A sulfonylurea-containing compound, and a preparation method and application thereof

Abstract

The application discloses a sulfonylurea-containing compound and a preparation method and application thereof, and relates to the technical field of preparation and application of pharmaceutical inhibitors. The sulfonylurea-containing compound has the structure of: The preparation method is realized through three steps: raw materials are subjected to a Suzuki coupling reaction to synthesize an intermediate 1, subjected to a Sonogashira coupling reaction to obtain an intermediate 2, and subjected to a Williamson reaction to synthesize a target compound. Through the synergistic effect of a sulfonyl group and a urea group, precise recognition and efficient embedding of a kinase ATP binding pocket are realized, and the technical bottlenecks of poor selectivity, easy drug resistance and complex synthesis process of traditional c-Met inhibitors are solved.

Description

Technical Field

[0001] This invention relates to the field of preparation and application technology of pharmaceutical inhibitor compounds, specifically to a compound containing a sulfonylurea structure, its preparation method, and its application. Background Technology

[0002] Protein kinases play a central role in cell signal transduction pathways, and abnormalities in their catalytic activity are closely related to the development and progression of various diseases, especially in the field of oncology. Overexpression or mutation of receptor tyrosine kinases is a key mechanism driving tumor proliferation, invasion, and metastasis. c-Met receptor tyrosine kinase, as an important member of this pathway, has had its signaling pathway abnormally activated, and its association with the progression, poor prognosis, and drug resistance development of various solid tumors, including lung cancer, gastric cancer, colon cancer, and breast cancer, proven significant. Developing highly efficient and selective c-Met kinase inhibitors has become an important direction in anti-tumor drug research and development.

[0003] Currently, some small-molecule c-Met inhibitors have entered clinical research or application stages, but they still face many challenges in practical application. First, many existing inhibitors suffer from insufficient selectivity, potentially inhibiting other kinases simultaneously, leading to off-target effects and dose-limiting toxicity, thus restricting their clinical application window. Second, secondary resistance mutations are prone to occur during treatment, resulting in decreased drug sensitivity and treatment failure. Furthermore, some compounds exhibit poor metabolic stability in vivo, low oral bioavailability, or complex synthetic routes and high costs, making it difficult to meet the needs of industrial production and clinical use.

[0004] Sulfonylureas exhibit promising regulatory potential in medicinal chemistry due to their unique molecular skeleton and electron distribution characteristics. The sulfonyl group in this structure acts as a strong electron-withdrawing group, while the urea group provides hydrogen bonding capability; their synergy may enable efficient and precise targeting of the ATP-binding pocket of the kinase. However, systematic research on the application of this structure to c-Met kinase inhibitors is still insufficient, especially regarding in-depth exploration of their structure-activity relationship, selective regulation, and druggability.

[0005] Therefore, there is an urgent need in this field for a new type of c-Met kinase inhibitor that is structurally novel, highly active, highly selective, and has a feasible synthetic process. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing c-Met inhibitors, such as poor selectivity, easy development of drug resistance, and complex synthesis processes, and to provide a novel sulfonylurea-containing compound with excellent activity and good drug-like properties, as well as its preparation method and application.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] In a first aspect, the present invention provides a compound containing a sulfonylurea structure, wherein the sulfonylurea compound is a compound represented by Formula 1:

[0009] Formula 1;

[0010] R1 is selected from: alkyl groups having 1-10 carbon atoms, alkoxy groups having 1-10 carbon atoms, aryl groups having 6-15 carbon atoms, and heteroaryl groups having 5-10 carbon atoms;

[0011] Or R1 may be selected from: aryl groups with 6-15 carbon atoms substituted by alkyl groups with 1-10 carbon atoms.

[0012] Furthermore, the alkyl group having 1-10 carbon atoms is selected from: , , , , ;

[0013] The alkoxy groups with 1-10 carbon atoms are selected from: , ;

[0014] The This is a linking site.

[0015] Furthermore, the aryl groups with 6-15 carbon atoms are selected from: , , ;

[0016] Furthermore, the heteroaryl groups with 4-10 carbon atoms are selected from: , , , , , .

[0017] Furthermore, the aryl group substituted with an alkyl group having 1-10 carbon atoms and having 6-15 carbon atoms is selected from:

[0018] , , , .

[0019] Furthermore, the sulfonylurea-containing compound is selected from compounds with the following structures:

[0020] ;

[0021] ;

[0022] ;

[0023] ;

[0024] ;

[0025] ;

[0026] ;

[0027] ;

[0028] ;

[0029] .

[0030] Furthermore, the compound can be prepared into pharmaceutically acceptable salts or isotopes.

[0031] Furthermore, the pharmaceutically acceptable salt is a hydrochloride, sulfate, phosphate, trifluoroacetate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, tartrate, maleate, fumarate, succinate, or malate.

[0032] Furthermore, the isotope is H in the compound is replaced with deuterium.

[0033] Secondly, the present invention provides a method for preparing a compound containing a sulfonylurea structure, comprising the following steps:

[0034]

[0035] In the first step, raw material 1 and raw material 2 were synthesized into intermediate 1 via a Suzuki coupling reaction;

[0036] In the second step, intermediate 1 and raw material 3 undergo a coupling reaction to obtain intermediate 2;

[0037] In the third step, intermediate 2 and raw material 4 are synthesized by Williamson reaction to obtain the compound shown in Formula 1, which is a compound containing a sulfonylurea structure.

[0038] Furthermore, the raw material 1 is selected from compounds with the following structures: , , , , , , , , , , , , , , , , , , , Any one of them.

[0039] Thirdly, the present invention provides a sulfonylurea-containing compound and its pharmaceutically acceptable salt or isotope for use in the preparation of products that regulate protein kinase catalytic activity.

[0040] Furthermore, the protein kinase is a c-Met receptor tyrosine kinase.

[0041] Fourthly, the present invention provides the use of a sulfonylurea-containing compound and its pharmaceutically acceptable salt or isotope in the preparation of drugs for lung cancer, gastric cancer, colon cancer and / or breast cancer.

[0042] The sulfonylurea-containing compound provided by this invention addresses key issues of existing c-Met inhibitors, such as poor selectivity, easy development of drug resistance, and complex synthesis processes, through its unique molecular design. In its core sulfonylurea skeleton, the sulfonyl group, as a strong electron-withdrawing group, synergistically interacts with the urea group through hydrogen bonding, enabling the molecule to precisely recognize and efficiently embed into the ATP-binding pocket of c-Met kinases. This significantly enhances the selective inhibition of the target kinase and effectively avoids toxic side effects caused by off-target effects. This rigid skeleton structure also endows the compound with excellent resistance to drug resistance, maintaining a stable hydrogen bond interaction network even in the face of common mutations. Furthermore, this invention employs a three-step synthetic route involving Suzuki coupling, sage coupling, and Williamson reaction, utilizing readily available raw materials and mild conditions, significantly improving process feasibility and economy. The compound's excellent drug-like properties, including improved solubility through salt formation, extended metabolic half-life through deuteration, and a balanced lipid-water partition coefficient, collectively demonstrate a comprehensive advantage over existing technologies in terms of inhibitory activity, selectivity, and clinical applicability.

[0043] Compared with the prior art, the beneficial effects of the present invention are:

[0044] 1. Significantly improves target selectivity: Through the synergistic effect of the unique sulfonylurea structure, it achieves precise recognition and efficient insertion into the ATP-binding pocket of c-Met kinase, effectively reducing off-target effects and lowering potential toxic side effects.

[0045] 2. Enhanced resistance to drug resistance: The rigid molecular skeleton and stable hydrogen bond network design enable the compound to maintain inhibitory activity in the face of common mutations, overcoming the problem of traditional inhibitors easily developing drug resistance.

[0046] 3. Optimize the synthesis process and drug-like properties: A simple three-step synthesis route (Suzuki coupling, Sophora flavescens coupling, Williamson reaction) is adopted, with mild conditions and readily available raw materials, which greatly improves the feasibility and economy of the process; at the same time, the solubility and metabolic stability are further improved through salt formation and isotope substitution strategies (such as deuteration), enhancing clinical applicability. Attached Figure Description

[0047] Figure 1 The NMR spectrum of chemical substance 4 (i.e., raw material 2 in the examples) described in this invention;

[0048] Figure 2 The NMR spectrum of chemical substance 7 (i.e., raw material 4 in the examples) described in this invention;

[0049] Figure 3 The NMR spectrum of compound 1 described in Example 1 of this invention;

[0050] Figure 4 The NMR spectrum of compound 4 described in Example 2 of this invention;

[0051] Figure 5 The NMR spectrum of compound 6 described in Example 3 of this invention;

[0052] Figure 6 The NMR spectrum of compound 10 described in Example 4 of this invention;

[0053] Figure 7 The NMR spectrum of compound 12 described in Example 5 of this invention;

[0054] Figure 8 This is the NMR spectrum of compound 18 described in Example 6 of the present invention. Detailed Implementation

[0055] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are merely some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0056] This invention, based on the sulfonylurea core structure, focuses on molecular design and optimization to overcome the shortcomings of existing technologies. It aims to provide a compound with comprehensive advantages in activity, selectivity, stability, and synthetic feasibility, offering a novel drug candidate and solution for the treatment of c-Met-related tumors. The invention is further described in detail below through specific embodiments.

[0057] Preparation Example 1

[0058] ;

[0059] Under a nitrogen atmosphere, 4 g of chemical substance 1 and 50 ml of dichloromethane were added sequentially to the reaction system. After stirring until homogeneous, 21.90 g of N,N-diisopropylethylamine was added and stirred until homogeneous. The air was then replaced with nitrogen twice, and the system temperature was lowered to 0°C. A 15 ml dichloromethane solution containing 7.54 g of triphosgene was slowly added dropwise, and the system temperature was maintained at 0°C. The mixture was stirred for 2 hours. Then, a 5 ml dichloromethane solution containing 0.76 g of chemical substance 2 was added to the reaction system, and the system was brought to room temperature and stirred for another 14 hours. After the reaction was complete, 300 ml of 0°C water was added for quenching. After stirring, shaking, and separation, the organic phase was retained. The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of n-heptane and ethyl acetate as the eluent. Eluent was evaporated to dryness to obtain 3.24 g of chemical substance 3. MS [MS+1]: 306.

[0060] Under a nitrogen atmosphere, 3.24 g of chemical substance 3 and 30 ml of ultra-dry tetrahydrofuran were added sequentially to the reaction system. After stirring until homogeneous, the system temperature was lowered to -70°C, and 1 ml of n-butyllithium was added dropwise. After the addition was complete, the mixture was stirred for 1 h, and then 2.98 g of triisopropyl borate was added dropwise. After the addition was complete, the mixture was allowed to naturally rise to room temperature and reacted for 10 h. After the reaction was completed, under ice bath cooling (0°C) and nitrogen protection, a saturated ammonium chloride aqueous solution was slowly added dropwise. The reaction mixture was transferred to a separatory funnel and extracted three times repeatedly with 20 ml of ethyl acetate. The organic phases were combined and purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent. The eluent was evaporated to dryness to obtain 2.54 g of chemical substance 4. Mass spectrometry (MS) [MS+1]: 273; NMR: see [link to NMR data]. Figure 1 .

[0061] Preparation Example 2

[0062] ;

[0063] Under a nitrogen atmosphere, 4 g of chemical substance 5 and 60 ml of dichloromethane were added sequentially to the reaction system. After stirring until homogeneous, 32.31 g of N,N-diisopropylethylamine was added, and the mixture was stirred until homogeneous. The air was then purged twice with nitrogen, and the system temperature was lowered to 0°C. A 20 ml dichloromethane solution containing 11.13 g of triphosgene was slowly added dropwise, and the system temperature was maintained at 0°C. The mixture was stirred for 2 hours. Then, an 11 ml dichloromethane solution containing 1.18 g of chemical substance 6 was added to the reaction system, and the system was brought to room temperature and stirred for another 16 hours. After the reaction was complete, 400 ml of water at 4°C was added for quenching. After stirring, shaking, and separation, the organic phase was retained and dried with anhydrous sodium sulfate. The desiccant was removed by filtration, and the crude product was obtained by rotary evaporation. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent. The eluent was evaporated to obtain 3.86 g of chemical substance 7. Mass spectrometry (MS[MS+1]): 232; NMR results are shown below. Figure 2 .

[0064] Example 1

[0065] Preparation of compound 1:

[0066] ;

[0067] Raw material 2 is chemical substance 4 prepared in preparation example 1;

[0068] Raw material 4 is chemical substance 7 prepared in preparation example 2;

[0069] In the first step, under a nitrogen atmosphere, 20.00 g of raw material 1, 31.77 g of raw material 2, 26.90 g of anhydrous potassium carbonate, and 220 g of toluene were added sequentially to the reaction system. The mixture was stirred thoroughly, and the nitrogen atmosphere was purged twice. Under nitrogen protection, 3.37 g of tetrakis(triphenylphosphine)palladium was added to the reaction system, and the nitrogen atmosphere was purged twice again. The mixture was heated to 95°C and refluxed for 10 hours. The heating was turned off, and the mixture was cooled to room temperature. The mixture was allowed to stand and separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The mixture was then subjected to silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as eluent. The solution was evaporated to dryness to obtain 27.68 g of intermediate 1.

[0070] In the second step, under a nitrogen atmosphere and with dry ice bath cooling, 27.68 g of intermediate 1 and 2.73 g of tetra(triphenylphosphine)palladium were dissolved in 300 ml of anhydrous tetrahydrofuran. Then, 11.12 g of starting material 3 and 5.53 g of n-butyllithium were added to the reaction system, and the mixture was cooled to 0°C and stirred for 4 h. The reaction mixture was then naturally warmed to room temperature and reacted for 10 h. After the reaction was complete, it was carefully quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. The filtrate was filtered and concentrated to obtain the crude product, which was finally purified by silica gel column chromatography (petroleum ether / ethyl acetate system) to obtain 29.12 g of intermediate 2.

[0071] In the third step, under a nitrogen atmosphere, 29.12 g of intermediate 2, 18.74 g of starting material 4, and 320 ml of anhydrous N,N-dimethylformamide were added to a dry reaction flask as solvent. After stirring and mixing in an ice bath, 1.61 g of sodium hydride was slowly added. The mixture was stirred at 0°C for 30 min. The cold bath was removed, and the reaction mixture was slowly heated to 80°C and stirred continuously at this temperature for 10 hours. After the reaction was complete, the system was cooled to room temperature, and the reaction solution was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed successively with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated by rotary evaporation to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether / ethyl acetate system), and after concentration, 9.80 g of pure compound 1 was obtained.

[0072] Structural assessment data:

[0073] Mass spectrometry (MS) of intermediate 1 [MS+1]: 353;

[0074] Mass spectrometry (MS) of intermediate 2 [MS+1]: 435;

[0075] Mass spectrometry of compound 1 (MS[MS+1]): 587;

[0076] The NMR spectra of compound 1 are shown in [reference needed]. Figure 3 .

[0077] Examples 2-6

[0078] The compounds synthesized in Examples 2-6 were prepared according to the method in Example 1, except that raw material 1 was replaced, while the rest remained the same as in Example 1. The specific structures of raw material 1, compound structures, and structural identification data (MS [MS+1] data) are shown in Table 1 below, and NMR data are shown below. Figures 4-8 .

[0079] Table 1. Structures and MS [MS+1] data of raw material 1 and the obtained compounds in Examples 2-6

[0080]

[0081] Performance testing:

[0082] The pharmacological experiments of this invention used the sulfonylrhodamine B colorimetric method.

[0083] Tumor cells tested: HT-460 (human large cell lung cancer cells), MKN-45 (human gastric cancer cells), HT-29 (human colon cancer cells).

[0084] The tumor cells were cultured in RPMI-1640 medium containing 10% bovine fetal serum (FBS). The tumor cells were seeded into 96-well plates and cultured for 3-5 × 10⁶ cells per well. 3 Cells were cultured in DMSO solution at concentrations of 10, 20, 50, 100, 150, and 300 nM. After 72 hours of culture, pre-chilled trifluoroacetic acid (50%, w / v) was added to each well to fix the cells, followed by 30 minutes of fixation in a refrigerator. After the 96-well plate was air-dried at room temperature, 0.04% (w / v) SRB staining solution (prepared with 1% acetic acid) was added to each well. After staining for 30 minutes, the staining solution was discarded, and the cells were rinsed four times with acetic acid to remove unbound dye. The cells were then air-dried at room temperature. The dye bound to cell proteins was dissolved in 100 µL of unbuffered Tris-base solution, and the plate was shaken on a horizontal shaker for 20 minutes. The absorbance at 515 nm was measured using an Elx800 microplate reader, and the IC50 was calculated. 50 The data is shown in Table 2.

[0085] Comparative compound 1: ;

[0086] Comparative compound 2: Comparative compound 2 is Foretinib (CAS No.: 849217-64-7).

[0087] Table 2. Compound IC of Examples 1-6 and Comparative Examples 1-2 50 data

[0088]

[0089] The sulfonylurea-containing compounds of this invention exhibit superior inhibitory activity against three tested tumor cell types—lung cancer, gastric cancer, and colon cancer—compared to comparative compounds 1 and 2 in the comparative examples. Compared to comparative compound 2 (furetinib), which showed weaker inhibitory activity in some tumor cell types (such as lung and colon cancer cells), the compounds of this invention maintain superior inhibitory activity in all three different types of tumor cells, demonstrating broader tumor cell inhibitory activity. The compounds of this invention, optimized through the synergistic effect of the sulfonylurea and urea groups, demonstrate advantages over traditional inhibitors in regulating c-Met kinase activity and inhibiting tumor cell proliferation.

[0090] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A compound containing a sulfonylurea structure, characterized in that, The sulfonylurea-containing compound is the compound shown in Formula 1; Formula 1; R1 is selected from: alkyl groups having 1-10 carbon atoms, alkoxy groups having 1-10 carbon atoms, aryl groups having 6-15 carbon atoms, and heteroaryl groups having 5-10 carbon atoms; Or R1 may be selected from: aryl groups with 6-15 carbon atoms substituted by alkyl groups with 1-10 carbon atoms.

2. A compound containing a sulfonylurea structure according to claim 1, characterized in that, The alkyl group having 1-10 carbon atoms is selected from: , , , , ; The alkoxy groups with 1-10 carbon atoms are selected from: , ; The This is a linking site.

3. A compound containing a sulfonylurea structure according to claim 1, characterized in that, The aryl groups with 6-15 carbon atoms are selected from: , , ; The heteroaryl groups with 5-10 carbon atoms are selected from: , , , , , .

4. A compound containing a sulfonylurea structure according to claim 1, characterized in that, The aryl group, which is substituted by an alkyl group having 1-10 carbon atoms and has 6-15 carbon atoms, is selected from: 、 、 、 。 5. A compound containing a sulfonylurea structure according to claim 1, characterized in that, The sulfonylurea-containing compound is selected from compounds with the following structures: ； ； ； ； ； ； ； ； ； 。 6. A pharmaceutically acceptable salt of a sulfonylurea compound according to claim 1, characterized in that, The pharmaceutically acceptable salts are hydrochloride, sulfate, phosphate, trifluoroacetate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, tartrate, maleate, fumarate, succinate, or malate.

7. A method for preparing a sulfonylurea-containing compound according to any one of claims 1-5, characterized in that, Includes the following steps: In the first step, raw material 1 and raw material 2 were synthesized into intermediate 1 via a Suzuki coupling reaction; In the second step, intermediate 1 and raw material 3 undergo a coupling reaction to obtain intermediate 2; In the third step, intermediate 2 and raw material 4 are synthesized by Williamson reaction to obtain the compound shown in Formula 1, which is a compound containing a sulfonylurea structure.

8. The method for preparing a sulfonylurea-containing compound according to claim 7, characterized in that, The raw material 1 is selected from compounds with the following structures: , , , , , , , , , , , , , , , , , , , Any one of them.

9. Use of a pharmaceutically acceptable salt of a sulfonylurea compound according to any one of claims 1-5 or a sulfonylurea compound according to claim 6 in the preparation of medicaments for lung cancer, gastric cancer, and / or colon cancer.

Images