N-(Benzoyl)-phenylalanine compounds, pharmaceutical compositions containing the same, and uses thereof

Abstract

The present invention belongs to the field of medicinal chemistry, and includes N-(benzoyl)-phenylalanine compounds as α4β7 integrin antagonists, their pharmaceutical compositions, and their uses. Specifically, the present invention relates to a compound represented by general formula (1), which exhibits good α4β7 integrin binding inhibitory activity and can be used as an efficient α4β7 integrin antagonist for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, etc. [Formula 1] TIFF2024503138000272.tif49170

Description

Technical Field

[0001] Cross - reference to related applications The present invention claims the priority of the following invention patent application filed in China on January 20, 2021. All the contents of the patent claims are incorporated into the text by reference. Invention patent application name: "N - (benzoyl) - phenylalanine compounds, pharmaceutical compositions containing the same, and their uses"; application number: 202110075764.7.

[0002] The present invention belongs to the field of medicinal chemistry and relates to N - (benzoyl) - phenylalanine compounds as α4β7 integrin antagonists, including the use of the compounds as pharmaceutical compositions with drug - active ingredients and their use in the prevention and / or treatment of diseases related to α4β7 integrin (such as autoimmune diseases and inflammatory diseases).

Background Art

[0003] Integrin, also called integrin (different expressions in Chinese), belongs to the integral protein family and is ubiquitously present on the cell surface of vertebrates and depends on a heterodimeric cell - surface protein of Ca 2+ or Mg 2+ It mediates the mutual recognition and adhesion between cells and between cells and the extracellular matrix, and has the function of connecting the relationship between the cell exterior and the intracellular structure.

[0004] Integrin is a transmembrane heterodimer composed of two non - covalently bound transmembrane subunits (i.e., α and β subunits). The extracellular head can bind to extracellular matrix proteins, and the intracellular tail is connected to actin. Both subunits of integrin are glycosylated and bound non - covalently.

[0005] Currently, a total of 18 α -subunits and 8 β -subunits are known. Among them, α4β7 integrin is expressed on the surface of lymphocytes and recognizes the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) of extracellular ligands. The latter is expressed on the microvenules of the intestinal mucosa and the high endothelial venules (HEVs) of gut-associated lymphoid tissue (GALT) associated with the intestinal tract. α4β7 integrin controls the migration of lymphocytes to intestinal tissues and their retention in the intestine through interaction with MAdCAM-1. Some people claim that suppressing the interaction between integrin and its ligand is an effective way to treat various autoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1 interaction has shown a therapeutic effect on inflammatory bowel diseases. For example, for Crohn's disease (CD) and ulcerative colitis (UC).

[0006] Therefore, there is an urgent need to develop α4β7 integrin antagonists for the prevention and / or treatment of autoimmune and inflammatory diseases (especially inflammatory bowel diseases).

Summary of the Invention

[0007] The object of the present invention is to provide an N-(benzoyl)-phenylalanine compound that has high selectivity and inhibitory activity against α4β7 integrin, is orally administrable, and has a structurally novel structure.

[0008] Another object of the present invention is also to provide a pharmaceutical composition containing the above compound as a drug active ingredient.

[0009] Another object of the present invention is also to provide the use of the above compound or pharmaceutical composition for the prevention and / or treatment of α4β7 integrin-related diseases (such as autoimmune and inflammatory diseases).

[0010] Specifically, the above object of the present invention is achieved by the following solutions.

[0011] [1] As represented by the compound shown in general formula (1) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled or prodrug thereof,

Chemical formula

[0012] Each X3 is independently hydrogen or halogen; A is a group represented by the general formula (2-1), (2-2) or (2-3).

[0013]

Chemical formula

[0014] When present, each R2 is independently hydrogen, C 1~6 Alkyl group, C 1~6 Halogenated alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Alkanoyl group, C 1~6 Alkoxycarbonyl group, C 1~6 Alkylamino group, carbamoyl group, C 1~6 Alkylcarbamoyl group, 2(C 1~6 Alkyl)carbamoyl group, C3~6 A cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, C 6~10 An aryl group, a 5- to 10-membered heteroaryl group, C 6~10 An arylcarbonyl group, a 5- to 10-membered heteroarylcarbonyl group, C 6~10 An aryloxycarbonyl group, a 5- to 10-membered heteroaryloxycarbonyl group, C 6~10 An arylcarbamoyl group or a 5- to 10-membered heteroarylcarbamoyl group, and the above groups are optionally substituted with at least one of the following substituents: halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl.

[0015] [2] The following are a compound or its pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled or prodrug: (1) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5’,6’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propionic acid; (2) (S)-3-(4-(7’-chloro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionic acid; (3) (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(5’,6’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propionic acid; (4) (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7’-methoxy-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propionic acid; (5) (S)-3-(4-(6’-chloro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)-2-(2,6-dichlorobenzoylamino)propionic acid; (6)(S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid; (7)(S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid; (8)(S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid; (9)(S)-3-(4-(7-Chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (10)(S)-3-(4-(6'-Chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (11)(S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid; (12)(S)-3-(4-(7-Chloro-3,3-dimethyl-2-oxoindolin-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (13)(S)-3-(4-(5'-Chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (14)(S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid; (15) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid; (16) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid; (17) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid; (18) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid; (19) (S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)propionic acid; (20) (S)-3-(4-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,4,6-trichlorobenzoylamino)propionic acid; (21) (S)-3-(4-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(diethylamino)benzoylamino)propionic acid; (22) (S)-3-(4-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzoylamino)propionic acid; (23) (2S)-2-(4-(2-Oxa-5-azabicyclo[2.1]hept-5-yl)-2,6-dichlorobenzoylamino)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid; (24) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinopiperidin-1-yl)benzoylamino)propanoic acid; (25) (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (26) (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzoylamino)propanoic acid; (27) (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzoylamino)propanoic acid; (28) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzoylamino)propanoic acid; (29) (S)-3-(4-(7-chloro-3-methyl-2-thio-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (30) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (31) (S)-3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (32) (S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propanoic acid; (33) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (34) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (35) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (36) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (37) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (38) (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid; (39) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid; (40) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid; (41) (S)-3-(4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,4,6-trichlorobenzoylamino)propionic acid; and (42) (S)-3-(4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzoylamino)propionic acid.

[0016] [3] One pharmaceutical composition comprises the above compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled form or prodrug thereof.

[0017] [4] The above compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled form or prodrug thereof, or the above pharmaceutical composition, is for use in the preparation of a medicament for preventing and / or treating a disease and / or condition mediated at least in part by α4β7 integrin.

[0018] [5] The above compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled form or prodrug thereof, or the above pharmaceutical composition, is used for the prevention and / or treatment of a disease and / or condition mediated at least in part by α4β7 integrin.

[0019] [6]A method for preventing and / or treating a disease and / or illness at least partially through α4β7 integrin comprises the following steps: administering the above compound or its pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled form or prodrug, or the above pharmaceutical composition, to an individual in need thereof.

[0020] The novel N-(benzoyl)-phenylalanine compounds in the present invention have excellent α4β7 integrin binding inhibitory activity. Therefore, the novel N-(benzoyl)-phenylalanine compounds in the present invention can provide a therapeutic or preventive agent for α4β7-dependent autoimmune diseases and inflammatory bowel diseases (Crohn's disease and ulcerative colitis). The compounds in the present invention have high blood concentration and bioavailability during oral administration and are useful as oral dosage forms. Furthermore, the compounds of the present invention have good stability in acidic and alkaline solutions and can also be used for the development of various dosage forms.

Modes for Carrying Out the Invention

[0021] Definition of Terms Unless otherwise defined, the meanings of the terms used in the text are the same as those commonly understood by those skilled in the art. The technical intentions used in the text are the technologies commonly understood in the art and include changes and equivalent substitutions of technologies that are obvious to those skilled in the art. The following terms are easy for those skilled in the art to understand, but for better explaining the present invention, they are described as follows.

[0022] The terms "comprise", "include", "have" or "relate to" and other variant forms thereof in the text refer to an inclusive or open collective concept and do not negate other unlisted elements or method steps. Those skilled in the art should understand that the above terms such as "include" also include the meaning of "consisting of...".

[0023] The term "one or more" or a similar expression "at least one" refers to a number or type of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0024] When the lower and upper limits of a numerical range are disclosed, any numerical value or any sub-range included in this range shall be specifically disclosed. In particular, each numerical range of the parameters disclosed in the text (for example, in the form of "from about a to b", or equivalently "roughly from a to b", or equivalently "about a - b") should be understood to cover any numerical value and sub-range among them. For example, "C1-6" covers any sub-range and all point values therein, such as C 2~5 , C3-4, C1-2, C 1~3 , C 1~4 , C 1~5 , etc., and includes C1, C2, C3, C4, C5, C6, etc. Also, for example, "3-6 membered" covers any sub-range and each numerical value therein, such as 3-4 membered, 3-5 membered, 3-6 membered, 4-5 membered, 4-6 membered, 5-6 membered, etc., and also includes 3, 4, 5, 6 membered, etc.

[0025] The term "pharmaceutically acceptable salt" refers to salts that are substantially non-toxic to a living body. The salts of the compounds of the present invention generally (but not limited thereto) include salts formed from the compounds of the present invention and pharmaceutically acceptable inorganic acids / organic acids / acidic amino acids or inorganic bases / organic bases / basic amino acids. These salts are also called acid addition salts or alkali addition salts. For appropriate salts, refer to "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Pharmaceutically acceptable salts of the compounds of the present invention include (but are not limited to) the following: metal salts (e.g., sodium salt, potassium salt, ammonium, calcium salt, magnesium salt, zinc salt, aluminum salt, etc.) formed by acidic groups (e.g., carboxyl group), organic amine salts (e.g., dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, and diisopropylethylamine salt, etc.), basic amino acids (e.g., lysine salt, arginine salt, etc.); inorganic acid salts (e.g., hydrochloride, sulfate, phosphate, etc.) formed from basic groups (e.g., amino), organic acid salts (e.g., maleate, tartrate, succinate, citrate, acetate, etc.).

[0026] The term "ester" refers to substances that are basically non-toxic to a living body. Esters of the compounds of the present invention include (but are not limited thereto) esters formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic acids / organic acids / acidic amino acids for the hydroxyl groups of the compounds, or by the reaction of the carboxyl groups of the compounds with other compounds having pharmaceutically acceptable alcohols / phenols / hydroxyl groups.

[0027] The term "solvate compound" refers to a complex formed by the interaction of the compounds of the present invention with pharmaceutically acceptable solvents, having a certain spatial arrangement and a solute / solvent molecule molar ratio. Generally, it includes (but is not limited thereto) solvate compounds formed from the compounds of the present invention and polar protic solvents / polar aprotic solvents / non-polar solvents. For example, hydrates, alcoholates, etc.

[0028] The term "optical isomer" refers to a plurality of isomers having different optical activities resulting from the compound of the present invention having a chiral element (e.g., chiral center, chiral axis, chiral plane, etc.), and generally includes (but is not limited to) the enantiomers and diastereomers of the compound of the present invention.

[0029] The term "tautomer" refers to a plurality of isomers having different structural formulas resulting from the compound of the present invention having tautomerism, and generally includes (but is not limited to) keto-enol tautomers, amide-iminol tautomers, etc.

[0030] The term "isotope labeling" refers to a compound formed by substituting at least one atom of the compound of the present invention with its isotope atom, and generally includes (but is not limited to) deuterated compounds in which a hydrogen atom is substituted with a deuterium atom.

[0031] The term "prodrug" refers to an induced compound that generates the compound of the present invention directly or indirectly after administration to an individual (for example, it is converted into the compound of the present invention by the action of enzymes, gastric acid oxidation, reduction, hydrolysis, etc. under physiological conditions in the body). A more preferred situation is that the derivative compound or prodrug is a compound that enhances the bioavailability of the compound of the present invention when administered to an individual (for example, it is more easily taken up into the blood), or a compound that promotes the delivery of the parent compound to the site of action (for example, the lymphatic system). For appropriate prodrugs, see T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems[J], American Chemical Society, Vol. 14, 1975. Note that the present invention covers the compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection is necessary and / or desirable for sensitive or reactive groups on any related molecules, thereby forming chemical protection of the compounds of the present invention. For example, when the compound of the present invention has a carboxyl group, the corresponding prodrug can be prepared by esterification or amidation; when the compound of the present invention has an amino group, the corresponding prodrug can be prepared by amidation, phosphorylation or alkylation; when the compound of the present invention has a hydroxyl group, the corresponding prodrug can be prepared by esterification, phosphorylation or alkylation. For appropriate protecting groups, see T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis[M], John Wiley & Sons, 2006. These protecting groups can be removed at appropriate subsequent stages using known methods in this field.

[0032] Unless otherwise specified, the term "halogen" used in this text refers to fluorine (F), chlorine (Cl), bromine (Br), and / or iodine (I).

[0033] Unless otherwise specified, the term "hydroxyl group" used in this text refers to -OH.

[0034] Unless otherwise specified, the term "amino" as used in this text refers to -NH2, and the term "substituted amino group" refers to the mono-substituted form -NHR or the di-substituted form -NRR' of the amino group.

[0035] Unless otherwise specified, the term "aldehyde group" as used in this text refers to -CH(=O).

[0036] Unless otherwise specified, the term "carboxyl group" as used in this text refers to -C(=O)OH.

[0037] Unless otherwise specified, the term "cyano" as used in this text refers to -CN.

[0038] Unless otherwise specified, the term "nitro" as used in this text refers to -N(=O)2.

[0039] Unless otherwise specified, the term "alkyl" as used in this text refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. For example, the term "C1-6 alkyl" as used in this text refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., which is optionally substituted by one or more (e.g., 1 to 3) of the substituents described in this text (e.g., when substituted by a halogen, this group is a "C1-6 halogenated alkyl", such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, etc.).

[0040] Unless otherwise specified, the term "alkenyl" as used in this text refers to a straight-chain or branched-chain aliphatic hydrocarbon group having one or more (e.g., 1 to 3) carbon-carbon double bonds. For example, the term "C 2~6"Alkenyl" means an alkenyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds (e.g., vinyl group, 1-propenyl group, 2-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-2-propenyl group, 4-methyl-3-pentenyl group, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described in this text.

[0041] Unless otherwise specified, the term "alkynyl" as used in this text means a straight-chain or branched-chain aliphatic hydrocarbon group in which one or more (e.g., 1 to 3) carbon atoms are bonded to each other. For example, the term "C 2~6 alkynyl" as used in this text refers to an alkynyl having 2 to 6 carbon atoms and one, two or three carbon-carbon bonds (e.g., ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentyl, 3-pentyl, 4-pentyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described in this text.

[0042] Unless otherwise specified, the term "alkoxy" as used in this text means the above alkyl group linked to the parent molecular moiety through an oxygen atom, i.e., -O-alkyl group. For example, the term "C 1~6 alkoxy" as used in this text refers to an alkoxy group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms) (e.g., methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described in this text (e.g., when substituted with a halogen, this group becomes "C 1~6 halogenated alkoxy", e.g., -OCF3, -OC2F5, -OCHF2, -OCH2Cl, etc.).

[0043] Unless otherwise specified, the term "alkylthio group" as used in this text refers to the above alkyl group linked to the parent molecular moiety through a sulfur atom, i.e., an -S-alkyl group. For example, the term "C 1~6 alkylthio group" as used in this text is an alkylthio group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), such as a methylthio group, an ethylthio group, an isopropylthio group, a tert-butylthio group, etc., which is substituted by one or more (e.g., 1 to 3) substituents described in this text (e.g., when substituted by a halogen, this group becomes a "C 1~6 halogenated alkylthio group", such as -SCF3, -SC2F5, -SCHF2, -SCH2Cl, etc.).

[0044] Unless otherwise specified, the term "alkanoyl" as used in this text refers to the above alkyl group linked to the parent molecular moiety through a carbonyl group, i.e., a -C(=O)-alkyl group. For example, the term "C 1~6 alkanoyl" as used in this text is an alkanoyl having 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6 carbon atoms), such as acetyl, isobutyryl, etc.

[0045] Unless otherwise specified, the term "(di)alkylamino" as used in this text refers to the above alkyl group linked to the parent molecular moiety through a nitrogen atom, i.e., -NH-alkyl or -N(alkyl)2. For example, the term "C 1~6 alkylamino group" as used in this text refers to an alkylamino group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), such as an ethylamino group, an isopropylamino group, etc. The term "bis(C 1~6 alkyl)amino" used in this text is a dialkylamino group having two sets of 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6 carbon atoms), such as dimethylamino, diethylamino, etc.

[0046] Unless otherwise specified, the term "alkoxycarbonyl" as used in this text refers to the above alkyl group linked to the parent molecular moiety through an oxygen atom and a carbonyl group in sequence, that is, a -C(=O)-O-alkyl group. For example, the term "C 1~6 alkoxycarbonyl" as used in this text is an alkoxycarbonyl group having 1 to 6 carbon atoms (for example, 1, 2, 3, 4, 5, or 6 carbon atoms) (such as ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl group, etc.).

[0047] Unless otherwise specified, the term "alkanoyloxy" as used in this text refers to the above alkyl group linked to the parent molecular moiety through a carbonyl group and an oxygen atom in sequence, that is, an -O-C(=O)-alkyl group. For example, the term "C1-6 alkanoyloxy" as used in this text is an alkanoyloxy group having 1 to 6 carbon atoms (for example, 1, 2, 3, 4, 5, or 6 carbon atoms) (such as acetoxy, isobutyryloxy, pivaloyloxy group, etc.).

[0048] Unless otherwise specified, the term "alkylamide" as used in this text refers to the above alkyl group linked to the parent molecular moiety through a carbonyl group and a nitrogen atom in sequence, that is, a -NH-C(=O)-alkyl group. For example, the term "C 1~6 alkylamide" as used in this text is an alkylamide group having 1 to 6 carbon atoms (for example, 1, 2, 3, 4, 5, or 6 carbon atoms) (such as acetylamino group, isobutylamino group, neopentylamino group, etc.).

[0049] Unless otherwise specified, the term "carbamoyl" as used in this text is -C(=O)-NH2, and "(di)alkylcarbamoyl" refers to the above alkyl group linked to the parent molecular moiety through an amino group and a carbonyl group in sequence, that is, -C(=O)-NH-alkyl or -C(=O)-N(alkyl)2. For example, the term "C 1~6"Alkylcarbamoyl" refers to an alkylcarbamoyl group having 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6 carbon atoms) (for example, ethylcarbamoyl, isopropylcarbamoyl group, etc.). The term "bis(C 1~6 alkyl)carbamoyl" used in this article is a dialkylcarbamoyl having two sets of 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6 carbon atoms) (for example, diethylcarbamoyl, diisopropylcarbamoyl group, etc.).

[0050] Unless otherwise specified, the term "alkoxysulfonyl" used in this article is the above alkyl group that sequentially connects an oxygen atom and a sulfone group to the parent molecular moiety, that is, a -S(=O)2-O-alkyl group. The term "C 1~6 alkoxysulfonyl" used in this manuscript is an alkoxysulfonyl group having 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6 carbon atoms) (for example, ethoxysulfonyl, isopropoxysulfonyl, tert-butoxysulfonyl, etc.).

[0051] Unless otherwise specified, the term "alkylsulfonyloxy" used in this article is the above alkyl group sequentially connected to the parent molecular moiety through a sulfone group and an oxygen atom, that is, an -O-S(=O)2-alkyl group. The term "C 1~6 alkylsulfonyloxy" used in this manuscript refers to an alkylsulfonyloxy group having 1 to 6 carbon atoms (1, 2, 3, 4, 5, or 6 carbon atoms) (for example, ethylsulfonyloxy, isopropoxide, tert-butylsulfonyloxyl group, etc.).

[0052] Unless otherwise specified, the term "alkylsulfonamide" used in this article is the above alkyl group sequentially connected to the parent molecular moiety through a sulfone group and a nitrogen atom, that is, an -NH-S(=O)2-alkyl group. For example, the term "C 1~6"Alkylsulfonamide" is an alkylsulfonamide having 1 to 6 carbon atoms (for example, 1, 2, 3, 4, 5, or 6 carbon atoms) (for example, ethylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, etc.).

[0053] Unless otherwise specified, the term "aminosulfonyl" used in this text means -S(=O)2-NH2, and the term "(di)alkylaminosulfonyl" means the above alkyl group linked to the parent molecular moiety through the nitrogen atom and the sulfone group in sequence, that is, -S(=O)2-NH-alkyl or -S(=O)2-N(alkyl)2. For example, the term "C 1~6 alkylaminosulfonyl" used in this text is an alkylaminosulfonyl group having 1 to 6 carbon atoms (for example, 1, 2, 3, 4, 5, or 6 carbon atoms) (for example, ethylaminosulfonyl group, isopropylaminosulfonyl group, etc.). The term "bis(C 1~6 alkyl)aminosulfonyl" used in this text is a dialkylaminosulfonyl group having two sets of 1 to 6 carbon atoms (for example, 1, 2, 3, 4, 5, or 6 carbon atoms) (for example, diethylaminosulfonyl, diisopropylaminosulfonyl group, etc.).

[0054] Unless otherwise specified, the term "cycloalkyl" used in this text is a cyclic saturated aliphatic hydrocarbon group. For example, the term "C 3~6 cycloalkyl" used in this text is a cycloalkyl group having 3 to 6 cyclic carbon atoms (for example, 3, 4, 5, or 6 carbon atoms) (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group, etc.). Unless otherwise specified, the term "cycloalkylene group" used in this text is a cyclic saturated aliphatic hydrocarbon group, and this group connects two other fragments at the same time. For example, the term "C 3~6 cycloalkylene" used in this text is a cycloalkylene group having 3 to 6 ring carbon atoms (for example, 3, 4, 5, or 6 carbon atoms) (for example, cyclopropylidene group, etc.).

[0055] Unless otherwise specified, the term "heterocycloalkyl" as used in this text refers to a saturated aliphatic hydrocarbon group, and its ring contains one or more (1, 2, 3, 4, 5, 6, 7, 8, or 9) carbon atoms and one or more (e.g., 1, 2, 3, or 4) fragments independently selected from -O-, -S-, -S(=O)-, -S(=O)2-, and -NR- (where R represents a hydrogen atom or a substituent, such as alkyl or cycloalkyl). For example, the term "3- to 7-membered heterocycloalkyl" as used in this text refers to a heterocycloalkyl having 3 to 7 ring atoms (e.g., 3, 4, 5, 6, or 7 atoms) (e.g., ethylene oxide (oxetanyl), cyclothioethylalkyl (thioheterocyclopropyl), cycloazoethylalkyl (nitrogen heterocyclopropyl), nitrogen heterocyclobutyl, oxetanyl, thioheterocyclobutyl, tetrahydrofuran, 1,3-dioxetanyl, tetrahydrothiophene, pyrrolidine, pyrrolidone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiuranyl, piperidinyl, nitrogen heteroxenyl, morpholine, thiomorpholine group, 1,4-thioxalkyl group, 1,4-dioxacyclo group, 1,4-dithioxalkyl group, piperazine group, 1,3,5-trioxalkyl group, 1,3,5-trithioxalkyl group, 1,4-thioxadialkyl group, etc.). Unless otherwise specified, the term "heterocycloalkylene group" as used in this text refers to a saturated aliphatic hydrocarbon group, and its ring contains one or more (1, 2, 3, 4, 5, 6, 7, 8, or 9) carbon atoms and one or more (1, 2, 3, or 4) fragments independently selected from -O-, -S-, -S(=O)-, -S(=O)2-, and -NR- (where R represents a hydrogen atom or a substituent, such as alkyl or cycloalkyl), and simultaneously links two other fragments. For example, the term "3- to 7-membered heterocycloalkylene group" as used in this text refers to a heterocycloalkylene group having 3 to 7 ring atoms (e.g., 3, 4, 5, 6, or 7 atoms) (e.g., tetrahydro-2H-pyran-4-yl, etc.).

[0056] Unless otherwise specified, the term "aryl" as used in this text refers to a monocyclic or fused-ring aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C 6~10 aryl" as used in this text refers to an aryl group having 6 to 10 (for example, 6, 7, 8, 9, or 10) ring carbon atoms (such as a phenyl group, a naphthyl group, etc.), which is substituted by one or more of the substituents described in this text (for example, a tolyl group disubstituted with a C1-6 alkyl group, a chlorophenyl group substituted with a halogen, etc.).

[0057] Unless otherwise indicated, as used in this specification, the term "heteroaryl" refers to a monocyclic or fused-ring aromatic group having a conjugated π-electron system, and the ring contains one or more (1, 2, 3, or 4) carbon atoms and one or more (1, 2, 3, or 4) fragments each independently selected from -O-, -S-, -S(=O)-, -S(=O)2-, -N=, and -NR- (where R represents a hydrogen atom or a substituent such as alkyl or cycloalkyl). As used in this specification, "5- to 10-membered heteroaryl" refers to a heteroaryl having 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms (e.g., thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or their benzo derivatives such as indazolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, etc., or pyrazopyridinyl, pyrrolidinyl, pyrrolidinyl, pyrazopyrimidine, etc.), which is optionally substituted with one or more substituents described in this specification (e.g., a methylpyridyl group substituted with a C1-C6 alkyl group, a chloropyridyl group substituted with a halogen, etc.). When the valence bond requirements are satisfied, heteroaryl can be linked to the parent molecular moiety by any one ring atom. When the valence bond requirements are satisfied, heteroaryl can be linked to another group (or fragment) by any carbon atom or heteroatom (e.g., an N atom) in the ring. Also, a heteroaryl group can be selectively fused to an aryl, heterocycloalkyl group, or cycloalkyl group, and the ring bonded to the parent structure therein is a heteroaryl group.

[0058] Unless otherwise indicated, as used in this specification, the terms "aryloxy" and "heteroaryloxy" refer to the above aryl or heteroaryl linked to the parent molecular moiety through an oxygen atom, i.e., -O-aryl (e.g., phenoxy, naphthalen-1-yloxyl group, etc.) and -O-heteroaryl (e.g., furan-2-yloxyl group and pyridin-4-yloxyl group, etc.).

[0059] Unless otherwise indicated, the terms "arylthio" and "heteroarylthio" as used in this text refer to the above aryl or heteroaryl groups linked to the parent molecular moiety through a sulfur atom, i.e., -S-aryl (such as phenylthio group, naphthalen-1-ylthio group, etc.) and -S-heteroaryl (such as furan-2-ylthio, pyridin-4-ylthio group, etc.).

[0060] Unless otherwise indicated, the terms "arylcarbonyl group" and "heteroarylcarbonyl" as used in this text refer to the above aryl or heteroaryl groups linked to the parent molecular moiety through a carbonyl group, i.e., -C(=O)-aryl (such as benzoyl, 1-naphthoyl group, etc.) and -C(=O)-heteroaryl (such as furfuryl group, nicotinyl group, etc.).

[0061] Unless otherwise indicated, the terms "arylamino" and "heteroarylamino" as used in this text refer to the above aryl or heteroaryl groups linked to the parent molecular moiety through a nitrogen atom, i.e., -NH-aryl (such as phenylamino, naphthalen-1-ylamino, etc.) and -NH-heteroaryl (such as furan-2-yloxyl group, pyridin-4-yloxyl group, etc.).

[0062] Unless otherwise indicated, the terms "aryloxyacyl" and "heteroaryloxyacyl" as used in this text refer to the above aryl or heteroaryl groups linked to the parent molecular moiety successively through an oxygen atom and a carbonyl group, i.e., -C(=O)-O-aryl (such as phenoxyformyl) and -C(=O)-O-heteroaryl (such as furan-2-yloxyformyl).

[0063] Unless otherwise specified, the terms "arylformyloxy" and "heteroarylformyloxy" as used in this text refer to the above aryl or heteroaryl groups that are sequentially linked 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 group).

[0064] Unless otherwise specified, the terms "arylformylamino group" and "heteroarylformylamino group" as used in this text refer to the above aryl or heteroaryl groups that are sequentially linked 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).

[0065] Unless otherwise specified, the terms "arylcarbamoyl" and "heteroarylcarbamoyl" as used in this text refer to the above aryl or heteroaryl groups that are sequentially linked to the parent molecular moiety through a nitrogen atom and a carbonyl group, i.e., -C(=O)-NH-aryl (such as phenylcarbamoyl) and -C(=O)-NH-heteroaryl (such as furan-2-ylcarbamoyl).

[0066] Unless otherwise specified, the terms "aryloxysulfonyl" and "heteroaryloxysulfonyl" as used in this text refer to the above aryl or heteroaryl groups that are sequentially linked to the parent molecular moiety through an oxygen atom and a sulfone group, i.e., -S(=O)2-O-aryl (such as phenoxysulfonyl) and -S(=O)2-O-heteroaryl (such as furan-2-yloxysulfonyl).

[0067] Unless otherwise specified, the terms "arylsulfonyloxy" and "heteroarylsulfonyloxy" as used in this text refer to the above aryl or heteroaryl groups that are sequentially linked to the parent molecular moiety through a sulfone group and an oxygen atom, i.e., -O-S(=O)2-aryl (benzenesulfonyloxy) and -O-S(=O)2-heteroaryl (e.g., furan-2-sulfonyloxy).

[0068] Unless otherwise specified, the terms "arylsulfonylamino" and "heteroarylsulfonylamino" as used in this text refer to the above aryl or heteroaryl groups that are sequentially connected to the parent molecular moiety through a sulfone group and a nitrogen atom, i.e., -NH-S(=O)2-aryl (e.g., benzenesulfonylamino) and -NH-S(=O)2-heteroaryl (e.g., furan-2-sulfonylamino group).

[0069] Unless otherwise specified, the terms "arylaminosulfonyl" and "heteroarylaminosulfonyl" as used in this text refer to the above aryl or heteroaryl groups that are sequentially linked to the parent molecular moiety through a nitrogen atom and a sulfone group, i.e., -S(=O)2-NH-aryl (e.g., phenylaminosulfonyl) and -S(=O)2-NH-heteroaryl (e.g., furan-2-ylaminosulfonyl).

[0070] Unless otherwise specified, the term "each independently" as used in this text refers to the fact that two or more groups (or fragments) with the same or nearly the same range of numerical values present in the structure can have the same or different meanings under specific circumstances. For example, if R1 and R2 are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl group, when R1 is hydrogen, R2 can be hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl group; similarly, when R2 is hydrogen, R1 can be hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl group.

[0071] Unless otherwise specified, as used in this text, the term "substitution" and its variant forms refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or atomic groups (e.g., hydrogen atoms) on a specified atom by other equivalents. The condition is that it does not exceed the normal valence of the specified atom or atomic group under the current situation and can form a stable compound. Unless otherwise specified, the linking site of the substituent in this text can be any appropriate position of the substituent.

[0072] General formula compound The present invention provides a compound represented by general formula (1) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof.

[0073]

Chemical formula

[0074] Each X3 is independently hydrogen or a halogen; A is a group represented by the general formula (2-1), (2-2) or (2-3).

[0075] [Chemical formula] Ring H is C 3~6 a cycloalkylene group or a 3- to 7-membered heterocycloalkylene group, the above group being substituted with at least one of the following substituents: a halogen, C 1~6 an alkyl group, C 3~6 a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, C 6~10 an aryl group and a 5- to 10-membered heteroaryl; Y is O or S; Each Z is independently CR1 or N; When present, each R1 is independently hydrogen, a halogen, a hydroxyl group, an amino group, an aldehyde group, a carboxyl group, a cyano group, a nitro group, C 1~6 an alkyl group, C 1~6 a haloalkyl group, C 2~6 an alkenyl group, C 2~6 an alkynyl group, C 1~6 an alkoxy group, C 1~6 a haloalkoxy group, C 1~6 an alkyloxy group, C 1~6 a haloalkyloxy group, C 1~6 an alkylamino group, di(C 1~6 alkyl)amino group, C 1~6 an alkoxycarbonyl group, C 1~6 an alkyloxy group, C 1~6 an alkyloxy group, C 1~6Alkylamino group, carbamoyl group, C 1~6 Alkylcarbamoyl group, di(C 1~6 Alkyl)carbamoyl group, C 1~6 Alkoxysulfone group, C 1~6 Alkylsulfonic acid oxy group, C 1~6 Alkylsulfonic acid amino group, sulfamoyl group, C 1~6 Alkylsulfamoyl group, di(C 1~6 Alkyl)sulfamoyl group, C 3~6 Cycloalkyl group, 3- to 7-membered heterocycloalkyl group, C 6~10 Aryl group, 5- to 10-membered heteroaryl group, C 6~10 Aryloxy group, 5- to 10-membered heteroaryloxy group, C 6~10 Member heteroaryl sulfur group, C 6~10 Arylamino group, 5- to 10-membered heteroarylamino group, C 6~1 0 Arylcarbonyl group, 5- to 10-membered heteroarylcarbonyl group, C 6~10 Aryloxycarbonyl group, 5- to 10-membered heteroaryloxycarbonyl group, C 6~10 Arylformyloxy group, 5- to 10-membered heteroarylformyloxy group, C 6~10 Arylformylamino group, 5- to 10-membered heteroarylformylamino group, C 6~10 Member heteroarylcarbamoyl group, 5- to 10-membered heteroaryloxysulfonyl group, 5- to 10-membered heteroaryloxysulfonyl group, C 6~10 Arylsulfonyloxy group, 5- to 10-membered heteroarylsulfonyloxy group, C 6~10 Arylsulfonylamino group, 5- to 10-membered heteroarylsulfonylamino group, C 6~10 Member arylaminosulfonyl group or 5- to 10-membered heteroarylaminosulfonyl group, and is substituted with at least one of the following substituents: halogen group, C 1~6 Alkyl group, C 3~6 Cycloalkyl group, 3- to 7-membered heterocycloalkyl group, C 6~10 Aryl group and 5- to 10-membered heteroaryl group.

[0076] When present, each R2 is independently hydrogen, C 1~6 alkyl group, C 1~6 halogenated alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 1~6 alkanoyl group, C 1~6 alkoxycarbonyl group, C 1~6 alkylamino group, carbamoyl group, C 1~6 alkylcarbamoyl group, 2(C 1~6 alkyl)carbamoyl group, C 3~6 cycloalkyl group, 3- to 7-membered heterocycloalkyl group, C 6~10 aryl group, 5- to 10-membered heteroaryl group, C 6~10 arylcarbonyl group, 5- to 10-membered heteroarylcarbonyl group, C 6~10 aryloxycarbonyl group, 5- to 10-membered heteroaryloxycarbonyl group, C 6~10 arylcarbamoyl group or 5- to 10-membered heteroarylcarbamoyl group, and the above groups are optionally substituted with at least one of the following substituents: halogen, C 1~6 alkyl, C 3~6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6~10 aryl and 5- to 10-membered heteroaryl.

[0077] In one embodiment of the present invention, R3 in the compound represented by the general formula (1) is hydrogen, C 1~6 alkyl group, C 1~6 halogenated alkyl group, C 3~6 cycloalkyl group, 3- to 7-membered heterocycloalkyl group, C 6~10 aryl group or 5- to 10-membered heteroaryl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C 1~6 alkyl, C 3~6 cycloalkyl group, 3- to 7-membered heterocycloalkyl group; preferably, R3 is hydrogen, C 1~6 alkyl group, C 1~6 halogenated alkyl group, C 3~6 cycloalkyl group or 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen and C1~6 Alkyl group; more preferably, R3 is hydrogen or methyl; even more preferably, both R3 are hydrogen.

[0078] In one embodiment of the present invention, each R4 in the compound represented by the general formula (1) is independently hydrogen, fluorine, chlorine or bromine; preferably, each R4 is independently hydrogen, fluorine or chlorine; more preferably, all R4 are hydrogen.

[0079] In one embodiment of the present invention, each X1 in the compound represented by the general formula (1) is independently fluorine, chlorine or bromine; preferably, each X1 is independently fluorine or chlorine.

[0080] In one embodiment of the present invention, X2 in the compound represented by the general formula (1) is hydrogen, halogen, C 1~6 alkylamino group, bis(C 1~6 alkyl)amino group, C 3~6 cycloalkyl group or 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C 1~6 alkyl, C 3~6 cycloalkyl group and 3- to 7-membered heterocycloalkyl group; preferably, X2 is hydrogen, halogen, bis(C 1~6 alkyl)amino group or 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C 1~6 alkyl, C 3~6 cycloalkyl group and 3- to 7-membered heterocycloalkyl group; more preferably, X2 is hydrogen, chlorine, diethylamino, morpholino( [Chemical formula] ), 2-oxa-5-azabicyclo[2.2.1]hept-5-yl( [Chemical formula] ), or 4-morpholinopiperidin-1-yl( [Chemical formula] ) is.

[0081] In one embodiment of the present invention, each X3 in the compound represented by the general formula (1) is independently hydrogen or fluorine; preferably, all X3 are hydrogen.

[0082] In one preferred embodiment of the present invention, in the compound represented by the general formula (1)

Chemical formula

[0083]

Chemical formula

Chemical formula

[0084]

Chemical formula

Chemical formula

[0085]

Chemical formula

[0086]

Chemical formula

Chemical formula

Chemical formula

[0087] When A is a group represented by the general formula (2-1-1), two of the four R1s are each independently halogen, C 1~6 an alkyl group, C 1~6 an alkoxy group or a bis(C 1~6 alkyl)amino group, and the others are hydrogen; or, one of the four R1s is halogen, a C1-6 alkyl group, a C1-6 alkoxy group or a bis(C 1~6 alkyl)amino group, and the rest are hydrogen; or, all four R1s are hydrogen; preferably, two of the four R1s are each independently halogen or a bis(C 1~6 alkyl)amino group, and the rest are hydrogen; or, one of the four R1s is halogen, C 1~6 an alkoxy group or a bis(C 1~6 alkyl)amino group, and the others are hydrogen; or, all four R1s are hydrogen; more preferably, two of the four R1s are each independently fluorine, chlorine or dimethylamino, and the rest are hydrogen; or, one of the four R1s is fluorine, chlorine, methoxy or dimethylamino, and the rest are hydrogen; or, all four R1s are hydrogen.

[0088] When A is a group represented by the general formula (2-1-1’), two of the three R1s are each independently halogen, C 1~6 alkyl group, C 1~6 alkoxy group or bis(C 1~6 alkyl)amino group, and the remainder is hydrogen; alternatively, one of the three R1s is halogen, C 1~6 alkyl group, C 1~6 alkoxy group or bis(C 1~6 alkyl)amino group, and the remainder is hydrogen; alternatively, all three R1s are hydrogen; preferably, two of the three R1s are each independently halogen or bis(C 1~6 alkyl)amino group, and the remainder is hydrogen; alternatively, one of the three R1s is halogen, C 1~6 alkoxy or bis(C 1~6 alkyl)amino group, and the others are hydrogen; alternatively, all three R1s are hydrogen; more preferably, all three R1s are hydrogen.

[0089] In one preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-1-2):

Chemical formula

[0090] In one more preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-1-3),

Chemical formula

[0091] In one preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-1-2’):

Chemical formula

[0092] In one more preferred embodiment of the present invention, the compound represented by general formula (1) is the compound represented by general formula (2-1-3’),

Chemical formula

[0093] 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).

[0094]

Chemical formula

[0095] Two of the four R1s are each independently halogen, C 1~6 alkyl group, C 1~6 alkoxy or bis(C 1~6 alkyl)amino group, and the rest are hydrogen; alternatively, one of the four R1s is halogen, C 1~6 alkyl group, C 1~6 alkoxy group or bis(C 1~6 alkyl)amino group, and the rest are hydrogen; preferably, two of the four R1s are each independently halogen, and the rest are hydrogen; alternatively, one of the four R1s is halogen, C 1~6 alkoxy group or bis(C 1~6 alkyl)amino group, and the others are hydrogen; more preferably, two of the four R1s are each independently fluorine or chlorine, and the rest are hydrogen; alternatively, one of the four R1s is fluorine, chlorine, methoxy or dimethylamino, and the rest are hydrogen.

[0096] R2 is hydrogen, C1~6 an alkyl group, C 1~6 a halogenated alkyl group, C 3~6 a cycloalkyl group or a 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C 1~6 alkyl, C 3~6 a cycloalkyl group and a 3- to 7-membered heterocycloalkyl group; preferably, R2 is C 1~6 an alkyl group, C 3~6 a cycloalkyl group or a 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with a C1-6 alkyl group; more preferably, R2 is methyl, cyclopropyl, tetrahydro-2H-pyran-4-yl ( [Chemical formula] ) or 1-methylpiperidin-4-yl ( [Chemical formula] ).

[0097] In one preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-2-2), [Chemical formula] wherein Y, R1, R2, R3, R4, X1, X2 and X3 are as described in the present invention.

[0098] In one more preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-2-3), [Chemical formula] wherein Y, R1, R2, R3, R4, X1, X2 and X3 are as described in the present invention.

[0099] In one embodiment of the present invention, A in the compound represented by the general formula (1) is the group represented by the general formula (2-3-1), [Chemical formula] Y is O or S, preferably Y is O; One of the four R1s is halogen, C 1~6 alkyl group, C 1~6 alkoxy or bis(C 1~6 alkyl)amino group, and the rest are hydrogen; preferably, one of the four R1s is chlorine and the rest are hydrogen; Each R2 is independently hydrogen, C 1~6 alkyl group, C 1~6 halogenated alkyl group, C 3~6 cycloalkyl group or 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C 1~6 alkyl, C 3~6 cycloalkyl group and 3- to 7-membered heterocycloalkyl group; preferably, each R2 is independently C 1~6 alkyl group; more preferably, all R2s are methyl groups.

[0100] In one preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-3-2),

Chemical formula

[0101] In one more preferred embodiment of the present invention, the compound represented by the general formula (1) is the compound represented by the general formula (2-3-3),

Chemical formula

[0102] In one preferred embodiment of the present invention, among the compounds represented by general formula (2-1-1), (2-1-2), (2-1-3), (2-2-1), (2-2-2), (2-2-3), (2-3-1), (2-3-2) or (2-3-3),

Chem.

[0103]

Chem.

Chem.

[0104]

Chem.

Chem.

[0105]

Chem.

Chem.

[0106] The present invention provides the following compounds or pharmaceutically acceptable salts, esters, solvates, optical isomers, tautomers, isotope labels or prodrugs thereof.

[0107] [Chemical formula] Preparation method of general formula compound

[0108] The compound shown in general formula (1) in the present invention (for example, having a carboxyl group at the end, that is, R3 is hydrogen) can be prepared by the following method.

[0109] [Chemical formula] Among them, R4, X1, X2, X3 and A are as described in general formula (1); W1 is bromine or iodine, W2 is a hydroxyl group or chlorine, and R is an amino protecting group.

[0110] First, intermediate M1 is obtained by the coupling reaction of intermediate P1 and intermediate H-A; preferably, the coupling reaction is carried out in the presence of a metal catalyst (such as cuprous iodide, etc.), a ligand (such as N,N-dimethylglycine or its hydrochloride, etc.), a base (such as cesium carbonate, etc.) and an organic solvent that does not adversely affect this reaction (such as acetonitrile, 1,4-dioxane, etc.).

[0111] Next, intermediate M2 is obtained by the deprotection reaction of intermediate M1; preferably, the deprotection reaction is carried out in the presence of an acid (such as trifluoroacetic acid, etc.) and an organic solvent that does not adversely affect this reaction (such as dichloromethane, etc.).

[0112] Furthermore, intermediate M3 is obtained by the condensation reaction of intermediate M2 and intermediate P2; preferably, the condensation reaction is carried out in the presence of a base (such as N,N-diisopropylethylamine, triethylamine, etc.) and an organic solvent that does not adversely affect this reaction (such as dichloromethane).

[0113] Finally, the target product is obtained through the hydrolysis reaction of intermediate M3; preferably, the hydrolysis reaction is carried out in the presence of a base (such as sodium hydroxide, etc.) and a mixed solvent that does not adversely affect this reaction (such as tetrahydrofuran / water, etc.).

[0114] The compound shown in general formula (1) in the present invention (for example, having an ester group at the end, that is, R3 is as defined in general formula (1) but not hydrogen) can be prepared by the following method.

[0115] Scheme 1:

Chemical formula

[0116] According to the preparation method of the general formula (1) compound having a carboxyl group at the end (that is, R3 is hydrogen), intermediate M4 is obtained, and then the target product is obtained by the esterification reaction with R3-OH; preferably, the esterification reaction is carried out in the presence of a condensation aid (such as 1-hydroxybenzotriazole (HOBt), 1,3-dicyclohexylcarbodiimide (DCC), O-(7-azabenzotriazol-1-yl)-N,N,N ’ 、N ’ -tetramethylurea hexafluorophosphate (HATU), etc.), a base (such as N,N-diisopropylethylamine, triethylamine, pyridine, etc.) and an organic solvent that does not adversely affect this reaction (such as dichloromethane, tetrahydrofuran, acetonitrile, etc.).

[0117] Scheme 2:

Chemical formula

[0118] First, intermediate M5 is obtained by the coupling reaction of intermediate P3 and intermediate H-A; preferably, the coupling reaction is carried out in the presence of a metal catalyst (such as cuprous iodide, etc.), a ligand (such as N,N-dimethylglycine or its hydrochloride, etc.), a base (such as cesium carbonate, etc.) and an organic solvent that does not have an adverse effect on this reaction (such as acetonitrile, 1,4-dioxane, etc.).

[0119] Next, intermediate M6 is obtained by the deprotection reaction of intermediate M5; preferably, the deprotection reaction is carried out in the presence of an acid (such as trifluoroacetic acid, etc.) and an organic solvent that does not have an adverse effect on this reaction (such as dichloromethane, etc.).

[0120] Furthermore, the target product is obtained by the condensation reaction of intermediate M6 and intermediate P2; preferably, the condensation reaction is carried out in the presence of a base (such as N,N-diisopropylethylamine, triethylamine, etc.) and an organic solvent that does not have an adverse effect on this reaction (such as dichloromethane).

[0121] Pharmaceutical composition The present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug thereof.

[0122] In one embodiment of the present invention, the pharmaceutical composition includes, as a drug active ingredient, the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug thereof, and also includes one or more pharmaceutically acceptable adjuvants. The adjuvants include (but are not limited to) the following components: diluents, adhesives, lubricants, coflow agents, surfactants, flavoring agents, odor-correcting agents, pH adjusters, fragrances, sweeteners, etc.

[0123] In one embodiment of the present invention, the pharmaceutical composition includes, as a drug active ingredient, the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug thereof, and one or more other drug active ingredients that, when used in combination, cause an increase in efficacy and / or a decrease in toxicity.

[0124] In one embodiment of the present invention, the pharmaceutical composition exists in a specific form, and the form includes (but is not limited to) the following types: tablets, capsules, tablets, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, detergents, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

[0125] In one embodiment of the present invention, the pharmaceutical composition per unit quantity or per unit dosage form contains 0.01 to 1000 mg of the compound represented by the general formula (1) or an equivalent amount of a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug.

[0126] Pharmaceutical use related to α4β7 integrin According to pharmacological experiments, the compound of the present invention has a certain inhibitory activity against α4β7 integrin, and thus can be used for the prevention and / or treatment of diseases and / or pathological conditions mediated at least in part by α4β7 integrin. The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label or prodrug thereof, or the pharmaceutical composition of the present invention, in the preparation of a drug for use in the prevention and / or treatment of diseases and / or pathological conditions mediated at least in part by α4β7 integrin.

[0127] The present invention also provides a method for preventing and / or treating a disease and / or disorder that is at least partially mediated by α4β7 integrin, the method comprising the following steps: administering a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope-labeled form or prodrug thereof, or a pharmaceutical composition of the present invention, to an individual in need thereof.

[0128] In one embodiment of the present invention, diseases and / or disorders that are at least partially mediated by α4β7 integrin include autoimmune diseases, inflammatory diseases, and the proliferation and metastasis of tumor cells, but are not limited thereto.

[0129] In one embodiment of the present invention, autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS), but are not limited thereto.

[0130] In one embodiment of the present invention, inflammatory diseases include inflammatory bowel disease (IBD), but are not limited thereto; preferably, inflammatory bowel disease includes ulcerative colitis (UC) and Crohn's disease (CD), but is not limited thereto.

[0131] The present invention will be described in detail below through examples. These examples are merely the optimal embodiments of the present invention and should not be regarded as limitations on the present invention. Also, unless otherwise specified, the equipment, chemicals, reagents, consumables, etc. used in the following examples can be obtained through ordinary commercial means.

[0132] It should be noted that Intermediate Preparation Example 1 shows a synthesis example of Intermediate P-1 having the general formula P1, Intermediate Preparation Examples 2 to 33 show synthesis examples of Intermediates P-2 to P-33 having the general formula H-A, Intermediate Preparation Examples 34 to 38 show synthesis examples of Intermediates P-34 to P-38 having the general formula P2, and Examples 1 to 39 show synthesis examples of the compounds of the present invention.

[0133] Intermediate Preparation Example 1: Synthesis of Methyl 3-(4-iodophenyl)-2-(triphenylmethylamino)propionate (P-1) (Step 1) Methyl (S)-2-amino-3-(4-iodophenyl)propionate [Chemical formula] Dissolve 4-iodo-L-phenylalanine (29.1 g, 10 mmol) in anhydrous methanol (290 mL) and cool in an ice bath. Add dichlorosulfone (17.9 g, 15 mmol) and N,N-dimethylformamide (2.9 mL), and react at 40 °C for 24 h. After concentrating the reaction solution under reduced pressure, a white solid is obtained, which is the title compound (29 g, 95%). ESI-QQQ-MS: m / z 306 [M+H] + .

[0134] (Step 2) Methyl 3-(4-iodophenyl)-2-(triphenylmethylamino)propionate (P-1) [Chemical formula] Dissolve methyl (S)-2-amino-3-(4-iodophenyl)propionate (24.4 g, 8 mmol) in dichloromethane (480 mL) and cool in an ice bath. Add triethylamine (12.1 g, 12 mmol) and 1.2 eq triphenylchloromethane (26.8 g, 9.6 mmol), and react at room temperature for 8 h. After concentrating the reaction solution under reduced pressure, the concentrate is purified by silica column chromatography (petroleum ether / ethyl acetate = 4:10:1) to obtain the title compound (30.7 g, 70%). ESI-QQQ-MS: m / z 548 [M+H] + .

[0135] Intermediate Preparation Example 2: Synthesis of Spiro[cyclopropane-1,3'-indolin]-2'-one (P-2) [Chemical formula] Nidoline-2-one (0.27 g, 2 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), cooled to -40 °C, LDA (2 mol / L, 0.4 mL, 8 mmol) was added, stirred for 30 minutes, heated to 0 °C, 1,2-dibromoethane (1.14 g, 6 mmol) was added, and reacted at room temperature for 24 h. Saturated ammonium chloride aqueous solution (5 mL) and water (15 mL) were added to the reaction system, 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, concentrated under reduced pressure, and the concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.19 g, 60%). ESI-QQQ-MS: m / z 160 [M+H] + 。

[0136] Intermediate Preparation Example 3: Synthesis of 7'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-3)

Chemical formula

[0137] Intermediate Preparation Example 4: Synthesis of 6'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-4)

Chemical formula

[0138] Intermediate Preparation Example 5: Synthesis of 5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-5)

Chemical Structure

[0139] Intermediate Preparation Example 6: Synthesis of 7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one (P-6)

Chemical Structure

[0140] Intermediate Preparation Example 7: Synthesis of 6'-chlorogai[cyclopropane-1,3'-indoline]-2'-one (P-7)

Chemical formula

[0141] Intermediate Preparation Example 8: Synthesis of 5'-chlorogai[cyclopropane-1,3'-indoline]-2'-one (P-8)

Chemical formula

[0142] Intermediate Preparation Example 9: Synthesis of 7'-methoxyspiro[cyclopropane-1,3'-indoline]-2'-one (P-9)

Chemical formula

[0143] Intermediate Preparation Example 10: Synthesis of 5',6'-difluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-10)

Chemical formula

[0144] Intermediate Preparation Example 11: Synthesis of 6'-chloro-5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-11)

Chemical Structure

[0145] Intermediate Preparation Example 12: Synthesis of 6',7'-difluorospiro[cyclopropane-1,3'-indolin]-2'-one (P-12) (Step 1) (E)-N-(2,3-Difluorophenyl)-2-(hydroxyamino)acetamide

Chem.

[0146] (Step 2) 6,7-Difluoroindoline-2,3-dione

Chem.

[0147] (Step 3) 6,7-Difluoroindolin-2-one

Chem.

[0148] (Step 4) 6’,7’-Difluoro[cyclopropane-1,3’-dihydroindole]-2’-ketone (P-12)

Chemical formula

[0149] Intermediate Preparation Example 13: Synthesis of 7-chloro-3,3-dimethylindolin-2-one (P-13)

Chemical formula

[0150] Intermediate Production Example 14: Synthesis of 7-chloro-2’,3’,5’,6’-tetrahydrospiro[indoline-3,4’-pyran]-2-one (P-14)

Chemical formula

[0151] Intermediate Preparation Example 15: Synthesis of 5’-(dimethylamino)spiro[cyclopropane-1,3’-indoline]-2’-one (P-15) (Step 1) 5-(Dimethylamino)indolin-2-one [Chemistry] Dissolve 5-aminoindoline-2-one (0.30 g, 2 mmol) in glacial acetic acid (4 mL), and successively add sodium cyanoborohydride (0.31 g, 5 mmol) and paraformaldehyde (0.48 g, 16 mmol), and react at room temperature for 24 h. Concentrate the reaction system under reduced pressure, add water (20 mL) to the reaction system, extract twice with ethyl acetate (10 mL each time), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the concentrate by silica column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound (0.24 g, 68%). ESI-QQQ-MS: m / z 177 [M+H] + 。

[0152] (Step 2) 5'-(Dimethylamino)spiro[cyclopropane-1,3'-indoline]-2'-one (P-15) [Chemistry] Dissolve 5-(dimethylamino)indoline-2-one (0.24 g, 1.35 mmol) in anhydrous tetrahydrofuran (3 mL), cool to -40 °C, add LDA (2 mol / L, 2.7 mL, 5.4 mmol), stir for 30 min, heat to 0 °C, add 1,2-dibromoethane (0.76 g, 4.05 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride aqueous solution (5 mL) and water (15 mL) to the reaction system, extract twice with ethyl acetate (10 mL each time), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the concentrate by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.11 g, 40%). ESI-QQQ-MS: m / z 203 [M+H] + 。

[0153] Intermediate Preparation Example 16: Synthesis of 6'-(dimethylamino)-5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-16) (Step 1) 6-(Dimethylamino)-5-fluoroindoline-2-one [Chemical formula] Dissolve 6-amino-5-fluoroindoline-2-one (0.33 g, 2 mmol) in glacial acetic acid (4 mL), and sequentially add sodium cyanoborohydride (0.31 g, 5 mmol) and paraformaldehyde (0.48 g, 16 mmol), and react at room temperature for 24 h. Concentrate the reaction system under reduced pressure, add water (20 mL) and ethyl acetate (10 mL) to the reaction system, let it stand and separate into two layers, extract ethyl acetate twice more, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the concentrate by silica column chromatography (dichloroalcohol = 30:1) to obtain the title compound (0.25 g, 65%). ESI-QQQ-MS: m / z 195 [M+H] + .

[0154] (Step 2) 6'-(Dimethylamino)-5'-fluorospiro[cyclopropane-1,3'-indoline]-2'-one (P-16) [Chemical formula] Dissolve 6-(dimethylamino group)-5-fluoroindoline-2-one (0.24 g, 1.3 mmol) in anhydrous tetrahydrofuran (3 mL), cool to -40 °C, add LDA (2 mol / L, 2.6 mL, 5.2 mmol), stir for 30 minutes, heat to 0 °C, add 1,2-dibromoethane (0.73 g, 3.9 mmol), and react at room temperature for 24 h. Add saturated ammonium chloride aqueous solution (5 mL) and water (15 mL) to the reaction system, extract twice with ethyl acetate (10 mL each time), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the concentrate by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (0.12 g, 42%). ESI-QQQ-MS: m / z 221 [M+H] + .

[0155] Intermediate Preparation Example 17: Synthesis of Spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one (P-17) [Chemical Formula] Dissolve 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.27 g, 2 mmol) in anhydrous tetrahydrofuran (3 mL), cool to -40 °C, add LDA (2 mol / L, 4 mL, 8 mmol), stir for 30 minutes, heat to 0 °C, add 1,2-dibromoethane (1.14 g, 6 mmol), and react at room temperature for 24 hours. Add saturated aqueous ammonium chloride solution (5 mL) and water (15 mL) to the reaction system, extract with ethyl acetate three times (10 mL each time), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate is purified by silica column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound (0.11 g, 34%). ESI-QQQ-MS: m / z 161 [M+H] + .

[0156] Intermediate Preparation Example 18: Synthesis of 4-chloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-18) (Step 1) 3-chloro-N-methyl-2-nitroaniline [Chemical Formula] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in anhydrous ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and 33% methylamine ethanol solution (0.23 g, 2.4 mmol), heat to reflux, and stir for 20 hours. Concentrate the reaction solution under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (0.37 g, 98%). ESI-QQQ-MS: m / z 187 [M+H] + .

[0157] (Step 2) 3-Chloro-N1-methylbenzene-1,2-diamine [Chemical formula] Dissolve 3-chloro-N-methyl-2-nitroaniline (0.3 g, 1.6 mmol) in anhydrous methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50 °C, and stir for 3 h. Filter the reaction solution, wash the filter cake twice with anhydrous ethanol (2 mL each time), combine the filtrates, concentrate under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine respectively, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain the title compound (0.24 g, 98%). ESI-QQQ-MS: m / z 157 [M+H] + .

[0158] (Step 3) 4-Chloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-18) [Chemical formula] Dissolve 3-chloro-N1-methylbenzene-1,2-diamine (0.2 g, 1.3 mmol) in dichloromethane (2 mL), lower the temperature to 0 °C, add triethylamine (0.16 g, 1.6 mmol), and slowly add triphosgene / dichloromethane solution (0.15 g / 1 mL) to the reaction system. React at room temperature for 1 h. Concentrate the reaction solution under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine respectively, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the concentrate by silica column chromatography (petroleum ether / acetic acid = 4:1) to obtain the title compound (0.19 g, 80%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0159] Intermediate Preparation Example 19: Preparation of 6-Chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-19) (Step 1) 5-Chloro-N-cyclopropyl-2-nitroaniline [Chemical Formula] Dissolve 4-chloro-2-fluoro-1-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and cyclopropanamine (0.14 g, 2.4 mmol), heat to reflux, and stir for 20 hours. Concentrate the reaction solution under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (0.35 g, 82%). ESI-QQQ-MS: m / z 213 [M+H] + .

[0160] (Step 2) 5-Chloro-N1-cyclopropylbenzene-1,2-diamine [Chemical Formula] Dissolve 5-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in absolute methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50 °C, and stir for 3 h. Filter the reaction solution, wash the filter cake twice with absolute ethanol (2 mL each time), combine the filtrates, concentrate under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (0.27 g, 92%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0161] (Step 3) 6-Chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-19) [Chemical formula] 5-Chloro-N1-cyclopropylbenzene-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 triphosgene / dichloromethane solution (0.15 g / 1 mL) was slowly added to the reaction system, and the reaction was carried out at room temperature for 1 h. The reaction solution was 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, 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 silica column chromatography (petroleum ether / acetic acid = 4:1) to obtain the title compound (0.20 g, 74%). ESI-QQQ-MS: m / z 209 [M+H] + 。

[0162] Intermediate Preparation Example 20: Synthesis of 5-chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-20) (Step 1) 4-Chloro-N-cyclopropyl-2-nitroaniline [Chemical formula] 4-Chloro-1-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 cyclopropanamine (0.14 g, 2.4 mmol) were added, heated to reflux, and stirred for 20 h. The reaction solution was 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, 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 (0.35 g, 85%). ESI-QQQ-MS: m / z 213 [M+H] + 。

[0163] (Step 2) 4-Chloro-N1-cyclopropylbenzene-1,2-diamine [Chemical formula] 4-Chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) was dissolved in anhydrous methanol (4.5 mL), zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol) were added, heated to 50 °C, and stirred for 3 h. The reaction solution was filtered, the filter cake was washed twice with anhydrous ethanol (2 mL each time), the filtrates were combined, concentrated under reduced pressure, water (20 mL) was added to the concentrate, and 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 to obtain the title compound (0.26 g, 90%). ESI-QQQ-MS: m / z 183 [M+H] + 。

[0164] (Step 3) 5-Chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-20)

Chemical formula

[0165] Intermediate Preparation Example 21: Synthesis of 4-chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-21) (Step 1) 3-Chloro-N-cyclopropyl-2-nitroaniline [Chemical formula] Dissolve 1-chloro-3-fluoro-2-nitrobenzene (0.35 g, 2 mmol) in absolute ethanol (4 mL), add N,N-diisopropylethylamine (0.34 g, 2.6 mmol) and cyclopropamine (0.14 g, 2.4 mmol), heat to reflux, concentrate the reaction solution under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine respectively, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the title compound (0.37 g, 87%). ESI-QQQ-MS: m / z 213 [M+H] + .

[0166] (Step 2) 3-chloro-N1-cyclopropylbenzene-1,2-diamine [Chemical formula] Dissolve 3-chloro-N-cyclopropyl-2-nitroaniline (0.34 g, 1.6 mmol) in absolute methanol (4.5 mL), add zinc powder (1 g, 16 mmol) and ammonium chloride (0.43 g, 8 mmol), heat to 50 °C and stir for 3 hours. Filter the reaction solution, wash the filter cake twice with absolute ethanol (2 mL each time), combine the filtrates, concentrate under reduced pressure, add water (20 mL) to the concentrate, extract with dichloromethane three times (10 mL each time), combine the organic layers, wash once with water and once with saturated brine respectively, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the title compound (0.27 g, 93%). ESI-QQQ-MS: m / z 183 [M+H] + .

[0167] (Step 3) 4-chloro-1-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (P-21) [Chemical formula] 3-Chloro-N1-cyclopropylbenzene-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 triphosgene / dichloromethane solution (0.15 g / 1 mL) was slowly added to the reaction system, and the reaction was carried out at room temperature for 1 h. The reaction solution was 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, 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 silica column chromatography (petroleum ether / acetic acid = 4:1) to obtain the title compound (0.18 g, 66%). ESI-QQQ-MS: m / z 209 [M+H] + 。

[0168] Intermediate Preparation Example 22: Synthesis of 4-chloro-1-methyl-1H-benzo[d]imidazole-2(3H)-thione (P-22)

Chemical Structure

[0169] Intermediate Preparation Example 23: Synthesis of 4-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-23) (Step 1) N-(3-chloro-2-nitrophenyl)tetrahydro-2H-pyran-4-amine

Chem.

[0170] (Step 2) 3-Chloro-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

Chem.

[0171] (Step 3) 4-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-23)

Chem.

[0172] Intermediate Preparation Example 24: Synthesis of 4-chloro-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-24) (Step 1) N-(3-chloro-2-nitrophenyl)-1-methylpiperidin-4-amine

Chemical formula

[0173] (Step 2) 3-chloro-N1-(1-methylpiperidin-4-yl)benzene-1,2-diamine

Chemical formula

[0174] (Step 3) 4-Chloro-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (P-24)

Chemical formula

[0175] Intermediate Preparation Example 25: Synthesis of 4-Fluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-25) (Step 1) 3-Fluoro-N-methyl-2-nitroaniline

Chem.

[0176] (Step 2) 3-Fluoro-N1-methylbenzene-1,2-diamine

Chem.

[0177] (Step 3) 4-Fluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-25)

Chem.

[0178] Intermediate Preparation Example 26: Synthesis of 4,6-difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-26) (Step 1) 3,5-Difluoro-N-methyl-2-nitroaniline

Chemical formula

[0179] (Step 2) 3,5-Difluoro-N1-methylbenzene-1,2-diamine

Chemical formula

[0180] (Step 3) 4,6-Difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-26)

Chem.

[0181] Intermediate Preparation Example 27: Synthesis of 5,6-dichloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-27) (Step 1) 4,5-Dichloro-N-methyl-2-nitroaniline

Chem.

[0182] (Step 2) 4,5-Dichloro-N1-methylbenzene-1,2-diamine

Chemical formula

[0183] (Step 3) 5,6-Dichloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-27)

Chemical formula

[0184] Intermediate Preparation Example 28: Synthesis of 1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-2(3H)-one (P-28) (Step 1) N-Cyclopropyl-3-fluoro-2-nitroaniline

Chemical formula

[0185] (Step 2) N1-Cyclopropyl 3-fluorobenzene-1,2-diamine

Chemical formula

[0186] (Step 3) 1-Cyclopropyl-4-fluoro-1H-benzo[d]imidazol-2(3H)-one (P-28)

Chem.

[0187] Intermediate Preparation Example 29: Synthesis of 4,5-difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-29) (Step 1) 1,2,4-Trifluoro-3-nitrobenzene

Chem.

[0188] (Step 2) 3,4-Difluoro-N-methyl-2-nitroaniline

Chem.

[0189] (Step 3) 3,4-Difluoro-N1-methylbenzene-1,2-diamine

Chem.

[0190] (Step 4) 4,5-Difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-29)

Chemical formula

[0191] Intermediate Preparation Example 30: Synthesis of 6,7-difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-30) (Step 1) 2,3-Difluoro-N-methyl-6-nitroaniline

Chemical formula

[0192] (Step 3) 5,6-Difluoro-N1-methylbenzene-1,2-diamine

Chem.

[0193] (Step 4) 6,7-Difluoro-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-30)

Chem.

[0194] Intermediate Preparation Example 31: Synthesis of 4-methoxy-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-31) (Step 1) 3-Methoxy-N-methyl-2-nitroaniline

Chemical formula

[0195] (Step 2) 3-Methoxy-N1-methylbenzene-1,2-diamine

Chemical formula

[0196] (Step 3) 4-Methoxy-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-31)

Chemical formula

[0197] Intermediate Preparation Example 32: Synthesis of 5-(dimethylamino)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-32) (Step 1) N1-Methyl-4-nitrobenzene-1,2-diamine

Chemical formula

[0198] (Step 2) 1-Methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

Chem.

[0199] (Step 3) 5-Amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one

Chem.

[0200] (Step 4) 5-(Dimethylamino)-1-methyl

Chemical formula

[0201] Intermediate Preparation Example 33: Synthesis of 6-(dimethylamino group)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-33) (Step 1) 1-Methyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

Chemical formula

[0202] (Step 2) 6-Amino-1-methyl-1H-benzo[d]imidazol-2(3H)-one

Chemical formula

[0203] (Step 3) 6-(Dimethylamino)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (P-33)

Chemical formula

[0204] Intermediate Preparation Example 34: Synthesis of 2,4,6-trichlorobenzoyl chloride (P-34)

Chemical formula

[0205] Intermediate Preparation Example 35: Synthesis of 2,6-dichloro-4-(diethylamino)benzoyl chloride (P-35) (Step 1) Methyl 4-bromo-2,6-dichlorobenzoate

Chemical formula

[0206] (Step 2) Methyl 2,6-dichloro-4-(diethylamino)benzoate

Chem.

[0207] (Step 3) 2,6-Dichloro-4-(diethylamino)benzoyl chloride (P-35)

Chem.

[0208] Intermediate Preparation Example 36: Synthesis of 2,6-dichloro-4-morpholinobenzoyl chloride (P-36) (Step 1) Methyl 2,6-dichloro-4-morpholinobenzoate

Chemical formula

[0209] (Step 2) 2,6-dichloro-4-morpholinobenzoyl chloride (P-36)

Chemical formula

[0210] Intermediate Preparation Example 37: Synthesis of 4-(2-oxo-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzoyl chloride (P-37) (Step 1) 4-(2-oxo-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzoate

Chemical formula

[0211] (Step 2) 4-(2-Oxo-5-azabicyclo[2.2.1]heptyl-5-yl)-2,6-dichlorobenzoyl chloride

Chem.

[0212] Intermediate Preparation Example 38: Synthesis of 2,6-dichloro-4-(4-morpholinylpiperidin-1-yl)benzoyl chloride (P-38) (Step 1) Methyl 2,6-dichloro-4-(4-morpholinylpiperidin-1-yl)benzoate

Chem.

[0213] (Step 2) 2,6-Dichloro-4-(4-morpholinylpiperidin-1-yl)benzoyl chloride (P-38)

Chemical formula

[0214] Example 1: Synthesis of Compound 1 (Step 1) Methyl (S)-3-(4-(5',6'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylmethylamino)propionate [Chem.] Dissolve P-10 (98 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) in anhydrous acetonitrile (3 mL), add N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and copper(I) iodide (24 mg, 0.125 mmol) to the reaction system, protect with nitrogen, heat to 100 °C and react for 36 h. Then cool, filter through diatomaceous earth, wash the filter cake twice with acetonitrile (1 mL each time), combine the filtrates, concentrate under reduced pressure, and purify the concentrate by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (215 mg, 70%). ESI-QQQ-MS: m / z 615 [M+H] + .

[0215] (Step 2) Methyl (S)-2-amino-3-(4-(5’,6’-difluoro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)propionate [Chem.] Dissolve methyl (S)-3-(4-(5’,6’-difluoro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)phenyl)-2-(triphenylmethylamino)propionate (154 mg, 0.25 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (228 mg, 2 mmol), and react at room temperature for 1 h. Concentrate under reduced pressure, add dichloromethane (3 mL) to the concentrate, adjust the pH to 8 - 9 with saturated aqueous sodium bicarbonate solution, let stand to separate into two layers, extract the aqueous layer twice with dichloromethane, combine the organic layers, wash the organic layers once with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the title compound (86 mg, 92%). ESI-QQQ-MS: m / z 373 [M+H] + .

[0216] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5’,6’-difluoro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)phenyl)propionate

Chem.

[0217] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(5’,6’-difluoro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)phenyl)propionic acid

Chem.

[0218] Example 2: Synthesis of Compound 2 (Step 1) Methyl (S)-3-(4-(7’-chloro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)-2-(trimethylamino)propionate

Chemical Structure

[0219] (Step 2) Methyl (S)-2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)propionate

Chemical formula

[0220] (Step 3) Methyl (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionate [Chemistry] (S)-Methyl 2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)propionate (85 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the temperature was lowered to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added to the reaction system, followed by reaction at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand and separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, and the combined organic layer 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 (112 mg, 92%). ESI-QQQ-MS: m / z 527 [M+H] + .

[0221] (Step 4) (S)-3-(4-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionic acid [Chemistry] (S)-Methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionate (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, followed by reaction 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 organic layers were combined, 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 (55 mg, 63%). ESI-QQQ-MS: m / z 513 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 12.84 (brs, 1H), 9.19 (d, J = 8.1 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.33 - 7.23 (M, 4H), 7.19 - 7.17 (m, 1H), 7.08 - 7.02 (m, 2H), 4.72 - 4.67 (m, 1H), 3.22 (dd, J = 14.1, 4.3 Hz, 1H), 3.01 (dd, J = 14.1, 10.3 Hz, 1H), 1.78 - 1.76 (m, 2H), 1.68 - 1.66 (m, 2H).

[0222] Example 3: Synthesis of Compound 4 (Step 1) (S)-Methyl 3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(trimethylamino)propionate [Chemical formula] P-9 (95 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system, N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and copper(I) iodide (24 mg, 0.125 mmol) were added. The system was protected with nitrogen, heated to 100 °C, and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (188 mg, 62%). ESI-QQQ-MS: m / z 609 [M+H] + 。

[0223] (Step 2) Methyl (S)-2-amino-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)propionate

Chemical Structure

[0224] (Step 3) Methyl (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate [Chemical formula] (S)-Methyl 2-amino-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)propionate (83 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 to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand and separated into two 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 obtain the title compound (109 mg, 88%). ESI-QQQ-MS: m / z 539 [M+H] + .

[0225] (Step 4) (S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolyl]-1'-yl)phenyl)propionic acid [Chemical formula] (S)-Methyl 2-(2,6-dichlorobenzoylamino)-3-(4-(7'-methoxy-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (92 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), 0.5 mol / L aqueous sodium hydroxide solution (0.4 mL, 0.2 mmol) was added, and the reaction was carried out 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 with dichloromethane three times (2 mL each time). The organic layers were combined, washed once with water and once with saturated brine respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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]+. 1H NMR (500 MHz, DMSO-d6): δ 12.74 (brs, 1H), 9.15 (d, J = 8.2 Hz, 1H), 7.46 - 7.32 (m, 5H), 7.19 (d, J = 8.2 Hz, 2H), 7.02 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 4.74 - 4.69 (m, 1H), 3.46 (s, 3H), 3.19 (dd, J = 14.0, 4.7 Hz, 1H), 2.99 (dd, J = 14.0, 9.8 Hz, 1H), 1.68 - 1.64 (m, 2H), 1.62 - 1.58 (m, 2H).

[0226] Example 4: Synthesis of Compound 6 (Step 1) Methyl (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(trimethylamino)propionate [Chemical formula] P-4 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system were added N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), copper(I) iodide (24 mg, 0.125 mmol), and the system was protected with nitrogen. The temperature was raised to 100 °C and the reaction was carried out for 36 h. After cooling, the mixture was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (202 mg, 68%). ESI-QQQ-MS: m / z 597 [M+H] + 。

[0227] (Step 2) Methyl (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)propionate

Chemical Structure

[0228] (Step 3) Methyl (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolyl]-1'-yl)phenyl)propionate [Chemical] (S)-Methyl 2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)propionate (84 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 to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand and separated into two 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 obtain the title compound (108 mg, 89%). ESI-QQQ-MS: m / z 527 [M+H] + .

[0229] (Step 4) (S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid [Chemical] (S)-Methyl 2-(2,6-dichlorobenzoylamino)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (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, followed by reaction 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 organic layers were combined, 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]+. 1H NMR (500 MHz, DMSO-d6): δ 12.75 (brs, 1H), 9.13 (d, J = 8.4 Hz, 1H), 7.51 - 7.49 (m, 2H), 7.45 - 7.32 (M, 5H), 7.15 - 7.13 (m, 1H), 6.93 - 6.79 (m, 1H), 6.53 - 6.51 (m, 1H), 4.83 - 4.71 (m, 1H), 3.25 (dd, J = 14.0, 4.3 Hz, 1H), 2.99 (dd, J = 13.9, 10.7 Hz, 1H), 1.75 - 1.71 (m, 2H), 1.64 - 1.60 (m, 2H).

[0230] Example 5: Synthesis of Compound 7 (Step 1) Methyl (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(trimethylamino)propionate [Chemical Structure Diagram] 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 copper iodide (24 mg, 0.125 mmol) were added to the reaction system. It was protected with nitrogen, heated to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (182 mg, 61%). ESI-QQQ-MS: m / z 597 [M+H] + 。

[0231] (Step 2) Methyl (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)propionate

Chemical Structure

[0232] (Step 3) Methyl (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate [Chemical formula] (S)-Methyl 2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)propionate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane, cooled to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, and it was allowed to stand and separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time). The organic layers were combined, and the combined organic layer 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 (109 mg, 90%). ESI-QQQ-MS: m / z 527 [M+H] + .

[0233] (Step 4) (S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)propionic acid [Chemical formula] (S)-Methyl 2-(2,6-dichlorobenzoylamino)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (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, followed by reaction 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 organic layers were combined, washed once with water and once with saturated brine respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (51 mg, 58%). ESI-QQQ-MS: m / z 513 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 12.79 (brs, 1H), 9.15 (d, J = 8.3 Hz, 1H), 7.44 - 7.37 (m, 5H), 7.35 - 7.31 (M, 2H), 7.11 - 7.01 (m, 2H), 6.97 - 6.91 (m, 1H), 4.74 - 4.72 (m, 1H), 3.22 (dd, J = 14.1, 4.3 Hz, 1H), 2.99 (dd, J = 14.1, 10.4 Hz, 1H), 1.79 - 1.74 (m, 2H), 1.69 - 1.64 (m, 2H).

[0234] Example 6: Synthesis of Compound 8 (Step 1) Methyl (S)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0235] (Step 2) Methyl (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate

Chem.

[0236] (Step 3) Methyl (S)-2-(2,6-dichlorobenzoylamino)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate

Chem.

[0237] (Step 4) (S)-2-(2,6-Dichlorobenzoylamino)-3-(4-(2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionic acid

Chemical formula

[0238] Example 7: Synthesis of Compound 9 (Step 1) Methyl (S)-3-(4-(7-chloro-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-1-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0239] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-2-oxo-2’,3’,5’,6’-tetrahydrospiro[indoline-3,4’-pyran]-1-yl)phenyl)propionate

Chem.

[0240] (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

Chem.

[0241] (Step 4) (S)-3-(4-(7-chloro-2-oxo-2’,3’,5’,6’-tetrahydrospiro[indoline-3,4’-pyran]-1-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamido)propionic acid

Chem.

[0242] Example 8: Synthesis of Compound 10 (Step 1) (S)-Methyl 3-(4-(6’-chloro-5’-fluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure Diagram] P-11 (112 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) are dissolved in anhydrous acetonitrile (3 mL), and N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and copper(I) iodide (24 mg, 0.125 mmol) are added to the reaction system. It is protected with nitrogen, the temperature is raised to 100 °C, and the reaction is carried out for 36 h. After cooling, it is filtered through diatomaceous earth, the filter cake is washed twice with acetonitrile (1 mL each time), the filtrates are combined, concentrated under reduced pressure, and the concentrate is 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] + 。

[0243] (Step 2) Methyl (S)-2-amino-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)propionate

Chem.

[0244] (Step 3) Methyl (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzoylamino)propionate

Chem.

[0245] (Step 4) (S)-3-(4-(6'-chloro-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propionic acid

Chem.

[0246] Example 9: Synthesis of Compound 11 (Step 1) (S)-Methyl 3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(trimethylamino)propionate [Chemical formula] P-5 (89 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system, N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and copper(I) iodide (24 mg, 0.125 mmol) were added. The system was protected with nitrogen, the temperature was raised to 100 °C, and the reaction was carried out for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (197 mg, 66%). ESI-QQQ-MS: m / z 597 [M+H] + 。

[0247] (Step 2) Methyl (S)-2-amino-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)propionate

Chemical Structure

[0248] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolyl]-1'-yl)phenyl)propionate [Chemical formula] (S)-Methyl 2-amino-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)propionate (84 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the temperature was lowered to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, and after standing, it was separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time). The organic layers were combined, and the combined organic layer 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 (107 mg, 88%). ESI-QQQ-MS: m / z 511 [M+H] +

[0249] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionic acid [Chemical formula] (S)-Methyl 2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (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, followed by reaction at room temperature for 2 hours. 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 organic layers were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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]+. 1H NMR (500 MHz, DMSO-d6): δ 12.86 (brs, 1H), 9.17 (d, J = 8.3 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.39 - 7.23 (m, 4H), 7.13 - 7.00 (m, 2H), 6.75 - 6.72 (m, 1H), 4.76 - 4.71 (m, 1H), 3.25 (dd, J = 14.0, 4.5 Hz, 1H), 3.00 (dd, J = 14.0, 10.4 Hz, 1H), 1.80 - 1.76 (m, 2H), 1.68 - 1.64 (m, 2H).

[0250] Example 10: Synthesis of Compound 12 (Step 1) Methyl (S)-3-(4-(7-chloro-3,3-dimethyl-2-oxoindolin-1-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure Diagram] P-13 (97 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system, 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. The system was protected with nitrogen, heated to 100 °C, and reacted for 36 h. The temperature was lowered, and the mixture was extracted and filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (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 (154 mg, 50%). ESI-QQQ-MS: m / z 615 [M+H] + 。

[0251] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-3,3-dimethyl-2-oxoindolin-1-yl)phenyl)propionate

Chem.

[0252] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate

Chem.

[0253] (Step 4) (S)-2-(2-Chloro-6-fluorophenylamino)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid

Chemical formula

[0254] Example 11: Synthesis of Compound 14 (Step 1) Methyl (S)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure Diagram] P-16 (110 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). N,N-Dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and copper(I) iodide (24 mg, 0.125 mmol) were added to the reaction system, protected with nitrogen, heated to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (160 mg, 50%). ESI-QQQ-MS: m / z 640 [M+H] + 。

[0255] (Step 2) Methyl (S)-2-amino-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propyl)propanoate

Chemical Structure

[0256] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propylacetate

Chem.

[0257] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(6'-(dimethylamino)-5'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propanoic acid

Chem.

[0258] Example 12: Synthesis of Compound 15 (Step 1) Methyl (S)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(triphenylmethylamino)propylacetate

Chemical Structure

[0259] (Step 2) Methyl (S)-2-amino-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)benzyl)propanoate

Chemical Structure

[0260] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoate

Chem.

[0261] (Step 4) (S)-2-(2-Chloro-6-fluorophenylamino)-3-(4-(5'-(dimethylamino)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid

Chem.

[0262] Example 13: Synthesis of Compound 16 (Step 1) Methyl (S)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0263] (Step 2) Methyl (S)-2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate

Chemical Structure

[0264] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate [Chemical formula] (S)-Methyl 2-amino-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoate (81 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the temperature was lowered to 0 °C, and 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.25 mmol) was added to the reaction system, followed by reaction at room temperature for 1 h. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand and separated into two 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 obtain the title compound (105 mg, 90%). ESI-QQQ-MS: m / z 511 [M+H] + .

[0265] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamino)-3-(4-(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid [Chemical formula] (S)-Methyl 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. The reaction was carried out 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 with dichloromethane three times (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. 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]+. 1H 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).

[0266] Example 14: Synthesis of Compound 17 (Step 1) Methyl (S)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(triphenylmethylamino)propanoate

Chemical Structure

[0267] (Step 2) Methyl (S)-2-amino-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate

Chem.

[0268] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate

Chem.

[0269] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamino)-3-(4-(7'-fluoro-2'-oxyspiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid

Chem.

[0270] Example 15: Synthesis of Compound 18 (Step 1) Methyl (S)-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)benzyl)-2-(triphenylmethylamino)propanoate [Chemical Structure] P-12 (98 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). N,N-Dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and copper(I) iodide (24 mg, 0.125 mmol) were added to the reaction system. The system was protected with nitrogen, heated to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (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 = 4:1) to obtain the title compound (206 mg, 67%). ESI-QQQ-MS: m / z 615 [M + H] + .

[0271] (Step 2) Methyl (S)-2-amino-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propanoate [Chemical Structure] (S)-Methyl 3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)-2-(triphenylmethylamino)propionate (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 hour. Concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, the pH was adjusted to 8 - 9 with saturated aqueous sodium bicarbonate solution, allowed to stand and separated into two layers. The aqueous layer was extracted twice with dichloromethane, the organic layers were combined, the organic layer was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the title compound (87 mg, 94%). ESI-QQQ-MS: m / z 373 [M+H] + 。

[0272] (Step 3) (S)-Methyl 2-(2-chloro-6-fluorobenzamido)-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propionate

Chemical formula

[0273] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)phenyl)propanoic acid

Chem.

[0274] Example 16: Synthesis of Compound 19 (Step 1) (S)-Methyl 3-(4-(2’-oxospiro[cyclopropane-1,3’-pyrrolo[2,3-b]pyridine]-1’(2’H)-yl)benzyl)-2-(triphenylmethylamino)propanoate

Chem.

[0275] (Step 2) Methyl (S)-2-amino-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)-yl)phenyl)propanoate

Chemical Structure

[0276] (Step 3) Methyl (S)-2-(2,6-dichlorophenylamino)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)propanoate

Chem.

[0277] (Step 4) (S)-2-(2,6-Dichlorophenylamino)-3-(4-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)phenyl)propanoic acid

Chem.

[0278] Example 17: Synthesis of Compound 20 (Step 1) Methyl (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2,4,6-trichlorobenzylamino)propionate

Chemical Structure

[0279] (Step 2) (S)-3-(4-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,4,6-trichlorobenzylamino)propanoic acid

Chemical formula

[0280] Example 18: Synthesis of Compound 21 (Step 1) (S)-Methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(diethylamino)benzylamino)propionate

Chemical Structure

[0281] (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2,6-dichloro-4-(diethylamino)phenylamino) acid

Chemical formula

[0282] Example 19: Synthesis of Compound 22 (Step 1) (S)-Methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-morpholinylbenzylamino)propanoate [Chemical Structure] (S)-Methyl 2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (85 mg, 0.23 mmol, for details of the manufacturing process, refer to Example 2) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), cooled to 0 °C, and intermediate P-36 (74 mg, 0.25 mmol) was added to the reaction system, followed by reaction at room temperature for 1 h. Water (5 mL) was added to the reaction system, and after standing, it separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, and the combined organic layer 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 (123 mg, 85%). ESI-QQQ-MS: m / z 628 [M+H] + .

[0283] (Step 2) (S)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzylamino)propanoic acid [Chemical formula] (S)-Methyl 3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzoylamino)propionate (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 further added to the reaction system, followed by reaction 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 with dichloromethane three times (2 mL each time). The organic layers were combined, washed once with water and once with saturated brine respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound. ESI-QQQ-MS: m / z 614 [M+H]+. 1H 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).

[0284] Example 20: Synthesis of Compound 23 (Step 1) (2S)-2-(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2,6-dichlorobenzylamino)-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl) [Chemical Structure Diagram] (S)-Methyl 2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (85 mg, 0.23 mmol, see Example 2 for detailed manufacturing process) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), cooled to 0 °C, and intermediate P-37 hept-5-yl (77 mg, 0.25 mmol) was added to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, and it was allowed to stand and separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, and the combined organic layer 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 (109 mg, 74%). ESI-QQQ-MS: m / z 640 [M+H] + 。

[0285] (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-1,3'-indolin]-1'-yl)phenyl)

Chemical formula

[0286] Example 21: Synthesis of Compound 24 (Step 1) (S)-3-(4-(7’-Chloro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinopyridin-1-yl)benzoylamino)propionic acid methyl ester

Chemical Structure

[0287] (Step 2) (S)-3-(4-(7'-Chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)-2-(2,6-dichloro-4-(4-morpholinopyridin-1-yl)benzamido)propanoic acid

Chemical Structure

[0288] Example 22: Synthesis of Compound 25 (Step 1) Methyl (S)-3-(4-(7-chloro-3-methyl-2-oxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propanoate [Chemical formula] P-18 (91 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). N,N-Dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol) and copper(I) iodide (24 mg, 0.125 mmol) were added to the reaction system. The system was protected with nitrogen, heated to 100 °C and reacted for 36 h. Then the temperature was lowered, and the mixture was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (180 mg, 60%). ESI-QQQ-MS: m / z 602 [M + H] + .

[0289] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-3-methyl-2-oxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate [Chemical formula] (S)-Methyl 3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzyl)-2-(triphenylmethylamino)propanoate (150 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added, followed by reaction at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8 - 9 with saturated aqueous sodium hydrogen carbonate solution. After standing, the mixture separated into two layers. The aqueous layer was extracted twice with dichloromethane, the organic layers were combined, the combined organic layer was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the title compound (85 mg, 95%). ESI-QQQ-MS: m / z 360 [M+H] + .

[0290] (Step 3) (S)-Methyl 3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-chlorobenzylamino)propanoate [Chemical formula] (S)-Methyl 2-amino-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionate (86 g, 0.24 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 to the reaction system. The reaction was carried out at room temperature for 1 h. Water (5 mL) was added to the reaction system, and after standing, the mixture separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, the combined organic layer was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the title compound (105 mg, 85%). ESI-QQQ-MS: m / z 516 [M+H] + .

[0291] (Step 4) (S)-3-(4-(7-chloro-3-methyl-2-oxide-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-chlorophenylamino)propanoic acid

Chem.

[0292] Example 23: Synthesis of Compound 26 (Step 1) (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxide-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl-2-(triphenylmethylamino)propanoic acid methyl ester

Chem.

[0293] (Step 2) Methyl (S)-2-amino-3-(4-(5-chloro-3-cyclopropyl-2-oxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chemical Structure

[0294] (Step 3) Methyl (S)-3-(4-(5-chloro-3-cyclopropyl-2-oxide-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzylamino)propanoate [Chemical formula] (S)-Methyl 2-amino-3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate (88 mg, 0.23 mmol) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), the temperature was lowered to 0 °C, and 2,6-dichlorobenzoyl chloride (48 mg, 0.25 mmol) was added to the reaction system, followed by reaction at room temperature for 1 hour. Water (5 mL) was added to the reaction system, and the mixture was allowed to stand and separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time), the organic layers were combined, and the combined organic layer 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 (112 mg, 87%). ESI-QQQ-MS: m / z 558 [M+H] + .

[0295] (Step 4) (S)-3-(4-(5-Chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzylamino)propanoic acid [Chemical formula] (S)-Methyl 3-(4-(5-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzoylamino)propionate (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 further added to the reaction system, and the reaction was carried out 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 the organic layer was washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the title compound (57 mg, 62%). ESI-QQQ-MS: m / z 544 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 12.76 (brs, 1H), 9.13 (d, J = 8.4 Hz, 1H), 7.51 - 7.31 (m, 8H), 7.12 - 7.10 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.79 -

[0296] Example 24: Synthesis of Compound 27 (Step 1) (S)-Methyl 3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure] P-20 (104 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system, 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. The system was protected with nitrogen, heated to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (182 mg, 58%). ESI-QQQ-MS: m / z 628 [M+H] + 。

[0297] (Step 2) Methyl (S)-2-amino-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chemical formula

[0298] (Step 3) Methyl (S)-3-(4-(6-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzylamino)propanoate

Chemical formula

[0299] (Step 4) (S)-3-(4-(6-Chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzylamino)propanoic acid

Chemical Structure

[0300] Example 25: Synthesis of Compound 28 (Step 1) (S)-Methyl 3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl-2-(triphenylmethylamino)propanoate

Chemical Structure

[0301] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chemical Structure

[0302] (Step 3) Methyl (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)propionate

Chem.

[0303] (Step 4) (S)-3-(4-(7-chloro-3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorobenzamido)propanoic acid

Chem.

[0304] Example 26: Synthesis of Compound 29 (Step 1) Methyl (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0305] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate [Chemical formula] Methyl (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propanoate (155 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL). Further, trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, and it was reacted at room temperature for 1 h. It was concentrated under reduced pressure. Dichloromethane (3 mL) was added to the concentrate, and the pH was adjusted to 8 - 9 with a saturated aqueous sodium bicarbonate solution. It was allowed to stand and separated into two layers. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined. The organic layer 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 (86 mg, 92%). ESI-QQQ-MS: m / z 376 [M+H] + .

[0306] (Step 3) Methyl (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chlorobenzylamino)propanoate

Chem.

[0307] (Step 4) (S)-3-(4-(7-chloro-3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzylamino)propanoic acid

Chem.

[0308] Example 27: Synthesis of Compound 30 (Step 1) Methyl (S)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical formula] P-28 (96 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system, N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and copper(I) iodide (24 mg, 0.125 mmol) were added. The system was protected with nitrogen, heated to 100 °C, and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (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 = 4:1) to obtain the title compound (193 mg, 63%). ESI-QQQ-MS: m / z 612 [M+H] + 。

[0309] (Step 2) Methyl (S)-2-amino-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0310] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(3-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionate

Chem.

[0311] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(3-cyclopropyl-7-fluoro-2-oxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionic acid

Chem.

[0312] Example 28: Synthesis of Compound 31 (Step 1) (S)-Methyl 3-(4-(7-chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure Diagram] P-23 (126 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). To the reaction system, N,N-dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), copper(I) iodide (24 mg, 0.125 mmol) were added, and the system was protected with nitrogen. The temperature was raised to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica 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] + 。

[0313] (Step 2) Methyl (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)propionate

Chemical Structure

[0314] (Step 3) Methyl (S)-3-(-(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

Chem.

[0315] (Step 4) (S)-3-(4-(7-Chloro-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2-chloro-6-fluorobenzamido)propanoic acid

Chem.

[0316] Example 29: Synthesis of Compound 32 (Step 1) (S)-Methyl 3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure] P-24 (133 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL), and further 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. It was protected with nitrogen, heated to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time), the filtrates were combined, concentrated under reduced pressure, and the concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (151 mg, 44%). ESI-QQQ-MS: m / z 685 [M+H] + 。

[0317] (Step 2) Methyl (S)-2-amino-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzyl)propanoate

Chemical Structure

[0318] (Step 3) Methyl (S)-3-(4-(7-chloro-3-(1-methylpiperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzyl)-2-(2-chloro-fluorobenzylamino)propanoate

Chem.

[0319] (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-fluorophenylamino)propanoic acid

Chem.

[0320] Example 30: Synthesis of Compound 33 (Step 1) Methyl (S)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0321] (Step 2) Methyl (S)-2-amino-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0322] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0323] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chemical formula

[0324] Example 31: Synthesis of Compound 34 (Step 1) Methyl (S)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propanoate [Chemical Structure] P-26 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). N,N-Dimethylglycine hydrochloride (52 mg, 0.375 mmol), cesium carbonate (489 mg, 1.5 mmol), and copper(I) iodide (24 mg, 0.125 mmol) were added to the reaction system. The temperature was lowered, and the mixture was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (166 mg, 55%). ESI-QQQ-MS: m / z 604 [M + H] + .

[0325] (Step 2) Methyl (S)-2-amino-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate [Chemical Structure] (T)-Methyl 3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate (151 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (228 mg, 2 mmol) was added to the reaction system, followed by reaction at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL) was added to the concentrate, and the pH of the concentrate was adjusted to 8 - 9 with saturated aqueous sodium bicarbonate solution. After standing, the mixture separated into two layers. The aqueous layer was extracted twice with dichloromethane, the organic layers were combined, and the combined organic layer 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 (86 mg, 95%). ESI-QQQ-MS: m / z 362 [M+H] + 。

[0326] (Step 3) (S)-Methyl 2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionate

Chemical Structure

[0327] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoyl amino)-3-(4-(5,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chemical formula

[0328] Example 32: Synthesis of Compound 35 (Step 1) (S)-Methyl 3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical formula

[0329] (Step 2) Methyl (S)-2-amino-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chemical Structure

[0330] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0331] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(5,6-dichloro-3-methyl-2-oxid-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chem.

[0332] Example 33: Synthesis of Compound 36 (Step 1) Methyl (S)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate [Chemical Structure Diagram] P-29 (92 mg, 0.5 mmol) and P-1 (274 mg, 0.5 mmol) were dissolved in anhydrous acetonitrile (3 mL). Further, 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. Under nitrogen protection, the temperature was raised to 100 °C and reacted for 36 h. After cooling, it was filtered through diatomaceous earth. The filter cake was washed twice with acetonitrile (1 mL each time). The filtrates were combined and concentrated under reduced pressure. The concentrate was purified by silica column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (196 mg, 65%). ESI-QQQ-MS: m / z 604 [M+H] + 。

[0333] (Step 2) Methyl (S)-2-amino-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chemical Structure

[0334] (Step 3) Methyl (S)-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

Chem.

[0335] (Step 4) (S)-2-(2-Chloro-6-fluorobenzamido)-3-(4-(6,7-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chem.

[0336] Example 34: Synthesis of Compound 37 (Step 1) Methyl (S)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0337] (Step 2) Methyl (S)-2-amino-3-(4-(4,5-difluoro-3-methyl-2-oxid-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionate

Chem.

[0338] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0339] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(4,5-difluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chem.

[0340] Example 35: Synthesis of Compound 38 (Step 1) Methyl (S)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(tritylamino)propionate

Chemical Structure

[0341] (Step 2) Methyl (S)-2-amino-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0342] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionate

Chem.

[0343] (Step 4) (S)-2-(2-Chloro-6-fluorobenzoylamino)-3-(4-(7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chem.

[0344] Example 36: Synthesis of Compound 39 (Step 1) Methyl (S)-3-(4-(6-(dimethylamino)-3-methyl-2-oxid-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propionate

Chemical Structure

[0345] (Step 2) Methyl (S)-2-amino-3-(4-(6-(dimethylamino)-3-methyl-2-oxide-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chemical Structure

[0346] (Step 3) Methyl (S)-2-(2-chloro-6-fluorophenylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0347] (Step 4) (S)-2-(2-Chloro-6-fluorobenzylamino)-3-(4-(6-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chem.

[0348] Example 37: Synthesis of Compound 40 (Step 1) Methyl (S)-3-(4-(5-(dimethylamino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(triphenylmethylamino)propanoate

Chemical Structure

[0349] (Step 2) Methyl (S)-2-amino-3-(4-(5-(dimethylamino)-3-methyl-2-oxido-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propionate

Chem.

[0350] (Step 3) Methyl (S)-2-(2-chloro-6-fluorobenzylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxido-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoate

Chem.

[0351] (Step 4) (S)-2-(2-Chloro-6-fluorobenzylamino)-3-(4-(5-(dimethylamino)-3-methyl-2-oxido-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)propanoic acid

Chem.

[0352] Example 38: Synthesis of Compound 41 (Step 1) Methyl (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,4,6-trichlorobenzoylamino)propionate

Chemical Structure

[0353] (Step 2) (S)-3-(4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,4,6-trichlorobenzylamino)propanoic acid

Chemical Structure

[0354] Example 39: Synthesis of Compound 42 (Step 1) Methyl (S)-3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzylamino)propanoate [Chemical formula] (S)-Methyl 2-amino-3-(4-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionate (83 mg, 0.23 mmol, for details of the manufacturing process, see Example 22) and triethylamine (30 mg, 0.3 mmol) were dissolved in dichloromethane (2 mL), cooled to 0 °C, and intermediate P-36 (74 mg, 0.25 mmol) was added to the reaction system, followed by reaction at room temperature for 1 h. Water (5 mL) was added to the reaction system, and after standing, it was separated into two layers. The aqueous layer was extracted twice with dichloromethane (2 mL each time). The organic layers were combined, and the combined organic layer 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 (113 mg, 80%). ESI-QQQ-MS: m / z 617 [M + H] + .

[0355] (Step 2) (S)-3-(4-(7-Chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichloro-4-morpholinobenzylamino)propanoic acid [Chemical formula] (S)-Methyl 3-(4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-(2,6-dichlorophenoxy)-N-morpholinopropionamide (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, followed by reaction 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 organic layers were combined, 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 (45 mg, 44%). ESI-QQQ-MS: m / z 603 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6): δ 12.77 (brs, 1H), 8.91 (d, J = 7.5 Hz, 1H), 7.43 - 7.41 (m, 2H), 7.31 - 7.22 (m, 3H), 7.16 - 7.01 (m, 2H), 6.93 (s, 2H), 4.68 - 4.64 (m, 1H), 3.70 - 3.68 (m, 4H), 3.39 (s, 3H), 3.21 (s, 1H), 3.19 - 3.17 (m, 4H), 3.04 - 2.99 (m, 1H).

[0356] Experimental Example: Evaluation Test for Inhibiting MAdCAM-1 / α4β7 Integrin Protein Binding Activity (α4β7-MAdCAM-1 ELISA)

[0357] Coat microplates (Costar) at 50 μL / well with recombinant human MAdCAM-1 (R&D Systems) solution, incubate overnight at 4°C, wash the microplates three times at 150 μL / well with TBS buffer, block the microplates at 150 μL / well with blocking buffer, block for 1 h at 37°C, wash the microplates three times at 150 μL / well with TBS buffer, dilute recombinant human integrin protein α4β7 (R&D Systems) with TBS buffer containing 0.1% bovine serum albumin (BSA), then add to the microplates at 50 μL / well, add 1 μL of the test compound or DMSO solution to each well, cover with a lid and incubate at room temperature for 2 h, wash the microplates three times at 150 μL / well with TBS buffer, add the anti-β7 antibody (R&D Systems) solution in 0.1% BSA TBS buffer to the 96-well microplates at 50 μL / well, cover with a lid and incubate at room temperature for 1 h, wash the microplates three times at 150 μL / well with TBS buffer, add streptavidin-HRP (R&D Systems) to the 96-well microplates at 50 μL / well, incubate at room temperature for 20 min, wash the microplates three times at 150 μL / well with TBS buffer, add 50 μL of TMB chromogenic solution (Sigma) to each well, incubate at room temperature for 5 - 30 min, add 25 μL of stop solution to each well to stop the reaction, and finally read the absorbance at 450 nm using an enzyme marker (SpectraMax 340PC, Molecular Devices). Repeat the experiment, take the absorbance of the wells without the test substance as 100%, calculate the binding rate of cells at each concentration, calculate the concentration IC50 of 50% binding inhibition, and summarize the results in Table 1.

[0358] It should be explained that the free form of the compound synthesized in the above example is used as the test compound.

Table 1

[0359] The compounds of the present invention have high blood drug concentrations and bioavailability upon oral administration, and are useful as oral dosage forms.

[0360] Furthermore, the compounds of the present invention have good stability in acidic and alkaline solutions and are used in the development of various dosage forms.

[0361] Except for the embodiments described herein, according to the foregoing description, various modifications of the present invention will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and other publications) is hereby incorporated by reference in its entirety into the text.

Claims

1. A compound represented by the general formula (1) or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof. 【Chemical 1】 Among them, R ３ is hydrogen; Each R ４ is hydrogen; Each X １ is independently hydrogen or a halogen; X ２ is hydrogen, halogen, di(C １～６ alkyl)amino group, or a 3- to 7-membered heterocycloalkyl group Each X ３ is hydrogen; A is a group represented by general formula (2-1), (2-2), (2-3) or (2-1-1'); [Chemical Formula 2] [Chemical Formula 3] Ring H is C ３～６ a cycloalkylene group or a 3- to 7-membered heterocycloalkylene group, said group being substituted with at least one of the following substituents: halogen, C １～６ an alkyl group, C ３～６ a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, C ６～１０ an aryl group and a 5- to 10-membered heteroaryl; Y is O or S; Each Z is CH; Each R1 is hydrogen; When present, each R ２ is independently hydrogen, C １～６ alkyl, C ３～６ cycloalkyl, or a 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with at least one of the following substituents: halogen, C １～６ alkyl, C ３～６ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６～１０ aryl and 5- to 10-membered heteroaryl.

2. Each X １ is independently fluorine, chlorine or bromine The compound according to Claim 1 or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof.

3. A is a group represented by general formula (2-2-1) The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof. 【Chemical Formula 4】 Y is O or S; Four Rs １ are hydrogen; R ２ is hydrogen, C １～６ alkyl group, C ３～６ cycloalkyl group or a 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C １～６ alkyl, C ３～６ cycloalkyl and 3- to 7-membered heterocycloalkyl.

4. A is a group represented by general formula (2-3-1) The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof. 【Chemical Formula 5】 Y is O or S; Four Rs １ are hydrogen; Each R ２ is independently hydrogen, C １～６ alkyl, C ３～６ ycloalkyl group or a 3- to 7-membered heterocycloalkyl group, and the above groups are optionally substituted with one or more of the following substituents: halogen, C １～６ alkyl, C ３～６ ycloalkyl and 3- to 7-membered heterocycloalkyl.

5. The following compound or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof. 【Chemical Formula 6】

6. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof.

7. Use of the compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof, or the pharmaceutical composition according to Claim 6, in the preparation of a drug for preventing and / or treating a disease and / or disorder mediated at least in part by α4β7 integrin.

8. The compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt, solvate, optical isomer, tautomer, or isotope-labeled form thereof, or the pharmaceutical composition according to Claim 6, for use in the prevention and / or treatment of a disease and / or disorder mediated at least in part by α4β7 integrin.

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