to dryness under reduced pressure to give the title compound which was used directly in the next reaction.

[0504] Example 1: Synthesis of Compound 1

[0505] (Step 1) (S)-Methyl 3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1 '- yl)phenyl)-2-(triphenylmethylamino)propanoate

[0506]

[0507] P-10 (98 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (215 mg, 70%). ESI-QQQ-MS: m / z 615 [M+H] + .

[0508] (S)-2-amino-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid

[0509]

[0510] (S)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (154 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (86 mg, 92%). ESI-QQQ-MS: m / z 373 [M+H] + .

[0511] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-l'-phenyl)propanoic acid methyl ester

[0512]

[0513] Methyl (S)-2-amino-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoate (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the phases were allowed to separate. The aqueous phase was extracted twice with dichloromethane (2 mL each time), and the combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (107 mg, 88%). ESI-QQQ-MS: m / z 529 [M+H] + .

[0514] (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-l'-yl)phenyl)propanoic acid

[0515]

[0516] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-l'-yl)phenyl)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (57 mg, 65%). ESI-QQQ-MS: m / z 515 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.90 (br s, 1H), 9.16 (d, J = 8.3 Hz, 1H), 7.50-7.42 (m, 3H), 7.39-7.28 (m, 4H), 7.24 (t, J = 8.6 Hz, 1H), 6.74-6.70 (m, 1H), 4.77-4.72 (m, 1H), 3.25 (dd, J = 14.0, 4.4 Hz, 1H), 3.00 (dd, J = 13.9, 10.5 Hz, 1H), 1.79-1.77 (m, 2H), 1.66-1.63 (m, 2H).

[0517] Example 2: Synthesis of compound 2

[0518] (Step 1) (S)-methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(triphenylmethylamino)propanoate

[0519]

[0520] P-6 (97 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (178 mg, 58%). ESI-QQQ-MS: m / z 613 [M+H] + .

[0521] (Step 2) (S)-methyl 2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoate

[0522]

[0523] (S)-methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (triphenylmethylamino)propanoate (153 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (83 mg, 90%). ESI-QQQ-MS: m / z 371 [M+H] + .

[0524] (Step 3) (S)-methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (2-chloro-6-fluorobenzamido)propanoate

[0525]

[0526] Methyl (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were allowed to separate. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the organic layers were combined. The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (112 mg, 92%). ESI-QQQ-MS: m / z 527 [M+H] + .

[0527] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2-chloro-6- fluorobenzamido)propanoic acid

[0528]

[0529] Methyl (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2-chloro- 6-fluorobenzamido)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction mixture was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to give the title compound (55 mg, 63%). ESI-QQQ-MS: m / z 513 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.84 (br s, 1H), 9.19 (d, J = 8.1 Hz, 1H), 7.47-7.40 (m, 3H), 7.33-7.23 (m, 4H), 7.19-7.17 (m, 1H), 7.08-7.02 (m, 2H), 4.72-4.67 (m, 1H), 3.22 (dd, J = 14.1, 4.3 Hz, 1H), 3.01 (dd, J = 14.1, 10.3 Hz, 1H), 1.78-1.76 (m, 2H), 1.68-1.66 (m, 2H).

[0530] Example 3: Synthesis of compound 4

[0531] (Step 1) (S)-methyl 3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)-2-(triphenylmethylamino)propanoate

[0532]

[0533] P-9 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction was protected by nitrogen, and the temperature was raised to 100 °C. After 36 h, the temperature was lowered, and the reaction mixture was filtered through diatomite. The filter cake was washed twice with acetonitrile (1 mL each time), and the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (188 mg, 62%). ESI-QQQ-MS: m / z 609 [M+H] + .

[0534] (Step 2) (S)-methyl 2-amino-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)propanoate

[0535]

[0536] (S)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (152 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane, the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (83 mg, 91%). ESI-QQQ-MS: m / z 367 [M+H] + .

[0537] (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid methyl ester

[0538]

[0539] (S)-2-amino-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid methyl ester (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0°C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (109 mg, 88%). ESI-QQQ-MS: m / z 539 [M+H] + .

[0540] (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid

[0541]

[0542] (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid methyl ester (92 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the combined organic layers were washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (52 mg, 59%). ESI-QQQ-MS: m / z 525 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.74 (br s, 1H), 9.15 (d, J = 8.2 Hz, 1H), 7.46-7.32 (m, 5H), 7.19 (d, J = 8.2 Hz, 2H), 7.02 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 4.74-4.69 (m, 1H), 3.46 (s, 3H), 3.19 (dd, J = 14.0, 4.7 Hz, 1H), 2.99 (dd, J = 14.0, 9.8 Hz, 1H), 1.68-1.64 (m, 2H), 1.62-1.58 (m, 2H).

[0543] Example 4: Synthesis of compound 6

[0544] (Step 1) (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester

[0545]

[0546] P-4 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (202 mg, 68%). ESI-QQQ-MS: m / z 597 [M+H] + .

[0547] (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid

[0548]

[0549] (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (triphenylmethylamino)propanoic acid methyl ester (149 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (84 mg, 95%). ESI-QQQ-MS: m / z 355 [M+H] + .

[0550] (S)-2-(2,6-dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoic acid methyl ester

[0551]

[0552] Methyl (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the phases were allowed to separate. The aqueous phase was extracted twice with dichloromethane (2 mL each time), and the organic phases were combined. The organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (108 mg, 89%). ESI-QQQ-MS: m / z 527 [M+H] + .

[0553] (S)-2-(2,6-Dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]- 1'-yl)phenyl)propanoic acid

[0554]

[0555] Methyl (S)-2-(2,6-dichlorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic phases were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m / z 513 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.75 (br s, 1H), 9.13 (d, J = 8.4 Hz, 1H), 7.51-7.49 (m, 2H), 7.45-7.32 (m, 5H), 7.15-7.13 (m, 1H), 6.93-6.79 (m, 1H), 6.53-6.51 (m, 1H), 4.83-4.71 (m, 1H), 3.25 (dd, J = 14.0, 4.3 Hz, 1H), 2.99 (dd, J = 13.9, 10.7 Hz, 1H), 1.75-1.71 (m, 2H), 1.64-1.60 (m, 2H).

[0556] Example 5: Synthesis of compound 7

[0557] (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester

[0558]

[0559] P-3 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (182 mg, 61%). ESI-QQQ-MS: m / z 597 [M+H] + .

[0560] (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester

[0561]

[0562] (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (149 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (85 mg, 96%). ESI-QQQ-MS: m / z 355 [M+H] + .

[0563] (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester

[0564]

[0565] Methyl (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were allowed to separate. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (109 mg, 90%). ESI-QQQ-MS: m / z 527 [M+H] + .

[0566] (S)-2-(2,6-Dichlorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]- 1'-yl)phenyl)propanoic acid

[0567]

[0568] Methyl (S)-2-(2,6-dichlorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to give the title compound (51 mg, 58%). ESI-QQQ-MS: m / z 513 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.79 (br s, 1H), 9.15 (d, J = 8.3 Hz, 1H), 7.44-7.37 (m, 5H), 7.35-7.31 (m, 2H), 7.11-7.01 (m, 2H), 6.97-6.91 (m, 1H), 4.74-4.72 (m, 1H), 3.22 (dd, J = 14.1, 4.3 Hz, 1H), 2.99 (dd, J = 14.1, 10.4 Hz, 1H), 1.79-1.74 (m, 2H), 1.69-1.64 (m, 2H).

[0569] Example 6: Synthesis of compound 8

[0570] (Step 1) (S)-methyl 3-(4-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(triphenylmethylamino)propanoate

[0571]

[0572] P-2 (80 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen, and the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (197 mg, 68%). ESI-QQQ-MS: m / z 579 [M+H] + .

[0573] (Step 2) (S)-methyl 2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoate

[0574]

[0575] (S)-3-(4-(2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (145 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane, the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (79 mg, 94%). ESI-QQQ-MS: m / z 337 [M+H] + .

[0576] (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid methyl ester

[0577]

[0578] (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid methyl ester (77 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (111 mg, 95%). ESI-QQQ-MS: m / z 509 [M+H] + .

[0579] (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid

[0580]

[0581] Methyl (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoate (87 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was reacted at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and dichloromethane was extracted three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 64%). ESI-QQQ-MS: m / z 495 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.85 (br s, 1H), 9.14 (d, J = 8.4 Hz, 1H), 7.51-7.33 (m, 7H), 7.20-7.19 m, 1H), 7.13-7.03 (m, 2H), 6.76 (d, J = 7.9 Hz, 1H), 4.78-4.76 (m, 1H), 3.25 (dd, J = 14.0, 4.4 Hz, 1H), 3.00 (dd, J = 14.0, 10.5 Hz, 1H), 1.73-1.69 (m, 2H), 1.65-1.61 (m, 2H).

[0582] Example 7: Synthesis of compound 9

[0583] (Step 1) Methyl (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indolin-3,4'- pyran]-l-yl)phenyl)-2-(tritylamino)propanoate

[0584]

[0585] P-14 (119 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. After being protected by nitrogen, the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, diatomite was filtered, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4: 1) to obtain the title compound (180 mg, 55%). ESI-QQQ-MS: m / z 657 [M+H]+ .

[0586] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-phenyl)propionate

[0587]

[0588] Methyl (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)-2-(triphenylmethylamino)propionate (164 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The mixture was concentrated under reduced pressure, and dichloromethane (3 mL) was added to the concentrate. The pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and separate into layers. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined and washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (98 mg, 95%). ESI-QQQ-MS: m / z 415 [M+H] + .

[0589] (Step 3) Methyl (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionate

[0590]

[0591] Methyl (S)-2-amino-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-phenyl)propionate (95 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), cooled to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time). The organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (118 mg, 90%). ESI-QQQ-MS: m / z 571 [M+H] + .

[0592] (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid

[0593]

[0594] (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid methyl ester (97 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 57%). ESI-QQQ-MS: m / z 557 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.87 (br s, 1H), 9.15 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.47-7.36 (m, 3H), 7.31-7.21 (m, 5H), 7.09 (d, J = 7.8 Hz, 1H), 4.70-4.65 (m, 1H), 4.06 (t, J = 10.6 Hz, 2H), 3.87-3.79 (m, 2H), 3.22 (dd, J = 14.1, 4.3 Hz, 1H), 3.01 (dd, J = 14.0, 10.1 Hz, 1H), 2.00-1.93 (m, 2H), 1.87-1.83 (m, 2H).

[0595] Example 8: Synthesis of compound 10

[0596] (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0597]

[0598] P-11 (112 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (211 mg, 67%). ESI-QQQ-MS: m / z 631 [M+H] + .

[0599] (S)-2-amino-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoic acid

[0600]

[0601] (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (158 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and then the mixture was allowed to stand to separate into layers, and the aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (89 mg, 92%). ESI-QQQ-MS: m / z 389 [M+H] + .

[0602] (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (158 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and then the mixture was allowed to stand to separate into layers, and the aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (89 mg, 92%). ESI-QQQ-MS: m / z 389 [M+H]

[0603]

[0604] (S)-2-amino-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid methyl ester (89 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (113 mg, 90%). ESI-QQQ-MS: m / z 545 [M+H] + .

[0605] (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid methyl ester

[0606]

[0607] (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid methyl ester (93 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 60%). ESI-QQQ-MS: m / z 531 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.89 (br s, 1H), 9.13 (d, J = 8.3 Hz, 1H), 7.51-7.42 (m, 3H), 7.38-7.34 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 7.24 (t, J = 8.6 Hz, 1H), 6.77 (d, J = 6.0 Hz, 1H), 4.77-4.73 (m, 1H), 3.26 (d, J = 4.1 Hz, 1H), 2.99 (dd, J = 13.8, 10.8 Hz, 1H), 1.86-1.81 (m, 2H), 1.72-1.64 (m, 2H).

[0608] Example 9: Synthesis of compound 11

[0609] (S)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester

[0610]

[0611] P-5 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and warmed to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (197 mg, 66%). ESI-QQQ-MS: m / z 597 [M+H] + .

[0612] (S)-2-amino-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoic acid methyl ester

[0613]

[0614] (S)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (149 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane, the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (84 mg, 95%). ESI-QQQ-MS: m / z 355 [M+H] + .

[0615] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)propanoic acid methyl ester

[0616]

[0617] (S)-2-amino-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoic acid methyl ester (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (107 mg, 88%). ESI-QQQ-MS: m / z 511 [M+H] + .

[0618] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)propanoic acid

[0619]

[0620] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-1 '-yl)phenyl)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was reacted at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and dichloromethane was extracted three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (50 mg, 57%). ESI-QQQ-MS: m / z 497 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.86 (br s, 1H), 9.17 (d, J = 8.3 Hz, 1H), 7.51-7.41 (m, 3H), 7.39-7.23 (m, 4H), 7.13-7.00 (m, 2H), 6.75-6.72 (m, 1H), 4.76-4.71 (m, 1H), 3.25 (dd, J = 14.0, 4.5 Hz, 1H), 3.00 (dd, J = 14.0, 10.4 Hz, 1H), 1.80-1.76 (m, 2H), 1.68-1.64 (m, 2H).

[0621] Example 10: Synthesis of compound 12

[0622] (Step 1) Methyl (S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindolin-1-yl)phenyl)-2- (tritylamino)propanoate

[0623]

[0624] P-13 (97 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. After being protected by nitrogen, the reaction was heated to 100°C for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (154 mg, 50%). ESI-QQQ-MS: m / z 615 [M+H] + .

[0625] (S)-2-amino-3-(4-(3,3-dimethyl-2-oxoindolin-1-yl)phenyl)propanoic acid

[0626]

[0627] (S)-3-(4-(3,3-dimethyl-2-oxoindolin-1-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (154 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and the layers were separated by standing. The aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, and the organic layer was washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (89 mg, 95%). ESI-QQQ-MS: m / z 373 [M+H] + .

[0628] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindolin-1- yl)phenyl)propanoic acid methyl ester

[0629]

[0630] (S)-2-amino-3-(4-(3,3-dimethyl-2-oxoindolin-1-yl)phenyl)propanoic acid methyl ester (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0°C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were separated by standing, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, and the organic layer was washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (114 mg, 94%). ESI-QQQ-MS: m / z 529 [M+H] + .

[0631] (S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindolin-1-yl)phenyl)-2-(2-chloro-6- fluorobenzamido)propanoic acid

[0632]

[0633] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-chloro-3,3-dimethyl-2- oxindolin-1-yl)phenyl)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was reacted at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and dichloromethane was extracted three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (49 mg, 54%). ESI-QQQ-MS: m / z 515 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.81 (br s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 7.47-7.39 (m, 4H), 7.34-7.23 (m, 4H), 7.21-7.19 (m, 1H), 7.11-7.04 (m, 1H), 4.70-4.68 (m, 1H), 3.22 (dd, J = 14.1, 4.3 Hz, 1H), 3.00 (dd, J = 14.1, 10.3 Hz, 1H), 1.40 (s, 6H).

[0634] Example 11: Synthesis of compound 14

[0635] (Step 1) Methyl (S)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)-2-(tritylamino)propanoate

[0636]

[0637] P-16 (110 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. After being protected with nitrogen, the temperature was raised to 100°C, and the reaction was carried out for 36 h. After cooling, diatomite was filtered, the filter cake was washed with acetonitrile twice (1 mL each time), the filtrates were combined, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (160 mg, 50%). ESI-QQQ-MS: m / z 640 [M+H] + .

[0638] (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid

[0639]

[0640] (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid + .

[0641] (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid

[0642]

[0643] (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid + .

[0644] (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid

[0645]

[0646] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'- oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid methyl ester (94 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (38 mg, 42%). ESI-QQQ-MS: m / z 540 [M+H] + . 1 HNMR (500 MHz, DMSO-d6): δ 12.97 (br s, 1H), 9.13 (d, J = 8.2 Hz, 1H), 7.51-7.18 (m, 7H), 7.01 (d, J = 12.2 Hz, 1H), 6.37 (d, J = 7.3 Hz, 1H), 4.82-4.68 (m, 1H), 3.25 (d, J = 3.9 Hz, 1H), 2.99 (dd, J = 13.8, 10.9 Hz, 1H), 2.66 (s, 6H), 1.68-1.64 (m, 2H), 1.58-1.53 (m, 2H).

[0647] Example 12: Synthesis of compound 15

[0648] (S)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0649]

[0650] P-15 (101 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (162 mg, 52%). ESI-QQQ-MS: m / z 622 [M+H] + .

[0651] (S)-2-amino-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoic acid

[0652]

[0653] (S)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (155 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the water layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (89 mg, 94%). ESI-QQQ-MS: m / z 380 [M+H] + .

[0654] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane- 1,3'-indolin]-1'-yl)phenyl)propanoic acid methyl ester

[0655]

[0656] Methyl (S)-2-amino-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoate (87 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were allowed to separate. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (114 mg, 90%). ESI-QQQ-MS: m / z 536 [M+H] + .

[0657] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(5'-(dimethylamino)-2'- oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid

[0658]

[0659] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-(dimethylamino)-2'- oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoate (94 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to give the title compound (34 mg, 38%). ESI-QQQ-MS: m / z 522 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 8.86 (d, J = 6.7 Hz, 1H), 7.43 (t, J = 8.0 Hz, 3H), 7.34-7.28 (m, 3H), 7.26-7.23 (m, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.60-6.54 (m, 2H), 4.64-4.60 (m, 1H), 3.24 (dd, J = 13.7, 3.8 Hz, 1H), 3.01 (dd, J = 13.4, 9.6 Hz, 1H), 2.83 (s, 6H), 1.70-1.64 (m, 2H), 1.60-1.54 (m, 2H).

[0660] Example 13: Synthesis of compound 16

[0661] (Step 1) (S)-methyl 3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(triphenylmethylamino)propanoate

[0662]

[0663] P-4 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction was protected by nitrogen, and the temperature was raised to 100 °C. After 36 h, the temperature was lowered, and the reaction mixture was filtered through diatomite. The filter cake was washed twice with acetonitrile (1 mL each time), and the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (210 mg, 70%). ESI-QQQ-MS: m / z 597 [M+H] + .

[0664] (Step 2) (S)-methyl 2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)propanoate

[0665]

[0666] (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (149 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane, the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (81 mg, 92%). ESI-QQQ-MS: m / z 355 [M+H] + .

[0667] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid methyl ester

[0668]

[0669] (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid methyl ester (81 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (105 mg, 90%). ESI-QQQ-MS: m / z 511 [M+H] + .

[0670] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid

[0671]

[0672] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-1 '-yl)phenyl)propanoate (87 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 60%). ESI-QQQ-MS: m / z 497 [M+H] + . 1 H NMR (500 MHz, DMSO): δ 12.89 (s, 1H), 9.15 (d, J = 8.3 Hz, 1H), 7.51-7.42 (m, 3H), 7.38 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 7.24 (t, J = 8.6 Hz, 1H), 7.16-7.12 (m, 1H), 6.92-6.84 (m, 1H), 6.53 (dd, J = 9.4, 2.3 Hz, 1H), 4.77-4.73 (m, 1H), 3.26 (dd, J = 14.0, 4.4 Hz, 1H), 3.00 (dd, J = 13.9, 10.5 Hz, 1H), 1.75-1.71 (m, 2H), 1.64-1.60 (m, 2H).

[0673] Example 14: Synthesis of compound 17

[0674] (Step 1) Methyl (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1 '- yl)phenyl)-2-(tritylamino)propanoate

[0675]

[0676] P-3 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (216 mg, 72%). ESI-QQQ-MS: m / z 597 [M+H] + .

[0677] (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid

[0678]

[0679] (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2- (triphenylmethylamino)propanoic acid methyl ester (149 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (82 mg, 91%). ESI-QQQ-MS: m / z 355 [M+H] + .

[0680] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid methyl ester

[0681]

[0682] Methyl (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoate (81 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the phases were allowed to separate. The aqueous phase was extracted twice with dichloromethane (2 mL each time), and the organic phases were combined. The organic phase was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (102 mg, 87%). ESI-QQQ-MS: m / z 511 [M+H] + .

[0683] (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoic acid

[0684]

[0685] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-l'-yl)phenyl)propanoate (87 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic phases were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (53 mg, 62%). ESI-QQQ-MS: m / z 497 [M+H] + . 1 H NMR (500 MHz, DMSO): δ 12.85 (s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 7.48-7.21 (m, 7H), 7.09-7.05 (m, 2H), 6.98-6.94 (m, 1H), 4.72-4.68 (m, 1H), 3.22 (dd, J = 14.1, 4.4 Hz, 1H), 3.00 (dd, J = 14.1, 10.3 Hz, 1H), 1.78-1.74 (m, 2H), 1.69-1.65 (m, 2H).

[0686] Example 15: Synthesis of compound 18

[0687] (Step 1) (S)-methyl 3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)-2-(tritylamino)propanoate

[0688]

[0689] P-12 (98 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (206 mg, 67%). ESI-QQQ-MS: m / z 615 [M+H] + .

[0690] (Step 2) (S)-methyl 2-amino-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'- indolin]-1'-yl)phenyl)propanoate

[0691]

[0692] (S)-methyl 3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'- yl)phenyl)-2-(tritylamino)propanoate (154 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (87 mg, 94%). ESI-QQQ-MS: m / z 373 [M+H] + .

[0693] (Step 3) (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(6',7'-difluoro-2'- oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoate

[0694]

[0695] Methyl (S)-2-amino-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-l,3'- indolin]-l'-yl)phenyl)propanoate (86 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were allowed to separate. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (107 mg, 88%). ESI-QQQ-MS: m / z 529 [M+H] + .

[0696] (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane- 1,3'-indolin]-l'-yl)phenyl)propanoic acid

[0697]

[0698] Methyl (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoate (90 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to give the title compound (49 mg, 56%). ESI-QQQ-MS: m / z 515 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.87 (br s, 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 = 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).

[0699] Example 16: Synthesis of compound 19

[0700] (Step 1) (S)-methyl 3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)- yl)phenyl)-2-(triphenylmethylamino)propanoate

[0701]

[0702] P-17 (80 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction was protected by nitrogen, and then the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (145 mg, 50%). ESI-QQQ-MS: m / z 580 [M+H] + .

[0703] (Step 2) (S)-methyl 2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)- yl)phenyl)propanoate

[0704]

[0705] (S)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (145 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (78 mg, 92%). ESI-QQQ-MS: m / z 338 [M+H] + .

[0706] (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]- 1'(2'H)-yl)phenyl)propanoic acid methyl ester

[0707]

[0708] (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)-yl)phenyl)propanoic acid methyl ester (78 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (100 mg, 85%). ESI-QQQ-MS: m / z 510 [M+H] + .

[0709] (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]- 1'(2'H)-yl)phenyl)propanoic acid

[0710]

[0711] (S)-2-(2,6-dichlorobenzamido)-3-(4-(2'-oxospiro[cyclopropane-l,3'- pyrrolo[2,3-b]pyridine]-l'(2'H)-yl)phenyl)propanoic acid methyl ester (87 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the combined organic layer was washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (33 mg, 40%). ESI-QQQ-MS: m / z 496 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.07 (d, J = 4.4 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.42-7.30 (m, 8H), 7.11-7.01 (m, 1H), 4.68-4.62 (m, 1H), 3.24 (d, J = 4.1 Hz, 1H), 3.03 (dd, J = 13.3, 9.1 Hz, 1H), 1.82-1.78 (m, 2H), 1.72-1.66 (m, 2H).

[0712] Example 17: Synthesis of compound 20

[0713] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,4,6- trichlorobenzamido)propanoic acid methyl ester

[0714]

[0715] (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid methyl ester (85 mg, 0.23 mmol, see preparation in example 2) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and intermediate P-34 (61 mg, 0.25 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (125 mg, 94%). ESI-QQQ-MS: m / z 577 [M+H] + .

[0716] (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(2,4,6-trichlorobenzamido)propanoic acid

[0717]

[0718] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(2,4,6-trichlorobenzamido)propanoic acid methyl ester (98 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 56%). ESI-QQQ-MS: m / z 562 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.91 (br s, 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).

[0719] Example 18: Synthesis of compound 21

[0720] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(diethylamino)benzamido)propanoic acid

[0721]

[0722] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(diethylamino)benzamido)propanoic acid + .

[0723] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(diethylamino)benzamido)propanoic acid

[0724]

[0725] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(diethylamino)benzamido)propanoic acid + . 1H NMR (500 MHz, DMSO-d6): δ 12.67 (br s, 1H), 8.79 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.3 Hz, 2H), 7.20-7.15 (m, 1H), 7.09-7.01 (m, 2H), 6.57 (s, 2H), 4.64-4.60 (m, 1H), 3.33-3.20 (m, 4H), 3.17 (dd, J = 14.1, 4.2 Hz, 1H), 3.00 (dd, J = 14.0, 10.1 Hz, 1H), 1.78-1.74 (m, 2H), 1.68-1.64 (m, 2H), 1.05 (t, J = 7.0 Hz, 6H).

[0726] Example 19: Synthesis of compound 22

[0727] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-morpholinobenzamido)propanoic acid

[0728]

[0729] (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid methyl ester (85 mg, 0.23 mmol, see example 2 for preparation) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and intermediate P-36 (74 mg, 0.25 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were separated after standing. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (123 mg, 85%). ESI-QQQ-MS: m / z 628 [M+H] + .

[0730] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzamido)propanoic acid

[0731]

[0732] Methyl (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-morpholinobenzamido)propanoate (107 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 52%). ESI-QQQ-MS: m / z 614 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 8.54 (s, 1H), 7.40-7.38 (m, 2H), 7.24-7.17 (m, 3H), 7.09-7.02 (m, 2H), 6.93 (s, 2H), 4.59-4.52 (m, 1H), 3.72-3.66 (m, 4H), 3.21 (s, 1H), 3.21-3.17 (m, 4H), 3.04 (dd, J = 13.4, 9.1 Hz, 1H), 1.78-1.74 (m, 2H), 1.68-1.64 (m, 2H).

[0733] Example 20: Synthesis of compound 23

[0734] (Step 1) Methyl (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-morpholinobenzamido)propanoate

[0735]

[0736] Methyl (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoate (85 mg, 0.23 mmol, see Example 2 for preparation) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and intermediate P-37 heptan-5-yl (77 mg, 0.25 mmol) was added dropwise. The reaction system was allowed to react at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were allowed to separate. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the organic layers were combined. The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (109 mg, 74%). ESI-QQQ-MS: m / z 640 [M+H] + .

[0737] (Step 2) (2S)-2-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzamido)-3-(4-(7'- chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid

[0738]

[0739] Methyl (2S)-methyl 2-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzamido)-3-(4-(7'- chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoate (109 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction system was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (52 mg, 49%). ESI-QQQ-MS: m / z 626 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.76 (br s, 1H), 8.81 (d, J = 5.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.27-7.17 (m, 3H), 7.11-7.01 (m, 2H), 6.63 (s, 2H), 4.67 (s, 1H), 4.62 (s, 2H), 3.73 (d, J = 7.3 Hz, 1H), 3.58 (d, J = 7.5 Hz, 1H), 3.45 (d, J = 9.4 Hz, 1H), 3.23-3.13 (m, 1H), 3.05-2.95 (m, 2H), 1.91-1.83 (m, 2H), 1.77-1.66 (m, 4H).

[0740] Example 21: Synthesis of compound 24

[0741] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(4-morpholinylpiperidin-l-yl)benzamido)propanoic acid

[0742]

[0743] (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoic acid methyl ester (85 mg, 0.23 mmol, see example 2 for preparation) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and intermediate P-38 (94 mg, 0.25 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were separated after standing. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (129 mg, 79%). ESI-QQQ-MS: m / z 711 [M+H] + .

[0744] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinylpiperidin-l-yl)benzamido)propanoic acid

[0745]

[0746] (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)-2-(2,6- dichloro-4-(4-morpholinylpiperidin-l-yl)benzamido)propanoic acid methyl ester (121 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (59 mg, 50%). ESI-QQQ-MS: m / z 696 [M+H] + . 1 HNMR (500 MHz, DMSO-d6): δ 12.75 (br s, 1H), 8.87 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.27-7.25 (m, 2H), 7.20-7.16 (m, 1H), 7.09-7.02 (m, 2H), 6.90 (s, 2H), 4.65-4.61 (m, 1H), 3.82 (d, J = 12.9 Hz, 2H), 3.55 (s, 4H), 3.17 (dd, J = 14.1, 4.3 Hz, 1H), 3.00 (dd, J = 14.0, 10.2 Hz, 1H), 2.76 (t, J = 11.9 Hz, 2H), 2.45 (s, 4H), 2.37-2.29 (m, 1H), 1.81-1.75 (m, 4H), 1.67-1.65 (m, 2H), 1.41-1.35 (m, 2H).

[0747] Example 22: Synthesis of compound 25

[0748] (Step 1) (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0749]

[0750] P-18 (91 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (180 mg, 60%). ESI-QQQ-MS: m / z 602 [M+H] + .

[0751] (S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)propanoic acid

[0752]

[0753] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (150 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution, and then the mixture was allowed to stand to separate into layers. The aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (85 mg, 95%). ESI-QQQ-MS: m / z 360 [M+H] + .

[0754] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid methyl ester

[0755]

[0756] Methyl (S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (86 g, 0.24 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (105 mg, 85%). ESI-QQQ-MS: m / z 516 [M+H] + .

[0757] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)-2-(2- chloro-6-fluorobenzamido)propanoic acid

[0758]

[0759] Methyl (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)-2-(2- chloro-6-fluorobenzamido)propanoate (88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (60 mg, 70%). ESI-QQQ-MS: m / z 502 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.86 (br s, 1H), 9.19 (d, J = 8.1 Hz, 1H), 7.48-7.38 (m, 3H), 7.33-7.22 (m, 5H), 7.12 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 4.73-4.68 (m, 1H), 3.39 (s, 3H), 3.23 (dd, J = 14.1, 4.1 Hz, 1H), 3.02 (dd, J = 13.9, 10.5 Hz, 1H).

[0760] Example 23: Synthesis of compound 26

[0761] (Step 1) (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0762]

[0763] P-19 (104 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and warmed to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (198 mg, 63%). ESI-QQQ-MS: m / z 628 [M+H] + .

[0764] (Step 2) (S)-2-amino-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoic acid methyl ester

[0765]

[0766] (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (157 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction system was stirred at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (88 mg, 91%). ESI-QQQ-MS: m / z 386 [M+H] + .

[0767] (Step 3) (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid methyl ester

[0768]

[0769] Methyl (S)-2-amino-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (88 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2,6-Dichlorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were allowed to separate. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the organic layers were combined. The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (112 mg, 87%). ESI-QQQ-MS: m / z 558 [M+H] + .

[0770] (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid

[0771]

[0772] Methyl (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoate (95 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction mixture was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to give the title compound (57 mg, 62%). ESI-QQQ-MS: m / z 544 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.76 (br s, 1H), 9.13 (d, J = 8.4 Hz, 1H), 7.51-7.31 (m, 8H), 7.12-7.10 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.79-4.74 (m, 1H), 3.24 (dd, J = 14.0, 4.5 Hz, 1H), 3.03-2.93 (m, 2H), 1.10-1.06 (m, 2H), 0.97-0.93 (m, 2H).

[0773] Example 24: Synthesis of compound 27

[0774] (Step 1) (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0775]

[0776] P-20 (104 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen, and then the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain the title compound (182 mg, 58%). ESI-QQQ-MS: m / z 628 [M+H] + .

[0777] (Step 2) (S)-2-amino-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoic acid methyl ester

[0778]

[0779] (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid (Step 4) + .

[0780] (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid (Step 4)

[0781]

[0782] (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid (Step 4) + .

[0783] (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid (Step 4)

[0784]

[0785] (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid methyl ester (95 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (56 mg, 61%). ESI-QQQ-MS: m / z 544 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.85 (br s, 1H), 9.12 (d, J = 8.4 Hz, 1H), 7.50-7.48 (m, 2H), 7.45-7.38 (m, 5H), 7.30 (d, J = 8.3 Hz, 1H), 7.20-7.18 (m, 1H), 6.87 (d, J = 1.8 Hz, 1H), 4.80-4.75 (m, 1H), 3.26 (dd, J = 14.0, 4.4 Hz, 1H), 3.01-2.95 (m, 2H), 1.09-1.05 (m, 2H), 0.97-0.93 (m, 2H).

[0786] Example 25: Synthesis of compound 28

[0787] (Step 1) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0788]

[0789] P-21 (104 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (157 mg, 50%). ESI-QQQ-MS: m / z 628 [M+H] + .

[0790] (S)-2-amino-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)propanoic acid

[0791]

[0792] (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (157 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (92 mg, 95%). ESI-QQQ-MS: m / z 386 [M+H] + .

[0793] (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid methyl ester

[0794]

[0795] Methyl (S)-2-amino-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (89 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and 2,6-dichlorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (115 mg, 90%). ESI-QQQ-MS: m / z 558 [M+H] + .

[0796] (Step 4) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid

[0797]

[0798] Methyl (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(2,6-dichlorobenzamido)propanoate (95 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system. The reaction was stirred at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (49 mg, 53%). ESI-QQQ-MS: m / z 544 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.84 (br s, 1H), 9.17 (d, J = 8.2 Hz, 1H), 7.47-7.37 (m, 5H), 7.29 (t, J = 7.8 Hz, 3H), 7.13 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 4.75-4.70 (m, 1H), 3.22 (dd, J = 14.1, 4.2 Hz, 1H), 3.06-2.93 (m, 2H), 1.09-1.05 (m, 2H), 0.97-0.92 (m, 2H).

[0799] Example 26: Synthesis of compound 29

[0800] (Step 1) (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0801]

[0802] P-22 (99 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain the title compound (173 mg, 56%). ESI-QQQ-MS: m / z 618 [M+H] + .

[0803] (Step 2) (S)-2-amino-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)propanoic acid methyl ester

[0804]

[0805] (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (155 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (86 mg, 92%). ESI-QQQ-MS: m / z 376 [M+H] + .

[0806] (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid

[0807]

[0808] (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid methyl ester (91 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m / z 518 [M+H] + .

[0809] (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid

[0810]

[0811] (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid methyl ester (91 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m / z 518 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.88 (br s, 1H), 9.08 (s, 1H), 7.57 (s, 1H), 7.44-7.12 (m, 9H), 4.65-4.63 (m, 1H), 3.76 (s, 3H), 3.16 (dd, J = 14.1, 4.1 Hz, 1H), 2.92 (dd, J = 13.9, 10.5 Hz, 1H).

[0812] Example 27: Synthesis of compound 30

[0813] (Step 1) (S)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0814]

[0815] P-28 (96 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen, and the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered through diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4: 1) to obtain the title compound (193 mg, 63%). ESI-QQQ-MS: m / z 612 [M+H] + .

[0816] (Step 2) (S)-2-amino-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoic acid methyl ester

[0817]

[0818] Methyl (S)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)-2-(tritylamino)propanoate (153 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was followed by addition of dichloromethane (3 mL) to the concentrate, adjustment of the pH to 8-9 with saturated aqueous sodium bicarbonate solution, separation of the layers, extraction of the aqueous layer with dichloromethane twice, washing of the combined organic layers with water and saturated brine once each, drying over anhydrous sodium sulfate, and filtration under suction. Concentration under reduced pressure gave the title compound (88 mg, 95%). ESI-QQQ-MS: m / z 370 [M+H] + .

[0819] (Step 3) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid methyl ester

[0820]

[0821] Methyl (S)-2-amino-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'- yl)phenyl)propanoate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted with dichloromethane twice (2 mL each time), the combined organic layers were washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered under suction, and concentrated under reduced pressure to give the title compound (109 mg, 90%). ESI-QQQ-MS: m / z 526 [M+H] + .

[0822] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid

[0823]

[0824] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6',7'-difluoro-2'- oxospiro[cyclopropane-1,3'-indolin]-1 '-yl)phenyl)propanoate (89 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was reacted at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and dichloromethane was extracted three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (47 mg, 54%). ESI-QQQ-MS: m / z 512 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.86 (br s, 1H), 9.18 (d, J = 8.0 Hz, 1H), 7.48-7.22 (m, 7H), 7.17-7.10 (m, 2H), 6.99-6.82 (m, 1H), 4.71-4.68 (m, 1H), 3.22 (dd, J = 14.1, 4.2 Hz, 1H), 3.05-2.93 (m, 2H), 1.10-1.04 (m, 2H), 0.97-0.93 (m, 2H).

[0825] Example 28: Synthesis of compound 31

[0826] (Step 1) Methyl (S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3- dihydro-1 H-benzo[d]imidazol-1 -yl)phenyl)-2-(tritylamino)propanoate

[0827]

[0828] P-23 (126 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. After being protected by nitrogen, the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, diatomite was filtered, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (175 mg, 0.52%). ESI-QQQ-MS: m / z 672 [M+H] +.

[0829] (S)-2-amino-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoic acid

[0830]

[0831] (S)-2-amino-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoic acid + .

[0832] (S)-2-amino-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoic acid

[0833]

[0834] (S)-2-amino-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoic acid + .

[0835] (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-fluorobenzamido)propanoic acid

[0836]

[0837] Methyl (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-fluorobenzamido)propanoate (100 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was reacted at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (53 mg, 54%). ESI-QQQ-MS: m / z 572 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.81 (br s, 1H), 9.18 (d, J = 7.9 Hz, 1H), 7.56-7.19 (m, 8H), 7.15-7.03 (m, 2H), 4.74-4.68 (m, 1H), 4.55-4.47 (m, 1H), 4.00 (d, J = 8.0 Hz, 2H), 3.49 (t, J = 11.6 Hz, 2H), 3.26-3.21 (m, 1H), 3.07-2.95 (m, 1H), 2.47-2.42 (m, 2H), 1.76-1.70 (m, 2H).

[0838] Example 29: Synthesis of compound 32

[0839] (S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0840]

[0841] P-24 (133 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen, and then the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (151 mg, 44%). ESI-QQQ-MS: m / z 685 [M+H] + .

[0842] (S)-methyl 2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate

[0843]

[0844] (S)-methyl 2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate + .

[0845] (S)-methyl 2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate

[0846]

[0847] Methyl (S)-2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate (102 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were separated by standing. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (117 mg, 85%). ESI-QQQ-MS: m / z 599 [M+H] + .

[0848] (Step 4) (S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid

[0849]

[0850] Methyl (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-fluorobenzamido)propanoate (102 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, and the reaction was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (40 mg, 40%). ESI-QQQ-MS: m / z 585 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 9.01 (d, J = 7.6 Hz, 1H), 7.48-7.37 (m, 4H), 7.34-7.19 (m, 4H), 7.12-7.00 (m, 2H), 4.70-4.64 (m, 1H), 4.43-4.34 (m, 1H), 3.32-2.95 (m, 6H), 2.60-2.53 (m, 2H), 2.43 (s, 3H), 1.84-1.80 (m, 2H).

[0851] Example 30: Synthesis of compound 33

[0852] (Step 1) (S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0853]

[0854] P-25 (83 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (187 mg, 64%). ESI-QQQ-MS: m / z 586 [M+H] + .

[0855] (Step 2) (S)-2-amino-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)propanoic acid methyl ester

[0856]

[0857] (S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2- (tritylamino)propanoic acid methyl ester (146 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layer was washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (81 mg, 94%). ESI-QQQ-MS: m / z 344 [M+H] + .

[0858] (Step 3) (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(7-fluoro-3-methyl- 2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate

[0859]

[0860] (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(7-fluoro-3-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate (85 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was then allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 using 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (56 mg, 68%). ESI-QQQ-MS: m / z 486 [M+H] + .

[0861] (Step 4) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-fluoro-3-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid

[0862]

[0863] (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(7-fluoro-3-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate (85 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was then allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 using 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (56 mg, 68%). ESI-QQQ-MS: m / z 486 [M+H] + . 1H NMR (500 MHz, DMSO-d6): δ 12.84 (br s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 7.47-7.36 (m, 5H), 7.33-7.23 (m, 2H), 7.14-7.10 (m, 2H), 6.96-6.88 (m, 1H), 4.73-4.65 (m, 1H), 3.40 (s, 3H), 3.25-3.18 (m, 1H), 3.01 (dd, J = 13.9, 10.3 Hz, 1H).

[0864] Example 31: Synthesis of compound 34

[0865] (Step 1) (S)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0866]

[0867] P-26 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen, and the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (166 mg, 55%). ESI-QQQ-MS: m / z 604 [M+H] + .

[0868] (Step 2) (S)-2-amino-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester

[0869]

[0870] Methyl (S)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoate (151 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (86 mg, 95%). ESI-QQQ-MS: m / z 362 [M+H] + .

[0871] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,7-difluoro-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate

[0872]

[0873] Methyl (S)-2-amino-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (105 mg, 88%). ESI-QQQ-MS: m / z 518 [M+H] + .

[0874] (Step 4) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,7-difluoro-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid

[0875]

[0876] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate (88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (50 mg, 59%). ESI-QQQ-MS: m / z 504 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) 12.52 (br s, 1H), 9.15 (d, J = 8.1 Hz, 1H), 7.46-7.16 (m, 8H), 6.99-6.92 (m, 1H), 4.72-4.68 (m, 1H), 3.40-3.36 (m, 4H), 3.25-3.21 (m, 2H), 3.03-2.96 (m, 1H).

[0877] Example 32: Synthesis of compound 35

[0878] (Step 1) Methyl (S)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)-2-(tritylamino)propanoate

[0879]

[0880] P-27 (109 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction was protected by nitrogen, warmed to 100°C, and reacted for 36 h. After cooling, the reaction mixture was filtered through diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (207 mg, 65%). ESI-QQQ-MS: m / z 636 [M+H] + .

[0881] (Step 2) (S)-methyl 2-amino-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate

[0882]

[0883] Methyl (S)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoate (159 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was allowed to react at room temperature for 1 h. Concentration under reduced pressure was followed by addition of dichloromethane (3 mL) to the concentrate, adjustment of the pH to 8-9 with saturated aqueous sodium bicarbonate solution, standing to separate the layers, extraction of the aqueous layer with dichloromethane twice, washing of the combined organic layers with water and saturated brine once each, drying over anhydrous sodium sulfate, suction filtration, and concentration under reduced pressure to give the title compound (94 mg, 95%). ESI-QQQ-MS: m / z 394 [M+H] + .

[0884] (Step 3) (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(5,6-dichloro-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

[0885]

[0886] Methyl (S)-2-amino-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)propanoate (91 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0°C, and 2-chloro-6- fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, which was allowed to react at room temperature for 1 h. Water (5 mL) was added to the reaction system, which was allowed to stand to separate the layers, the aqueous layer was extracted with dichloromethane twice (2 mL each time), the combined organic layers were washed with water and saturated brine once each, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give the title compound (110 mg, 87%). ESI-QQQ-MS m / z 550 [M+H] + .

[0887] (Step 4) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

[0888]

[0889] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate (94 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (54 mg, 59%). ESI-QQQ-MS: m / z 536 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.87 (s, 1H), 9.14 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.52-7.42 (m, 5H), 7.33-7.21 (m, 2H), 7.05 (s, 1H), 4.77-4.72 (m, 1H), 3.40 (s, 3H), 3.27 (dd, J = 14.0, 4.5 Hz, 1H), 3.00 (dd, J = 13.9, 10.5 Hz, 1H).

[0890] Example 33: Synthesis of compound 36

[0891] (Step 1) Methyl (S)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoate

[0892]

[0893] P-29 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (196 mg, 65%). ESI-QQQ-MS: m / z 604 [M+H] + .

[0894] (Step 2) (S)-methyl 2-amino-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate

[0895]

[0896] (S)-methyl 3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoate (151 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (85 mg, 94%). ESI-QQQ-MS: m / z 362 [M+H] + .

[0897] (Step 3) (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(6,7-difluoro-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

[0898]

[0899] Methyl (S)-2-amino-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (83 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C. 2-Chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the phases were allowed to separate. The aqueous phase was extracted twice with dichloromethane (2 mL each time), and the combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (104 mg, 87%). ESI-QQQ-MS: m / z 518 [M+H] + .

[0900] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid

[0901]

[0902] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate (88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to give the title compound (45 mg, 52%). ESI-QQQ-MS: m / z 504 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.89 (br s, 1H), 9.17 (d, J = 8.1 Hz, 1H), 7.47-7.40 (m, 5H), 7.31 (d, J = 8.1 Hz, 1H), 7.28-7.15 (m, 2H), 7.09-7.07 (m, 1H), 4.74-4.69 (m, 1H), 3.39 (s, 3H), 3.24 (dd, J = 14.1, 4.5 Hz, 1H), 3.01 (dd, J = 14.1, 10.3 Hz, 1H).

[0903] Example 34: Synthesis of compound 37

[0904] (Step 1) (S)-methyl 3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)-2-(tritylamino)propanoate

[0905]

[0906] P-30 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen and warmed to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (205 mg, 68%). ESI-QQQ-MS: m / z 604 [M+H] + .

[0907] (Step 2) (S)-methyl 2-amino-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate

[0908]

[0909] (S)-methyl 3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoate (151 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layer was washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (86 mg, 95%). ESI-QQQ-MS: m / z 362 [M+H] + .

[0910] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester

[0911]

[0912] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester (88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was then allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 using 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m / z 504 [M+H] + .

[0913] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester

[0914]

[0915] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester (88 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was then allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 using 2 mol / L dilute hydrochloric acid, and the reaction system was extracted three times with dichloromethane (2 mL each time). The organic layers were combined and washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (48 mg, 55%). ESI-QQQ-MS: m / z 504 [M+H] + . 1H NMR (500 MHz, DMSO): δ 12.89 (s, 1H), 9.16 (d, J = 7.5 Hz, 1H), 7.56-7.37 (m, 5H), 7.32-7.24 (m, 2H), 7.14-7.06 (m, 1H), 6.71 (d, J = 6.1 Hz, 1H), 4.76-4.68 (m, 1H), 3.55 (s, 3H), 3.28-3.22 (m, 1H), 3.04-2.96 (m, 1H).

[0916] Example 35: Synthesis of compound 38

[0917] (Step 1) (S)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0918]

[0919] P-31 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen, and the temperature was raised to 100 °C. The reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (155 mg, 52%). ESI-QQQ-MS: m / z 598 [M+H] + .

[0920] (Step 2) (S)-2-amino-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)propanoic acid methyl ester

[0921]

[0922] Methyl (S)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoate (149 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 h. Concentration under reduced pressure was performed, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (85 mg, 96%). ESI-QQQ-MS: m / z 356 [M+H] + .

[0923] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-methoxy-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate

[0924]

[0925] Methyl (S)-2-amino-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (82 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, the layers were allowed to separate, the aqueous layer was extracted twice with dichloromethane (2 mL each time), the combined organic layers were washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (104 mg, 88%). ESI-QQQ-MS: m / z 512 [M+H] + .

[0926] (Step 4) (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-methoxy-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid

[0927]

[0928] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-methoxy-3-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate (87 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (42 mg, 50%). ESI-QQQ-MS: m / z 498 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 12.84 (br s, 1H), 9.19 (d, J = 8.1 Hz, 1H), 7.47-7.42 (m, 1H), 7.36-7.31 (m, 3H), 7.27-7.25 (m, 3H), 7.11-7.09 (m, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 4.72-4.68 (m, 1H), 3.56 (s, 3H), 3.36 (s, 3H), 3.21 (dd, J = 14.1, 4.5 Hz, 1H), 3.01 (dd, J = 14.0, 10.0 Hz, 1H).

[0929] Example 36: Synthesis of compound 39

[0930] (Step 1) Methyl (S)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)-2-(tritylamino)propanoate

[0931]

[0932] P-32 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system, which was protected by nitrogen, and then the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, the reaction system was filtered with diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time), and then the combined filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound (147 mg, 48%). ESI-QQQ-MS: m / z 611 [M+H] + .

[0933] (Step 2) (S)-methyl 2-amino-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoate

[0934]

[0935] (S)-methyl 3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoate (153 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, which was reacted at room temperature for 1 h. After concentration under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (86 mg, 94%). ESI-QQQ-MS: m / z 369 [M+H] + .

[0936] (Step 3) (S)-methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(6-(dimethylamino)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

[0937]

[0938] Methyl (S)-2-amino-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)phenyl)propanoate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), and the reaction system was cooled to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (111 mg, 92%). ESI-QQQ-MS: m / z 525 [M+H] + .

[0939] (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoic acid

[0940]

[0941] Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)phenyl)propanoate (89 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (37 mg, 42%). ESI-QQQ-MS: m / z 511 [M+H] + . 1 HNMR (500 MHz, DMSO-d6): δ 12.91 (br s, 1H), 9.18 (d, J = 8.3 Hz, 1H), 7.52-7.39 (m, 5H), 7.33-7.09 (m, 3H), 7.02-6.21 (m, 2H), 4.77-4.73 (m, 1H), 3.26 (dd, J = 14.1, 4.3 Hz, 1H), 3.00 (dd, J = 14.0, 10.6 Hz, 1H), 2.89 (s, 6H), 2.54 (s, 3H).

[0942] Example 37: Synthesis of compound 40

[0943] (Step 1) (S)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)-2-(tritylamino)propanoic acid methyl ester

[0944]

[0945] P-33 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and then N, N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and cuprous iodide (24 mg, 0.125 mmol) were added to the reaction system. The reaction system was protected by nitrogen and heated to 100 °C for 36 h. After cooling, the reaction system was filtered by diatomite, and the filter cake was washed with acetonitrile twice (1 mL each time). The combined filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound (153 mg, 50%). ESI-QQQ-MS: m / z 611 [M+H] + .

[0946] (Step 2) (S)-2-amino-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester

[0947]

[0948] (S)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)phenyl)-2-(tritylamino)propanoic acid methyl ester (153 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the aqueous layer was extracted with dichloromethane twice, and the combined organic layers were washed with water and saturated brine once, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (87 mg, 95%). ESI-QQQ-MS: m / z 369 [M+H] + .

[0949] (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

[0950]

[0951] (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester (89 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (35 mg, 40%). ESI-QQQ-MS: m / z 511 [M+H] + .

[0952] (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

[0953]

[0954] (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid methyl ester (89 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.6 mL, 0.29 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and extracted with dichloromethane three times (2 mL each time). The organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (35 mg, 40%). ESI-QQQ-MS: m / z 511 [M+H] + . 1HNMR (500 MHz, DMSO-d6): δ 12.93 (br s, 1H), 9.13 (d, J = 8.2 Hz, 1H), 7.50-7.36 (m, 5H), 7.35-7.20 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.47 (dd, J = 8.7, 2.3 Hz, 1H), 4.74-4.69 (m, 1H), 3.36 (s, 3H), 3.23 (dd, J = 14.0, 4.6 Hz, 1H), 3.00 (dd, J = 13.9, 10.2 Hz, 1H), 2.89 (s, 6H).

[0955] Example 38: Synthesis of compound 41

[0956] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,4,6-trichlorobenzamido)propanoic acid

[0957]

[0958] (S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)propanoic acid (83 mg, 0.23 mmol, see example 22 for preparation) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and intermediate P-34 (61 mg, 0.25 mmol) was added dropwise. The reaction was allowed to react at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the layers were separated after standing. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed with water and saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (124 mg, 95%). + .

[0959] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,4,6-trichlorobenzamido)propanoic acid

[0960]

[0961] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,4,6-trichlorobenzamido)propanoic acid methyl ester (96 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 54%). ESI-QQQ-MS: m / z 552 [M+H] + . 1 H NMR (500 MHz, DMSO-d6): δ 9.05 (d, J = 7.8 Hz, 1H), 7.66 (s, 2H), 7.35 (dd, J = 58.9, 8.0 Hz, 4H), 7.23 (d, J = 7.8 Hz, 1H), 7.15-6.99 (m, 2H), 4.70-4.64 (m, 1H), 3.39 (s, 3H), 3.24 (dd, J = 13.9, 3.8 Hz, 1H), 3.01 (dd, J = 13.8, 10.0 Hz, 1H).

[0962] Example 39: Synthesis of compound 42

[0963] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)phenyl)-2-(2,4,6-trichlorobenzamido)propanoic acid methyl ester (96 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system, which was allowed to react at room temperature for 2 h. The reaction system was adjusted to pH 1-2 with 2 mol / L dilute hydrochloric acid, extracted with dichloromethane three times (2 mL each time), and the organic layers were combined and washed with water and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 54%). ESI-QQQ-MS: m / z 552 [M+H]

[0964]

[0965] (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)phenyl)propanoic acid methyl ester (83 mg, 0.23 mmol, see preparation of example 22) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the reaction system was cooled to 0 °C, and intermediate P-36 (74 mg, 0.25 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand to separate into layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), and the combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (113 mg, 80%). ESI-QQQ-MS: m / z 617 [M+H] + .

[0966] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzamido)propanoic acid

[0967]

[0968] (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzamido)propanoic acid methyl ester (105 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction system was adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, and the mixture was extracted three times with dichloromethane (2 mL each time). The combined organic layers were washed once with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (45 mg, 44%). ESI-QQQ-MS: m / z 603 [M+H] + . 1 HNMR (500 MHz, DMSO-d6): δ 12.77 (br s, 1H), 8.91 (d, J = 7.5 Hz, 1H), 7.43-7.41 (m, 2H), 7.31-7.22 (m, 3H), 7.16-7.01 (m, 2H), 6.93 (s, 2H), 4.68-4.64 (m, 1H), 3.70-3.68 (m, 4H), 3.39 (s, 3H), 3.21 (s, 1H), 3.19-3.17 (m, 4H), 3.04-2.99 (m, 1H).

[0969] Test Example: Evaluation Test for MAdCAM-1 / α4β7 Integrin Binding Inhibitory Activity (α4β7-MAdCAM-1 ELISA)

[0970] A 96-well microtiter plate (Costar) was coated with a solution of recombinant human MAdCAM-1 (R&D Systems) at 50 μL / well, incubated at 4°C overnight, washed with TBS buffer at 150 μL / well 3 times, then blocked with blocking buffer at 150 μL / well, blocked at 37°C for 1 h, washed with TBS buffer at 150 μL / well 3 times, and a solution of recombinant human integrin α4β7 (R&D Systems) diluted in TBS buffer containing 0.1% bovine serum albumin (BSA) was added to the 96-well plate at 50 μL / well, 1 μL of a test compound or a DMSO solution was added to each well, the lid was put on, and incubation was performed at room temperature for 2 h. The plate was washed with TBS buffer at 150 μL / well 3 times, a solution of anti-β7 antibody (R&D Systems) in 0.1% BSA TBS buffer was added to the 96-well plate at 50 μL / well, the lid was put on, and incubation was performed at room temperature for 1 h. The plate was washed with TBS buffer at 150 μL / well 3 times, and streptavidin-HRP (R&D Systems) was added to the 96-well plate at 50 μL / well, and incubation was performed at room temperature for 20 min. The plate was washed with TBS buffer at 150 μL / well 3 times, 50 μL of TMB coloring solution (Sigma) was added to each well, and incubation was performed at room temperature for 5 to 30 min. The reaction was stopped by adding 25 μL of a stop solution to each well, and the absorbance was measured at 450 nm with a microplate reader (SpectraMax 340PC, Molecular Devices). The test was repeated, the absorbance of the well containing no test substance was taken as 100%, and the concentration of the test substance that caused 50% inhibition of binding was calculated as IC50. 50 The results obtained are shown in Table 1.

[0971] It should be noted that, as the test compound, the free form of the compound synthesized in the above-described example was used.

[0972] Table 1. Results of MAdCAM-1 / α4β7 Integrin Binding Inhibitory Activity

[0973]

[0974] As described above, the novel N-(benzoyl)-phenylalanine compound of the present application has excellent α4β7 integrin binding inhibitory activity, and thus, the novel N-(benzoyl)-phenylalanine compound of the present application can provide a therapeutic or prophylactic agent for α4β7-dependent autoimmune diseases and inflammatory bowel diseases (Crohn's disease and ulcerative colitis).

[0975] The compound of the present application is useful as an oral administration preparation because of high blood concentration or bioavailability when orally administered.

[0976] In addition, the compound of the present application is stable in acidic and basic solutions, and can be used for development of various dosage forms.

[0977] In addition to those embodiments described herein, various modifications to the present application will be apparent to those of ordinary skill in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each of the references cited in the present application, including all patents, patent applications, journal articles, books, and any other publications, are incorporated herein by reference in their entireties.

Claims

1. A compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen; R4 is hydrogen; each X1 is independently fluorine, chlorine or bromine; X2is hydrogen, halogen, di(Ci-C4-alkyl)amino or 3- to 7-membered heterocycloalkyl; 1～6 alkyl)amino or 3- to 7-membered heterocycloalkyl; X3 is hydrogen; A is a group represented by the general formula (2-1), (2-2) or (2-3), Ring H is C 3～6 Cycloalkylene or 3- to 7-membered heterocycloalkylene; Y is O or S; each Z is independently CR1 or N; each R1, if present, is independently hydrogen, halogen, C 1～6 alkyl, C 1～6 alkyl, C 1～6 alkyl, C 3～6 alkyl, C 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each X1 is independently fluorine or chlorine.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X2 is hydrogen or 3- to 7-membered heterocycloalkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein selected from 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the general formula (2-1-1) or (2-1-1'), Ring H is C 3～6 Cycloalkylene or 3- to 7-membered heterocycloalkylene; Y is O or S; when A is a group represented by the general formula (2-1-1), two of the four R1are each independently halogen, C 1～6 alkyl)oxy, or di(C 1～6 alkyl)amino, the others being hydrogen; or one of the four R1is halogen, C 1～6 alkyl)oxy, or di(C 1～6 alkyl)amino, the others being hydrogen; or, four R1s are hydrogen; when A is a group represented by the general formula (2-1-1'), two of the three R1are each independently halo, C 1～6 alkyl)oxy, or di(C 1～6 alkyl)amino, the remainder being hydrogen; or, one of the three R1is halo, C 1～6 alkyl)oxy, or di(C 1～6 alkyl)amino, the remainder being hydrogen; or, three R1s are hydrogen.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the general formula (2-2-1), Y is O or S; two of the four R1are each independently halogen, C 1～6 alkyl)oxy, or di(C 1～6 alkyl)amino, the others being hydrogen; or one of the four R1is halogen, C 1～6 alkyl)oxy, or di(C 1～6 alkyl)amino, the others being hydrogen; R2is C 1～6 alkyl, C 3～6 cycloalkyl or 3- to 7-membered heterocycloalkyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the general formula (2-3-1), Y is O or S; one of the four R1is halogen, C 1～6 alkoxy or di(C 1～6 alkyl)amino, the others being hydrogen; each R2is independently C 1～6 alkyl, C 3～6 cycloalkyl or 3- to 7-membered heterocycloalkyl.

8. The compound according to any one of claims 5 to 7 or a pharmaceutically acceptable salt thereof, wherein selected from 9. The following compound or a pharmaceutically acceptable salt thereof, 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the prevention and / or treatment of a disease and / or disorder mediated at least in part by α4β7 integrin.

12. The use according to claim 11, wherein the disease and / or disorder mediated at least in part by α4β7 integrin is selected from the group consisting of autoimmune diseases, inflammatory diseases and tumor cell proliferation and metastasis.

13. The use according to claim 12, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.

14. The use according to claim 12, wherein the inflammatory disease is selected from the group consisting of inflammatory bowel diseases.

15. The use according to claim 14, wherein the inflammatory bowel disease is selected from the group consisting of ulcerative colitis and Crohn's disease.

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