Aromatic fused ring compound as well as preparation method and application thereof
By using bromopyridone derivatives as starting materials, aromatic heterocyclic compounds with fused aromatic ring-heteroaromatic ring skeletons were constructed, solving the problems of insufficient structural novelty and functional adaptability in the prior art, and achieving the effects of efficient synthesis and strong biological interaction.
Patent Information
- Application Number
- CN202511726178.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-24
- Publication Date
- 2026-02-17
AI Technical Summary
Existing aromatic heterocyclic compounds lack structural novelty and functional adaptability in drug applications, making it difficult to meet the needs of novel targets. Their synthesis methods are complex and require harsh conditions, making it difficult to construct complex skeletons.
Starting with bromopyridone derivatives, an ethylene glycol ketal structure was introduced through LHMDS activation, followed by condensation and Suzuki coupling reactions to construct an aromatic ring-heteroaromatic ring fused skeleton, forming a compound with a novel molecular topology.
It achieves improved compound structural novelty and functional adaptability, with a yield of up to 87%, and can be used as a drug active molecule or for scientific research purposes to enhance the interaction strength with biological targets.
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Abstract
Description
Technical Field
[0001] This invention belongs to the fields of biomedicine and organic synthesis technology, specifically relating to an aromatic heterocyclic compound, its preparation method, and its application. Background Technology
[0002] Aromatic heterocyclic compounds, as the core molecular framework in medicinal chemistry, possess unique structural characteristics that make them irreplaceable in drug development, biological probe preparation, and research tool development. In drug applications, aromatic heterocyclic fragments can precisely regulate signaling pathways or metabolic processes in organisms by forming hydrogen bonds, hydrophobic interactions, and π-π stacking interactions with biological targets. They have become key components of clinical drugs in areas such as tumor therapy, inflammation suppression, and antiviral therapy. Simultaneously, these compounds can serve as specific probes in metabolic mechanism research, helping to elucidate key biological processes such as energy metabolism and nucleic acid synthesis in tumor cells, providing support for the discovery of novel therapeutic targets. Furthermore, in the research field, structurally tunable aromatic heterocyclic compounds can also serve as intermediates in organic synthesis to construct more complex functional molecules, or as functional units in materials chemistry, expanding their application potential in optoelectronic materials, sensors, and other fields.
[0003] However, existing aromatic heterocyclic compounds face significant limitations in their applications, with the core bottlenecks being insufficient structural novelty and a lack of functional adaptability. On the one hand, most reported aromatic heterocyclic molecules are designed based on traditional skeletons (such as single pyridine rings or indole rings), resulting in severe structural homogeneity. This leads to a single binding mode with biological targets, easily inducing drug resistance, and making it difficult to meet the precise requirements of novel targets for molecular spatial configuration and electronic effects. On the other hand, although some aromatic heterocyclic compounds possess certain biological activities, their limited structural modification sites result in poor water solubility and insufficient in vivo metabolic stability, restricting their transformation from lead compounds to clinical drugs. Furthermore, existing synthetic methods struggle to efficiently construct complex skeletons fused with aromatic rings and heteroaromatic rings. Most routes rely on multi-step functional group transformations, with harsh reaction conditions and poor regioselectivity, further hindering the application expansion of novel aromatic heterocyclic compounds.
[0004] The aromatic heterocyclic compounds described in this patent achieve a key breakthrough in structural novelty: unlike traditional single aromatic heterocyclic or simply substituted aromatic heterocyclic structures, this patent uses bromopyridone derivatives as the core starting material, introduces an ethylene glycol ketal structure through LHMDS activation, and then constructs a "aromatic ring-heteroaromatic ring" fused skeleton through condensation and Suzuki coupling reactions, forming compounds (Ia-Im) with novel molecular topologies. These compounds not only possess tunable electronic effects (achieved through the selection of R1 and R2 substituents) but also have abundant structural modification sites (such as hydroxyl and amino functional groups), allowing for precise modification according to different application requirements. Simultaneously, their unique fused-ring coplanar structure enhances the interaction strength with biological targets, providing a structural basis for improving the compound's bioactivity and targeting, effectively filling the gap in the synergistic optimization of structural novelty and functional adaptability of existing aromatic heterocyclic compounds, and providing a novel solution for expanding the application boundaries of aromatic heterocyclic compounds in drug development and scientific research. Summary of the Invention
[0005] The purpose of this invention is to provide a novel class of aromatic heterocyclic compounds and their preparation method. These compounds use a bromopyridone derivative as the core, introducing an ethylene glycol ketal structure through LHMDS activation. A key intermediate is formed by condensation with an aromatic aldehyde in an acetic anhydride / triethylamine system, followed by a Suzuki coupling reaction in a Pd(OAc)2 / JohnPhos–KOAc / DMF system, achieving efficient construction of the aromatic-heteroaromatic ring skeleton. This route is simple, mild, and yields up to 87%. The resulting compounds have novel structures and tunable electronic effects, making them suitable for use as pharmaceutical active molecules, lead compounds, or research applications. Attached Figure Description
[0006] Figure 1 This is the 1H NMR spectrum of compound 3.
[0007] Figure 2 This is the 1H NMR spectrum of compound 4.
[0008] Figure 3 This is the 1H NMR spectrum of compound 6.
[0009] Figure 4 This is the carbon NMR spectrum of compound 6.
[0010] Figure 5 The image shows the hydrogen NMR spectrum of compound 8.
[0011] Figure 6 This is the carbon NMR spectrum of compound 8.
[0012] Figure 7 The image shows the proton NMR spectrum of compound 10.
[0013] Figure 8 The image shows the carbon NMR spectrum of compound 10. Detailed Implementation
[0014] The present invention will be described in detail below with reference to specific embodiments, but the present invention is not limited thereto. It should be noted that the description and embodiments given herein are merely for illustrating specific implementations of the present invention to enable those skilled in the art to more readily understand the present invention, and are not intended to limit the scope of the present invention.
[0015] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.
[0016] Example 1: Preparation and NMR data of compound 3
[0017]
[0018] Compound 1 (2.12 g, 10 mmol) and Compound 2 (2.39 g, 10 mmol) were added to a 50 mL round-bottom flask, followed by 20 mL of acetic anhydride (Ac₂O). After stirring until homogeneous, triethylamine (Et₃N, 1.5 mL, 10.8 mmol) was added. Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and most of the acetic anhydride was removed by vacuum distillation. Then, 50 mL of ethyl acetate was added to the residue, and the mixture was washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, v / v) to give Compound 2 (3.2 g, yield approximately 85%).
[0019] The 1H NMR spectrum data of compound 3 are as follows:
[0020] 1H NMR (300 MHz, DMSO) δ 9.17 (dt, J = 4.4, 1.7 Hz, 1H), 9.08 (ddd, J = 8.2, 2.4, 1.3 Hz, 1H), 8.46 (dd, J = 1.7, 1.0 Hz, 1H), 8.21 (dt, J = 7.7,1.6 Hz, 1H), 8.01 – 7.80 (m, 3H), 7.61 – 7.50 (m, 1H), 4.42 (qd, J = 7.1, 1.1Hz, 2H), 1.37 (tt, J = 7.1, 1.5 Hz, 3H).
[0021] Example 2: Preparation and NMR data of compound 4
[0022]
[0023] Under a nitrogen atmosphere, compound 3 (336 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), potassium carbonate (276 mg, 2.0 mmol), and ethanol (10 mL) were added sequentially to a dry 50 mL two-necked round-bottom flask. The reaction mixture was heated to 80 °C under nitrogen protection and stirred at this temperature for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) gave compound 4 (312 mg, 91% yield) as a white solid.
[0024] The 1H NMR spectrum data of compound 4 are as follows:
[0025] 1 H NMR (300 MHz, CDCl3) δ 8.63 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 7.9Hz, 1H), 8.15 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.69 – 7.58 (m, 1H), 7.49 –7.29 (m, 3H), 7.21 (dd, J = 8.1, 4.8 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.29(t, J = 7.1 Hz, 3H).
[0026] Example 3: Preparation and NMR data of compound 6
[0027]
[0028] Compound 5 (3.76 g, 10 mmol), palladium catalyst (0.5 mmol), and ligand L* (e.g., XPhos, 0.58 g, 1.2 mmol) were added to a 50 mL round-bottom flask. Cesium carbonate (6.52 g, 20 mmol) was then added as a base, followed by 20 mL of 1,4-dioxane as a solvent. The reaction mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was distilled under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to give compound 6 (2.8 g, yield approximately 82%).
[0029] The following are the 1H and 1C NMR spectra of compound 6:
[0030] 1 H NMR (300 MHz, CDCl3) δ 10.87 (s, 1H), 9.59 (s, 1H), 9.11 – 9.01 (m,2H), 8.37 (dd, J = 7.9, 1.7 Hz, 1H), 7.79 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H),7.73 – 7.60 (m, 2H), 7.52 – 7.41 (m, 1H), 3.61 (td, J = 6.9, 5.4 Hz, 2H),1.80 – 1.63 (m, 3H), 1.60 – 1.42 (m, 2H), 1.27 (d, J = 15.6 Hz, 2H), 1.00 (t,J = 7.3 Hz, 3H).
[0031] 13 C NMR (126 MHz, CDCl3) δ 151.48, 134.88, 132.75, 130.74, 126.73,125.16, 121.41, 118.00, 77.27, 39.64, 31.73, 29.71, 20.51, 13.93.
[0032] Example 4: Preparation and NMR data of compound 8
[0033]
[0034] Compound 7 (4.04 g, 10 mmol), a palladium catalyst precursor (e.g., Pd2(dba)3, 0.23 g, 0.25 mmol), and ligand L* (e.g., SPhos, 0.24 g, 0.6 mmol) were added to a 50 mL round-bottom flask. Potassium carbonate (2.76 g, 20 mmol) was then added as a base, followed by 20 mL of toluene as a solvent. Under nitrogen protection, the reaction system was heated to 110 °C and stirred for 10 hours. After the reaction was complete, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was then distilled under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1, v / v) to give compound 8 (2.9 g, yield approximately 80%).
[0035] The following are the 1H and 1C NMR data for compound 8:
[0036] 1 H NMR (300 MHz, CDCl3) δ 10.92 (s, 1H), 9.55 (d, J = 2.2 Hz, 1H), 9.14 – 8.98 (m, 2H), 8.34 (dd, J = 8.0, 1.8 Hz, 1H), 7.84 – 7.58 (m, 2H), 7.45 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 3.69 (td, J = 6.8, 5.6 Hz, 1H), 3.69(s, 1H), 3.57 (t, J = 6.2 Hz, 2H), 3.40 (t, J = 2.9 Hz, 1H), 3.40 (s, 2H),2.07 – 1.93 (m, 2H).
[0037] 13 C NMR (126 MHz, CDCl3) δ 151.50, 134.93, 132.78, 130.88, 126.84,125.21, 121.43, 118.01, 77.25, 70.87, 58.83, 37.22, 29.67.
[0038] Example 5: Preparation and NMR data of compound 10
[0039]
[0040] Compound 9 (4.01 g, 10 mmol), a palladium catalyst precursor (e.g., Pd(PPh3)4, 0.58 g, 0.5 mmol), and ligand L* (e.g., DavePhos, 0.30 g, 0.6 mmol) were added to a 50 mL round-bottom flask. Potassium phosphate (4.25 g, 20 mmol) was then added as a base, followed by 20 mL of xylene as a solvent. Under nitrogen protection, the reaction system was heated to 120 °C and stirred for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, and insoluble matter was removed by filtration. The filtrate was then distilled under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, v / v) to give compound 10 (2.7 g, yield approximately 78%).
[0041] The proton and carbon NMR spectra of compound 10 are as follows:
[0042] 1 H NMR (300 MHz, CDCl3) δ 10.91 (s, 2H), 9.55 (s, 1H), 9.09 – 8.98 (m,3H), 8.34 (dd, J = 8.0, 1.7 Hz, 1H), 7.83 – 7.72 (m, 2H), 7.72 – 7.58 (m,3H), 7.45 (t, J = 7.5 Hz, 2H), 5.29 (s, 1H), 3.65 (q, J = 6.6 Hz, 4H), 2.45(t, J = 7.4 Hz, 4H), 2.29 (s, 1H), 1.91 (q, J = 7.1 Hz, 4H).
[0043] 13 C NMR (126 MHz, CDCl3) δ 151.50, 134.91, 132.76, 130.79, 126.77, 125.19, 121.43, 118.00, 57.54, 45.63, 38.03, 27.72.
[0044] VI. Technical Effects
[0045] Through synthetic route optimization and structural design, the aromatic heterocyclic compounds of this invention exhibit excellent chemical stability, scalability, and modifiability. Their molecular skeletons possess a coplanar structure of aromatic and heteroaromatic rings, enabling them to form π–π and hydrogen bond interactions with various biological targets, making them suitable as drug lead compounds or biological probes.
[0046] VII. Optimization of Reaction Conditions
[0047] To obtain the best coupling reaction efficiency, the types of palladium catalysts, ligands and bases were systematically screened, and the results are shown in Table 1.
[0048] Table 1. Relationship between coupling reaction efficiency and palladium catalyst, ligand, and base.
[0049] Entry Pd L Base(solvent) Time Y 1 <![CDATA[Pd(OAc)2]]> JohnPhos KOAc(DMF) 1 87 2 <![CDATA[Pd(Ph3)4]]> none KOAc(DMF) overnight <30 3 <![CDATA[Pd(Ph3)2Cl2]]> none KOAc(DMF) overnight - 4 <![CDATA[Pd(OAc)2]]> S-Phos KOAc(DMF) 10h 43 5 <![CDATA[Pd(OAc)2]]> Xphos KOAc(DMF) 4h 80 6 <![CDATA[Pd(OAc)2]]> Tri(o-tolyl)phosphine KOAc(DMF) 10h 30 7 <![CDATA[Pd(OAc)2]]> Dppf KOAc(DMF) 8h <10 8 <![CDATA[Pd(OAc)2]]> P(Cy)3 KOAc(DMF) 4h 56 9 <![CDATA[Pd(OAc)2]]> Tri(2-furyl)P KOAc(DMF) 16h 50 10 <![CDATA[Pd(OAc)2]]> <![CDATA[ t Bu3P]]> KOAc(DMF) 4h 24 11 <![CDATA[Pd(OAc)2]]> JohnPhos <![CDATA[K2CO3(DMF)]]> 4 Tace 12 <![CDATA[Pd(OAc)2]]> JohnPhos KOAc(2eqeuiv)(DMF) 8 Tace 13 <![CDATA[Pd(OAc)2(10%)]]> JohnPhos KOAc(DMF) 8 39 14 <![CDATA[Pd(OAc)2(5%)]]> JohnPhos KOAc(DMF) 8 Tace 15 <![CDATA[Pd(OAc)2]]> JohnPhos KOAc(MeCN) 8 NR 16 <![CDATA[Pd(OAc)2]]> JohnPhos KOAc(dioxane) 8 NR
Claims
1. A heteroaromatic compound having the general structure of formula (I) wherein R1 is a substituted alkyl group and R2 is an oxo or a thia alkyl group.
2. The compound according to claim 1, wherein R1 is preferably a hydroxyl or an amino group.
3. The compound according to claim 1 or 2, selected from the group consisting of Ia-Im.
4. A method for preparing the heteroaromatic compound according to any one of claims 1 to 3, comprising the following steps: (a) introducing an ester or amide group into a bromoaromatic alkyl derivative of formula (II) by activation with LHMDS to form an intermediate of formula (III); (b) condensing the intermediate of step (a) with a substituted aromatic aldehyde of formula (IV) in the presence of acetic anhydride and triethylamine to form a key intermediate of formula (V); (c) performing a Suzuki coupling reaction of the intermediate of formula (V) in a Pd(OAc)2 / JohnPhos-KOAc / DMF system to form the aromatic-heteroaromatic skeleton of formula (I); and (d) purifying and post-treating the product to obtain the target compound.
5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, together with a pharmaceutically acceptable carrier and / or adjuvant.
6. Use of the heteroaromatic compound according to any one of claims 1 to 3 for the preparation of a medicament or reagent for studying tumors or related metabolic mechanisms.