1, 7-disubstituted pyrrolo [1, 2-a] pyrazine compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a 1, 7-disubstituted pyrrolo [1, 2-a] pyrazine compound, a preparation method thereof and application of the 1, 7-disubstituted pyrrolo [1, 2-a] pyrazine compound in preparation of anti-tumor and anti-inflammatory drugs. The compounds are 1, 7-disubstituted pyrrolo [1, 2-a] pyrazine compounds as shown in a general formula M and salts and hydrates thereof, substituent groups are defined in the specification, and the compounds have the effect of inhibiting tubulin polymerization and have good prospects in development of anti-tumor drugs and anti-inflammatory drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound, a preparation method thereof, and an application thereof in the preparation of anti-tumor and anti-inflammatory drugs. Background Art

[0002] Malignant tumors are one of the main causes of human death. Currently, the commonly used anti-tumor drugs in clinical practice have problems such as unsatisfactory activity and serious adverse reactions. At the same time, cytokine storms caused by viral infections and the like pose a threat to human life, and the existing drug treatments have poor effects. Therefore, it is crucial to seek more efficient and safer anti-tumor and anti-inflammatory drugs.

[0003] Microtubules are an important part of the cytoskeleton. The kinetic characteristics of continuous polymerization and depolymerization of microtubules enable them to play an important role in various physiological processes of cells. Microtubules are one of the effective targets for anti-tumor and anti-inflammatory drug research.

[0004] Alkaloids refer to a class of nitrogen-containing organic compounds mainly derived from the biological world, mainly plants. Most alkaloid molecules have complex ring structures and diverse biological activities. The characteristic of fused-ring pyrrole alkaloids is the formation of a six-membered or seven-membered fused ring at the 1,2- or 2,3-position of the pyrrole ring, and this type of compound only has pharmacological activities such as antibacterial, antiviral, and liver protection.

[0005] The 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound involved in the present invention is an analogue of alkaloids, and there are few literature reports on it, and its anti-tumor and anti-inflammatory activities have not been reported in the literature so far. Summary of the Invention

[0006] The purpose of the present invention is to design and synthesize 1,7-disubstituted pyrrolo[1,2-a]pyrazine compounds with definite biological activities, a preparation method thereof, and an application thereof in the preparation of anti-tumor and anti-inflammatory drugs.

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

[0008] A 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound, the compound is a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound shown in general formula M, its salts and hydrates:

[0009]

[0010] In general formula M,

[0011] R 1 、R 2 、R 3 are each independently the same or different and are selected from C1 -C 6 alkoxy group;

[0012] is a single bond or a double bond;

[0013] The structure of Ar is as follows:

[0014]

[0015] wherein, Y is O, S, N-R 9 ;

[0016] R 4 、R 5 、R 6 、R 7 、R 8 are each independently the same or different and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, acetyl, nitro, amino, hydroxyl, amino substituted by at least one C 1 -C 6 alkyl;

[0017] R 9 is hydrogen, C 1 -C 6 alkyl.

[0018] Preferably, the compound is a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound represented by the general formula M, and its salts and hydrates,

[0019] In the general formula M, R 1 、R 2 、R 3 are each independently the same or different and are selected from C 1 -C 3 alkoxy;

[0020] is a single bond or a double bond;

[0021] The structure of Ar is as shown in claim 1, wherein, Y is O, S, N-R 9 ;

[0022] R 4 、R 5 、R 6 、R 7 、R 8 are each independently the same or different and are selected from hydrogen, C 1 -C 3 alkyl, C1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogen, acetyl, nitro, amino, hydroxy, at least one C 1 -C 3 alkyl-substituted amino;

[0023] R 9 is hydrogen, C 1 -C 3 alkyl.

[0024] More preferably, the compound is a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound represented by the general formula M, and its salts and hydrates:

[0025] In the general formula M, R 1 , R 2 , R 3 are each independently methoxy;

[0026] is a single bond or a double bond;

[0027] is as shown in the structural claim 1 of Ar, wherein Y is O, S, N-R 9 ;

[0028] R 4 , R 5 , R 6 , R 7 , R 8 are each independently the same or different and are hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, acetyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino or hydroxy;

[0029] R 9 is hydrogen, methyl or ethyl.

[0030] Even more preferably, the compound is the following compound and its salts and hydrates;

[0031] Compound 1

[0032] 7-(2-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0033] Compound 2

[0034] 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0035] Compound 3

[0036] 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0037] Compound 4

[0038] 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0039] Compound 5

[0040] 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0041] Compound 6

[0042] 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0043] Compound 7

[0044] 7-phenyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0045] Compound 8

[0046] 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0047] Compound 9

[0048] 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0049] Compound 10

[0050] 7-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0051] Compound 11

[0052] 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0053] Compound 12

[0054] 7-(4-Aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0055] Compound 13

[0056] 7-(4-Methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0057] Compound 14

[0058] 7-(3-Fluoro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0059] Compound 15

[0060] 7-(3-Chloro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0061] Compound 16

[0062] 7-(1H-Indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0063] Compound 17

[0064] 7-(1H-Indol-3-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0065] Compound 18

[0066] 7-(1H-Indol-5-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine

[0067] Compound 19

[0068] 7-(2-Fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0069] Compound 20

[0070] 7-(3-Fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0071] Compound 21

[0072] 7-(3-Chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0073] Compound 22

[0074] 7-(3-Hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0075] Compound 23

[0076] 7-(3-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0077] Compound 24

[0078] 7-(3-Aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0079] Compound 25

[0080] 7-Phenyl-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0081] Compound 26

[0082] 7-(4-Fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0083] Compound 27

[0084] 7-(4-Chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0085] Compound 28

[0086] 7-(4-Aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0087] Compound 29

[0088] 7-(4-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0089] Compound 30

[0090] 7-(4-Hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0091] Compound 31

[0092] 7-(4-Methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0093] Compound 32

[0094] 7-(3-Fluoro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine

[0095] Compound 33

[0096] 7-(3-Hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine Compound 34

[0097] 7-(1H-Indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-pyrrolo[1,2-a]pyrazine Compound 32

[0098] 7-(1H-Indol-3-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine Compound 36

[0099] 7-(1H-Indol-5-yl)-1-(3,4,5-trimethoxyphenyl)-pyrrolo[1,2-a]pyrazine

[0100] The salt of the said compound is the salt formed by the compound of general formula M with an acid or a base. The said acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid, etc.; the said base is selected from sodium hydroxide, sodium carbonate, potassium hydroxide, etc.; the number of crystal water molecules of the hydrate of general formula M is any real number from 0 to 16.

[0101] A preparation method of the said 1,7-disubstituted pyrrolo[1,2-a]pyrazine compounds:

[0102]

[0103] Specifically:

[0104] (1) Dissolve the substituted 3,4,5-trisubstituted benzoic acid (I) in dichloroethane, add DMF dropwise, add oxalyl chloride dropwise with stirring, stir the reaction, and then add morpholine and stir the reaction to obtain compound II;

[0105] (2) Stir and react compound II with phosphorus oxychloride, then add a dichloromethane solution of pyrrole and stir the reaction to obtain compound III;

[0106] (3) Dissolve compound III in tetrahydrofuran, add NBS and stir the reaction to obtain compound IV;

[0107] (4) Dissolve compound IV and N-Boc-bromoethylamine in DMF, add sodium hydride and stir the reaction to obtain compound V;

[0108] (5) Stir and react compound V with trifluoroacetic acid to obtain compound VI;

[0109] (6) Dissolve compound VI and the substituted arylboronic acid in a mixed solvent of 1,4-dioxane and water, add Pd(Ph 3 P) 2 Cl 2 and sodium carbonate, and carry out the Suzuki reaction under nitrogen protection to obtain 1,7-disubstituted-3,4-dihydropyrrolo[1,2-a]pyrazine compounds with the general structural formula M;

[0110] (7) Dissolve compound IV, 2-bromo-1,1-diethoxyethane and cesium carbonate in DMF and stir the reaction to obtain compound VII;

[0111] (8) Dissolve compound VII and ammonium acetate in acetic acid and stir the reaction to obtain compound VIII;

[0112] (9) Dissolve compound VIII and arylboronic acid in a mixed solvent of 1,4-dioxane and water, add Pd(Ph 3 P) 2 Cl 2 and sodium carbonate, and carry out the Suzuki reaction under nitrogen protection to obtain 1,7-disubstituted pyrrolo[1,2-a]pyrazine compounds with the general structural formula M.

[0113] Furthermore,

[0114] In step (1), the molar ratio of 3,4,5-trimethoxybenzoic acid (I), oxalyl chloride and morpholine is 1:1-2:2-4, the reaction temperature is 0-30 °C, and the reaction time is 1-12 h;

[0115] In step (2), the molar ratio of compound II, phosphorus oxychloride and pyrrole in the feed is 1:2 - 5:1 - 1.2, the reaction temperature is 0 - 50 °C, and the reaction time is 5 - 24 h;

[0116] In step (3), the molar ratio of compound III and NBS in the feed is 1:1 - 1.2, the reaction temperature is -10 - 35 °C, and the reaction time is 1 - 12 h;

[0117] In step (4), the molar ratio of compound IV, N-Boc-bromoethylamine and sodium hydride in the feed is 1:1 - 2:1 - 2, the reaction temperature is 0 - 50 °C, and the reaction time is 5 - 12 h;

[0118] In step (5), the molar ratio of compound V and trifluoroacetic acid in the feed is 1:1 - 10, the reaction temperature is 0 - 50 °C, and the reaction time is 10 - 60 min;

[0119] In step (6), the molar ratio of compound VI, arylboronic acid, Pd(PPh 3 ) 2 Cl 2 and Na 2 CO 3 in the feed is 1:1 - 1.5:0.03 - 0.1:2 - 5, the reaction temperature is 60 - 110 °C, the reaction time is 1 - 12 h, and the volume ratio of 1,4-dioxane to water is 2 - 10:1;

[0120] In step (7), the molar ratio of compound IV, 2-bromo-1,1-diethoxyethane and cesium carbonate in the feed is 1:1 - 2:1 - 4, the reaction temperature is 50 - 120 °C, and the reaction time is 5 - 12 h;

[0121] In step (8), the molar ratio of compound VII and ammonium acetate in the feed is 1:1 - 5, the reaction temperature is 80 - 120 °C, and the reaction time is 1 - 12 h;

[0122] In step (9), the molar ratio of compound VIII, arylboronic acid, Pd(PPh 3 ) 2 Cl 2 and Na 2 CO 3 in the feed is 1:1 - 1.5:0.03 - 0.1:2 - 5, the reaction temperature is 60 - 100 °C, the reaction time is 1 - 12 h, and the volume ratio of 1,4-dioxane to water is 2 - 10:1.

[0123] The substituted arylboronic acid is preferably 4-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-chlorophenylboronic acid, 3-chlorophenylboronic acid, 3-hydroxyphenylboronic acid, 3-hydroxy-4-methoxyphenylboronic acid, 4-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 4-nitrophenylboronic acid, 4-ethoxyphenylboronic acid, 3-aminophenylboronic acid, 4-hydroxyphenylboronic acid, 3-fluoro-4-methylphenylboronic acid, 3-chloro-4-methylphenylboronic acid, 2,4-difluorophenylboronic acid, 3,5-dimethylphenylboronic acid, 3,5-difluorophenylboronic acid, 3,5-dichlorophenylboronic acid, 2-indoleboronic acid, 3-indoleboronic acid, 4-indoleboronic acid, 5-indoleboronic acid, 6-indoleboronic acid. The pinacol ester of the substituted arylboronic acid is preferably 4-aminophenylboronic acid pinacol ester.

[0124] A pharmaceutical composition comprising the 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound, its salts and hydrates as described above and a pharmaceutically acceptable carrier.

[0125] Use of the 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound, its salts and hydrates as described above or the pharmaceutical composition as described above in the preparation of anti-tumor and anti-inflammatory drugs.

[0126] The method for preparing the 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound provided by the present invention is simple, feasible and has a high yield.

[0127] The present invention further provides the use of the 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound, its salts and hydrates as described above or the pharmaceutical composition as described above in the preparation of drugs for treating tumors and inflammatory diseases. The tumors are human solid tumors and non-solid tumors, including breast cancer, gastric adenocarcinoma, colon cancer, actinic keratosis, leukemia, etc.; the inflammation is the body's defensive reaction of living tissues to exogenous or endogenous injury factors, including cytokine storms caused by viruses, etc.

[0128] The 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound has definite anti-tumor and anti-inflammatory activities and has good development prospects in the development of anti-tumor and anti-inflammatory drugs. Description of the Drawings

[0129] Figure 1 It is the experimental result of the inhibition of tubulin polymerization by Compound 28 provided in the examples of the present invention.

[0130] Figure 2 It is the experimental result of the immunofluorescence staining of Compound 28 provided in the examples of the present invention.

[0131] Figure 3 It is the experimental result of the cell cycle arrest of Compound 28 provided in the examples of the present invention.

[0132] Figure 4 The anti-cell migration experimental results of compound 28 provided by the embodiments of the present invention.

[0133] Figure 5 The anti-colony formation experimental results of compound 28 provided by the embodiments of the present invention. Detailed implementation manners

[0134] The following examples will help to understand the present invention, but the content of the present invention is not limited to the examples given.

[0135] All the reagents used in the present invention are commercially available. The nuclear magnetic resonance spectrum was measured by a Bruker AVANCE 600 nuclear magnetic resonance spectrometer, and the high-resolution mass spectrum was measured by an Agilent Accurate-Mass Q-TOF 6530 (Agilent, Santa Clara, CA, USA) mass spectrometer.

[0136] Example 1: Preparation of morpholine(3,4,5-trimethoxyphenyl)methanone (IIa)

[0137] Dissolve 3,4,5-trimethoxybenzoic acid (Ia) (10 g, 47.2 mmol) and DMF (0.5 mL) in 200 mL of dichloromethane. Slowly add oxalyl chloride (9.01 g, 70.9 mmol) dropwise to the reaction system and stir at room temperature for 3 h. Subsequently, slowly add morpholine (16 g, 184 mmol) and stir at room temperature for 1 h. After the reaction is completed, add 200 mL of water to quench the reaction, and extract with dichloromethane (3×200 mL). Combine the organic layers, wash them with 1 M hydrochloric acid and saturated sodium bicarbonate respectively, dry over anhydrous sodium sulfate, filter, and concentrate to remove the organic solvent to obtain 12.8 g of white solid (IIa) with a yield of 97%.

[0138] Example 2: Preparation of (1H-pyrrol-2-yl)(3,4,5-trimethoxyphenyl)methanone (IIIa)

[0139] Morpholino(3,4,5-trimethoxyphenyl)methanone (IIa) (5 g, 18 mmol) and POCl 3 (6 g, 39 mmol) were stirred at 35 °C for 2 h under nitrogen protection. Subsequently, a dichloromethane (70 mL) solution of pyrrole (1.14 g, 18 mmol) was added to the reaction system and stirred at room temperature overnight. Quench the reaction with a large amount of saturated sodium bicarbonate solution, extract with dichloromethane (3×200 mL), wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and evaporate the organic solvent to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain 3.8 g of white solid (IIIa) with a yield of 80%; mp: 134.8 - 135.4 °C; 11H NMR (600 MHz, CDCl 3 ): δ 9.69 (s, 1H), 7.19 (s, 2H), 7.15 (s, 1H), 6.92 (s, 1H), 6.35 - 6.36 (m, 1H), 3.93 (s, 3H), 3.92 (s, 6H).

[0140] Example 3: Preparation of (4 - bromo - 1H - pyrrol - 2 - yl)(3,4,5 - trimethoxyphenyl)methanone (IVa)

[0141] Dissolve (1H - pyrrol - 2 - yl)(3,4,5 - trimethoxyphenyl)methanone (IIIa) (3 g, 11.5 mmol) in anhydrous tetrahydrofuran (150 mL), and place the reaction in a - 10 °C environment under nitrogen protection. Slowly add a solution of NBS (2.25 g, 12.6 mmol) in tetrahydrofuran (40 mL), and stir at the current temperature for 1 h. After the reaction is complete, add water (200 mL), and extract with ethyl acetate (3 × 150 mL); wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. After filtration and evaporation of the organic solvent, 3.8 g of crude product white solid (IVa) is obtained, with a yield of 98%; mp: 146.2 - 147.0 °C; 1 1H NMR (600 MHz, CDCl 3 ): δ 9.79 (s, 1H), 7.15 (s, 2H), 7.13 - 7.14 (m, 1H), 6.89 - 6.90 (m, 1H), 3.94 (s, 3H), 3.93 (s, 6H).

[0142] Example 4: Preparation of 7 - bromo - 1 - (3,4,5 - trimethoxyphenyl)-3,4 - dihydropyrrolo[1,2 - a]pyrazine (VIa)

[0143] Dissolve (4 - bromo - 1H - pyrrol - 2 - yl)(3,4,5 - trimethoxyphenyl)methanone (IVa) (3.39 g, 10 mmol) in DMF (20 mL), add sodium hydride (288 mg, 12 mmol) at 0 °C, and stir for 30 min. Subsequently, add N - Boc - bromoethylamine (2.69 g, 12 mmol) and stir at room temperature overnight. After the reaction is complete, pour the reaction into 100 mL of ice water and stir for 15 min. Filter and dry to obtain 4.5 g of crude product (Va) with a yield of 93%. The crude product is directly used in the next step without separation and purification.

[0144] (1-(2-Boc-aminoethyl)-4-bromo-1H-pyrrol-2-yl)(3,4,5-trimethoxyphenyl)methanone (V) (4 g, 8.3 mmol) was dissolved in trifluoroacetic acid (30 mL) and stirred at room temperature for 30 min. After the reaction was completed, the solvent was evaporated to dryness, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 80 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and evaporation of the organic solvent, the crude product was obtained as a white solid (VIa) (3 g). The yield was 98%. The crude product was directly used in the next step without separation and purification. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.25 (d, J = 1.57 Hz, 1H), 7.00 (s, 2H), 6.47 (d, J = 1.57 Hz, 1H), 3.98 (t, J = 6.28 Hz, 1H), 3.87 (t, J = 6.28 Hz, 1H), 3.81 (s, 6H), 3.72 (, 3H); MS calcd for C 16 H 17 BrN 2 O 3 [M + H] + : 365.04, found: 365.05, 367.04.

[0145] Example 5: Preparation of 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13)

[0146] 7-Bromo-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (VIa) (100 mg, 0.28 mmol), 4-methylphenylboronic acid (49 mg, 0.36 mmol), Pd(Ph 3 P) 2 Cl 2 (6.8 mg, 0.012 mmol) and Na 2 CO 3 (32 mg, 0.3 mmol) were dissolved in a mixture of 1,4-dioxane / water (2.5 mL, v / v = 4:1). Under nitrogen protection, the reaction was carried out at 110 °C for 5 h. After the reaction was completed, the solvent was evaporated to dryness, and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine, orange solid (64 mg, 73%); mp: 61.7 - 62.5 °C; 1 H NMR (600 MHz, DMSO-d 6): δ 7.51 (d, J = 1.19 Hz, 1H), 7.49 (d, J = 8.01 Hz, 2H), 7.13 (d, J = 7.85 Hz, 2H), 7.07 (s, 2H), 6.78 (d, J = 1.19 Hz, 1H), 4.04 (t, J = 6.25 Hz, 2H), 3.90 (t, J = 6.25 Hz, 2H), 3.83 (s, 6H), 3.74 (s, 3H), 2.27 (s, 3H); 13 13C NMR (150 MHz, DMSO-d 6 ): δ 160.1, 153.1 (2C), 140.0, 136.0, 132.7, 131.7, 129.5 (2C), 125.5, 125.1 (2C), 124.7, 120.9, 110.3, 106.0 (2C), 61.0, 56.3 (2C), 47.5, 42.3, 21.1; HRMS calcd for C 23 H 24 N 2 O 3 [M + H] + : 377.1865, found: 377.1904.

[0147] Example 6: Preparation of 7-(2-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 1)

[0148] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13), using 2-fluorobenzeneboronic acid as the raw material, the target compound 7-(2-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (79%); mp: 168.6 - 169.3 °C; 1 1H NMR (600 MHz, CDCl 3 ): δ 7.50 - 7.53 (m, 1H), 7.33 (s, 1H), 7.16 - 7.20 (m, 1H), 7.10 - 7.16 (m, 2H), 7.09 (s, 2H), 6.84 (s, 1H), 4.06 - 4.12 (m, 4H), 3.92 (s, 3H), 3.92 (s, 6H); 13 13C NMR (150 MHz, CDCl 3): δ 160.1(2C), 159.6(d, J = 246.9 Hz), 153.1(2C), 140.0, 127.7(d, J = 4.41 Hz), 127.3(d, J = 8.23 Hz), 124.4(d, J = 2.94 Hz), 124.3, 122.3(d, J = 12.87 Hz), 118.7, 116.2(d, J = 22.93 Hz), 111.5, 106.0(2C), 98.4, 61.0, 56.3(2C), 47.4, 42.3; HRMS calcd for C 22 H 21 FN 2 O 3 [M + H] + : 381.1614, found: 381.1650.

[0149] Example 7: Preparation of 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 2)

[0150] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 3-fluorobenzeneboronic acid as the raw material, the target compound 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (82%); mp: 150.3 - 151.1 °C; 1 1H NMR (600 MHz, CDCl 3 ): δ 7.28 - 7.32(m, 1H), 7.25(m, 1H), 7.16 - 7.18(m, 1H), 7.14(d, J = 1.56 Hz, 1H), 7.06(s, 2H), 6.88 - 6.91(m, 1H), 6.68(d, J = 1.56 Hz, 1H), 4.04 - 4.08(m, 4H), 3.92(s, 9H); 13 13C NMR (150 MHz, CDCl 3): δ 163.3 (d, J = 248.0 Hz), 160.1, 153.1 (2C), 140.1, 136.9 (d, J = 8.02 Hz), 132.5, 130.3 (d, J = 8.89 Hz), 124.9, 124.3, 121.3, 120.7 (d, J = 2.74 Hz), 112.9 (d, J = 21.30 Hz), 111.9 (d, J = 21.99 Hz), 110.3, 106.0 (2C), 61.0, 56.3 (2C), 47.4, 42.3; HRMS calcd for C 22 H 21 FN 2 O 3 [M + H] + : 381.1614, found: 381.1653.

[0151] Example 8: Preparation of 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 3)

[0152] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 3-chlorophenylboronic acid as the raw material, the target compound 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (77%); mp: 144.1 - 145.0 °C; 1 1H NMR (600 MHz, CDCl 3 ): δ 7.46 (m, 1H), 7.35 - 7.36 (m, 1H), 7.26 - 7.29 (m, 1H), 7.17 - 7.19 (m, 1H), 7.17 (d, J = 1.43 Hz, 1H), 7.07 (s, 2H), 6.72 (d, J = 1.22 Hz, 1H), 4.06 - 4.10 (m, 4H), 3.92 (s, 9H); 13 13C NMR (150 MHz, CDCl 3 ): δ 160.0, 153.1 (2C), 140.1, 136.5, 134.7, 132.6, 130.1, 126.2, 125.2, 124.9, 124.0, 123.2, 121.3, 110.2, 105.9 (2C), 61.0, 56.3 (2C), 47.5, 42.3; HRMS calcd for C 22 H 21 ClN 2 O3 [M+H] + : 397.1319, found: 397.1364.

[0153] Example 9: Preparation of 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 4)

[0154] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 3-hydroxybenzeneboronic acid as the raw material, the target compound 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, Pale yellow solid (52%); mp: 214.6 - 215.3 °C; 1 HNMR(600MHz, CDCl 3 ): δ7.19 - 7.22(m, 1H), 7.13(s, 1H), 7.09(s, 2H), 7.04(d, J = 7.65Hz, 1H), 6.95(s, 1H), 6.75(s, 1H), 6.69(dd, J = 1.80Hz, J = 6.18Hz, 1H), 5.88(brs, 1H), 4.07 - 4.10(m, 4H), 3.91(s, 3H), 3.89(s, 6H); 13 C NMR(150MHz, CDCl 3 ): δ160.5, 156.9, 153.0(2C), 139.9, 136.1, 132.7, 129.9, 125.2, 124.8, 121.1, 117.1, 113.4, 112.3, 110.4, 105.9(2C), 60.9, 56.2(2C), 47.5, 42.2; HRMS calcd for C 22 H 22 N 2 O 4 [M+H] + : 379.1658, found: 379.1701.

[0155] Example 10: Preparation of 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 5)

[0156] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13), using 3-methoxyphenylboronic acid as the raw material, the target compound 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (72%); mp: 147.9 - 148.8 °C; 1 H NMR(600MHz,CDCl 3 ): δ2.26 - 2.29(m,1H), 7.16(d,J=1.37Hz,1H), 7.08 - 7.09(m,1H), 7.07(s,2H), 7.01 - 7.02(m,1H), 6.77(dd,J=2.27Hz,J=5.85Hz,1H), 6.73(d,J=1.26Hz,1H), 4.05 - 4.10(m,4H), 3.92(s,3H), 3.91(s,6H), 3.83(s,3H); 13 C NMR(150MHz,CDCl 3 ): δ160.1, 160.0, 153.0(2C), 139.9, 135.9, 132.6, 129.8, 125.2, 124.7, 121.2, 117.7, 111.3, 111.1, 110.3, 105.9(2C), 60.9, 56.2(2C), 55.2, 47.4, 42.2; HRMS calcd forC 23 H 24 N 2 O 4 [M+H] + : 393.1814, found: 393.1858.

[0157] Example 11: Preparation of 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 6)

[0158] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13), using 3-aminophenylboronic acid as the raw material, the target compound 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (52%); mp: 177.8 - 178.4 °C; 1 H NMR(600MHz,CDCl 3): δ 7.18 (s, 1H), 7.15 (t, J = 7.87 Hz, 1H), 7.11 (s, 2H), 6.90 (d, J = 7.70 Hz, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.57 (dd, J = 1.65 Hz, J = 6.20 Hz, 1H), 4.08 - 4.12 (m, 4H), 3.93 (s, 6H), 3.93 (s, 3H), 3.64 (brs, 2H); 13 C NMR (150 MHz, CDCl 3 ): δ 160.2, 156.7, 153.2 (2C), 146.8, 136.0, 135.3, 132.3, 129.8 (2C), 124.3, 120.3, 115.8, 113.4, 111.9, 110.1 (2C), 106.3, 61.0, 56.4, 42.4, 29.7; HRMS calcd for C 22 H 23 N 3 O 3 [M + H] + : 378.1818, found: 378.1858.

[0159] Example 12: Preparation of 7-Phenyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 7)

[0160] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using phenylboronic acid as the raw material, the target compound 7-phenyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, brown solid (82%); mp: 158.2 - 159.0 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.49 (dd, J = 0.87 Hz, J = 7.17 Hz, 2H), 7.34 - 7.37 (m, 2H), 7.20 - 7.23 (m, 1H), 7.15 (d, J = 1.00 Hz, 1H), 7.08 (s, 2H), 6.73 (s, 1H), 4.03 - 4.09 (m, 4H), 3.92 (s, 9H); 13 C NMR (150 MHz, CDCl 3): δ 160.2, 153.2 (2C), 140.0, 134.8, 133.2, 129.0 (2C), 126.3, 125.4, 125.3 (2C), 125.0, 121.0, 110.0, 106.0 (2C), 61.1, 56.4 (2C), 47.9, 42.4; HRMS calcd for C 22 H 22 N 2 O 3 [M + H] + : 363.1709, found: 363.1748.

[0161] Example 13: Preparation of 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 8)

[0162] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 4-fluorophenylboronic acid as the raw material, the target compound 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, brown solid (78%); mp: 151.9 - 152.5 °C; 1 1H NMR (600 MHz, CDCl 3 ): δ 7.42 - 7.45 (m, 2H), 7.10 (d, J = 1.37 Hz, 1H), 7.07 (s, 2H), 7.02 - 7.06 (m, 2H), 6.67 (d, J = 1.33 Hz, 1H), 4.04 - 4.09 (m, 4H), 3.91 (s, 9H); 13 13C NMR (150 MHz, CDCl 3 ): δ 161.6 (d, J = 244.8 Hz), 160.0, 153.1 (2C), 140.0, 133.0, 130.8 (d, J = 2.99 Hz), 126.7 (d, J = 7.66 Hz, 2C), 124.9, 124.4, 120.6, 115.7 (d, J = 21.62 Hz, 2C), 109.8, 105.9 (2C), 61.0, 56.3 (2C), 47.7, 42.2; HRMS calcd for C 22 H 21 FN 2 O 3 [M + H] + : 381.1614, found: 381.1654.

[0163] Example 14: Preparation of 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 9)

[0164] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) described above, using 4-chlorophenylboronic acid as the raw material, the target compound 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (72%); mp: 165.8 - 166.7 °C; 1 HNMR(600MHz,CDCl 3 ): δ7.40 - 7.42(m, 2H), 7.30 - 7.32(m, 2H), 7.14(d, J = 1.29Hz, 1H), 7.07(s, 2H), 6.69(d, J = 0.96Hz, 1H), 4.04 - 4.09(m, 4H), 3.92(s, 3H), 3.91(s, 6H); 13 C NMR(150MHz,CDCl 3 ): δ160.0, 153.1(2C), 140.0, 133.1, 132.8, 131.8, 128.9(2C), 126.4(2C), 125.0(2C), 124.2, 120.9, 109.8, 105.9, 61.0, 56.3(2C), 47.7, 42.3; HRMS calcd forC 22 H 21 ClN 2 O 3 [M + H] + : 397.1319, found: 397.1358.

[0165] Example 15: Preparation of 7-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 10)

[0166] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) described above, using 4-hydroxyphenylboronic acid as the raw material, the target compound 7-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (62%); mp: 176.5 - 177.1 °C; 11H NMR (600 MHz, CDCl 3 ): δ 7.30 - 7.32 (m, 2H), 7.06 (s, 2H), 7.05 (d, J = 1.54 Hz, 1H), 6.77 - 6.80 (m, 2H), 6.66 (d, J = 1.49 Hz, 1H), 4.03 - 4.08 (m, 4H), 3.89 (s, 3H), 3.86 (s, 6H); 13 13C NMR (150 MHz, CDCl 3 ): δ 160.5, 155.2 (2C), 153.0, 139.7, 132.8, 126.6, 126.4 (2C), 125.3, 124.7, 120.2, 115.8 (2C), 110.0, 105.9 (2C), 60.9, 56.2 (2C), 47.5, 42.2; HRMS calcd for C 22 H 22 N 2 O 4 [M + H] + : 379.1658, found: 379.1701.

[0167] Example 16: Preparation of 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 11)

[0168] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 4-methoxyphenylboronic acid as the raw material, the target compound 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, yellow solid (75%); mp: 124.3 - 125.1 °C; 1 1H NMR (600 MHz, CDCl 3 ): δ 7.40 - 7.42 (m, 2H), 7.08 (s, 2H), 7.08 (s, 1H), 6.90 - 6.92 (m, 2H), 6.67 (s, 1H), 4.06 (m, 4H), 3.92 (s, 9H), 3.82 (s, 3H); 13 13C NMR (150 MHz, CDCl 3): δ 160.0, 158.3, 153.1 (2C), 139.9, 133.0, 127.4, 126.3 (2C), 125.1, 124.7, 120.3, 114.3 (2C), 109.8, 105.9 (2C), 61.0, 56.3 (2C), 55.3, 47.7, 42.2; HRMS calcd for C 23 H 24 N 2 O 4 [M + H] + : 393.1814, found: 393.1857.

[0169] Example 17: Preparation of 7-(4-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 12)

[0170] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 4-aminophenylboronic acid as the raw material, the target compound 7-(4-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, orange solid (52%); mp: 135.5 - 136.2 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.28 - 7.30 (m, 2H), 7.08 (s, 2H), 7.05 (d, J = 0.98 Hz, 1H), 6.68 - 6.70 (m, 2H), 6.66 (s, 1H), 4.04 - 4.08 (m, 4H), 3.92 (s, 6H), 3.91 (s, 3H), 3.66 (brs, 2H); 13 C NMR (150 MHz, CDCl 3 ): δ 160.0, 153.1 (2C), 144.9 (2C), 139.9, 132.9, 126.3 (2C), 125.7, 125.2, 124.6, 120.3, 115.5 (2C), 109.8, 106.0, 61.0, 56.3 (2C), 47.6, 42.2; HRMS calcd for C 22 H 23 N 3 O 3 [M + H] + : 378.1818, found: 378.1863.

[0171] Example 18: Preparation of 7-(3-Fluoro,4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 14)

[0172] According to the method for preparing 7-(4-Methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 3-Fluoro,4-methylphenylboronic acid as the raw material, the target compound 7-(3-Fluoro,4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, orange solid (78%); mp: 154.5 - 155.2 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.14 - 7.16 (m, 2H), 7.10 - 7.12 (m, 2H), 7.06 (s, 2H), 6.67 (d, J = 1.50 Hz, 1H), 4.06 (t, J = 2.93 Hz, 4H), 3.92 (s, 3H), 3.91 (s, 6H), 2.26 (d, J = 1.50 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 161.8 (d, J = 244.2 Hz), 160.1, 153.2 (2C), 140.0, 134.4 (d, J = 8.09 Hz), 133.2, 131.8 (d, J = 5.79 Hz), 125.1, 124.3, 122.5 (d, J = 17.24 Hz), 120.7, 120.6 (d, J = 2.48 Hz), 111.7 (d, J = 23.35 Hz), 109.7, 105.9 (2C), 61.1, 56.4 (2C), 48.0, 42.3, 14.4 (d, J = 3.24 Hz); HRMS calcd for C 23 H 23 FN 2 O 3 [M + H] + : 395.1771, found: 395.1817.

[0173] Example 19: Preparation of 7-(3-Chloro,4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 15)

[0174] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13), using 3-chloro-4-methylphenylboronic acid as a raw material, the target compound 7-(3-chloro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, brown solid (77%); mp: 146.6 - 147.4 °C; 1 H NMR(600MHz,CDCl 3 ): δ7.46(d,J=1.77Hz,1H),7.26 - 7.28(m,1H),7.19(d,J=7.88Hz,1H),7.13(d,J=1.37Hz,1H),7.06(s,2H),6.68(d,J=0.91Hz,1H),4.04 - 4.09(m,4H),3.92(s,3H),3.92(s,6H),2.36(s,3H); 13 C NMR(150MHz,CDCl 3 ): δ160.0,153.1(2C),140.0,134.8,134.0,133.6,132.9,131.2,125.6,124.9,124.0,123.3,120.8,109.8,105.9(2C),61.0,56.3(2C),47.7,42.2,19.8; HRMS calcd for C 23 H 23 ClN 2 O 3 [M + H] + : 411.1475, found: 411.1528.

[0175] Example 20: Preparation of 7-(1H-indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 16)

[0176] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13), using 1H-indol-2-ylboronic acid as a raw material, the target compound 7-(1H-indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, brown solid (67%); mp: 140.3 - 141.7 °C; 1 H NMR(600MHz,CDCl 3): δ 8.37 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 7.05 (t, J = 6.0 Hz, 1H), 7.01 (t, J = 6.0 Hz, 1H), 6.99 (s, 2H), 6.63 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 3.98 (t, J = 6.4 Hz, 4H), 3.84 (s, 3H), 3.83 (s, 6H); 13 C NMR (150 MHz, CDCl 3 ): δ 158.90, 152.09 (2C), 139.05, 135.21, 132.12, 131.09, 131.02, 128.29, 127.58, 127.50, 123.69, 120.50, 119.04, 118.91, 109.53, 104.94 (2C), 96.89, 59.94, 55.32 (2C), 46.48, 41.25; HRMS calcd for C 24 H 23 N 3 O 3 [M + H] + : 402.1739, found: 402.1807.

[0177] Example 21: Preparation of 7-(1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 17)

[0178] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 1H-indol-3-ylboronic acid as the raw material, the target compound 7-(1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, brown solid (70%); mp: 140.1 - 141.4 °C; 1 H NMR (600 MHz, DMSO-d 6): δ 11.07 (d, J = 2.5 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.12 (s, 2H), 7.11 (t, J = 7.9 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.85 (s, 6H), 3.75 (s, 3H); 13 C NMR (150 MHz, DMSO-d6): δ 158.50, 153.02 (2C), 139.33, 137.00, 133.75, 125.65, 123.71, 122.26, 121.53, 121.01, 119.66, 119.44, 118.92, 112.11, 110.47, 109.45, 105.92 (2C), 60.55, 56.32 (2C), 48.00, 41.85. HRMS calculated for C 24 H 23 N 3 O 3 [M + H] + : 402.1739; found: 402.1808.

[0179] Example 22: Preparation of 7-(1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 18)

[0180] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (Compound 13) above, using 1H-indol-5-ylboronic acid as the raw material, the target compound 7-(1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine was synthesized, brown solid (63%); mp: 140.1 - 141.6 °C; 1 H NMR (600 MHz, DMSO-d 6): δ 8.00 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.10 (s, 2H), 6.66 (d, J = 3.5 Hz, 1H), 6.48 (d, J = 1.6 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 3.82 (s, 6H), 3.73 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ): δ 158.58, 153.06 (2C), 149.54, 139.50, 133.17, 131.24, 130.06, 126.80, 124.04, 122.20, 117.28, 115.28, 112.64, 108.76, 108.07, 105.90, 105.75 (2C), 60.54, 56.35 (2C), 47.63, 41.58; HRMS calcd for C 24 H 23 N 3 O 3 [M + H] + : 402.1739, found: 402.1809.

[0181] Example 23: Preparation of (4-bromo-1-(2,2-diethoxy)-1H-pyrrol-2-yl)(3,4,5-trimethoxyphenyl)methanone (VIIa)

[0182] (4-Bromo-1H-pyrrol-2-yl)(3,4,5-trimethoxyphenyl)methanone (IVa) (2.0 g, 5.9 mmol), bromoacetaldehyde diethyl acetal (6.94 g, 35.4 mmol) and cesium carbonate (13 g, 41.4 mmol) were dissolved in DMF (70 mL), protected by nitrogen, and refluxed overnight at 110 °C. After completion of the reaction, the reaction mixture was poured into 200 mL of ice water and stirred for 15 min. The precipitate was filtered, dried to give 2.6 g of crude product (VIIa) with a yield of 97%. The crude product was used directly in the next step without separation and purification.

[0183] Example 24: Preparation of 7-bromo-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (VIIIa)

[0184] (4-Bromo-1-(2,2-diethoxy)-1H-pyrrol-2-yl)(3,4,5-trimethoxyphenyl)methanone (VIIa) (2.0 g, 4.4 mmol) and ammonium acetate (9 g, 118 mmol) were dissolved in acetic acid (20 mL) and refluxed for 2 h. After completion of the reaction, the reaction mixture was poured into 100 mL of ice water and stirred for 15 min. The pH was adjusted to 10 with 2 M sodium hydroxide solution, and the mixture was extracted with ethyl acetate (3 × 80 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the organic phase was evaporated to give a crude product as a white solid (1.6 g, 98% yield). The crude product was used directly in the next step without separation and purification. 1 HNMR(600MHz,CDCl 3 ): δ 7.73 (d, J = 4.71 Hz, 1H), 7.65 (d, J = 4.76 Hz, 1H), 7.51 (d, J = 1.14 Hz, 1H), 7.16 (s, 2H), 7.00 (s, 1H), 3.95 (s, 6H), 3.93 (s, 3H).

[0185] Example 25: Preparation of 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31)

[0186] 7-Bromo-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (VIIIA) (130 mg, 0.36 mmol), 4-methylphenylboronic acid (50 mg, 0.36 mmol), Pd(PPh 3 ) 2 Cl 2 (6.8 mg, 0.012 mmol) and Na 2 CO 3 (32 mg, 0.3 mmol) were dissolved in a mixture of 1,4-dioxane / water (2.5 mL, v / v = 4:1). Under nitrogen protection, the reaction was carried out at 110 °C for 5 h. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine, brown solid (84 mg, 82%); mp: 152.7 - 153.4 °C; 1 HNMR(600MHz,CDCl 3): δ 7.79 (dd, J = 0.55 Hz, J = 4.72 Hz, 1H), 7.76 (d, J = 1.17 Hz, 1H), 7.63 (d, J = 4.74 Hz, 1H), 7.55 (d, J = 8.12 Hz, 2H), 7.25 (s, 2H), 7.23 (d, J = 7.79 Hz, 2H), 7.21 (s, 1H), 3.96 (s, 6H), 3.95 (s, 3H), 2.39 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 153.5 (2C), 153.3, 139.7, 137.4, 133.5, 131.3, 129.8 (2C), 127.6, 127.1, 126.4 (2C), 116.9, 112.5, 106.0 (2C), 105.8, 102.3, 61.1, 56.5 (2C), 21.3; HRMS calcd for C 23 H 22 N 2 O 3 [M + H] + : 375.1709, found: 375.1753.

[0187] Example 26: Preparation of 7-(2-Fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 19)

[0188] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) described above, using 2-fluorophenylboronic acid as the raw material, the target compound 7-(2-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (72%); mp: 198.5 - 199.1 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.92 - 7.93 (m, 1H), 7.81 (dd, J = 0.82 Hz, J = 4.73.34 Hz, 1H), 7.66 - 7.69 (m, 1H), 7.65 (d, J = 4.76 Hz, 1H), 7.27 - 7.30 (m, 1H), 7.26 (s, 2H), 7.15 - 7.22 (m, 2H), 3.96 (s, 6H), 3.95 (s, 3H); 13 C NMR (150 MHz, CDCl 3): δ 160.1 (d, J = 249.0 Hz), 161.0, 159.4, 153.6, 153.5 (2C), 139.7, 129.0 (d, J = 3.62 Hz), 128.8 (d, J = 8.42 Hz), 127.3, 127.0, 124.7 (d, J = 3.26 Hz), 124.5, 116.9, 116.5 (d, J = 22.43 Hz), 114.9 (d, J = 9.04 Hz), 105.9 (2C), 103.6, 61.1, 56.5 (2C); HRMS calcd for C 22 H 19 FN 2 O 3 [M + H] + : 379.1458, found: 379.1499.

[0189] Example 27: Preparation of 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 20)

[0190] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) described above, using 3-fluorobenzeneboronic acid as the raw material, the target compound 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (77%); mp: 123.8 - 124.4 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.82 (d, J = 4.61 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J = 4.76 Hz, 1H), 7.42 - 7.43 (m, 1H), 7.37 - 7.40 (m, 1H), 7.32 - 7.34 (m, 1H), 7.26 (d, J = 6.71 Hz, 2H), 7.23 (s, 1H), 6.99 - 7.02 (m, 1H), 3.97 (s, 6H), 3.95 (s, 3H); 13 C NMR (150 MHz, CDCl 3): δ 163.3 (d, J = 245.7 Hz), 153.4 (2C), 139.9, 136.3 (d, J = 5.39 Hz), 130.5 (d, J = 8.51 Hz), 130.0, 128.6, 128.5, 127.5, 127.0, 122.0 (d, J = 2.91 Hz), 116.9, 114.2 (d, J = 20.98 Hz), 113.2 (d, J = 22.44 Hz), 112.9, 105.9 (2C), 102.6, 61.0, 56.4 (2C); HRMS calcd for C 22 H 19 FN 2 O 3 [M + H] + : 379.1458, found: 379.1513.

[0191] Example 28: Preparation of 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 21)

[0192] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) described above, using 3-chlorophenylboronic acid as the raw material, the target compound 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (80%); mp: 119.0 - 119.8 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.81 (dd, J = 0.76 Hz, J = 4.76 Hz, 1H), 7.78 (d, J = 1.37 Hz, 1H), 7.66 (d, J = 4.80 Hz, 1H), 7.62 - 7.63 (m, 1H), 7.51 - 7.53 (m, 1H), 7.34 - 7.36 (m, 1H), 7.27 - 7.29 (m, 1H), 7.22 (s, 2H), 7.20 (s, 1H), 3.96 (s, 6H), 3.95 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 153.5, 153.4 (2C), 139.8, 135.9, 134.9 133.1, 130.2, 129.7, 127.6, 127.4, 127.1, 126.4, 124.5, 116.9, 112.8, 105.9 (2C), 102.5, 61.0, 56.4 (2C); HRMS calcd for C 22 H 19ClN 2 O 3 [M+H] + :395.1162,found:395.1210.

[0193] Example 29: Preparation of 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 22)

[0194] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) described above, using 3-hydroxybenzeneboronic acid as the raw material, the target compound 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized. Pale yellow solid (67%); mp: 220.7 - 221.6 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.79 (dd, J = 0.86 Hz, J = 4.74 Hz, 1H), 7.71 (d, J = 1.42 Hz, 1H), 7.63 (d, J = 4.75 Hz, 1H), 7.26 - 7.28 (m, 1H), 7.23 (s, 2H), 7.19 - 7.21 (m, 1H), 7.18 (s, 1H), 7.10 - 7.11 (m, 1H), 6.77 - 6.78 (m, 1H), 5.99 (brs, 1H), 3.93 (s, 3H), 3.92 (s, 6H); 13 C NMR (150 MHz, CDCl 3 ): δ 156.5, 153.5, 153.4 (2C), 139.5, 135.7, 133.5, 130.7, 130.2, 127.5, 127.2, 118.7, 116.9, 114.5, 113.4, 112.6, 105.8 (2C), 102.3, 61.0, 56.3 (2C); HRMS calcd for C 22 H 20 N 2 O 4 [M+H] + : 377.1501, found: 377.1578.

[0195] Example 30: Preparation of 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 23)

[0196] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31), using 3-methoxyphenylboronic acid as the raw material, the target compound 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (76%); mp: 195.1 - 196.0 °C; 1 H NMR(600MHz,CDCl 3 ): δ 7.80 (d, J = 4.28 Hz, 1H), 7.77 (d, J = 1.01 Hz, 1H), 7.64 (d, J = 4.73 Hz, 1H), 7.33 - 7.36 (m, 1H), 7.24 - 7.25 (m, 3H), 7.22 (s, 1H), 7.17 - 7.18 (m, 1H), 6.86 - 6.88 (m, 1H), 3.96 (s, 6H), 3.95 (s, 3H), 3.87 (s, 3H); 13 C NMR(150MHz,CDCl 3 ): δ 160.1, 153.4 (2C), 139.7, 135.5, 133.4, 131.0, 130.0, 127.5, 127.0, 119.0, 116.8, 112.7, 112.5, 112.4 (2C), 105.8, 102.5, 61.0, 56.4 (2C), 55.3; HRMS calcd for C 23 H 22 N 2 O 4 [M + H] + : 391.1658, found: 391.1707.

[0197] Example 31: Preparation of 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 24)

[0198] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31), using 3-aminophenylboronic acid as the raw material, the target compound 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, yellow solid (52%); mp: 183.1 - 183.9 °C; 1 H NMR(600MHz,CDCl 3): δ 7.79 (dd, J = 0.60 Hz, J = 4.72 Hz, 1H), 7.74 (d, J = 1.21 Hz, 1H), 7.63 (d, J = 4.77 Hz, 1H), 7.24 (s, 2H), 7.19 - 7.22 (m, 2H), 7.04 - 7.06 (m, 1H), 6.96 - 6.97 (m, 1H), 6.64 - 6.66 (m, 1H), 3.96 (s, 6H), 3.94 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 153.4 (2C), 147.0, 139.6, 135.1, 133.4, 132.1, 131.3, 129.9, 127.4, 126.9, 116.9, 116.8, 114.3, 113.0 (2C), 112.7, 105.9, 102.5, 61.0, 56.4 (2C); HRMS calcd for C 22 H 21 N 3 O 3 [M + H] + : 376.1661, found: 376.1712.

[0199] Example 32: Preparation of 7 - phenyl - 1-(3,4,5 - trimethoxyphenyl)pyrrolo[1,2 - a]pyrazine (Compound 25)

[0200] According to the method for preparing 7-(4 - methylphenyl)-1-(3,4,5 - trimethoxyphenyl)pyrrolo[1,2 - a]pyrazine (Compound 31) above, using phenylboronic acid as the raw material, the target compound 7 - phenyl - 1-(3,4,5 - trimethoxyphenyl)pyrrolo[1,2 - a]pyrazine was synthesized, yellow solid (79%); mp: 118.9 - 119.6 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.80 (d, J = 4.73 Hz, 1H), 7.78 (d, J = 1.22 Hz, 1H), 7.65 - 7.66 (m, 1H), 7.64 - 7.65 (m, 2H), 7.41 - 7.44 (m, 2H), 7.30 - 7.33 (m, 1H), 7.25 (s, 2H), 7.23 (s, 1H), 3.96 (s, 6H), 3.95 (s, 3H); 13 C NMR (150 MHz, CDCl 3): δ 153.5(2C), 153.4, 139.7, 134.2, 133.6, 131.2, 129.1(2C), 127.7, 127.6, 127.2, 126.5(2C), 117.0, 112.6, 105.9(2C), 102.4, 61.1, 56.5(2C); HRMS calcd for C 22 H 20 N 2 O 3 [M + H] + : 361.1552, found: 363.1591.

[0201] Example 33: Preparation of 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 26)

[0202] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) above, using 4-fluorophenylboronic acid as the raw material, the target compound 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (71%); mp: 177.2 - 178.0 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.80 (dd, J = 0.82 Hz, J = 3.73 Hz, 1H), 7.73 (d, J = 1.43 Hz, 1H), 7.65 (d, J = 4.74 Hz, 1H), 7.58 - 7.62 (m, 2H), 7.24 (s, 2H), 7.16 (s, 1H), 7.10 - 7.17 (m, 2H), 3.96 (s, 6H), 3.94 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 162.3 (d, J = 246.6 Hz), 153.4(2C), 153.3, 139.7, 133.4, 130.3 (d, J = 2.79 Hz), 130.1, 128.0 (d, J = 7.82 Hz, 2C), 127.6, 127.2, 116.8, 116.0 (d, J = 21.51 Hz, 2C), 112.3, 105.8(2C), 102.1, 61.0, 56.4(2C); HRMS calcd for C 22 H 19 FN 2 O 3 [M + H] +: 379.1458, found: 379.1506.

[0203] Example 34: Preparation of 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 27)

[0204] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) above, using 4-chlorophenylboronic acid as the raw material, the target compound 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (78%); mp: 196.7 - 197.5 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.79 (dd, J = 0.81 Hz, J = 3.93 Hz, 1H), 7.74 (d, J = 1.43 Hz, 1H), 7.65 (d, J = 4.74 Hz, 1H), 7.56 - 7.58 (m, 2H), 7.37 - 7.40 (m, 2H), 7.23 (s, 2H), 7.17 (s, 1H), 3.96 (s, 6H), 3.94 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 153.6, 153.5 (2C), 139.8, 133.6, 133.3, 132.8, 129.8, 129.3 (2C), 127.8, 127.7 (2C), 127.5, 116.9, 112.4, 105.9 (2C), 102.1, 61.1, 56.5 (2C); HRMS calculated for C 22 H 19 ClN 2 O 3 [M + H] + : 395.1162, found: 395.1219.

[0205] Example 35: Preparation of 7-(4-aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 28)

[0206] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) above, using 4-aminophenylboronic acid as the raw material, the target compound 7-(4-aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, orange solid (52%); mp: 183.5 - 184.2 °C;1 H NMR (600 MHz, DMSO-d 6 ): δ 8.18 (d, J = 4.62 Hz, 1H), 8.08 (s, 1H), 7.57 (d, J = 4.62 Hz, 1H), 7.49 (d, J = 8.34 Hz, 2H), 7.26 (s, 2H), 7.21 (s, 1H), 6.62 (d, J = 8.38 Hz, 2H), 5.20 (d, 2H), 3.89 (s, 6H), 3.77 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ): δ 152.8 (2C), 151.0, 148.2, 138.6, 133.6, 131.0, 279, 126.9 (2C), 126.5, 126.4, 121.2, 117.3, 114.2 (2C), 111.7, 105.5 (2C), 99.7, 60.1, 56.0 (2C); HRMS calcd for C 22 H 21 N 3 O 3 [M + H] + : 376.1661, found: 376.1706.

[0207] Example 36: Preparation of 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 29)

[0208] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) above, using 4-methoxyphenylboronic acid as the raw material, the target compound 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (82%); mp: 163.0 - 163.8 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.79 (dd, J = 0.65 Hz, J = 4.72 Hz, 1H), 7.72 (d, J = 1.12 Hz, 1H), 7.62 (d, J = 4.74 Hz, 1H), 7.56 - 7.59 (m, 2H), 7.25 (s, 2H), 7.17 (s, 1H), 6.95 - 6.98 (m, 2H), 3.96 (s, 6H), 3.94 (s, 3H), 3.85 (s, 3H); 13 C NMR (150 MHz, CDCl 3): δ 159.2, 153.4 (2C), 153.0, 139.6, 137.5, 133.4, 131.0, 127.5 (2C), 126.9, 126.6, 116.8, 114.5 (2C), 112.1, 105.8, 101.9 (2C), 61.0, 56.4 (2C), 55.4; HRMS calcd for C 23 H 22 N 2 O 4 [M + H] + : 391.1658, found: 391.1660.

[0209] Example 37: Preparation of 7-(4-Hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 30)

[0210] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) described above, using 4-hydroxybenzeneboronic acid as the raw material, the target compound 7-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, yellow solid (62%); mp: 114.7 - 115.5 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.79 (dd, J = 0.82 Hz, J = 4.77 Hz, 1H), 7.70 (d, J = 1.43 Hz, 1H), 7.61 (d, J = 4.76 Hz, 1H), 7.46 - 7.48 (m, 2H), 7.23 (s, 2H), 7.15 (s, 1H), 6.85 - 6.87 (m, 2H), 3.92 (s, 3H), 3.91 (s, 6H); 13 C NMR (150 MHz, CDCl 3 ): δ 156.3, 153.5 (2C), 153.2, 139.6, 133.3, 131.4, 127.8 (2C), 127.6, 126.7, 126.1, 117.1, 116.2 (2C), 112.3, 106.0 (2C), 102.2, 61.1, 56.4 (2C); HRMS calcd for C 22 H 20 N 2 O 4 [M + H] + : 377.1501, found: 377.1546.

[0211] Example 38: Preparation of 7-(3-Fluoro,4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 32)

[0212] According to the method for preparing 7-(4-Methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) above, using 3-Fluoro,4-methylphenylboronic acid as the raw material, the target compound 7-(3-Fluoro,4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, brown solid (82%); mp: 153.3 - 154.0 °C; 1 H NMR (600 MHz, CDCl 3 ): δ 7.79 (dd, J = 0.67 Hz, J = 4.71 Hz, 1H), 7.75 (d, J = 1.36 Hz, 1H), 7.65 (d, J = 4.77 Hz, 1H), 7.31 - 7.33 (dd, J = 1.70 Hz, J = 7.75 Hz, 1H), 7.27 (dd, J = 1.62 Hz, J = 10.72 Hz, 1H), 7.20 - 7.23 (m, 3H), 7.18 (s, 1H), 3.96 (s, 6H), 3.95 (s, 3H), 2.30 (d, J = 1.32 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ): δ 161.7 (d, J = 245.0 Hz), 153.4 (2C), 153.3, 139.7, 133.6 (d, J = 8.06 Hz), 133.2, 131.9 (d, J = 5.37 Hz), 130.1, 127.6, 127.1, 123.9 (d, J = 17.45 Hz), 121.7 (d, J = 3.19 Hz), 116.8, 112.8 (d, J = 23.0 Hz), 112.5, 105.8 (2C), 102.3, 61.0, 56.4 (2C), 14.4 (d, J = 3.28 Hz); HRMS calcd for C 23 H 22 F N 2 O 3 [M + H] + : 393.1614, found: 393.1629.

[0213] Example 39: Preparation of 7-(3-Hydroxy,4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 33)

[0214] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31), using 3-hydroxy-4-methoxyphenylboronic acid as a raw material, the target compound 7-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, yellow solid (52%); mp: 165.2 - 166.1 °C; 1 HNMR(600MHz,DMSO-d 6 ): δ 9.01 (s, 1H), 8.21 (d, J = 4.61 Hz, 1H), 8.14 (s, 1H), 8.21 (d, J = 4.66 Hz, 1H), 7.26 (s, 2H), 7.19 - 7.22 (m, 3H), 6.96 (d, J = 8.31 Hz, 1H), 3.89 (s, 6H), 3.79 (s, 3H), 3.77 (s, 3H); 13 C NMR(150MHz,DMSO-d 6 ): δ 152.8 (2C), 151.4, 147.2, 146.8, 138.7, 133.5, 130.0, 126.7, 126.7, 126.5, 117.4, 117.2, 113.4, 112.6, 112.5, 105.5 (2C), 100.5, 60.1, 60.0 (2C), 55.7; HRMS calcd for C 23 H 22 N 2 O 5 [M + H] + : 407.1607, found: 407.1620.

[0215] Example 40: Preparation of 7-(1H-indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-pyrrolo[1,2-a]pyrazine (Compound 34)

[0216] According to the above method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31), using 1H-indol-2-ylboronic acid as a raw material, the target compound 7-(1H-indol-2-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, yellow solid (69%); mp: 161.2 - 162.8 °C; 1 H NMR(600MHz,CDCl 3): δ 8.72 (s, 1H), 7.69 (s, 1H), 7.68 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 4.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.12 (s, 2H), 7.10 - 7.09 (m, 2H), 7.04 (t, J = 6.0 Hz, 1H), 6.68 - 6.67 (m, 1H), 3.85 (s, 3H), 3.82 (s, 6H); 13 C NMR (150 MHz, CDCl 3 ): δ 152.33 (2C), 152.23, 138.56, 135.70, 132.33, 131.35, 128.16, 126.49, 126.31, 122.14, 121.22, 119.36, 119.27, 115.75, 111.25, 109.81, 104.79 (2C), 100.52, 99.05, 59.96, 55.32 (2C); HRMS calcd for [M + H] + : 400.1583, found: 400.1645.

[0217] Example 41: Preparation of 7-(1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 35)

[0218] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) above, using 1H-indol-3-ylboronic acid as the raw material, the target compound 7-(1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, yellow solid (62%); mp: 161.3 - 162.1 °C; 1 H NMR (600 MHz, DMSO-d 6 ): δ 11.34 (d, J = 2.6 Hz, 1H), 8.34 (d, J = 1.4 Hz, 1H), 8.27 (d, J = 4.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.61 (d, J = 4.6 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.35 (s, 1H), 7.32 (s, 2H), 7.17 (t, J = 6.8 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 3.91 (s, 6H), 3.78 (s, 3H); 13¹³C NMR (150 MHz, DMSO-d6): δ 153.33 (2C), 151.17, 139.07, 137.20, 134.18, 126.65, 125.68, 125.64, 124.45, 121.88, 120.01, 119.62, 117.82, 112.94, 112.39, 109.69, 106.00 (2C), 101.24, 60.59, 56.42 (2C). HRMS calculated for C 24 H 21 N 3 O 3 [M + H] + : 400.1583; found: 400.1647.

[0219] Example 42: Preparation of 7-(1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 36)

[0220] According to the method for preparing 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine (Compound 31) described above, using 1H-indol-5-ylboronic acid as the starting material, the target compound 7-(1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine was synthesized, yellow solid (61%); mp: 161.3 - 162.9 °C; 1 ¹H NMR (600 MHz, CDCl 3 ₃): δ 8.55 (s, 1H), 7.84 (s, 1H), 7.72 (d, J = 4.4 Hz, 1H), 7.71 (s, 1H), 7.54 (d, J = 4.7 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.20 (s, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 2.8 Hz, 1H), 6.50 (t, J = 2.9 Hz, 1H), 3.88 (s, 6H), 3.87 (s, 3H); 13 ¹³C NMR (150 MHz, CDCl 3): δ 152.37 (2C), 152.18, 138.52, 134.75, 131.06, 130.99, 128.85, 127.77, 127.69, 126.54, 125.88, 122.51, 118.84, 115.97, 111.96, 111.55, 109.78, 104.80 (2C), 101.72, 60.00, 55.32 (2C); HRMS calcd for [M+H] + : 400.1583, found: 400.1647.

[0221] Example 43: In vitro anti-tumor activity test of the compounds of the present invention

[0222] The in vitro activity test method and results are as follows: Colchicine is the positive experimental group.

[0223] Screening method: Microculture tetrazolium (MTT) reduction method

[0224] Cell lines: MCF-7 (human breast cancer), SGC-7901 (human gastric adenocarcinoma), and HCT-116 (human colon cancer)

[0225] Action time: 72 hours

[0226] Specific operation: (1) Take cells in the logarithmic growth phase and inoculate them into 96-well plates at a density of 3 - 5×10 3 / well. (2) After incubating in a CO2 incubator at 37°C for 12 hours, dilute the compounds with different concentration gradients with serum-free medium, take 20 μL and add it to the 96-well plates, and continue to incubate for 72 hours. (3) Discard the supernatant, add 20 μL of freshly prepared 5 mg / mL MTT to each well, and incubate at 37°C for 4 hours. (4) Discard the supernatant, add 150 μL of DMSO to each well and shake for 15 minutes to fully dissolve the formazan, and measure the absorbance (OD) at a wavelength of 492 nm. The cell viability value is OD sample / OD control ×100%, and calculate the corresponding inhibition rate.

[0227] The inhibition rates (10 μg / mL) of each compound on the growth of the three tumor cells are shown in Table 1.

[0228] Table 1

[0229]

[0230]

[0231] Example 44: In vitro study on the inhibitory effect of the compounds of the present invention on tubulin polymerization

[0232] To verify whether the compound would interfere with the dynamic behavior of microtubules, Compound 28 was selected to evaluate its ability to inhibit tubulin polymerization. Colchicine (a microtubule polymerization inhibitor) was used as the positive control, and paclitaxel (a microtubule stabilizer) was used as the negative control.

[0233] Specific steps: (1) Set the microplate reader to read once per minute for a total of 80 minutes. The excitation wavelength was 365 nm and the emission wavelength was 450 nm; (2) Place the 96-well plate in the microplate reader and preheat it at 37 °C for 10 minutes; (3) Dilute the test compound to 10 times the concentration to be tested; (4) Take out Buffer1, GTP stock, Tubulin Glycerol Buffer, and tubulin, quickly thaw them at room temperature, and then place them on ice; (5) Mix the above reagents in amounts of 205 μL, 150 μL, 4.4 μL, and 85 μL to prepare the reaction solution; (6) Take out the 96-well plate, add 5 μL of the test compound and 50 μL of the reaction solution to each well, and place the 96-well plate in the microplate reader to monitor the changes in microtubules within 80 minutes (such as Figure 1 ).

[0234] The experimental results are as follows Figure 1 As shown, Compound 28 inhibits tubulin polymerization in a dose-dependent manner.

[0235] Example 45: Immunofluorescence staining experiment study of the compounds of the present invention

[0236] To evaluate the effect on the microtubule network, Compound 28 (10 nM) was selected to conduct an experiment on its ability to affect microtubule morphology. Colchicine (a microtubule disruptor) was used as the positive control, and the untreated sample was used as the control.

[0237] Specific steps: (1) Take SGC-7901 cells in the logarithmic growth phase at 5×10 4Inoculate cells at a density of [density of the holes] into a 12-well plate and incubate in an incubator for 24 hours. (2) Treat the cells with the compound to be tested (10 nM) and incubate for 24 hours. (3) Discard the supernatant, wash once with 1 mL of PBS, and add 500 μL of 4% paraformaldehyde to each well to fix at room temperature for 30 minutes. (4) Discard the supernatant, wash twice with 1 mL of PBS, and add 500 μL of 0.2% Triton X-100 to each well to permeabilize at room temperature for 30 minutes. (5) Discard the supernatant, wash twice with 1 mL of PBS, and add 500 μL of 5% BSA to each well to block at room temperature for 30 minutes. (5) Discard the supernatant, wash twice with 1 mL of PBS, and add 100 μL of rabbit anti-α-tubulin monoclonal antibody (diluted 1:100 in antibody diluent) to each well and incubate overnight at 4°C. (6) Discard the supernatant, wash twice with 1 mL of PBS, and add 100 μL of goat anti-mouse IgG H&L / FITC (diluted 1:100 in antibody diluent) to each well and incubate for 3 hours at room temperature in the dark. (7) Discard the supernatant, wash twice with 1 mL of PBS, and add 100 μL of DAPI (10 μg / mL) to each well to counterstain the cell nuclei and incubate at room temperature for 30 minutes. (8) Discard the supernatant, wash twice with 1 mL of PBS, pre-drop 10 μL of anti-fluorescence quenching agent on a glass slide, carefully take out the cell culture slides and invert them on the glass slide. (9) Store at -20°C and take pictures under a confocal microscope (see Figure 2 ).

[0238] The experimental results are as follows Figure 2 As shown, untreated cells maintain a hairy fiber microtubule network around the cell nucleus (blue), and the cytoskeleton is spindle-shaped. After treatment with compound 28, the cell fiber structure is dispersed around the cell nucleus, and the cytoskeleton becomes round. Compound 28 and the positive control show similar effects.

[0239] Example 46: Experimental study on cell cycle arrest of the compounds of the present invention

[0240] It has been confirmed that tubulin inhibitors can induce cell mitotic arrest at the G2 / M phase and ultimately lead to apoptosis. Therefore, compound 28 was selected to evaluate its effect on the cell cycle of SGC-7901 cells. Cells were treated with different concentrations of compound 28 (5 nM, 10 nM, 15 nM) for 24 h, and the results were analyzed by flow cytometry (see Figure 3 ).

[0241] Specific steps: (1) Take cells in the logarithmic growth phase at 2×10 5Inoculate at a density of / holes in a 6-well plate and incubate in an incubator for 24 hours. (2) Treat the cells with the test compound 28 (5 nM, 10 nM, 15 nM) and incubate for 24 hours. (3) Collect the supernatant, wash twice with 1 mL of PBS and then collect. After trypsin digestion, centrifuge the collected suspension at 1500 revolutions per second for 5 minutes. (4) Discard the supernatant, wash once with 1 mL of pre-cooled PBS and centrifuge at 1500 revolutions per second for 5 minutes. (5) Discard the supernatant, add 250 μL of pre-cooled PBS, disperse the cells appropriately, and while shaking, add 750 μL of pre-cooled absolute ethanol and incubate overnight at 4 °C. (6) Centrifuge to collect the cells and resuspend the cells with 1 mL of pre-cooled PBS. (7) Centrifuge to collect the cells, add 500 μL of staining solution (Meilun, MA0334), incubate at 37 °C in the dark for 30 minutes, and then detect by flow cytometry after passing through a 200-mesh nylon sieve.

[0242] The experimental results showed that after treatment, the cell cycle was significantly arrested at the G2 / M phase. The proportion of the G2 / M phase increased from 26% to 67%, and it was concentration-dependent. These phenomena indicate that compound 28 may act on tubulin.

[0243] Example 47: Anti-cell migration study of the compounds of the present invention

[0244] 90% of cancer patients die from the spread and metastasis of tumors, and metastasis remains the main obstacle to cancer treatment. Tubulin and microtubules have been shown to play important roles in cell migration and movement. Therefore, verify whether compound 28 can affect cell migration through microtubule destabilization, and at the same time use the drug-free group as a blank control.

[0245] At the start of the experiment (0 h) and when treated with different concentrations of compound 28 (5, 10 nM) for 24 h, as follows Figure 4 As shown, compared with the 32% wound area recovery in the control group, the coverage rates in the 5 nM and 10 nM groups were 20% and 6% respectively. Therefore, compound 28 has a dose-dependent inhibitory effect on the migration of cancer cells.

[0246] Example 48: Anti-colony formation study of the compounds of the present invention

[0247] To further verify its in vitro activity, an anti-colony formation experiment was carried out.

[0248] Specific steps: (1) SGC-7901 cells in the logarithmic growth phase were seeded in 6-well plates at a density of 1000 cells / well and incubated in an incubator for 24 hours. (2) Different concentrations (5, 10, and 15 nM) of compound 28 were added and incubation was continued for 24 hours. (3) The culture medium was discarded and the cells were washed once with 1 mL of PBS, then the cells were cultured in a culture medium containing 10% serum, and the medium was changed every three days for two consecutive weeks. (4) The cells were fixed with 4% paraformaldehyde for 30 min and stained with 0.1% crystal violet for 15 min. (5) After washing with PBS, the cells were photographed and quantitatively analyzed using Image J software.

[0249] as follows Figure 5 As shown below, the colonies formed after treating SGC-7901 cells with different concentrations (5, 10, and 15 nM) of compound 28 were significantly reduced. The colony formation of SGC-7901 cells treated with 10 nM was significantly decreased by 99% compared with the control group, indicating that compound 28 significantly inhibited the colony formation of SGC-7901 cells in a concentration-dependent manner.

[0250] Example 49: Antitumor activity test of the compounds of the present invention in animals

[0251] Compound 28 with good in vitro activity was selected for the antitumor activity test in animals. The model used was the mouse S-180 sarcoma model, and the positive control drug was the commonly used clinical antitumor drug fluorouracil (5-Fu).

[0252] Experimental method: Female Kunming mice weighing 18 - 22 g and well-grown S-180 tumor seeds at 7 - 11 days old were selected. The tumor tissue was made into a cell suspension and inoculated subcutaneously into the right axilla of the mice, about 1.0 - 2.0×10 6 cells / mouse. After 24 hours of inoculation, the mice were randomly divided into cages and administered intraperitoneally for 7 consecutive days. The animals were sacrificed 24 hours after stopping the drug administration, the body weight and tumor weight were measured, the average tumor weight of each group was calculated, and the tumor inhibition rate was calculated according to the following formula and a t-test was performed.

[0253] Tumor inhibition rate = [(average tumor weight of the blank control group - average tumor weight of the treatment group) / (average tumor weight of the blank control group)] × 100%

[0254] The experimental results are shown in Table 2

[0255] Table 2

[0256]

[0257] Example 50: Anti-inflammatory activity test of the compounds of the present invention in animals

[0258] Compound 28 with good in vitro activity was selected for in vivo anti-inflammatory activity testing in animals. The model used was a mouse acute inflammation model induced by phorbol ester (TPA), and the positive control drug was indomethacin, a commonly used anti-inflammatory drug in clinical practice.

[0259] Experimental method: Forty female Kunming mice weighing 18 - 22 g were selected. The mice were randomly divided into groups of 10 each. Each group of mice was intraperitoneally injected with the compound (3 mg / kg), the control (saline), or dexamethasone (3 mg / kg, positive control). 30 minutes later, TPA (2.5 μg / ear, 20 μL acetone) was topically applied to both sides of the right ear of each mouse to induce edema. 6 hours after inflammation induction, the mice in each group were sacrificed by cervical dislocation. Then, ear pieces were punched out at symmetrical positions on the left and right ears using a punch with a diameter of 7 mm, weighed on a balance, their masses were recorded, and the swelling degree and swelling inhibition rate were calculated.

[0260] Swelling degree = average mass of the right ear piece - average mass of the left ear piece

[0261] Swelling inhibition rate = [(swelling degree of the blank group - swelling degree of the drug-administered group) / (swelling degree of the blank group)] × 100%

[0262] The experimental results are shown in Table 3

[0263] Table 3

[0264]

[0265] From the research results in Table 3, it can be seen that the compound protected by the present invention has good in vivo anti-inflammatory activity in animals, and its swelling inhibition rate is comparable to that of dexamethasone, a commonly used anti-inflammatory drug in clinical practice.

Claims

1. A 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound, characterized in that: The compound is a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound represented by general formula M, and its salts and hydrates: In general formula M, R 1 、R 2 、R 3 are each independently selected from the same or different C 1 -C 6 alkoxy groups; is a single key or a double key; The structure of Ar is as follows: wherein, Y is O, S, N-R 9 ; R 4 、R 5 、R 6 、R 7 、R 8 each independently and identically or differently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, acetyl, nitro, amino, hydroxy, amino substituted with at least one C 1 -C 6 alkyl; R 9 is hydrogen, C 1 -C 6 alkyl group.

2. The compound according to claim 1, characterized in that: The compound is a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound represented by general formula M, and its salts and hydrates, In general formula M, R 1 , R 2 , R 3 are each independently the same or different and are each selected from C 1 -C 3 alkoxy groups; is a single or double key; The Ar structure is as shown in claim 1, wherein Y is O, S, N-R 9 ; R 4 、R 5 、R 6 、R 7 、R 8 are each independently the same or different and are selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogen, acetyl, nitro, amino, hydroxy, amino substituted with at least one C 1 -C 3 alkyl; R 9 is hydrogen, C 1 -C 3 alkyl group.

3. The compound according to claim 2, characterized in that: The compound is a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound represented by general formula M, and its salts and hydrates: In general formula M, R 1 , R 2 , R 3 are each independently a methoxy group; is a single key or a double key; As shown in claim 1 of the Ar structure, where Y is O, S, N-R 9 ; R 4 、R 5 、R 6 、R 7 、R 8 each independently is the same as or different from one another and is hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, acetyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino or hydroxy; R 9 is hydrogen, methyl or ethyl.

4. The compound according to claim 3, characterized in that: The compound is the following compound and its salts and hydrates; Compound 1: 7-(2-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 2: 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 3: 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 4: 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 5: 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 6: 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 7: 7-phenyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 8: 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 9: 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 10: 7-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 11: 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 12: 7-(4-aminophenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 13: 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 14: 7-(3-fluoro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 15: 7-(3-chloro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 16: 7-(1H-indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 17: 7-(1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 18: 7-(1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine; Compound 19: 7-(2-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 20: 7-(3-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 21: 7-(3-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 22: 7-(3-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 23: 7-(3-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 24: 7-(3-aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 25: 7-phenyl-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 26: 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 27: 7-(4-chlorophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 28: 7-(4-aminophenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 29: 7-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 30: 7-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 31: 7-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 32: 7-(3-fluoro-4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 33: 7-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 34: 7-(1H-indol-2-yl)-1-(3,4,5-trimethoxyphenyl)-pyrrolo[1,2-a]pyrazine; Compound 35: 7-(1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine; Compound 36: 7-(1H-indol-5-yl)-1-(3,4,5-trimethoxyphenyl)pyrrolo[1,2-a]pyrazine.

5. The compound according to any one of claims 1 to 4, characterized in that: The salt of the compound is a salt formed by a compound of general formula M with an acid or a base. The acids are selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid, etc.; the bases are selected from sodium hydroxide, sodium carbonate, potassium hydroxide, etc.; the number of crystal water molecules of the hydrate of general formula M is any real number from 0 to 16.

6. A method for preparing a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound according to any one of claims 1 to 5, characterized in that:

7. According to the preparation method described in claim 6, characterized in that: (1) Dissolve the substituted 3,4,5-trisubstituted benzoic acid (I) in dichloroethane, add DMF dropwise, add oxalyl chloride dropwise under stirring, stir and react, then add morpholine and stir and react to obtain compound II; (2) Stir and react compound II and phosphorus oxychloride, then add a dichloromethane solution of pyrrole and stir and react to obtain compound III; (3) Dissolve compound III in tetrahydrofuran, add NBS and stir and react to obtain compound IV; (4) Dissolve compound IV and N-Boc-bromoethylamine in DMF, add sodium hydride and stir and react to obtain compound V; (5) Stir and react compound V and trifluoroacetic acid to obtain compound VI; (6) Dissolve compound VI and the substituted arylboronic acid in a mixed solvent of 1,4-dioxane and water, add Pd(Ph 3 P) 2 Cl 2 and sodium carbonate, and carry out the Suzuki reaction under nitrogen protection to obtain 1,7-disubstituted-3,4-dihydropyrrolo[1,2-a]pyrazine compounds with the general structural formula M; (7) Dissolve compound IV, 2-bromo-1,1-diethoxyethane and cesium carbonate in DMF and stir and react to obtain compound VII; (8) Dissolve compound VII and ammonium acetate in acetic acid and stir and react to obtain compound VIII; (9) Dissolve compound VIII and arylboronic acid in a mixed solvent of 1,4-dioxane and water, add Pd(Ph 3 P) 2 Cl 2 and sodium carbonate, and carry out the Suzuki reaction under nitrogen protection to obtain 1,7-disubstituted pyrrolo[1,2-a]pyrazine compounds with the general structural formula M.

8. According to the preparation method described in claim 7, characterized in that: In step (1), the molar ratio of 3,4,5-trimethoxybenzoic acid (I), oxalyl chloride and morpholine is 1:1 - 2:2 - 4, the reaction temperature is 0 - 30 °C, and the reaction time is 1 - 12 h; In step (2), the molar ratio of compound II, phosphorus oxychloride and pyrrole is 1:2 - 5:1 - 1.2, the reaction temperature is 0 - 50 °C, and the reaction time is 5 - 24 h; In step (3), the molar ratio of compound III and NBS is 1:1 - 1.2, the reaction temperature is -10 - 35 °C, and the reaction time is 1 - 12 h; In step (4), the molar ratio of compound IV, N-Boc-bromoethylamine and sodium hydride is 1:1 - 2:1 - 2, the reaction temperature is 0 - 50 °C, and the reaction time is 5 - 12 h; In step (5), the molar ratio of compound V and trifluoroacetic acid is 1:1 - 10, the reaction temperature is 0 - 50 °C, and the reaction time is 10 - 60 min; In step (6), the molar ratio of the feed of compound VI, arylboronic acid, Pd(PPh 3 ) 2 Cl 2 and Na 2 CO 3 is 1:1 - 1.5:0.03 - 0.1:2 - 5, the reaction temperature is 60 - 110 °C, the reaction time is 1 - 12 h, and the volume ratio of 1,4-dioxane to water is 2 - 10:1; In step (7), the molar ratio of the feed of compound IV, 2-bromo-1,1-diethoxyethane and cesium carbonate is 1:1-2:1-4, the reaction temperature is 50-120 °C, and the reaction time is 5-12 h; In step (8), the molar ratio of the feed of compound VII and ammonium acetate is 1:1-5, the reaction temperature is 80-120 °C, and the reaction time is 1-12 h; In step (9), the molar ratio of the feed of compound VIII, arylboronic acid, Pd(PPh 3 ) 2 Cl 2 and Na 2 CO 3 is 1:1 - 1.5:0.03 - 0.1:2 - 5, the reaction temperature is 60 - 100 °C, the reaction time is 1 - 12 h, and the volume ratio of 1,4-dioxane to water is 2 - 10:

1.

9. A pharmaceutical composition, characterized in that: it comprises a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound and its salt and hydrate according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

10. Use of a 1,7-disubstituted pyrrolo[1,2-a]pyrazine compound and its salt and hydrate according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of an anti-tumor and anti-inflammatory drug.

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