4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline and a process and use thereof

Abstract

This invention relates to the field of medicinal chemistry, specifically disclosing 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, its preparation method, and its applications. A novel N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamide compound prepared from this intermediate is a dual inhibitor targeting EGFR and c-Met. The quinazoline core and sulfonamide biaryl side chain in its molecular structure can specifically recognize and bind to mutant EGFR and abnormally activated c-Met, significantly enhancing its selective killing effect on tumor cells. Pharmacodynamic studies show that it exhibits excellent inhibitory activity against the human lung cancer cell line (NCI-H1975) at the cellular level, with an IC50 of [missing information - likely an IC50 value] against p-EGFR. 50 A value of 1.56 nM for p-Met IC 50 The value is 1.8nM.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, its preparation method, and its application. Background Technology

[0002] Malignant tumors are among the leading diseases threatening human health worldwide. Traditional chemotherapy drugs face significant limitations in clinical application due to their poor selectivity and strong toxic side effects. In recent years, with the development of molecular targeted therapy technology, small molecule inhibitors targeting specific tumor cells have become a hot topic in anti-tumor drug research. These inhibitors precisely block signaling pathways related to tumor cell proliferation and survival, thereby improving treatment efficacy while reducing toxic side effects.

[0003] Among numerous tumor-related targets, c-Met and EGFR are two key receptor tyrosine kinases (RTKs). EGFR participates in regulating cell proliferation, differentiation, and apoptosis in normal cells. Mutations or overexpression of EGFR can lead to the continuous activation of downstream signaling pathways such as PI3K-AKT and RAS-MAPK, thereby driving the unlimited proliferation of tumor cells. Currently, single-target kinase inhibitors targeting EGFR are used clinically, but long-term use can easily lead to drug resistance due to secondary EGFR mutations (such as T790M) or bypass activation (such as c-Met amplification). c-Met, as a receptor for hepatocyte growth factor (HGF), can also promote tumor cell proliferation, invasion, metastasis, and angiogenesis through abnormal activation, and c-Met amplification is one of the main mechanisms of EGFR kinase inhibitor resistance. To address the problems of EGFR resistance mutations and bypass activation caused by c-Met amplification, developing dual-target kinase inhibitors that can simultaneously inhibit EGFR and c-Met has become an important strategy. These inhibitors can effectively inhibit tumor cell proliferation by simultaneously blocking two tumor-driving pathways, and can also avoid bypass activation resistance caused by single pathway inhibition in advance, which has important clinical significance and application prospects.

[0004] N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamides are a commonly used skeletal structure in c-Met / EGFR dual-target kinase inhibitors. Studies have shown that introducing a hydrophilic group at the 7-position of quinazolin and a biarylsulfonamide active fragment at the 4-position of phenoxy group can effectively enhance inhibitory activity. Currently, the synthetic methods of N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamides reported in the literature are as follows: starting from a nitro compound, an amine intermediate is obtained by catalytic hydrogenation; subsequently, the amine intermediate reacts with a bromine-containing aromatic sulfonyl chloride to generate a sulfonamide; finally, under palladium catalysis, the bromine-containing aromatic sulfonamide and a five-membered heteroarylboronic acid undergo a Suzuki coupling reaction in 1,2-dimethoxyethane under microwave irradiation at 140 °C to obtain N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamides.

[0005]

[0006] However, this synthesis method has obvious shortcomings: First, the sulfonyl chloride used in the sulfonation reaction has poor stability and is easily hydrolyzed, which affects the yield of large-scale production; second, the last step, the Suzuki coupling reaction, depends on microwave radiation equipment, which is expensive and limits its application in large-scale production. If the reaction is carried out by conventional heating, there will be more impurities and the yield will be low.

[0007] Therefore, developing an efficient, stable, and large-scale synthetic method suitable for N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamides (especially compounds with c-Met / EGFR dual-target inhibitory activity) is of great practical significance and application value. Summary of the Invention

[0008] To address the technical shortcomings of existing synthetic methods for N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide dual-target inhibitors, such as poor stability of sulfonyl chlorides, dependence on microwave radiation equipment, and limitations in large-scale production, as well as the lack of universal intermediates, this invention provides 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin, its preparation method, and its applications. This compound can serve as a key intermediate for the synthesis of N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compounds. The compounds prepared using this intermediate exhibit excellent inhibitory activity against EGFR and c-Met proteins, effectively inhibiting tumor cell proliferation while demonstrating good selective inhibition, i.e., minimal impact on normal cells, showing broad prospects for clinical application in oncology.

[0009] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: In a first aspect, the present invention provides 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, the structure of which is shown in formula (I):

[0010] Equation (Ⅰ).

[0011] The 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline provided by this invention can serve as a key intermediate for the preparation of N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamides. This quinazoline intermediate, with its pre-constructed key structural units such as the quinazoline core, methoxy group, piperazine propoxy group, and 4-fluoro-3-iodophenoxy group, significantly shortens the synthetic route in the preparation of N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamides. Simultaneously, the iodine atom at the 2-position phenoxy group provides an efficient coupling site for the diversified introduction of biarylsulfonamide fragments. Furthermore, this intermediate is stable, has a mature synthetic route, and is easy to store, transport, and scale up industrially, providing strong support for the efficient synthesis and structural optimization of N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamides.

[0012] Secondly, the present invention provides a method for preparing the above-mentioned 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, comprising the following steps: Under the conditions of S1, phosphine activator and azo reagent, 4-chloro-6-methoxyquinazoline-7-ol and 1-(3-hydroxypropyl)-4-methylpiperazine were subjected to the Mitsunobu reaction in aprotic solvent a to obtain compound A-1 as shown in formula (II);

[0013] Formula (II) S2, under alkaline conditions, compound A-1 and 2-fluoro-4-iodophenol undergo an SNAr reaction in aprotic solvent b to give 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (compound A). The specific reaction route is as follows:

[0014] The present invention provides a method for preparing 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline. In step S1, the Mitsunobu reaction is used to couple 4-chloro-6-methoxyquinazoline-7-ol with 1-(3-hydroxypropyl)-4-methylpiperazine, precisely introducing a propoxy side chain containing methylpiperazine onto the quinazoline core, avoiding redundant steps of hydroxyl protection and deprotection, and improving atom economy. Secondly, in step S2, the SNAr reaction is used to nucleophilically substitute the 4-chloroquinazoline site of compound A-1 with 2-fluoro-4-iodophenol, precisely constructing the 4-aryloxyquinazoline skeleton. At the same time, the inductive effect of fluorine and iodine atoms enhances the acidity of the phenolic hydroxyl group, improves the reactivity, and ensures high selectivity and product purity. The overall route requires only two core reactions, resulting in high synthetic efficiency. It provides a reliable pathway for the efficient and large-scale preparation of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline.

[0015] As a specific embodiment of the present invention, the specific steps of S1 are as follows: 4-Chloro-6-methoxyquinazoline-7-ol, 3-(4-methylpiperazin-1-yl)prop-1-ol and phosphine activator were dissolved in an aprotic solvent. Under nitrogen protection, an azo reagent was added at -5℃ to 5℃. After the addition was complete, the temperature was naturally raised to 15℃ to 30℃ and the reaction continued for 8 to 16 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The organic phase was separated by silica gel column chromatography to obtain compound A-1.

[0016] Furthermore, in S1, the molar ratio of 4-chloro-6-methoxyquinazoline-7-ol to 1-(3-hydroxypropyl)-4-methylpiperazine is 1:1.2 to 1:2.5.

[0017] Further, in S1, the molar ratio of 4-chloro-6-methoxyquinazoline-7-ol to phosphine activator is 1:2 to 1:4.

[0018] Further, in S1, the phosphine activator is selected from one or both of triphenylphosphine (PPh3) or tributylphosphine (PBu3), preferably triphenylphosphine (PPh3).

[0019] Further, in S1, the molar ratio of 4-chloro-6-methoxyquinazoline-7-ol to the azo reagent is 1:2 to 1:4.

[0020] Further, in S1, the azo reagent is selected from at least one of diethyl azodicarbonate (DEAD), di-tert-butyl azodicarbonate (DBAD), or diisopropyl azodicarbonate (DIAD), preferably di-tert-butyl azodicarbonate (DBAD).

[0021] Furthermore, in S1, the aprotic solvent a is tetrahydrofuran.

[0022] Furthermore, in S1, the mass-to-volume ratio of 4-chloro-6-methoxyquinazoline-7-ol to aprotic solvent a is 1 g: (15~20) / mL.

[0023] Furthermore, in S1, the temperature of the Mitsunobu reaction is 25°C, and the reaction time is 16 hours.

[0024] Further, in S1, the eluent for silica gel chromatography separation is dichloromethane and methanol in a volume ratio of 30:1 to 100:1.

[0025] As a specific embodiment of the present invention, step S2 is as follows: Compound A-1 and 2-fluoro-4-iodophenol were dissolved in an aprotic solvent, and an alkaline reagent was added. The mixture was heated to 80℃~120℃ and stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature, water was added and the mixture was slurried, filtered, and washed with ethyl acetate to obtain 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin.

[0026] Furthermore, in S2, the molar ratio of compound A-1 to 2-fluoro-4-iodophenol is 1:1.2 to 1:2.

[0027] Furthermore, in S2, the molar ratio of compound A-1 to the basic reagent is 1:2 to 1:3.5.

[0028] Further, in S2, the alkaline reagent is selected from at least one of triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N-diisopropylethylamine (DIEA), preferably N,N-diisopropylethylamine (DIEA).

[0029] Furthermore, in S2, the aprotic solvent b is selected from one or both of toluene and acetonitrile, preferably toluene.

[0030] Furthermore, in S2, the mass-to-volume ratio of compound A-1 to aprotic solvent b is 1 g: (10~20) mL.

[0031] Furthermore, in S2, the SNAr reaction is carried out at a temperature of 120°C for a reaction time of 16 hours.

[0032] Thirdly, the present invention provides the use of the above-mentioned 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin in the preparation of N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compounds.

[0033] Fourthly, the present invention provides an N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound, the structure of which is shown in formula (a):

[0034] Formula (a).

[0035] The quinazoline core and sulfonamide biaryl side chain of the above compound can specifically recognize and bind to mutant EGFR and abnormally activated c-Met, significantly enhancing its selective killing effect on tumor cells. Pharmacodynamic studies showed that this compound exhibited excellent inhibitory activity in the human lung cancer cell line (NCI-H1975), with an IC50 of [missing information - likely related to EGFR phosphorylation or p-EGFR]. 50 The IC50 value for phosphorylated c-Met (p-Met) is 1.56 nM. 50 With a value of 1.8 nM, it demonstrates strong dual-target inhibition potential, laying a material foundation for solving the challenges of EGFR-TKI resistance and c-Met-driven tumor treatment.

[0036] Fifthly, the present invention provides a method for preparing the above-mentioned N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound, comprising the following steps: In step a, under palladium catalyst and inorganic base conditions, 3-bromobenzenesulfonamide and 3-thiopheneboronic acid were subjected to a Suzuki coupling reaction in a solvent to obtain compound B as shown in formula (III);

[0037] Formula (III) In step b, under copper catalyst, alkaline reagent, and ligand conditions, 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline and compound B were subjected to the Ullmann reaction in an aprotic solvent to yield the N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamide compound shown in formula (a). The reaction route is as follows:

[0038] Each step of this method utilizes mature transition metal catalytic coupling technology, with easily scaled-up reaction conditions and precisely controllable product structures. This provides a reliable pathway for the large-scale preparation and structural diversification of target compounds, while also laying an efficient synthetic foundation for the development of dual-target inhibitors targeting EGFR / c-Met.

[0039] As a specific embodiment of the present invention, step a is as follows: 3-Bromobenzenesulfonamide, 3-thiopheneboronic acid, palladium catalyst and inorganic base were added to the solvent. Under nitrogen protection, the temperature was raised to 90℃~125℃ and the reaction was carried out for 11h~19h. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The solution was then separated by silica gel chromatography to obtain compound B.

[0040] Further, in step a, the molar ratio of 3-bromobenzenesulfonamide to 3-thiopheneboronic acid is 1:1.2 to 1:2.

[0041] Further, in step a, the molar ratio of 3-bromobenzenesulfonamide to palladium catalyst is 1:0.05 to 1:0.1.

[0042] Further, in step a, the palladium catalyst is selected from at least one of Pd(PPh3)4, Pd(PPh3)3Cl2 or Pd(dppf)Cl2, preferably Pd(PPh3)4.

[0043] Further, in step a, the molar ratio of 3-bromobenzenesulfonamide to inorganic base is 1:2 to 1:3.5.

[0044] Further, in step a, the inorganic base is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, or cesium carbonate, preferably cesium carbonate.

[0045] Further, in step a, the solvent is an aqueous solution of dioxane, an aqueous solution of methanol, an aqueous solution of ethanol, or an aqueous solution of N,N-dimethylformamide.

[0046] Specifically, in step a, the solvent is a 1,4-dioxane-aqueous solution with a volume ratio of (3~8):1, a methanol-aqueous solution with a volume ratio of (3~5):1, an ethanol-aqueous solution with a volume ratio of (3~5):1, or an N,N-dimethylformamide-aqueous solution with a volume ratio of (3~6):1. Preferably, it is a 1,4-dioxane-aqueous solution with a volume ratio of (3~8):1.

[0047] Further, in step a, the mass-to-volume ratio of 3-bromobenzenesulfonamide to solvent is 1 g: (10~20) mL.

[0048] Further, in step a, the temperature of the Suzuki coupling reaction is 95℃~110℃, and the reaction time is 15h~18h. Preferably, the reaction temperature is 100℃, and the reaction time is 16h.

[0049] Further, in step a, the eluent for silica gel chromatography is petroleum ether and ethyl acetate in a volume ratio of 60:1 to 100:1.

[0050] As a specific embodiment of the present invention, step b is as follows: 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, compound B, copper catalyst, basic reagent and ligand were added to a reaction flask. After nitrogen purging, an aprotic solvent was added, and the reaction solution was stirred at 60℃~80℃ for 6h~10h. After the reaction was completed, the reaction solution was cooled to room temperature, ammonia was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness and separated by silica gel column chromatography to obtain compound I.

[0051] Further, in step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to compound B is 1:1 to 1:1.5.

[0052] Further, in step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the copper catalyst is 1:0.05 to 1:0.1.

[0053] Further, in step b, the copper catalyst is selected from one or both of cuprous iodide or cuprous bromide, preferably cuprous iodide.

[0054] Further, in step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the ligand is 1:0.5 to 1:1.

[0055] Further, in step b, the ligand is selected from one or two of 2,2'-bipyrido[1,10]o-phenanthroline (Bphen) or N,N-dimethylethylenediamine (DMEDA), preferably N,N-dimethylethylenediamine (DMEDA).

[0056] Further, in step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the alkaline reagent is 1:2 to 1:3.5.

[0057] Furthermore, in step b, the alkaline reagent is selected from potassium carbonate (K2CO3), potassium phosphate (K3PO4), etc., preferably K2CO3.

[0058] Further, in step b, the aprotic solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile, preferably acetonitrile.

[0059] Further, in step b, the mass-to-volume ratio of the 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the aprotic solvent is 1 g: (10~20) mL.

[0060] Furthermore, in step b, the Ullmann reaction is carried out at a temperature of 70°C for 8 hours.

[0061] Further, in step b, the eluent for silica gel chromatography separation is dichloromethane and methanol in a volume ratio of 10:1 to 20:1.

[0062] In a sixth aspect, the present invention also provides the use of the above-mentioned N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compounds and / or their pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, polymorphs, and isotope-labeled compounds in the preparation of inhibitors targeting EGFR and c-Met proteins.

[0063] In a seventh aspect, the present invention also provides a pharmaceutical composition comprising the above-described N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound and / or its pharmaceutically acceptable salt, stereoisomer, prodrug, solvate, polymorph, or isotope label.

[0064] It should be noted that the pharmaceutically acceptable salts described in this invention refer to those prepared from the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compounds of this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.

[0065] Specifically, the pharmaceutically acceptable salt is a salt formed by the corresponding compound and a base, including but not limited to one or more of sodium salts, potassium salts, magnesium salts, and ammonium salts.

[0066] Furthermore, the pharmaceutical compositions of this invention also include stereoisomers of the compounds of this invention (such as enantiomers and diastereomers), prodrugs (which can be metabolized or transformed in vivo to release the active ingredient), solvates (such as hydrates), polymorphs (different crystal forms), and isotope-labeled compounds (such as deuterated compounds). All of the above forms possess similar or improved pharmacokinetic properties and pharmacodynamic activities, and can be selected according to actual formulation requirements.

[0067] Eighthly, the present invention also provides a pharmaceutical formulation which is a pharmaceutically acceptable dosage form made of the above-mentioned N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound and / or its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, polymorphs, and isotope-labeled compounds as active components and pharmaceutically acceptable excipients.

[0068] The dosage forms include conventional diluents, excipients, fillers, binders, humectants, disintegrants, absorption promoters, surfactants, adsorbents, lubricants, etc. in the pharmaceutical field, and flavorings, sweeteners, etc. may be added as needed.

[0069] Specifically, the dosage form can be any one of tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powder for injection, or injections. All of the above dosage forms can be prepared using conventional methods in the pharmaceutical field, and this invention does not impose any special limitations.

[0070] In a ninth aspect, the present invention also provides the use of the above-mentioned N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compounds and / or their pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, polymorphs, and isotope-labeled compounds in the preparation of antitumor drugs.

[0071] Furthermore, the indications for the aforementioned antitumor drugs include lung cancer, colorectal cancer, gastric cancer, and bile duct cancer.

[0072] To address the process defects in the synthesis of N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamides in existing technologies, this invention provides a key intermediate compound A (4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline). Its preparation method utilizes readily available raw materials and is simple, effectively avoiding the risk of hydrolysis of sulfonyl chloride in traditional synthetic routes, significantly improving process stability. Furthermore, it does not rely on harsh reaction conditions such as microwave radiation; the reaction conditions are mild and safe, suitable for industrial production. The novel N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamides prepared from this intermediate are dual inhibitors targeting EGFR and c-Met. The quinazoline core and the sulfonamide biaryl side chain in its molecular structure can specifically recognize and bind to mutant EGFR and abnormally activated c-Met, significantly enhancing the selective killing effect on tumor cells. Pharmacodynamic studies showed that this compound exhibited excellent inhibitory activity in the human lung cancer cell line (NCI-H1975), with an IC50 of 10⁻⁶ for p-EGFR. 50 A value of 1.56 nM for p-Met IC 50 With a value of 1.8 nM, it can effectively overcome the drug resistance problem easily caused by single-target inhibitors, and has both excellent clinical application potential and industrial application prospects. Detailed Implementation

[0073] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0074] This invention provides a method for preparing a quinazoline derivative, comprising the following steps: Under the conditions of S1, phosphine activator and azo reagent, 4-chloro-6-methoxyquinazoline-7-ol and 1-(3-hydroxypropyl)-4-methylpiperazine were subjected to the Mitsunobu reaction in aprotic solvent a to give compound A-1. S2, under alkaline reagent conditions, compound A-1 and 2-fluoro-4-iodophenol were subjected to an SNAr reaction in aprotic solvent b to give 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (compound A). Under S3 conditions with palladium catalyst and inorganic base, 3-bromobenzenesulfonamide and 3-thiopheneboronic acid undergo a Suzuki coupling reaction in solvent to give compound B. Under conditions of S4, copper catalyst, basic reagent, and ligand, 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline and compound B were reacted in an aprotic solvent via the Ullmann reaction to yield N-[4-(quinazoline-4-yl)oxyphenyl]biarylsulfonamide (compound I). The specific reaction route is as follows:

[0075] To better illustrate the present invention, further examples are provided below.

[0076] Example 1 Synthetic method of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (compound A):

[0077] Step 1: Mitsunobu reaction: 4-chloro-6-methoxyquinazoline-7-ol (100.0 g, 0.475 mol), THF (2000 mL), 1-(3-hydroxypropyl)-4-methylpiperazine (187.9 g, 1.188 mol), and triphenylphosphine (373.8 g, 1.425 mol) were added sequentially to a reaction flask. Then, under nitrogen protection, di-tert-butyl azodicarbonate (DBAD) (328.1 g, 1.425 mol) was added at 0 °C. The mixture was then naturally heated to 25 °C and reacted for 16 h. After the reaction was complete, the reaction solution was poured into water and extracted three times with ethyl acetate. The reaction solution was concentrated to dryness, and the residue was separated by silica gel column chromatography (DCM / MeOH = 100 / 1~30 / 1). The residue was evaporated to dryness to give compound A-1 (115.5 g, yellow solid), yield: 69.3%.

[0078] 1 H NMR (500 MHz, DMSO- d 6) δ 9.56 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 4.24 (t, J = 5.6 Hz, 2H), 3.83 (t, J = 5.6 Hz, 3H), 2.46 (t, J = 5.6 Hz, 2H), 2.23 (m, 8H), 2.14 (s, 3H), 1.82 (m, 2H).

[0079] ESI-MS (m / z): 351.15 [M+H] + .

[0080] Step 2: SNAr reaction: Compound A-1 (50.0 g, 0.143 mol) and 2-fluoro-4-iodophenol (50.9 g, 0.214 mol) prepared above were added sequentially to the reaction flask and dissolved in toluene (1000 mL). Then N,N-diisopropylethylamine (55.4 g, 0.429 mol) was added. The reaction solution was stirred overnight at 120 °C. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to form a slurry, and the mixture was filtered. The slurry was washed with EA, and the filter cake was dried to obtain compound A (63.8 g, white solid). Yield: 80.8%.

[0081] The proton NMR spectrum characteristics of compound A are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.63 (d,J = 8.2 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 7.16 (d,J = 8.1 Hz, 1H), 6.57 (d, J = 7.8 Hz, 1H), 4.02 (t, J = 4.6 Hz, 2H), 3.91 (t,J = 5.6 Hz, 3H), 2.47 (t, J = 5.6 Hz, 2H), 2.29 (m, 8H), 2.13 (m, 3H), 1.81(s, 2H).

[0082] The characteristics detected by nuclear magnetic resonance are: ESI-MS (m / z): 553.39 [M+H] + . The synthesis method of compound A can also employ other reaction conditions defined in this invention, and as long as they are within the scope defined in this invention, they can achieve technical effects that are substantially equivalent to those described above.

[0083] Example 2 Synthetic method of N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl]oxyphenyl]-3-(thiophen-3-yl)benzenesulfonamide (compound I):

[0084] Step 1: Suzuki coupling reaction: 3-bromobenzenesulfonamide (100.0 g, 0.424 mol), 3-thiopheneboronic acid (65.1 g, 0.509 mol), Pd(PPh3)4 (24.3 g, 0.021 mol) and Cs2CO3 (276.3 g, 0.848 mol) were added to dioxane (1000 mL) and water (200 mL). The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The reaction solution was concentrated to dryness, and the residue was separated by silica gel column chromatography (PE / EA = 100 / 1~60 / 1). The residue was evaporated to dryness to give compound B (90.3 g, white solid), yield: 89.0%.

[0085] Step 2: Ullmann reaction: Compound A (60.0 g, 0.109 mol), compound B (31.3 g, 0.131 mol), CuI (0.95 g, 0.005 mol), K2CO3 (31.5 g, 0.228 mol), and N,N-dimethylethylenediamine (DMEDA) (4.8 g, 0.055 mol) prepared above were added sequentially to the reaction flask. After nitrogen purging, acetonitrile (600 mL) was added. The reaction mixture was stirred at 70 °C for 8 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and ammonia was slowly added to the reaction mixture. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (DCM / MeOH = 20 / 1~10 / 1), and evaporated to dryness to obtain compound I (40.8 g, yellow solid), yield: 56.4%.

[0086] 1 H NMR: (500 MHz, DMSO- d6) δ 10.17 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 3.8 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.44 (d, J= 7.8 Hz, 1H), 7.38 (d, J = 3.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.64 (d, J= 8.8 Hz, 1H), 6.55 (dd, J = 8.8, 2.4 Hz, 1H), 4.25 (t, J = 6.3 Hz, 2H), 4.00(s, 3H), 2.48 - 2.43 (m, 10H), 2.15 (s, 3H), 2.01 - 1.94 (m, 2H).

[0087] ESI-MS (m / z): 664.36 [M+H] + .

[0088] The synthesis method of compound I can also employ other reaction conditions defined in this invention, and as long as they are within the scope defined in this invention, they can achieve technical effects that are substantially equivalent to those described above.

[0089] Example 3 In vitro bioactivity test The effects of target compound I on the total protein levels and phosphorylation levels of p-EGFR and p-Met were detected by Western blot (WB) assay in the human lung adenocarcinoma cell line (NCI-H1975). The experimental results are shown in Table 1.

[0090] Western blot assay: NCI-H1975 cells were seeded at a concentration of 400,000 / mL in 12-well plates and cultured for 24 h. Different concentrations of compound I were then added and incubated in an incubator. After 24 h of drug treatment, the plates were collected, and all cells were transferred to 1.5 mL centrifuge tubes. The cells were centrifuged at 4000 rpm for 3 min at 4 ℃, the supernatant was discarded, and the cells were washed once with 1 mL of PBS. The cells were centrifuged again, the supernatant was discarded, and the cells were placed in liquid nitrogen to lyse the cell membranes to terminate stimulation. Cell lysis buffer containing 1% PMSF protease inhibitor and 1% phosphatase inhibitor was added. After lysing the cells for 10 min, the cells were centrifuged at 12000 rpm for 10 min at 4 ℃. The supernatant was used for BCA quantification, and 20 μg of protein was loaded for Western blot analysis.

[0091] Table 1 Results of bioactivity evaluation

[0092] The results showed that compound I exhibited good inhibitory activity against both p-MET and p-EGFR, with an IC50 inhibitory activity against p-MET of [value missing]. 50 The value was 1.8 nM, and the IC50 value for the inhibitory activity against p-EGFR was 1.8 nM. 50 The value is 1.56 nM, which provides a new research direction and a certain research foundation for the subsequent development of dual-target inhibitors.

[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1,4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, characterized in that, Its structure is shown in equation (Ⅰ): Equation (Ⅰ).

2. The method for preparing 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline according to claim 1, characterized in that, Includes the following steps: Under the conditions of S1, phosphine activator and azo reagent, 4-chloro-6-methoxyquinazoline-7-ol and 1-(3-hydroxypropyl)-4-methylpiperazine were subjected to the Mitsunobu reaction in aprotic solvent a to obtain compound A-1 as shown in formula (II); Formula (II) S2, under alkaline reagent conditions, compound A-1 and 2-fluoro-4-iodophenol undergo an SNAr reaction in aprotic solvent b to give 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin.

3. The method for preparing 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline as described in claim 2, characterized in that, In S1, the molar ratio of 4-chloro-6-methoxyquinazoline-7-ol to 1-(3-hydroxypropyl)-4-methylpiperazine is 1:1.2 to 1:2.5; and / or In S1, the molar ratio of 4-chloro-6-methoxyquinazoline-7-ol to the phosphine activator is 1:2 to 1:4; and / or In S1, the molar ratio of 4-chloro-6-methoxyquinazoline-7-ol to the azo reagent is 1:2 to 1:4; and / or In S1, the temperature of the Mitsunobu reaction is 15°C to 30°C; and / or In S1, the phosphine activator is selected from one or both of triphenylphosphine and tributylphosphine; and / or In S1, the azo reagent is selected from at least one of diethyl azodicarbonate, di-tert-butyl azodicarbonate, or diisopropyl azodicarbonate; and / or In S1, the aprotic solvent a is tetrahydrofuran; and / or In S2, the molar ratio of compound A-1 to 2-fluoro-4-iodophenol is 1:1.2 to 1:2; and / or In S2, the molar ratio of compound A-1 to the basic reagent is 1:2 to 1:3.5; and / or In S2, the SNAr reaction temperature is 80℃~120℃; and / or In S2, the basic reagent is selected from at least one of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or N,N-diisopropylethylamine; and / or In S2, the aprotic solvent b is selected from one or both of toluene and acetonitrile.

4. The use of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin of claim 1 in the preparation of N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compounds.

5. N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound, characterized in that, Its structure is shown in equation (a): Formula (a).

6. The method for preparing the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound according to claim 5, characterized in that, Includes the following steps: In step a, under palladium catalyst and inorganic base conditions, 3-bromobenzenesulfonamide and 3-thiopheneboronic acid were subjected to a Suzuki coupling reaction in a solvent to obtain compound B as shown in formula (III); Formula (III) In step b, under the conditions of copper catalyst, alkaline reagent and ligand, 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin and compound B are subjected to the Ullmann reaction in an aprotic solvent to obtain the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound shown in formula (a).

7. The method for preparing the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound as described in claim 6, characterized in that, In step a, the molar ratio of 3-bromobenzenesulfonamide to 3-thiopheneboronic acid is 1:1.2 to 1:2; and / or In step a, the molar ratio of 3-bromobenzenesulfonamide to palladium catalyst is 1:0.05 to 1:0.1; and / or In step a, the molar ratio of 3-bromobenzenesulfonamide to the inorganic base is 1:2 to 1:3.5; and / or In step a, the palladium catalyst is selected from at least one of Pd(PPh3)4, Pd(PPh3)3Cl2, or Pd(dppf)Cl2; and / or In step a, the inorganic base is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, or cesium carbonate; and / or In step a, the solvent is an aqueous solution of dioxane, an aqueous solution of methanol, an aqueous solution of ethanol, or an aqueous solution of N,N-dimethylformamide; and / or In step a, the temperature of the Suzuki coupling reaction is 90°C to 125°C; and / or In step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to compound B is 1:1 to 1:1.5; and / or In step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the copper catalyst is 1:0.05 to 1:0.1; and / or In step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the ligand is 1:0.5 to 1:1; and / or In step b, the molar ratio of 4-(2-fluoro-4-iodophenoxy)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline to the basic reagent is 1:2 to 1:3.5; and / or In step b, the copper catalyst is selected from one or both of cuprous iodide and cuprous bromide; and / or In step b, the ligand is selected from one or both of 2,2'-bipyrido[1,10]o-phenanthroline or N,N-dimethylethylenediamine; and / or In step b, the aprotic solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile; and / or In step b, the temperature of the Ullmann reaction is 60°C to 80°C.

8. The use of the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound of claim 5 and / or its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, polymorphs, and isotope-labeled compounds in the preparation of inhibitors targeting EGFR and c-Met proteins.

9. A pharmaceutical composition, characterized in that, Includes the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound of claim 5 and / or its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, polymorphs, and isotope-labeled compounds.

10. A pharmaceutical preparation, characterized in that, It is a pharmaceutically acceptable dosage form made with the N-[4-(quinazolin-4-yl)oxyphenyl]biarylsulfonamide compound as described in claim 5 and / or its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, polymorphs, and isotope-labeled compounds as active components and pharmaceutically acceptable excipients.

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