3-amino substituted 2-quinolinone compound as well as preparation method and application thereof

Abstract

The invention discloses a 3-amino substituted 2-quinolinone compound as well as a preparation method and application thereof, and belongs to the technical field of compound synthesis. According to the present invention, 2-chloro-3-(chloromethyl)-1H-indole derivatives and aniline derivatives are adopted as substrates, and under the catalysis of an alkali, skeleton editing is performed on indole molecules so as to achieve direct jump from indole to a 2-quinolinone structure, such that a series of 3-amino substituted 2-quinolinone compounds are synthesized; according to the method, a one-pot method is adopted, the step of separating an intermediate is omitted, the dosage of reagents is reduced, the requirements of green chemistry are better met, and the method is simpler, more economical and more efficient.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of compound synthesis, and particularly relates to a 3-amino-substituted 2-quinoxaline ketone compound and a preparation method and application thereof. BACKGROUND

[0002] Natural products as an important source of bioactive compounds, their structure modification and function optimization are the main source of inspiration for drug discovery and development in the past few decades. 2-quinoxaline ketone, also known as quinolone or 1-azacoumarin, is a kind of dominant heterocyclic skeleton, which is initially found in alkaloids mainly from plants of the Rutaceae family, and has become the core pharmacophore of a variety of marketed drugs. Many artificially synthesized 2-quinoxaline ketone derivatives have been confirmed to have a wide range of biological activities such as antibacterial, anti-Alzheimer's disease, anticancer and anti-diabetic, and the inherent photoactive properties of its unique conjugated system also make the skeleton be used for luminescent materials, cationic metal sensors, and other functional organic materials.

[0003] Cancer has become a global health problem due to its great difficulty in treatment, high cost, long cycle, etc. With the uncontrollability of cell carcinogenesis, more and more cancers have threatened people's life and health, and the most common types are leukemia, lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer and skin cancer, and lung cancer, colorectal cancer, gastric cancer, liver cancer and breast cancer are the most common causes of cancer death. The increasing threat of drug resistance makes the efficacy of currently used anticancer drugs worse and worse, and many structurally novel and diverse anticancer candidate drugs are being evaluated in the clinic, but still show deficiencies. In order to prevent or treat this deadly disease, it is imperative to develop more efficient anticancer drugs.

[0004] Although some researches on 2-quinoxaline ketone compounds have been reported at present, there are still problems such as difficult source of raw materials, limited synthesis method by multi-step reaction, use of valuable and toxic metal reagents, and poor substrate functional group tolerance. Therefore, it is still a technical problem to be solved at present to develop a green and efficient synthesis method of 2-quinoxaline ketone with easy-to-obtain raw materials, so as to provide available compounds for the research and development of antitumor drugs. SUMMARY

[0005] To solve the above technical problems, the application provides a 3-amino-substituted 2-quinoxaline ketone compound and a preparation method and application thereof.

[0006] To achieve the above purpose, the application provides the following technical solutions.

[0007] The application provides a 3-amino-substituted 2-quinoxaline ketone compound, the structural formula of which is as follows:

[0008]

[0009] Among them, R 1 is selected from H, halogen or methyl; R 2 is selected from H, methyl, methoxy, halogen, nitro, heterocyclic group or benzene ring.

[0010] Furthermore, the R 1 and R 2 The halogen in is independently selected from F, Cl or Br.

[0011] Furthermore, the heterocyclic group is selected from dioxolanyl or thiazolyl.

[0012] Furthermore, the 3-amino substituted 2-quinolinone compound is selected from the following compounds:

[0013]

[0014]

[0015] The present invention provides a method for preparing the 3-amino-substituted 2-quinolinone compound described in the above technical solution, wherein 2-chloro-3-(chloromethyl)-1H-indole derivatives and aniline derivatives are used as reaction substrates, NaH is used as a catalyst, and the 3-amino-substituted 2-quinolinone compound is synthesized through a one-pot reaction in an organic solvent.

[0016] The present invention uses 2-chloro-3-(chloromethyl)-1H-indole derivatives and aniline derivatives as substrates. Under the catalysis of base, the skeleton of the indole molecule is edited to achieve a direct jump from indole to 2-quinolinone structure, thereby synthesizing a series of 3-amino-substituted 2-quinolinone compounds.

[0017] In the present invention, the reaction route for synthesizing 3-amino-substituted 2-quinolinone compounds 3 using 2-chloro-3-(chloromethyl)-1H-indole derivatives 1 and aniline derivatives 2 as substrates is as follows:

[0018]

[0019] Furthermore, the molar ratio of the 2-chloro-3-(chloromethyl)-1H-indole derivatives to the aniline derivatives is 1:1.2; and / or the molar ratio of NaH to the 2-chloro-3-(chloromethyl)-1H-indole derivatives is 2:1.

[0020] Furthermore, the organic solvent is selected from dichloromethane; the usage ratio of the organic solvent to the 2-chloro-3-(chloromethyl)-1H-indole derivative is 1 mL:0.1 mmol.

[0021] Furthermore, the one-pot reaction temperature is room temperature and the reaction time is 5 hours.

[0022] The present invention also provides the use of the 3-amino-substituted 2-quinolinone compounds described in the above technical solution in the preparation of anti-tumor drugs.

[0023] Compared with the prior art, the present invention has the following advantages and technical effects:

[0024] The present invention adopts a one-pot method to prepare 3-amino-substituted 2-quinolinone compounds. Compared with the step-by-step method, the one-pot method can simplify the multi-step reactions in the step-by-step reaction. Starting from relatively simple and easily available raw materials, the reaction conditions are mild, and there is no need to separate intermediates to directly obtain complex structural compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings, which constitute part of the present invention, are intended to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are intended to explain the present invention and do not constitute an undue limitation of the present invention. In the accompanying drawings:

[0026] Figure 1 Shown are the structural formula and single crystal structure of compound 3aa. DETAILED DESCRIPTION

[0027] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0028] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0029] The room temperature in the embodiments of the present invention refers to "25±2°C".

[0030] Unless otherwise specified, the raw materials in the examples of the present invention were purchased from commercial sources.

[0031] Example 1

[0032] Into a 10 mL reaction tube equipped with a stir bar, 2-chloro-3- (chloromethyl)-lH-indole la (0.1 mmol, 1 equiv) and base (0.2 mmol, 2 equiv) were added, followed by 1 mL of organic solvent, and finally aniline 2a (0.12 mmol, 1.2 equiv). The reaction was stirred at 25 °C, and TLC was used to monitor the completion of the reaction (eluent: dichloromethane:methanol = 60: 1 (volume ratio)). After the reaction was completed, the organic solvent was removed under reduced pressure, and the target compound 3aa was purified by column chromatography. The type of base, the type of organic solvent, and the reaction time are shown in Table 1, and the reaction scheme is as follows:

[0033]

[0034] Table 1

[0035] Group alkali organic solvents time Yield a 1 <![CDATA[Cs2CO3]]> DCM 24h trace 2 NaOH DCM 24h 21％ 3 KOH DCM 24h 12％ 4 <![CDATA[ t Full]]> DCM 24h NR 5 <![CDATA[K3PO4]]> DCM 24h NR 6 <![CDATA[Ba(OH)2]]> DCM 24h trace 7 NaH DCM 24h 44％ 8 <![CDATA[CaH2]]> DCM 24h NR 9 <![CDATA[K2CO3]]> DCM 24h NR 10 NaH EtOAc 24h NR 11 NaH EtOH 24h 17％ 12 NaH Toluene 24h 38％ 13 NaH 1,4-dioxane 24h NR 14 NaH MeCN 24h NR 15 NaH Et2O 24h 22％ 16 NaH <![CDATA[CHCl3]]> 24h 13％ 17 NaH DCE 24h 44％ 18 NaH THF 24h NR 19 NaH DCM 5h 44％ <![CDATA[20 b ]]> NaH DCM 3h 33％ <![CDATA[21 c ]]> NaH DCM 48h 30％ <![CDATA[22 d ]]> NaH DCM 5h 39％ <![CDATA[23 e ]]> NaH DCM 5h 52％ <![CDATA[24 f ]]> NaH DCM 5h 50％

[0036] Note: In the absence of special notes, the substrate la (0.1 mmol, 1 equiv) and the substrate 2a (0.12 mmol, 1.2 equiv) were reacted at 25 °C with the specified base (0.2 mmol, 2 equiv) and solvent (1 mL). [a] The yield is the isolated yield of the target compound 3aa after purification. [b] The reaction temperature was 40 °C. [c] The amount of NaH used was 1 equiv. [d] The amount of NaH used was 3 equiv. [e] The amount of aniline 2a used was 1.2 equiv. [f] The amount of aniline 2a used was 1.5 equiv. trace indicates that a small amount of the target compound was obtained. N.R. indicates that the target compound was not obtained.

[0037] From Table 1, it can be seen that comparing groups 1-9, NaH is a suitable base for the one-pot reaction. Comparing groups 10-18, it can be seen that both DCM and DCE are suitable solvents, and considering the temperature control later combined with the boiling point of the reaction solvent, DCM is selected as the optimal solvent. Comparing groups 19-20, it can be seen that after increasing the reaction temperature, the yield does not increase, only the reaction rate is slightly accelerated, based on the consideration of green chemistry, 25°C is selected as the reaction temperature. Subsequently, by adjusting the amount of base (groups 21-22) and increasing the amount of substrate 2a (groups 23-24), finally compound 2-quinolinone 3aa is obtained with a yield of 52%. Therefore, through a series of condition screening of the reaction, the optimal conditions of group 23 are finally determined, i.e. 2-chloro-3-(chloromethyl)-1H-indole 1a (0.1 mmol, 1 equiv) and aniline 2a (0.12 mmol, 1.2 equiv) are used as substrates, NaH (2 equiv) is used as catalyst, DCM (1 mL) is used as solvent, and the reaction is carried out at 25°C for 5h, and this reaction condition is used for the synthesis of 3-amino substituted 2-quinolinone compounds subsequently.

[0038] In order to determine the structure of compound 3aa, solvent evaporation method (dichloromethane:methanol = 1:1 (by volume)) was used to culture the crystal of compound 3aa, and after X-Ray crystal diffraction test analysis, the single crystal structure of compound 3aa was obtained, see Figure 1 According to the single crystal structure of compound 3aa, the structures of other compounds are inferred.

[0039] Comparative Example 1 (step-by-step method)

[0040] (1) At room temperature, the weighed substrate 1a (0.1 mmol, 1 equiv) and potassium carbonate (0.2 mmol, 2 equiv) were added to a round-bottom flask equipped with a stirrer, dissolved in chloroform (1 mL), and then the substrate 2a (2 equiv) was added to the reaction bottle. Stir the reaction, monitor the reaction by TLC (developing agent: petroleum ether: ethyl acetate = 2:1 (by volume)). After the reaction is completed, the solvent is removed under reduced pressure, extracted with water and ethyl acetate (3x5 mL), and the combined organic phase is dried with anhydrous Na2SO4. The solvent is removed under reduced pressure, and the residue is separated and purified by silica gel column chromatography to obtain compound A; the reaction scheme is as follows:

[0041]

[0042] (2) At room temperature, compound A obtained in (1) (1 equiv) and sodium hydride (2 equiv) were added to a round-bottom flask equipped with a stirrer, dissolved in dichloromethane (1 mL), stirred, and the reaction was monitored by TLC (developing agent: petroleum ether: ethyl acetate = 2:1 (by volume)). After the reaction was completed, it was filtered, diluted with water and EtOAc, the water layer was extracted with ethyl acetate (3 x 5 mL), and the combined organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain compound 3aa, with a final yield of 52%; the reaction scheme is as follows:

[0043]

[0044] As can be seen by comparing Example 1 and Comparative Example 1, the one-pot method used in the present application has little difference in the yield of the compound compared with the step-by-step method, but the one-pot method saves the step of separating intermediate A and reduces the amount of reagent used, which is more in line with the requirements of green chemistry, and is more simple, economical and efficient.

[0045] Example 2

[0046] Based on the optimal conditions of group 23 in Example 1, compound 1a (0.4 mmol, 1 equiv) and compound 2 (0.48 mmol, 1.2 equiv) were used as substrates, NaH (0.8 mmol, 2 equiv) and DCM (4 mL) were added, and the reaction was stirred at 25°C for 5h to synthesize 3-amino substituted 2-quinolinone compound 3, and the synthesis route is as follows:

[0047]

[0048] wherein R 1 is H, methyl, F, Br, Cl or nitro; the reaction product and yield are shown in Table 2.

[0049] Table 2

[0050]

[0051]

[0052] Conditions: 1a (0.4 mmol, 1 equiv), 2 (0.48 mmol, 1.2 equiv), NaH (0.8 mmol, 2 equiv), DCM (4 mL), 25°C, air, 5h.

[0053] As can be seen from Table 2, when the same substitution position on the phenyl ring of the compound quinolinone contains a methyl electron-donating group (3ba) and a halogen electron-withdrawing group (3fa, 3ka), the product yield is almost equivalent. The same substituent (3ba, 3ca, 3da, 3ea) or (3fa, 3ga, 3ha) or (3ia, 3ja) or (3ka, 3la) replaces at different positions on the phenyl ring of quinolinone, and the yield is also almost equivalent. However, when the strong electron-withdrawing group -NO2 is replaced (3ma, 3na), the target compound is not obtained. In general, the electronic effect of the electron-donating substituent and the weak electron-withdrawing substituent on the phenyl ring of quinolinone and the different substitution positions have less influence on the synthesis of the target product, which shows that the reaction has good compatibility with the substrates substituted on the phenyl ring of 2-quinolinone.

[0054] Example 3

[0055] Based on the optimal conditions of group 23 in Example 1, compound 1a (0.4 mmol, 1 equiv) and compound 2 (0.48 mmol, 1.2 equiv) were used as substrates, and NaH (0.8 mmol, 2 equiv) and DCM (4 mL) were added. The reaction was stirred at 25°C for 5 h to synthesize 3-amino-substituted 2-quinolinone compound 3. The synthetic route is as follows:

[0056]

[0057] where R 2 is methoxy, methyl, F, Br, Cl, benzene ring, dioxolanyl, thiazolyl or nitro; the reaction products and yields are shown in Table 3.

[0058] Table 3

[0059]

[0060]

[0061] Conditions: 1a (0.4mmol, 1equiv), 2 (0.48mmol, 1.2equiv), NaH (0.8mmol, 2equiv), DCM (4mL), 25℃, air, 5h.

[0062] As shown in Table 3, after expanding upon the aniline derivatives of substrate 2, 17 target compounds 3 with substituents on the phenyl ring of the aniline were successfully synthesized. It can be seen that when the same substitution position on the phenyl ring of the aniline contains a methyl or methoxy electron-donating group (3ab, 3ae) and a halogen electron-withdrawing group (3ah, 3ak, 3al), the yield of the halogen electron-withdrawing group is slightly reduced, and the yield of the strong electron-withdrawing nitro group is even more reduced (3aq). When the same substituent (3ab, 3ac, 3ad) or (3ah, 3ai, 3aj) is substituted at different positions on the phenyl ring of the aniline, it is found that, regardless of whether the substituent is an electron-donating or electron-withdrawing group, the yield of the ortho-position substitution is lower than that of the meta-position substitution, the meta-position substitution is lower than that of the para-position substitution, and the yield difference between the ortho-position substitution and the para-position substitution is even greater. This indicates that the electronic effect of the electron-donating and weak electron-withdrawing substituents on the phenyl ring of the aniline has little influence on the synthesis of the target product, while the main influence is the position of the substitution, which is speculated to be due to steric hindrance. In addition, several heterocyclic amine (3ao, 3ap) and naphthylamine (3am, 3an) substituted compounds were synthesized in moderate yields, which provides a possibility for increasing the diversity of substituents in the compounds.

[0063] Example 4

[0064] In order to investigate the potential of the reaction of the present invention in industrial production, the scale-up reaction of compound 3aa was carried out to synthesize compounds 3aa-1 to 3aa-3:

[0065] (1) Amplification reaction of compound 3aa

[0066] The amount of substrate 2-chloro-3-(chloromethyl)-1H-indole 1a was increased to 1 g, and the amounts of substrate aniline 2a, NaH, and DCM were increased accordingly based on the optimal conditions of Group 23 in Example 1. The reaction temperature and time were the same as those of Group 23 in Example 1. Finally, the target compound 3aa was obtained with a yield of 41%. The synthetic route is as follows:

[0067]

[0068] It can be seen from the above amplified reaction of compound 3aa that, compared with Group 23 in Example 1, the yield of the target compound after the amplified reaction is not significantly affected, indicating that the method of the present invention has certain industrial production applicability.

[0069] (2) Synthesis of compound 3aa-1: Quinolinone compound 3aa (0.1 mmol, 1 equiv) weighed was added to a round-bottom flask equipped with a stirrer, and DMF was added to the flask to dissolve 3aa. The reaction flask was pre-cooled at 0°C, and then NaH (0.12 mmol, 1.2 equiv) was added to the flask and stirred. When no more bubbles were generated, CH3I (0.15 mmol, 1.5 equiv) was slowly added to the reaction. After sufficient stirring, the reaction was moved to room temperature. The reaction was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 4:1 (volume ratio)). After the reaction was completed, the solvent was removed under reduced pressure, and compound 3aa-1 (14.8 mg, yield 59%) was obtained by silica gel column separation and purification. The synthetic route is as follows:

[0070]

[0071] (3) Synthesis of compound 3aa-2: Quinolinone compound 3aa (0.1 mmol, 1 equiv) and Lawesson's reagent (0.2 mmol, 2 equiv) were dissolved in dry toluene, and refluxed at 110°C for 4 h. After cooling to room temperature, the reaction was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 5:1 (volume ratio)). After the reaction was completed, water was added to the reaction system, and then extracted with ethyl acetate, separated, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3aa-2 (13.6 mg, yield 54%). The synthetic route is as follows:

[0072]

[0073] (4) Synthesis of compound 3aa-3: Quinolinone compound 3aa (0.1 mmol, 1 equiv) was dissolved in 1,4-dioxane (0.5 mL), and then POCl3 (0.15 mmol, 1.5 equiv) was added thereto. The reaction was refluxed at 90°C for 5 h until the reaction was completed. The reaction was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 5:1 (volume ratio)). After the reaction was completed, the reaction system was poured into ice water to quench, and then extracted with CH2Cl2, separated, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3aa-3 (11.9 mg, yield 47%). The synthetic route is as follows:

[0074]

[0075] The structural characterization data of the above-synthesized compounds 3aa~3la, 3ab~3ar, and 3aa-1~3aa-3 are as follows:

[0076] 3-(phenylamino)quinolin-2(1H)-one (3aa):

[0077] Yellow solid, 12.2 mg, 0.05 mmol, yield 52%; mp: 223-225°C; 1 HNMR (400MHz, CDCl3): δ11.58(s,1H),7.46-7.27(m,7H),7.22-7.06(m,2H); 13 C NMR (101MHz, CDCl3): δ159.8,140.8,133.3,132.1,129.7,126.1,125.8,123.4,122.9,121.9,120.3,115.5,108.7; HRMS (ESI) m / zcalcd for C 15 H 13 N2O[M+H] + :237.1028,Found:237.1031.

[0078] 5-Methyl-3-(phenylamino)quinolin-2(1H)-one (3ba): Yellow solid, 33.9 mg, 0.14 mmol, yield 34%; mp: 189-191°C; 1 HNMR (400MHz, DMSO-d6): δ12.10(s,1H),7.95(s,1H),7.47(s,1H),7.44-7.32(m,4H),7.16-6.94(m,4H),2.41(s,3H); 13 CNMR (101MHz, DMSO-d6): δ157.9,141.2,132.7,132.2,129.3,129.2,125.3,123.4,121.6,119.3,119.3,113.0,104.4,18.6; HRMS(ESI)m / z calcd for C 16 H 15 N2O[M+H]+:251.1184,Found:251.1187.

[0079] 6-methyl-3-(phenylamino)quinolin-2(1H)-one (3ca): Yellow solid, 24.2 mg, 0.10 mmol, yield 25%; mp: 145-147 °C; 1 H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.88 (s, 1H), 7.39-7.29 (m, 6H), 7.20-6.92 (m, 3H), 2.30 (s, 3H); 13 C NMR (101 MHz, DMSO-d6): δ 158.0, 141.2, 132.8, 131.0, 130.5, 129.2, 126.7, 125.3, 121.4, 120.8, 119.2, 114.5, 107.7, 20.6; HRMS (ESI) m / z calcd for C 16 H 15 N2O [M+H] + : 251.1184, Found: 251.1187.

[0080] 7-methyl-3-(phenylamino)quinolin-2(lH)-one (3da): Yellow solid, 24.6 mg, 0.10 mmol, yield 25%; mp: 154-156 °C; 1 H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 7.88 (s, 1H), 7.39-7.29 (m, 6H), 7.20-6.92 (m, 3H), 2.30 (s, 3H); 13 C NMR (101 MHz, DMSO-d6): δ 158.3, 141.3, 135.2, 132.7, 132.1, 129.2, 125.5, 123.6, 121.3, 119.4, 119.0, 118.6, 114.5, 108.2, 21.1; HRMS (ESI) m / z calcd for C 16 H 15 N2O [M+H] + : 251.1184, Found: 251.1181.

[0081] 8-methyl-3-(phenylamino)quinolin-2(lH)-one (3ea):

[0082] Yellow solid, 51.0 mg, 0.20 mmol, yield 51%; mp: 190-191°C; 1 HNMR (400MHz, DMSO-d6): δ11.29(s,1H),7.94(s,1H),7.44(s,1H),7.41-7.30(m,5H),7.12-6.93(m,3H),2.44(s,3H); 13 CNMR (101MHz, DMSO-d6): δ158.7,141.2,132.6,130.9,129.2,127.2,123.8,122.9,122.0,121.4,120.9,119.2,108.6,17.3.HRMS(ESI)m / z calcd for C 16 H 15 N2O[M+H] + :251.1184,Found:251.1188.

[0083] 5-fluoro-3-(phenylamino)quinolin-2(1H)-one (3fa):

[0084] White solid, 47.2 mg, 0.19 mmol, yield 47%; mp: 171-173°C; 1 HNMR (400MHz, CDCl3): δ11.75(s,1H),7.57(s,1H),7.46-7.31(m,4H),7.27-6.87(m,5H); 13 CNMR (101MHz, CDCl3): δ158.9, 158.1 (d, J = 341.2Hz), 140.3, 133.3 (d, J = 11.5Hz), 129.8, 129.3, 126 .0(d,J=9.0Hz),123.3,120.4,117.4,111.3(d,J=3.7Hz),108.6(d,J=20.2Hz),100.7(d,J=5.0Hz); 19 FNMR (376MHz, CDCl3): δ-122.99 (dd, J=10.2, 5.5Hz); HRMS (ESI) m / z calcd for C 15 H 12 N2OF[M+H] + :255.0934,Found:255.0937.

[0085] 6-fluoro-3-(phenylamino)quinolin-2(1H)-one (3ga):

[0086] Yellow solid, 31.7 mg, 0.12 mmol, yield 32%; mp: 227-228°C; 1 HNMR (400MHz, DMSO-d6): δ12.17(s,1H),8.03(s,1H),7.42-7.31(m,6H),7.25(dd,J=8.9,5.0Hz,1H),7.13-6.96(m,2H); 13 CNMR (101MHz, DMSO-d6): δ157.8,157.6(d,J=236.6Hz),140.7,134.0,129.2,129.0,122.2(d,J=9.9H z), 122.0, 119.8, 116.1 (d, J = 9.0Hz), 112.9 (d, J = 24.6Hz), 110.3 (d, J = 23.5Hz), 106.3 (d, J = 3.2Hz); 19 F NMR (376MHz, DMSO-d6): δ-121.01 (td, J=9.5, 5.0Hz); HRMS (ESI) m / z calcd for C 15 H 12 N2OF[M+H] + :255.0934,Found:255.0934.

[0087] 7-fluoro-3-(phenylamino)quinolin-2(1H)-one (7-fluoro-3-(phenylamino)quinolin-2(1H)-one, 3ha):

[0088] White solid, 34.0 mg, 0.13 mmol, yield 34%; mp: 207-208°C; 1 HNMR (400MHz, DMSO-d6): δ12.19(s,1H),7.87(s,1H),7.58(dd,J=8.7,6.1Hz,1H),7.46(s,1H),7.40-7.29(m,4H),7.06-6.93(m,3H); 13C NMR (101MHz, DMSO-d6): δ160.2(d,J=241.5Hz),158.4,141.1,133.5(d,J=11.5Hz),132.2(d,J=2.5Hz),129 .2,127.5(d,J=9.6Hz),121.5,119.3,117.8(d,J=2.1Hz),110.0(d,J=22.8Hz),107.6,100.7(d,J=25.7Hz); 19 F NMR (376MHz, DMSO-d6): δ-115.59 (td, J=9.5, 6.1Hz); HRMS (ESI) m / z calcd for C 15 H 12 N2OF[M+H] + :255.0934,Found:255.0934.

[0089] 6-bromo-3-(phenylamino)quinolin-2(1H)-one (3ia):

[0090] Yellow solid, 57.5 mg, 0.18 mmol, yield 46%; mp: 272-273°C; 1 HNMR (400MHz, DMSO-d6): δ12.23(s,1H),8.05(s,1H),7.76(d,J=2.2Hz,1H),7.43-7.30(m,6H),7.19(d,J=8.6Hz,1H),7.00(tt,J=7.1,1.4Hz,1H); 13 C NMR (101MHz, DMSO-d6): δ158.0,140.7,133.8,131.4,129.2,127.7,127.3,123.1,121.9,119.7,116.6,114.0,106.0; HRMS(ESI)m / z calcd forC 15 H 12 N2OBr[M+H] + :315.0133,Found:315.0132.

[0091] 7-bromo-3-(phenylamino)quinolin-2(1H)-one (7-bromo-3-(phenylamino)quinolin-2(1H)-one, 3ja):

[0092] Yellow solid, 67.3 mg, 0.21 mmol, yield 54%; mp: 272-274°C; 1 HNMR (400MHz, DMSO-d6): δ12.19(s,1H),8.01(s,1H),7.47(d,J=8.5Hz,1H), 7.44-7.29(m,6H),7.24(dd,J=8.4,2.0Hz,1H),7.00(tt,J=7.0,1.5Hz,1H); 13 C NMR (101MHz, DMSO-d6): δ158.0,140.8,133.5,133.4,129.2,127.3,124.9,121.9,120.2,119.7,117.5,116.7,106.7; HRMS(ESI)m / z calcd forC 15 H 12 N2OBr[M+H] + :315.0133,Found:315.0125.

[0093] 5-chloro-3-(phenylamino)quinolin-2(1H)-one (3ka):

[0094] White solid, 61.3 mg, 0.23 mmol, yield 57%; mp: 240-241°C; 1 HNMR (400MHz, DMSO-d6): δ12.36(s,1H),8.21(d,J=3.3Hz,1H),7.53-7.33(m,5H),7.23(q,J=4.0Hz,3H),7.05(dq,J=6.8,3.6,3.2Hz,1H); 13 C NMR (101MHz, DMSO-d6): δ157.8,140.5,134.7,133.5,129.3,127.9,125.7,122.6,120.4,118.6,114.0,101.7; HRMS(ESI)m / z calcd for C 15 H 12 N2OCl[M+H] + :271.0638,Found:271.0638.

[0095] 6-chloro-3-(phenylamino)quinolin-2(1H)-one (3la):

[0096] Yellow solid, 56.8 mg, 0.21 mmol, yield 53%; mp: 257-258°C; 1 HNMR (400MHz, DMSO-d6): δ11.29(s,1H),7.94(s,1H),7.44(s,1H),7.41-7.30(m,5H),7.12-6.93(m,3H),2.44(s,3H); 13 CNMR (101MHz, DMSO-d6): δ158.7,141.2,132.6,130.9,129.2,127.2,123.8,122.9,122.0,121.4,120.9,119.2,108.6,17.3; HRMS(ESI)m / z calcd for C 15 H 12 N2OCl[M+H] + :271.0638,Found:271.0632.

[0097] 3-((4-methoxyphenyl)amino)quinolin-2(1H)-one (3-((4-methoxyphenyl)amino)quinolin-2(1H)-one, 3ab):

[0098] Yellow solid, 78.4 mg, 0.29 mmol, yield 74%; mp: 200-202°C; 1 H NMR (400MHz, DMSO-d6): δ12.06(s,1H),7.70(s,1H),7.43(dd,J=7.9,1.4Hz,1H),7.33-7.03(m,6H),6.98-6.90(m,2H),3.74(s,3H); 13 C NMR (101MHz, DMSO-d6): δ158.1,154.8,134.4,133.9,132.2,125.2,124.9,1 22.4,122.1,121.3,114.6,114.5,114.5,114.5,105.4,55.2; HRMS(ESI)m / z calcd forC 16 H 14 N2O2Na[M+Na] + :289.0953,Found:289.0952.

[0099] 3-(3-methoxyphenyl)amino)quinolin-2(1H)-one (3ac):

[0100] White solid, 45.5 mg, 0.17 mmol, yield 43%; mp: 196-197°C; 1 H NMR (400MHz, DMSO-d6): δ12.13(s,1H),7.90(s,1H),7.54(d,J=7.8Hz,1H),7.46(s,1H),7.32-6.86(m,6H),6.56(dd,J=8.2,2.4Hz,1H),3.75(s,3H); 13 C NMR (101MHz, DMSO-d6): δ160.1,158.2,142.4,132.7,132.6,129.9,125.7,1 25.6,122.2,120.9,114.6,111.3,108.4,107.2,105.0,55.0; HRMS(ESI)m / z calcd for C 16 H 14 N2O2Na[M+Na] + :289.0953,Found:289.0952.

[0101] 3-((2-methoxyphenyl)amino)quinolin-2(1H)-one (3-((2-methoxyphenyl)amino)quinolin-2(1H)-one, 3ad):

[0102] Orange solid, 23.6 mg, 0.09 mmol, yield 23%; mp: 213-215°C; 1 HNMR (400MHz, DMSO-d6): δ12.21(s,1H),7.76(s,1H),7.59(dd,J=7.5,2.1Hz,2H),7.50(s,1H),7.35-6.84(m,6H),3.88(s,3H); 13 C NMR (101MHz, DMSO-d6): δ158.2,148.8,132.3,131.7,129.9,125.8,125.7,122 .3,121.5,121.1,120.9,116.3,114.8,111.0,107.8,55.7; HRMS(ESI)m / zcalcd forC 16 H14 N2O2Na [M+Na] + : 289.0953, Found: 289.0956.

[0103] 3-(p-tolylamino)quinolin-2(lH)-one (3-(p-tolylamino)quinolin-2(lH)-one, 3ae):

[0104] Yellow solid, 64.2 mg, 0.09 mmol, yield 65%; mp: 245-246 °C; 1 HNMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.79 (s, 1H), 7.48 (dd, J = 7.8, 1.3 Hz, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 4H), 7.22-7.03 (m, 3H), 2.27 (s, 3H); 13 C NMR (101 MHz, DMSO-d6): δ 158.2, 138.4, 133.5, 132.3, 130.8, 129.6, 125.4, 125.2, 122.2, 121.1, 119.9, 114.6, 106.7, 20.4; HRMS (ESI) m / z calcd for C 16 H 15 N2O [M+H] + : 251.1184, Found: 251.1183.

[0105] 3-(m-tolylamino)quinolin-2(lH)-one (3-(m-tolylamino)quinolin-2(lH)-one, 3af):

[0106] Yellow solid, 38.1 mg, 0.15 mmol, yield 39%; mp: 183-185 °C; 1 HNMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.79 (s, 1H), 7.48 (dd, J = 7.8, 1.3 Hz, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 4H), 7.22-7.03 (m, 3H), 2.27 (s, 3H); 13C NMR (101MHz, DMSO-d6): δ158.2,141.0,138.5,133.0,132.5,129.0,125.6,1 25.5,122.5,122.2,121.0,120.0,116.5,114.6,107.6,21.2.HRMS(ESI)m / z calcdfor C 16 H 15 N2O[M+H] + :251.1184,Found:251.1188.

[0107] 3-(o-tolylamino)quinolin-2(1H)-one (3-(o-tolylamino)quinolin-2(1H)-one, 3ag):

[0108] Yellow solid, 19.7 mg, 0.08 mmol, yield 20%; mp: 164-166°C; 1 HNMR (400MHz, DMSO-d6): δ12.12(s,1H),7.48-7.18(m,7H),7.07(q,J=7.3Hz,2H),6.85(s,1H),2.22(s,3H); 13 C NMR(101MHz,DMSO-d6)δ158.1,138.8,134.1,132.2,130.9,130.9,126.8,1 25.3,125.2,123.7,122.2,122.1,121.1,114.7,106.3,17.5; HRMS(ESI)m / z calcd for C 16 H 15 N2O[M+H] + :251.1184,Found:251.1185.

[0109] 3-((4-fluorophenyl)amino)quinolin-2(1H)-one (3ah):

[0110] Yellow solid, 54.8 mg, 0.22 mmol, yield 54%; mp: 212-213 ° C; 1 HNMR (400MHz, DMSO-d6): δ12.10(s,1H),7.95(s,1H),7.50-7.36(m,3H),7.32-7.05(m,6H); 13C NMR (101MHz, DMSO-d6): δ158.1, 157.4 (d, J = 238.2Hz), 137.5 (d, J = 2.4Hz), 133. 5,132.5,125.5,125.4,122.2,121.8,121.7,121.0,115.8,115.6,114.6,106.9; 19 F NMR (376MHz, DMSO-d6): δ-121.2; HRMS (ESI) m / z calcd for C 15 H 12 N2OF[M+H] + :255.0934,Found:255.0937.

[0111] 3-((3-fluorophenyl)amino)quinolin-2(1H)-one (3ai):

[0112] Yellow solid, 31.4 mg, 0.12 mmol, yield 31%; mp: 176-178°C; 1 HNMR (400MHz, DMSO-d6): δ12.14(s,1H),8.15(s,1H),7.61-7.52(m,2H),7.40-7.05(m,6H),6.74(td,J=8.4,2.5Hz,1H); 13 CNMR (101MHz, DMSO-d6): δ162.9(d,J=241.6Hz),158.1,143.4(d,J=11.0Hz),132.9,132.1,130.7(d,J=9.9H z), 126.1, 125.9, 122.2, 120.7, 114.6, 114.4 (d, J = 2.5Hz), 109.9, 107.5 (d, J = 21.2Hz), 105.4 (d, J = 24.9Hz); 19 F NMR(376MHz, DMSO-d6)δ-112.04(dt,J=12.1,7.7Hz); HRMS(ESI)m / z calcd for C 15 H 12 N2OF[M+H] + :255.0934,Found:255.0935.

[0113] 3-((2-fluorophenyl)amino)quinolin-2(lH)-one (3-((2-fluorophenyl)amino)quinolin-2(lH)-one, 3aj):

[0114] Yellow solid, 16.2 mg, 0.06 mmol, yield 16%; mp: 182-184 °C; 1 HNMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 7.67 (s, 1H), 7.63-7.50 (m, 2H), 7.36-7.19 (m, 4H), 7.12 (ddt, J = 10.5, 5.4, 2.3 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6): δ 158.0, 154.2 (d, J = 244.0 Hz), 132.7, 128.7 (d, J = 11.0 Hz), 125.9, 125.8, 125.1 (d, J = 3.5 Hz), 123.6 (d, J = 7.7 Hz), 122.3, 122.0, 120.8, 116.0, 115.8, 114.8, 108.5; 19 F NMR (376 MHz, DMSO-d6): δ -125.6; HRMS (ESI) m / z calcd for C 15 H 12 N2OF [M+H] + : 255.0934, Found: 255.0927.

[0115] 3-((4-bromophenyl)amino)quinolin-2(lH)-one (3-((4-bromophenyl)amino)quinolin-2(lH)-one, 3ak):

[0116] Yellow solid, 57.7 mg, 0.18 mmol, yield 46%; mp: 276-278 °C; 1 HNMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.10 (s, 1H), 7.55-7.43 (m, 4H), 7.39-7.23 (m, 4H), 7.11 (ddd, J = 8.2, 5.0, 3.4 Hz, 1H); 13C NMR (101MHz, DMSO-d6): δ158.1,140.7,132.8,132.5,131.8,125.9,125.7,122.2,121.1,120.7,114.6,112.5,108.9; HRMS(ESI)m / z calcd for C 15 H 12 N2OBr[M+H] + :315.0133,Found:315.0129.

[0117] 3-((4-chlorophenyl)amino)quinolin-2(1H)-one (3al):

[0118] Yellow solid, 56.0 mg, 0.21 mmol, yield 52%; mp: 251-252°C; 1 HNMR (400MHz, DMSO-d6): δ12.14(s,1H),8.10(s,1H),7.52(d,J=7.8Hz,1H),7.45-7.21(m,7H),7.11(ddd,J=8.2,6.0,2.4Hz,1H); 13 C NMR (101MHz, DMSO-d6): δ158.1,140.3,132.8,132.6,128.9,125.8,125.7,124.8,122.2,120.8,120.7,114.6,108.7; HRMS(ESI)m / z calcd for C 15 H 12 N2OCl[M+H] + :271.0638,Found:271.0638.

[0119] 3-(naphthalen-1-ylamino)quinolin-2(1H)-one (3am)

[0120] White solid, 25.1 mg, 0.09 mmol, yield 22%; mp: 200-201°C; 1HNMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 8.02-7.93 (m, 3H), 7.75 (dt, J = 7.6, 3.8 Hz, 1H), 7.55 (ddt, J = 8.9, 6.8, 4.2 Hz, 4H), 7.38-7.18 (m, 3H), 7.05 (td, J = 7.5, 1.2 Hz, 1H), 6.84 (s, 1H); 13 C NMR (101 MHz, DMSO-d6): δ 158.2, 136.4, 135.1, 134.3, 132.4, 128.4, 128.0, 126.3, 126.2, 126.1, 125.3, 125.3, 124.2, 122.3, 122.2, 121.0, 119.3, 114.7, 107.4; HRMS (ESI) m / z calcd for C 19 H 15 N2O[M+H] + : 287.1184, Found: 287.1181.

[0121] 3-(naphthalen-2-ylamino)quinolin-2(lH)-one (3an):

[0122] Yellow solid, 46.3 mg, 0.16 mmol, yield 41%; mp: 235-236 °C; 1 HNMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 8.02-7.93 (m, 3H), 7.75 (dt, J = 7.6, 3.8 Hz, 1H), 7.55 (ddt, J = 8.9, 6.8, 4.2 Hz, 4H), 7.38-7.18 (m, 3H), 7.05 (td, J = 7.5, 1.2 Hz, 1H), 6.84 (s, 1H); 13 C NMR (101 MHz, DMSO-d6): δ 158.2, 136.4, 135.1, 134.3, 132.4, 128.4, 128.0, 126.3, 126.2, 126.1, 125.3, 125.3, 124.2, 122.3, 122.2, 121.0, 119.3, 114.7, 107.4; HRMS (ESI) m / z calcd for C 19 H 14 N2ONa[M+Na] + : 309.1004, Found: 309.1006.

[0123] 3-(benzo[d][l,3]dioxol-5-ylamino)quinolin-2(lH)-one (3-(benzo[d][l,3]dioxol-5- ylamino)quinolin-2(lH)-one, 3ao):

[0124] Orange solid, 50.6 mg, 0.18 mmol, 46% yield; mp: 207-208 °C; 1 H NMR (400 MHz, DMSO-d6): δ 12.07 (s, 1H), 7.75 (s, 1H), 7.47 (dd, J = 8.0, 1.3 Hz, 1H), 7.28-7.16 (m, 3H), 7.12-6.96 (m, 2H), 6.92-6.79 (m, 2H), 6.00 (s, 2H); 13 C NMR (101 MHz, DMSO-d6): δ 158.1, 147.7, 142.5, 135.3, 134.0, 132.3, 125.3, 125.1, 122.1, 121.2, 114.6, 113.3, 108.4, 106.3, 102.9, 101.0; HRMS (ESI) m / z calcd for C 16 H 12 N2O3Na[M+Na] + : 303.0746, Found: 303.0750.

[0125] 3-(benzo[d]thiazol-5-ylamino)quinolin-2(lH)-one (3-(benzo[d]thiazol-5-ylamino)quinolin- 2(lH)-one, 3ap):

[0126] Yellow solid, 63.3 mg, 0.22 mmol, 54% yield; mp: 298-299 °C; 1 H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 9.37 (s, 1H), 8.19 (s, 1H), 8.12-8.04 (m, 2H), 7.59-7.51 (m, 3H), 7.34-7.03 (m, 3H); 13C NMR (101MHz, DMSO-d6): δ158.2,156.7,154.2,140.1,133.1,132.7,126.4,125.7,122.7,122.2,120.9,119.4,114.6,112.2,108.2; HRMS (ESI) m / z calcd for C 16 H 12 N3OS[M+H] + :294.0701,Found:294.0705.

[0127] 3-((3-nitrophenyl)amino)quinolin-2(1H)-one (3aq):

[0128] Orange solid, 21.0 mg, 0.07 mmol, yield 19%; mp: 201-203°C; 1 HNMR (400MHz, DMSO-d6): δ12.18(s,1H),8.54(d,J=4.6Hz,1H),8.17(q,J=2.6Hz,1H),7.84-7.50(m,5H),7.37-7.08(m,3H); 13 C NMR (101MHz, DMSO-d6): δ158.2,148.6,143.1,133.4,132.0,130.4,126.6,126.1,124.3,122.3,120.4,115.1,114.7,112.7,111.6; HRMS(ESI)m / zcalcd for C 15 H 11 N3O3Na[M+Na] + :304.0698,Found:304.0693.

[0129] 3-(3,5-dimethoxyphenyl)amino)quinolin-2(1H)-one (3-((3,5-dimethoxyphenyl)amino)quinolin-2(1H)-on, 3ar):

[0130] Yellow solid, 21.4 mg, 0.07 mmol, yield 19%; mp: 126-128°C; 1H NMR (400MHz, DMSO-d6): δ12.12(s,1H),7.86(s,1H),7.58(d,J=7.8Hz,1H),7.48(s,1H),7.29-7. 22(m,2H),7.12(dt,J=8.2,4.1Hz,1H),6.56(d,J=2.2Hz,2H),6.14(t,J=2.2Hz,1H),3.74(s,6H); 13 C NMR (101MHz, DMSO-d6): δ161.0,158.2,142.9,132.6,132.5,125.8,125.8,122.2,120.9,114.6,109.2,97.4,93.7,55.1; HRMS(ESI)m / z calcd for C 17 H 17 N2O3[M+H] + :297.1239,Found:297.1242.

[0131] 1-methyl-3-(phenylamino)quinolin-2(1H)-one (1-methyl-3-(phenylamino)quinolin-2(1H)-one, 3aa-1):

[0132] White solid, 14.8 mg, 0.06 mmol, yield 59%; mp: 91-92°C; 1 H NMR (400MHz, DMSO-d6): δ7.97 (s, 1H), 7.58 (dd, J = 7.8, 1.5Hz, 1H), 7.50-7.29 (m,7H),7.20(td,J=7.5,1.1Hz,1H),6.99(tt,J=6.8,1.6Hz,1H),3.76(s,3H); 13 C NMR (101MHz, DMSO-d6): δ157.8,141.1,133.8,132.2,129.2,126.3,125.9,122.5,121.7,121.4,119.6,114.2,107.2,30.1; HRMS(ESI)m / zcalcd for C 16 H 15 N2O[M+H] + :251.1184,Found:251.1185.

[0133] 3-(phenylamino)quinoline-2(1H)-thione (3aa-2):

[0134] Yellow solid, 13.6 mg, 0.05 mmol, yield 54%; mp: 181-183°C; 1 HNMR (500MHz, CDCl3): δ12.34(s,1H),7.88(s,1H),7.50(dd,J=13.9,8.1Hz,2H),7.45-7.27(m,7H),7.14(t,J=7.3Hz,1H); 13 CNMR(126MHz, CDCl3): δ173.5,140.6,140.1,133.1,129.7,126.9,126.0,125.3,124.9,123.9,121.8,115.6,107.1; HRMS(ESI)m / z calcd for C 15 H 13 N2S[M+H] + :253.0799,Found:253.0790.

[0135] 2-chloro-N-phenylquinolin-3-amine (2-chloro-N-phenylquinolin-3-amin, 3aa-3):

[0136] White oil, 11.9 mg, 0.05 mmol, yield 47%; 1 H NMR (500MHz, CDCl3): δ7.92(d,J=8.2Hz,1H),7.76(s,1H),7.59(dd,J=8.1,1.5Hz, 1H),7.52-7.37(m,4H),7.28(d,J=7.9Hz,2H),7.16(t,J=7.4Hz,1H),6.32(s,1H); 13 C NMR (126MHz, CDCl3): δ142.2,142.0,140.4,135.2,129.9,128.8,128.2,127.5,127.0,126.1,124.1,121.3,116.0; HRMS (ESI) m / z calcd forC 15 H 12 N2Cl[M+H] + :255.0689,Found:255.0688.

[0137] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A 3-amino substituted 2-quinolinone compound, characterized in that: The structural formula is as follows: Among them, R 1 is selected from H, halogen or methyl; R 2 is selected from H, methyl, methoxy, halogen, nitro, heterocyclic group or benzene ring.

2. The 3-amino-substituted 2-quinolinone compound according to claim 1, characterized in that The R 1 and R 2 The halogen in is independently selected from F, Cl or Br.

3. The 3-amino-substituted 2-quinolinone compound according to claim 1, characterized in that The heterocyclic group is selected from dioxolanyl or thiazolyl.

4. The 3-amino-substituted 2-quinolinone compound according to claim 1, characterized in that Selected from the following compounds:

5. A method for preparing the 3-amino-substituted 2-quinolinone compound according to any one of claims 1 to 4, characterized in that: The 3-amino-substituted 2-quinolinone compounds are synthesized by a one-pot reaction in an organic solvent using 2-chloro-3-(chloromethyl)-1H-indole derivatives and aniline derivatives as reaction substrates and NaH as a catalyst.

6. The method for preparing the 3-amino-substituted 2-quinolinone compound according to claim 5, wherein: The molar ratio of the 2-chloro-3-(chloromethyl)-1H-indole derivatives to the aniline derivatives is 1:1.2; and / or the molar ratio of NaH to the 2-chloro-3-(chloromethyl)-1H-indole derivatives is 2:

1.

7. The method for preparing 3-amino-substituted 2-quinolinone compounds according to claim 5, characterized in that: The organic solvent is selected from dichloromethane; the usage ratio of the organic solvent to the 2-chloro-3-(chloromethyl)-1H-indole derivative is 1 mL:0.1 mmol.

8. The method for preparing 3-amino-substituted 2-quinolinone compounds according to claim 5, characterized in that: The one-pot reaction was carried out at room temperature for 5 h.

9. Use of the 3-amino-substituted 2-quinolinone compound according to any one of claims 1 to 4 in the preparation of anti-tumor drugs.

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