Application of 3-fluoroalkyl quinoxalinone derivative in preparation of anti-glioma drugs

Abstract

The invention discloses an application of a 3-fluoroalkyl quinoxalinone derivative in preparation of anti-glioma drugs, and belongs to the technical field of medicines. The 3-fluoroalkyl quinoxalinone derivative has excellent anti-glioma activity, especially has a remarkable inhibition effect on glioma Glioma 261 cells, the inhibition effect of the 3-fluoroalkyl quinoxalinone derivative is remarkably superior to that of temozolomide which is widely applied at present, and the 3-fluoroalkyl quinoxalinone derivative has good development value and wide application prospects.

Description

Technical Field

[0001] The present invention relates to a new use of a quinoxalinone derivative, and in particular to the use of a 3-fluoroalkylquinoxalinone derivative in the preparation of an anti-glioma drug, belonging to the field of medical technology. Background Art

[0002] Gliomas are the most common primary intracranial malignant tumors, accounting for approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. As the tumor progresses, it can form a mass effect, causing clinical manifestations such as headaches, vomiting, visual impairment, and neurological dysfunction. Some patients experience hemiplegia or seizures. As the disease progresses, glioma cells invade neurons and nerve fibers, leading to progressive neurological deficits and ultimately threatening the patient's life.

[0003] The treatment of brain gliomas faces severe challenges, and a comprehensive approach of surgical resection combined with postoperative concurrent chemoradiotherapy is adopted clinically. Among chemotherapy drugs, temozolomide has become a first-line drug recommended by international guidelines due to its high oral bioavailability, excellent central penetrance, and safety of single-drug application. However, as the number of medications increases, temozolomide will gradually develop a certain degree of drug resistance, and the in situ recurrence rate is high. The existing treatment system has obvious limitations in controlling tumor progression and improving prognosis. The development of new anti-glioma drugs with high selectivity, low toxicity, and breakthrough of drug resistance mechanisms has become an urgent need in the current field of neuro-oncology.

[0004] Quinoxalinone is a commonly used pharmacophore in pharmaceutical research. Its parent structure can be used to derive a variety of physiologically and pharmacologically active drugs, widely used as anticancer, antitumor, and antibacterial agents. It represents a class of potential multi-purpose lead compounds with broad development and application prospects. In fact, the modified functional groups on the quinoxalinone structure, rather than just the parent quinoxalinone structure itself, collectively influence the drug and biological activities of the molecule. Therefore, modifying the quinoxalinone parent structure with different substituents and studying the structure-activity relationship have become increasingly research hotspots.

[0005] The existing literature ("Metal-Free Trifluoroalkylation of Quinoxalin-2(1H)-ones with Unactivated Alkenes and Langlois' Reagent", Meng Na, et al, J. Org. Chem., 2020, 85, 6888-6896) publicly synthesized a series of 3-fluoroalkylquinoxalinone derivatives for the first time, but did not disclose the specific uses of 3-fluoroalkylquinoxalinone, let alone its use in anti-tumor drugs. Summary of the Invention

[0006] In response to the deficiencies of the prior art, the present invention aims to provide a new use of 3-fluoroalkylquinoxalinone derivatives. 3-fluoroalkylquinoxalinone derivatives have excellent anti-glioma activity, especially a significant inhibitory effect on the activity of Glioma 261 cells. Their inhibitory effect is significantly superior to that of the existing anti-tumor drug temozolomide, and they have good development value and broad application prospects.

[0007] In order to achieve the above technical objectives, the present invention provides an application of a 3-fluoroalkylquinoxalinone derivative for preparing an anti-tumor drug;

[0008] The 3-fluoroalkylquinoxalinone derivative has the following chemical structural formula:

[0009]

[0010] in,

[0011] R1 and R2 are independently selected from hydrogen, C1-C5 alkane, C1-C5 alkoxy, halogen substituent, nitro or trifluoromethyl;

[0012] R3 is selected from hydrogen, C1-C5 aliphatic hydrocarbon group, benzyl group, C2-C5 ester group, benzyloxycarbonyl group, p-methoxybenzyl group or cyano group;

[0013] R4 is selected from phenyl, naphthyl or phenyl containing a substituent; the substituent on the phenyl ring in the phenyl containing a substituent includes at least one of a C1-C5 alkyl group, a halogen substituent, a trifluoromethyl group, an acetyl group, and a cyano group;

[0014] R5 is selected from C1 to C5 alkane;

[0015] Alternatively, R4 and R5 form a cyclic alkane group.

[0016] The 3-fluoroalkylquinoxalinone derivatives of the present invention are based on quinoxalinone as the parent structure (quinoxalinone molecular structure: ), this type of parent structure compound is currently reported to have biological activities such as antifungal, anticancer, and aldose reductase inhibition, but quinoxalinone has almost no inhibitory effect on the activity of Glioma 261 cells. The present invention unexpectedly discovered that a new parent structure 3-fluoroalkylquinoxalinone (3-fluoroalkylquinoxalinone molecular structure is as follows) is formed by introducing a special structure of fluoroalkyl at the 3-carbon position of quinoxalinone: ), which can significantly improve the inhibitory effect on the activity of Glioma 261 cells compared to quinoxalinone. At the same time, further substitution optimization of the alkyl chain and benzene ring on the parent structure of 3-fluoroalkylquinoxalinone has been carried out. After extensive experimental studies, it has been shown that almost all compounds with a 3-fluoroalkylquinoxalinone parent structure have anti-Glioma 261 cell activity. In addition, some 3-fluoroalkylquinoxalinone derivatives have better inhibitory effects on Glioma 261 cell activity than the commercial anti-tumor drug temozolomide on the market, indicating that they have clinical application and commercial value.

[0017] In the 3-fluoroalkylquinoxalinone derivatives of the present invention, R1, R2, R3, R4, and R5 are conventional small molecule modifying groups. Modification of the 3-fluoroalkylquinoxalinone parent structure by these groups can have a certain impact on its anti-glioma 261 cell activity. R1 and R2 are substituents on the phenyl ring, and both are independently selected from hydrogen, C1-C5 alkyl groups (specifically, methyl, ethyl, isopropyl, isobutyl, butyl, etc.), C1-C5 alkoxy groups (specifically, methoxy, ethoxy, isobutoxy, etc.), halogen substituents (specifically, chlorine, bromine, fluorine, etc.), nitro, or trifluoromethyl. R3 is a substituent group on the nitrogen atom, which can be selected from hydrogen, a C1-C5 aliphatic hydrocarbon group (including saturated aliphatic hydrocarbon groups and unsaturated aliphatic hydrocarbon groups; the saturated aliphatic hydrocarbon group is an alkane group, specifically for example, methyl, ethyl, isopropyl, isobutyl, cyclopropylbutyl, etc.; the unsaturated aliphatic hydrocarbon group contains an alkenyl and / or alkynyl group in the main chain, and the number and position of the alkenyl or alkyne are not limited, specifically for example, propenyl, propynyl, etc.), benzyl, C2-C5 ester group, benzyloxycarbonyl, p-methoxybenzyl or cyano group. R4 and R5 are substituents introduced onto the fluoroalkyl group. R4 can be selected from phenyl, naphthyl, or a substituted phenyl group. The substituents on the phenyl ring of the substituted phenyl group include at least one of a C1-C5 alkyl group (specifically, methyl, ethyl, isopropyl, isobutyl, butyl, etc.), a halogen substituent (specifically, chlorine, bromine, fluorine, etc.), a trifluoromethyl group, an acetyl group, and a cyano group. The substituents on the phenyl ring can be one or more, and typically contain one or two substituents. R5 can be selected from a C1-C5 alkyl group (specifically, methyl, ethyl, isopropyl, isobutyl, butyl, etc.). Alternatively, R4 and R5 can form a cyclic alkane group.

[0018] Preferred 3-fluoroalkylquinoxalinone derivatives have the following chemical formula:

[0019]

[0020]

[0021]

[0022] The most preferred 3-fluoroalkylquinoxalinone derivative has the following chemical formula:

[0023]

[0024] The most preferred 3-fluoroalkylquinoxalinone derivative of the present invention has a significantly better inhibitory effect on Glioma261 cells than the existing anti-tumor drug temozolomide.

[0025] As a preferred solution, the anti-tumor drug has an inhibitory effect on Glioma 261 cells.

[0026] Compared with the existing technology, the technical solution of the present invention brings the following beneficial technical effects:

[0027] The present invention first discovered that 3-fluoroalkylquinoxalinone derivatives have a good inhibitory effect on brain glioma, especially have a significant inhibitory effect on brain glioma Glioma 261 cells, and can be used to prepare anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the H NMR spectrum of (R)-1-methyl-3-(3,3,3-trifluoro-1-phenylpropyl)quinoxalin-2(1H)-one (compound 4aaa).

[0029] Figure 2 This is the C NMR spectrum of (R)-1-methyl-3-(3,3,3-trifluoro-1-phenylpropyl)quinoxalin-2(1H)-one (compound 4aaa).

[0030] Figure 3 This is the NMR fluorine spectrum of (R)-1-methyl-3-(3,3,3-trifluoro-1-phenylpropyl)quinoxalin-2(1H)-one (compound 4aaa).

[0031] Figure 4 This is a comparison of the inhibitory effects of several 3-fluoroalkylquinoxalinone derivatives and temozolomide on the activity of Glioma 261 cells. DETAILED DESCRIPTION

[0032] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. The following specific embodiments do not limit the scope of protection of the claims.

[0033] Example 1

[0034] The synthetic routes of the 3-fluoroalkylquinoxalinone derivatives in the following specific examples are as follows:

[0035]

[0036] 1) Ethyl 2-oxyacetate (111.11 mmol) was added to a solution of 1,2-diaminobenzene compound (92.59 mmol) in ethanol (200 ml), and the mixture was heated to 45 degrees Celsius and kept reacting for 8 hours. The resulting precipitate was filtered, washed thoroughly with water, and dried under vacuum to obtain a quinolinone derivative.

[0037]

[0038] 2) A quinolinone derivative (5.0 mmol) and DMF (15.0 ml) were added to a 100 ml round-bottom flask equipped with a stir bar, followed by potassium carbonate (828 mg, 6.0 mmol), and then the halogenated compound R3-X (8 ml) was added dropwise. The reaction mixture was then stirred at room temperature for 6 hours, poured into brine, and extracted with diethyl ether. The extracts were combined, dried over anhydrous sodium sulfate, filtered, and then evaporated. The residue was purified by column chromatography (petroleum ether / diethyl ether) to yield a 1-substituted quinolinone derivative.

[0039]

[0040] 3) At room temperature, in a nitrogen atmosphere, a 1-substituted quinolinone derivative 1 (0.2 mmol), an olefin compound 2 (0.3 mmol), a fluoroalkylsulfonyl chloride compound 3 (0.3 mmol), a Nd@g-C3N4 photocatalyst (synthesized with reference to existing literature, 5 mg), and ethanol (2 ml) were added sequentially to a 30 ml Schlenk flask. The reaction was carried out under ultrasonic wave (22 kHz, 30 W) and irradiation with a 7-watt blue LED for 4 h. The mixture was filtered, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product 4.

[0041] Referring to the above preparation method, the following 3-fluoroalkylquinoxalinone derivative target products were synthesized using different substrates:

[0042]

[0043]

[0044]

[0045] Structural characterization:

[0046] 1 1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 8.0 Hz, 1H), 7.55–7.52 (m, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.25 (s, 1H), 7.22–7.19 (m, 1H), 5.07 (t, J = 7.0 Hz, 1H), 3.63–3.61 (m, 3H), 3.50–3.43 (m, 1H), 2.79 (ddd, J = 15.8, 10.6, 5.7 Hz, 1H).

[0047] 13 13C NMR (126 MHz, CDCl3) δ = 158.65, 154.20, 139.55, 133.29, 132.51, 130.37, 130.32, 128.80, 128.56, 127.47, 126.89 (q, J = 360.04 Hz), 123.82, 113.77, 41.33 (q, J = 2.52 Hz), 37.60 (q, J = 27.72 Hz), 29.34.

[0048] 19 19F NMR (471 MHz, CDCl3) δ = -64.27, -64.29, -64.31.

[0049] Structural characterization:

[0050] 1 1H NMR (500 MHz, Chloroform-d) δ 7.94 (dd, J = 8.1, 1.5 Hz, 1H), 7.54 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.47 (dd, J = 7.3, 1.6 Hz, 2H), 7.37–7.34 (m, 1H), 7.29 (dd, J = 8.4, 6.6 Hz, 3H), 7.22 (t, J = 7.4 Hz, 1H), 5.09 (t, J = 7.0 Hz, 1H), 4.30 (dt, J = 14.0, 7.2 Hz, 1H), 4.19 (dd, J = 14.0, 7.1 Hz, 1H), 3.47 (dddd, J = 15.0, 11.1, 7.5, 3.6 Hz, 1H), 2.82 (dtd, J = 15.2, 10.8, 4.5 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H). 1313C NMR (126 MHz, CDCl3) δ = 158.71, 153.65, 139.62, 132.81, 132.22, 130.58, 130.31, 128.76, 128.55, 127.40, 126.90 (q, J = 271.22 Hz), 123.59, 113.61, 41.23 (q, J = 2.52 Hz), 37.68 (q, J = 28.04 Hz), 37.64, 12.49.

[0051] 19 19F NMR (471 MHz, CDCl3) δ = -64.25, -64.27, -64.30.

[0052] Structural characterization:

[0053] 1 1H NMR (500 MHz, Chloroform-d) δ 7.92 (dd, J = 8.1, 1.5 Hz, 1H), 7.54–7.50 (m, 1H), 7.46–7.43 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 5.7 Hz, 2H), 7.26 (d, J = 4.5 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 5.07 (t, J = 7.0 Hz, 1H), 4.25–4.19 (m, 1H), 4.10–4.05 (m, 1H), 3.45 (dtd, J = 15.0, 7.7, 4.1 Hz, 1H), 2.83–2.76 (m, 1H), 1.68 (td, J = 7.2, 3.3 Hz, 2H), 1.34 (dq, J = 6.7, 3.3 Hz, 4H), 0.89–0.86 (m, 3H).

[0054] 13 13C NMR (126 MHz, CDCl3) δ = 158.66, 153.86, 139.60, 132.77, 132.43, 130.53, 130.25, 128.75, 128.52, 127.39, 126.84 (q, J = 279.41 Hz), 123.56, 113.76, 42.64, 41.​​​​​​HRMS:calcd for C 22 H 24 F3N2O + [M+H] + 389.1836, found 389.1832.

[0057] Structural characterization:

[0058] 1 H NMR(500MHz,Chloroform-d)δ7.95(dd,J=8.0,1.5Hz,1H),7.56–7.53(m,1H),7.46(d,J=7.4Hz,2 H),7.41–7.35(m,2H),7.29(t,J=7.6Hz,2H),7.22(t,J=7.4Hz,1H),5.09(t,J=7.0Hz,1H),4.12(d q,J=14.3,8.0,7.3Hz,2H),3.46(dddd,J=14.4,10.9,7.5,3.7Hz,1H),2.88–2.80(m,1H),1.24(t d,J=7.4,4.4Hz,1H),0.58–0.54(m,1H),0.51(dd,J=8.1,5.2Hz,2H),0.43(dt,J=9.1,4.6Hz,1H).

[0059] 13 C NMR(126MHz, CDCl3)δ=158.87,154.14,139.58,132.68,132.67,130.50,130.21,128.72,128.52,127.37,12 6.82(q,J=285.08Hz),123.58,114.04,46.39,41.35(d,J=2.52Hz),37.63(q,J=28.04Hz),9.68,4.40,4.03.

[0060] 19 F NMR (471MHz, CDCl3) δ = -64.15, -64.17, -64.20.

[0061] HRMS:calcd for C 21 H 20 F3N2O + [M+H] + 373.1523, found 73.1528.

[0062] Structural characterization:

[0063] 1 1H NMR (500 MHz, Chloroform-d) δ 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.53–7.49 (m, 1H), 7.46–7.43 (m, 2H), 7.39–7.36 (m, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 5.08–5.01 (m, 2H), 4.85 (d, J = 17.3 Hz, 1H), 4.19 (tq, J = 7.1, 3.8 Hz, 2H), 3.44 (dddd, J = 14.5, 10.9, 7.5, 3.9 Hz, 1H), 2.85 (dddd, J = 15.0, 10.8, 7.6, 4.2 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H).

[0064] 13 13C NMR (126 MHz, CDCl3) δ = 167.01, 158.50, 153.76, 139.22, 132.51, 132.39, 130.61, 130.54, 128.79, 128.50, 127.49, 126.79 (q, J = 277.83 Hz), 124.11, 113.22, 62.17, 43.75, 40.40 (d, J = 3.78 Hz), 37.62 (q, J = 27.72 Hz), 14.08.

[0065] 19 19F NMR (471 MHz, CDCl3) δ = -64.18, -64.20, -64.22.

[0066] Structural characterization:

[0067] 1 1H NMR (500 MHz, Chloroform-d) δ 8.11 (dd, J = 7.8, 1.9 Hz, 1H), 7.85 (dd, J = 7.9, 1.8 Hz, 1H), 7.68 (ddd, J = 9.5, 7.8, 1.7 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 15.1 Hz, 2H), 7.24–7.21 (m, 1H), 5.14 (d, J = 15.5 Hz, 1H), 5.08 (d, J = 15.5 Hz, 1H), 4.86 (t, J = 6.9 Hz, 1H), 3.60 (dtd, J = 15.1, 7.4, 4.3 Hz, 1H), 2.96–2.87 (m, 1H).

[0068] 13 13C NMR (126 MHz, CDCl3) δ = 152.52, 148.23, 139.43, 139.26, 138.94, 130.31, 129.02, 128.95, 128.38, 128.00, 127.65, 127.13, 126.74 (q, J = 277.83 Hz), 114.97, 50.65, 41.04 (d, J = 2.52 Hz), 37.83 (q, J = 27.72 Hz).

[0069] 19 19F NMR (471 MHz, CDCl3) δ = -64.22, -64.25, -64.27.

[0070] HRMS: calcd for C 19 H 15 F3N3O + [M + H] + 358.1162, found 358.1158.

[0071] Structural characterization:

[0072] 1 1H NMR (500 MHz, Chloroform-d) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.51–7.48 (m, 1H), 7.46–7.43 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 2.1 Hz, 2H), 7.25 (d, J = 3.1 Hz, 1H), 7.24–7.18 (m, 2H), 5.85 (ddd, J = 17.3, 10.4, 5.2 Hz, 1H), 5.20 (d, J = 10.5 Hz, 1H), 5.10–5.05 (m, 2H), 4.92–4.87 (m, 1H), 4.75–4.70 (m, 1H), 3.45 (ddd, J = 15.0, 11.0, 7.8 Hz, 1H), 2.81 (ddd, J = 15.1, 7.5, 4.4 Hz, 1H).

[0073] 1313C NMR (126 MHz, CDCl3) δ = 158.73, 153.75, 139.50, 132.67, 132.49, 130.61, 130.41, 130.28, 128.79, 128.53, 127.45, 126.83 (q, J = 277.83 Hz), 123.80, 118.24, 114.31, 44.80, 41.33 (d, J = 2.52 Hz), 37.66 (q, J = 28.04 Hz).

[0074] 19 19F NMR (471 MHz, CDCl3) δ = -64.23, -64.26, -64.28.

[0075] HRMS: calcd for C 20 H 18 F3N2O + [M + H] + 359.1366, found 359.1300.

[0076] Structure characterization:

[0077] 1 1H NMR (500 MHz, Chloroform-d) δ 7.95 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 16.2 Hz, 3H), 7.40 (t, J = 7.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 5.09–5.03 (m, 2H), 4.89 (dd, J = 17.5, 2.5 Hz, 1H), 3.45 (ddd, J = 15.1, 11.0, 7.6 Hz, 1H), 2.82 (ddd, J = 15.3, 10.7, 6.2 Hz, 1H), 2.26 (t, J = 2.5 Hz, 1H).

[0078] 13 13C NMR (126 MHz, CDCl3) δ = 158.59, 153.19, 139.28, 132.67, 131.77, 130.49, 130.46, 128.83, 128.57, 127.54, 126.77 (q, J = 277.83 Hz), 124.21, 114.30, 76.73, 73.51, 41.38 (d, J = 2.52 Hz), 37.66 (q, J = 27.7 (q, J = 27.72 Hz), 31.78.

[0079] 19 F NMR (471MHz, CDCl3) δ = -58.65, -58.67, -58.70.

[0080] Structural characterization:

[0081] 1 H NMR(500MHz,Chloroform-d)δ7.99(dd,J=8.0,1.6Hz,1H),7.54(dd,J=7.5,1.6 Hz,2H),7.49–7.45(m,1H),7.40–7.35(m,3H),7.34–7.31(m,3H),7.30–7.27(m, 2H),7.18(d,J=6.9Hz,2H),5.59(d,J=15.7Hz,1H),5.36(d,J=15.8Hz,1H),5.20 (t,J=7.0Hz,1H),3.56(dddd,J=15.0,11.0,7.4,3.6Hz,1H),2.93–2.86(m,1H).

[0082] 13 C NMR(126MHz, CDCl3)δ=158.86,154.31,139.50,135.16,132.76,132.58,130.43,130.36,129.07,128.82,128.55,1 27.81,127.50,126.87,126.84(q,J=261.18Hz),123.88,114.57,46.14,41.46(d,J=2.52Hz),37.67(q,J=28.04Hz).

[0083] 19 F NMR (471MHz, CDCl3) δ = -63.03, -63.05, -63.08.

[0084] HRMS:calcd for C 25 H 20 F3N2O3 + [M+H] + 453.1421, found 453.1417.

[0085] Structural characterization:

[0086] 11H NMR (500 MHz, Chloroform-d) δ 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.50–7.47 (m, 2H), 7.43–7.40 (m, 1H), 7.34–7.30 (m, 3H), 7.29–7.27 (m, 2H), 7.25–7.20 (m, 3H), 7.14–7.11 (m, 2H), 5.53 (d, J = 15.8 Hz, 1H), 5.31 (d, J = 15.7 Hz, 1H), 5.14 (dd, J = 7.8, 6.3 Hz, 1H), 3.53–3.46 (m, 1H), 2.88–2.80 (m, 1H).

[0087] 13 13C NMR (126 MHz, CDCl3) δ = 158.87, 154.31, 139.51, 135.17, 132.77, 132.60, 130.43, 130.35, 129.07, 128.82, 128.55, 127.81, 127.49, 127.01 (q, J = 278.78 Hz), 126.87, 123.87, 114.57, 46.15, 41.47 (d, J = 2.52 Hz), 37.68 (q, J = 28.04 Hz).

[0088] 19 19F NMR (471 MHz, CDCl3) δ = -64.20, -64.22, -64.24.

[0089] Structural characterization:

[0090] 1 1H NMR (500 MHz, Chloroform-d) δ 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.49–7.46 (m, 2H), 7.43–7.40 (m, 1H), 7.32–7.28 (m, 3H), 7.26–7.22 (m, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 5.45 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz, 1H), 5.14 (t, J = 7.0 Hz, 1H), 3.73 (s, 3H), 3.48 (dtd, J = 15.0, 7.7, 4.2 Hz, 1H), 2.83 (ddd, J = 15.0, 10.7, 6.2 Hz, 1H).

[0091] 1313C NMR (126 MHz, CDCl3) δ = 159.18, 158.86, 154.29, 139.54, 132.77, 132.58, 130.41, 130.29, 128.80, 128.55, 128.38, 127.47, 127.25, 126.87 (q, J = 277.83 Hz), 123.80, 114.54, 114.42, 55.36, 45.60, 41.43 (d, J = 2.52 Hz), 37.68 (q, J = 27.72 Hz).

[0092] 19 19F NMR (471 MHz, CDCl3) δ = -64.17, -64.19, -64.22.

[0093] HRMS: calcd for C 25 H 20 F3N2O2 + [M + H] + 439.1628, found 439.1631.

[0094] Structure characterization:

[0095] 1 1H NMR (500 MHz, Chloroform-d) δ 12.54 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.32–7.27 (m, 3H), 7.23 (d, J = 7.4 Hz, 1H), 5.11 (t, J = 7.0 Hz, 1H), 3.55–3.47 (m, 1H), 2.87 (ddd, J = 15.9, 10.7, 5.9 Hz, 1H).

[0096] 13 13C NMR (126 MHz, CDCl3) δ = 159.01, 156.00, 139.40, 132.64, 131.06, 130.43, 129.31, 128.77, 128.58, 127.52, 126.84 (q, J = 277.83 Hz), 124.41, 115.91, 40.76 (d, J = 2.52 Hz), 37.53 (q, J = 27.72 Hz).

[0097] 19 19F NMR (471 MHz, CDCl3) δ = -64.25, -64.28, -64.30.

[0098] HRMS:calcd for C 17 H 14 F3N2O + [M+H] + 319.1053, found 319.1049.

[0099] Structural characterization:

[0100] 1 H NMR(500MHz,Chloroform-d)δ7.47–7.44(m,2H),7.40(d,J=2.7Hz,1H),7.30–7.27(m,2H),7.21(t,J=2.5Hz,1H),7.19– 7.17(m,2H),5.08(dd,J=7.9,6.0Hz,1H),3.93(s,3H),3.62(s,3H),3.46(dq,J=6.9,4.0,3.5Hz,1H),2.82–2.76(m,1H).

[0101] 13 C NMR (126MHz, CDCl3) δ=159.13,156.14,153.85,139.56,133.26,128.79,128.55,127.45,126.84(q,J= 279.40Hz), 119.54, 114.69, 111.72, 110.88, 55.93, 41.38 (d, J = 2.52Hz), 37.59 (q, J = 28.04Hz), 29.48.

[0102] 19 F NMR (471MHz, CDCl3) δ = -64.30, -64.32, -64.34.

[0103] HRMS:calcd for C 19 H 18 F3N2O2 + [M+H] + 363.1315, found 363.1310.

[0104] Structural characterization:

[0105] 11H NMR (500 MHz, Chloroform-d) δ 7.62 (dd, J = 8.7, 2.9 Hz, 1H), 7.45–7.42 (m, 2H), 7.30–7.25 (m, 3H), 7.22–7.18 (m, 2H), 5.07 (dd, J = 8.1, 5.9 Hz, 1H), 3.60 (s, 3H), 3.49–3.41 (m, 1H), 2.81–2.73 (m, 1H).

[0106] 13 13C NMR (126 MHz, CDCl3) δ = 160.20, 159.80, 157.86, 153.81, 139.17, 133.00 (d, J = 11.34 Hz), 129.94 (d, J = 2.52 Hz), 128.85, 128.54, 127.59, 126.73 (q, J = 277.83 Hz), 118.10 (d, J = 23.94 Hz), 115.69 (d, J = 22.68 Hz), 114.88 (d, J = 8.82 Hz), 41.37 (q, J = 2.52 Hz), 37.50 (q, J = 28.04 Hz), 29.58.

[0107] 19 19F NMR (471 MHz, CDCl3) δ = -64.34, -64.37, -64.39, -118.82, -118.83, -118.84, -118.85, -118.85, -118.86.

[0108] HRMS: calcd for C 18 H 15 F4N2O + [M+H] + 351.1116, found 351.1119.

[0109] Structural characterization:

[0110] 1 1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 2.4 Hz, 1H), 7.48–7.45 (m, 1H), 7.44–7.42 (m, 2H), 7.29–7.26 (m, 2H), 7.22–7.15 (m, 2H), 5.07 (dd, J = 8.2, 5.8 Hz, 1H), 3.58 (s, 3H), 3.48–3.41 (m, 1H), 2.80–2.72 (m, 1H).

[0111] 1313C NMR (126 MHz, CDCl3) δ = 160.05, 153.81, 139.09, 132.92, 131.94, 130.32, 129.56, 129.12, 128.85, 128.51, 127.60, 126.69 (q, J = 277.83 Hz), 114.91, 41.31 (d, J = 2.52 Hz), 37.47 (q, J = 27.72 Hz), 29.47.

[0112] 19 19F NMR (471 MHz, CDCl3) δ = -64.32, -64.34, -64.37.

[0113] HRMS: calcd for C 18 H 15 ClF3N2O + [M + H] + 367.0820, found 367.0814.

[0114] Structure characterization:

[0115] 1 1H NMR (500 MHz, Chloroform-d) δ 7.77 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 8.5, 2.0 Hz, 1H), 7.43 (dd, J = 8.0, 1.7 Hz, 3H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 (td, J = 5.5, 5.1, 2.6 Hz, 1H), 5.05 (dd, J = 8.0, 5.9 Hz, 1H), 3.59 (s, 3H), 3.49–3.41 (m, 1H), 2.77 (ddd, J = 14.9, 10.7, 5.9 Hz, 1H).

[0116] 13 13C NMR (126 MHz, CDCl3) δ = 158.99, 153.85, 139.17, 134.29, 131.49, 131.30, 128.52, 127.60, 127.10, 126.72 (q, J = 277.83 Hz), 124.47, 116.85, 41.36 (d, J = 2.52 Hz), 37.50 (q, J = 28.04 Hz), 29.47.

[0117] 19 19F NMR (471 MHz, CDCl3) δ = -64.16, -64.18, -64.21.

[0118] HRMS:calcd for C 18 H 15 BrF3N2O + [M+H] + 411.0315, found 411.0314.

[0119] Structural characterization:

[0120] 1 H NMR(500MHz,Chloroform-d)δ8.20(d,J=2.2Hz,1H),7.74(dd,J=8.8,2.1Hz,1H),7.44–7.41(m,2H),7.35(d,J=8.8Hz,1H),7. 27(dd,J=8.4,6.8Hz,2H),7.23–7.19(m,1H),5.07(dd,J=8.3,5.7Hz,1H),3.63(s,3H),3.52–3.44(m,1H),2.81–2.72(m,1H).

[0121] 13 C NMR (126MHz, CDCl3) δ = 160.43, 154.01, 138.93, 135.59, 131.81, 128.93, 128.53, 128.48 (q, J = 48.82Hz), 127.46 (d, J = 172.62Hz), 126.71(q,J=3.46Hz), 126.18(q,J=33.70Hz), 125.25(d,J=80.64Hz), 114.48, 41.36(d,J=2.52Hz), 37.47(d,J=26.78Hz), 29.61.

[0122] 19 F NMR (471MHz, CDCl3) δ = -61.93, -64.41, -64.43, -64.46.

[0123] HRMS:calcd for C 19 H 15 F6N2O + [M+H] + 401.1084, found 401.1082.

[0124] Structural characterization:

[0125] 11H NMR (500 MHz, Chloroform-d) δ 8.78 (d, J = 2.6 Hz, 1H), 8.36 (dd, J = 9.2, 2.6 Hz, 1H), 7.43–7.40 (m, 2H), 7.35 (d, J = 9.3 Hz, 1H), 7.28 (d, J = 7.4 Hz, 2H), 7.23–7.21 (m, 1H), 5.06 (dd, J = 8.4, 5.6 Hz, 1H), 3.65 (s, 3H), 3.51–3.44 (m, 1H), 2.76 (ddd, J = 15.6, 10.5, 5.3 Hz, 1H).

[0126] 13 13C NMR (126 MHz, CDCl3) δ = 161.36, 153.77, 143.49, 138.51, 137.86, 131.52, 128.99, 128.52, 127.85, 126.62 (q, J = 270.27 Hz), 125.91, 124.88, 114.49, 41.42 (d, J = 2.52 Hz), 37.38 (q, J = 28.35 Hz), 29.94.

[0127] 19 19F NMR (471 MHz, CDCl3) δ = -64.40, -64.42, -64.45.

[0128] HRMS: calcd for C 18 H 15 F3N3O3 + [M + H] + 378.1061, found 378.1057.

[0129] Structural characterization:

[0130] 1 1H NMR (500 MHz, Chloroform-d) δ 8.10 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 8.9, 2.3 Hz, 1H), 7.44–7.42 (m, 2H), 7.30–7.28 (m, 2H), 7.24–7.22 (m, 1H), 7.15 (d, J = 8.9 Hz, 1H), 5.09–5.06 (m, 1H), 3.61 (s, 3H), 3.48–3.43 (m, 1H), 2.79–2.73 (m, 1H).

[0131] 1313C NMR (126 MHz, CDCl3) δ = 158.87, 152.68, 137.94, 132.11, 131.95, 131.51, 131.26, 127.72, 127.37, 126.35 (q, J = 228.38 Hz), 126.47, 115.24, 114.07, 40.16 (d, J = 2.52 Hz), 36.34 (q, J = 28.04 Hz), 28.35.

[0132] 19 19F NMR (471 MHz, CDCl3) δ = -64.32, -64.34, -64.36.

[0133] HRMS: calcd for C 18 H 15 BrF3N2O + [M + H] + 411.0315, found 411.0318.

[0134] Structure characterization:

[0135] 1 1H NMR (500 MHz, Chloroform-d) δ 7.69 (s, 1H), 7.46–7.43 (m, 2H), 7.28 (d, J = 7.5 Hz, 2H), 7.22–7.18 (m, 1H), 7.03 (s, 1H), 5.05 (dd, J = 7.8, 6.2 Hz, 1H), 3.60 (s, 3H), 3.45 (dtd, J = 14.9, 7.8, 4.1 Hz, 1H), 2.82–2.74 (m, 1H), 2.39 (d, J = 18.6 Hz, 6H).

[0136] 13 13C NMR (126 MHz, CDCl3) δ = 157.32, 154.26, 140.22, 139.85, 132.75, 131.27, 130.93, 130.35, 128.73, 128.51, 127.34, 126.83 (q, J = 277.83 Hz), 114.33, 41.20 (d, J = 3.78 Hz), 38.14 (q, J = 28.35 Hz), 29.24, 20.70, 19.30.

[0137] 19 19F NMR (471 MHz, CDCl3) δ = -64.28, -64.30, -64.33.

[0138] HRMS:calcd for C 20 H 20 F3N2O + [M+H] + 361.1523, found 361.1524.

[0139] Structural characterization:

[0140] 1 H NMR(500MHz,Chloroform-d)δ8.03(s,1H),7.42(dd,J=7.1,1.7Hz,2H),7.36(s,1H),7.30(t,J=7.6Hz, 2H),7.24–7.21(m,1H),5.05(dd,J=8.3,5.6Hz,1H),3.58(s,3H),3.47–3.41(m,1H),2.78–2.72(m,1H).

[0141] 13 C NMR(126MHz, CDCl3)δ=160.16,153.60,138.86,134.52,132.66,131.48,131.06,128.93,128.51,1 27.73, 127.68, 126.66 (q, J = 282.87Hz), 115.32, 41.35 (d, J = 2.52Hz), 37.44 (q, J = 28.35Hz), 29.62.

[0142] 19 F NMR (471MHz, CDCl3) δ = -64.40, -64.42, -64.44.

[0143] HRMS:calcd for C 18 H 14 Cl2F3N2O + [M+H] + 401.0430,found 401.0424.

[0144] Structural characterization:

[0145] 11H NMR (500 MHz, Chloroform-d) δ 7.91 (dd, J = 8.1, 1.5 Hz, 1H), 7.55 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.49–7.45 (m, 2H), 7.37 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.29 (dd, J = 8.5, 1.2 Hz, 1H), 7.02–6.97 (m, 2H), 5.10 (dd, J = 8.1, 5.8 Hz, 1H), 3.64 (s, 3H), 3.52–3.43 (m, 1H), 2.78 (ddd, J = 14.9, 10.6, 5.9 Hz, 1H), 2.26 (s, 3H).

[0146] 13 13C NMR (126 MHz, CDCl3) δ = 168.38, 157.23, 153.01, 148.80, 135.81, 132.11, 131.32, 129.32, 129.13, 128.46, 125.64 (q, J = 268.38 Hz), 122.69, 120.67, 112.65, 39.46 (d, J = 2.52 Hz), 36.34 (q, J = 28.04 Hz), 20.10.

[0147] 19 19F NMR (471 MHz, CDCl3) δ = -64.34, -64.37, -64.39.

[0148] HRMS: calcd for C 19 H 18 F3N2O + [M + H] + 347.1366, found 347.1365.

[0149] Structural characterization:

[0150] 11H NMR (500 MHz, Chloroform-d) δ 7.93 (dd, J = 8.0, 1.5 Hz, 1H), 7.53 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.36 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H), 7.26–7.23 (m, 3H), 7.18–7.15 (m, 1H), 7.01 (ddd, J = 7.6, 2.1, 1.1 Hz, 1H), 5.04 (dd, J = 8.1, 5.7 Hz, 1H), 3.62 (s, 3H), 3.49 (ddd, J = 15.0, 10.8, 8.1 Hz, 1H), 2.75 (ddd, J = 15.0, 10.8, 5.8 Hz, 1H), 2.30 (s, 3H).

[0151] 13 13C NMR (126 MHz, CDCl3) δ = 158.67, 154.20, 139.51, 138.41, 133.27, 132.50, 130.30, 129.21, 128.64, 128.26, 126.75 (q, J = 266.49 Hz), 125.52, 123.76, 113.73, 41.21 (d, J = 2.52 Hz), 38.12 (q, J = 27.72 Hz), 29.31, 21.56.

[0152] 19 19F NMR (471 MHz, CDCl3) δ = -64.28, -64.31, -64.33.

[0153] HRMS: calcd for C 19 H 18 F3N2O + [M + H] + 347.1366, found 347.1360.

[0154] Structure characterization:

[0155] 11H NMR (500 MHz, Chloroform-d) δ 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.57–7.53 (m, 3H), 7.52 (d, J = 1.5 Hz, 4H), 7.41–7.37 (m, 3H), 7.30 (ddd, J = 14.7, 7.8, 1.3 Hz, 2H), 5.13 (dd, J = 7.9, 6.0 Hz, 1H), 3.65 (s, 3H), 3.52 (ddd, J = 15.1, 11.0, 7.9 Hz, 1H), 2.84 (ddd, J = 15.1, 10.6, 6.0 Hz, 1H).

[0156] 13 13C NMR (126 MHz, CDCl3) δ = 158.56, 154.26, 140.84, 140.38, 138.58, 133.32, 132.56, 130.43, 130.35, 128.94, 128.85, 127.56, 127.39, 127.18, 126.84 (d, J = 278.46 Hz), 123.86, 113.81, 41.05 (q, J = 2.84 Hz), 37.58 (q, J = 28.04 Hz), 29.38.

[0157] 19 19F NMR (471 MHz, CDCl3) δ = -64.26, -64.29, -64.31.

[0158] HRMS: calcd for C 24 H 20 F3N2O + [M + H] + 409.1523, found 409.1524.

[0159] Structural characterization:

[0160] 1 1H NMR (500 MHz, Chloroform-d) δ 7.91 (dd, J = 8.0, 1.5 Hz, 1H), 7.52 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.37–7.32 (m, 3H), 7.26–7.24 (m, 1H), 7.08 (d, J = 7.9 Hz, 2H), 5.03 (dd, J = 7.

[0161] 13 C NMR (126MHz, CDCl3) δ = 158.78, 154.18, 137.13, 136.50, 133.27, 132.51, 130.29, 129.55, 129.50, 128. 41,126.87(q,J=278.14Hz),123.78,113.74,40.97(d,J=2.52Hz),37.57(q,J=27.72Hz),29.32,21.19.

[0162] 19 F NMR (471MHz, CDCl3) δ = -64.27, -64.29, -64.32.

[0163] Structural characterization:

[0164] 1 H NMR(500MHz,Chloroform-d)δ7.89(dd,J=7.9,1.6Hz,1H),7.50–7.47(m,1H),7.36–7.30(m,3H),7.28–7.26(m,2H),7.22– 7.20(m,1H),5.05(dd,J=8.5,5.3Hz,1H),3.59(s,3H),3.54–3.47(m,1H),2.72(ddd,J=11.0,9.6,5.3Hz,1H),1.23(s,9H).

[0165] 13 C NMR (126MHz, CDCl3) δ = 158.78, 154.25, 150.21, 136.51, 133.25, 132.54, 130.25, 128.09,

[0166] 127.97,126.75(q,J=285.08Hz),125.73,123.75,113.71,40.74(d,J=2.52Hz),37.54(q,J=28.35Hz),34.54,31.40,29.31.

[0167] 19 F NMR (471MHz, CDCl3) δ = -64.42, -64.44, -64.46.

[0168] Structural characterization:

[0169] 11H NMR (500 MHz, Chloroform-d) δ 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.56 (dd, J = 8.6, 7.2 Hz, 1H), 7.42 (dd, J = 8.5, 5.4 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.97 (t, J = 8.6 Hz, 2H), 5.06 (t, J = 7.0 Hz, 1H), 3.66–3.62 (m, 4H), 3.43–3.37 (m, 1H), 2.79 (ddd, J = 15.1, 7.6, 4.3 Hz, 1H).

[0170] 13 13C NMR (126 MHz, CDCl3) δ = 163.15, 161.19, 158.45, 154.12, 135.14 (d, J = 2.52 Hz), 133.25,

[0171] 132.44, 130.41 (d, J = 25.2 Hz), 130.14 (d, J = 7.56 Hz), 126.74 (q, J = 277.83 Hz), 123.91, 115.66 (d, J = 22.68 Hz), 113.83, 40.64, 40.62, 37.64 (q, J = 28.04 Hz), 29.36.

[0172] 19 19F NMR (471 MHz, CDCl3) δ = -64.20, -64.22, -64.24, -115.18, -115.19, -115.19, -115.21, -115.22, -115.22, -115.24.

[0173] Structural characterization:

[0174] 1 1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 8.0 Hz, 1H), 7.58–7.54 (m, 1H), 7.39 (d, J = 8.1 Hz, 3H), 7.29 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 5.04 (t, J = 7.0 Hz, 1H), 3.64 (s, 3H), 3.40 (ddd, J = 15.0, 11.0, 7.4 Hz, 1H), 2.80 (ddd, J = 15.0, 10.8, 6.7 Hz, 1H).

[0175] 13C NMR (126MHz, CDCl3) δ=158.20,154.09,137.93,133.39,133.26,132.43,130.58,130.33,

[0176] 129.93, 128.95, 126.70 (q, J = 277.83Hz), 123.94, 113.84, 40.82 (d, J = 2.52Hz), 37.48 (q, J = 28.35Hz), 29.36.

[0177] 19 F NMR (471MHz, CDCl3) δ = -64.04, -64.07, -64.09.

[0178] Structural characterization:

[0179] 1 H NMR(500MHz,Chloroform-d)δ7.92(dd,J=8.0,1.5Hz,1H),7.58–7.55(m,1H),7.42–7.38(m,3H),7.35–7.32(m,2H),7 .29(dd,J=8.4,1.2Hz,1H),5.03(t,J=7.0Hz,1H),3.64(s,3H),3.40(dtd,J=15.0,7.3,4.2Hz,1H),2.84–2.77(m,1H).

[0180] 13 C NMR(126MHz, CDCl3)δ=158.10,154.07,138.45,133.24,132.40,131.89,130.59,130.32,130.29,1 26.66(q,J=275.62Hz),123.93,121.55,113.83,40.88(d,J=2.52Hz),37.40(q,J=28.04Hz),29.35.

[0181] 19 F NMR (471MHz, CDCl3) δ = -64.14, -64.17, -64.19.

[0182] Structural characterization:

[0183] 11H NMR (500 MHz, Chloroform-d) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.58–7.51 (m, 5H), 7.39–7.35 (m, 1H), 7.27 (dd, J = 8.5, 1.3 Hz, 1H), 5.12 (t, J = 7.0 Hz, 1H), 3.62 (s, 3H), 3.42 (dtd, J = 15.1, 7.2, 4.3 Hz, 1H), 2.83 (dddd, J = 15.1, 10.8, 7.5, 4.1 Hz, 1H).

[0184] 13 13C NMR (126 MHz, CDCl3) δ = 157.87, 154.10, 143.51, 133.29, 132.43, 130.74, 130.38, 129.72 (q, J = 32.76 Hz), 128.97, 126.66 (d, J = 278.46 Hz), 125.72 (q, J = 3.78 Hz), 124.19 (q, J = 272.16 Hz), 124.01, 113.87, 41.28 (d, J = 2.52 Hz), 37.44 (q, J = 28.35 Hz), 29.35.

[0185] 19 19F NMR (471 MHz, CDCl3) δ = -62.58, -64.19, -64.21, -64.23.

[0186] Structural characterization: [[ID=十四]]

[0187] 1 1H NMR (500 MHz, Chloroform-d) δ 7.9 (dt, J = 8.0, 1.2 Hz, 1H), 7.56–7.52 (m, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.38–7.35 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.04–6.98 (m, 2H), 5.10 (dd, J = 8.1, 5.9 Hz, 1H), 3.65–3.62 (m, 3H), 3,48 (dddd, J = 13.7, 10.8, 7.5, 3.5 Hz, 1H), 2.83–2.75 (m, 1H), 2.27–2.23 (m, 3H).

[0188] 13 13C NMR (126 MHz, CDCl3) δ = 169.53, 158.36, 154.15, 149.95, 136.96, 133.25, 132.46, 130.47,

[0189] 130.03, 129.60, 126.78 (q, J = 285.08 Hz), 123.84, 121.82, 113.80, 40.60 (d, J = 3.78 Hz), 37.49 (q, J = 27.72 Hz), 29.34, 21.23.

[0190] 19 19F NMR (471 MHz, CDCl3) δ = -64.34, -64.36, -64.38.

[0191] HRMS: calcd for C 20 H 18 F3N2O2 + [M + H] + 375.1315, found 375.1316.

[0192] Structural characterization:

[0193] 1 1H NMR (500 MHz, Chloroform-d) δ 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.58 (s, 5H), 7.41–7.38 (m, 1H), 7.31 (dd, J = 8.4, 1.2 Hz, 1H), 5.10 (t, J = 7.1 Hz, 1H), 3.64 (s, 3H), 3.38 (dddd, J = 14.7, 10.7, 7.5, 4.1 Hz, 1H), 2.89–2.79 (m, 1H).

[0194] 13 13C NMR (126 MHz, CDCl3) δ = 157.36, 153.99, 144.74, 133.23, 132.52, 132.33, 130.90, 130.36,

[0195] 129.40, 126.50 (q, J = 277.83 Hz), 124.07, 118.74, 113.91, 111.38, 41.52 (q, J = 3.15 Hz), 37.28 (q, J = 28.35 Hz), 29.37.

[0196] 19 19F NMR (471 MHz, CDCl3) δ = -64.06, -64.08, -64.10.

[0197] HRMS: calcd for C 19 H 15 F3N3O+ [M+H] + 358.1162, found 358.1160.

[0198] Structural characterization:

[0199] 1 H NMR(500MHz,Chloroform-d)δ7.87(dd,J=8.0,1.5Hz,1H),7.78(d,J=1.9Hz,1H),7.66(td,J=8.2,7.6,2.5Hz,3H),7.50(dd,J=8.6,1.8Hz,1H),7.45–7.41( m,1H),7.33–7.29(m,2H),7.29–7.26(m,1H),7.16–7.13(m,1H),5.15(t,J=6. 9Hz,1H),3.49(s,3H),3.44(ddt,J=14.0,7.2,3.2Hz,1H),2.83–2.76(m,1H).

[0200] 13 C NMR (126MHz, CDCl3) δ=158.54,154.20,136.91,133.50,133.29,132.75,132.50,130.41,

[0201] 130.35,128.54,128.03,127.72,127.49,126.86(q,J=278.14Hz),126.44,126.22,126.04,123.83,

[0202] 113.78, 41.43 (d, J = 2.52Hz), 37.59 (q, J = 28.04Hz), 29.32.

[0203] 19 F NMR (471MHz, CDCl3) δ = -64.19, -64.21, -64.23.

[0204] Structural characterization:

[0205] 11H NMR (500 MHz, Chloroform-d) δ 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.39–7.36 (m, 1H), 7.29–7.26 (m, 3H), 7.24–7.19 (m, 3H), 3.93–3.83 (m, 1H), 3.53 (s, 3H), 2.96 (dt, J = 15.0, 11.3 Hz, 1H), 1.95–1.93 (m, 3H).

[0206] 13 13C NMR (126 MHz, CDCl3) δ = 161.03, 153.23, 144.85, 133.74, 131.96, 130.64, 130.36, 128.60, 127.21 (q, J = 26.46 Hz), 126.73, 125.41, 123.64, 113.63, 46.66 (d, J = 1.26 Hz), 41.56 (q, J = 281.30 Hz), 31.89, 29.05, 25.38.

[0207] 19 19F NMR (471 MHz, CDCl3) δ = -58.67, -58.70, -58.72.

[0208] HRMS: calcd for C 19 H 18 F3N2O + [M + H] + 347.1366, found 347.1365.

[0209] Structural characterization:

[0210] 1 1H NMR (500 MHz, Chloroform-d) δ 7.94–7.91 (m, 1H), 7.54 (ddd, J = 7.1, 4.6, 1.4 Hz, 3H), 7.36 (d, J = 6.9 Hz, 1H), 7.27–7.24 (m, 3H), 7.18 (td, J = 6.0, 2.5 Hz, 1H), 5.41 (d, J = 11.

[0211] 1313C NMR (126 MHz, CDCl3) δ = 166.26, 156.83, 154.10, 136.33, 133.25, 132.42, 130.58, 130.35, 129.64, 128.57, 127.95, 126.88 (q, J = 284.13 Hz), 123.89, 113.80, 61.71, 53.05 (q, J = 26.14 Hz), 29.43, 13.69.

[0212] 19 19F NMR (471 MHz, CDCl3) δ = -65.41, -65.43.

[0213] HRMS: calcd for C 21 H 20 F3N2O3 + [M + H] + 405.1421, found 405.1439.

[0214] Structural characterization:

[0215] 1 1H NMR (500 MHz, Chloroform-d) δ 7.81 (dd, J = 8.0, 1.5 Hz, 1H), 7.53 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.35–7.29 (m, 2H), 3.70 (s, 3H), 3.58–3.51 (m, 1H), 3.05 (s, 1H), 2.14–2.10 (m, 1H), 1.93–1.89 (m, 2H), 1.83 (dd, J = 10.1, 3.8 Hz, 1H), 1.74 (d, J = 12.6 Hz, 1H), 1.44 (ddd, J = 22.8, 10.2, 2.9 Hz, 3H).

[0216] 13 13C NMR (126 MHz, CDCl3) δ = 161.94, 154.53, 133.09, 132.78, 130.00, 129.88, 127.92 (q, J =

[0217] 334.84 Hz), 123.70, 113.73, 60.55, 43.48 (q, J = 23.94 Hz), 30.98, 29.29, 25.40, 25.18 (d, J = 2.52 Hz), 24.52.

[0218] 19F NMR (471MHz, CDCl3) δ = -69.94, -69.95.

[0219] Structural characterization:

[0220] 1 H NMR (500MHz, Chloroform-d) δ7.87 (dd, J=8.0, 1.5Hz, 1H), 7.54 (ddd, J=8.6, 7.2, 1.6Hz,

[0221] 1H),7.37–7.33(m,1H),7.31(dd,J=8.3,1.2Hz,1H),3.87–3.84(m,1H),3.71(s,3H),3.37–3.32(m,1H),2.92(d,J=4.3Hz,1H),2.58–2.56(m, 1H),1.99(d,J=10.1Hz,1H),1.62–1.58(m,1H),1.47(dtd,J=12.1,6.7,5.3,3.2Hz,2H),1.32–1.27(m,1H),1.12(ddt,J=8.1,6.3,2.3Hz,1H).

[0222] 13 C NMR (126MHz, CDCl3) δ = 158.07, 155.04, 133.22, 132.32, 130.31, 130.06, 128.04 (q, J = 278.46Hz) ,123.68,113.69,46.43(d,J=2.52Hz),46.00(q,J=26.78Hz),40.69,39.69,38.32,29.74,29.23.

[0223] 19 F NMR (471MHz, CDCl3) δ = -69.87, -69.89.

[0224] Example 2

[0225] The anticancer activities of several typical 3-fluoroalkylquinoxalinone derivatives were tested as follows:

[0226] Test methods and effect standards:

[0227] Test method:

[0228] The in vitro antitumor activity against mouse brain glioma Glioma 261 cells was assessed using the CCK-8 cell proliferation assay (Dojindo Cell Counting Kit-8 CCK-8). Glioma 261 cancer cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% dual-antibody (penicillin and streptomycin). Well-growing cells were digested and counted. 5 × 10 cells were added to each well of a 96-well plate. 3 Cells were plated and set up as a blank group (no cells), a control group (untreated), and an experimental group (drug-treated), with three replicates for each group. After the cells adhered, the original culture medium was discarded and the cells were washed three times with PBS. 100 μL of culture medium was added to the blank and control groups. A concentration gradient of 0 to 3.0 mmol / L was set in the experimental group wells. The drug to be tested was mixed with the culture medium and added to the experimental group wells of a 96-well plate, also in a volume of 100 μL (for example, to prepare a single concentration: 10 μL of a 1 mmol / L sample and 90 μL of a mixture of culture medium were added to the experimental group wells, resulting in a drug concentration of 0.1 mmol / L in each well). After 24 hours of incubation, the original liquid in all wells was discarded, and 10 μL of CCK-8 reagent and 90 μL of culture medium were added to each well. After 2 to 4 hours of incubation, the absorbance was measured with a microplate reader, and the inhibition rate was calculated according to the formula:

[0229] Cell inhibition rate (%) = [A (experimental group) - A (blank group)] / [A (control group) - A (blank group)] × 100%

[0230] IC 50 The values ​​were calculated using GraphPad Prism 8.0 software.

[0231] Efficacy criteria:

[0232] Using the commercial broad-spectrum anticancer drug temozolomide as a reference:

[0233] Table 1 Anticancer activity effect

[0234]

[0235]

[0236]

[0237] As can be seen from Table 1, several types of 3-fluoroalkylquinoxalinone derivatives have a good inhibitory effect on Glioma 261 cells, which is better than the existing commercial Temozolomide, and can be used to prepare anti-tumor drugs.

[0238] It will be understood by those skilled in the art that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the present disclosure (including the claims) is limited to these examples. Within the scope of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of clarity. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A use of a 3-fluoroalkylquinoxalinone derivative, characterized in that: For preparing anti-glioma drugs; The 3-fluoroalkylquinoxalinone derivative has the following chemical structural formula: in, R1 and R2 are independently selected from hydrogen, C1-C5 alkane, C1-C5 alkoxy, halogen substituent, nitro or trifluoromethyl; R3 is selected from hydrogen, C1-C5 aliphatic hydrocarbon group, benzyl group, C2-C5 ester group, benzyloxycarbonyl group, p-methoxybenzyl group or cyano group; R4 is selected from phenyl group, naphthyl group or phenyl group containing a substituent; the substituent on the phenyl ring of the phenyl group containing a substituent includes at least one of C1-C5 alkyl group, halogen substituent, trifluoromethyl group, acetyl group and cyano group; R5 is selected from C1 to C5 alkane; Alternatively, R4 and R5 form a cyclic alkane group.

2. The use of a 3-fluoroalkylquinoxalinone derivative according to claim 1, characterized in that: The 3-fluoroalkylquinoxalinone derivative has the following chemical structural formula:

3. The use of a 3-fluoroalkylquinoxalinone derivative according to claim 2, characterized in that: The 3-fluoroalkylquinoxalinone derivative has the following chemical structural formula:

4. The use of a 3-fluoroalkylquinoxalinone derivative according to any one of claims 1 to 3, characterized in that: The anti-glioma drug has an inhibitory effect on glioma Glioma 261 cells.

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