Anti-tumor compound as UPR agonist and application thereof

Abstract

The invention belongs to the field of medical chemistry, relates to an anti-tumor compound serving as a UPR agonist and application of the anti-tumor compound, and particularly provides a compound shown in a formula (I) or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of the compound. The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the composition in preparation of medicines for treating tumors. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to anti-tumor compounds as UPR agonists or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, their preparation methods, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions in preparing drugs for treating tumors. Background Art

[0002] About 75% of breast cancer patients are estrogen receptor α (ERα, ESR1) positive. Estrogen (Estrogen, E2) mainly acts through ERα to promote proliferation and survival. In clinical practice, ERα-positive breast cancer is mainly treated with endocrine therapy, such as aromatase inhibitors, selective ERα modulators (SERMs) and selective ERα degraders (SERDs), all of which work by inhibiting ERα function; and drug resistance caused by ERα mutations is an urgent problem to be solved in clinical practice.

[0003] An imbalance in the protein folding environment of the endoplasmic reticulum (ER) may lead to ER stress, resulting in the activation of the unfolded protein response (UPR). The UPR constitutes a set of highly conserved and complexly regulated pathways that restore ER homeostasis through adaptation or apoptosis. Sustained UPR activation triggers cell death. Estrogen (Estrogen, E2) induces rapid UPR pre-activation through estrogen receptor α (ERα) and promotes tumor proliferation and survival through the adaptive UPR pathway. Increased expression of UPR-related genes is associated with tamoxifen resistance. Strong and sustained activation of the UPR leads to rapid cell death. If the strong and sustained activation of the UPR pathway is induced by ERα, it will be converted into cytotoxicity, promoting rapid necrosis of ERα+ cells. Currently, UPR agonists are a potential treatment for ERα+ tumors.

[0004] There is already a certain foundation for drug development of the α-UPR pathway, most of which are in the preclinical development stage. In recent years, literature reports have shown that some highly selective UPR agonists have significant therapeutic effects on ERα-positive tumors by pre-activating the UPR pathway through ERα. At present, agonists targeting the α-UPR pathway still need to have higher activity and selectivity in order to specifically target ERα-positive tumors and increase the safety window. Summary of the invention

[0005] One object of the present invention is to provide a class of compounds having tumor therapeutic activity represented by general formula (I), general formula (II), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs.

[0006] Another object of the present invention is to provide a method for preparing the compounds of the general formula (I), general formula (II), general formula (III), general formula (IV) of the present invention or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs.

[0007] Another object of the present invention is to provide a composition comprising a compound of the present invention of general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier, as well as a composition comprising a compound of the present invention of general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and one or more other drugs.

[0008] Another object of the present invention is to provide a method for treating tumors using the compounds of the present invention of general formula (I), general formula (II), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, as well as the use of the compounds of the present invention of general formula (I), general formula (II), general formula (III), general formula (IV) or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs in the preparation of drugs for treating tumors.

[0009] In view of the above-mentioned invention object, the present invention provides the following technical solutions:

[0010] In the first aspect, the present invention provides compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV) or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof,

[0011]

[0012] in,

[0013] R 1 is selected from 5-14 membered heterocyclic group, C 2-10 Alkenyl, C 2-10 Alkynyl, aryl and heteroaryl, which are optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 radical substitution with heterocyclic groups, dimethylphosphoryl groups and oxo groups;

[0014] R 2 , R3 , R 4 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 heterocyclic group; or R 2 and R 3 or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 5-8 membered heterocyclic group, a 5-8 membered aryl group or a 5-8 membered heteroaryl group, which is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano and amino group substitution;

[0015] R 5 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, aryl, heteroaryl, C 1-6 Alkyl C 3-8 Cycloalkyl, C 1-6 Alkyl C 3-8 Heterocyclic group, C 1-6 Alkyl aryl, C 1-6 Alkyl heteroaryl, which is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano and amino groups are substituted.

[0016] In some preferred embodiments, the compound of the present invention is a compound of the general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 is selected from 5-14 membered heterocyclic groups, C 2-8 Alkenyl, C 2-8 Alkynyl, 6-14 membered aryl, 6-14 membered heteroaryl, which is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 The 5- to 14-membered heterocyclic group and the 6- to 14-membered heteroaryl group may be substituted with a group selected from O, N, and S.

[0017] In some preferred embodiments, the compound of the present invention is a compound of general formula (I), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

[0018] R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl and C 3-8 Heterocyclic group.

[0019] In some embodiments, the compound of the present invention is a compound of formula (I), formula (III, formula (IV)), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

[0020] R 2 and R 3 or R 3 and R 4Together with the carbon atoms to which they are attached, they form a 5-8 membered heterocyclic group, a 5-8 membered aryl group or a 5-8 membered heteroaryl group, wherein the heteroatom is selected from N, O, S, P, and the 5-8 membered heterocyclic group, the 5-8 membered aryl group or the 5-8 membered heteroaryl group is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano and amino groups are substituted.

[0021] In some specific embodiments, the compound of the present invention is a compound of formula (IV) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

[0022] R 5 Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, 5-12 membered aryl group, 5-12 membered heteroaryl group, C 1-6 Alkyl C 3-8 Cycloalkyl, C 1-6 Alkyl C 3-8 Heterocyclic group, C 1-6 Alkyl 5-12 membered aryl, C 1-6 Alkyl 5-12 membered heteroaryl, which is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 The alkylene group is substituted with alkoxy, nitro, carboxyl, cyano and amino groups, and the heteroatom is selected from N, O, S and P.

[0023] In some specific embodiments, the compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Selected from It is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano and amino groups are substituted.

[0024] In some embodiments, the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the general formula (I) has the following structure of the general formula (Ia),

[0025]

[0026] Among them, R 1 It has the meaning given above for formula (I).

[0027] In some specific embodiments, according to the compound represented by general formula (Ia), general formula (II), general formula (III) of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 Selected from

[0028] It is optionally substituted by one or more selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, di-C 1-3 Alkylamino, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-14 Aryl, C 5-14 The heteroaryl and oxo groups are substituted by radicals, wherein the heteroatoms of the heterocyclic and heteroaryl groups are selected from O, N, and S.

[0029] In some embodiments, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

[0030]

[0031] in,

[0032] X 1 , X 2 are each independently selected from CH2, NH and O;

[0033] R a , R b Each is independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino.

[0034] In some preferred embodiments, the compound of the present invention is a compound of formula (Ib) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R a , R b Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl and di-C 1-6 Alkylamino.

[0035] In some specific embodiments, according to the compound of formula (Ia), formula (II), formula (III) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof of the present invention, wherein R 1 Selected from

[0036] The present invention provides the following specific compounds or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:

[0037]

[0038]

[0039]

[0040] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

[0041] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound or pharmaceutical composition is used to treat a tumor. In some specific embodiments, the tumor is an ERα-positive tumor, such as breast cancer, ovarian cancer, uterine cancer, cervical cancer, or endometrial cancer.

[0042] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.

[0043] The compound of the present invention or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation, suitable for oral or parenteral administration. The method of administration includes, but is not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The preparation can be administered by any route, such as by infusion or push injection, by the route of absorption through the epithelium or skin mucosa (such as oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of oral administration preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art, and includes carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0044] In a third aspect, the present invention provides a method for treating a tumor and a use of a compound represented by formula (I), (Ia) and (Ib), general formula (II), general formula (III), general formula (IV) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition comprising the same in the preparation of a drug for treating a tumor. In some specific embodiments, the tumor is an ERα-positive tumor, such as breast cancer, ovarian cancer, uterine cancer, cervical cancer, or endometrial cancer.

[0045] In some preferred embodiments, the present invention provides compounds represented by general formula (I), (Ia) and (Ib), general formula (II), general formula (III), general formula (IV) of the present invention or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, or pharmaceutical compositions comprising the same for use in methods for treating tumors and in the preparation of drugs for treating tumors, wherein the tumor is preferably an ERα-positive tumor, including but not limited to breast cancer, ovarian cancer, uterine cancer, cervical cancer, or endometrial cancer.

[0046] Definition of terms

[0047] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0048] The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium and deuterium, and isotopes of carbon include 12 C. 13 C and 14 C, oxygen isotopes include 16 O and 18 O etc.

[0049] The "isomer" of the present invention refers to a molecule with the same atomic composition and connection mode, but different three-dimensional spatial arrangement, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefix D, L or (+), (-) is used to name the sign of rotation of plane polarized light of the compound, (-) or L means that the compound is left-handed, and the prefix (+) or D means that the compound is right-handed. The chemical structure of these stereoisomers is the same, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is usually called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0050] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0051] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0052] The "halogen" of the present invention refers to fluorine, chlorine, bromine, and iodine. The "halogenated" of the present invention refers to substitution with fluorine, chlorine, bromine, or iodine.

[0053] The "alkyl" of the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group containing 1 to 6 carbon atoms, and further preferably a straight or branched group containing 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

[0054] The "haloalkyl group" of the present invention refers to an alkyl group substituted with at least one halogen.

[0055] The "hydroxyalkyl group" of the present invention refers to an alkyl group substituted with at least one hydroxy group.

[0056] The "alkoxy" of the present invention refers to -O-alkyl. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, etc. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

[0057] The "heterocyclyl" of the present invention refers to a group of a 5- to 12-membered non-aromatic ring system having 1 to 4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon) ("5-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as valence permits. The heterocyclyl group can be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiral ring system (e.g., a bicyclic system (also known as a "bicyclic heterocyclyl")) and can be saturated or partially unsaturated. Suitable heterocyclyls include, but are not limited to, piperidinyl, azetidinyl, aziridine, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, N-heterospirocyclyl, etc. Each instance of heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

[0058] The "aryl" of the present invention refers to an aromatic system that may contain a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic ring, containing 6 to 12 carbon atoms, preferably containing about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any usable point of attachment.

[0059] The "heteroaryl" of the present invention refers to an aryl group in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5-14 atoms (5-14-membered heteroaryl), and more preferably composed of 5-14 atoms (5-14-membered heteroaryl), wherein the heteroatom is O, S, or N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furyl, 1,3-dihydroisobenzofuranyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, 1,3-dioxo[4,5-B]pyridyl, 1,6-dihydro-2-oxopyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, indolazolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxinyl, benzopyrazolyl , benzimidazolyl, benzofuranyl, benzopyranyl, benzothiophenyl, 2,2-oxo-1,3-dihydrobenzo[c]thiophenyl, benzoxazolyl, 2(3H)-ketobenzo[d]oxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, imidazo[1,2-a]pyrazinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

[0060] The "pharmaceutically acceptable salt" of the present invention refers to the salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity.

[0061] The "solvate" of the present invention refers to a complex formed by the combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense. The solvent refers to a solvent known to or easily determined by a person skilled in the art. If it is water, the solvate is usually referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative thereof.

[0062] The in vivo effects of the compounds of formula (I), formula (II), formula (III), and formula (IV) may be partially exerted by one or more metabolites formed in the human or animal body after administration of the compounds of formula (I), formula (II), formula (III), and formula (IV). As described above, the in vivo effects of the compounds of formula (I), formula (II), formula (III), and formula (IV) may also be exerted via metabolism of precursor compounds ("prodrugs"). The "prodrug" of the present invention refers to a compound that is converted into a compound of the present invention under physiological conditions in an organism by reaction with an enzyme, gastric acid, etc., i.e., a compound that is converted into a compound of the present invention by oxidation, reduction, hydrolysis, etc. of an enzyme and / or a compound that is converted into a compound of the present invention by a hydrolysis reaction of gastric acid, etc.

[0063] The term "crystalline" in the present invention refers to a solid whose internal structure is formed by regularly repeating constituent atoms (or groups thereof) in three dimensions, and is distinguished from an amorphous solid that does not have such a regular internal structure.

[0064] The "pharmaceutical composition" of the present invention refers to a mixture comprising any one of the compounds of the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and / or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The composition is generally used to prepare a drug for the treatment and / or prevention of a disease mediated by one or more kinases.

[0065] The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Unless any conventional carrier medium is incompatible with the compound of the present invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.

[0066] The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols. DETAILED DESCRIPTION

[0067] The present invention is further described in detail below in conjunction with the examples, but the present invention is not limited to these examples. The materials used in the following examples are commercially available unless otherwise specified.

[0068] Intermediate 1: 6,7-difluoro-2,3-dihydro-1H-indole-2,3-dione

[0069]

[0070] Step 1: Preparation of (Z)-N-(2,3-difluorophenyl)-2-(hydroxyimino)acetamide

[0071]

[0072] Weigh 2,3-difluoroaniline (0.8 g, 6.2 mmol) in a 250 mL three-necked flask, add chloral hydrate (1.54 g, 9.3 mmol), hydroxylamine hydrochloride (1.55 g, 2.2 mmol), and anhydrous sodium sulfate (7 g, 49 mmol) and dissolve in 35 mL of water, protect with argon, stir overnight at 50 ° C, monitor the reaction by LC-MS, and after the reaction is completed, cool the reaction solution to room temperature, add 3 mL of hydrochloric acid (2N) and stir at room temperature for 30 min, filter, collect the filter cake, and dry to obtain 1.2 g of white solid powder (1.2 g, yield 100%). ESI-MS m / z: 199.1 [MH] - .

[0073] Step 2: Preparation of 6,7-difluoro-2,3-dihydro-1H-indole-2,3-dione

[0074]

[0075] Weigh (E)-N-(2,3-difluorophenyl)-2-(hydroxyimino)acetamide (1.2 g, 6 mmol) in a 100 mL three-necked flask, add 6 mL of concentrated sulfuric acid, protect with argon, stir at 80 ° C, after 30 minutes, monitor the reaction by LC-MS, cool the reaction solution to room temperature, dilute with water, extract with ethyl acetate, wash twice with water, wash once with saturated brine, collect the organic phase, dry with anhydrous sodium sulfate, concentrate, and column chromatography (25% EA in PE) to obtain the title compound (0.67 g, yield 67%). ESI-MS m / z: 182.0 [MH] - .

[0076] Intermediate 2: 7,8-dihydro-1H-furo[2,3-g]indole-2,3-dione

[0077]

[0078] Step 1: Preparation of (E)-N-(2,3-dihydrobenzofuran-4-yl)-2-(hydroxyimino)acetamide

[0079]

[0080] Weigh 2,3-dihydrobenzofuran-4-amine (2.0 g, 14.8 mmol) in a 250 ml three-necked flask, add chloral hydrate (3.66 g, 22.2 mmol), hydroxylamine hydrochloride (3.68 g, 53.3 mmol), anhydrous sodium sulfate (16.8 g, 118.4 mmol) and dissolve in 160 mL of water, protect with argon, stir at 50 ° C overnight, monitor the reaction by LC-MS, cool the reaction solution to room temperature, filter, collect the filter cake, add ethyl acetate to wash the filter cake, and spin dry the filtrate to obtain the product (1.4 g, yield: 47%). ESI-MS m / z: 207.0 [M+H] + .

[0081] Step 2: Preparation of 7,8-dihydro-1H-furo[2,3-g]indole-2,3-dione

[0082]

[0083] (E)-N-(2,3-dihydrobenzofuran-4-yl)-2-(hydroxyimino)acetamide (0.5 g, 2.24 mmol) was weighed into a 100 mL single-necked bottle, 5 mL of methanesulfonic acid was added, and the mixture was stirred at room temperature under argon protection. After 1 hour, the reaction was completed as monitored by LC-MS. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was collected and dried to obtain a crude product (0.45 g). ESI-MS m / z: 190.0 [M+H] + .

[0084] Intermediate 3: 2,2-difluoro-5H-[1,3]dioxacyclo[4,5-f]indole-6,7-dione

[0085]

[0086] Step 1: Preparation of (Z)-N-(2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)-2-(hydroxyimino)acetamide

[0087]

[0088] 5-amino-2,2-difluoro-1,3-benzodioxole (1g, 5.78mmol) was weighed into a 250mL three-necked flask, and chloral hydrate (1.43g, 8.67mmol), hydroxylamine hydrochloride (1.44g, 20.81mmol), and anhydrous sodium sulfate (6.57g, 46.24mmol) were added and dissolved in 150mL water. Under argon protection, the mixture was stirred at 50°C overnight. After the reaction was completed by LC-MS monitoring, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected. The filter cake was washed three times with water and dried to obtain a gray solid crude product (1.08g). ESI-MS m / z: 245.0[M+H] + .

[0089] Step 2: Preparation of 2,2-difluoro-5H-[1,3]dioxacyclo[4,5-f]indole-6,7-dione

[0090]

[0091] (Z)-N-(2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)-2-(hydroxyimino)acetamide (1 g crude product) was weighed into a 100 mL three-necked flask, 20 mL of methanesulfonic acid was added, and the mixture was stirred at 50°C for 60 min. After the reaction was completed as monitored by LC-MS, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed twice with water and once with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (0.87 g, yield 89%), ESI-MS m / z: 227.9 [M+H] + .

[0092] Intermediate 4: 5-Fluoro-7,8-dihydrofuro[2,3-g]indole-2,3-dione

[0093]

[0094] Step 1: Preparation of N-(4-fluoro-3-methoxyphenyl)pivalamide

[0095]

[0096] 4-Fluoro-3-methoxyaniline (6.4 g, 45 mmol) was weighed into a 500 mL three-necked flask, and pivaloyl chloride (5.45 g, 45 mmol) was added and dissolved in 170 mL of dichloromethane. At 0°C, 6.3 mL of triethylamine was added dropwise. After the addition was completed, the temperature was restored to room temperature and the reaction was carried out for 2 h. After the reaction was completed under LC-MS monitoring, the reaction solution was poured into water and extracted with dichloromethane and water. After extraction three times, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.

[0097] Step 2: Preparation of N-(4-fluoro-2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide

[0098]

[0099] N-(4-fluoro-3-methoxyphenyl) pivalamide (5 g) was weighed into a 500 mL three-necked flask and dissolved with 100 mL THF. Under Ar protection and at 0°C, 22.2 mL of n-butyl lithium (2.5 M) was slowly added to the reaction solution, stirred at 0°C for 2 h, and then a tetrahydrofuran solution of ethylene oxide was added thereto. The mixture was stirred at 0°C for 1 h, and stirred at room temperature for 1 h. After the reaction was completed under LC-MS monitoring, the mixture was diluted with water, extracted with ethyl acetate, washed twice with water, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the title compound (3.2 g) was obtained by column chromatography. ESI-MS m / z: 270.0 [M+H] + .

[0100] Step 3: Preparation of 7-fluoro-2,3-dihydrobenzofuran-4-amine

[0101]

[0102] Dissolve N-(4-fluoro-2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide (5g, 18.59mmol) in 60mLHBr (aq, 40%), heat to 100℃, condense and reflux, react overnight, monitor the reaction by LC-Ms, pour the reaction solution into water and dilute, adjust the pH to 9 to 10 with NaOH, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain the target product (2.169g, 76%) by column chromatography. ESI-MS m / z: 154.0[M+H] + .

[0103] Step 4: Preparation of (Z)-N-(7-fluoro-2,3-dihydrobenzofuran-4-yl)-2-hydroxyiminoacetamide

[0104]

[0105] 7-Fluoro-2,3-dihydrobenzofuran-4-amine (1g, 6.53mmol) was weighed into a 250mL three-necked flask, and chloral hydrate (1.62g, 9.80mmol), hydroxylamine hydrochloride (1.62g, 23.52mmol), and anhydrous sodium sulfate (7.42g, 52.27mmol) were added and dissolved in 70mL of water. The mixture was protected by argon and stirred at 50°C overnight. After the reaction was completed by LC-MS monitoring, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected. The filter cake was washed with water several times and dried to obtain a gray solid powder crude product. ESI-MS m / z: 223.1[MH] - .

[0106] Step 5: Preparation of 5-fluoro-7,8-dihydrofuro[2,3-g]indole-2,3-dione

[0107]

[0108] (Z)-N-(7-Fluoro-2,3-dihydrobenzofuran-4-yl)-2-hydroxyiminoacetamide (500 mg, 2.23 mmol) was weighed into a 50 mL three-necked flask, 6 mL of concentrated sulfuric acid was added, and the mixture was stirred at room temperature for reaction. After 1 h, the reaction was completed as monitored by LC-MS. The reaction solution was poured into ice for dilution, extracted with ethyl acetate, washed twice with water, and once with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (325 mg, yield 70%), ESI-MS m / z: 207.9 [M+H] + .

[0109] Example 1: 3-(2,3-dihydrobenzofuran-6-yl)-6,7-difluoro-3-(4-hydroxyphenyl)indol-2-one

[0110]

[0111] Step 1: Preparation of 3-(2,3-dihydrobenzofuran-6-yl)-6,7-difluoro-3-hydroxyindol-2-one

[0112]

[0113] Dissolve 6-bromo-2,3-dihydrobenzofuran (0.2g, 1.01mmol) in tetrahydrofuran (10mL) in a 50mL two-necked bottle, cool to -78℃ with liquid nitrogen, protect with argon, add n-butyl lithium (2.5M, 0.8mL) dropwise, keep the temperature for 1 hour, then dissolve 6,7-difluoroindoline-2,3-dione (0.131g, 0.0.71mmol) in tetrahydrofuran (1mL) dropwise to the reaction solution, keep the temperature for 1 hour, monitor the reaction by LC-MS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, concentrate, and obtain the target product by column chromatography. ESI-MS m / z: 302.3[MH] - .

[0114] Step 2: Preparation of 3-(2,3-dihydrobenzofuran-6-yl)-6,7-difluoro-3-(4-hydroxyphenyl)indol-2-one

[0115]

[0116] Weigh 3-(2,3-dihydrobenzofuran-6-yl)-6,7-difluoro-3-hydroxyindole-2-one (0.16 g, 0.53 mmol) and phenol (0.15 g, 1.59 mmol) in a 50 mL single-necked bottle, add 9 drops of boron trifluoride ether under ice bath, stir and react at room temperature for 1 hour, and after the reaction is completed by LC-MS monitoring, the reaction solution is diluted with water, extracted twice with ethyl acetate, the organic phase is collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to obtain a crude product, which is purified by HPLC to obtain 50 mg. ESI-MS m / z: 379.9 [M+H] + .

[0117] 1 H NMR (400 MHz, DMSO-d6) δ11.42(s,1H),9.48(s,1H),7.14(d,J=7.6 Hz,1H),7.07-6.98(m,2H),6.95(d,J=8.6 Hz,2H),6.70(d,J=8.5 Hz, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.47 (s, 1H), 4.49 (t, J = 8.6 Hz, 2H), 3.13 (t, J = 8.5 Hz, 2H).

[0118] Example 2: 3-(2,3-dihydrobenzofuran-5-yl)-6,7-difluoro-3-(4-hydroxyphenyl)indol-2-one

[0119]

[0120] The preparation method is the same as that of Example 1, except that the raw material 6-bromo-2,3-dihydrobenzofuran is replaced with 5-bromo-2,3-dihydrobenzofuran to obtain the title compound. ESI-MS m / z: 380.0 [M+H] + .

[0121] 1 H NMR (400 MHz, DMSO-d6) δ11.35(s,1H),9.44(s,1H),7.00-6.85(m,5H),6.79(d,J=7.9 Hz,1H),6.65(t,J=8.8 Hz,3H),4.44(t,J=8.5 Hz,2H),3.06(t,J=8.3 Hz,2H).

[0122] Example 3: 6,7-difluoro-3-(4-hydroxyphenyl)-3-(naphthalen-2-yl)indol-2-one

[0123]

[0124] The preparation method is the same as that of Example 1, except that the raw material 6-bromo-2,3-dihydrobenzofuran is replaced with 2-bromonaphthalene to obtain the title compound. ESI-MS m / z: 387.9 [M+H] + .

[0125] 1 H NMR (400 MHz, DMSO-d6) δ11.52(s,1H),9.51(s,1H),7.92-7.80(m,3H),7.61(s,1H),7.54-7.45(m,2H),7.33(d,J=8.5 Hz,1H),7.18-7.12(m,1H),7.09-7.02(m,1H),6.99(d,J=8.4 Hz,2H),6.73(d,J=8.4 Hz,2H).

[0126] Example 4: 3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1,3,7,8-tetrahydro-2H-furan[2,3-g]indol-2-one

[0127]

[0128] Step 1: Preparation of 3-(4-fluorophenyl)-3-hydroxy-1,3,7,8-tetrahydro-2H-furo[2,3-g]indol-2-one

[0129]

[0130] Dissolve 1-bromo-4-fluorobenzene (1g, 5.75mmol) in tetrahydrofuran (20mL) in a 100mL two-necked bottle, cool to -78℃ with liquid nitrogen, protect with argon, add n-butyl lithium (2.5M, 2.3mL) dropwise, keep the temperature for 1 hour, then add 7,8-dihydro-1H-furano[2,3-g]indole-2,3-dione (0.54g, 2.88mmol) to the reaction solution, keep the temperature for 1 hour, monitor the reaction by LC-MS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, concentrate, and obtain the target product by column chromatography. ESI-MS m / z: 267.9[M-OH] + .

[0131] Step 2: Preparation of 3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1,3,7,8-tetrahydro-2H-furano[2,3-g]indol-2-one

[0132]

[0133] Weigh phenol (0.197 g, 2.1 mmol) in a 50 mL single-mouth bottle, add TfOH (6 drops), cool to 0 ° C, then dissolve 3-(4-fluorophenyl)-3-hydroxy-1,3,7,8-tetrahydro-2H-furano[2,3-g]indol-2-one (0.2 g, 0.701 mmol) in DCM, add to the reaction solution, stir and react at room temperature for 1 hour, LCMS monitoring after the reaction is completed, the reaction solution is diluted with water, extracted twice with ethyl acetate, the organic phase is collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product is obtained by column chromatography to prepare (45 mg). ESI-MS m / z: 361.9 [M+H] + .

[0134] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.41(s,1H),7.13(dd,J=15.3,6.8Hz,4H),6.94(d,J=8.2Hz,2H),6.88 (d,J=8.0Hz,1H),6.69(d,J=8.2Hz,2H),6.40(d,J=8.0Hz,1H),4.56(t,J=8.4Hz,2H),3.13(t,J=8.4Hz,2H).

[0135] Example 5: 3-(4-Hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-1,3,7,8-tetrahydro-2H-furan[2,3-g]indol-2-one

[0136]

[0137] The preparation method is the same as that of Example 4, except that the raw material p-bromofluorobenzene is replaced with p-bromotrifluoromethoxybenzene to obtain the title compound. ESI-MS m / z: 428.1 [M+H] + .

[0138] 1 H NMR (400 MHz, DMSO-d6) δ10.89(s,1H),9.45(s,1H),7.31(d,J=7.4 Hz,2H),7.24(d,J=7.3Hz,2H),6.96(d,J=7.7 Hz,2H),6.91(d,J=7.8 Hz, 1H), 6.70 (d, J = 7.5 Hz, 2H), 6.41 (d, J = 7.7 Hz, 1H), 4.57 (t, J = 7.6 Hz, 2H), 3.14 (d, J = 7.6 Hz, 2H).

[0139] Example 6: 3-(2,3-dihydro-1H-inden-5-yl)-5-fluoro-3-(4-hydroxyphenyl)-1,3,7,8-tetrahydro-2H-furo[2,3-g]indol-2-one

[0140]

[0141] Step 1: Preparation of 3-(2,3-dihydro-1H-inden-5-yl)-5-fluoro-3-hydroxy-1,3,7,8-tetrahydro-2H-furano[2,3-g]indol-2-one

[0142]

[0143] Dissolve 5-bromo-2,3-dihydro-1H-indene (314.90 mg, 1.73 mmol) in tetrahydrofuran (15 mL) in a 50 mL two-necked flask, cool to -78°C with liquid nitrogen, protect with argon, drop n-butyl lithium (2.5 M, 0.77 mL), keep the temperature for 1 hour, then dissolve 5-fluoro-7,8-dihydrofurano[2,3-g]indole-2,3-dione (200 mg, 0.97 mmol) in tetrahydrofuran (0.5 mL) and drop into the reaction solution, keep the temperature for 1 hour, monitor the reaction by LC-MS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the target crude product. ESI-MS m / z: 326.1[M+H] + .

[0144] Step 2: Preparation of 3-(2,3-dihydro-1H-inden-5-yl)-5-fluoro-3-(4-hydroxyphenyl)-1,3,7,8-tetrahydro-2H-furano[2,3-g]indol-2-one

[0145]

[0146] The crude product of 3-(2,3-dihydro-1H-inden-5-yl)-5-fluoro-3-hydroxy-1,3,7,8-tetrahydro-2H-furan[2,3-g]indol-2-one and phenol (0.218 g, 2.32 mmol) were placed in a 50 mL single-mouth bottle, dissolved with 15 mL DCM, and added dropwise with boron trifluoride etherate (0.36 mL) under ice bath. The mixture was stirred at room temperature for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was obtained by column chromatography. The target product 43 mg was obtained by HPLC purification. ESI-MS m / z: 401.9 [M+H] + .

[0147] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.41(s,1H),7.13(d,J=7.8Hz,1H),6.98(d,J=7.9Hz,3H),6.89(t,J=7.7H z,2H),6.69(d,J=8.2Hz,2H),4.67(t,J=8.4Hz,2H),3.20(t,J=8.3Hz,2H),2.85-2.55(m,4H),2.03-1.90(m,2H).

[0148] Example 7: 3-(2,3-dihydrobenzofuran-6-yl)-5-fluoro-3-(4-hydroxyphenyl)-1,3,7,8-tetrahydro-2H-furan[2,3-g]indol-2-one

[0149]

[0150] The preparation method is the same as that of Example 6, except that the raw material 5-bromo-2,3-dihydro-1H-indene is replaced with 6-bromo-2,3-dihydrobenzofuran to obtain the title compound. ESI-MS m / z: 404.1 [M+H] + .

[0151] 1H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.42(s,1H),7.12(d,J=7.7Hz,1H),6.96(d,J=8.3Hz,2H),6.90(d,J=10.4Hz,1H),6.69(d,J=8.3 Hz,2H),6.58(d,J=7.6Hz,1H),6.47(s,1H),4.67(t,J=8.4Hz,2H),4.49(t,J=8.6Hz,2H),3.19(t,J=8.4Hz,2H),3.12(t,J=8.5Hz,2H).

[0152] Example 8: 5-Fluoro-3-(4-hydroxyphenyl)-3-(4-trifluoromethoxy)phenyl)-1,3,7,8-tetrahydro-2H-furan[2,3-g]indol-2-one

[0153]

[0154] The preparation method is the same as that of Example 6, except that the raw material 5-bromo-2,3-dihydro-1H-indene is replaced with p-bromotrifluoromethoxybenzene to obtain the title compound. ESI-MS m / z: 446.1 [M+H] + .

[0155] 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 9.48 (s, 1H), 7.29 (dd, J = 22.5, 8.4Hz, 4H), 7. 03-6.93(m,3H),6.71(d,J=8.2Hz,2H),4.69(t,J=8.4Hz,2H),3.21(t,J=8.4Hz,2H).

[0156] Example 9: 3-(2.3-dihydro-1H-indene-5-yl)-5,6,7-trifluoro-3-(4-hydroxyphenyl)indol-2-one

[0157]

[0158] The preparation method is the same as that of Example 6, except that the raw material 5-fluoro-7,8-dihydrofurano[2,3-g]indole-2,3-dione is replaced with 5,6,7-trifluoroindoline-2.3-dione to obtain the title compound. ESI-MS m / z: 396.1 [M+H] + .

[0159] 1H NMR (400MHz, DMSO-d6) δ11.41(s,1H),9.52(s,1H),7.31(t,1H),7.16(d,J=7.8Hz,1H),7.01-6 .94(m,3H),6.89(d,J=7.7Hz,1H),6.71(d,J=8.2Hz,2H),2.90-2.50(m,4H),2.06-1.88(m,2H).

[0160] Example 10: 7-(2,3-dihydrobenzofuran-5-yl)-2,2-difluoro-7-(4-hydroxyphenyl)-5,7-dihydro-6H-[1,3]dioxa[4,5-f]indol-6-one

[0161]

[0162] Step 1: Preparation of 7-(2,3-dihydrobenzofuran-5-yl)-2,2-difluoro-7-hydroxy-5,7-dihydro-6H-[1,3]dioxa[4,5-f]indol-6-one

[0163]

[0164] 5-Bromo-2,3-dihydrobenzofuran (174.61 mg, 0.882 mmol) was dissolved in tetrahydrofuran (10 mL) in a 50 mL two-necked bottle, cooled to -78 °C with liquid nitrogen, protected by argon, and n-butyl lithium (2.5 M, 0.53 mL) was added dropwise, and the temperature was maintained for 1 hour. Then 2,2-difluoro-5H-[1,3]dioxopentan[4,5-f]indole-6,7-dione (0.1 g, 0.441 mmol) was dissolved in tetrahydrofuran (1 mL) and added dropwise to the reaction solution, and the temperature was maintained for 1 hour. After the reaction was completed, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target crude product. ESI-MS m / z: 348.1 [M+H] + .

[0165] Step 2: Preparation of 7-(2,3-dihydrobenzofuran-5-yl)-2,2-difluoro-7-(4-hydroxyphenyl)-5,7-dihydro-6H-[1,3]dioxa[4,5-f]indol-6-one

[0166]

[0167] The crude product of 7-(2,3-dihydrobenzofuran-5-yl)-2,2-difluoro-7-hydroxy-5,7-dihydro-6H-[1,3]dioxa[4,5-f]indol-6-one (0.153 g) and phenol (198.8 mg, 2.11 mmol) were placed in a 50 ml single-mouth bottle, and boron trifluoride etherate (0.415 mL) was added dropwise under ice bath. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was obtained by column chromatography. The target product 22 mg was obtained by HPLC purification. ESI-MS m / z: 423.9 [M+H] + .

[0168] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.45(s,1H),7.38(s,1H),7.05-6.90(m,4H),6.8 5(d,J=7.7Hz,1H), 6.68(t,J=8.2Hz,3H), 4.49(t,J=8.5Hz,2H), 3.11(t,J=8.5Hz,2H).

[0169] Example 11: 7-(2,3-dihydro-1H-indene-5-yl)-2,2-difluoro-7-(4-hydroxyphenyl)-5,7-dihydro-6H-[1,3]dioxa[4,5-f]indol-6-one

[0170]

[0171] The preparation method is the same as that of Example 10, except that the raw material 5-bromo-2,3-dihydrobenzofuran is replaced by 5-bromo-2,3-dihydro-1H-indene to obtain the title compound. ESI-MS m / z 422.1[M+H] + .

[0172] 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.45(s,1H),7.38(s,1H),7.15(d,J=7.8Hz,1H),7.03-6 .95(m,4H),6.89(d,J=7.6Hz,1H),6.70(d,J=8.4Hz,2H),2.85-2.55(m,4H),2.02-1.93(m,2H).

[0173] Example 12: 7-(4-trifluoromethoxyphenyl)-2,2-difluoro-7-(4-hydroxyphenyl)-5,7-dihydro-6H-[1,3]dioxa[4,5-f]indol-6-one

[0174]

[0175] The preparation method is the same as that of Example 10, except that the raw material 5-bromo-2,3-dihydrobenzofuran is replaced with p-bromotrifluoromethoxybenzene to obtain the title compound. ESI-MS m / z 465.9 [M+H] + .

[0176] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.53(s,1H),7.48(s,1H),7.30(dd,J= 23.0,8.4Hz,4H),7.04(s,1H),6.98(d,J=8.3Hz,2H),6.73(d,J=8.3Hz,2H).

[0177] Example 13: 6,7-difluoro-3-(4-hydroxyphenyl)-3-(3,3,4,4-tetrafluoropyrrolidin-1-yl)indol-2-one

[0178]

[0179] Step 1: Preparation of (4-bromophenoxy)(tert-butyl)dimethylsilane

[0180]

[0181] Dissolve p-bromophenol (2g, 12mmol) in 30mL DMF, then place in an ice-water bath, add imidazole (2.4g, 36mmol), TBSCl (2.4g, 16mmol), and react at room temperature for 3 hours. After the reaction is complete by LC-MS, add water to quench, extract twice with ethyl acetate, wash the organic phase with water twice, wash once with saturated brine, collect the organic phase, dry with anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain a liquid (3.8g). ESI-MS m / z: 283.2[M+H] + .

[0182] Step 2: Preparation of 3-(4-(tert-butyldimethylsilyl)oxy)phenyl)-6,7-difluoro-3-hydroxyindole-2-one

[0183]

[0184] Dissolve (4-bromophenoxy)(tert-butyl)dimethylsilane (9.7g, 18.6mmol) in 60mL tetrahydrofuran, protect with argon and cool to -78℃, slowly add n-butyl lithium (2.5mol / L, 8.5mL) dropwise to the solution, keep -78℃ for 1 hour after adding. Dissolve 6,7-difluoroindoline-2,3-dione (3.6g, 9.2mmol) in 10mL tetrahydrofuran, and slowly add the solution dropwise to the system at -78℃, keep -78℃ for 1 hour after adding. After the reaction is completed by LC-MS monitoring, move to room temperature and continue stirring for 1 hour, then add water to the system to quench, extract twice with ethyl acetate, wash twice with water, wash once with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, and concentrate to obtain brown viscous liquid (3.2g). ESI-MS m / z:392.1[M+H] + .

[0185] Step 3: Preparation of 3-(4-(tert-butyldimethylsilyl)oxy)phenyl)-6,7-difluoro-3-chloroindol-2-one

[0186]

[0187] Dissolve 3-(4-(tert-butyldimethylsilyl)oxy)phenyl)-6,7-difluoro-3-hydroxyindole-2-one (3.6g, 0.95mmol) in 25mL tetrahydrofuran. Add pyridine (2.2mL, 2.85mmol) and cool to 0°C. Slowly add thionyl chloride (3.5mL) dropwise into the system. After the addition, move the reaction solution to room temperature and react at room temperature for 0.5h. After the reaction is completed by spot plate monitoring, quench with ice water first, then extract twice with ethyl acetate, wash twice with water, wash once with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, and concentrate to obtain 4g of crude compound.

[0188] Step 4: Preparation of 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-6,7-difluoroindol-2-one

[0189]

[0190] 6,6-difluoro-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate (4g, 0.202mmol) was dissolved in 4mL of dichloromethane, cesium carbonate (9g, 0.8mmol) was added, and then 3-(4-(tert-butyldimethylsilyl)oxy)phenyl)-6,7-difluoro-3-chloroindol-2-one (2g, 0.242mmol) was added and reacted overnight. After the reaction was completed by spot plate monitoring, it was quenched with ice water, extracted with dichloromethane twice, washed with water twice, washed once with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain 4g of crude compound.

[0191] Step 5: Preparation of 6,7-difluoro-3-(4-hydroxyphenyl)-3-(3,3,4,4-tetrafluoropyrrolidin-1-yl)indol-2-one

[0192]

[0193] 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-6,7-difluoroindol-2-one (4g, 0.19mmol) was dissolved in 30mL tetrahydrofuran, and 15mL TBAF was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed by spot plate monitoring, the mixture was quenched with ice water, extracted twice with ethyl acetate, washed twice with water, and washed once with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain 18mg of the standard compound. ESI-MS m / z: 401.1[MH] - .

[0194] 1 H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 9.63 (s, 1H), 7.22 (t, J = 8.4Hz, 3H), 7. 11-7.01(m,1H),6.78(d,J=8.6Hz,2H),3.29-3.20(m,2H),3.16-3.07(m,2H).

[0195] Example 14: 3-(2,3-dihydrobenzofuran-6-yl)-3-(4-hydroxyphenyl)-5-(trifluoromethoxy)indol-2-one

[0196]

[0197] Step 1: Preparation of 3-(2,3-dihydrobenzofuran-6-yl)-3-hydroxy-5-(trifluoromethoxy)indol-2-one

[0198]

[0199] Dissolve 6-bromo-2,3-dihydrobenzofuran (0.1 g, 0.505 mmol) in 5 mL tetrahydrofuran, cool to -78 °C under argon protection, slowly add n-butyl lithium (2.5 mol / L, 0.3 mL) dropwise to the solution, and keep -78 °C for 1 h after adding. Dissolve 5-(trifluoromethoxy)indoline-2,3-dione (0.07 g, 0.303 mmol) in 1 mL tetrahydrofuran, and slowly add the solution dropwise to the system at -78 °C, and keep -78 °C for 1 h after adding. After the reaction is completed by LC-MS monitoring, move to room temperature and continue stirring for 1 h, then add 10 mL of water to the system to quench, extract twice with ethyl acetate, wash twice with water, wash once with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, and concentrate to obtain the standard compound. ESI-MS m / z: 351.9 [M+H] + .

[0200] Step 2: Preparation of 3-(2,3-dihydrobenzofuran-6-yl)-3-(4-hydroxyphenyl)-5-(trifluoromethoxy)indol-2-one

[0201]

[0202] Weigh 3-(2,3-dihydrobenzofuran-6-yl)-3-hydroxy-5-(trifluoromethoxy)indol-2-one (0.11 g, 0.313 mmol) and phenol (0.088 g, 0.094 mmol) in a 50 ml single-mouth bottle, add 6 drops of boron trifluoride ether under ice bath, protect with argon, stir and react at room temperature for 1 hour, monitor the reaction by LC-MS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, concentrate, obtain the crude product by column chromatography, and purify by HPLC to obtain (34 mg). ESI-MS m / z: 427.9 [M+H] + .

[0203] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),9.47(s,1H),7.24(d,J=12.9Hz,2H),7.15(d,J=7.8Hz,1H),7.01(d,J=8.3Hz,1H),6. 96(d,J=8.5Hz,2H),6.70(d,J=8.5Hz,2H),6.57(d,J=7.6Hz,1H),6.48(s,1H),4.49(t,J=8.6Hz,2H),3.13(t,J=8.6Hz,2H).

[0204] Example 15: 2'-(3,5-difluorophenyl)-6,7-difluoro-5'-hydroxyspiro[indoline-3,1'-isoindoline]-2,3'-dione

[0205]

[0206] Step 1: Preparation of 2-bromo-N-(1-(2-bromo-3,4-difluorophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3,5-difluorophenyl)-4-methoxybenzamide

[0207]

[0208] A methanol solution (5 mL) of 2-bromo-3,4-difluorobenzaldehyde (1.04 g, 4.73 mmol) was added with sodium sulfate (1.5 g), 3,5-difluoroaniline (648 mg, 5 mmol), 2-bromo-4-methoxyphenylamine (1.15 g, 5 mmol) and tert-butyl isonitrile (415 mg, 5 mmol) in a screw cap bottle equipped with a magnetic stirring bar. The reaction mixture was stirred at room temperature for 48 h in a sealed bottle. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL) and extracted with water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a residue, which was chromatographed on a silica gel column (5% petroleum ether in dichloromethane) to obtain the desired product 2.0 g.

[0209] Step 2: Preparation of 1-(tert-butyl)-2'-(3,5-difluorophenyl)-6,7-difluoro-5'-methoxyspiro[indole-3,1'-isoindole]-2,3'-dione

[0210]

[0211] 2-Bromo-N-(1-(2-bromo-3,4-difluorophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3,5-difluorophenyl)-4-methoxybenzamide (1.7 g, 2.64 mmol of substrate), palladium acetate (5 mol%), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5 mol%) and cesium carbonate (2 equivalents) were placed in a screw cap bottle along with dry toluene (20 mL). The reaction bottle was evacuated, backfilled with nitrogen 5 times, and stirred at 120°C for 24 h. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 mL) and extracted with water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a residue, which was chromatographed on a silica gel column (5-20% ethyl acetate in petroleum ether) to give the desired product 0.5 g. ESI-MS m / z:485.1[M+H] + .

[0212] Step 3: Preparation of 2'-(3,5-difluorophenyl)-6,7-difluoro-5'-methoxyspiro[indoline-3,1'-isoindoline]-2,3'-dione

[0213]

[0214] The compound 1-(tert-butyl)-2'-(3,5-difluorophenyl)-6,7-difluoro-5'-methoxyspiro[indole-3,1'-isoindole]-2,3'-dione (500 mg) was added to a mixture of trifluoromethanesulfonic acid (2 mL) and trifluoroacetic acid (2 mL), stirred at room temperature for 3.5 h, and then quenched with NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (2 mL×3), the organic layer was combined, dried with Na2SO4, and concentrated in vacuo to obtain 700 mg of the product. ESI-MS m / z: 429.1 [M+H] + .

[0215] Step 4: Preparation of 2'-(3,5-difluorophenyl)-6,7-difluoro-5'-hydroxyspiro[indoline-3,1'-isoindoline]-2,3'-dione

[0216]

[0217] 2'-(3,5-difluorophenyl)-6,7-difluoro-5'-methoxyspiro[indoline-3,1'-isoindoline]-2,3'-dione was placed in a 100mL single-mouth bottle and dissolved in 10mL DCM. Under argon protection, 8mL (1mol / L) boron tribromide solution was added dropwise under ice bath and stirred at room temperature for 3h. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (2mL×3). The organic layer was combined, dried over sodium sulfate, and concentrated in vacuo for separation. ESI-MS m / z:415.1[M+H] + .

[0218] 1 H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 8.35 (s, 1H), 7.22 (s, 1H), 7.16 (t, J = 9.2Hz, 1H), 7.12-6.81 (m, 6H).

[0219] Example 16: 2'-(Cyclopropylmethyl)-6,7-difluoro-5'-hydroxyspiro[indoline-3,1'-isoindoline]-2,3'-dione

[0220]

[0221] The preparation method is the same as that of Example 15, except that the raw material 3,5-difluoroaniline is replaced by cyclopropylmethylamine to obtain the title compound. ESI-MS m / z: 357.1 [M+H] + .

[0222] 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),10.16(s,1H),7.15(s,1H),7.10-6. 94(m,3H),6.87(s,1H),3.26-3.02(m,2H),0.70(s,1H),0.33-0.02(m,4H).

[0223] Example 17: 6-Chloro-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[0224]

[0225] Step 1: Preparation of 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[0226]

[0227] Weigh 6-chloro-1H-pyrrolo[2,3-b]pyridine (3.0 g, 19.66 mmol) in a 250 mL single-mouth bottle, add 150 mL of tert-butyl alcohol, add pyridinium tribromide (18.86 g, 58.98 mmol), react at room temperature for two hours, and after the reaction is completed by LC-MS monitoring, add water to quench, then add ethyl acetate, spin dry the organic phase, and pass through a column to obtain the product (5 g). ESI-MS m / z: 322.0 [MH] - .

[0228] Step 2: Preparation of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2,3-dione

[0229]

[0230] Weigh 3,3-dibromo-6-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (4.0 g, 12.27 mmol) in a 500 mL single-mouth bottle, add 250 mL CH3CN, add silver nitrate (4.8 g, 28 mmol), add 13.2 mL water, stir at room temperature, after 2 hours, LC-MS monitoring after the reaction is complete, filter the reaction solution, and discard the solid. The liquid is spin-dried, and the body is washed with dichloromethane to obtain a crude product. ESI-MS m / z: 180.7 [MH]- .

[0231] Step 3: Preparation of 6-chloro-3-hydroxy-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[0232]

[0233] 1-Bromo-4-(trifluoromethoxy)benzene (1g, 4.19mmol) was dissolved in tetrahydrofuran (20mL) in a 100mL two-necked bottle, cooled to -78℃ with liquid nitrogen, protected by argon, and n-butyl lithium (2.5M, 1.67mL) was added dropwise, and the temperature was maintained for 1 hour. Then 6-chloro-1H-pyrrolo[2,3-b]pyridine-2,3-dione (0.38g, 2.09mmol) was dissolved in tetrahydrofuran (2mL) and added to the reaction solution, and the temperature was maintained for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with water, extracted twice with ethyl acetate, and the organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. ESI-MS m / z: 334.9[M+H] + .

[0234] Step 4: Preparation of 6-chloro-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[0235]

[0236] Weigh 6-chloro-3-hydroxy-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (0.35 g, 1.02 mmol) and phenol (0.190 g, 2.02 mmol) in a 50 ml single-mouth bottle, add 10 mL of DCM, add TfOH (1 mL) dropwise under ice bath, stir and react at room temperature for 2 hours, after LCMS monitoring, the reaction solution is diluted with water, extracted twice with ethyl acetate, the organic phase is collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product is obtained by column chromatography to prepare (45 mg). ESI-MS m / z: 420.8 [M+H] + .

[0237] 1H NMR (400MHz, DMSO-d6) δ11.70(s,1H),9.59(s,1H),7.77(d,J=7.7Hz,1H),7.35(d,J=8.0Hz,2 H),7.28(d,J=8.2Hz,2H),7.15(d,J=7.7Hz,1H),6.99(d,J=8.1Hz,2H),6.75(d,J=8.1Hz,2H).

[0238] Example 18: 7-Chloro-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0239]

[0240] Step 1: Preparation of 3,3-dibromo-7-chloro-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0241]

[0242] 7-Chloro-1H-pyrrolo[2,3-c]pyridine (2.0 g, 13.1 mmol) was weighed into a 250 mL single-mouth bottle, 100 mL of t-BuOH and pyridinium tribromide (12.57 g, 39.32 mmol) were added, and the reaction was carried out at room temperature for three hours. After the reaction was completed by LC-MS monitoring, water was added to quench the reaction, and ethyl acetate was added. The organic phase was dried by spin drying, and the product was 2.5 g by column chromatography. ESI-MS m / z: 324.7 [M+H] + .

[0243] Step 2: Preparation of 7-chloro-1H-pyrrolo[2,3-c]pyridine-2,3-dione

[0244]

[0245] Weigh 7-chloro-1H-pyrrolo[2,3-c]pyridine-2,3-dione (3.25g, 12.27mmol) in a 500mL single-mouth bottle, add 250mL acetonitrile, add silver nitrate (3.89, 22.9mmol), add 11mL water, stir at 80°C for reaction, after 12 hours, LC-MS monitoring after the reaction is complete, filter the reaction solution, and discard the solid. Dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and obtain the title compound by column chromatography. ESI-MSm / z:180.7[MH] - .

[0246] Step 3: Preparation of 7-chloro-3-hydroxy-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0247]

[0248] 1-Bromo-4-(trifluoromethoxy)benzene (1.92g, 4.79mmol) was dissolved in tetrahydrofuran (20mL) in a 100mL two-necked bottle, cooled to -78°C with liquid nitrogen, protected by argon, and n-butyl lithium (2.5M, 1.92mL) was added dropwise, and the temperature was maintained for 1 hour. Then 7-chloro-1H-pyrrolo[2,3-c]pyridine-2,3-dione (0.35g, 1.92mmol) was dissolved in tetrahydrofuran (2mL) and added to the reaction solution, and the temperature was maintained for 1 hour. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with water, extracted twice with ethyl acetate, and the organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. ESI-MS m / z: 334.9[M+H] + .

[0249] Step 4: Preparation of 7-chloro-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0250]

[0251] Weigh 7-chloro-3-hydroxy-3-(4-(trifluoromethoxy)phenyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one (0.64 g, 1.86 mmol) and phenol (0.699 g, 7.4 mmol) in a 50 mL single-mouth bottle, add 10 mL of DCM, add TfOH (2 mL) dropwise under an ice bath, stir and react at room temperature for 2 hours. After the reaction is completed by LCMS monitoring, the reaction solution is diluted with water, extracted twice with ethyl acetate, the organic phase is collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product is obtained by column chromatography to prepare the title compound. ESI-MS m / z: 420.8 [M+H] + .

[0252] 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),9.60(s,1H),8.14(d,J=5.9Hz,1H),7.44(d,J=4.6Hz,1 H),7.35(d,J=8.4Hz,2H),7.27(d,J=8.4Hz,2H),6.99(d,J=8.3Hz,2H),6.75(d,J=8.2Hz,2H).

[0253] Example 19: 3-(2,3-dihydrobenzofuran-5-yl)-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0254]

[0255] Step 1: Preparation of tert-butyl 7-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

[0256]

[0257] 7-Bromo-1H-pyrrolo[2,3-c]pyridine (5.0 g, 25.5 mmol) was weighed into a 250 mL single-mouth bottle, and 70 mL of acetonitrile, di-tert-butyl dicarbonate (6.12 g, 28.06 mmol), and 4-dimethylaminopyridine (3.1 g, 25.5 mmol) were added to react overnight at room temperature. After the reaction was completed by LC-MS monitoring, water was added to quench, and ethyl acetate was added. The organic phase was spin-dried and the title compound was obtained by column chromatography. ESI-MS m / z: 296.9 [M+H] + .

[0258] Step 2: Preparation of tert-butyl 7-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

[0259]

[0260] Weigh 7-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (10 g, 35.7 mmol) in a 250 mL single-mouth bottle, dissolve in 80 mL of N,N-dimethylformamide, add cuprous iodide (6.8 g, 35.7 mmol), difluorosulfonyl difluoroacetic acid methyl ester (20.57 g, 107.14 mmol), react at 80°C for two hours, and after the reaction is completed by LC-MS monitoring, add water to quench, then add ethyl acetate, spin dry the organic phase, and column chromatograph the title compound. ESI-MS m / z: 287 [M+H] + .

[0261] Step 3: Preparation of 7-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine

[0262]

[0263] Weigh 7-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (6.3 g, 21.9 mmol) in a 250 mL single-mouth bottle, add 15 mL of dichloromethane to dissolve, add 15 mL of trifluoroacetic acid, stir at room temperature for two hours, and after the reaction is completed by LC-MS monitoring, add water to quench, then add ethyl acetate, spin dry the organic phase, and column chromatograph the title compound. ESI-MSm / z:187.0[M+H] + .

[0264] Step 4: Preparation of 3,3-dibromo-7-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0265]

[0266] 7-(Trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine (8.0 g, 43.0 mmol) was weighed into a 250 mL single-mouth bottle, 200 mL of tert-butyl alcohol and pyridinium tribromide (41.25 g, 129 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by LC-MS, water was added to quench the reaction, and ethyl acetate was added. The organic phase was then dried to obtain a crude product. ESI-MS m / z: 358.8 [M+H] + .

[0267] Step 5: Preparation of 7-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2,3-dione

[0268]

[0269] Weigh 3,3-dibromo-7-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one (15.4 g, 43 mmol) in a 500 mL single-mouth bottle, add 500 mL CH3CN, add silver nitrate (316.8 g, 98.9 mmol), add 25 mL water, stir at 80 ° C, after 12 hours, LC-MS monitoring after the reaction is complete, filter the reaction solution, and discard the solid. The reaction solution is diluted with water, extracted with ethyl acetate twice, the organic phase is collected, washed with water twice, washed with saturated brine once, dried over anhydrous sodium sulfate, and column chromatography to obtain the title compound. ESI-MS m / z: 215.09 [MH] - .

[0270] Step 6: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-3-hydroxy-7-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0271]

[0272] Dissolve 5-bromo-2,3-dihydrobenzofuran (0.05 g, 0.152 mmol) in tetrahydrofuran (10 mL) in a 50 mL two-necked bottle, cool to -78 °C with liquid nitrogen, protect with argon, add n-butyl lithium (2.5 M, 0.212 mL) dropwise, keep the temperature for 1 hour, then add 7-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2,3-dione (0.033 g, 0.152 mmol) in tetrahydrofuran (1 mL) and add to the reaction solution, keep the temperature for 1 hour, monitor the reaction by LC-MS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. ESI-MS m / z: 336.9 [M+H] + .

[0273] Step 7: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one

[0274]

[0275] Weigh 3-(2,3-dihydrobenzofuran-5-yl)-3-hydroxy-7-(trifluoromethyl)-1,3-dihydro-2H-pyrrolo[2,3-c]pyridin-2-one (0.05 g, 0.15 mmol) and phenol (0.042 g, 0.45 mmol) in a 50 mL single-mouth bottle, add 10 mL of DCM, add 10 drops of boron trifluoride etherate (10 drops) dropwise under ice bath, stir and react at room temperature for 1 hour, monitor the reaction by LCMS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, concentrate, and obtain the product by column chromatography to prepare the title compound. ESI-MS m / z: 412.9 [M+H] + .

[0276] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),9.59(s,1H),8.40(s,1H),7.63(s,1H),6.98(d,J=9. 7Hz, 3H), 6.84 (d, J = 8.0Hz, 1H), 6.73 (d, J = 7.6Hz, 3H), 4.49 (t, J = 8.5Hz, 2H), 3.11 (s, 2H).

[0277] Example 20: 6-Cyclopropyl-7-fluoro-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)indol-2-one

[0278]

[0279] Step 1: Preparation of 3-cyclopropyl-2-fluoroaniline

[0280]

[0281] 3-Bromo-2-fluoroaniline (5 g, 26.8 mmol) was weighed into 250 mL and dissolved in 100 mL of dioxane. Cyclopropylboronic acid pinacol ester (6.2 g, 35.6 mmol), tetrakistriphenylphosphine palladium (1.5 g, 1.3 mmol), cesium carbonate (17.2 g, 52.6 mmol) and 20 mL of water were added. The mixture was protected by argon and stirred at 100 °C overnight. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate twice. The organic phase was collected, washed with water twice, washed with saturated brine once, dried over anhydrous sodium sulfate, and the title compound was obtained by column chromatography. ESI-MS m / z: [MH] - Step 2: Preparation of (Z)-N-(3-cyclopropyl-2-fluorophenyl)-2-(hydroxyimino)acetamide

[0282]

[0283] 3-Cyclopropyl-2-fluoroaniline (3 g, 19.7 mmol) was weighed into a 250 mL three-necked flask, and chloral hydrate (4.88 g, 29.6 mmol), hydroxylamine hydrochloride (4.9 g, 71.5 mmol), and anhydrous sodium sulfate (22 g, 157.8 mmol) were added and dissolved in 100 mL of water. The mixture was protected by argon and stirred at 50 °C overnight. After the reaction was completed by LC-MS monitoring, the reaction solution was cooled to room temperature, and ethyl acetate was added to extract twice. The organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. ESI-MS m / z: [MH] - .

[0284] Step 3: Preparation of 6-cyclopropyl-7-fluoroindoline-2,3-dione

[0285]

[0286] Weigh (Z)-N-(3-cyclopropyl-2-fluorophenyl)-2-(hydroxyimino)acetamide (4 g, 19.7 mmol) in a 100 mL three-necked flask, add 20 mL of methanesulfonic acid, protect with argon, stir at 50°C for 1 hour, monitor the reaction with LC-MS, and after completion, cool the reaction solution to room temperature, dilute with water, extract with ethyl acetate, wash twice with water, wash once with saturated brine, collect the organic phase, dry with anhydrous sodium sulfate, concentrate, and obtain the title compound by column chromatography (25% EA in PE). ESI-MS m / z: [MH] - .

[0287] Step 4: Preparation of 6-cyclopropyl-7-fluoro-3-hydroxy-3-(4-(trifluoromethoxy)phenyl)indol-2-one

[0288]

[0289] Dissolve p-bromotrifluoromethoxybenzene (0.02g, 0.083mmol) in tetrahydrofuran (10mL) in a 50mL two-necked bottle, cool to -78℃ with liquid nitrogen, protect with argon, add n-butyl lithium (2.5M, 0.05mL) dropwise, keep the temperature for 1 hour, then dissolve 6-cyclopropyl-7-fluoroindoline-2,3-dione (0.g, 0.0.71mmol) in tetrahydrofuran (1mL) dropwise to the reaction solution, keep the temperature for 1 hour, monitor the reaction after LCMS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, concentrate, and obtain the target product by column chromatography. ESI-MS m / z: 302.3[MH] - .

[0290] Step 5: Preparation of 6-cyclopropyl-7-fluoro-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)indol-2-one

[0291]

[0292] Weigh 6-cyclopropyl-7-fluoro-3-hydroxy-3-(4-(trifluoromethoxy)phenyl)indol-2-one (0.16g, 0.53mmol) and phenol (0.15g, 1.59mmol) in a 50mL single-mouth bottle, add 9 drops of boron trifluoride ether under ice bath, protect with argon, stir and react at room temperature for 1 hour, monitor the reaction by LCMS, dilute the reaction solution with water, extract twice with ethyl acetate, collect the organic phase, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, concentrate, obtain the crude product by column chromatography, and purify by HPLC to obtain 50mg. ESI-MS m / z: 379.9[M+H] + .

[0293] 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),9.51(s,1H),7.33(d,J=8.2Hz,2H),7.25(d,J=8.6Hz,2H),7.17(t,J=7.1Hz,1H),7.04(d,J=7 .8Hz,1H),6.96(d,J=8.4Hz,2H),6.72(d,J=8.4Hz,2H),6.51(d,J=16.2Hz,1H),6.38(dd,J=15.7,6.6Hz,1H),1.89(d,J=6.0Hz,3H).

[0294] Example 21: 3-(2,3-dihydro-1H-indene-5-yl)-6,7-difluoro-3-(4-hydroxyphenyl)indol-2-one

[0295]

[0296] The preparation method is the same as that of Example 6, except that the raw material 5-fluoro-7,8-dihydrofurano[2,3-g]indole-2,3-dione is replaced with 6,7-difluoro-2,3-dihydro-1H-indole-2,3-dione to obtain the title compound. ESI-MS m / z: 378.0 [M+H] + .

[0297] 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),9.48(s,1H),7.15(d,J=7.7Hz,1H),7.06-6.99(m,2H),6.96( d,J=6.9Hz,3H),6.87(d,J=7.6Hz,1H),6.70(d,J=8.3Hz,2H),2.82-2.67(m,4H),2.03-1.92(m,2H).

[0298] Using different raw materials and referring to the above synthesis method, the example compounds in the following Table 1 were prepared.

[0299] Table 1

[0300]

[0301]

[0302]

[0303] Example 36: 3-(2,3-dihydrobenzofuran-5-yl)-3-(4-hydroxyphenyl)-7-trifluoromethylindolin-2-one

[0304]

[0305] Step 1: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-3-hydroxy-7-trifluoromethylindolin-2-one

[0306]

[0307] 6-Bromo-2,3-dihydrobenzofuran (368.22 mg, 1.86 mmol) was dissolved in tetrahydrofuran (10 mL) in a 50 mL two-necked flask, cooled to -78 °C with liquid nitrogen, protected by argon, and n-butyl lithium (2.5 M, 1.12 mL) was added dropwise, and the temperature was maintained for 1 hour. Then, 7-(trifluoromethyl)indoline-2,3-dione (0.2 g, 0.93 mmol) was dissolved in tetrahydrofuran (1 mL) and added dropwise to the reaction solution, and the temperature was maintained for 1 hour. After the reaction was completed by monitoring by LCMs, the reaction solution was diluted with water, extracted twice with ethyl acetate, and the organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the target crude product.

[0308] Step 2: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-3-(4-hydroxyphenyl)-7-trifluoromethylindolin-2-one

[0309]

[0310] The crude product of 3-(2,3-dihydrobenzofuran-5-yl)-3-hydroxy-7-trifluoromethylindolin-2-one and phenol (209.90 mg, 2.232 mmol) were placed in a 50 mL single-mouth bottle, and boron trifluoride etherate (0.415 mL) was added dropwise under ice bath. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was collected, washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was obtained by column chromatography. HPLC purification gave 30 mg of the title compound. ESI-MS m / z: 411.9 [M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.49(s,1H),7.51(dd,J=13.9,7.7Hz,2H),7.19(t,J=7.7Hz,1H),6.96 (d, J=9.1Hz, 3H), 6.84 (d, J=8.1Hz, 1H), 6.71 (t, J=7.5Hz, 3H), 4.49 (t, J=8.5Hz, 2H), 3.11 (t, J=8.5Hz, 2H).

[0312] Experimental Example 1: Evaluation of in vitro cell activity of compounds

[0313] 1. Experimental Materials

[0314] Test compounds: the compounds of the present invention prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO, and finally diluted to 10 concentrations for detection. The final concentrations of the compounds in the T-47D cell experiment were 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, and 0.051 nM.

[0315] ERα+ human breast ductal carcinoma T-47D cells were purchased commercially.

[0316] 2. Experimental Methods

[0317] 2.1 Cell culture and passaging

[0318] (1) All cells were cultured according to the method recommended by ATCC, and the experiments were performed in the exponential growth phase.

[0319] (2) Cell culture medium: RPMI 1640 medium, 10% FBS, 1% penicillin-streptomycin.

[0320] (3) Cell culture conditions: 37°C, 5% CO2, 95% air.

[0321] (4) Depending on the growth of the cells, the culture medium should be changed every 2-3 days or the cells should be subcultured.

[0322] 2.2 Cell plating

[0323] Remove cells from the cell culture flask and resuspend in fresh culture medium. Inoculate 100 μL of the cell resuspension into a 96-well culture plate.

[0324] 2.3 Administration

[0325] On the basis of the original culture medium (100 μL), the drug administration group was added with 100 nL of drugs of different concentrations, and the DMSO group was added with 100 nL DMSO. Two replicate wells were set for each concentration group, and the cells were placed in a 5% CO2 incubator for 1 day. The compound was prepared as follows: 1-2 mg of the compound was weighed in advance and prepared into a 10 mM stock solution using DMSO. The drug was diluted with DMSO, with the drug concentration starting at 10 mM as the highest concentration, and then diluted to 10 concentration gradients in a 1:4 gradient. The final drug administration concentration was: 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.051 nM.

[0326] 2.4 Detection

[0327] One day after drug treatment, the Celltiter Glo assay kit was taken out 30 minutes in advance and equilibrated to room temperature. Then 100 μL of Celltiter-Glo reagent was added to the PC wells, dosing wells, and DMSO wells and shaken for 2 minutes. After incubation at room temperature in the dark for 28 minutes, the luminescent signal was detected. According to the LUM value, the inhibition rate of each well relative to the solvent control well was calculated: Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L) × 100, Note: H = Ave (DMSO), L = Ave (Medium). According to different drug concentrations and their corresponding inhibition rates, GraphPad 5.0 software was used for IC 50 Draw curves, analyze data, and obtain final IC 50 The experimental results are shown in Table 2.

[0328] 3. Experimental results

[0329] Table 2

[0330]

[0331] It can be seen from the above experiments that the compounds of the present invention have a good killing effect on ERα+ breast cancer cells.

[0332] Experimental Example 2: Evaluation of in vitro cell activity of compounds

[0333] 1. Experimental Materials

[0334] Test compounds: The compounds of the present invention prepared in the above examples, each compound was prepared into a 10 mM stock solution with DMSO, and finally diluted to 10 concentrations for detection. The final concentrations of the compounds in each cell experiment were 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, and 0.051 nM.

[0335] MCF-7, MCF-7Y537S, and MCF-7D538G cells were purchased commercially.

[0336] 2. Experimental Methods

[0337] 2.1 Cell culture and passaging

[0338] (1) All cells were cultured according to the method recommended by ATCC, and the experiments were performed in the exponential growth phase.

[0339] (2) Cell culture medium:

[0340] MCF-7 cells: MEM (containing NEAA) medium, 10% FBS, 1% penicillin-streptomycin.

[0341] MCF-7Y537S cells: MEM (containing NEAA) medium, 10% FBS, 1% penicillin-streptomycin.

[0342] MCF-7D538G cells: MEM (containing NEAA) medium, 10% FBS, 1% penicillin-streptomycin.

[0343] (3) MCF-7, MCF-7Y537S, and MCF-7D538G cell culture conditions: 37°C, 5% CO2, and 95% air.

[0344] (4) Depending on the growth of the cells, the culture medium should be changed every 2-3 days or the cells should be subcultured.

[0345] 2.2 Cell plating

[0346] MCF-7, MCF-7Y537S, MCF-7D538G cells: Remove cells from the cell culture flask and resuspend in fresh culture medium. Inoculate 100 μL of the cell resuspension into a 96-well culture plate.

[0347] 2.3 Administration

[0348] MCF-7, MCF-7Y537S, MCF-7D538G cells: On the basis of the original culture medium (100 μL), 100 nL of drugs of different concentrations were added to the drug administration group, and 100 nL DMSO was added to the DMSO group. Two replicate wells were set for each concentration group, and the cells were placed in a 5% CO2 incubator for 1 day. The compound was prepared as follows: 1-2 mg of the compound was weighed in advance and prepared into a 10 mM stock solution using DMSO. The drug was diluted with DMSO, with the drug concentration starting at 10 mM as the highest concentration, and then diluted to 10 concentration gradients in a 1:4 gradient. The final drug administration concentration was: 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.051 nM.

[0349] 2.4 Detection

[0350] MCF-7, MCF-7Y537S, MCF-7D538G cells: After 3 days of drug treatment, take out the CelltiterGlo assay kit 30 minutes in advance and equilibrate to room temperature. Then add 100 μL of Celltiter-Glo reagent to the PC wells, drug-dosing wells, and DMSO wells and shake for 2 minutes. After incubation at room temperature in the dark for 28 minutes, detect the luminescent signal. According to the LUM value, calculate the inhibition rate of each well relative to the solvent control well: Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L) × 100, Note: H = Ave (DMSO), L = Ave (Medium). According to different drug concentrations and their corresponding inhibition rates, use GraghPad 5.0 software for IC 50 Draw curves, analyze data, and obtain final IC 50 The experimental results are shown in Table 3.

[0351] 3. Experimental results

[0352] Table 3

[0353]

[0354] Note: - indicates not detected

[0355] MCF-7 is an ERα+ positive and PR positive breast cancer cell line. The Y537S and D538G mutations in MCF-7Y537S and MCF-7D538G lead to constitutive activation of ERα, driving tumor growth independent of estrogen and resulting in drug resistance.

[0356] It can be seen from the above experiments that the compounds of the present invention have good killing effect and selectivity on ERα+ breast cancer cells and ERα+ mutation-resistant breast cancer cells.

[0357] Although the present invention has been described in detail above, it is understood by those skilled in the art that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, in, R 1 is selected from 5-14 membered heterocyclic group, C 2-10 Alkenyl, C 2-10 Alkynyl, aryl and heteroaryl, which are optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 group substitution with heterocyclic group, dimethylphosphoryl group and oxo group; and R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 heterocyclic group; or R 2 and R 3 or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 5-8 membered heterocyclic group, a 5-8 membered aryl group or a 5-8 membered heteroaryl group, which is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano and amino groups are substituted.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 is selected from 5-14 membered heterocyclic groups, C 2-8 Alkenyl, C 2-8 Alkynyl, 6-14 membered aryl, 6-14 membered heteroaryl, which is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 heterocyclic group, dimethylphosphoryl group and oxo group; and R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl and C 3-8 Heterocyclic group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ia), in, R 1 is selected from 5-14 membered heterocyclic groups, C 2-8 Alkenyl, C 2-8 Alkynyl, 6-14 membered aryl, 6-14 membered heteroaryl, which is optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, C 3-8 Cycloalkyl, C 3-8 Group substitutions include heterocyclic groups, dimethylphosphoryl groups and oxo groups.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 Selected from It is optionally substituted by one or more selected from halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxyl C 1-3 Alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 Alkylamino, C 1-3 Alkyl acylamino, C 1-3 Alkyl acyl, di-C 1-3 Alkylamino, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-14 Aryl, C 5-14 Group substitution of heteroaryl and oxo groups.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 Selected from 6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the general formula (I) has the structure of the following general formula (Ib), in, X 1 , X 2 are each independently selected from CH2, NH and O; and R a , R b Each is independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino.

7. The compound according to claim 6 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R a , R b are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, C 1-6 Alkyl acylamino, C 1-6 Alkyl acyl, amino acyl, C 1-6 Alkylaminoacyl and di-C 1-6 Alkylamino.

8. A compound or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound is selected from the following compounds:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating tumors.

Images