Halogenated indolinone compound and preparation method therefor and use thereof, halogenated indolinone derivative and use thereof, and pharmaceutical composition and use thereof

Abstract

The present application provides a halogenated indolinone compound and a preparation method therefor and a use thereof, a halogenated indolinone derivative and a use thereof, and a pharmaceutical composition and a use thereof, relating to the technical field of biomedicine. The halogenated indolinone compound provided in the present application, through kinase profiling analysis, shows that in addition to having inhibitory activities against VEGFR, FGFR, and PDGFR kinases, it also has very strong inhibitory activity against AXL kinase, with an IC50 value reaching a low nanomolar level, which is 45 times that of nintedanib in inhibiting AXL kinase activity. The halogenated indolinone compound provided in the present application exhibits better antitumor activity than nintedanib at both the cellular level and in vivo in animals, has a better effect than nintedanib in inhibiting tumor invasion and metastasis, and can effectively treat malignant tumors and the invasion and metastasis thereof.

Description

Halogenated indole ketones and their preparation methods and applications, halogenated indole ketone derivatives and their applications, pharmaceutical compositions and their applications

[0001] This application claims priority to Chinese Patent Application No. CN2024115884390, filed on November 8, 2024, entitled "Halogenated Indoleketone Compounds and Preparation Methods and Applications Thereof, Halogenated Indoleketone Derivatives and Applications Thereof, Pharmaceutical Compositions and Applications Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of biomedical technology, specifically to halogenated indole ketone compounds and their preparation methods and applications, halogenated indole ketone derivatives and their applications, and pharmaceutical compositions and their applications. Background Technology

[0003] Indoleone derivatives possess a wide range of biological activities. Nintedanib (NDN), approved by the US FDA in 2014 as a treatment for idiopathic pulmonary fibrosis (IPF), is a derivative with an ester group (methoxyacyl group) substituted at the 6th carbon of an indoleone. IPF is a chronic, progressive fibrotic lung disease of unknown etiology, with a complex and still unclear pathogenesis. Nintedanib is a triple-receptor tyrosine kinase inhibitor that acts on vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR). In addition to FDA approval for clinical use in the treatment of idiopathic pulmonary fibrosis, the European Medicines Agency has also approved nintedanib in combination with docetaxel for the treatment of advanced locally recurrent non-small cell lung cancer after first-line chemotherapy. Literature reports that nintedanib has very low bioavailability in vivo, only 5-10%. Therefore, there is still room for structural optimization of nintedanib.

[0004] Tumor metastasis is the leading cause of death in most cancer patients. Tumor metastasis is a multi-step process, mainly including three stages: 1) Invasion: In situ tumor cells increase their invasiveness through epithelial-mesenchymal transition (EMT), invading surrounding tissues and migrating to areas near blood vessels or lymphatic vessels. They then exit the bloodstream and enter the circulatory system, becoming circulating tumor cells (CTCs); 2) Circulation: Platelets directly adhere to the surface of CTCs, forming "microthrombi" structures that reduce the recognition and clearance by the immune system; 3) Colonization: CTCs colonize in "pre-metastatic niches" in distant organs, which are inflammatory environments with immunosuppressive characteristics formed under the influence of cytokines or exosomes secreted by the in situ tumor tissue, conducive to tumor cell colonization. Inhibiting tumor metastasis is one of the important strategies in cancer treatment.

[0005] AXL kinase belongs to the TAM family of receptor tyrosine kinases and is highly expressed in various cancers, including non-small cell lung cancer and breast cancer. Aberrant expression of AXL can activate and antagonize tumor cell apoptosis, promote tumor cell invasion and metastasis, and promote tumor angiogenesis, thereby driving tumor development and progression. Furthermore, high AXL expression is also associated with drug resistance to antitumor drugs. AXL has also become a popular target in antitumor drug development in recent years.

[0006] The pathogenesis of malignant tumors is highly complex, often involving multiple mechanisms, pathological processes, and genes, resulting from the combined effects of various factors. Multi-target drugs can simultaneously act on multiple pathological processes and mechanisms of the same disease, potentially leading to better therapeutic outcomes. However, existing nintedanib drugs have low AXL kinase activity, resulting in insufficient anti-tumor efficacy. Summary of the Invention

[0007] In view of this, the purpose of this application is to provide halogenated indole ketone compounds, their preparation methods and applications, halogenated indole ketone derivatives and their applications, and pharmaceutical compositions and their applications. The halogenated indole ketone compounds and their derivatives provided in this application, in addition to possessing VEGFR, FGFR, and PDGFR kinase inhibitory activities, also exhibit strong AXL kinase inhibitory activity, thus demonstrating high antitumor activity as multi-target drugs.

[0008] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0009] This application provides haloindolone compounds, including racemic compounds having the structure shown in Formula I or chiral compounds having the structure shown in Formula II:

[0010] Wherein, R1 is a halogen;

[0011] R2 includes hydrogen or C1-C4 alkyl groups;

[0012] R4 includes C1-C4 alkyl groups;

[0013] R3 includes C1-C4 alkyl, cycloalkyl, hydrocarbon group containing unsaturated bonds, heterocyclic group or alkylamine group;

[0014] In Equation II, the wavy line represents the R configuration or the S configuration.

[0015] Preferably, the cycloalkyl group comprises cyclopropyl or cyclobutyl;

[0016] The hydrocarbon group containing unsaturated bonds includes an alkenyl group;

[0017] The heterocyclic group includes any of the following structures:

[0018] The alkylamine group includes N,N,N-trimethylethylenediamine, 2-(N,N-dimethylamino)ethoxy, or 2-(N,N-dimethylamino)ethylthio.

[0019] Preferably, it has any one of the following structures:

[0020] This application also provides a method for preparing the haloindolone compounds described in the above technical solution, comprising the following steps:

[0021] Intermediate 3 and intermediate 4 were subjected to a substitution reaction to obtain the haloindolone compound;

[0022] The intermediate 3 includes a racemic intermediate 3 or a chiral intermediate 3;

[0023] Preferably, the preparation method of the racemic intermediate 3 includes the following steps:

[0024] The acyl chloride was substituted with N-methyl-4-nitroaniline to give intermediate 1;

[0025] The intermediate 1 was subjected to a nucleophilic substitution reaction with HR3 to obtain racemic intermediate 2;

[0026] The racemic intermediate 2 was subjected to a hydrogenation reduction reaction to obtain the racemic intermediate 3;

[0027] Where X is a halogen.

[0028] Preferably, the method for preparing the chiral intermediate 3 includes the following steps:

[0029] The p-toluenesulfonyl chloride was substituted with a 2-hydroxycarboxylic acid ester to give compound 1;

[0030] The compound 1 was subjected to a hydrolysis reaction to obtain compound 2;

[0031] Compound 2 was subjected to a substitution reaction with thionyl chloride to obtain compound 3;

[0032] Compound 3 was subjected to a substitution reaction with N-methyl-4-nitroaniline to obtain compound 4;

[0033] Compound 4 was subjected to a nucleophilic substitution-transconfiguration reaction with HR3 to obtain chiral intermediate 2;

[0034] The chiral intermediate 2 was subjected to a hydrogenation reduction reaction to obtain the chiral intermediate 3;

[0035] The configuration of chiral intermediate 2 is different from that of 2-hydroxycarboxylic acid ester, compound 1, compound 2, compound 3 and compound 4.

[0036] Preferably, the preparation method of the intermediate 4 includes the following steps:

[0037] N-acetylindolone and triethyl orthobenzoate were condensed to give intermediate 4;

[0038] This application also provides halogenated indole ketone derivatives, including pharmaceutically acceptable salts and / or solvates of the halogenated indole ketone compounds described in the above-described technical solutions.

[0039] This application also provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients; the active ingredient comprising one or more of the halogenated indolone compounds and halogenated indolone derivatives described in the above-described technical solutions.

[0040] This application also provides the use of the haloindolone compounds or haloindolone derivatives described in the above technical solutions in the preparation of drugs for treating kinase-mediated diseases;

[0041] The kinases include one or more of the following: tyrosine protein kinase receptor, serine / threonine protein kinase, tyrosine protein kinase, vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor-α, fibroblast growth factor receptor 1, neurotrophic factor receptor 2, non-receptor tyrosine kinase, tyrosine protein kinase, 5'-AMP-activated protein kinase subunit α1 / β1 / γ1, glycogen synthase kinase-3β, ribosomal protein S6 kinase α-1, tyrosine protein kinase, bispecific mitogen-activated protein kinase kinase 1, aurora kinase B, bispecific protein kinase, epidermal growth factor type A receptor 2, insulin-like growth factor 1 receptor, epidermal growth factor type B receptor 4, mitogen-activated protein kinase kinase 1, serine / threonine protein kinase, nonspecific serine / threonine protein kinase, nonspecific serine / threonine protein kinase, and glucokinase.

[0042] The halogenated indole ketone compounds provided in this application, through kinase spectrum analysis, show that they have multi-target activity. In addition to the VEGFR, FGFR, and PDGFR kinase inhibitory activities possessed by nintedanib, they also exhibit strong AXL kinase inhibitory activity. 50 The value reached a low nanomolar level, which is 45 times more effective than nintedanib in inhibiting AXL kinase activity. The halogenated indole ketone compounds provided in this application exhibit better antitumor activity than nintedanib at both the cellular and in vivo levels, and show better inhibition of tumor invasion and metastasis. Furthermore, the halogenated indole ketone compounds provided in this application show inhibitory activities exceeding 90% against serine / threonine protein kinase (QIK), tyrosine protein kinase (LCK), platelet-derived growth factor receptor-α (PDGFRα), fibroblast growth factor receptor 1 (FGFR1), neurotrophic factor receptor 2 (TRKB), non-receptor tyrosine kinase (SRC), and tyrosine protein kinase (ABL1), demonstrating high kinase inhibitory activity and the ability to effectively treat malignant tumors and their invasion and metastasis.

[0043] The method for preparing halogenated indole ketones provided in this application is simple in process, easy to operate, and has low production cost, making it suitable for industrial production. Attached Figure Description

[0044] Figure 1 shows the inhibitory activity of target compound 1 (X529) prepared in Example 1 against 80 kinases;

[0045] Figure 2 shows the changes in tumor volume in mice under the action of the blank group, the nintedanib group, and the target compound (11b) group prepared in Example 1 during the process of anti-pancreatic cancer activity.

[0046] Figure 3 shows the changes in tumor weight in mice under the action of the blank group, nintedanib group, and the target compound (11b) group prepared in Example 1 during the process of anti-pancreatic cancer activity.

[0047] Figure 4 shows the H&E staining (a) and Western Blot analysis (b) of mouse tumor tissues containing the control group, nintedanib group, and target compound 1 (11b) prepared in Example 1. In Figure a, 1, 2, 3, and 4 represent sites randomly selected from the full-view lung sections of mice in each group, and their magnified microscopic images are provided. Detailed Implementation

[0048] This application provides haloindolone compounds, including racemic compounds having the structure shown in Formula I or chiral compounds having the structure shown in Formula II:

[0049] Wherein, R1 is a halogen; R2 includes hydrogen or C1-C4 alkyl; R4 includes C1-C4 alkyl; R3 includes C1-C4 alkyl, cycloalkyl, hydrocarbon group containing unsaturated bond, heterocyclic group or alkylamine group; the wavy line in Formula II represents the R configuration or S configuration.

[0050] In this application, the halogen preferably includes fluorine, chlorine, or bromine.

[0051] In this application, the C1 to C4 alkyl groups in R2, R3 and R4 preferably include methyl, ethyl, propyl or butyl.

[0052] In this application, the cycloalkyl group includes cyclopropyl or cyclobutyl.

[0053] In this application, the hydrocarbon group containing unsaturated bonds preferably includes an alkenyl group, which in specific embodiments may be a vinyl or propenyl group.

[0054] In this application, the heterocyclic group preferably comprises any of the following structures:

[0055] In this application, the alkylamine group preferably includes N,N,N-trimethylethylenediamine, 2-ethoxy-N,N-dimethylamine (i.e., 2-(N,N-dimethylamine)ethoxy) or 2-ethylthio-N,N-dimethylamine (i.e., 2-(N,N-dimethylamine)ethylthio).

[0056] In this application, the haloindolone compound preferably has any one of the following structures:

[0057] This application also provides a method for preparing the haloindolone compound described in the above technical solution, comprising the following steps: subjecting intermediate 3 and intermediate 4 to a substitution reaction to obtain the haloindolone compound; wherein intermediate 3 includes racemic intermediate 3 or chiral intermediate 3;

[0058] Wherein, the definitions of R2 and R3 in the racemic intermediate 3 are the same as the definitions of R2 and R3 in Formula I; the definitions of R3 and R4 in the chiral intermediate 3 are the same as the definitions of R3 and R4 in Formula II; and the definition of R1 in the intermediate 4 is the same as the definition of R1 in Formula I or Formula II.

[0059] Unless otherwise specified, all materials and equipment used in this application are commercially available products in this field.

[0060] In this application, the substitution reaction preferably includes: mixing intermediate 3, intermediate 4, and an organic solvent (denoted as the first organic solvent), carrying out a first substitution reaction under a protective atmosphere, and then adding an organic base (denoted as the first organic base) to carry out a second substitution reaction. In this application, the molar ratio of intermediate 3 to intermediate 4 is preferably 1:1 to 1.2, and in specific embodiments it can be 1:1, 1:1.05, 1:1.1, 1:1.15, or 1:1.2. In this application, the first organic solvent preferably includes one or more of dimethylformamide, acetonitrile, and dimethyl sulfoxide. This application does not have a special limitation on the amount of the first organic solvent, as long as it is sufficient to ensure the smooth progress of the first substitution reaction. In this application, the first organic base preferably includes piperidine and / or dimethylamine. In this application, the molar ratio of intermediate 3 to the first organic base is preferably 1:1.5 to 3, and in specific embodiments it can be 1:1.5, 1:2, 1:2.5, or 1:3. In this application, the protective atmosphere preferably includes nitrogen, argon, or helium.

[0061] In this application, the temperature of the substitution reaction is preferably 70-90°C, and in specific embodiments it can be 70°C, 75°C, 80°C, 85°C or 90°C; the time of the first substitution reaction is preferably 1-2 hours, and in specific embodiments it can be 1 hour, 1.5 hours or 2 hours; the time of the second substitution reaction is preferably 2-3 hours, and in specific embodiments it can be 2 hours, 2.5 hours or 3 hours.

[0062] In this application, when racemic intermediate 3 is used as a starting material, a haloindolone compound having the structure shown in Formula I is obtained, and when chiral intermediate 3 is used as a starting material, a haloindolone compound having the structure shown in Formula II is obtained.

[0063] After the substitution reaction is completed, this application preferably further includes: adding water to the reaction system obtained by the substitution reaction to precipitate a solid, filtering, grinding the obtained solid with methanol, filtering, washing the obtained filter cake with methanol and ethyl acetate, and drying to constant weight to obtain the haloindolone compound.

[0064] In this application, the method for preparing the racemic intermediate 3 preferably includes the following steps:

[0065] The acyl chloride was substituted with N-methyl-4-nitroaniline to give intermediate 1;

[0066] The intermediate 1 was subjected to a nucleophilic substitution reaction with HR3 to obtain racemic intermediate 2;

[0067] The racemic intermediate 2 was subjected to a hydrogenation reduction reaction to obtain the racemic intermediate 3;

[0068] Wherein, X is a halogen, which preferably includes fluorine, chlorine, bromine or iodine, and the definitions of R2 and R3 are the same as those in Formula I.

[0069] In this application, the preparation route of the racemic intermediate 3 is as follows:

[0070] In this application, the preferred method for preparing the acyl chloride includes the following steps: subjecting a halocarboxylic acid and thionyl chloride to a substitution reaction (referred to as a third substitution reaction) to obtain the acyl chloride;

[0071] The definition of R2 in the halocarboxylic acid is the same as the definition of R2 in Formula I.

[0072] In this application, the molar ratio of the halocarboxylic acid to thionyl chloride is preferably 1:1 to 5, and in specific embodiments it can be 1:1, 1:2, 1:3, 1:4 or 1:5. In this application, the halogen in the halocarboxylic acid preferably includes fluorine, chlorine, bromine or iodine.

[0073] In this application, the third substitution reaction is preferably carried out in the absence of a solvent or in the presence of an organic solvent (denoted as the second organic solvent). In this application, the second organic solvent preferably includes chloroform and / or acetonitrile. This application does not have a particular limitation on the amount of the second organic solvent used, as long as it is sufficient to ensure the smooth progress of the third substitution reaction.

[0074] In this application, the temperature of the third substitution reaction is preferably 65-85°C, and in specific embodiments it can be 65°C, 70°C, 75°C, 80°C or 85°C; the time of the third substitution reaction is preferably 2-8h, and in specific embodiments it can be 2h, 3h, 4h, 5h, 6h, 7h or 8h.

[0075] After completing the third substitution reaction, this application preferably further includes: removing unreacted raw materials (e.g., thionyl chloride) from the reaction system obtained by the third substitution reaction under reduced pressure to obtain acyl chloride, which is then directly carried out in the next reaction without purification.

[0076] After obtaining the acyl chloride, this application subjectes the acyl chloride to a substitution reaction (referred to as the fourth substitution reaction) with N-methyl-4-nitroaniline to obtain intermediate 1.

[0077] In this application, the molar ratio of the acyl chloride to N-methyl-4-nitroaniline is preferably 1 to 1.2:1, and in specific embodiments it can be 1:1, 1.05:1, 1.1:1, 1.15:1 or 1.2:1.

[0078] In this application, the fourth substitution reaction is preferably carried out in the presence of a catalyst (denoted as the first catalyst), an acid remover (denoted as the first acid remover), and an organic solvent (denoted as the third organic solvent). In this application, the first catalyst preferably comprises N,N-dimethylaminopyridine (DMAP) and / or pyridine. In this application, the molar ratio of N-methyl-4-nitroaniline to the first catalyst is preferably 1:0.05 to 0.2, and in specific embodiments may be 1:0.05, 1:0.1, 1:0.13, 1:0.15, or 1:2. In this application, the first acid remover preferably comprises an organic amine, and in specific embodiments may include triethylamine and / or N-ethyl-N,N-diisopropylamine. In this application, the molar ratio of N-methyl-4-nitroaniline to the first deacidifying agent is preferably 1:1 to 1.5, and in specific embodiments it can be 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, or 1:1.5. In this application, the third organic solvent preferably includes one or more of anhydrous acetonitrile, tetrahydrofuran, and dichloromethane. This application does not have a specific limitation on the amount of the third organic solvent used, as long as it is sufficient to ensure the smooth progress of the fourth substitution reaction.

[0079] In this application, the temperature of the fourth substitution reaction is preferably 15-45°C, and in specific embodiments it can be 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C; the time of the fourth substitution reaction is preferably 2-3 hours, and in specific embodiments it can be 2 hours, 2.5 hours or 3 hours.

[0080] After completing the fourth substitution reaction, this application preferably further includes: removing the solvent under reduced pressure, adding water to separate the layers, obtaining an organic phase and an aqueous phase respectively; extracting the aqueous phase with dichloromethane to obtain a dichloromethane phase; combining the organic phase and the dichloromethane phase, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain intermediate 1. In this application, the eluent used for the silica gel column chromatography purification preferably includes petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 4:1 to 1:1, which can be 4:1, 3:1, 2:1 or 1:1 in specific embodiments.

[0081] After obtaining intermediate 1, this application performs a nucleophilic substitution reaction between intermediate 1 and HR3 to obtain racemic intermediate 2.

[0082] In this application, the molar ratio of intermediate 1 to HR3 is preferably 1:1 to 3, and in specific embodiments it can be 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In this application, HR3 preferably comprises any of the following structures:

[0083] In this application, the nucleophilic substitution reaction is preferably carried out in the presence of an acid-scavenging agent (denoted as the second acid-scavenging agent) and an organic solvent (denoted as the fourth organic solvent). In this application, the second acid-scavenging agent preferably comprises an organic amine, more preferably triethylamine and / or N-ethyl-N,N-diisopropylamine. In this application, the molar ratio of intermediate 1 to the second acid-scavenging agent is preferably 1:1 to 3, and in specific embodiments it can be 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In this application, the fourth organic solvent preferably comprises acetonitrile and / or dioxane. This application does not have a specific limitation on the amount of the fourth organic solvent, as long as it is sufficient to ensure the smooth progress of the nucleophilic substitution reaction.

[0084] In this application, the temperature of the nucleophilic substitution reaction is preferably 80-100°C, and in specific embodiments it can be 80°C, 85°C, 90°C, 95°C or 100°C; the time of the nucleophilic substitution reaction is preferably 10-20h, and in specific embodiments it can be 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h or 20h.

[0085] After completing the nucleophilic substitution reaction, this application preferably further includes: removing the solvent from the reaction system obtained by the nucleophilic substitution reaction under reduced pressure, and purifying it by silica gel column chromatography to obtain racemic intermediate 2. In this application, the eluent used for the silica gel column chromatography purification preferably includes ethyl acetate and a dichloromethane-methanol mixed solvent in sequence. The volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 4 to 10:1, and in specific embodiments it can be 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1.

[0086] After obtaining racemic intermediate 2, this application subjectes racemic intermediate 2 to a hydrogenation reduction reaction (referred to as the first hydrogenation reduction reaction) to obtain racemic intermediate 3.

[0087] In this application, the first hydrogenation reduction reaction preferably includes: mixing racemic intermediate 2, a first hydrogenation catalyst, and an organic solvent (denoted as the fifth organic solvent), and carrying out the first hydrogenation reduction reaction under a hydrogen atmosphere. In this application, the first hydrogenation catalyst preferably comprises palladium on carbon. In this application, the mass of the first hydrogenation catalyst is preferably 5-20% of the mass of racemic intermediate 2, and in specific embodiments, it can be 5%, 10%, 15%, or 20%. In this application, the fifth organic solvent preferably comprises anhydrous ethanol and / or methanol; this application does not have a special limitation on the amount of the fifth organic solvent, as long as it is sufficient to ensure the smooth progress of the first hydrogenation reduction reaction.

[0088] In this application, the temperature of the first hydrogenation reduction reaction is preferably room temperature; the time of the first hydrogenation reduction reaction is preferably 12-48 hours, and in specific embodiments it can be 12 hours, 15 hours, 20 hours, 24 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours or 48 hours; the pressure of the hydrogen gas is preferably 0.1-0.505 MPa, and in specific embodiments it can be 0.101 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa or 0.505 MPa; as the hydrogen gas pressure increases, the time of the first hydrogenation reduction reaction is shortened.

[0089] After completing the first hydrogenation reduction reaction, this application preferably further includes: filtering the reaction system obtained from the first hydrogenation reduction reaction, removing the solvent from the filtrate under reduced pressure, and obtaining racemic intermediate 3.

[0090] In this application, the method for preparing the chiral intermediate 3 preferably includes the following steps:

[0091] The p-toluenesulfonyl chloride was substituted with a 2-hydroxycarboxylic acid ester to give compound 1;

[0092] The compound 1 was subjected to a hydrolysis reaction to obtain compound 2;

[0093] Compound 2 was subjected to a substitution reaction with thionyl chloride to obtain compound 3;

[0094] Compound 3 was subjected to a substitution reaction with N-methyl-4-nitroaniline to obtain compound 4;

[0095] Compound 4 was subjected to a nucleophilic substitution-transconfiguration reaction with HR3 to obtain chiral intermediate 2;

[0096] The chiral intermediate 2 was subjected to a hydrogenation reduction reaction to obtain the chiral intermediate 3;

[0097] The configuration of the chiral intermediate is different from that of the 2-hydroxycarboxylic acid ester, compound 1, compound 2, compound 3 and compound 4; the definitions of R3 and R4 are the same as those in Formula II.

[0098] In this application, the preparation route of the chiral intermediate 3 is as follows:

[0099] This application describes a substitution reaction (referred to as the fifth substitution reaction) of toluenesulfonyl chloride with a 2-hydroxycarboxylic acid ester to give compound 1.

[0100] In this application, the molar ratio of the 2-hydroxycarboxylic acid ester to p-toluenesulfonyl chloride is preferably 1:1 to 1.3, and in specific embodiments it can be 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25 or 1:1.3. In this application, the p-toluenesulfonyl chloride is preferably added dropwise under ice bath conditions.

[0101] In this application, the fifth substitution reaction is preferably carried out in the presence of an organic solvent (denoted as the sixth organic solvent) and an organic base (denoted as the second organic base).

[0102] In this application, the sixth organic solvent preferably includes dichloromethane and / or chloroform. This application does not have a specific limitation on the amount of the sixth organic solvent used, as long as it is sufficient to ensure the smooth progress of the fifth substitution reaction.

[0103] In this application, the second organic base preferably comprises an organic amine, more preferably triethylamine and / or N-ethyl-NN-diisopropylamine. In this application, the molar ratio of the 2-hydroxycarboxylic acid ester and the second organic base is preferably 1:1 to 2, and in specific embodiments it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.

[0104] In this application, the temperature of the fifth substitution reaction is preferably room temperature; the time of the fifth substitution reaction is preferably 10 to 30 hours, and in specific embodiments it can be 10 hours, 15 hours, 20 hours, 25 hours or 30 hours.

[0105] After completing the fifth substitution reaction, this application preferably further includes: adding water to the reaction system obtained from the fifth substitution reaction, separating the phases to obtain an organic phase and an aqueous phase, extracting the aqueous phase with dichloromethane to obtain a dichloromethane phase; combining the organic phase and the dichloromethane phase, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to constant weight to obtain compound 1, wherein compound 1 is directly carried out in the next reaction without purification.

[0106] After obtaining compound 1, this application performs a hydrolysis reaction on compound 1 to obtain compound 2.

[0107] In this application, the hydrolysis reaction is preferably carried out under alkaline conditions, and the alkaline condition preferably includes alkali metal hydroxides, more preferably NaOH and / or KOH; the alkaline is preferably used in the form of an alkaline aqueous solution, and the concentration of the alkaline aqueous solution is preferably 2-3 mol / L, which can be 2.1 mol / L, 2.2 mol / L, 2.3 mol / L, 2.4 mol / L, 2.5 mol / L, 2.6 mol / L, 2.7 mol / L, 2.8 mol / L, 2.9 mol / L or 3 mol / L in specific embodiments; the alkaline aqueous solution is preferably added dropwise under ice bath conditions.

[0108] In this application, the molar ratio of the 2-hydroxycarboxylic acid ester to the base is preferably 1:1.5 to 2, and in specific embodiments it can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0109] In this application, the hydrolysis reaction temperature is preferably room temperature; the hydrolysis reaction time is preferably 2 to 3 hours, and in specific embodiments it can be 2 hours, 2.5 hours or 3 hours.

[0110] After the hydrolysis reaction is completed, this application preferably further includes: under ice bath conditions, adding concentrated hydrochloric acid to the reaction system obtained from the hydrolysis reaction to adjust the pH value to 2-3, extracting three times with ethyl acetate, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain compound 2.

[0111] After obtaining compound 2, this application subjectes compound 2 to a substitution reaction (referred to as the sixth substitution reaction) with thionyl chloride to obtain compound 3.

[0112] In this application, the molar ratio of compound 2 to thionyl chloride is preferably 1:1 to 5, and in specific embodiments it can be 1:1, 1:2, 1:3, 1:4 or 1:5; the thionyl chloride is preferably added dropwise.

[0113] In this application, the sixth substitution reaction is preferably carried out in the presence of an organic solvent (denoted as the seventh organic solvent). In this application, the seventh organic solvent preferably includes dichloromethane and / or chloroform. This application does not have a specific limitation on the amount of the seventh organic solvent, as long as it is sufficient to ensure the smooth progress of the sixth substitution reaction.

[0114] In this application, the temperature of the sixth substitution reaction is preferably 65-85°C, and in specific embodiments it can be 65°C, 70°C, 75°C, 79°C, 80°C or 85°C; the time of the sixth substitution reaction is preferably 2-8h, and in specific embodiments it can be 2h, 3h, 4h, 5h, 6h, 7h or 8h.

[0115] After completing the sixth substitution reaction, this application preferably further includes: removing unreacted raw materials (e.g., thionyl chloride) from the reaction system obtained by the sixth substitution reaction under reduced pressure to obtain compound 3, wherein compound 3 is directly carried out in the next reaction without purification.

[0116] After obtaining compound 3, this application subjectes compound 3 to a substitution reaction (referred to as the seventh substitution reaction) with N-methyl-4-nitroaniline to obtain compound 4.

[0117] In this application, the molar ratio of compound 3 to N-methyl-4-nitroaniline is preferably 1 to 1.2:1, and in specific embodiments it can be 1:1, 1.05:1, 1.1:1, 1.15:1 or 1.2:1.

[0118] In this application, the seventh substitution reaction is preferably carried out in the presence of a catalyst (denoted as the second catalyst), an acid remover (denoted as the third acid remover), and an organic solvent (denoted as the eighth organic solvent). In this application, the second catalyst preferably comprises N,N-dimethylaminopyridine (DMAP) and / or pyridine; the molar ratio of N-methyl-4-nitroaniline to the second catalyst is preferably 1:0.05 to 0.2, and in specific embodiments may be 1:0.05, 1:0.1, 1:0.13, 1:0.15, or 1:2. In this application, the third acid-removing agent preferably comprises an organic amine, and in specific embodiments may include triethylamine and / or N-ethyl-N,N-diisopropylamine; the molar ratio of N-methyl-4-nitroaniline to the third acid-removing agent is preferably 1:1 to 2, and in specific embodiments may be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2. In this application, the eighth organic solvent preferably comprises one or more of anhydrous acetonitrile, tetrahydrofuran, and dichloromethane; this application does not have a special limitation on the amount of the eighth organic solvent, as long as it is sufficient to ensure the smooth progress of the seventh substitution reaction.

[0119] In this application, the temperature of the seventh substitution reaction is preferably 15-45°C, and in specific embodiments it can be 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C; the time of the seventh substitution reaction is preferably 2-3 hours, and in specific embodiments it can be 2 hours, 2.5 hours or 3 hours.

[0120] After completing the seventh substitution reaction, this application preferably further includes: removing the solvent from the reaction solution obtained from the seventh substitution reaction under reduced pressure, adding water to separate the layers, obtaining an organic phase and an aqueous phase respectively; extracting the aqueous phase with dichloromethane to obtain a dichloromethane phase; combining the organic phase and the dichloromethane phase, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain compound 4. In this application, the eluent used for the silica gel column chromatography purification preferably includes petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 4:1 to 1:1. In specific embodiments, the volume ratios of petroleum ether to ethyl acetate are 4:1 and 1:1, respectively.

[0121] After obtaining compound 4, this application carried out a nucleophilic substitution-transconfiguration reaction with HR3 to obtain chiral intermediate 2.

[0122] In this application, the molar ratio of compound 4 to HR3 is preferably 1:1 to 3, and in specific embodiments it can be 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0123] In this application, the HR3 preferably has any of the following structures:

[0124] In this application, the nucleophilic substitution-transconfiguration reaction is preferably carried out in the presence of an acid-scavenging agent (denoted as the fourth acid-scavenging agent) and an organic solvent (denoted as the ninth organic solvent). In this application, the fourth acid-scavenging agent preferably comprises an organic amine, more preferably triethylamine and / or N-ethyl-N,N-diisopropylamine; the molar ratio of compound 4 to the fourth acid-scavenging agent is preferably 1:1 to 3.5, and in specific embodiments can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, or 1:3.5. In this application, the ninth organic solvent preferably comprises acetonitrile and / or dioxane. This application does not have a specific limitation on the amount of the ninth organic solvent, as long as it is sufficient to ensure the smooth progress of the nucleophilic substitution-transconfiguration reaction.

[0125] In this application, the temperature of the nucleophilic substitution-transconfiguration reaction is preferably 80-100°C, and in specific embodiments it can be 80°C, 85°C, 90°C, 95°C or 100°C; the time of the nucleophilic substitution-transconfiguration reaction is preferably 10-24h, and in specific embodiments it can be 10h, 12h, 14h, 16h, 18h, 20h, 22h or 24h.

[0126] After completing the nucleophilic substitution-transconfiguration reaction, this application preferably further includes: removing the solvent from the reaction system obtained by the nucleophilic substitution-transconfiguration reaction under reduced pressure, and purifying it by silica gel column chromatography to obtain chiral intermediate 2. In this application, the eluent used for the silica gel column chromatography purification preferably includes ethyl acetate and a dichloromethane-methanol mixed solvent in sequence. The volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 4 to 10:1, and in specific embodiments it can be 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1.

[0127] After obtaining chiral intermediate 2, this application subjectes chiral intermediate 2 to a hydrogenation reduction reaction (referred to as the second hydrogenation reduction reaction) to obtain chiral intermediate 3. In this application, the conditions for the second hydrogenation reduction reaction are the same as those for the first hydrogenation reduction reaction, and will not be repeated here. In this application, the second hydrogenation reduction reaction can also be carried out in the absence of hydrogen gas. Specifically, chiral intermediate 2, stannous chloride, and a tenth organic solvent are mixed and a reduction reaction is carried out to obtain chiral intermediate 3. In this application, the molar ratio of chiral intermediate 2 to stannous chloride is preferably 1:6 to 10, and in specific embodiments, it can be 1:6, 1:7, 1:8, 1:9, or 1:10. In this application, the tenth organic solvent preferably includes methanol and / or ethanol; this application does not have a special limitation on the amount of the ninth organic solvent, as long as it ensures the smooth progress of the nucleophilic substitution-transconfiguration reaction. In this application, the temperature of the reduction reaction is preferably 25–60°C, and in specific embodiments, it can be 20°C, 25°C, 30°C, 40°C, 45°C, 50°C, 55°C, or 60°C; the time of the reduction reaction is preferably 6–10 h, and in specific embodiments, it can be 6 h, 7 h, 8 h, 9 h, or 10 h. After the reduction reaction is completed, the present invention preferably further includes: adjusting the pH value of the reaction system obtained by the reduction reaction to 7–8, filtering with diatomaceous earth to obtain filtrate and filter cake respectively; washing the filter cake with methanol to obtain washing liquid, combining the filtrate and washing liquid, removing the solvent, and purifying by silica gel column chromatography to obtain chiral intermediate 3. In the present invention, the alkaline reagent used to adjust the pH value to 7–8 preferably includes ammonia and / or sodium carbonate. In the present invention, the solvent removal method preferably includes rotary evaporation. In this invention, the eluent used for silica gel column chromatography purification preferably includes methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is preferably 1:5 to 10. In specific embodiments, it can be 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0128] In this application, the preparation method of intermediate 4 preferably includes the following steps: condensing N-acetylindolone and triethyl orthobenzoate to obtain intermediate 4.

[0129] In this application, the preparation route of intermediate 4 is as follows:

[0130] The definition of R1 in the N-acetylindolone is the same as the definition of R1 in Formula I or Formula II.

[0131] In this application, the molar ratio of N-acetylindolone to triethyl orthobenzoate is preferably 1:1 to 3.5, and in specific embodiments it can be 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4 or 1:3.5.

[0132] In this application, the condensation reaction is preferably carried out under acetic anhydride and a protective atmosphere. In this application, the molar ratio of N-acetylindolone to acetic anhydride is preferably 1:15 to 25, and in specific embodiments it can be 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, or 1:25. In this application, the protective atmosphere preferably includes nitrogen, argon, or helium.

[0133] In this application, the temperature of the condensation reaction is preferably 100-135°C, and in specific embodiments it can be 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C or 135°C; the time of the condensation reaction is preferably 1-4 hours, and in specific embodiments it can be 1 hour, 2 hours, 3 hours or 4 hours.

[0134] After the condensation reaction is completed, this application preferably further includes: cooling the reaction system obtained by the condensation reaction to room temperature, precipitating a solid, adding petroleum ether, stirring in an ice bath, filtering under reduced pressure, washing with petroleum ether, rinsing the filter cake with petroleum ether, and drying to constant weight to obtain intermediate 4.

[0135] This application also provides halogenated indole ketone derivatives, including pharmaceutically acceptable salts and / or solvates of the halogenated indole ketone compounds described in the above-described technical solutions.

[0136] In this application, the pharmaceutically acceptable salt preferably includes salts of organic acids or salts of inorganic acids. In this application, the organic acid preferably includes methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid. In this application, the inorganic acid salt preferably includes hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid.

[0137] This application does not impose any particular limitation on the preparation method of the pharmaceutically acceptable salt of the haloindolone compound, and any salt-forming method well known to those skilled in the art can be used.

[0138] In this application, the solvate preferably includes a hydrate.

[0139] This application also provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients; the active ingredient comprising one or more of the halogenated indolone compounds and halogenated indolone derivatives described in the above-described technical solutions.

[0140] In this application, the dosage form of the pharmaceutical composition preferably includes injections, tablets, capsules, pills, suspensions, or emulsions. In this application, the route of administration of the pharmaceutical composition preferably includes oral, spray, or injection, with the injection preferably including subcutaneous, intravenous, or intramuscular injection.

[0141] This application does not specifically limit the pharmaceutically acceptable excipients used; any pharmaceutically acceptable excipient well known to those skilled in the art can be used, specifically one or more of the following: solubilizers, antioxidants, osmotic pressure regulators, suspending agents, fillers, disintegrants, wetting agents, and lubricants. In this application, the solubilizer preferably includes one or more of polysorbate 80, lecithin, and polyethylene glycol. In this application, the antioxidant preferably includes vitamin C. In this application, the osmotic pressure regulator preferably includes sodium chloride and / or glucose. In this application, the suspending agent preferably includes glycerin. In this application, the filler preferably includes one or more of microcrystalline cellulose, starch, pregelatinized starch, calcium hydrogen phosphate, and calcium sulfate. In this application, the disintegrant preferably includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose, croscarmellose sodium, sodium carboxymethyl cellulose, and croscarmellose. In this application, the wetting agent preferably includes a 50-75 v / v% aqueous ethanol solution. In this application, the lubricant preferably includes one or more of sodium stearate fumarate, magnesium stearate, calcium stearate, or silicon dioxide.

[0142] In this application, the mass content of the active component in the pharmaceutical composition is preferably 1% to 90%, and in specific embodiments it can be 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.

[0143] This application also provides the use of the halogenated indole ketone compounds, halogenated indole ketone derivatives, or pharmaceutical compositions described in the above-mentioned technical solutions in the preparation of medicaments for treating kinase-mediated diseases; wherein the kinases include tyrosine protein kinase receptors, serine / threonine protein kinases, tyrosine protein kinases, vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor-α, fibroblast growth factor receptor 1, neurotrophic factor receptor 2, non-receptor tyrosine kinases, tyrosine protein kinases, and 5'-AMP-activated protein kinase subkinases. One or more of the following: α1 / β1 / γ1, glycogen synthase kinase-3β, ribosomal protein S6 kinase α-1, tyrosine protein kinase, bispecific mitogen-activated protein kinase 1, aurora kinase B, bispecific protein kinase, epidermal growth factor receptor type A 2, insulin-like growth factor 1 receptor, epidermal growth factor receptor type B 4, mitogen-activated protein kinase 1, serine / threonine protein kinase, nonspecific serine / threonine protein kinase, nonspecific serine / threonine protein kinase, nonspecific serine / threonine protein kinase, and glucokinase.

[0144] In this application, the drug preferably includes one or more of the following: antitumor drugs, anti-inflammatory drugs, antihypertensive drugs, drugs for treating cardiovascular diseases, drugs for treating diabetes, and drugs for treating autoimmune diseases. In this application, the tumor preferably includes one or more of the following: pancreatic cancer, colorectal cancer, lung cancer, liver cancer, and stomach cancer.

[0145] The halogenated indole ketone compounds provided in this application, through kinase spectrum analysis, showed that in addition to the VEGFR, FGFR, and PDGFR kinase inhibitory activities possessed by the lead compound nintedanib, they also exhibited strong AXL kinase inhibitory activity, IC50. 50 The value reached a low nanomolar level, which is 45 times more potent than nintedanib in inhibiting AXL kinase activity. The halogenated indole ketone compounds provided in this application exhibit better antitumor activity than nintedanib at both the cellular and in vivo levels, demonstrating superior inhibition of tumor invasion and metastasis. Furthermore, the halogenated indole ketone compounds provided in this application show inhibitory activities exceeding 90% against serine / threonine protein kinase (QIK), tyrosine protein kinase (LCK), platelet-derived growth factor receptor-α (PDGFRα), fibroblast growth factor receptor 1 (FGFR1), neurotrophic factor receptor 2 (TRKB), non-receptor tyrosine kinase (SRC), and tyrosine protein kinase (ABL1). This high kinase inhibitory activity effectively treats malignant tumors and their invasion and metastasis, demonstrating significant potential for application in the preparation of drugs for treating kinase-mediated diseases (especially tumors).

[0146] To further illustrate this application, the following detailed descriptions, in conjunction with embodiments, illustrate the halogenated indole ketone compounds and their preparation methods and applications, halogenated indole ketone derivatives and their applications, and pharmaceutical compositions and their applications. However, these descriptions should not be construed as limiting the scope of protection of this application.

[0147] Example 1

[0148] (1) Synthesis of intermediate 1: 2-Bromopropionic acid (1.51 g, 10 mmol) was dissolved in 3 mL of thionyl chloride and refluxed at 80 °C for 5 h. The remaining thionyl chloride was removed under reduced pressure, and the crude product was directly dissolved in 25 mL of acetonitrile to obtain a 0.4 M (mol / L) 2-bromopropionyl chloride solution. In another reaction flask, N-methyl-4-nitroaniline (10 mmol, 1.52 g), DMAP (1 mmol, 0.122 g), anhydrous acetonitrile (10 mL), and triethylamine (1.5 mL) were added. The 2-bromopropionyl chloride solution was added using a syringe under ice bath conditions, and the reaction was carried out at room temperature for 2–3 h. The reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, 5 mL of water was added, and the phases were separated to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with dichloromethane to obtain a dichloromethane phase. The organic phase and the dichloromethane phase were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio of 4:1 and 1:1, respectively) to obtain intermediate 1 with a yield of 75%.

[0149] (2) Synthesis of intermediate 2: Intermediate 1 (5 mmol, 1.43 g) was dissolved in 15 mL of 1,4-dioxane, and N-ethylpiperazine (7.5 mmol, 0.86 g) and diisopropylethylamine (10 mmol) were added. The reaction was heated to 100 °C for 16 h, and the reaction was confirmed to be complete by TLC. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluting successively with ethyl acetate and dichloromethane:methanol in a volume ratio of 5:1) to obtain intermediate 2 in 46% yield. 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J=9.0Hz,2H),7.48(d,J=9.0Hz,2H),3.72(q,J=6.7Hz,1H),3.36 (s, 3H), 2.61 (d, J = 6.7Hz, 2H), 2.42 (p, J = 6.7, 6.3Hz, 8H), 1.17 (d, J = 6.7Hz, 3H), 1.09 (t, J = 7.2Hz, 3H).

[0150] (3) Synthesis of intermediate 3: Intermediate 2 (5 mmol, 1.6 g) was dissolved in anhydrous ethanol (20 mL), 10% palladium on carbon (215 mg) was added, hydrogen gas (0.101 MPa) was passed through, and the reaction was carried out at room temperature for 24 h. The reaction was detected by TLC to be complete. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 1.3 g of brown oily product. 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J=9.0Hz,2H),7.48(d,J=9.0Hz,2H),3.36(s,3H ),3.31(m,1H),2.61(m,2H),2.42(m,8H),1.17(d,J=6.7Hz,3H),1.09(t,J=7.2Hz,3H).

[0151] (4) Synthesis of intermediate 4: 9 mL of acetic anhydride and 6-chloroacetylindolone (1.3 g, 5.6 mmol) were added sequentially, followed by the slow addition of triethyl orthobenzoate (3.8 g, 16.8 mmol). The reaction was carried out under nitrogen protection at 125 °C for 2 h (TLC monitoring, developing solvent: ethyl acetate: petroleum ether volume ratio = 1:4). After the reaction was complete, the mixture was cooled to room temperature, and a solid precipitated. Petroleum ether (40 mL) was added, and the mixture was stirred in an ice bath for 1 h. The mixture was then filtered under reduced pressure, washed with petroleum ether, and the filter cake was rinsed with petroleum ether (20 mL). The mixture was dried under vacuum at 45 °C to constant weight to obtain intermediate 4, a light yellow solid of 1.7 g, with a yield of 81%.

[0152] (5) Synthesis of target compound 1 (R1 is chlorine, R2 is methyl, R3 is N-ethylpiperazinyl): Intermediate 4 (1.27 mmol, 0.35 g) was dissolved in DMF (5 mL), and intermediate 3 (1.2 mmol, 0.438 g) was added. Under nitrogen protection, the mixture was heated to 80 °C and stirred for 1 h. Piperidine (0.22 mL) was added, and stirring was continued for 2 h. 10 mL of water was added to the reaction system to precipitate a solid. The solid was filtered, ground with 2 mL of methanol, filtered, and the filter cake was washed with 2 mL of methanol and 2 mL of ethyl acetate. The mixture was dried to constant weight to obtain target compound 1 (compound number X529 or 11b), a yellow solid with a yield of 38%. 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),10.96(s,1H),7.67-7.54(m,3H),7.52(d,J=7.0H z,1H),7.47(d,J=7.1Hz,1H),7.16(d,J=8.5Hz,2H),6.89(d,J=2.0Hz,2H),6.87(s,1H) ,6.61(dd,J=8.4,2.0Hz,1H),5.74(d,J=8.3Hz,1H),4.11-3.67(m,1H),3.06(s,3H),2. 96(m,4H),2.78-2.53(m,4H),2.35(m,2H),1.20(t,J=7.2Hz,3H),0.95(d,J=6.5Hz,3H). 13 C NMR (101MHz, DMSO) δ171.21,170.52,156.87,140.00,138.24,132.75,130.84,129.98,129.95,129.09,128.89,128.4 4,128.25,124.12,123.29,120.19,119.40,109.62,97.97,57.64,51.22,51.11,45.94,37.22,11.91,9.55.HR-ESI-MS for C 31 H 35 ClN5O2[M+H] + ,calculated for 544.2479, found ,544.2474.

[0153] Example 2

[0154] Synthesis of target compound 2 (R1 is chlorine, R2 is methyl, R3 is 4-(N,N-dimethyl)aminopiperidinyl): Target compound 2 was prepared according to the method of Example 1, except that N-ethylpiperazine was replaced with 4-(N,N-dimethyl)aminopiperidinyl.

[0155] Target compound 2: 1H NMR (400MHz, DMSO-d6) δ7.54 (ddd, J=38.8, 16.0, 7.2Hz, 5H), 7.13 (d, J=8.1Hz, 2H) ,6.88(d,J=8.8Hz,3H),6.61(d,J=8.2Hz,1H),5.74(d,J=8.2Hz,1H),3.05(s,3H), 3.03-2.95(m,1H),2.80(m,1H),2.68(m,1H),2.60(s,6H),2.25(m,1H),2.20-2.08 (m,1H),2.06-1.93(m,1H),1.83(m,2H),1.54-1.34(m,2H),0.93(d,J=6.2Hz,3H). 13 C NMR (101MHz, DMSO) δ171.60,170.38,156.76,140.35,138.09,132.70,130.86,129.97,129.91,129.05,128.90,128.38,12 8.24,124.13,123.97,123.27,120.19,119.39,109.57,97.88,62.70,57.88,48.14,46.56,37.21,26.51,11.86.HR-ESI-MS for C 32 H 37 ClN5O2[M+H] + ,calculated for 558.2636, found ,558.2630.

[0156] Example 3

[0157] Synthesis of target compound 3 (R1 is chlorine, R2 is methyl, R3 is morpholino): Target compound 3 was prepared according to the method of Example 1, except that N-ethylpiperazine was replaced with morpholino.

[0158] Target compound 3: 1H NMR(500MHz,Chloroform-d)δ11.84(s,1H),8.87(s,1H),7.47(dq,J=16.0,7.4Hz,3 H),7.38(d,J=7.2Hz,1H),7.32(d,J=7.3Hz,1H),6.92(d,J=8.6Hz,2H),6.88(s,1H), 6.70(d,J=8.5Hz,2H),6.55(d,J=8.3Hz,1H),5.80(d,J=8.3Hz,1H),3.52(m,4H),3. 11(s,3H),3.02-2.94(m,1H),2.41(m,2H),2.23-2.10(m,2H),1.02(d,J=6.6Hz,3H). 13 CNMR (126MHz, CDCl3) δ172.36,171.22,167.37,158.33,140.24,137.88,135.72,132.36,130.53,129.59,129.57,129.07,12 8.70,128.49,128.00,125.16,123.99,122.72,118.21,110.45,98.51,67.16,59.05,51.93,49.40,37.42,11.91.HR-ESI-MS for C 29 H 30 ClN4O3[M+H] + ,calculated for517.2006,found,517.2001.

[0159] Example 4

[0160] Synthesis of target compound 4 (R1 is chlorine, R2 is methyl, R3 is N-methylperiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that N-ethylperiperazine was replaced with N-methylperiperazine.

[0161] Target compound 4: 1H NMR (500MHz, Methanol-d4) δ7.61(dq,J=10.5,5.8,4.2Hz,3H),7.49(t,J=9.2Hz,2H),7.15(d,J=8.5Hz,2H),6.94(dd,J=5.1,3.2Hz,3H),6.58(dd,J=8.4, 1.8Hz,1H),5.87(d,J=8.4Hz,1H),3.48-3.38(m,1H),3.33(s,3H),3.30-3.1 7(m,6H),3.06-2.96(m,2H),2.90(s,3H),1.95(m,2H),1.10(d,J=6.0Hz,3H). 13 C NMR(126MHz,MeOD)δ170.90,156.90,137.53,132.69,130.18,129.67,129.35,129.12,128.67,128.57,127.68,127.22,124.8 5,123.81,122.74,120.05,119.38,109.31,98.10,58.29,57.97,54.76,50.68,44.18,43.56,42.52,36.36,24.74.HR-ESI-MS for C 31 H 35 ClN5O2[M+H] + ,calculated for 544.2479, found ,544.2474.

[0162] Example 5

[0163] Synthesis of target compound 5 (R1 is chlorine, R2 is hydrogen, R3 is N-methylpiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that bromoacetic acid was used instead of 2-bromopropionic acid and N-methylpiperazine was used instead of N-ethylpiperazine.

[0164] Target compound 5: 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),10.87(s,1H),7.57(q,J=6.7,6.3Hz,3H),7.49(d,J=7.1Hz,2H),7.11(d,J=8.2Hz,2H),6 .88-6.82(m,3H),6.61(dd,J=8.4,2.0Hz,1H),5.72(d,J=8.3Hz,1H),3.06(s,3H),2.79-2.64(m,2H),2.28(m,8H),2.16(s,3H). 13 C NMR (126MHz, DMSO) δ170.53,168.99,156.96,140.19,138.16,132.76,130.82,129.95,128.95,128 .19,123.96,123.33,120.19,119.38,109.55,97.86,59.46,54.88,52.51,45.91,37.13.HR-ESI-MS for C 29 H 30 ClN5O2[M+H] + ,calculated for 516.2144, found ,516.2161.

[0165] Example 6

[0166] Synthesis of target compound 6 (R1 is chlorine, R2 is hydrogen, R3 is N-ethylpiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that bromoacetic acid was used instead of 2-bromopropionic acid.

[0167] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),10.89(s,1H),7.58(q,J=6.9,6.4Hz,3H),7.49(d,J=6.9Hz,2H),7.12(d,J=8.2Hz,2H),6.9 0-6.79(m,3H),6.61(d,J=8.4Hz,1H),5.73(d,J=8.4Hz,1H),3.06(m,5H),2.81-2.33(m,8H),2.45(m,2H),1.09(t,J=7.1Hz,3H). 13CNMR(101MHz,DMSO)δ170.54,168.69,156.84,138.20,132.78,130.86,129.98,128.94,128.24,123.8 6,123.31,120.20,119.39,109.59,97.97,51.74,51.54,50.95,46.16,37.16,29.47,10.80.HR-ESI-MS for C 30 H 32 ClN5O2[M+H] + ,calculated for 530.2301,found,530.2317.

[0168] Example 7

[0169] Synthesis of target compound 7 (R1 is chlorine, R2 is hydrogen, R3 is N,N,N-trimethylethylenediamine): Target compound 2 was prepared according to the method of Example 1, except that bromoacetic acid was used instead of 2-bromopropionic acid and N,N,N-trimethylethylenediamine was used instead of N-ethylpiperazine.

[0170] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),10.87(s,1H),7.57(q,J=6.9,6.4Hz,3H),7.49(d,J=6.9Hz,2H),7.12(d,J=8.3Hz,2H),6.8 5(d,J=8.2Hz,3H),6.61(d,J=9.6Hz,1H),5.72(d,J=8.3Hz,1H),3.43(s,3H),3.01(m,4H),2.70(m,2H),2.50(s,6H),2.20(s,3H). 13 CNMR(101MHz,DMSO)δ170.54,168.83,156.96,140.22,138.19,137.57,132.78,130.79,129.92,128.96,12 8.20,123.93,123.34,120.18,119.38,109.57,97.90,70.26,66.54,59.89,53.28,46.11,37.22.HR-ESI-MS for C 29 H 32 ClN5O2[M+2H] +,calculated for 519.2215, found ,519.2185.

[0171] Example 8

[0172] Synthesis of target compound 8 (R1 is chlorine, R2 is methyl, R3 is 4-hydroxyethylpiperazine): Target compound 2 was prepared according to the method of Example 1, replacing N-ethylpiperazine with 4-hydroxyethylpiperazine.

[0173] Target compound 8: ¹H NMR (400MHz, DMSO-d6) δ 11.96 (s, 1H), 10.88 (s, 1H), 7.65–7.49 (m, 4H), 7.44 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.92–6.82 (m, 3H), 6.61 (dd, J = 8.4, 2.0 Hz, 1H), 5.74 (d, J = 8.3 Hz, 1H), 3.48 (m, 2H), 3.05 (s, 3H), 3.00 (d, J = 6.4 Hz, 1H), 2.46–2.25 (m, 8H), 2.10 (m, 2H), 0.92 (d, J = 6.4 Hz, 3H). 13 C NMR (101MHz, DMSO) δ171.55,170.55,157.00,140.35,138.19,137.90,132.74,130.77,129.94,129.13,128.81,128.38 ,128.20,124.07,123.33,120.18,119.38,109.56,97.87,60.42,58.57,57.95,53.72,48.09,37.15,11.70.HR-ESI-MS for C 31 H 34 ClN5O3[M+H] + ,calculated for 560.2423,found,560.2421.

[0174] Example 9

[0175] Synthesis of target compound 9 (R1 is bromine, R2 is methyl, R3 is N-methylpiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that N-methylpiperazine was used instead of N-ethylpiperazine and 6-bromo-N-acetylindolone was used instead of 6-chloro-N-acetylindolone.

[0176] Target compound 9: 1H NMR (400MHz, Methanol-d4) δ7.59 (dd, J=14.8, 6.7Hz, 3H), 7.45 (dd, J=15.4, 7.0 Hz,2H),7.19-7.03(m,3H),6.91(d,J=8.2Hz,2H),6.71(d,J=8.1Hz,1H),5.81(d ,J=8.3Hz,1H),3.16(s,3H),3.15-3.12(m,1H),2.84-2.76(m,2H),2.71-2.60(m ,2H),2.57(s,3H),2.49-2.38(m,2H),1.87-1.76(m,2H),1.09(d,J=6.5Hz,3H). 13 C NMR(101MHz,MeOD)δ172.69,170.71,157.14,139.53,138.45,137.73,132.66,130.18,129.33,128.68,128.52,127.80,12 3.87,123.20,122.93,119.72,116.54,112.16,98.00,58.35,54.09,44.32,43.31,36.37,22.37,21.68,11.48.HR-ESI-MS for C 30 H 33 BrN5O2[M+H] + ,calculated for 574.1818, found ,574.1812.

[0177] Example 10

[0178] Synthesis of target compound 10 (R1 is bromine, R2 is hydrogen, R3 is N-ethylpiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that 2-bromopropionic acid was replaced with 2-bromoacetic acid and 6-chloro-N-acetylindolone was replaced with 6-bromo-N-acetylindolone.

[0179] Target compound 10: 1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),10.88(s,1H),7.67-7.53(m,3H),7.4 9(dd,J=7.9,1.6Hz,2H),7.12(d,J=8.2Hz,2H),6.99(d,J=1.9Hz,1H),6.85 (d,J=8.5Hz,2H),6.74(dd,J=8.3,1.9Hz,1H),5.67(d,J=8.3Hz,1H),3.05( s,3H),2.75(s,2H),2.68-2.53(m,2H),2.39(m,8H),1.02(t,J=7.1Hz,3H). 13 C NMR (126MHz, DMSO) δ170.37,168.88,157.11,138.37,132.71,130.88,129.98,128.89,128.22,123.97 ,123.66,123.01,119.81,116.26,112.36,97.91,70.22,58.89,52.01,51.69,37.18,11.26.HR-ESI-MS for C 30 H 32 BrN5O2[M+2H] + ,calculated for 573.1739, found ,573.1748.

[0180] Example 11

[0181] Synthesis of target compound 11 (R1 is bromine, R2 is hydrogen, R3 is 4-(N,N-dimethyl)aminopiperidinyl): Target compound 2 was prepared according to the method of Example 1, except that 2-bromopropionic acid was replaced with 2-bromoacetic acid, N-ethylpiperazine was replaced with 4-(N,N-dimethyl)aminopiperidinyl, and 6-chloro-N-acetylindolone was replaced with 6-bromo-N-acetylindolone.

[0182] Target compound 11: 1H NMR (400MHz, DMSO-d6) δ11.99 (s, 1H), 10.87 (s, 1H), 7.57 (q, J = 6.5Hz, 3H), 7.49(d,J=6.5Hz,2H),7.11(d,J=8.3Hz,2H),6.99(d,J=1.8Hz,1H),6.84(d ,J=8.4Hz,2H),6.73(dd,J=8.3,1.9Hz,1H),5.68(d,J=8.3Hz,1H),3.05(s, 3H),2.70(s,2H),2.59(m,2H),2.26(s,6H),2.17(m,1H),1.89-1.65(m,6H). 13 C NMR (101MHz, DMSO) δ170.40,169.19,159.67,157.05,140.30,138.43,132.76,130.83,129.94,128.91,128 .01,123.70,122.98,119.79,116.21,112.29,97.91,61.95,59.43,52.32,41.36,37.18,27.86.HR-ESI-MS for C 31 H 34 BrN5O2[M+2H] + ,calculated for 589.1933, found ,589.2031.

[0183] Example 12

[0184] Synthesis of target compound 12 (R1 is bromine, R2 is hydrogen, R3 is morpholino): Target compound 2 was prepared according to the method of Example 1, except that 2-bromopropionic acid was replaced with 2-bromoacetic acid, N-ethylpiperazine was replaced with morpholino, and 6-chloro-N-acetylindolone was replaced with 6-bromo-N-acetylindolone.

[0185] Target compound 12: 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),10.87(s,1H),7.58(q,J=6.3Hz,3H),7.50(dd,J=7.6,1.9Hz,2H),7.11(d,J=8.3Hz,2H),7.00(d,J=1.9 Hz,1H),6.85(d,J=8.3Hz,2H),6.74(dd,J=8.4,1.9Hz,1H),5.67(d,J=8.4Hz,1H),3.51(s,3H),3.07(m,4H),2.90(s,2H),2.48-2.34(m,4H). 13 C NMR (101MHz, DMSO) δ170.39,169.85,156.95,138.44,132.76,130.87,130.00,128.88,128.11,123.77 ,123.67,122.99,119.80,116.27,112.35,98.02,70.25,56.44,53.48,44.94,42.63,37.23.HR-ESI-MS for C 28 H 27 BrN4O3[M+2H] + ,calculated for548.1246,found,548.1256.

[0186] Example 13

[0187] Synthesis of target compound 13 (R1 is bromine, R2 is hydrogen, R3 is N-methylperiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that 2-bromopropionic acid was replaced with 2-bromoacetic acid, N-ethylpiperazine was replaced with N-methylperiperazine, and 6-chloro-N-acetylindolone was replaced with 6-bromo-N-acetylindolone.

[0188] Target compound 13: 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),10.87(s,1H),7.58(d,J=7.3Hz,3H),7.49(d,J=7.0Hz,2H),7.11(d,J=8.1Hz,2H),7.00(s,1H),6.84( d,J=8.3Hz,2H),6.74(d,J=8.2Hz,1H),5.67(d,J=8.3Hz,1H),3.06(s,3H),2.94(s,2H),2.47(m,4H),2.39(m,4H),2.23(s,3H),1.59(m,2H). 13 C NMR (101MHz, DMSO) δ170.38,157.05,138.41,132.77,130.85,129.97,128.90,128.08,123.71,12 2.99,119.80,116.20,112.29,97.91,58.16,56.41,53.67,53.58,46.68,37.23,27.28.HR-ESI-MS for C 30 H 32 BrN5O2[M+2H] + ,calculated for 575.1875, found ,575.1921.

[0189] Example 14

[0190] Synthesis of target compound 14 (R1 is bromine, R2 is hydrogen, R3 is N,N,N-trimethylethylenediamine): Target compound 2 was prepared according to the method of Example 1, except that 2-bromopropionic acid was replaced with 2-bromoacetic acid, N-ethylpiperazine was replaced with N,N,N-trimethylethylenediamine, and 6-chloro-N-acetylindolone was replaced with 6-bromo-N-acetylindolone.

[0191] Target compound 14: 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.86(s,1H),7.56(q,J=7.2,6.5Hz,3H),7.48(d,J=6.7Hz,2H),7.12(d,J=8.3Hz,2H),6.99(d,J=1.8Hz,1H) ,6.85(d,J=8.3Hz,2H),6.73(dd,J=8.4,1.9Hz,1H),5.67(d,J=8.3Hz,1H ),3.43(s,3H),3.06(m,3H),2.82-2.64(m,2H),2.50(s,6H),2.20(m,4H). 13 C NMR (101MHz, DMSO) δ170.39,168.84,157.13,140.26,138.41,132.75,130.81,129.93,128.92, 128.10,123.71,122.99,119.84,116.21,112.33,97.89,70.25,66.52,53.27,46.21.HR-ESI-MS for C 29 H 32 BrN5O2[M+H] + ,calculated for562.1812,found,562.1803.

[0192] Example 15

[0193] Synthesis of target compound 15 (R1 is bromine, R2 is hydrogen, R3 is 4-hydroxyethylpiperazine): Target compound 2 was prepared according to the method of Example 1, except that 2-bromoacetic acid was used instead of 2-bromopropionic acid; 4-hydroxyethylpiperazine was used instead of N-ethylpiperazine; and 6-bromo-N-acetylindolone was used instead of 6-chloro-N-acetylindolone.

[0194] Target compound 15: 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.86(s,1H),7.57(t,J=7.4Hz,3H),7.48(d,J=6.5Hz,2H),7.11(d,J=8.4Hz,2H),6.99(s,1H),6.84( d,J=8.5Hz,2H),6.73(d,J=10.1Hz,1H),5.68(d,J=8.3Hz,1H),3.46(m,2H),3.45(s,3H),3.10(s,2H),2.79-2.64(m,2H),2.36-2.11(m,8H).13 C NMR (126MHz, DMSO) δ170.37,157.15,140.20,138.38,132.72,130.86,129.96,128.91,128.16,123.98 ,123.69,123.00,119.80,116.21,112.32,97.87,60.43,59.50,58.66,53.38,52.56,37.18.HR-ESI-MS for C 30 H 32 BrN5O3[M+2H] + ,calculated for591.1824,found,591.1768.

[0195] Example 16

[0196] Synthesis of target compound 16 (R1 is bromine, R2 is methyl, R3 is 4-hydroxyethylpiperazinyl): Target compound 2 was prepared according to the method of Example 1, except that N-ethylpiperazine was replaced with 4-hydroxyethylpiperazinepiperazine and 6-chloro-N-acetylindolone was replaced with 6-bromo-N-acetylindolone.

[0197] Target compound 16: 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.98(s,1H),7.59(p,J=7.8Hz,3H),7.4 9(dd,J=21.4,7.2Hz,2H),7.16(d,J=8.2Hz,2H),7.03(s,1H),6.88(d,J=8.3Hz ,2H),6.73(d,J=9.8Hz,1H),5.69(d,J=8.3Hz,1H),5.28(s,1H),3.74(m,2H),3 .23(t,J=7.4Hz,1H),2.95-2.79(m,2H),2.64(s,3H),2.51(m,8H),0.95(s,3H). 13 C NMR (126MHz, DMSO) δ171.19,170.34,157.04,140.10,138.51,138.10,132.73,130.86,129.97,129.08,128.86,128.44 ,124.19,123.66,122.96,119.80,116.24,112.37,97.95,58.42,57.66,52.50,52.31,45.84,37.22,11.74.HR-ESI-MS for C31 H 34 BrN5O3[MH] - ,calculated for 602.1772, found ,602.1750.

[0198] Example 17

[0199] Synthesis of target compound 17 (R1 is chlorine, R2 is methyl, R3 is N-ethylpiperazinyl): Target compound 2 was prepared according to the method of Example 1, the only difference from Example 1 being that the synthesis of intermediate 2 was as follows.

[0200] Synthesis of Compound 2: (R)-methyl lactate (60 mmol, 6.24 g) was dissolved in dichloromethane (36 mL), and triethylamine (11 mL) was added. A solution of p-toluenesulfonyl chloride (68.9 mmol, 13.14 g) in dichloromethane (45 mL) was added dropwise with stirring in an ice bath. The reaction was stirred at room temperature for 20 h, and TLC analysis showed complete reaction. Water (20 mL) was added to the reaction solution, the organic phase was separated, and the aqueous layer was extracted with dichloromethane (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (Compound 1), which was directly used for the next reaction. A solution of NaOH (103 mmol, 4.124 g) dissolved in 37 mL of water was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 2-3 h. TLC analysis showed complete reaction. The pH was adjusted to 2-3 by adding (10 mL) concentrated hydrochloric acid under ice bath conditions. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to constant weight to give compound 2. Compound 2: 1 H NMR (400MHz, Chloroform-d) δ10.77(s,1H),7.82(d,J=8.2Hz,2H),7.36(d,J=8.2Hz,2H),4.97(q,J=7.0Hz,1H),2.45(s,3H),1.54(d,J=7.0Hz,3H).

[0201] Synthesis of Compound 4: Compound 2 (49.3 mmol, 12.038 g) was dissolved in 1,2-dichloroethane (49 mL), and thionyl chloride (11 mL) was added dropwise under ice bath conditions. The mixture was refluxed at 79 °C for 6–7 h, and the solvent was removed under reduced pressure to obtain Compound 3. Acetonitrile (15 mL) was added to obtain a solution of Compound 3, which was directly used in the next reaction. In a reaction flask, N-methyl-4-nitroaniline (36.2 mmol, 5.5 g), DMAP (4.83 mmol, 0.59 g), anhydrous acetonitrile (49 mL), and triethylamine (10 mL) were added. The above solution of Compound 3 was added using a syringe under ice bath conditions. The reaction was carried out at room temperature for 2–3 h, and the reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, 20 mL of water was added, and the phases were separated to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with dichloromethane to obtain a dichloromethane phase. The organic and dichloromethane phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratios of 4:1 and 1:1, respectively) to obtain compound 4 in 50% yield. Compound 4: 1 H NMR(400MHz,Chloroform-d)δ8.32(d,J=8.9Hz,2H),7.74(d,J=8.3Hz,2H),7.44(d,J=8.9Hz,2H ),7.32(d,J=8.1Hz,2H),5.02(q,J=6.6Hz,1H),3.33(s,3H),2.44(s,3H),1.38(d,J=6.6Hz,3H).

[0202] Synthesis of intermediate 2: Compound 4 (5.3 mmol, 2 g) was dissolved in 15 mL of 1,4-dioxane, and N-ethylpiperazine (10 mmol) and diisopropylethylamine (18 mmol, 2.29 g) were added. The reaction was heated to 100 °C for 16 h, and the reaction was confirmed to be complete by TLC. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluents were ethyl acetate, dichloromethane:methanol, v / v = 5:1) to give intermediate 2 in 46% yield. 1 H NMR(400MHz,Chloroform-d)δ8.32(d,J=8.9Hz,2H),7.46(d,J=9.0Hz,2H),3.72(q,J=6.7Hz,1H) ,3.35(s,3H),3.06-2.84(m,6H),2.77-2.67(m,4H),1.20(d,J=6.7Hz,3H),0.9(t,J=7.1Hz,,3H).

[0203] Target compound 17: 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),10.96(s,1H),7.67-7.54(m,3H),7.52(d,J=7.0H z,1H),7.47(d,J=7.1Hz,1H),7.16(d,J=8.5Hz,2H),6.89(d,J=2.0Hz,2H),6.87(s,1H) ,6.61(dd,J=8.4,2.0Hz,1H),5.74(d,J=8.3Hz,1H),4.11-3.67(m,1H),3.06(s,3H),2. 96(m,4H),2.78-2.53(m,4H),2.35(m,2H),1.20(t,J=7.2Hz,3H),0.95(d,J=6.5Hz,3H).

[0204] Test Example 1

[0205] Using target compound 1 (denoted as X529) as a representative compound, the inhibitory activity against 80 kinases and the IC50 of inhibition against AXL and KDR (VEGFR2) kinases were analyzed. 50 Value test.

[0206] Nintedanib is a well-known oral small-molecule triple tyrosine kinase inhibitor. To explore whether the target compound provided in this application differs from the lead compound nintedanib in terms of its target site, the inhibitory activity of target compound 1 against 80 kinases was measured. The experimental procedures are as follows:

[0207] Transfer 250 nmol of the 20 μM compound solution to each well of a 384 reaction plate for later use. Add 250 nmol of 100% DMSO to each of the negative control and blank wells. Prepare a 2.5-fold final concentration of kinase solution using 1×Kinase buffer. Add 10 μol of the 2.5-fold final concentration of kinase solution to each of the compound and positive control wells; add 10 μol of 1×Kinase buffer to each of the negative control wells. Centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 10 minutes. Prepare a 25 / 15-fold final concentration mixture of ATP and Kinase substrate 2 using 1×Kinase buffer. Add 15 μol of the 25 / 15-fold final concentration mixture of ATP and substrate to initiate the reaction. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 60 minutes. Add 30 μL of stop assay solution to halt the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a Caliper EZ Reader II (microfluidic chip analyzer). Each kinase has duplicate wells, and the inhibition rate of each well is calculated using the following formula: Inhibition rate = (Compound well conversion rate - Blank conversion rate) / (Negative control conversion rate - Blank conversion rate) × 100%.

[0208] IC 50 The experimental design for the test is as follows:

[0209] Prepare 100-fold final concentration solutions of the compound in 384-well plates, starting at 1 μM and diluting 3-fold to create 10 concentration gradients. Using a pipette, transfer 250 nmol to each well of the 384-well plate according to the established protocol. Add 250 nmol of 100% DMSO to each negative control and blank control well. Prepare a 2.5-fold final concentration kinase solution using 1×Kinase buffer. Add 10 μL of the 2.5-fold final concentration kinase solution to each compound and positive control well; add 10 μL of 1×Kinase buffer to each negative control well. Centrifuge at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 10 min. Prepare a 25 / 15-fold final concentration mixture of ATP and Kinase substrate 2 using 1×Kinase buffer. Add 15 μL of the 25 / 15-fold final concentration ATP and substrate mixture to initiate the reaction. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 60 minutes. Add 30 μL of stop assay solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using Caliper EZ Reader II. After data processing, plot the logarithm of concentration on the X-axis and the percentage inhibition rate on the Y-axis. Use the log(inhibitor) vs. response-variable slope function of GraphPadPrism 8 software to fit dose-response curves, thereby obtaining the IC50 of each compound on the enzyme activity. 50 Value. Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * Hillslope)). Test results are shown in Table 1 and Figure 1.

[0210] Figure 1 shows the results of the inhibitory activity of target compound 1 (X529) prepared in Example 1 against 80 kinases.

[0211] Table 1. 25 kinases with inhibition rates greater than 50% among the 80 kinases measured by X529 (200 nM).

[0212] Table 1 shows the data on the inhibition rate of target compound 1 against 80 kinases greater than 50%. As shown in Figure 1 and Table 1, compared with the kinase targets of nintedanib reported in the literature (J. Med. Chem., 2015, 58, 1053-1063.), target compound 1, in addition to exhibiting good inhibitory activity against KDR, PDGFR, and FGFR, also showed good inhibitory effects against kinases AXL, QIK, TRKB, SRC, and ABL1.

[0213] According to the data published by the original research company, nintedanib showed only weak inhibitory activity against AXL. Given that AXL kinase is overexpressed or activated in various cancers and is a significant factor contributing to resistance to chemotherapy and receptor tyrosine kinase inhibitors (TKIs), further quantitative analyses of AXL and KDR kinases by target compounds 1, 9, and 17 were performed, with nintedanib as a positive control. The results are shown in Table 2.

[0214] Table 2. Quantitative inhibitory activity tests of halogenated indole ketones and nintedanib against AXL and KDR kinases.

[0215] Table 2 shows that the IC50 of target compound 1 against AXL kinase is... 50 The value is 3.75 nM, while the IC of Nydanib is 3.75 nM. 50 The concentration was 169.7 nM, with a difference of over 45-fold between the two. Furthermore, the inhibitory activity of target compound 1 and nintedanib against KDR was determined, showing similar results (IC50, IC50). 50 The values ​​were 1.525 nM and 1.046 nM, respectively. These results indicate that the KDR inhibitory activity of target compound 1 is similar to that of nintedanib, but it exhibits good inhibitory activity against AXL kinase, warranting further investigation.

[0216] Test Example 2

[0217] The halogenated indole ketone compounds prepared in the examples exhibited inhibitory activity (IC50) against tumor cells and tumor-associated fibroblasts. 50 Tests were conducted at μM.

[0218] The mouse fibroblast cell line (NIH3T3 cells, derived from Nanjing Kebai Biotechnology Co., Ltd.) was used. Its anti-fibroblast proliferation activity was tested using the CCK8 assay, with nintedanib as a positive control. The specific experimental steps are as follows: NIH3T3 cells were cultured in high-glucose DMEM containing 10 v / v% FBS, 1 v / v% penicillin, and streptomycin, and incubated at 37°C in a 5% CO2 saturated humidity incubator. The culture medium was replaced with fresh medium every other day. When the cells grew to cover 80-90% of the bottom wall of the culture flask, they were digested with 0.25% trypsin and passaged at a ratio of 1:3 to 1:5. Cells in the logarithmic growth phase were collected, and the cell suspension concentration was adjusted to 5 × 10⁶ cells / mL. 3Cells were seeded per well into 96-well plates and incubated at 37°C with 5% CO2 for 12 hours. After cell attachment, the old culture medium was discarded, and FBS-free medium was added. Six concentration gradients were prepared for each compound, with three replicates for each concentration. After adding the medium, the plates were incubated for 48 hours. Then, 10 μL of CCK8 solution was added to each well in the dark, and the plates were incubated in a CO2 incubator for another 2–4 hours. The absorbance (OD value) at 450 nM was measured using a microplate reader. Finally, the data were analyzed, and the inhibition rate at each concentration was calculated using the following formula:

[0219] The half-maximal inhibitory concentration (IC50) was calculated using GraphPad Prism 5.02 software. Each experiment was independently repeated three times, and the average value was taken to obtain the final data. The results are shown in Table 3.

[0220] Table 3. Inhibitory activity of halogenated indole ketones against tumor cells and tumor-associated fibroblasts (IC50) 50 (μM)

[0221] As shown in Table 3, compared with the lead compound nintedanib, the halogenated indole ketone compounds provided in this application have better inhibitory activity against tumor cells such as pancreatic cancer cells Bxpc-3, triple-negative breast cancer cells MM231, and tumor-associated fibroblasts NIH / 3T3 due to changes in structure and target site.

[0222] Test Example 3

[0223] In vivo antitumor activity assay of target compound 1 (11b) in nude mice

[0224] The in vivo antitumor activity assay in nude mice was performed using BALB / c nude mice (5 weeks old, 18–20 g). Bxpc-3 pancreatic cancer cells (derived from Pronosei Biotechnology Co., Ltd.) cultured to passage 3–5 in the logarithmic growth phase were digested with trypsin and then prepared into a 1.0 × 10⁻⁶ medium. 7 Cell suspensions at a concentration of [number] cells / mL were injected subcutaneously into the right axilla of nude mice to establish a nude mouse Bxpc-3 pancreatic cancer xenograft model after tumor formation. When the tumor volume reached 100–150 mm², [further details needed]. 3Mice were randomly divided into four groups (control group, nintedanib-50 mg / kg, 11b-25 mg / kg, and 11b-50 mg / kg), with six mice in each group. Mice were orally administered the test compound once daily at the set dose for 14 consecutive days. Figure 2 shows the changes in tumor volume in mice under the action of the blank group, the nintedanib group, and the target compound group prepared in Example 1 during the anti-pancreatic cancer activity process. It can be seen that the tumor inhibition rate (TGI, calculated by volume) of target compound 1 at a dose of 25 mg / kg was 83.03%, and the TGI of nintedanib at a dose of 50 mg / kg was 68.10%. When the dose of target compound 1 was increased to 50 mg / kg, the TGI increased to 96.71%.

[0225] After euthanizing the mice, fluid was found in the tumor vesicles during tumor resection, particularly in the control group and the nintedanib group. Figure 3 shows the changes in tumor weight in mice under the action of the blank group, the nintedanib group, and the target compound group prepared in Example 1 during the anti-pancreatic cancer activity process. It can be seen that after removing the fluid from the tumor vesicles, the TGI (based on tumor weight) of target compound 1 was 56.46% and 71.00% at doses of 25 mg / kg and 50 mg / kg, respectively, while the TGI of nintedanib was 55.84% at a dose of 50 mg / kg.

[0226] The differences in weight and volume of TGI were thought to be related to the exudation of the interstitial fluid. Throughout the administration period, mice in the nintedanib group experienced weight loss, and one mouse died on day eleven. Mice in the control group and the target compound 1 group showed no significant changes in weight, and their behavior was normal.

[0227] Test Example 4

[0228] Target compound 1 (11b) inhibited lung metastasis of tumors in nude mice.

[0229] After the in vivo antitumor treatment in mice, lung tissue from one nude mouse was randomly selected from each experimental group and observed after hematoxylin-eosin (H&E) staining. Figure 4 shows the H&E staining images (a) and Western blotting analysis (b) of mouse tumor tissues from the control group, nintedanib group, and the target compound prepared in Example 1. In a, 1, 2, 3, and 4 represent sites randomly selected from the full-view lung sections of mice in each group, and their magnified microscopic images are provided. Lung tissues from mice in the control group and nintedanib group showed fibrotic-like pulmonary nodules, which is inconsistent with the normal physiological structural characteristics of the lungs. Under a high-power microscope, the pulmonary nodule cells showed diffuse expansion, densely stained nuclei, and a large number of cells, similar to cancer cells, which can be identified as lung metastases of tumors. In contrast, the low-concentration target compound 1 treatment group showed only a few small nodules, while the high-concentration group showed no obvious nodules, which was significantly different from the control group and nintedanib group. Under high magnification, nude mice treated with 50 mg / kg of halogenated indole ketones showed thinner alveolar septa and no abnormal enlargement of alveoli and cell nuclei.

[0230] Tumor metastasis is always accompanied by epithelial-mesenchymal transition (EMT), a crucial stage in the invasive growth of tumor cells. Through EMT, tumor cells infiltrate the surrounding stroma, creating a microenvironment that promotes tumor growth and metastasis. Studies have shown that most signaling pathways related to EMT are associated with the downregulation of E-cadherin expression. E-cadherin is a calcium-dependent transmembrane glycoprotein expressed in most epithelial tissues; its reduced expression can decrease cell adhesion, making tumor cells more susceptible to migration and metastasis. To investigate the effect of target compounds on the expression of EMT-related proteins, two tumor tissues were randomly selected from each group of mice for Western blotting analysis. As shown in Figure 4b, E-cadherin expression disappeared in the control and nintedanib groups, while no change was observed in the halogenated indole ketone groups. The loss of E-cadherin expression in the control and nintedanib groups is consistent with tumor metastasis. The results in Figure 4b also show that halogenated indole ketones can effectively inhibit AXL kinase phosphorylation in a dose-dependent manner. Compared with the control group and the nintedanib group, the phosphorylation expression of AXL kinase was significantly reduced in the 25 mg / kg 11b group, while the phosphorylation expression of AXL kinase was completely absent in the 50 mg / kg 11b group. This indicates that halogenated indolone compounds can prevent the reduction of E-cadherin by inhibiting AXL activation, thereby inhibiting the EMT process.

[0231] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

Halogenated indole ketone compounds, characterized in that, This includes racemic compounds having the structure shown in Formula I or chiral compounds having the structure shown in Formula II: Wherein, R1 is a halogen; R2 includes hydrogen or C1-C4 alkyl groups; R4 includes C1-C4 alkyl groups; R3 includes C1-C4 alkyl, cycloalkyl, hydrocarbon group containing unsaturated bonds, heterocyclic group or alkylamine group; In Equation II, the wavy line represents the R configuration or the S configuration. The haloindolone compound according to claim 1 is characterized in that, The cycloalkyl group includes cyclopropyl or cyclobutyl; The hydrocarbon group containing unsaturated bonds includes an alkenyl group; The heterocyclic group includes any of the following structures: The alkylamine group includes N,N,N-trimethylethylenediamine, 2-ethoxy-N,N-dimethylamine, or 2-ethylthio-N,N-dimethylamine. The haloindolone compound according to claim 1 or 2 is characterized in that, It has any of the following structures: The method for preparing the haloindolone compound according to any one of claims 1 to 3 is characterized in that, Includes the following steps: Intermediate 3 and intermediate 4 were subjected to a substitution reaction to obtain the haloindolone compound; The intermediate 3 includes a racemic intermediate 3 or a chiral intermediate 3; The preparation method according to claim 4 is characterized in that, The substitution reaction includes: mixing intermediate 3, intermediate 4 and a first organic solvent, carrying out a first substitution reaction under a protective atmosphere, and then adding a first organic base to carry out a second substitution reaction. The preparation method according to claim 4 or 5 is characterized in that, The molar ratio of intermediate 3 to intermediate 4 is 1:1 to 1.

2. The preparation method according to claim 5 is characterized in that, The first organic solvent includes one or more of dimethylformamide, acetonitrile, and dimethyl sulfoxide. The preparation method according to claim 5 is characterized in that, The first organic base includes piperidine and / or dimethylamine; the molar ratio of intermediate 3 to the first organic base is 1:1.5 to 3. The preparation method according to claim 4, 5, 7 or 8 is characterized in that, The temperature for the substitution reaction is 70–90 °C. The preparation method according to claim 5, 7 or 8 is characterized in that, The first substitution reaction takes 1 to 2 hours, and the second substitution reaction takes 2 to 3 hours. The preparation method according to claim 4 is characterized in that, The preparation method of the racemic intermediate 3 includes the following steps: The acyl chloride was subjected to a fourth substitution reaction with N-methyl-4-nitroaniline to give intermediate 1; The intermediate 1 was subjected to a nucleophilic substitution reaction with HR3 to obtain racemic intermediate 2; The racemic intermediate 2 was subjected to a first hydrogenation reduction reaction to obtain the racemic intermediate 3; Where X is a halogen. The preparation method according to claim 11 is characterized in that, The preparation method of the acyl chloride includes the following steps: A halocarboxylic acid and thionyl chloride undergo a third substitution reaction to yield an acyl chloride; The preparation method according to claim 12 is characterized in that, The molar ratio of the halocarboxylic acid to thionyl chloride is 1:1 to 5; The third substitution reaction is carried out in the absence of a solvent or in the presence of a second organic solvent; The second organic solvent includes chloroform and / or acetonitrile; The third substitution reaction is carried out at a temperature of 65–85°C for 2–8 hours. The preparation method according to claim 11 is characterized in that, The molar ratio of the acyl chloride to N-methyl-4-nitroaniline is 1 to 1.2:1; The fourth substitution reaction is carried out in the presence of the first catalyst, the first deacidifying agent and the third organic solvent; The first catalyst comprises N,N-dimethylaminopyridine and / or pyridine; the molar ratio of N-methyl-4-nitroaniline to the first catalyst is 1:0.05 to 0.2; The first acid-removing agent comprises an organic amine; the molar ratio of N-methyl-4-nitroaniline to the first acid-removing agent is 1:1 to 1.5; The third organic solvent includes one or more of anhydrous acetonitrile, tetrahydrofuran, and dichloromethane; The fourth substitution reaction is carried out at a temperature of 15–45°C for 2–3 hours. The preparation method according to claim 11 is characterized in that, The HR3 includes any of the following structures: The molar ratio of intermediate 1 to HR3 is 1:1 to 3; The nucleophilic substitution reaction is carried out in the presence of a second scavenging agent and a fourth organic solvent; The second deacidifying agent comprises an organic amine; the molar ratio of intermediate 1 to the second deacidifying agent is 1:1 to 3; The fourth organic solvent includes acetonitrile and / or dioxane; The nucleophilic substitution reaction is carried out at a temperature of 80–100 °C for a time of 10–20 h. The preparation method according to claim 11 is characterized in that, The first hydrogenation reduction reaction includes: mixing racemic intermediate 2, hydrogenation catalyst and fifth organic solvent, and carrying out the first hydrogenation reduction reaction under a hydrogen atmosphere; The hydrogenation catalyst comprises palladium on carbon or stannous chloride; the mass of the hydrogenation catalyst is 5-20% of the mass of racemic intermediate 2; The fifth organic solvent includes anhydrous ethanol and / or methanol; The first hydrogenation reduction reaction takes 12 to 48 hours, and the hydrogen pressure is 0.1 to 0.505 MPa. The preparation method according to claim 4 is characterized in that, The preparation method of the chiral intermediate 3 includes the following steps: The p-toluenesulfonyl chloride was reacted with a 2-hydroxycarboxylic acid ester in a fifth substitution reaction to give compound 1; The compound 1 was subjected to a hydrolysis reaction to obtain compound 2; Compound 2 was subjected to a sixth substitution reaction with thionyl chloride to give compound 3; Compound 3 was reacted with N-methyl-4-nitroaniline in a seventh substitution reaction to give compound 4; Compound 4 was subjected to a nucleophilic substitution-transconfiguration reaction with HR3 to obtain chiral intermediate 2; The chiral intermediate 2 is subjected to a second hydrogenation reduction reaction to obtain the chiral intermediate 3; The configuration of chiral intermediate 2 is different from that of 2-hydroxycarboxylic acid ester, compound 1, compound 2, compound 3 and compound 4. The preparation method according to claim 17 is characterized in that, The molar ratio of the 2-hydroxycarboxylic acid ester to p-toluenesulfonyl chloride is 1:1 to 1.3; The toluenesulfonyl chloride is added dropwise under ice bath conditions; The fifth substitution reaction is carried out in the presence of a sixth organic solvent and a second organic base; The sixth organic solvent includes dichloromethane and / or chloroform; The second organic base includes an organic amine; the molar ratio of the 2-hydroxycarboxylic acid ester to the second organic base is 1:1 to 2; The fifth substitution reaction takes 10–30 hours. The preparation method according to claim 17 is characterized in that, The hydrolysis reaction is carried out under alkaline conditions, and the alkaline conditions include alkali metal hydroxides. The molar ratio of the 2-hydroxycarboxylic acid ester to the base is 1:1.5 to 2; The hydrolysis reaction time is 2 to 3 hours. The preparation method according to claim 17 is characterized in that, The molar ratio of compound 2 to thionyl chloride is 1:1 to 5; The thionyl chloride is added dropwise; The sixth substitution reaction is carried out in the presence of a seventh organic solvent; The seventh organic solvent includes dichloromethane and / or chloroform; The sixth substitution reaction is carried out at a temperature of 65–85°C for 2–8 hours. The preparation method according to claim 17 is characterized in that, The molar ratio of compound 3 to N-methyl-4-nitroaniline is 1 to 1.2:1; The seventh substitution reaction is carried out in the presence of the second catalyst, the third acid remover and the eighth organic solvent; The second catalyst comprises N,N-dimethylaminopyridine and / or pyridine; the molar ratio of N-methyl-4-nitroaniline to the second catalyst is 1:0.05 to 0.2; The third deacidifying agent includes an organic amine; the molar ratio of N-methyl-4-nitroaniline to the third deacidifying agent is 1:1 to 2; The eighth organic solvent includes one or more of anhydrous acetonitrile, tetrahydrofuran, and dichloromethane; The seventh substitution reaction is carried out at a temperature of 15–45°C for 2–3 hours. The preparation method according to claim 17 is characterized in that, The molar ratio of compound 4 to HR3 is 1:1 to 3; The nucleophilic substitution-transconfiguration reaction was carried out in the presence of the fourth deacidifying agent and the ninth organic solvent; The fourth deacidifying agent includes an organic amine; the molar ratio of compound 4 to the fourth deacidifying agent is 1:1 to 3.5; The ninth organic solvent includes acetonitrile and / or dioxane; The nucleophilic substitution-transconfiguration reaction is carried out at a temperature of 80–100 °C for a time of 10–24 h. The preparation method according to claim 17 is characterized in that, The second hydrogenation reduction reaction takes 12 to 48 hours. The preparation method according to claim 17 or 23 is characterized in that, The second hydrogenation reduction reaction includes: mixing the chiral intermediate 2, stannous chloride, and the tenth organic solvent to carry out a reduction reaction. The preparation method according to claim 24 is characterized in that, The tenth organic solvent includes methanol and / or ethanol. The preparation method according to claim 4 or 5 is characterized in that, The preparation method of the intermediate 4 includes the following steps: N-acetylindolone and triethyl orthobenzoate were condensed to give intermediate 4; The preparation method according to claim 26 is characterized in that, The molar ratio of N-acetylindolone to triethyl orthobenzoate is 1:1 to 3.5; The condensation reaction was carried out in the presence of acetic anhydride and under a protective atmosphere; The molar ratio of N-acetylindolone to acetic anhydride is 1:15-25; The condensation reaction is carried out at a temperature of 100–135°C for 1–4 hours. Halogenated indole ketone derivatives, characterized in that... Pharmaceutically acceptable salts and / or solvates of the halogenated indole ketones according to any one of claims 1 to 3. The haloindolone derivative according to claim 28 is characterized in that, The pharmaceutically acceptable salts include salts of organic acids or salts of inorganic acids. The haloindolone derivative according to claim 29 is characterized in that, The organic acids include methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid. The haloindolone derivative according to claim 29 is characterized in that, The inorganic acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. The haloindolone derivative according to claim 28 is characterized in that, The solvate includes hydrates. A pharmaceutical composition, characterized in that, It includes an active ingredient and pharmaceutically acceptable excipients; the active ingredient includes one or more of the haloindolone compounds according to any one of claims 1 to 3 and the haloindolone derivatives according to any one of claims 28 to 32. The pharmaceutical composition according to claim 33 is characterized in that, The dosage forms of the pharmaceutical composition include injections, tablets, capsules, pills, suspensions, or emulsions. The pharmaceutical composition according to claim 33 or 34 is characterized in that, The drug composition can be administered orally, by spray, or by injection, with the injection including subcutaneous injection, intravenous injection, or intramuscular injection. The pharmaceutical composition according to claim 33 or 34 is characterized in that, The active ingredient in the pharmaceutical composition has a mass content of 1-90%. The pharmaceutical composition according to claim 33 or 34 is characterized in that, Pharmaceutically acceptable excipients include one or more of the following: solubilizers, antioxidants, osmotic pressure regulators, suspending agents, fillers, disintegrants, wetting agents, and lubricants. The pharmaceutical composition according to claim 36 is characterized in that, The co-solvent includes one or more of polysorbate 80, lecithin, and polyethylene glycol; The antioxidants include vitamin C; The osmotic pressure regulator includes sodium chloride and / or glucose; The suspending agent includes glycerin; The filler includes one or more of microcrystalline cellulose, starch, pregelatinized starch, dicalcium phosphate and calcium sulfate; The disintegrant includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose, croscarmellose sodium, sodium carboxymethyl cellulose, and croscarmellose. The wetting agent comprises a 50-75 v / v% aqueous ethanol solution; The lubricant includes one or more of sodium stearate fumarate, magnesium stearate, calcium stearate, or silicon dioxide. The use of the haloindolone compound according to any one of claims 1 to 3, or the haloindolone derivative according to any one of claims 28 to 32, or the pharmaceutical composition according to any one of claims 33 to 35 in the preparation of a medicament for treating kinase-mediated diseases; The kinases include one or more of the following: tyrosine protein kinase receptor, serine / threonine protein kinase, tyrosine protein kinase, vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor-α, fibroblast growth factor receptor 1, neurotrophic factor receptor 2, non-receptor tyrosine kinase, tyrosine protein kinase, 5'-AMP-activated protein kinase subunit α1 / β1 / γ1, glycogen synthase kinase-3β, ribosomal protein S6 kinase α-1, tyrosine protein kinase, bispecific mitogen-activated protein kinase kinase 1, aurora kinase B, bispecific protein kinase, epidermal growth factor type A receptor 2, insulin-like growth factor 1 receptor, epidermal growth factor type B receptor 4, mitogen-activated protein kinase kinase 1, serine / threonine protein kinase, nonspecific serine / threonine protein kinase, nonspecific serine / threonine protein kinase, and glucokinase. The application according to claim 39 is characterized in that, The drugs include one or more of the following: antitumor drugs, anti-inflammatory drugs, antihypertensive drugs, drugs for treating cardiovascular diseases, drugs for treating diabetes, and drugs for treating autoimmune diseases. The application according to claim 40 is characterized in that, The tumors include one or more of pancreatic cancer, colorectal cancer, lung cancer, liver cancer, and stomach cancer.

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