Preparation and application of FGFR-targeted 3-amino-pyrazine-2-amide derivative

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a preparation method and application of a 3-amino-pyrazine-2-amide derivative taking FGFR as a target spot. The derivative has a structural general formula as shown in the following formula (I), wherein R1 and R2 substituent groups can be combined at will. The compound can effectively inhibit phosphorylation of FGFR kinase, and is used for treating tumor diseases related to FGFR kinase mutation. Particularly, the compound SN23 has a good selective inhibition effect on FGFR2 kinase, has a remarkable inhibition effect on proliferation of various tumor cells, and can be used for research and development of antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a preparation method and application of a 3-amino-pyrazine-2-amide derivative targeting FGFR. Background Art

[0002] Fibroblast growth factor receptors (FGFRs) are a member of the receptor tyrosine kinase superfamily. Their abnormally activated signaling pathways are closely related to the occurrence and development of tumor diseases and are important therapeutic targets for tumor diseases. Currently, the drugs targeting FGFR on the market include Erdafitinib (2019), Pemigatinib (2020), Infigratinib (2021) and Futibatinib (2022). There are also many FGFR small molecule inhibitors under development, including covalent inhibitors and non-covalent inhibitors, which have entered the clinical trial stage. Most of the FGFR inhibitors reported so far are ATP competitive inhibitors, and the "ATP pockets" they bind to are highly conserved, resulting in poor targeting selectivity, large toxic side effects, and easy drug resistance. For example, most of the FGFR inhibitors that have been marketed are accompanied by the toxic side effect of hyperphosphatemia. In addition, the four subtypes of FGFR (FGFR1-4) are highly similar in structure, and there are differences in the types and ratios of mutations in different cancer types. Although the second-generation Futibatinib has been approved for marketing, there is still a lack of FGFR inhibitors with good selectivity. Therefore, the development of FGFR inhibitors with excellent specificity is of great significance and quite challenging, and is also one of the important directions for the development of FGFR inhibitors. Summary of the invention

[0003] In order to improve the deficiencies of the above-mentioned technology, the present invention provides a preparation method and use of 3-amino-pyrazine-2-amide derivatives targeting FGFR. This type of compound can effectively inhibit the phosphorylation of FGFR and can be used to treat various FGFR-related tumors.

[0004] In order to achieve the above technical effects, the present invention is implemented through the following technical solutions:

[0005] A 3-amino-pyrazine-2-amide derivative targeting FGFR, wherein the derivative has a general structural formula as shown in the following formula (I):

[0006]

[0007] Among them, R1 can be selected from any one of methyl (-CH3) or hydrogen (-H).

[0008] The R2 group can be selected from any of the following substituent groups: The wavy line indicates the position of the substituent group.

[0009]

[0010] The above R1 and R2 groups can be combined arbitrarily.

[0011] Furthermore, the 3-amino-pyrazine-2-amide derivative targeted FGFR small molecule inhibitor is one of compounds SN1-SN28, and R1 and R2 in SN1-SN28 are shown in the following table.

[0012]

[0013] The present invention also provides a method for preparing the above-mentioned 3-amino-pyrazine-2-amide derivative targeting FGFR, comprising the following steps:

[0014] The synthesis steps of compounds SN1-SN6 are as follows:

[0015] (1) Synthesis of compound SN6: 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (500 mg, 1.42 mmol), (4-(hydroxymethyl)phenyl)boric acid (260 mg, 1.71 mmol) and sodium carbonate (301 mg, 2.84 mmol) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1, 8 mL in total) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes. Pd(dppf)Cl2-CH2Cl2 (63 mg, 0.086 mmol) was then added as a catalyst, and the reaction mixture was heated at 90°C for 10 h. After the reaction was completed, TLC was used to monitor the reaction. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (6 mL*3 times). The obtained organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=1 / 3) to obtain the target compound SN6 as a light brown solid (459 mg, yield 85%).

[0016] (2) General method for the synthesis of compound SN1-4: In a 20 mL dry round-bottom flask, compound SN6 (118 mg, 0.38 mmol), catalytic amount of 4-dimethylaminopyridine (4.68 mg, 0.038 mmol) and triethylamine (0.106 mL, 0.76 mmol) and dry dichloromethane (4 mL) were added in sequence. The resulting mixture was stirred at room temperature for 15 minutes, and p-toluenesulfonyl chloride (62.96 mg, 0.57 mmol) was slowly added. The mixture was stirred at room temperature for 5 minutes, and then the corresponding fatty amine and cesium carbonate were added until the reaction was complete. 5 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6 mL*3 times). Purification was performed by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) to obtain the target compounds SN1-4.

[0017] (3) Synthesis of compound SN5: First, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (100 mg, 0.28 mmol), (4-(hydroxyethylpiperazine)phenyl)boric acid (0.42 mmol) and sodium carbonate (60 mg, 0.56 mmol) were added to a 20 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1, 4 mL in total) was added to form a suspension. The suspension was degassed under nitrogen bubbling for 10 minutes, and then Pd(dppf)Cl2-CH2Cl2 (12 mg, 0.0817 mmol) was added as a catalyst. After the reaction mixture was heated at 90°C for 6 hours, tetrabutylammonium fluoride (2 mL) was added and reacted at room temperature for 2 hours. After the reaction was completed, 5 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6 mL*3 times). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) gave the target compound SN5 as a light yellow solid (20 mg).

[0018] General method for the synthesis of compounds SN7-SN14: The synthesis of compounds SN7-SN14 includes two steps. The first step is to synthesize the intermediate boric acid ester. Commercially available 4-ethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution were added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and secondary fatty amine (4.0mmol, 2.0 equivalent) were added dropwise under stirring. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50mL) was added for dilution, saturated brine was washed (20mL, 3 times), the organic phase was separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain the crude boric acid ester intermediate as an off-white solid powder, which was used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), boric acid ester (1.5 equivalents) obtained in step 1 and sodium carbonate (2.5 equivalents) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture was heated at 100°C for 6-9 hours. After the reaction was completed by TLC monitoring. Water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compounds SN7-SN14 as solid powders with a yield of 10-85%.

[0019] General method for the synthesis of compounds SN15-SN-28: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), boric acid ester (1.5 equivalents) obtained in step 1 of the synthesis of SN7-SN14, and sodium carbonate (2.5 equivalents) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture was heated at 100°C for 6-9 hours. After the reaction was completed, water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon protecting group to obtain the target compounds SN15-SN-28 as solid powders with a yield of 22-99%.

[0020] The present invention provides a use of a 3-amino-pyrazine-2-amide derivative targeting FGFR, and the use is used in the preparation of an anti-tumor drug.

[0021] The 3-amino-pyrazine-2-amide derivative of the present invention exhibits certain anti-tumor cell proliferation activity. As a further preferred embodiment, the 3-amino-pyrazine-2-amide derivative is compound SN23.

[0022] Compared with the existing technology, the technical effect of the present invention is reflected in: the present invention provides a small molecule inhibitor targeting FGFR with a novel structure, and the compound SN23 shows excellent selectivity for FGFR2 and has a significant proliferation inhibitory effect on a variety of tumor cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The preparation process flow chart of compounds SN1-SN28

[0024] Figure 2 The inhibitory activity of compounds SN1-SN28 on FGFR1-4

[0025] Figure 3 The inhibitory activity of compound SN23 on tumor cell proliferation DETAILED DESCRIPTION

[0026] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0027] The present invention is a 3-amino-pyrazine-2-amide derivative targeting FGFR, the derivative has the general structural formula shown below (I), and the preparation process flow chart of the structure is shown in the attached specification Figure 1 :

[0028]

[0029] The present invention adopts the following general characterization method for the following embodiments:

[0030] Product testing conditions in the following examples: The characterization of the examples was performed using 600 Hz nuclear magnetic resonance spectroscopy (Bruker AVANCE III 600), with deuterated chloroform or deuterated dimethyl sulfoxide as solvent; and tetramethylsilane (TMS) as internal standard. The nuclear magnetic resonance data of the example compounds are reported as follows: 1 H NMR chemical shift, in δ; peak shape: s = singlet, d = doublet, t = triplet, m = multiplet, coupling constant J (in Hz); 13C NMR data are reported as chemical shifts; the example compounds were further verified by liquid chromatography-mass spectrometry (LC-MS, instrument model Agilent 7000D, Agilent Technologies, USA).

[0031] Example 1

[0032] Compound SN1 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazine-2-amide

[0033] The specific structural formula of compound SN1 is: The preparation method of compound SN1 is as follows:

[0034] In a 20mL dry round-bottom flask, compound SN6 (118mg, 0.38mmol), catalytic amount of 4-dimethylaminopyridine (4.68mg, 0.038mmol) and triethylamine (0.106mL, 0.76mmol) and dry dichloromethane (4mL) were added in sequence. The resulting mixture was stirred at room temperature for 15 minutes, and p-toluenesulfonyl chloride (62.96mg, 0.57mmol) was slowly added. The mixture was continued to be stirred at room temperature for 5 minutes, and then 1-ethylpiperazine and cesium carbonate (1.5 equivalents) were added until the reaction was complete. 5mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6mL*3 times). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) gave the target compound SN1 as a light yellow solid in a yield of 50%. Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ = 9.87 (s, 1H), 8.65 (s, 1H), 7.83–7.81 (m, 2H), 7.46–7.45 (m, 2H), 6.94 (d, J = 2.2Hz, 2H) ,6.29(t,J=2.2Hz,1H),3.82(s,6H),3.58(s,2H),2.52(s,6H),2.43(q,J=7.2Hz,4H),1.09(t,J=7.2Hz,3H). 13 C NMR(150MHz, CDCl3)δ=164.12,161.29,154.13,144.79,140.45,139.25,139.12,134.97,129.95,1 25.67,124.58,98.28,97.00,62.77,55.58,53.18,52.92,52.42,12.06.LC-MS(ESI)calculatedfor C 26 H 33N6O3,[M+H] + =477.25; found:477.30.

[0035] Example 2

[0036] Compound SN2 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((4-methylpiperazin-1-yl)methyl)

[0037] The specific structural formula of the 2-phenylpyrazine-2-amide compound SN2 is: The preparation method of compound SN2 is as follows:

[0038] In a 20mL dry round-bottom flask, compound SN6 (118mg, 0.38mmol), catalytic amount of 4-dimethylaminopyridine (4.68mg, 0.038mmol) and triethylamine (0.106mL, 0.76mmol) and dry dichloromethane (4mL) were added in sequence. The resulting mixture was stirred at room temperature for 15 minutes, and p-toluenesulfonyl chloride (62.96mg, 0.57mmol) was slowly added. The mixture was continued to be stirred at room temperature for 5 minutes, and then 1-methylpiperazine and cesium carbonate (1.5 equivalents) were added until the reaction was complete. 5mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6mL*3 times). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) gave the target compound SN2 as a light yellow solid in a yield of 60%. Its structural characterization data are as follows: 1 HNMR (600MHz, CDCl3) δ = 9.87 (s, 1H), 8.65 (s, 1H), 7.83 (d, J = 8.2Hz, 2H), 7.46 (d, J = 8.0Hz, 2H), 6 .94(d,J=2.2Hz,2H),6.29(t,J=2.3Hz,1H),3.83(s,6H),3.59(s,2H),2.57(s,8H),2.35(s,3H). 13 CNMR(151MHz, CDCl3)δ=164.09,161.26,154.12,144.77,140.35,139.22,138.93,135.02,129 .91,125.68,124.55,98.25,96.94,62.61,55.56,55.09,52.85,45.88.LC-MS(ESI)calculated for C 25 H 31 N6O3[M+H] + =463.24; found:463.20.

[0039] Example 3

[0040] Compound SN3 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-(piperazin-1-ylmethyl)phenyl)pyrazine-2-carboxamide.

[0041] The specific structural formula of compound SN3 is: The preparation method of compound SN3 is as follows:

[0042] In a 20mL dry round-bottom flask, compound SN6 (118mg, 0.38mmol), catalytic amount of 4-dimethylaminopyridine (4.68mg, 0.038mmol) and triethylamine (0.106mL, 0.76mmol) and dry dichloromethane (4mL) were added in sequence. The resulting mixture was stirred at room temperature for 15 minutes, and p-toluenesulfonyl chloride (62.96mg, 0.57mmol) was slowly added. The mixture was continued to be stirred at room temperature for 5 minutes, and then piperazine and cesium carbonate (1.5 equivalents) were added until the reaction was complete. 5mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6mL*3 times). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) gave the target compound SN3 as a light yellow solid with a yield of 48%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.28 (s, 1H), 8.90 (s, 1H), 8.16 (d, J = 8.3Hz, 2H), 7.66 (s, 2H), 7.43 (d, J = 8.1Hz, 2H), 7.13 (d, J =2.2Hz,2H),6.32(t,J=2.3Hz,1H),3.77(s,6H),3.59(s,2H),3.04(t,J=5.0Hz,4H),2.61(t,J=1.9Hz,1H),2.56(s,4H). 13 C NMR(150MHz,DMSO-d6)δ=164.59,160.46,154.18,144.73,139.60,138.51,137.38,134.78,1 29.38,125.72,123.75,99.06,96.21,55.28,48.93,45.27,42.75.LC-MS(ESI)calculatedfor C 24 H 29 N6O3[M+H] + =,449.22; found:449.20.

[0043] Example 4

[0044] Compound SN4 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-(morpholinemethyl)phenyl)pyrazine-2-carboxamide. The specific structural formula of compound SN4 is: The preparation method of compound SN4 is as follows:

[0045] In a 20mL dry round-bottom flask, compound SN6 (118mg, 0.38mmol), catalytic amount of 4-dimethylaminopyridine (4.68mg, 0.038mmol) and triethylamine (0.106mL, 0.76mmol) and dry dichloromethane (4mL) were added in sequence. The resulting mixture was stirred at room temperature for 15 minutes, and p-toluenesulfonyl chloride (62.96mg, 0.57mmol) was slowly added. The mixture was continued to be stirred at room temperature for 5 minutes, and then morpholine and cesium carbonate (1.5 equivalents) were added until the reaction was complete. 5mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6mL*3 times). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=1 / 2) gave the target compound SN4 as a light yellow solid in a yield of 56%. Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ = 9.85 (s, 1H), 8.64 (s, 1H), 7.82 (d, J = 7.9Hz, 2H), 7.46 (d, J = 7.9Hz, 2H), 6.94 (d, J = 2.2Hz,2H),6.28(t,J=2.2Hz,1H),3.82(s,6H),3.74(t,J=4.7Hz,4H),3.56(s,2H),2.49(t,J=4.7Hz,4H). 13 C NMR (150MHz, CDCl3) δ = 164.05, 161.25, 154.13, 144.71, 140.24, 139.21, 135.08, 129. 92,125.66,124.55,98.26,96.89,67.06,63.11,55.54,53.71.LC-MS(ESI)calculated for C 24 H 28 N5O4[M+H] + =450.20; found:450.20.

[0046] Example 5

[0047] Compound SN5 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-(4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)pyrazine-2-carboxamide.

[0048] The specific structural formula of compound SN5 is: The preparation method of compound SN5 is as follows:

[0049] 3-Amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (100 mg, 0.28 mmol), (4-(hydroxyethylpiperazine)phenyl)boric acid (0.42 mmol) and sodium carbonate (60 mg, 0.56 mmol) were added to a 20 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1, 4 mL in total) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (12 mg, 0.0817 mmol) as a catalyst. After the reaction mixture was heated at 90°C for 6 hours, tetrabutylammonium fluoride (2 mL) was added and reacted at room temperature for 2 hours. After the reaction was completed, 5 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (6 mL*3 times). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) gave the target compound SN5 as a light yellow solid. Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ = 9.88 (s, 1H), 8.67 (s, 1H), 7.86–7.83 (m, 2H), 7.47 (d, J = 7.9Hz, 2H), 6.95 (d, J = 2.2Hz, 2H), 6 .30(t,J=2.2Hz,1H),3.84(s,6H),3.67(t,J=5.3Hz,2H),3.61(s,2H),3.35(d,J=8.7Hz,2H),2.64(t,J=5.2Hz,8H). 13 C NMR(150MHz, CDCl3)δ=164.13,161.34,154.18,144.81,140.41,139.25,135.21,130.00,125.80 ,124.69,98.36,97.03,62.52,59.57,59.13,57.60,55.63,53.00,52.56.LC-MS(ESI)calculated for C 26 H 33 N6O4[M+H] + =493.25; found:493.20.

[0050] Example 6

[0051] Compound SN6 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-(hydroxymethyl)phenyl)pyrazine-2-carboxamide. The specific structural formula of compound SN6 is: The preparation method of compound SN6 is as follows:

[0052] 3-Amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (500 mg, 1.42 mmol), (4-(hydroxyethyl)phenyl)boric acid (260 mg, 1.71 mmol) and sodium carbonate (301 mg, 2.84 mmol) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1, 8 mL in total) was added to form a suspension, which was degassed for 10 minutes under nitrogen bubbling, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (63 mg, 0.086 mmol) as a catalyst, and the reaction mixture was heated at 90 ° C for 10 h. After the reaction was completed by TLC monitoring. Water (5 mL) was added to quench the reaction, and extracted with ethyl acetate (6 mL*3 times). The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound SN6 as a light brown solid with a yield of 85%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.28 (s, 1H), 8.90 (s, 1H), 8.15 (d, J = 8.3Hz, 2H), 7.63 (brs, 2H), 7.43 ( d,J=8.3Hz,2H),7.13(d,J=2.2Hz,2H),6.32(t,J=2.2Hz,1H),4.56(d,J=5.7Hz,2H),3.77(s,6H). 13 C NMR(150MHz,DMSO-d6)δ=164.60,160.45,154.15,144.60,142.68,139.59,138.70,1 34.18,126.77,125.47,123.69,99.08,96.19,62.65,55.23.LC-MS(ESI)calculated for C 20 H 21 N4O4,[M+H] + =381.15; found:381.10.

[0053] Example 7

[0054] Compound SN7 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazine-2-carboxamide

[0055] The specific structural formula of compound SN7 is: The preparation method of compound SN7 is as follows:

[0056] Commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution were added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and tetrahydropyrrole (4.0mmol, 2.0 equivalent) were added dropwise under stirring. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50mL) was added for dilution, saturated brine was washed (20mL, 3 times), the organic phase was separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder for the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), boric acid ester (1.5 equivalents) obtained in step 1 and sodium carbonate (2.5 equivalents) were added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 6 hours. After the reaction was completed, water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain the target compound SN7 as a light yellow solid with a yield of 46%. Its structural characterization data are as follows: 46%. 1 H NMR (600MHz, CDCl3) δ=9.87(s,1H),8.66(s,1H),7.85–7.83(m,2H),7.49(d,J=8.0Hz,2H),6.95(d,J= 2.2Hz,2H),6.29(t,J=2.2Hz,1H),3.83(s,6H),3.72(s,2H),2.61–2.58(m,4H),1.83(p,J=3.1Hz,4H). 13 CNMR(150MHz, CDCl3)δ=164.15,161.31,154.14,144.84,140.49,139.26,135.00,129.79,1 25.77,124.61,98.30,97.06,77.16,60.30,55.60,54.22,23.59LC-MS(ESI)calculatedfor C 24 H 28 N5O3,[M+H] + =434.21; found:434.20.

[0057] Example 8

[0058] Compound SN8 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((4-methylpiperidin-1-yl)methyl)

[0059] Phenyl)pyrazine-2-carboxamide.

[0060] The specific structural formula of compound SN8 is: The preparation method of compound SN8 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and 4-methylpiperidine (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is spin-dried, ethyl acetate (50mL) is added for dilution, saturated brine is washed (20mL, 3 times), the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), the boric acid ester obtained in step 1 (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 6 hours. After the reaction was completed, TLC monitoring was performed. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN8 was a light yellow solid with a yield of 16%. Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ=9.87(s,1H),8.66(s,1H),7.84–7.82(m,2H),7.47(d,J=8.1Hz,2H),6.95(d,J=2.2Hz,2H),6.29(t,J=2.2Hz,1H),3.83(s,6 H),3.60(s,2H),2.93(dt,J=11.9,3.3Hz,2H),2.06–2.02(m,2H),1.65–1 .61(m,2H),1.42–1.34(m,2H),1.28–1.23(m,1H),0.93(d,J=6.2Hz,3H). 13C NMR(150MHz, CDCl3)δ=164.14,161.31,154.14,144.81,140.47,139.25,135.03,130.20,125.67 ,124.63,98.31,97.06,77.16,62.96,55.60,53.92,34.12,30.75,21.94.LC-MS(ESI)calculated for C 26 H 32 N5O3,[M+H] + =462.24; found:462.20.

[0061] Example 9

[0062] Compound SN9 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((1,1-dioxythiomorpholino)methyl)phenyl)pyrazine-2-carboxamide.

[0063] The specific structural formula of compound SN9 is: The preparation method of compound SN9 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and thiomorpholine-1,1-dioxide (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is dried, ethyl acetate (50mL) is added for dilution, saturated brine is washed (20mL, 3 times), and the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), the boric acid ester obtained in step 1 (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 6 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN9 was a light yellow solid with a yield of 10%. Its structural characterization data are as follows: 1HNMR (600MHz, CDCl3) δ = 9.85 (s, 1H), 8.66 (s, 1H), 7.86 (d, J = 7.8Hz, 2H), 7.46 (d, J = 7.8Hz, 2H), 6.95(d,J=2.2Hz,2H),6.30(t,J=2.2Hz,1H),3.83(s,6H),3.74(s,2H),3.07(d,J=30.6Hz,8H). 13 C NMR(150MHz, CDCl3)δ=164.11,161.46,154.35,144.85,140.18,139.29,135.85,129.6 4,126.10,124.82,ss98.57,97.07,61.37,55.65,51.75,50.87.LC-MS(ESI)calculated for C 24 H 28 N5O5S,[M+H] + =498.17; found:498.10.

[0064] Example 10

[0065] Compound SN10 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((4-methyl-1,4-diazepine-1-yl)methyl)phenyl)pyrazine-2-amide.

[0066] The specific structural formula of compound SN10 is: The preparation method of compound SN10 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and N-methyl homopiperazine (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is spin-dried, ethyl acetate (50mL) is added for dilution, saturated brine is washed (20mL, 3 times), the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), the boric acid ester obtained in step 1 (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 6 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN10 was a light yellow solid with a yield of 54%. Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ = 9.84 (s, 1H), 8.65 (s, 1H), 7.84–7.83 (m, 2H), 7.44 (d, J = 5.5Hz, 2H), 6.94 (d, J = 2.2Hz, 2H), 6.29 (d, J =2.2Hz,1H),3.82(s,6H),3.74(s,2H),3.34(d,J=5.1Hz,2H),3.17(s,2H),2.96(s,3H),2.85(s,2H),2.78(d,J=1.2Hz,4H). 13 C NMR (150MHz, CDCl3) δ = 164.02, 161.30, 154.22, 144.77, 139.98, 139.19, 129.73, 125.99, 125.96, 124. 64,98.37,96.86,66.25,62.15,55.60,54.96,53.66,49.04,44.52,23.82.LC-MS(ESI)calculatedfor C 26 H 33 N6O3,[M+H] + =477.25; found:477.20.

[0067] Embodiment 11

[0068] Compound SN11 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)pyrazine-2-carboxamide.

[0069] The specific structural formula of compound SN11 is: The preparation method of compound SN11 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and 4-dimethylaminopiperidine (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is spin-dried, ethyl acetate (50mL) is added for dilution, saturated brine is washed (20mL, 3 times), the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), the boric acid ester obtained in step 1 (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 6 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN11 was a light yellow solid with a yield of 54%. Its structural characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ = 9.87 (s, 1H), 8.65 (s, 1H), 7.83–7.81 (m, 2H), 7.44 (d, J = 8. 2Hz,2H),6.94(d,J=2.2Hz,2H),6.29(t,J=2.2Hz,1H),3.82(s,6H),3.55(s,2H), 2.98–2.95(m,2H),2.58(d,J=7.2Hz,4H),2.53(dt,J=11.6,3.7Hz,1H),2.02–1.9 8(m,2H),1.75–1.72(m,2H),1.60(dd,J=12.1,3.8Hz,2H),1.04(t,J=7.2Hz,6H). 13C NMR (150MHz, CDCl3) δ = 164.13, 161.28, 154.11, 144.79, 140.48, 139.57, 139.25, 134.84, 129.83, 125. 61,124.55,98.28,96.97,62.77,58.32,55.57,53.66,43.72,28.55,13.78.LC-MS(ESI)calculatedfor C 29 H 39 N6O3,[M+H] + =519.30; found:519.30.

[0070] Example 12

[0071] Compound SN12 of this example: 3-amino-6-(4-((4-(diethylamino)piperidin-1-yl)methyl)phenyl)-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide.

[0072] The specific structural formula of compound SN12 is: The preparation method of compound SN12 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and 4-diethylaminopiperidine (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is spin-dried, ethyl acetate (50mL) is added for dilution, saturated brine is washed (20mL, 3 times), the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), the boric acid ester obtained in step 1 (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 6 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN12 was a light yellow solid with a yield of 53%. Its structural characterization data are as follows: 1H NMR (600MHz, CDCl3) δ = 9.87 (s, 1H), 8.65 (s, 1H), 7.84–7.82 (m, 2H), 7.44 (d, J=8.1Hz,2H),6.95(d,J=2.2Hz,2H),6.29(t,J=2.2Hz,1H),3.83(s,6H),3.8 2(s,2H),3.57(s,2H),3.01(dd,J=9.5,6.4Hz,2H),2.61(td,J=8.1,4.0Hz,1 H), 2.45 (s, 6H), 2.06 (td, J = 11.9, 2.3Hz, 2H), 1.90 (dt, J = 12.9, 2.8Hz, 2H). 13 C NMR(150MHz, CDCl3)δ=164.06,161.24,154.12,144.69,140.26,139.20,138.87,135.00,129 .82,125.64,98.26,96.89,62.37,62.18,55.53,52.57,40.28,27.10.LC-MS(ESI)calculated for C 27 H 35 N6O3,[M+H] + =491.2726; found:491.2.

[0073] Embodiment 13

[0074] Compound SN13 of this example: 3-amino-N-(3,5-dimethoxyphenyl)-6-(4-((4-(4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)pyrazine-2-carboxamide.

[0075] The specific structural formula of compound SN13 is: The preparation method of compound SN13 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dried round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and 4-pyrrolidin-1-yl-piperidine (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is spin-dried, ethyl acetate (50mL) is added to dilute, saturated brine is washed (20mL, 3 times), the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude borate intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), boric acid ester (1.5 equivalents) obtained in step 1 and sodium carbonate (2.5 equivalents) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture was heated at 100 ° C for 8 hours. After the reaction was completed, water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN13 was a light yellow solid with a yield of 35%. Its structural characterization data are as follows: 1 HNMR (600MHz, CDCl3) δ = 9.88 (s, 1H), 8.66 (s, 1H), 7.84–7.81 (m, 2H), 7.47–7. 44(m,2H),6.95(d,J=2.3Hz,2H),6.29(t,J=2.2Hz,1H),3.83(s,6H),3.56(s,2 H),2.93(dt,J=12.3,3.2Hz,2H),2.70(d,J=6.2Hz,5H),2.04(td,J=11.8,2.3H z,2H),1.92–1.88(m,2H),1.83(p,J=3.2Hz,4H),1.69(qd,J=12.0,3.9Hz,2H). 13 C NMR(150MHz, CDCl3)δ=164.16,161.30,154.12,144.82,140.53,139.52,139.26,134.89,129.75,125.67, 124.59,98.31,97.04,77.16,62.51,62.10,55.60,52.51,51.23,30.70,23.42.LC-MS(ESI)calculatedfor C29 H 37 N6O3,[M+H] + =517.28; found:517.30.

[0076] Embodiment 14

[0077] Compound SN14 of this example: 6-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-3-amino-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide.

[0078] The specific structural formula of compound SN14 is: The preparation method of compound SN14 is as follows: commercially available 4-bromomethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution are added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and 4-piperidinylpiperidine (4.0mmol, 2.0 equivalent) are added dropwise under stirring. The reaction mixture is stirred at room temperature for 4 hours. After the reaction is completed, the solvent is spin-dried, ethyl acetate (50mL) is added for dilution, saturated brine is washed (20mL, 3 times), the organic phase is separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude boric acid ester intermediate as an off-white solid powder, which is used in the next step without further purification. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), the boric acid ester obtained in step 1 (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalent) as a catalyst, and the reaction mixture was heated at 100°C for 8 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained target compound SN14 was a light yellow solid with a yield of 41%. Its structural characterization data are as follows: 1H NMR(600MHz, CDCl3)δ=9.87(s,1H),8.65(s,1H),7.83–7.81(m,2H),7.45–7 .42(m,2H),6.94(d,J=2.2Hz,2H),6.29(t,J=2.2Hz,1H),3.82(s,6H),3.55( s,2H),3.01–2.98(m,2H),2.66(s,4H),2.02(td,J=11.9,2.2Hz,2H),1.90(d ,J=12.1Hz,2H),1.71(ddd,J=24.3,11.4,4.7Hz,7H),1.49(d,J=8.3Hz,2H). 13 C NMR(150MHz, CDCl3)δ=164.13,161.30,154.13,144.81,140.45,139.28,139.24,134.97,129.83,125.69 ,124.59,98.31,96.99,63.29,62.57,55.60,53.20,50.16,27.37,25.43,24.27.LC-MS(ESI),calculated for C 30 H 39 N6O3,[M+H] + =531.30; found:531.20.

[0079] Embodiment 15

[0080] Compound SN15 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(4-ethylpiperazin-1-yl)methyl)phenyl)pyrazine-2-carboxamide.

[0081] The specific structural formula of compound SN15 is: The preparation method of compound SN15 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(4-ethylpiperazine-1-yl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 6-9 hours. After the reaction is completed, TLC monitoring is performed. Water is added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group to obtain the target compound SN15 as a light yellow solid with a yield of 35%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.06 (s, 1H), 9.25 (s, 1H), 8.86 (s, 1H), 8.09 (d, J = 8.1Hz, 2H), 7.59 (s, 2H), 7.39 (d, J = 8.1Hz, 2H), 6. 77(d,J=2.2Hz,2H),6.04(t,J=2.2Hz,1H),3.50(s,2H),3.36(s,4H),2.39(s,4H),2.31(d,J=7.2Hz,2H),0.97(t,J=7.2Hz,3H). 13 C NMR (150MHz, DMSO-d6)δ=164.65,158.87,154.59,144.93,139.65,139.01,138.90,134.99,129 .66,125.95,124.38,99.52,99.29,62.23,53.07,52.85,52.06,12.43.LC-MS(ESI)calculated for C 24 H 29 N6O3,[M+H] + =449.22; found:449.20.

[0082] Example 16

[0083] Compound SN16 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazine-2-carboxamide.

[0084] The specific structural formula of compound SN16 is: The preparation method of compound SN16 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-((4-methylpiperazin-1-yl)phenylboronic acid ester (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask in sequence. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0. 05 equivalent) as a catalyst, the reaction mixture was heated at 100 ° C for 8 hours. After the reaction was completed, TLC monitoring was performed. Water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2mL) was then added to remove the silicon-based protecting group, and the obtained target compound SN16 was a light yellow solid with a yield of 41%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ=10.08(s,1H),9.32(s,2H),8.88(s,1H),8.12(d,J=8.1Hz,2H),7.63(s,2H),7.41(d,J= 8.0Hz,2H),6.76(d,J=2.1Hz,2H),6.04(t,J=2.2Hz,1H),3.57(d,J=7.2Hz,2H),3.51–3.49(m,8H),3.38(s,3H). 13 C NMR (150MHz, DMSO-d6)δ=164.18,158.44,154.16,144.49,139.16,138.49,134.71,129.3 4,125.55,123.96,99.10,98.92,61.32,53.92,51.32,44.49.LC-MS(ESI)calculatedfor C 23 H 27 N6O3,[M+H] + =435.21; found:435.20.

[0085] Embodiment 17

[0086] Compound SN17 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(piperazin-1-ylmethyl)phenyl)pyrazine-2-carboxamide.

[0087] The specific structural formula of compound SN17 is:

[0088] The preparation method of compound SN17 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(piperazine-1-ylmethyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 6 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN17 was obtained as a light yellow solid powder with a yield of 31%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.12 (s, 1H), 9.94 (s, 2H), 8.95 (s, 1H), 8.29 (d, J = 8.1Hz, 2H), 7.79 ( d,J=8.0Hz,2H),6.76(d,J=2.1Hz,2H),6.06(t,J=2.2Hz,1H),3.56(s,2H),3.53–3.44(m,8H). 13 C NMR (150MHz, DMSO-d6) δ = 164.10, 158.42, 154.34, 144.61, 139.10, 137.63, 136.98, 132. 08,128.70,125.93,124.34,99.30,98.97,66.38,58.05,47.17.LC-MS(ESI)calculated for C 22 H 25 N6O3,[M+H] + =421.19; found:421.20.

[0089] Embodiment 18

[0090] Compound SN18 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(morpholinomethyl)phenyl)pyrazine-2-carboxamide.

[0091] The specific structural formula of compound SN18 is:

[0092] The preparation method of compound SN18 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(morpholinemethyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 7 hours. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN18 was obtained as a light yellow solid with a yield of 64%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.06 (s, 1H), 9.25 (s, 2H), 8.86 (s, 1H), 8.10 (d, J = 8.0Hz, 2H), 7.59 (brs, 2H), 7.41 (d ,J=8.0Hz,2H),6.77(d,J=2.2Hz,2H),6.04(s,1H),3.58(t,J=4.6Hz,4H),3.51(s,2H),2.38(t,J=4.6Hz,4H).. 13 C NMR (150MHz, DMSO-d6) δ = 164.21, 158.43, 154.16, 144.50, 139.22, 138.54, 137.97, 134. 65,129.36,125.54,123.96,99.10,98.86,66.25,62.14,53.20.LC-MS(ESI)calculated for C 22 H 24 N5O4,[M+H] + =422.17; found:422.10.

[0093] Embodiment 19

[0094] Compound SN19 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)pyrazine-2-carboxamide.

[0095] The specific structural formula of compound SN19 is:

[0096] The preparation method of compound SN19 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(4-(2-hydroxyethyl)piperazine-1-yl)phenylboronic acid ester (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 7 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN19 was obtained as a light yellow solid with a yield of 89%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ=10.08(s,1H),9.32(s,2H),8.87(s,1H),8.12(d,J=8.0Hz,2H),7.64(s,2H),7.41(d,J=7.9H z,2H),6.77(d,J=2.2Hz,2H),6.05(t,J=2.2Hz,1H),4.66(s,1H),3.61–3.53(m,4H),2.61(s,6H),2.57–2.47(m,4H). 13 C NMR (150MHz, DMSO-d6)δ=164.17,158.41,154.15,144.49,139.16,138.46,134.72,129.35 ,125.54,123.95,99.07,98.87,69.78,61.33,59.46,57.45,52.56.LC-MS(ESI)calculated for C 24 H 29 N6O4,[M+H] + =465.22; found:465.20.

[0097] Embodiment 20

[0098] The specific structural formula of the compound SN20 of this embodiment: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(hydroxymethyl)phenyl)pyrazine-2-carboxamide compound SN20 is:

[0099] The preparation method of compound SN20 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(hydroxymethyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 7 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN20 was obtained as a light yellow solid with a yield of 46%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6)δ=10.88(s,1H),10.07(s,1H),9.44(s,2H),8.88(s,1H),8.13(d,J =7.9Hz,2H),7.63(s,2H),7.42(d,J=7.9Hz,2H),6.79–6.74(m,2H),4.55(d,J=4.8Hz,2H). 13 C NMR (150MHz, DMSO-d6)δ=164.1,158.5,154.1,144.4,142.8,139.0,138.6,134.1,126.8,125.3,123.8,99.0,57.5.LC-MS(ESI)m / z:calculated for C 18 H 17 N4O4,[M+H] + =353.12; found:353.10.

[0100] Embodiment 21

[0101] Compound SN21 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazine-2-carboxamide

[0102] The specific structural formula of compound SN21 is:

[0103] The preparation method of compound SN21 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(pyrrolidin-1-ylmethyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 7 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN21 was obtained as a light yellow solid with a yield of 92%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.10 (s, 1H), 9.31 (s, 2H), 8.89 (s, 1H), 8.15 (d, J = 8.0Hz, 2H), 7.70–7.61 (m, 2H) ),7.49(d,J=7.8Hz,2H),6.77(d,J=2.2Hz,2H),6.04(s,1H),3.85(s,2H),2.68(s,4H),1.80–1.76(m,4H). 13 C NMR (150MHz, DMSO-d6)δ=164.18,158.42,154.24,144.59,139.18,138.20,135.40,12 9.82,125.68,124.05,99.18,98.90,58.00,53.10,22.90.LC-MS(ESI)m / z:calculated for C 22 H 24 N5O3,[M+H] + =406.18; found:406.10.

[0104] Embodiment 22

[0105] Compound SN22 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-((4-methylpiperidin-1-yl)methyl)phenyl)pyrazine-2-carboxamide

[0106] The specific structural formula of compound SN22 is:

[0107] The preparation method of compound SN22 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-((4-methylpiperidin-1-yl)methyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 7 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN22 was obtained as a light yellow solid with a yield of 22%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 9.29 (s, 2H), 8.87 (s, 1H), 8.10 (d, J = 8.2Hz, 2H), 7 .62(brs,2H),7.39(d,J=7.9Hz,2H),6.77(d,J=2.2Hz,2H),6.03(t,J=2.2Hz ,1H),3.50(s,2H),2.79(dt,J=11.6,3.5Hz,2H),1.97–1.91(m,2H),1.59–1 .55(m,2H),1.22(d,J=2.9Hz,1H),1.17–1.12(m,2H),0.89(d,J=6.5Hz,3H). 13 C NMR (150MHz, DMSO-d6)δ=164.21,158.41,154.14,144.50,139.20,138.56,131.55,129.31,128 .69,125.50,123.94,99.10,98.85,69.80,54.92,53.22,33.85,21.82.LC-MS(ESI)calculated for C 25 H 32 N5O3,[M+H] + =450.24; found:450.20.

[0108] Embodiment 23

[0109] Compound SN23 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-((1,1-dioxothiomorpholino)methyl)phenyl)pyrazine-2-carboxamide

[0110] The specific structural formula of compound SN23 is:

[0111] The preparation method of compound SN23 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-((1,1-dioxothiomorpholino)methylphenylboronic acid ester (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask in sequence. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, and then Pd(dppf)Cl2-CH2Cl2 ( 0.05 equivalent) as a catalyst, the reaction mixture was heated at 100 ° C for 7 hours. After the reaction was completed, water was added to quench the reaction and extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN23 was obtained as a light yellow solid with a yield of 87%. Its structural characterization data are as follows: 1 HNMR (600MHz, DMSO-d6) δ = 10.10 (s, 1H), 9.30 (s, 2H), 8.88 (s, 1H), 8.13 (d, J = 8.0Hz, 2H), 7.64 (brs, 2H), 7.44 (d, J=8.0Hz,2H),6.77(d,J=2.1Hz,2H),6.03(t,J=2.2Hz,1H),3.73(s,2H),3.12(t,J=5.2Hz,4H),2.92–2.89(m,4H). 13 CNMR(150MHz,DMSO-d6)δ=164.20,158.40,154.16,144.53,139.21,138.44,137.71,134 .89,129.28,125.65,123.99,99.10,98.84,59.35,50.32,50.08.LC-MS(ESI)calculated for C 22 H 23 N5O5S,[M+H] + =470.14; found:470.10.

[0112] Embodiment 24

[0113] Compound SN24 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-(4-methyl-1,4-diazepine-1-yl)methyl)phenyl)pyrazine-2-carboxamide

[0114] The specific structural formula of compound SN24 is:

[0115] The preparation method of compound SN24 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-(4-methyl-1,4-diaza-1-yl)methyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 8 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN24 was obtained as a light yellow solid with a yield of 33%. Its structural characterization data are as follows: 1 HNMR (600MHz, DMSO-d6) δ = 10.1 (s, 1H), 9.3 (s, 4H), 8.9 (s, 1H), 8.1 (d, J = 8.3Hz, 2H), 7.6 (brs, 2H), 7.4 (d, J = 8.0Hz, 2H), 6.8 (d, J = 2.2Hz, 3H), 6. 1(t,J=2.2Hz,1H),3.7(s,2H),2.8(t,J=5.7Hz,3H),2.8(d,J=5.7Hz,2H) ,2.7–2.7(m,3H),2.7(t,J=6.1Hz,3H),2.4(s,4H),1.8(q,J=5.8Hz,2H). 13 C NMR (150MHz, DMSO-d6)δ=164.21,158.44,154.14,144.49,139.19,138.51,134.54,129.00,128.74,12 5.55,123.94,99.07,98.87,61.40,56.89,55.39,53.60,45.36,25.61,13.52.LC-MS(ESI)calculated for C 24 H29 N6O3,[M+H] + =449.22; found:449.20.

[0116] Embodiment 25

[0117] Compound SN25 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)pyrazine-2-carboxamide

[0118] The specific structural formula of compound SN25 is:

[0119] The preparation method of compound SN25 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 8 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN25 was obtained as a light yellow solid with a yield of 94%. Its structural characterization data are as follows: 1 HNMR (600MHz, DMSO-d6) δ=10.08(s,1H),8.87(s,1H),8.10(d,J=8.2Hz,2H),7.63(brs,2H),7.38(d,J=8.1Hz,2H),6.77(d,J=2.1Hz,2H),6.03(t,J= 2.2Hz,1H),3.48(s,2H),2.85(d,J=11.5Hz,2H),2.20(s,6H),2.18(s,1H) ,2.13(tt,J=11.2,3.7Hz,2H),1.95–1.91(m,2H),1.72(d,J=11.8Hz,2H). 13C NMR (150MHz, DMSO-d6)δ=164.19,158.44,154.13,144.48,139.19,138.77,138.57,134.48,129 .14,125.49,123.92,99.06,98.86,61.75,61.70,52.32,41.31,27.91.LC-MS(ESI)calculated for C 25 H 31 N6O3,[M+H] + =463.24; found:463.20.

[0120] Embodiment 26

[0121] Compound SN26 of this example: 3-amino-6-(4-((4-(diethylamino)piperidin-1-yl)methyl)phenyl)-N-(3,5-dihydroxyphenyl)pyrazine-2-carboxamide compound

[0122] The specific structural formula of SN26 is:

[0123] The preparation method of compound SN26 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-((4-(diethylamino)piperidin-1-yl)methyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 8 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN26 was obtained as a light yellow solid with a yield of 74%. Its structural characterization data are as follows: 1HNMR (600MHz, DMSO-d6) δ = 10.11 (s, 1H), 8.89 (s, 1H), 8.11 (d, J = 8.0Hz, 2H), 7. 67(s,2H),7.39(d,J=7.9Hz,2H),6.81(d,J=2.1Hz,2H),6.08(t,J=2.1Hz,1H),3 .49(s,2H),2.86(d,J=11.5Hz,2H),2.53–2.50(m,4H),2.48–2.44(m,1H),1.94 –1.91(m,2H),1.65(d,J=11.4Hz,2H),1.47–1.41(m,2H),0.96(t,J=7.1Hz,6H). 13 C NMR (150MHz, DMSO-d6)δ=164.18,158.46,154.15,144.47,139.19,138.74,138.59,134.47,129.15 ,125.46,123.91,99.05,98.89,61.77,57.68,52.76,42.97,28.12,13.49.LC-MS(ESI)calculated forC 27 H 34 N6O3,[M+H] + =491.27; found:491.20.

[0124] Embodiment 27

[0125] Compound SN27 of this example: 3-amino-N-(3,5-dihydroxyphenyl)-6-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)pyrazine-2-carboxamide

[0126] The specific structural formula of compound SN27 is:

[0127] The preparation method of compound SN27 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenylboronic acid ester (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 8 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN27 was obtained as a light yellow solid with a yield of 54%. Its structural characterization data are as follows: 1 H NMR (600MHz, DMSO-d6) δ = 10.01 (s, 1H), 8.87 (s, 1H), 8.09 (d, J = 8.0Hz, 2H), 7.67 (b rs,2H),7.38(d,J=7.9Hz,2H),6.73(d,J=2.1Hz,2H),6.09(t,J=2.3Hz,1H),3.46( s,2H),3.25(d,J=7.2Hz,1H),2.77(d,J=11.1Hz,2H),2.50(t,J=1.9Hz,2H),2.44( d,J=6.1Hz,4H),1.94(d,J=10.6Hz,2H),1.79–1.75(m,2H),1.63(q,J=3.5Hz,4H). 13 C NMR (150MHz, DMSO-d6)δ=173.40,164.03,159.21,154.22,144.47,138.88,138.83,138.54,134.46,12 9.21,125.41,123.90,99.35,98.70,61.96,54.98,51.85,31.08,23.50,22.97.LC-MS(ESI)calculated for C 27 H 33 N6O3,[M+H] + =489.25; found:489.20.

[0128] Embodiment 28

[0129] Compound SN28 of this example: 6-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-3-amino-N-(3,5-dihydroxyphenyl)pyrazine-2-carboxamide

[0130] The specific structural formula of compound SN28 is:

[0131] The preparation method of compound SN28 is as follows: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), 4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl borate (1.5 equivalents) and sodium carbonate (2.5 equivalents) are added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water (volume ratio of 4 / 1) is added to form a suspension, and the suspension is degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture is heated at 100°C for 8 hours. After the reaction is completed by TLC monitoring. Water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3). Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon-based protecting group, and the target compound SN28 was obtained as a light yellow solid with a yield of 54%. Its structural characterization data are as follows: 1 HNMR(600MHz, DMSO-d6)δ=10.09(s,1H),9.33(s,2H),8.88(s,1H),8.10(d,J=7.8 Hz,2H),7.65(brs,2H),7.37(d,J=7.9Hz,2H),6.78(d,J=2.2Hz,2H),6.05(d,J=2. 4Hz,1H),3.47(s,2H),2.85(d,J=11.1Hz,2H),2.26(s,1H),1.90(t,J=11.6Hz,2H ),1.69(d,J=12.0Hz,2H),1.47(ddt,J=16.4,12.0,4.2Hz,8H),1.38–1.35(m,2H). 13 C NMR (150MHz, DMSO-d6)δ=164.20,158.44,154.15,144.50,139.21,138.69,138.56,134.51,129.19,125 .48,123.91,99.06,98.85,62.13,61.76,52.65,49.64,27.33,25.62,14.11.LC-MS(ESI)calculatedfor C28 H 35 N6O3,[M+H] + =503.27; found:503.20.

[0132] Embodiment 29

[0133] In this example, the phosphorylation inhibitory activity of the compounds SN1-SN28 obtained in the above examples 1-28 was tested. The detailed process is as follows. Step 1: Dilute 5×kinase buffer with ultrapure water to 1.33×kinase buffer. Use 1.33×kinase buffer to dilute the FGFR1-4 protein with a concentration of 200ng / μL to 0.6, 1.4, 0.5, 4.0ng / μL, respectively, and the substrate peptide segment is diluted to 4μM, labeled as 2×kinase / peptide mixture. Next, ATP (10mM) is diluted to 10, 20, 300, 600μM with 1.33×kinase buffer, respectively, and labeled as 4×ATP. Finally, the compound stock solution is diluted to 4×compound with ultrapure water, and DMSO is also diluted in the same way. Use 1.33×kinase buffer to dilute the phosphorylated substrate peptide segment (10mM) to 4μM, labeled as 2×P-peptide. Step 2 is the kinase reaction. First, distribute the solution into a 384-well plate according to the following settings, mix well, and react at room temperature in the dark for 1 hour. Among them, experimental wells: 5μL 2× kinase / peptide mixture + 2.5μL 4× compound + 2.5μL 4×ATP; DMSO control wells: 5μL 2× kinase / peptide mixture + 2.5μL DMSO + 2.5μL 4×ATP; non-phosphorylation control wells: 5μL 2× kinase / peptide mixture + 2.5μL DMSO + 2.5μL 1.33×kinase buffer; 100% phosphorylation control wells: 5μL 2×P-peptide + 2.5μL DMSO + 2.5μL 1.33×kinase buffer. Step three is the Development reaction. Dilute the Development reagent with Development buffer to a 3% Development solution, add 5μL to each well, mix well, and react at room temperature for 1 hour. Add 5μL of reaction stop solution to each well, mix well, and terminate the reaction. The test results are attached to the instruction manual. Figure 2 .

[0134] Embodiment 30

[0135] In this example, the anti-tumor cell proliferation activity of compound SN23 obtained in the above example 23 was tested. (1) Cells and culture medium: NCI-H520, SNU-16, KMS-11, SW-780 and BaF3 cells were cultured with RPMI1640 complete culture medium, and MDA-MB-453 cells were cultured with DMEM complete culture medium. The complete culture medium was prepared with the corresponding culture medium + 10% FBS (fetal bovine serum) + 1% penicillin-streptomycin double antibody. (2) Cell proliferation test: Cell plating: Take a 10cm dish of cells, add 4mL PBS to wash once, and add 1mL trypsin. Then, digest for 1min at room temperature, add 4mL culture medium to terminate digestion, and use a pipette to gently blow to fully disperse the cells. Collect the cells into a 15mL centrifuge tube and centrifuge at 800rpm for 3min. After centrifugation, discard the supernatant, add 2ml culture medium to resuspend, and use a pipette to blow and mix the cell suspension. Finally, take 10 μL of the resuspended liquid from the mixed cell suspension to fill the pool, count the cells, and distribute the cells to a 96-well plate according to the number of cells, so that each well has 190 μL of culture medium and 1×10 4 cells and cultured them in a 37°C constant temperature CO2 (5%) incubator. Take out the compound stock solution from the -20°C refrigerator and dilute it 50 times with culture medium. Then, use a spray gun to add the diluted compound to the corresponding wells (10 μL to 190 μL) until it is diluted 1000 times, and the concentration of DMSO in each well is 0.1%. Place the 96-well plate in a 37°C constant temperature CO2 (5%) incubator for 72 hours. After 72 hours, take out the CellTiter-Glo reagent from the -20°C refrigerator and put it in a 37°C water bath to thaw. Take out the 96-well plate from the incubator and use a spray gun to aspirate 100 μL of the supernatant in each well. Use a spray gun to add 40 μL of CellTiter-Glo reagent to each well, cover the container, place it on a shaker device, and incubate it for 10 minutes at room temperature and in the dark. Place the 96-well plate in an ELISA reader, set the parameters, and measure the chemiluminescent signal. Data were collected and analyzed using GraphPad Prims 8 software. The results are shown in the attached manual. Figure 3 .

Claims

1. A 3-amino-pyrazine-2-amide derivative targeting FGFR, characterized in that: The derivative has the general structural formula shown in the following formula (I): Among them, R1 can be selected from any one of methyl (-CH3) or hydrogen (-H). The R2 group can be selected from any of the following substituent groups: The wavy line indicates the position of the substituent group. The above R1 and R2 groups can be combined arbitrarily.

2. A 3-amino-pyrazine-2-amide derivative targeting FGFR, characterized in that: One of the following compounds:

3. The method for preparing a 3-amino-pyrazine-2-amide derivative targeting FGFR according to claim 1, characterized in that The steps include: The synthesis steps of compounds SN1-SN6 are as follows: Synthesis of compound SN6: 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (500 mg, 1.42 mmol), (4-(hydroxymethyl)phenyl)boric acid (260 mg, 1.71 mmol) and sodium carbonate (301 mg, 2.84 mmol) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (63 mg, 0.086 mmol) as a catalyst, and the reaction mixture was heated at 90°C for 10 h. After the reaction was completed, TLC was used to monitor the reaction. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (6 mL*3 times). The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound SN6. General method for the synthesis of compound SN1-4: In a 20 mL dry round-bottom flask, compound SN6 (118 mg, 0.38 mmol), catalytic amount of 4-dimethylaminopyridine (4.68 mg, 0.038 mmol) and triethylamine (0.106 mL, 0.76 mmol) and dry dichloromethane (4 mL) were added in sequence. The resulting mixture was stirred at room temperature for 15 minutes, and p-toluenesulfonyl chloride (62.96 mg, 0.57 mmol) was slowly added. The mixture was continued to be stirred at room temperature for 5 minutes, and then the corresponding fatty amine and cesium carbonate were added until the reaction was complete. 5 mL of water was added to dilute the mixture, and then extracted with ethyl acetate 3 times. Purification by silica gel column chromatography gave the target compounds SN1-4 respectively. Synthesis of compound SN5: First, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (100 mg, 0.28 mmol), (4-(hydroxyethylpiperazine)phenyl)boric acid (0.42 mmol) and sodium carbonate (60 mg, 0.56 mmol) were added to a 20 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (12 mg, 0.0817 mmol) as a catalyst. After the reaction mixture was heated at 90°C for 6 hours, tetrabutylammonium fluoride (2 mL) was added and reacted at room temperature for 2 hours. After the reaction was completed, 5 mL of water was added to dilute the mixture, and then extracted with ethyl acetate 3 times. Purification by silica gel column chromatography gave the target compound SN5. General method for the synthesis of compounds SN7-SN14: The synthesis of compounds SN7-SN14 includes two steps. The first step is to synthesize the intermediate boric acid ester. Commercially available 4-ethylphenylboronic acid pinacol ester (2.0mmol, 1.0 equivalent) and acetonitrile (0.2M) solution were added to a 50mL dry round-bottom flask, and triethylamine (0.65mL, 2.0 equivalent) and secondary fatty amine (4.0mmol, 2.0 equivalent) were added dropwise under stirring. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50mL) was added for dilution, saturated brine was washed (20mL, 3 times), the organic phase was separated and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain the crude boric acid ester intermediate as an off-white solid powder. In the second step, 3-amino-6-bromo-N-(3,5-dimethoxyphenyl)pyrazine-2-carboxamide (1 equivalent), boric acid ester (1.5 equivalents) obtained in step 1 and sodium carbonate (2.5 equivalents) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture was heated at 100°C for 6-9 hours. After the reaction was completed, TLC was monitored. Water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the target compounds SN7-SN14 as solid powders. General method for the synthesis of compounds SN15-SN-28: 3-amino-N-(3,5-dihydroxyphenyl)-6-bromopyrazine-2-carboxamide (1 equivalent), boric acid ester (1.5 equivalents) obtained in step 1 of the synthesis of SN7-SN14, and sodium carbonate (2.5 equivalents) were added to a 50 mL dry round-bottom flask. A mixed solvent of 1,4-dioxane and water was added to form a suspension, and the suspension was degassed under nitrogen bubbling for 10 minutes, followed by the addition of Pd(dppf)Cl2-CH2Cl2 (0.05 equivalents) as a catalyst, and the reaction mixture was heated at 100°C for 6-9 hours. After the reaction was completed by TLC monitoring. Water was added to quench the reaction and extracted three times with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography. Tetrabutylammonium fluoride (2 mL) was then added to remove the silicon protecting group to obtain the target compounds SN15-SN-28 as solid powders with a yield of 22-99%.

4. The method for preparing a 3-amino-pyrazine-2-amide derivative targeting FGFR according to claim 3, characterized in that: Step: The compounds SN1-SN28 are separated and purified by silica gel column chromatography, and the eluent is petroleum ether / ethyl acetate with a gradient volume ratio of 3:1 to 2:

1.

5. The general method for synthesizing compounds SN7-SN14 according to claim 3, wherein the synthesized intermediate boric acid ester is characterized in that: No separation or purification is required.

6. The 1,4-dioxane and water mixed solvent according to claim 3, characterized in that: The volume ratio of 1,4-dioxane to water is 4 / 1.

7. The use of the 3-amino-pyrazine-2-amide derivative targeting FGFR according to claim 1, characterized in that: The application is application in the preparation of anti-tumor drugs.

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