Quinoxalinone diaryl methane compound as well as synthesis method and application thereof

Abstract

The invention relates to a quinoxalinone diaryl methane compound as well as a synthesis method and application thereof. The synthesis method comprises the following steps: under the action of an HAT catalyst and a photocatalyst, a compound a and a compound b react under the irradiation of blue light to obtain the quinoxalinone diaryl methane compound shown in the formula (I). The synthesis method of the quinoxalinone diaryl methane compound has the advantages of very high selectivity, high product yield, atom economy, simple method, high efficiency, mildness, greenness, environmental protection, low synthesis cost and the like, avoids the problems of metal residues and the like caused by the use of a transition metal catalyst, and is suitable for industrial production. The invention provides a simple and effective synthesis strategy and method for developing more heterocyclic diaryl methane derivative active drug molecules. The quinoxalinone diaryl methane compound prepared by the invention has certain anti-tumor activity and can be applied to preparation of medicines for treating tumors. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and medicine, and specifically relates to a quinoxalinone diarylmethane compound and a synthesis method and application thereof. Background Art

[0002] Diarylmethane derivatives are widely present in biologically active compounds such as drugs and natural products. Among them, the anti-tumor activity of heterocyclic diarylmethanes is particularly noteworthy. For example, the heterocyclic diarylmethane derivative letrozole can reduce estrogen levels by inhibiting aromatase, thereby eliminating the stimulating effect of estrogen on tumor growth and is used in the treatment of breast cancer.

[0003] The following are some drugs and natural products containing diarylmethane structures:

[0004]

[0005] Therefore, it is necessary to provide more efficient synthesis methods of heterocyclic diarylmethane derivatives to obtain a variety of heterocyclic diarylmethane derivatives for drug development. At present, there are few reports on quinoxalinone diarylmethane compounds and their synthesis methods, because the synthesis of such compounds is relatively difficult.

[0006] Hydrogen atom transfer (HAT) is one of the most attractive methods for C-H bond activation. It can be used to rapidly synthesize C-H coupling compounds with atom and step economy, and can also be used for the synthesis of heterocyclized diarylmethane derivatives. Various heteroatom radicals such as S, N, O and halogen-centered radicals can serve as effective HAT reagents. Among them, halogen radicals, especially bromine radicals, have attracted much attention due to their availability and high reactivity. Compared with chlorine, bromide anions are more easily oxidized, and the generated bromine radicals have weaker hydrogen evolution ability than chlorine radicals. This gives bromine radicals milder initiation conditions and superior HAT selectivity. The latest progress in using bromine radicals as HAT catalysts is mainly based on the photoactivation of metal bromine intermediates formed in situ, and the substrates are limited to activated alkanes (such as tertiary alkyl, benzyl, α-acyl, α-oxo, α-amino and allyl C sp 3 -H bond) and aldehydes, because their C-H bond dissociation energy (BDE) is close to the H-Br bonding energy (87 kcal mol -1 ), as shown in Formula 1 below.

[0007]

[0008] However, when there are multiple potential hydrogen donors and acceptors, the selectivity of organic molecular HATs is often difficult to control. How to achieve site-selective CH bond activation efficiently and controllably is crucial for the highly specific and selective functionalization of drugs. sp 2 -H bonds, there have been no reported cases of HAT-catalyzed activation, which is a limitation of the current methods of synthesizing substrates through HAT-catalyzed activation. For such substrates, in the presence of multiple potential hydrogen atom donors (such as benzyl, α-amino, α-oxygen, and allyl CH bonds), selective activation of N=C sp 2 The -H key will be a huge challenge. Summary of the invention

[0009] Based on this, the purpose of the present invention is to provide a method for synthesizing quinoxalinone diarylmethane compounds to obtain more heterocyclic diarylmethane derivatives for drug development.

[0010] The technical solutions for achieving the above-mentioned purpose include the following.

[0011] In a first aspect, the present invention provides a method for synthesizing a quinoxalinone diarylmethane compound, comprising the following steps:

[0012] Under the action of HAT catalyst and photocatalyst, compound a and compound b react under the irradiation of visible light to obtain a quinoxalinone diarylmethane compound represented by formula (I);

[0013] The reaction formula is as follows:

[0014]

[0015] Among them, R 1 Selected from: substituted or unsubstituted alkyl;

[0016] Each R 2 are independently selected from: hydrogen, alkyl, halogen, aryl;

[0017] R 3 Selected from: hydrogen, alkyl, halogen, aryl;

[0018] R 4 Selected from: substituted or unsubstituted aryl;

[0019] n is selected from: 0, 1, 2, 3, 4;

[0020] The photocatalyst is Mes-Acr + ClO4 - .

[0021] In some embodiments, R1 Selected from: R 5 Substituted or unsubstituted C1-C6 alkyl;

[0022] R 5 Selected from:

[0023]

[0024] In some embodiments, R 1 Selected from: R 5 Substituted or unsubstituted C1-C3 alkyl.

[0025] In some embodiments, R 1 Selected from: methyl, ethyl, propyl, or selected from the following groups:

[0026]

[0027] In some embodiments, each R 2 Each is independently selected from: hydrogen, C1-C6 alkyl, halogen, phenyl, naphthyl.

[0028] In some embodiments, each R 2 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, propyl, fluorine, bromine, chlorine, phenyl, and naphthyl.

[0029] In some embodiments, R 3 Selected from: hydrogen, C1-C6 alkyl, halogen, phenyl, naphthyl.

[0030] In some embodiments, R 3 Selected from: hydrogen, methyl, ethyl, propyl, tert-butyl, fluorine, bromine, chlorine, phenyl, naphthyl.

[0031] In some embodiments, R 4 Selected from: R 6 Substituted or unsubstituted phenyl, R 6 Substituted or unsubstituted naphthyl; R 6 Selected from: hydrogen, C1-C6 alkyl, halogen, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl.

[0032] In some embodiments, R 6 Selected from: hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxyl.

[0033] In some embodiments, R 4 Selected from:

[0034]

[0035] In some embodiments, the compound a is selected from:

[0036]

[0037] The compound b is selected from:

[0038]

[0039] The quinoxalinone diarylmethane compound is selected from:

[0040]

[0041] In some of the embodiments, the HAT catalyst is N-bromosuccinimide, N-chlorosuccinimide and / or dibromomethane, preferably N-bromosuccinimide.

[0042] In some embodiments, the reaction is carried out in an organic solvent, and the organic solvent is dichloromethane or tetrahydrofuran.

[0043] In some embodiments, the visible light is blue light.

[0044] In some embodiments, the wavelength of the blue light is 430nm-460nm.

[0045] In some of the embodiments, the wavelength of the blue light is 450nm-456nm.

[0046] In some embodiments, the visible light irradiation is performed using a 10W blue light emitting diode.

[0047] In some embodiments, the molar ratio of compound a, compound b, HAT catalyst and photocatalyst is 1:1-2:0.2-0.6:0.01-0.05.

[0048] In some of the embodiments, the molar ratio of compound a, compound b, HAT catalyst and photocatalyst is 1:1.2-1.7:0.3-0.5:0.01-0.03.

[0049] In some embodiments, the reaction temperature is 15°C-40°C, and the reaction time is 8-16 hours.

[0050] In some embodiments, the reaction temperature is 20°C-30°C, and the reaction time is 10-14 hours.

[0051] In a second aspect, the present invention provides a series of quinoxalinone diarylmethane compounds having a structure shown in formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0052]

[0053] Among them, R 1 Selected from: substituted or unsubstituted alkyl;

[0054] Each R 2 are independently selected from: hydrogen, alkyl, halogen, aryl;

[0055] R 3 Selected from: hydrogen, alkyl, halogen, aryl;

[0056] R 4 Selected from: substituted or unsubstituted aryl;

[0057] n is selected from: 0, 1, 2, 3, 4.

[0058] In some embodiments, R 1 Selected from: R 5 Substituted or unsubstituted C1-C6 alkyl;

[0059] R 5 Selected from:

[0060]

[0061] In some embodiments, R 1 Selected from: R 5 Substituted or unsubstituted C1-C3 alkyl.

[0062] In some embodiments, R 1 Selected from: methyl, ethyl, propyl, or selected from the following groups:

[0063]

[0064] In some embodiments, each R 2 Each is independently selected from: hydrogen, C1-C6 alkyl, halogen, phenyl, naphthyl.

[0065] In some embodiments, each R 2 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, propyl, fluorine, bromine, chlorine, phenyl, and naphthyl.

[0066] In some embodiments, R 3 Selected from: hydrogen, C1-C6 alkyl, halogen, phenyl, naphthyl.

[0067] In some embodiments, R 3 Selected from: hydrogen, methyl, ethyl, propyl, tert-butyl, fluorine, bromine, chlorine, phenyl, naphthyl.

[0068] In some embodiments, R 4 Selected from: R6 Substituted or unsubstituted phenyl, R 6 Substituted or unsubstituted naphthyl;

[0069] R 6 Selected from: hydrogen, C1-C6 alkyl, halogen, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl.

[0070] In some embodiments, R 6 Selected from: hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxyl.

[0071] In some embodiments, R 4 Selected from:

[0072]

[0073] In some embodiments, the quinoxalinone diarylmethane compound is selected from:

[0074]

[0075] In a third aspect, the present invention also provides the use of the quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of an anti-tumor drug, wherein the tumor is preferably prostate cancer or pancreatic cancer.

[0076] In a fourth aspect, the present invention further provides an anti-tumor drug prepared from an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the quinoxalinone diarylmethane compound described in the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0077] The present invention has the following beneficial effects:

[0078] The present invention utilizes visible light and halogen free radicals to catalyze a cascade reaction, and by selecting a suitable photocatalyst and optimizing the halogen free radical precursor (HAT catalyst), successfully realizes the N=C sp 2 By selectively activating the -H bond, combined with suitable solvent and other reaction conditions, a series of quinoxalinone diarylmethane compounds were prepared with high efficiency and high yield using quinoxalinone compounds and p-methenquinone compounds as reaction raw materials, enriching the compound library of heterocyclic diarylmethane derivatives and providing a simple and effective synthetic strategy and method for developing more heterocyclic diarylmethane derivative active drug molecules.

[0079] The method for synthesizing the quinoxalinone diarylmethane compounds of the present invention has very high selectivity, high product yield, and has the advantages of atom economy, simplicity, high efficiency, mildness, green environmental protection, low synthesis cost, etc., while avoiding the problems of metal residues caused by the use of transition metal catalysts.

[0080] The quinoxalinone diarylmethane compounds prepared by the present invention have certain anti-tumor activity, can inhibit the proliferation of tumor cells in prostate cancer cell lines and pancreatic cancer cell lines, and can be used to prepare anti-tumor drugs for treating prostate cancer and pancreatic cancer. DETAILED DESCRIPTION

[0081] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0082] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers.

[0083] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0084] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0085] In the compounds described in the present invention, when any variable (such as R 2If a (, etc.) compound occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations render the compound stable. A line drawn from a substituent into a ring system or carbon chain indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0086] The term "alkyl" as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0087] The term "alkoxy" used in the present invention refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0088] The term "halogen" as used herein refers to chlorine, fluorine, bromine and iodine.

[0089] The room temperature in the present invention refers to 23°C-25°C.

[0090] The present invention is further described in detail below with reference to specific embodiments.

[0091] The starting materials and reagents used in the following examples are all commercially available conventional materials and reagents, or can be synthesized by known methods reported in the literature.

[0092] The photocatalyst Mes-Acr used in the following examples is + ClO4 - The structural formula is as follows:

[0093]

[0094] Example 1 Synthesis of Compound 1

[0095]

[0096] N-bromosuccinimide (NBS, 0.04 mmol, 0.4 eq., 7 mg), p-methenequinone b-1 (0.15 mmol, 1.5 eq.), Mes-Acr + ClO4 - (0.002 mmol, 2 mol%, 1.3 mg) and dry dichloromethane (DCM, 1 ml) were added to a 10 ml glass flask equipped with a magnetic stirring bar and a nitrogen inlet, and then quinoxalinone a-1 (0.1 mmol, 1 equivalent) was added. The mixture was purged by evacuating the flask three times and backfilling with nitrogen, and then placed in an irradiation device equipped with a 10W blue light-emitting diode (LED) band (its wavelength is 454nm). The resulting mixture was stirred for 12 hours at room temperature and nitrogen atmosphere. The crude product was purified by column chromatography (silica gel, EtOAc:n-Hexane=1:10~1:5) to obtain a yellow solid product 1 (yield 96%). The product structure was determined by X-ray single crystal diffraction, and its CCDC number is: 2377162. Its data can be obtained free of charge at www.ccdc.cam.ac.uk.

[0097] 1 H NMR(400MHz, CDCl3) δ7.86(d,J=7.6Hz,1H),7.54-7.48(m,1H),7.45(d,J=7.6Hz,2H),7.41(s,2H),7.30 (dd,J=15.0,7.5Hz,4H),7.18(t,J=7.3Hz,1H),6.24(s,1H),5.08(s,1H),3.68(s,3H),1.40(s,18H)ppm.

[0098] 13 C NMR (100MHz, CDCl3) δ161.1,154.8,152.6,142.3,135.4,133.0,132.7,131.2,13 0.3,129.8,129.2,128.2,126.5,126.3,123.4,113.4,51.5,34.4,30.4,29.4ppm.

[0099] HRMS(ESI)m / z calcd for C 30 H 35 N2O2 + (M+H) + 455.2693, found m / z 455.2697.

[0100] Example 2 Synthesis of Compound 1

[0101] Compound 1 was prepared by the method of Example 1 under the conditions shown in Table 1 below. The yield is shown in Table 1.

[0102] The preparation method and reaction conditions of this example are the same as those of Example 1 except for the differences shown in Table 1.

[0103] Table 1

[0104]

[0105]

[0106] [a] Using THF as solvent, product 1 can be produced in higher yield, but there are some by-products caused by the transfer of hydrogen atoms from THF itself.

[0107] Example 3

[0108] Substituting b-2, b-3 and b-4 for b-1 in Example 1 respectively, compound 2 to compound 4 were prepared according to the method and conditions of Example 1.

[0109]

[0110] 1. According to the synthesis steps of Example 1, a yellow solid product 2 (yield 80%) was obtained, and its structure is as follows:

[0111]

[0112] 1 H NMR (400MHz, CDCl3) δ7.84(d,J=7.9Hz,1H),7.49(t,J=7.8Hz,1H),7.40(s,2H),7.30(t,J=7.6Hz,1H),7.28-7.22(m,1H),7.08(s, 1H),6.95(d,J=8.2Hz,1H),6.81(d,J=8.2Hz,1H),6.15(s,1H),5.51(s,1H),5.08(s,1H),3.83(s,3H),3.67(s,3H),1.40(s,18H);

[0113] 13 C NMR (100MHz, CDCl3) δ161.2,154.8,152.5,146.3,144.3,135.4,134.0,133.0,132.7,131.6 ,130.2,129.8,126.3,123.5,121.9,114.0,113.5,112.2,55.8,51.0,34.4,30.4,29.4ppm;

[0114] HRMS(ESI)m / z calcd for C 31 H 37 N2O4 + (M+H) + 501.2748, found m / z 501.2751.

[0115] 2. According to the synthesis steps of Example 1, a yellow solid product 3 (yield 91%) was obtained, and its structure is as follows:

[0116]

[0117] 1 H NMR (400MHz, CDCl3) δ7.85 (dd, J = 7.9, 1.3Hz, 1H), 7.59-7.47 (m, 5H), 7.39 (s, 2H), 7.35-7. 30(m,1H),7.28(d,J=8.4Hz,1H),6.28(s,1H),5.13(s,1H),3.68(s,3H),1.41(s,18H)ppm;

[0118] 13 C NMR (100MHz, CDCl3) δ160.3, 154.7, 152.9, 146.5, 135.7, 132.8 (d, J = 38.9Hz), 130.3-130.2 (m), 12 9.4,129.0,128.5(q,J=32.4Hz),125.1-125.0(m),123.6,113.6,51.3,34.4,30.3,30.2,29.4ppm;

[0119] 19 F NMR(376MHz, CDCl3)δ-62.33(s);

[0120] HRMS(ESI)m / z calcd for C 31 H 34 F3N2O2 + (M+H) + 523.2567, found m / z 523.2566.

[0121] 3. According to the synthesis steps of Example 1, a yellow solid product 4 (yield 97%) was obtained, and its structure is as follows:

[0122]

[0123] 1H NMR (400MHz, CDCl3) δ7.86(dd,J=7.9,1.5Hz,1H),7.81(s,1H),7.75(dd,J=5.3,2.8Hz,3H),7.63(dd,J=8.6,1.6Hz,1H),7.54-7.44(m,3 H),7.39(dd,J=6.5,2.7Hz,2H),7.34-7.27(m,1H),7.24(dd,J=7.3,5.8Hz,1H),6.40(s,1H),5.10(s,1H),3.67(s,3H),1.41(s,18H)ppm;

[0124] 13 C NMR (100MHz, CDCl3) δ161.1,154.9,152.7,139.9,135.5,133.5,133.0,132.7,132.3,131.1,130.3,12 9.9,128.0,127.9,127.7,127.5,127.5,126.6,125.7,125.4,123.5,113.5,51.6,34.4,30.4,29.4ppm;

[0125] HRMS(ESI)m / z calcd for C 34 H 37 N2O2 + (M+H) + 505.2850, found m / z 505.2855.

[0126] Example 4

[0127] Substitute a-2, a-3, a-4, a-5, a-6, a-7, a-8 and a-9 for a-1 in Example 1, respectively, and prepare compounds 5 to 12 according to the method and conditions of Example 1.

[0128]

[0129] 1. According to the synthesis steps of Example 1, a colorless oil product 5 (yield 76%) was obtained, and its structure is as follows:

[0130]

[0131] 1H NMR (400MHz, CDCl3) δ7.66 (dd, J=10.3, 8.3Hz, 1H), 7.41 (d, J=7.2Hz, 2H), 7.35 (s, 2H), 7.28 (t, J=7.5Hz, 2H), 7.19(t,J=7.3Hz,1H),7.06(dd,J=11.3,7.0Hz,1H),6.19(s,1H),5.12(s,1H),3.62(s,3H),1.40(s,18H)ppm;

[0132] 13 C NMR (100MHz, CDCl3) δ161.9, 161.8, 154.4, 152.7, 152.5 (d, J = 14.7Hz), 150. 0(d,J=14.3Hz),147.9(d,J=13.9Hz),145.4(d,J=13.9Hz),141.8,135.5,130 .7,130.2(d,J=7.0Hz),129.2,128.9(dd,J=9.5,2.9Hz),128.3,126.6,126.4 ,117.8(dd,J=18.0,2.2Hz),102.2(d,J=23.1Hz),51.6,34.4,30.4,29.9ppm;

[0133] 19 F NMR (376MHz, CDCl3) δ-131.27 (ddd, J=22.5, 11.6, 8.5Hz), -142.34 (ddd, J=22.5, 10.2, 6.8Hz) ppm;

[0134] HRMS(ESI)m / z calcd for C 30 H 33 F2N2O2 + (M+H) + 491.2505, found m / z 491.2504.

[0135] 2. According to the synthesis steps of Example 1, a brown oil product 6 (yield 94%) was obtained, and its structure is as follows:

[0136]

[0137] 1H NMR (400MHz, CDCl3) δ7.58 (d, J=7.2Hz, 2H), 7.51 (s, 2H), 7.39 (ddd, J=12.5, 7.3, 2.4Hz, 3H), 7. 28(t,J=7.6Hz,3H),7.22-7.00(m,7H),6.19(s,1H),5.07(s,1H),3.28(s,3H),1.40(s,18H)ppm;

[0138] 13 C NMR (100MHz, CDCl3) δ157.7,155.5,152.5,142.7,138.0,136.4,135.3,132.8,132.0,131.8,130.1,13 0.0,129.4,129.3,129.2,129.1,128.3,128.2,127.5,126.7,126.5,126.2,51.1,34.4,34.3,30.4ppm;

[0139] HRMS(ESI)m / z calcd for C 38 H 41 N2O2 + (M+H) + 557.3163, found m / z 557.3170.

[0140] 3. According to the synthesis steps of Example 1, a yellow solid product 7 (yield 69%) was obtained, and its structure is as follows:

[0141]

[0142] 1 H NMR (400MHz, CDCl3) δ7.96(d,J=8.1Hz,1H),7.76(d,J=8.2Hz,1H),7.60(dd,J=15.0,8.3 Hz,2H),7.52(dd,J=14.2,7.5Hz,1H),7.38-7.27(m,4H),7.25-7.15(m,4H),6.74(dd,J= 8.6,2.3Hz,1H),6.71(d,J=2.2Hz,1H),6.25(d,J=9.4Hz,1H),5.92(s,1H),5.10(s,1H), 4.64(dd,J=8.2,3.7Hz,2H),3.90(t,J=6.1Hz,2H),2.31-2.13(m,2H),1.37(s,18H)ppm;

[0143] 13C NMR (100MHz, CDCl3) δ162.0,161.3,155.8,155.4,152.5,151.4,143.4,142.4,139.6,138.6,135.4,131.3,129.3,1 29.0,128.7,128.3126.5,126.4,126.4,126.4,113.2,112.9,112.6,101.6,65.0,62.8,53.1,34.4,30.3,29.7ppm;

[0144] HRMS(ESI)m / z calcd for C 41 H 43 N2O5 + (M+H) + 643.3166, found m / z 643.3172.

[0145] 4. According to the synthesis steps of Example 1, a yellow solid product 8 (yield 70%) was obtained, and its structure is as follows:

[0146]

[0147] 1 H NMR (400MHz, CDCl3) δ7.87 (d, J = 8.1Hz, 1H), 7.52-7.40 (m, 6H), 7.33-7.26 (m, 3H), 7.24-7.15 (m ,2H),6.72(dd,J=8.5,2.3Hz,1H),6.65(s,1H),6.23(s,1H),5.09(s,1H),4.56-4.32(m,2H),4. 04(t,J=5.6Hz,2H),2.89(dd,J=9.9,5.1Hz,2H),2.51(dd,J=18.8,8.5Hz,1H),2.44-2.35(m,1H ),2.31-1.89(m,7H),1.59-1.46(m,3H),1.47-1.35(m,20H),1.21-1.08(m,1H),0.91(s,3H)ppm;

[0148] 13C NMR (100MHz, CDCl3) δ160.9,156.7,154.6,152.6,142.4,137.9,135.4,133.0,132.5,132.2,131.3,130.5,130.0,129.1,128.3,126.5,126.5,1 26.4,123.4,114.6,113.6,112.3,65.3,51.3,50.5,48.1,44.0,40.2,38 .4,35.9,34.4,31.6,30.4,29.7,29.7,27.3,26.6,26.0,21.6,13.9ppm;

[0149] HRMS(ESI)m / z calcd for C 50 H 59 N2O4 + (M+H) + 751.4469, found m / z751.4474.

[0150] 5. According to the synthesis steps of the embodiment, a yellow solid product 9 (yield 92%) was obtained, and its structure is as follows:

[0151]

[0152] 1 H NMR (400MHz, CDCl3) δ7.91-7.75(m,1H),7.51-7.38(m,5H),7.35-7.24(m,4H),7 .18(ddd,J=7.2,2.1,1.0Hz,1H),7.05(qd,J=8.1,1.8Hz,4H),6.20(s,1H),5.09 (d,J=1.3Hz,1H),4.64-4.19(m,4H),3.52(dq,J=14.3,7.2Hz,1H),2.41(d,J=7. 2Hz,2H),1.82(dt,J=13.4,6.8Hz,1H),1.41(s,18H),0.88(d,J=6.6Hz,6H)ppm;

[0153] 13C NMR (100MHz, CDCl3) δ174.7,160.9,154.6,154.6,152.6,142.2,140.7,137.3,135.4,135.4,132.8,132.5,132.5,131.2,130.5,130.5,129.9,1 29.4,129.1,129.1,128.3,127.1,126.5,126.4,123.5,113.6,113.6,61 .0,61.0,51.4,51.3,45.0,45.0,41.1,34.4,30.4,30.2,22.4,18.3ppm;

[0154] HRMS(ESI)m / z calcd for C 44 H 53 N2O4 + (M+H) + 673.4000, found m / z 673.4004.

[0155] 6. According to the synthesis steps of Example 1, a yellow solid product 10 (yield 97%) was obtained, and its structure is as follows:

[0156]

[0157] 1 H NMR(400MHz, CDCl3)δ8.39(s,1H),7.97(s,1H),7.93-7.87(m,2H),7.83(dd,J=11.4,8 .7Hz,2H),7.77(dd,J=8.6,1.6Hz,1H),7.62-7.42(m,8H),7.36-7.29(m,1H),7.26(t,J =7.6Hz,2H),7.16(t,J=7.3Hz,1H),6.98(d,J=8.4Hz,1H),6.27(s,1H),5.10(s,1H),4. 87-4.47(m,4H),3.88(s,3H),2.18(s,6H),2.10(s,3H),1.80(s,6H),1.41(s,18H)ppm;

[0158] 13C NMR (100MHz, CDCl3) δ166.7,161.0,159.0,154.7,152.7,142.3,141.6,139.1 ,136.1,135.5,133.0,132.7,132.5,131.3,131.2,131.2,130.6,130.0,129.8 ,129.1,128.3,126.5,126.5,126.4,126.2,126.0,125.8,125.5,124.7,123.7 ,113.9,112.2,61.5,55.2,51.3,41.4,40.7,37.3,37.2,34.5,30.4,29.2ppm;

[0159] HRMS(ESI)m / z calcd for C 59 H 63 N2O5 + (M+H) + 879.4731, found m / z879.4727.

[0160] 7. According to the synthesis steps of Example 1, a yellow solid product 11 (yield 93%) was obtained, and its structure is as follows:

[0161]

[0162] 1 H NMR (400MHz, CDCl3) δ8.75 (t, J=1.4Hz, 1H), 8.38-8.32 (m, 1H), 8.23 ​​(td, J= 7.8,1.7Hz,1H),8.06-7.98(m,1H),7.92-7.81(m,1H),7.64-7.57(m,1H),7. 57-7.41(m,8H),7.34(dd,J=11.9,4.3Hz,1H),7.30-7.26(m,3H),7.18(d,J =7.2Hz,1H),6.26(s,1H),5.10(s,1H),4.77-4.41(m,4H),1.40(s,18H)ppm;

[0163] 13C NMR (100MHz, CDCl3) δ173.1 (d, J = 4.4Hz), 173.1, 167.9, 165.8, 162.1, 160.9, 159.5, 154.7 ,152.6,142.3,135.4,134.8(d,J=8.4Hz),132.9,132.5,132.3,132.0,131.2,131.1,130.6 ,130.4,130.2,129.2,129.1,129.1,128.9,128.3,127.3,126.5,126.4,124.8(d,J=4.0Hz) ,123.7,117.2(d,J=20.9Hz),113.6,112.7(d,J=11.4Hz),61.8,51.3,41.3,34.4,30.4ppm;

[0164] 19 F NMR(376MHz, CDCl3)δ-104.13--112.22(m)ppm;

[0165] HRMS(ESI)m / z calcd for C 46 H 44 FN4O5 + (M+H) + 751.3290, found m / z751.3293.

[0166] 8. According to the synthesis steps of Example 1, a yellow solid product 12 (yield 88%) was obtained, and its structure is as follows:

[0167]

[0168] 1H NMR (400MHz, CDCl3) δ7.99 (d, J = 8.4Hz, 2H), 7.93-7.84 (m, 3H), 7.50-7.42 (m, 6H), 7.36-7.27 (m, 3H), 7.18(t,J=7.3Hz,1H),6.23(s,1H),5.11(s,1H),5.07-4.86(m,1H),4.82-4.50(m,4H),2.44(dd,J=19 .1,8.6Hz,1H),2.15-2.02(m,1H),2.01-1.90(m,2H),1.86-1.73(m,4H),1.62-1.46(m,4H),1.40(s,1 8H),1.34-1.22(m,6H),1.21-0.97(m,3H),0.91(s,3H),0.87(s,3H),0.76(td,J=11.5,3.7Hz,1H)ppm;

[0169] 13 C NMR (100MHz, CDCl3) δ165.8,165.2,161.0,154.7,152.6,142.2,135.5,134.9 ,133.0,132.9,132.4,131.2,130.7,130.0,129.6,129.5,129.1,128.3,126.4 ,123.7,113.5,74.8,61.7,54.4,51.4,51.2,47.8,44.7,41.1,36.7,35.9,35 .7,35.1,34.4,34.0,31.6,30.8,30.4,28.3,27.5,21.8,20.5,13.8,12.3ppm;

[0170] HRMS(ESI)m / z calcd for C 58 H 69 N2O7 + (M+H) + 905.5099, found m / z 905.5102.

[0171] Example 5 Antitumor Activity Test

[0172] In this example, the anti-tumor activity of Compound 1 to Compound 12 was tested. Human prostate cancer cell DU145 and pancreatic cancer cell BxPC3 were selected for the experiment. These cell lines were purchased from the American Type Culture Collection (ATCC). DU145 was cultured in DMEM medium, and BxpC3 was cultured in RPMI1640 medium. All culture media were supplemented with 10% fetal bovine serum (FBS) to provide growth factors required for cell growth. The cell culture conditions were a constant temperature incubator at 37°C and 5% CO2. The culture steps were as follows:

[0173] (1) Tumor cells in the logarithmic growth phase were digested with trypsin and resuspended in complete medium. The cell concentration was measured using a cell counter and the cells were diluted to 3×10 4 Pieces / mL;

[0174] (2) Inoculate 100 μL of cell suspension in each well of a 96-well plate and incubate overnight in a cell culture incubator;

[0175] (3) Compounds 1-12 were diluted to 20 μM with the complete culture medium of the corresponding cells, and 100 μL of the compound dilutions were added to each well of a 96-well plate to make the final concentration of the compound 10 μM. Each compound was added to 3 replicates, and the control group was DMSO with the same volume as the compound. The cells were returned to the cell culture incubator and cultured for 72 hours;

[0176] (4) The inhibitory effects of Compound 1-Compound 12 on the survival of each tumor cell were detected by MTT assay. After the tumor cells were treated with the compounds for 72 hours, 20 μL of 5 mg / mL MTT solution was added to each well and incubated at 37°C for another 4 hours;

[0177] (5) Discard the cell culture medium, add 150 μL DMSO to dissolve the cells, and measure the OD value at 570 nm (OD570) using a microplate reader;

[0178] (6) Data processing: relative survival rate and inhibition rate were calculated based on OD570 of the compound-treated group and the control-treated group. Cell survival rate = OD570 化合物 / OD570 DMSO , inhibition rate equals 100% - cell survival rate.

[0179] The experimental results are shown in Table 2: The quinoxalinone diarylmethane compounds prepared by the present invention can inhibit the proliferation of tumor cells in prostate cancer cell lines and pancreatic cancer cell lines, have anti-tumor activity, and can be used as anti-tumor drugs for treating prostate cancer and pancreatic cancer.

[0180] Table 2

[0181]

[0182] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A quinoxalinone diarylmethane compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: in, R 1 Selected from: substituted or unsubstituted alkyl; Each R 2 are independently selected from: hydrogen, alkyl, halogen, aryl; R 3 Selected from: hydrogen, alkyl, halogen, aryl; R 4 Selected from: substituted or unsubstituted aryl; n is selected from: 0, 1, 2, 3, 4.

2. The quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R 1 Selected from: R 5 Substituted or unsubstituted C1-C6 alkyl; R 5 Selected from: Preferably, R 1 Selected from: R 5 Substituted or unsubstituted C1-C3 alkyl; Preferably, R 1 Selected from: methyl, ethyl, propyl, or selected from the following groups:

3. The quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: Each R 2 Each is independently selected from: hydrogen, C1-C6 alkyl, halogen, phenyl, naphthyl; Preferably, each R 2 Each is independently selected from the group consisting of: hydrogen, methyl, ethyl, propyl, fluorine, bromine, chlorine, phenyl, and naphthyl.

4. The quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R 3 Selected from: hydrogen, C1-C6 alkyl, halogen, phenyl, naphthyl; Preferably, R 3 Selected from: hydrogen, methyl, ethyl, propyl, tert-butyl, fluorine, bromine, chlorine, phenyl, naphthyl.

5. The quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R 4 Selected from: R 6 Substituted or unsubstituted phenyl, R 6 Substituted or unsubstituted naphthyl; R 6 Selected from: hydrogen, C1-C6 alkyl, halogen, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl; Preferably, R 6 Selected from: hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxyl; Preferably, R 4 Selected from:

6. The quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: The quinoxalinone diarylmethane compound is selected from:

7. A method for synthesizing the quinoxalinone diarylmethane compound according to any one of claims 1 to 6, characterized in that: The steps include: Under the action of HAT catalyst and photocatalyst, compound a and compound b react under the irradiation of visible light to obtain a quinoxalinone diarylmethane compound represented by formula (I); The reaction formula is as follows: Among them, R 1 , R 2 , R 3 , R 4 , n as described in any one of claims 1 to 6; The photocatalyst is Mes-Acr + ClO4 - .

8. The method for synthesizing quinoxalinone diarylmethane compounds according to claim 7, characterized in that: The HAT catalyst is N-bromosuccinimide, N-chlorosuccinimide and / or dibromomethane, preferably N-bromosuccinimide; and / or, The reaction is carried out in an organic solvent, and the organic solvent is dichloromethane or tetrahydrofuran; and / or, The visible light is blue light, and the wavelength of the blue light is preferably 430nm-460nm; and / or, The molar ratio of the compound a, the compound b, the HAT catalyst and the photocatalyst is 1:1-2:0.2-0.6:0.01-0.05; and / or, The reaction temperature is 15°C-40°C, and the reaction time is 8-16 hours.

9. Use of the quinoxalinone diarylmethane compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 6 in the preparation of an anti-tumor drug, wherein the tumor is preferably prostate cancer or pancreatic cancer.

10. An anti-tumor drug, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredient comprises the quinoxalinone diarylmethane compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

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