A quinazoline compound and its preparation method and application

Abstract

The invention discloses a quinazoline compound, which has a novel general structural formula skeleton and has good inhibitory activity on LSD1. The invention also discloses a preparation method of the above-mentioned compound, wherein aromatic rings, aromatic heterocycles, cyclic olefins and cyclic groups are introduced at the 2-position of quinazoline, and groups such as aliphatic amines, aromatic amines, and phenols are introduced at the 4-position of quinazoline. Different substituted flexible long chains, electron-donating and electron-withdrawing groups are introduced at the 6-position and 7-position of quinazoline, and a class of quinazoline compounds is designed and synthesized, which has the characteristics of mild reaction conditions, simple operation and high reaction yield. After testing, the above-mentioned quinazoline compound shows good LSD1 inhibitory activity, and provides a novel structural skeleton for the development of efficient anti-tumor drugs based on LSD1 targets.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry and relates to a quinazoline compound and a preparation method and application thereof. Background Art

[0002] Epigenetics refers to heritable changes in gene function that occur without changing the DNA sequence. [6] . DNA modification, histone modification, noncoding RNA modification and nucleosome remodeling are all epigenetic regulatory mechanisms. Abnormal epigenetic regulation can lead to incorrect gene expression, causing various diseases and even tumors. Among them, histone modification is one of the most important epigenetic modifications, including methylation, phosphorylation, ubiquitination and acetylation, among which acetylation and methylation are the most important. Studies have shown that they have a regulatory effect on gene transcription. In 2004, the first histone lysine demethylase 1 (Lysine Specific Demethylase l, LSD1) was discovered, confirming that histone demethylation is a reversible process. The methylation level on histone lysine residues in the body is regulated by two specific enzymes-histone methyltransferase and histone demethylase. LSD1 is a flavin adenine dinucleotide-dependent demethylase, which mainly acts as a transcription activator or transcription inhibitor to catalyze the removal of H3K4 monomethylation and dimethylation. When H3K4 is methylated, it can activate gene transcription.

[0003] LSD1 is highly expressed in a variety of tumor cells, including small cell lung cancer, bladder cancer, gastric cancer, prostate cancer, breast cancer and acute myeloid leukemia, and plays an important role in tumor differentiation, proliferation, metastasis or invasion. In some cancer cell lines, inhibition of LSD1 by RNAi knockdown can activate the expression of tumor suppressor genes (such as p53) and reduce the expression of related target genes. Therefore, LSD1 is a potential anti-tumor target. Research and development of highly efficient and low-toxic LSD1 inhibitors for tumor prevention and treatment is an important research direction and has become a hot spot in current tumor drug research. Summary of the invention

[0004] In order to overcome the deficiencies of the prior art, one of the objectives of the present invention is to provide a quinazoline compound having good inhibitory activity against LSD1.

[0005] A second object of the present invention is to provide a method for preparing a quinazoline compound.

[0006] The third object of the present invention is to provide the use of quinazoline compounds in the preparation of anti-tumor drugs targeting LSD1.

[0007] One of the purposes of the present invention is achieved by the following technical solution:

[0008] A quinazoline compound, wherein the quinazoline compound is a compound having a structural formula I, or a pharmaceutically acceptable salt of the compound shown in the structural formula I:

[0009]

[0010] wherein X is selected from O or NH;

[0011] The group R1 is selected from H, C1-C10 alkoxy, alkyl-substituted alkoxy; R2 is selected from H, alkyl, C1-C10 alkoxy, alkyl-substituted alkoxy or halogen;

[0012] R3 is selected from aromatic amine, aliphatic amine, aryl or heteroaryl;

[0013] R4 is selected from Me, One of them.

[0014] In some embodiments, R1 is selected from one of H, methoxy, and dimethoxyethane; R2 is selected from one of H, methyl, methoxy, chlorine, fluorine, and trifluoromethyl;

[0015] R3 is selected from

[0016] One of;

[0017] R4 is selected from Me, One of them.

[0018] In some embodiments, R1, R2, R3, and R4 are selected from the following groups:

[0019]

[0020]

[0021]

[0022]

[0023] The second object of the present invention is achieved by adopting the following technical solution:

[0024] The preparation method of quinazoline compounds as one of the purposes of the present invention comprises the following steps:

[0025]

[0026] Synthesis route a: Compound 1a-c and phosphorus oxychloride undergo chlorination reaction under the action of alkaline substances to obtain compound 2a-c;

[0027] Synthesis route b: Compounds 2a-c or 5a-h and an ammonia compound are dissolved in a mixed solution of an organic solvent and water, and a substitution reaction occurs under the action of an alkaline substance to obtain compounds I and 6a-q;

[0028] Synthesis route c: Compound 2b and N,N-dimethyl-p-phenylenediamine are dissolved in an alcohol solvent, and a substitution reaction occurs under the action of an acidic substance to obtain compound I.

[0029] Synthesis route d: Compounds 4a-h are obtained by reacting different substituted anthranilic acid compounds 3a-h with urea;

[0030] Synthesis route e: Compounds 4a-h and phosphorus oxychloride are dissolved in an organic solvent and reacted with alkaline substances to produce compounds 5a-h;

[0031] Synthesis route f: Compound 5a and aminophenol are dissolved in an organic solvent, and a substitution reaction occurs under the action of an alkaline substance to obtain compound 6r.

[0032] Synthesis route g: Compound 6a-r and a boronic acid compound are dissolved in a mixed solution of an organic solvent and water, and a Suzuki coupling reaction occurs under the catalysis of an alkaline substance and palladium to obtain compound I.

[0033] The X is NH or O.

[0034] In some embodiments, the reaction temperature for synthesizing compounds 2a-c from compounds 1a-c in the synthetic route a is 50°C-150°C; the reaction temperature for synthesizing compounds 1-3, 5, and 6a-q from compounds 2a-c or 5a-h in the synthetic route b is 60°C-130°C; the reaction temperature for synthesizing compound 4 from compound 2b in the synthetic route c is 45°C-120°C; the reaction temperature for synthesizing compounds 4a-h from compounds 3a-h in the synthetic route d is 90°C-180°C; the reaction temperature for synthesizing compounds 5a-h from compounds 4a-h in the synthetic route e is 60°C-140°C; the reaction temperature for synthesizing compounds 6r from compounds 5a in the synthetic route f is 45°C-120°C; the reaction temperature for synthesizing compounds 6-53 from compounds 6a-r in the synthetic route g is 45°C-125°C.

[0035] In some embodiments, the organic solvent in synthetic routes b, e, f, and g is selected from one of N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, and dioxane. The alcohol solvent in synthetic route c is selected from one of methanol, ethanol, n-butanol, and isopropanol.

[0036] In some embodiments, the alkaline substance in synthetic routes b, e, f, and g is selected from one of sodium carbonate, sodium acetate, potassium carbonate, sodium hydroxide, potassium hydroxide, N,N-dimethylaniline, and N,N-diisopropylethylamine.

[0037] In some embodiments, the acidic substance in synthetic route c is selected from one of glacial acetic acid, concentrated hydrochloric acid, and concentrated sulfuric acid.

[0038] In some embodiments, the palladium catalyst in the synthetic route g is one of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and bis(dibenzylideneacetone)palladium.

[0039] The third object of the present invention is achieved by adopting the following technical solution:

[0040] A use of a quinazoline compound, specifically the use of a quinazoline compound in the preparation of an anti-tumor drug based on a LSD1 target.

[0041] The present invention discloses a quinazoline compound with a novel skeleton and good inhibitory activity against LSD1. The present invention also discloses a preparation method of the above-mentioned compound, wherein aromatic rings, aromatic heterocycles, cyclic olefins and cyclic groups are introduced into the 2-position of quinazoline for modification, aliphatic amines, aromatic amines, phenols and other groups are introduced into the 4-position of quinazoline for modification, and different substituted flexible long chains, electron-donating and electron-withdrawing groups are introduced into the 6-position and 7-position of quinazoline, and a class of quinazoline compounds is designed and synthesized, which has the characteristics of mild reaction conditions, simple operation and high reaction yield. After testing, the above-mentioned quinazoline compound exhibits good LSD1 inhibitory activity, and provides a novel structural skeleton for the development of efficient anti-tumor drugs based on LSD1 targets.

[0042] The quinazoline compounds provided by the present invention are used in the preparation of anti-tumor drugs based on the LSD1 target. The quinazoline compounds involved show good inhibitory activity on LSD1, showing good drug development potential, and providing a new direction for drug research and development based on the LSD1 target. DETAILED DESCRIPTION

[0043] The present invention is further described below in conjunction with specific implementation methods. It should be noted that, under the premise of no conflict, the various embodiments or technical features described below can be arbitrarily combined to form a new embodiment.

[0044] The preparation process of compound 1-5 is as follows:

[0045]

[0046] Example 1

[0047] Preparation of compound 1: X=NH, R4=H.

[0048] (1) 1a (1 mmol) was used as the starting material and refluxed in a mixture of phosphorus oxychloride (3 mmol) and N,N-dimethylaniline (1.1 mmol) for 5 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, the mixture was cooled to room temperature and phosphorus oxychloride was distilled off under reduced pressure. The concentrated reaction system was poured into ice water, and a saturated aqueous sodium bicarbonate solution was added. After the pH was adjusted to neutral, ethyl acetate (25 mL×3) was added for extraction. The organic phase was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography to obtain intermediate 2a in a yield of 78.7%.

[0049] 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),7.47(s,1H),7.43(s,1H),4.39–4.33(m,4H),3.78–3.77(m,4H),3.36(d,J=3.3Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ158.62,154.50,148.73,146.25,137.40,114.65,107.03,104.49,70.05,69.87,68.50,68.36,58.33,58.30.

[0050] (2) Compound 2a (1 mmol) prepared in step (1), 4-(4-methylpiperazine)aniline (1.1 mmol), and sodium acetate (1.1 mmol) were dissolved in a mixed solution of tetrahydrofuran and water (V THF :V 水 =3:1, 8 mL), reacted at 65 ° C for 5 hours. The reaction was detected by thin layer chromatography. After the reaction was completed, ethyl acetate was added to the reaction system to dilute the reaction system, and the organic phase was washed with saturated brine (25 mL×3), and dried over anhydrous magnesium sulfate. Compound 1 was obtained by column chromatography separation and purification, and the yield was 56.5%.

[0051] 1H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.37(s,1H),7.88(s,1H),7.60(d,J=8.9Hz,2H),7.18(s,1H),6.99(d,J=9 .0Hz,2H),4.30–4.26(m,4H),3.81–3.70(m,4H),3.36(d,J=6.8Hz,6H),3.24(s,4H),2.80(s,4H),2.46(s,3H). 13 C NMR(100MHz,DMSO-d6)δ156.53,153.34,153.09,147.82,146.88,146.62,131.39,123.80,1 15.64,108.76,108.12,103.42,70.12,68.34,67.95,58.34,53.69,47.52.HRMS(ESI)calcd for C 25 H 33 N5O4[M+H] + ,468.2606;found,468.2613.

[0052] Example 2

[0053] Preparation of compound 2: X=NH, R4=H.

[0054] The difference between Example 2 and Example 1 is that 4-(4-methylpiperazine)aniline in step (2) is replaced by 4-amino-N,N-dimethylaniline, and the rest is the same as Example 1. Compound 2 is prepared with a yield of 64.3%.

[0055] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.34(s,1H),7.84(s,1H),7.50(d,J=8.9Hz,2H),7.16(s ,1H),6.77(d,J=9.0Hz,2H),4.30–4.24(m,4H),3.79–3.73(m,4H),3.37(s,6H),2.90(s,6H). 13 C NMR(100MHz,DMSO-d6)δ156.71,153.25,153.18,147.74,147.47,146.42,128.54,12 4.32,112.37,108.71,108.04,103.37,70.11,68.27,67.93,58.32.HRMS(ESI)calcd for C 22H 28 N4O4[M+H] + ,413.2184;found,413.2191.

[0056] Example 3

[0057] Preparation of compound 3: R1=H, R2=H, X=NH, R4=H.

[0058] (1) In step (1) of Example 1, 1a was replaced by 4-hydroxyquinazoline, and other conditions were the same as those in step (1) of Example 1. Compound 2b was prepared with a yield of 70.2%.

[0059] 1 H NMR (400 MHz, DMSO-d 6) δ8.96(s,1H),8.19(d,J=8.0Hz,1H),7.97(t,J=7.7Hz,1H),7.89(d,J=8.0Hz,1H),7.69(t,J=7.5Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ159.47,147.99,141.60,135.53,128.28,126.52,122.39,121.45.

[0060] (2) 2a in step (2) of Example 1 was replaced by 2b synthesized above, and other conditions were the same as step (2) of Example 1. Compound 3 was prepared with a yield of 46.1%.

[0061] 1 H NMR(400MHz, DMSO-d6)δ9.65(s,1H),8.55–8.48(m,2H),7.83(t,J=7.5Hz,1H),7.75(d,J=7.9Hz,1H),7 .62(dd,J=11.6,8.5Hz,3H),6.97(d,J=9.0Hz,2H),3.22–3.03(m,4H),2.49–2.43(m,4H),2.23(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.78,154.68,149.54,147.78,132.72,130.57,127.65 ,125.94,123.85,122.84,115.31,115.11,54.60,48.42,45.76.HRMS(ESI)calcd for C 19 H 21 N5[M+H]+ ,319.1797;found,319.1762.

[0062] Example 4

[0063] Preparation of compound 4: R1=H, R2=H, X=NH, R4=H.

[0064] (1) 2b (0.92 mmol) and N,N-dimethyl-p-phenylenediamine (1 mmol) were added to 5 mL of isopropanol in sequence, and then 3 drops of concentrated hydrochloric acid were added to the reaction system, and the mixture was reacted at 80° C. for 5 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, the excess solvent was removed by vacuum distillation, and the mixture was concentrated and separated and purified by column chromatography to obtain compound 4. The yield was 67.3%.

[0065] 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),9.11(d,J=8.3Hz,1H),8.93(s,1H),8.12(t,J=7.7Hz,1H) ,8.05(d,J=8.1Hz,1H),7.86(t,J=7.6Hz,1H),7.79(d,J=8.4Hz,2H),7.50(s,2H),3.09(s,6H). 13 C NMR(100MHz,DMSO-d6)δ159.66,150.63,138.09,136.25,128.60,126.08,125.18,119.22,113.45,48.54,43.34.HRMS(ESI)calcd for C 16 H 16 N4[M+H]+,265.1448; found,265.1452.

[0066] Example 5

[0067] Preparation of compound 5: R1=H, R2=H, X=NH, R4=CH3.

[0068] (1) In step (1) of Example 1, 1a was replaced by 2-methyl-4(3H)-quinazolinone, and other conditions were the same as those in step (1) of Example 1. Compound 2c was prepared with a yield of 74.3%.

[0069] 1H NMR (400MHz, CDCl3) δ8.22(d,J=8.3Hz,1H),8.00–7.85(m,2H),7.65(t,J=8.2Hz,1H),2.86(s,3H). 13 C NMR (100MHz, CDCl3) δ163.54,162.16,151.49,134.84,128.02,127.99,125.71,121.83,26.02.

[0070] (2) In step (2) of Example 1, 2a was replaced by 2c synthesized above, 4-(4-methylpiperazine)aniline was replaced by 4-amino-N,N-dimethylaniline, and other conditions were the same as those in step (2) of Example 1. Compound 5 was prepared with a yield of 41.7%.

[0071] 1 H NMR (400MHz, CDCl3) δ7.79(d,J=6.4Hz,2H),7.72(q,J=7.1Hz,1H),7.60(t,J=6.1Hz,2H ),7.44(t,J=7.1Hz,1H),7.29(s,1H),6.79(d,J=9.0Hz,2H),2.96(s,6H),2.66(s,3H). 13 C NMR(100MHz, CDCl3)δ164.35,157.46,150.54,148.06,132.54,128.14,125.32,123.22,120.30,113.05,40.94,26.69.HRMS(ESI)calcd for C 17 H 18 N4[M+H] + ,279.1604;found,279.1607.

[0072] The preparation process of compound 6-53 is as follows:

[0073]

[0074] Example 6

[0075] Preparation of compound 6: R1=H, R2=H, X=NH,

[0076] (1) 3a (7 mmol) and urea (35 mmol) were reacted at 160°C for 3 hours. After the reaction was completed, the reaction system was cooled to 100°C and 50 mL of water was added to quench the reaction system. The filter residue was filtered, washed with water and dried. The dried filter residue was added to 0.5 N sodium hydroxide solution, stirred at 50°C for one hour, cooled to 0°C, adjusted to neutral pH with concentrated hydrochloric acid and filtered. The dried filter residue was the intermediate 4a. The dried 4a (2 mmol) was dissolved in phosphorus oxychloride (5 mL), N,N-diisopropylethylamine (500 μL) and N,N-dimethylformamide (5 drops) were added, and the reaction was carried out at 90°C for 8 hours. After the reaction is complete, the excess phosphorus oxychloride is spun out, the reaction system is cooled and poured into ice water, a saturated sodium bicarbonate aqueous solution is added, the pH is adjusted to neutral, ethyl acetate (25 mL×3) is added for extraction, the organic phase is dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography to obtain intermediate 5a. The yield is 44.9%.

[0077] 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=8.4Hz,1H),8.19(t,J=7.7Hz,1H),8.06(d,J=8.4Hz,1H),7.92(t,J=7.7Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ163.40,153.72,151.77,136.99,130.10,127.50,125.94,121.96.

[0078] (2) Intermediate 5a (1 mmol), N,N-dimethyl-p-phenylenediamine (1.1 mmol), and sodium acetate (1.1 mmol) were added sequentially to a mixed solution of tetrahydrofuran and water (V THF :V 水 =3:1, 8 mL) and reacted at 65 ° C for 5 hours. The reaction progress was monitored by thin layer chromatography. After the reaction was completed, ethyl acetate (25 mL) was added to the reaction system, and the organic phase was washed with saturated brine (25 mL×3). The organic phase after extraction was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by column chromatography to obtain intermediate 6a. The yield was 51.7%.

[0079] 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),8.51(d,J=7.5Hz,1H),7.84(d,J=6.7Hz,1 H),7.74–7.57(m,2H),7.52(d,J=7.4Hz,2H),6.80(d,J=7.2Hz,2H),2.92(s,6H). 13C NMR (100MHz, DMSO-d6) δ159.36,156.64,150.67,148.06,133.72,127.13,126.73,126.28,124.52,123.27,113.76,112.24.

[0080] (3) The intermediate 6a (1 mmol), phenylboronic acid (1.5 mmol), potassium carbonate (1.75 mmol), and bis(triphenylphosphine)palladium dichloride (0.025 mmol) were added sequentially to a mixed solution of 1,4-dioxane and water (V 1,4-二氧六环 :V 水 =4:1, 10 mL), reacted at 85°C for 6 hours under nitrogen protection. The reaction was detected by thin layer chromatography. After the reaction was completed, the excess solvent was distilled off under reduced pressure, and compound 6 was obtained by column chromatography separation and purification. The yield was 32.2%

[0081] 1 H NMR (400MHz, CDCl3) δ8.53(dd,J=7.8,1.6Hz,2H),7.97(d,J=8.3Hz,1H),7.84(d,J=8.2Hz,1H),7.76(t,J= 7.6Hz,1H),7.70(d,J=9.0Hz,2H),7.47(q,J=6.1Hz,4H),7.36(s,1H),6.85(d,J=9.0Hz,2H),3.00(s,6H). 13 C NMR (100MHz, CDCl3) δ160.57,157.53,150.93,147.99,138.82,132.61,130.09,129. 12,128.51,128.29,125.74,123.23,120.29,113.85,113.03,40.99.HRMS(ESI)calcd for C 22 H 20 N4[M+H] + ,341.1761;found,341.1764.

[0082] Example 7

[0083] Preparation of compound 7: R1=H, R2=H, X=NH,

[0084] The difference between Example 7 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-biphenylboric acid, and the rest is the same as Example 6. Compound 7 is prepared with a yield of 74.4%.

[0085] 1 H NMR(400MHz, DMSO-d6)δ9.70(s,1H),8.53(t,J=8.1Hz,3H),7.85–7.83(m,3H),7.81(s,1H),7.78–7.76(m ,4H),7.59–7.55(m,1H),7.50(t,J=7.4Hz,2H),7.40(t,J=7.0Hz,1H),6.86(d,J=8.8Hz,2H),2.95(s,6H). 13 C NMR(100MHz,DMSO-d6)δ158.90,157.81,150.33,147.42,141.60,139.57,137.59,132.87,128.97,128.59,1 28.46,127.95,127.74,126.67,126.56,125.59,123.73,122.89,114.03,112.30,40.44.HRMS(ESI)calcdfor C 28 H 24 N4[M+H] + ,417.2014;found,417.2078.

[0086] Example 8

[0087] Preparation of compound 8: R1=H, R2=H, X=NH,

[0088] The difference between Example 8 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-fluorophenylboric acid, and the rest is the same as Example 6. Compound 8 is prepared with a yield of 82.0%.

[0089] 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.52(s,1H),8.46(dd,J=8.7,5.8Hz,2H),7.82(d,J=2.2Hz,2H) ,7.72(d,J=9.0Hz,2H),7.58–7.54(m,1H),7.32(t,J=8.9Hz,2H),6.84(d,J=9.0Hz,2H),2.94(s,6H). 13C NMR(100MHz,DMSO-d6)δ164.79,162.34,158.27,157.85,150.23,147.45,135.02,134.99,132.90,130.10, 130.02,128.45,127.87,125.59,123.78,122.90,115.26,115.05,113.91,112.28,40.42.HRMS(ESI)calcd for C 22 H 19 FN4[M+H] + ,359.1667;found,359.1667.

[0090] Example 9

[0091] Preparation of compound 9: R1=H, R2=H, X=NH,

[0092] The difference between Example 9 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-trifluoromethylphenylboric acid, and the rest is the same as Example 6. Compound 9 is prepared with a yield of 49.5%.

[0093] 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.60(d,J=8.1Hz,2H),8.56(d,J=8.3Hz,1H),7.88(s,1H),7. 86(d,J=3.4Hz,3H),7.73(d,J=9.0Hz,2H),7.63–7.59(m,1H),6.85(d,J=9.0Hz,2H),2.95(s,6H). 13 C NMR(100MHz,DMSO-d6)δ157.95,150.08,147.50,142.40,133.07,130.15,129.83,128.42,128.08, 126.18,125.66,125.31,125.27,124.50,123.81,122.95,114.19,112.28,40.40.HRMS(ESI)calcd for C 23 H 19 F3N4[M+H] + ,409.1635;found,409.1639.

[0094] Example 10

[0095] Preparation of compound 10: R1=H, R2=H, X=NH,

[0096] The difference between Example 10 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-methoxyphenylboric acid, and the rest is the same as Example 6. Compound 10 is prepared with a yield of 65.4%.

[0097] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=8.8Hz,2H),7.91(s,1H),7.79(s,1H),7.72(t,J=7.8Hz,1H),7.68(d,J=8.9Hz, 2H),7.42(t,J=7.4Hz,1H),7.32(s,1H),6.99(d,J=8.8Hz,2H),6.83(d,J=9.0Hz,2H),3.87(s,3H),2.99(s,6H). 13 C NMR (100MHz, CDCl3) δ161.45,160.31,157.43,151.01,147.95,132.54,131.54,130. 12,128.86,128.37,125.30,123.25,120.32,113.63,113.02,40.99.HRMS(ESI)calcd for C 23 H 22 N4O[M+H] + ,371.1867;found,371.1872.

[0098] Embodiment 11

[0099] Preparation of compound 11: R1=H, R2=H, X=NH,

[0100] The difference between Example 11 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-methylmercaptophenylboric acid, and the rest is the same as Example 6. Compound 11 is prepared with a yield of 76.2%.

[0101] 1H NMR (400MHz, CDCl3) δ8.45(d,J=8.5Hz,2H),7.92(s,1H),7.80(s,1H),7.73(d,J=7.2Hz,1H),7.67(d,J=9 .0Hz,2H),7.44(d,J=7.2Hz,1H),7.33(d,J=8.5Hz,3H),6.83(d,J=9.0Hz,2H),3.00(s,6H),2.53(s,3H). 13 C NMR (100MHz, CDCl3) δ160.12,157.47,150.97,147.98,141.08,135.60,132.60,129.03,128.87, 128.23,125.74,125.58,124.99,123.27,120.30,113.81,112.97,40.97,15.42.HRMS(ESI)calcd for C 23 H 22 N4S[M+H] + ,387.1638;found,387.1639.

[0102] Example 12

[0103] Preparation of compound 12: R1=H, R2=H, X=NH,

[0104] The difference between Example 12 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-cyanophenylboric acid, and the rest is the same as Example 6. Compound 12 is prepared with a yield of 91.8%.

[0105] 1 H NMR (400MHz, DMSO-d6) δ9.84(s,1H),8.59–8.54(m,3H),7.96(d,J=8.4Hz,2H),7.86(d,J=3.8H z,2H),7.71(d,J=9.0Hz,2H),7.62(dt,J=8.2,5.0Hz,1H),6.85(d,J=8.4Hz,2H),2.95(s,6H). 13C NMR(100MHz,DMSO-d6)δ157.92,157.49,149.91,147.46,142.70,134.12,133.06,132.32,128 .29,128.02,126.28,123.86,122.95,118.79,116.32,114.11,112.19,40.35.HRMS(ESI)calcd for C 23 H 19 N5[M+H] + ,366.1713;found,366.1716.

[0106] Embodiment 13

[0107] Preparation of compound 13: R1=H, R2=H, X=NH,

[0108] The difference between Example 13 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-hydroxyphenylboric acid, and the rest is the same as Example 6. Compound 13 is prepared with a yield of 74.1%.

[0109] 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),9.62(s,1H),8.50(d,J=8.3Hz,1H),8.28(d,J=8. 7Hz,2H),7.80–7.74(m,4H),7.50(t,J=6.2Hz,1H),6.86(t,J=8.6Hz,4H),2.94(s,6H). 13 CNMR(100MHz,DMSO-d6)δ159.54,159.15,157.49,147.25,132.67,129.57,128 .65,124.85,123.47,122.81,114.98,113.58,112.24,40.40.HRMS(ESI)calcd forC 22 H 20 N4O[M+H] + ,366.1713;found,366.1716.

[0110] Embodiment 14

[0111] Preparation of compound 14: R1=H, R2=H, X=NH,

[0112] The difference between Example 14 and Example 6 is that the phenylboronic acid in step (3) is replaced by 4-aminophenylboronic acid, and the rest is the same as Example 6. Compound 14 is prepared with a yield of 58.8%.

[0113] 1 H NMR (400MHz, CDCl3) δ8.36(d,J=8.5Hz,2H),7.90(d,J=8.3Hz,1H),7.90(d,J=8.3Hz,1H),7.72 –7.64(m,3H),7.54–7.44(m,1H),7.40(t,J=7.2Hz,1H),7.35(s,1H),3.87(s,2H),2.99(s,6H). 13 C NMR (100MHz, CDCl3) δ160.64,157.30,151.16,148.48,147.88,132.45,130.11,129.27,1 28.78,128.57,124.95,123.16,120.28,114.60,113.58,113.07,41.03.HRMS(ESI)calcd for C 22 H 21 N5[M+H] + ,356.187;found,356.1872.

[0114] Embodiment 15

[0115] Preparation of compound 15: R1=H, R2=H, X=NH,

[0116] The difference between Example 15 and Example 6 is that the phenylboronic acid in step (3) is replaced by 4-carbamoylphenylboronic acid, and the rest is the same as Example 6. Compound 15 is prepared with a yield of 55.8%.

[0117] 1 H NMR (400MHz, DMSO-d6) δ9.80(s,1H),8.57(d,J=8.3,1H),8.48(d,J=8.3Hz,2H),8.08(s,1H),8.01(d,J=8.3Hz,2H ),7.86(d,J=3.5Hz,2H),7.75(d,J=8.9Hz,2H),7.61–7.58(m,1H),7.45(s,1H),6.86(d,J=8.9,2H),2.95(s,6H). 13C NMR(100MHz,DMSO-d6)δ167.60,158.45,157.84,147.45,140.90,135.54,133.02,128.45,127 .85,127.58,127.55,125.95,124.49,123.80,122.98,114.06,112.27,40.45.HRMS(ESI)calcd forC 23 H 21 N5O[M+H] + ,384.1819;found,384.1820.

[0118] Example 16

[0119] Preparation of compound 16: R1=H, R2=H, X=NH,

[0120] The difference between Example 16 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-(N-methylformamido)phenylboric acid, and the rest is the same as Example 6. Compound 16 is prepared with a yield of 60.1%.

[0121] 1 H NMR(400MHz, DMSO-d6)δ9.74(s,1H),8.55–8.51(m,2H),8.47(d,J=8.4Hz,2H),7.96(d,J=8.4Hz,2H),7 .85(d,J=3.8Hz,2H),7.74(d,J=9.0Hz,2H),7.61–7.57(m,1H),6.84(s,2H),2.95(s,6H),2.82(s,3H). 13 C NMR(100MHz,DMSO-d6)δ168.29,159.15,157.63,150.23,147.29,139.36,139.09,132.86,128.72,128.56 ,127.83,125.59,123.40,122.89,122.76,120.87,118.73,114.04,112.44,40.45,24.02.HRMS(ESI)calcd for C 24 H 23 N5O[M+H] + ,398.1976;found,398.1976.

[0122] Embodiment 17

[0123] Preparation of compound 17: R1=H, R2=H, X=NH,

[0124] The difference between Example 17 and Example 6 is that the phenylboronic acid in step (3) is replaced by 4-(methylsulfonyl)phenylboronic acid, and the rest is the same as Example 6. Compound 17 is prepared with a yield of 65.1%.

[0125] 1 H NMR(400MHz, DMSO-d6)δ9.89(s,1H),8.64–8.59(m,3H),8.07(d,J=8.4Hz,2H),7.88–7.87(m,1 H),7.75(d,J=8.8Hz,1H),7.65–7.61(m,1H),6.88(d,J=6.5Hz,2H),3.27(s,3H),2.95(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.87,157.63,143.00,141.77,133.13,128.46,127.04 ,126.30,123.76,122.98,115.62,114.11,112.34,43.41,40.41.HRMS(ESI)calcd for C 23 H 22 N4O2S[M+H] + ,419.1536;found,419.1535.

[0126] Embodiment 18

[0127] Preparation of compound 18: R1=H, R2=H, X=NH,

[0128] The difference between Example 18 and Example 6 is that the phenylboronic acid in step (3) is replaced by 3-(methylsulfonyl)phenylboronic acid, and the rest is the same as Example 6. Compound 18 is prepared with a yield of 67.5%.

[0129] 1H NMR (400MHz, DMSO-d6) δ9.83(s,1H),8.98(s,1H),8.71(d,J=7.7Hz,1H),8.56(d,J=8.3Hz,2H),8.05(d,J=7.8Hz,1H),7.87(q,J= 8.5Hz,2H),7.80(t,J=7.8Hz,1H),7.74(d,J=8.8Hz,2H),7.62(t,J=7.3Hz,1H),6.85(d,J=8.9Hz,2H),3.29(s,3H),2.94(s,6H). 13 C NMR(100MHz,DMSO-d6)δ157.91,157.58,150.13,147.54,141.23,139.63,133.12,132.35,129.74 ,128.38,128.25,128.05,126.11,123.87,122.97,114.20,112.23,43.56,40.41.HRMS(ESI)calcd for C 23 H 22 N4O2S[M+H] + ,447.1849;found,447.1848.

[0130] Embodiment 19

[0131] Preparation of compound 19: R1=H, R2=H, X=NH,

[0132] The difference between Example 19 and Example 6 is that the phenylboric acid in step (3) is replaced by 3-acetamidophenylboric acid, and the rest is the same as Example 6. Compound 19 is prepared with a yield of 52.8%.

[0133] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.68(s,1H),8.64(s,1H),8.55(d,J=8.3Hz,1H),8.09(d,J=7.8Hz,1H), 7.86–7.77(m,5H),7.59–7.57(m,1H),7.41(t,J=7.9Hz,1H),6.87(d,J=9.1Hz,2H),2.94(s,6H),2.09(s,3H). 13C NMR(100MHz,DMSO-d6)δ166.30,158.47,157.83,150.17,147.47,140.81,135.72,132.98,128.45 ,127.99,127.63,127.11,125.90,123.77,122.91,114.07,112.25,40.43,26.25.HRMS(ESI)calcd forC 24 H 23 N5O[M+H] + ,398.1976;found,398.1979.

[0134] Embodiment 20

[0135] Preparation of compound 20: R1=H, R2=H, X=NH,

[0136] The difference between Example 20 and Example 6 is that the phenylboric acid in step (3) is replaced by 3-acetylphenylboric acid, and the rest is the same as Example 6. Compound 20 is prepared with a yield of 47.6%.

[0137] 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),9.04(s,1H),8.66(d,J=7.8Hz,1H),8.55(d,J=8.3Hz,1H),8.06(d,J=7.7Hz,1H),7.88–7 .83(m,2H),7.75(d,J=9.0Hz,2H),7.66(t,J=7.7Hz,1H),7.61–7.57(m,1H),6.85(d,J=9.0Hz,2H),2.94(s,6H),2.66(s,3H). 13 CNMR(100MHz,DMSO-d6)δ197.66,158.26,157.89,150.26,147.53,138.89,136.93,133.00,132.08,129.57 ,128.83,128.39,128.02,127.82,125.87,123.96,122.92,114.11,112.22,40.44,26.71.HRMS(ESI)calcd for C 24 H 22 N4O[M+H] + ,383.1867;found,383.1867.

[0138] Embodiment 21

[0139] Preparation of compound 21: R1=H, R2=H, X=NH,

[0140] The difference between Example 21 and Example 6 is that the phenylboric acid in step (3) is replaced by 4-cyano-3-fluorophenylboric acid, and the rest is the same as Example 6. Compound 21 is prepared with a yield of 64.2%.

[0141] 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),8.55(d,J=8.3Hz,1H),8.36(d,J=8.1Hz,1H),8.27(d,J=11.0 Hz,1H),8.11–7.98(m,1H),7.86(s,2H),7.65(d,J=8.8Hz,3H),6.84(d,J=9.0Hz,2H),2.95(s,6H). 13 C NMR (100MHz, DMSO-d6) δ161.30,158.05,156.48,149.84,147.69,146.13,146.05,134.09,133.25,128.20,127. 93,126.69,124.25,124.10,123.00,114.83,114.62,114.28,114.10,112.19,101.07,100.92.HRMS(ESI)calcd forC 23 H 18 FN5[M+H] + ,384.1637;found,384.1625.

[0142] Embodiment 22

[0143] Preparation of compound 22: R1=H, R2=H, X=NH,

[0144] The difference between Example 22 and Example 6 is that the phenylboric acid in step (3) is replaced by 3,4,5-trimethoxyphenylboric acid, and the rest is the same as Example 6. Compound 22 is prepared with a yield of 51.1%.

[0145] 1H NMR (400MHz, CDCl3) δ7.96(d,J=8.3Hz,1H),7.88(s,2H),7.84(d,J=8.1Hz,1H),7.76(t,J=7.7Hz,1H),7.68(d, J=9.0Hz,2H),7.47(t,J=8.0Hz,1H),7.37(s,1H),6.79(d,J=9.0Hz,2H),3.98(s,6H),3.91(s,3H),2.97(s,6H). 13 C NMR (100MHz, CDCl3) δ159.78,157.50,152.99,151.02,148.13,139.91,134.22,132.66,129.02, 128.19,125.66,123.77,120.39,113.69,112.67,105.51,60.94,55.99,40.96.HRMS(ESI)calcd forC 25 H 26 N4O3[M+H] + ,431.2078;found,431.2083.

[0146] Embodiment 23

[0147] Preparation of compound 23: R1=H, R2=H, X=NH,

[0148] The difference between Example 23 and Example 6 is that phenylboronic acid in step (3) is replaced by pyridine-3-boric acid, and the rest is the same as Example 6. Compound 23 is prepared with a yield of 91.8%.

[0149] 1 H NMR (400MHz, CDCl3) δ9.71(d,J=1.6Hz,1H),8.79(d,J=8.0Hz,1H),8.67(dd,J=4.7,1.3Hz,1H),7.96(d,J=8.4Hz,1H),7.90(d,J=8.2Hz ,1H),7.77(d,J=7.6Hz,1H),7.66(d,J=9.0Hz,1H),7.52–7.44(m,2H),7.40(dd,J=7.9,4.8Hz,1H),6.82(d,J=8.9Hz,2H),2.99(s,6H). 13C NMR (100MHz, CDCl3) δ158.58,157.75,150.57,150.25,148.13,135.86,134.33,132.86,132.14,132.04,1 28.96,128.61,128.49,127.75,126.22,123.55,123.24,120.59,114.06,112.89,40.87.HRMS(ESI)calcd for C 21 H 19 N5[M+H] + ,342.1713;found,342.1717.

[0150] Embodiment 24

[0151] Preparation of compound 24: R1=H, R2=H, X=NH,

[0152] The difference between Example 24 and Example 6 is that the phenylboric acid in step (3) is replaced by 6-methoxy-3-pyridineboric acid, and the rest is the same as Example 6. Compound 24 is prepared with a yield of 91.0%.

[0153] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.54 (d, J = 8.2Hz, 1H), 8.27–8.25 (m, 1H), 8.08–8.06 (m, 1H), 7.85–7. 77(m,4H),7.62–7.58(m,1H),7.10(dd,J=7.3,4.9Hz,1H),6.76(d,J=9.1Hz,2H),3.97(s,3H),2.89(s,6H). 13 C NMR(100MHz,DMSO-d6)δ161.02,159.69,157.19,150.09,147.29,147.06,139.63,132.76,128.78 ,127.75,125.87,123.66,123.24,122.76,116.74,113.58,112.24,53.24,40.46.HRMS(ESI)calcd for C 22 H 21 N5O[M+H] + ,372.1819;found,372.1826.

[0154] Embodiment 25

[0155] Preparation of compound 25: R1=H, R2=H, X=NH,

[0156] The difference between Example 25 and Example 6 is that the phenylboronic acid in step (3) is replaced by 5-pyrimidineboronic acid, and the rest is the same as Example 6. Compound 25 is prepared with a yield of 66.7%.

[0157] 1 H NMR (400MHz, CDCl3) δ9.75 (s, 2H), 9.28 (s, 1H), 7.96 (d, J = 8.2Hz, 1H), 7.90 (d, J = 8.2Hz, 1H), 7.81 (t,J=7.7Hz,1H),7.61(d,J=9.0Hz,2H),7.54(t,J=8.0Hz,2H),6.82(d,J=9.0Hz,2H),3.00(s,6H). 13 C NMR (100MHz, CDCl3) δ159.22,157.91,156.95,156.56,150.55,148.35,133.08,132.16,132.06,131. 95,129.23,128.58,128.46,127.25,126.68,123.78,120.49,114.22,112.81,40.80.HRMS(ESI)calcd for C 20 H 18 N6[M+H] + ,343.1666;found,343.1670.

[0158] Embodiment 26

[0159] Preparation of compound 26: R1=H, R2=H, X=NH,

[0160] The difference between Example 26 and Example 6 is that the phenylboric acid in step (3) is replaced by 2-aminopyrimidine-5-boric acid, and the rest is the same as Example 6. Compound 26 is prepared with a yield of 75.3%.

[0161] 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 9.11 (s, 2H), 8.51 (d, J = 8.2Hz, 1H), 7.81–7. 68(m,4H),7.51(t,J=6.9Hz,1H),7.10(s,2H),6.84(d,J=9.0Hz,2H),2.93(s,6H).13 CNMR(100MHz,DMSO-d6)δ164.05,158.05,157.61,157.02,147.49,132.92,128 .32,127.38,125.10,123.87,122.96,113.89,112.18,40.43.HRMS(ESI)calcd for C 20 H 19 N7[M+H] + ,358.1775;found,358.1777.

[0162] Embodiment 27

[0163] Preparation of compound 27: R1=H, R2=H, X=NH,

[0164] The difference between Example 27 and Example 6 is that phenylboronic acid in step (3) is replaced by 2-furanboronic acid, and the rest is the same as Example 6. Compound 27 is prepared with a yield of 63.6%.

[0165] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.3Hz,1H),7.81(d,J=8.2Hz,1H),7.73(t,J=8.1Hz,1H),7.67(d,J=9.0Hz,2H), 7.62(s,1H),7.44(t,J=7.2Hz,2H),7.28(d,J=3.2Hz,1H),6.81(d,J=9.0Hz,2H),6.54–6.53(m,1H),2.98(s,6H). 13 C NMR (100MHz, CDCl3) δ157.37,153.65,153.18,150.51,148.01,144.68,132.81,128.96,1 28.17,125.73,123.11,120.41,113.96,113.47,112.93,111.82,40.94.HRMS(ESI)calcd for C 20 H 18 N4O[M+H] + ,331.1554;found,331.1561.

[0166] Embodiment 28

[0167] Preparation of compound 28: R1=H, R2=H, X=NH,

[0168] The difference between Example 28 and Example 6 is that phenylboronic acid in step (3) is replaced by 2-thiopheneboronic acid, and the rest is the same as Example 6. Compound 28 is prepared with a yield of 72.2%.

[0169] 1 H NMR (400MHz, CDCl3) δ8.02(s,1H),7.87(s,1H),7.79(d,J=8.2Hz,1H),7.72(d,J=8.9Hz,3H),7.4 2(d,J=5.9Hz,2H),7.33(s,1H),7.13(dd,J=4.9,3.8Hz,1H),6.83(d,J=9.0Hz,2H),2.99(s,6H). 13 C NMR (100MHz, CDCl3) δ157.27,157.09,150.82,147.94,145.07,132.70,129.01,128.77,1 28.48,128.24,127.94,125.47,122.93,120.30,113.77,112.95,40.96.HRMS(ESI)calcd for C 20 H 18 N4S[M+H] + ,347.1325;found,347.1329.

[0170] Embodiment 29

[0171] Preparation of compound 29: R1=H, R2=H, X=NH,

[0172] The difference between Example 29 and Example 6 is that the phenylboric acid in step (3) is replaced by 1-methyl-4-pyrazoleboric acid, and the rest is the same as Example 6. Compound 29 is prepared with a yield of 98.0%.

[0173] 1 H NMR(400MHz, CDCl3)δ8.22(s,1H),8.08(s,1H),7.84–7.78(m,2H),7.70(t,J=7.6Hz,1H), 7.65(d,J=9.0Hz,2H),7.42–7.37(m,2H),6.81(d,J=9.0Hz,2H),3.95(s,3H),2.99(s,6H). 13C NMR (100MHz, CDCl3) δ157.45,157.14,150.90,147.98,140.20,132.61,131.34,128.29, 128.25,125.06,124.30,123.25,120.39,113.61,112.91,40.95,39.15.HRMS(ESI)calcd for C 20 H 20 N6[M+H] + ,345.1822;found,345.1830.

[0174] Embodiment 30

[0175] Preparation of compound 30: R1=H, R2=H, X=NH,

[0176] The difference between Example 30 and Example 6 is that the phenylboronic acid in step (3) is replaced by cyclopentene-1-ylboronic acid, and the rest is the same as Example 6. Compound 30 is prepared with a yield of 93.2%.

[0177] 1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.3Hz,1H),7.78(d,J=8.1Hz,1H),7.72–7.70(m,1H),7.67(d,J=9.0Hz,2H),7.42(t,J= 8.2Hz,1H),6.99–6.97(m,1H),6.82–6.78(m,2H),2.97(s,6H),2.95–2.91(m,2H),2.62–2.57(m,2H),2.10–2.02(m,2H). 13 C NMR (100MHz, CDCl3) δ159.75,156.75,150.78,147.79,145.03,136.75,132.35,128.97,128 .66,125.40,122.76,120.20,113.72,113.05,41.02,33.59,32.41,23.72.HRMS(ESI)calcd for C 21 H 22 N4[M+H] + ,331.1917;found,331.1923.

[0178] Embodiment 31

[0179] Preparation of compound 31: R1=H, R2=H, X=NH,

[0180] The difference between Example 31 and Example 6 is that the phenylboric acid in step (3) is replaced by cyclohexene-1-ylboric acid, and the rest is the same as Example 6. Compound 31 is prepared with a yield of 67.4%.

[0181] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.2Hz,1H),7.77(d,J=8.2Hz,1H),7.71–7.67(m,1H),7.66–7.62(m,2H),7.43–7.39(m,1H),7.28–7. 26(m,1H),7.23(s,1H),6.82–6.78(m,2H),2.97(s,6H),2.69–2.67(m,2H),2.32–2.29(m,2H),1.82–1.76(m,2H),1.71–1.66(m,2H). 13 CNMR (100MHz, CDCl3) δ162.23,156.72,150.74,147.78,137.32,133.18,132.30,128.96,128.6 2,125.20,122.84,120.20,113.75,113.09,41.03,26.29,25.56,22.92,22.26.HRMS(ESI)calcd for C 22 H 24 N4[M+H] + ,345.2074;found,345.2081.

[0182] Embodiment 32

[0183] Preparation of compound 32: R1=H, R2=H, X=NH,

[0184] The difference between Example 32 and Example 6 is that the phenylboric acid in step (3) is replaced by 5-indoleboric acid, and the rest is the same as Example 6. Compound 32 is prepared with a yield of 82.8%.

[0185] 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),9.59(s,1H),8.70(s,1H),8.50(d,J=8.3Hz,1H),8.27(d,J=10.0Hz,1H ),7.85–7.72(m,4H),7.54–7.44(m,2H),7.42–7.36(m,1H),6.88(d,J=9.0Hz,2H),6.57(s,1H),2.95(s,6H). 13 C NMR (100MHz, DMSO-d6) δ160.54,157.52,147.33,137.34,132.70,129.45,128.88,127.56,126. 10,124.81,123.54,122.83,121.55,120.69,113.72,112.36,110.95,102.26.HRMS(ESI)calcd for C 24 H 21 N5[M+H] + ,380.1870;found,380.1875.

[0186] Embodiment 33

[0187] Preparation of compound 33: R1=H, R2=H, X=NH,

[0188] The difference between Example 33 and Example 6 is that the phenylboric acid in step (3) is replaced by 1-methyl-5-indoleboric acid, and the rest is the same as Example 6. Compound 33 is prepared with a yield of 69.4%.

[0189] 1 H NMR (400MHz, CDCl3) δ8.86(d,J=1.1Hz,1H),8.48(dd,J=8.7,1.5Hz,1H),7.95(d,J=8.0Hz,1H),7.80(d,J=8.1Hz,3H),7.75–7.72(m ,2H),7.43–7.37(m,1H),7.33(s,1H),7.06(d,J=3.1Hz,1H),6.86(d,J=9.0Hz,2H),6.60(d,J=3.0Hz,1H),3.81(s,3H),3.00(s,6H). 13CNMR (100MHz, CDCl3) δ161.70,157.28,151.14,147.86,138.26,132.43,130.26,129.32,128.81,128.68,128 .54,125.03,123.14,122.57,122.12,120.35,113.66,113.10,108.83,102.38,41.05,32.95.HRMS(ESI)calcd for C 25 H 23 N5[M+H] + ,394.2026;found,394.2031.

[0190] Embodiment 34

[0191] Preparation of compound 34: R1=H, R2=H, X=NH,

[0192] The difference between Example 34 and Example 6 is that the phenylboric acid in step (3) is replaced by benzo-1,4-dioxane-6-boric acid, and the rest is the same as Example 6. Compound 34 is prepared with a yield of 38.7%.

[0193] 1 H NMR (400MHz, CDCl3) δ8.08–8.04(m,1H),7.91(d,J=8.3Hz,1H),7.79(d,J=8.2Hz,1H),7.73(t,J=7.7Hz,1H),7.67(d,J= 9.0Hz,2H),7.43(t,J=7.6Hz,1H),7.30(s,1H),6.95(d,J=8.4Hz,1H),6.83(d,J=9.0Hz,2H),4.30(s,4H),2.99(s,6H). 13 C NMR (100MHz, CDCl3) δ160.07,157.38,151.00,147.94,145.59,143.30,132.64,132.51,128.99,128.36, 125.37,123.12,122.17,120.26,117.71,117.00,113.69,113.06,64.64,64.24,41.00.HRMS(ESI)calcd for C 24 H 22 N4O2[M+H] + ,399.1816;found,399.1822.

[0194] Embodiment 35

[0195] Preparation of compound 35: R1=H, R2=H, X=NH,

[0196] The difference between Example 35 and Example 6 is that phenylboric acid in step (3) is replaced by quinoline-3-boric acid, and the rest is the same as Example 6. Compound 35 is prepared with a yield of 31.2%.

[0197] 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),9.30(s,1H),8.15(s,1H),8.00(dd,J=15.1,8.3Hz,2H),7.90(d,J=8.2Hz,1H), 7.83–7.73(m,2H),7.71(d,J=8.9Hz,2H),7.60–7.56(m,1H),7.55–7.51(m,2H),6.85(d,J=8.9Hz,2H),3.01(s,6H). 13 C NMR (100MHz, CDCl3) δ158.65,157.70,151.04,148.74,148.22,136.09,132.98,130.23,129. 13,129.02,127.77,126.72,126.27,123.55,120.52,114.01,112.92,40.89.HRMS(ESI)calcd forC 25 H 21 N5[M+H] + ,392.1870;found,392.1873.

[0198] Embodiment 36

[0199] Preparation of compound 36: R1=H, R2=H, X=NH,

[0200] The difference between Example 36 and Example 6 is that the phenylboric acid in step (3) is replaced by benzothiophene-2-boric acid, and the rest is the same as Example 6. Compound 36 is prepared with a yield of 80.7%.

[0201] 1H NMR (400MHz, CDCl3) δ8.27 (s, 1H), 7.93 (d, J = 8.2Hz, 1H), 7.89–7.84 (m, 2H), 7.81–7.7 3(m,4H),7.46(t,J=7.5Hz,1H),7.37–7.34(m,3H),6.87(d,J=9.4Hz,2H),3.01(s,6H). 13 C NMR (100MHz, CDCl3) δ157.40,157.09,150.70,148.02,145.10,141.76,140.36,132.81,128.96,128.11,1 25.91,125.18,125.12,124.61,124.26,123.01,122.58,120.32,113.93,112.98,40.96.HRMS(ESI)calcd for C 24 H 20 N4S[M+H] + ,397.1482;found,397.1487.

[0202] Embodiment 37

[0203] Preparation of compound 37: R1=H, R2=H, X=O,

[0204] (1) N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced with 4-dimethylaminophenol, 4-dimethylaminophenol (1 mmol) was dissolved in 5 mL of N,N-dimethylformamide (5 mL), potassium carbonate (2.5 mmol) was added to the reaction system, stirred for 5 minutes, and finally intermediate 5a was added to react at 80°C for 5 hours, and the reaction was detected by thin layer chromatography. After the reaction was completed, ethyl acetate (25 mL) was added to the reaction system, and the organic phase was washed with saturated brine (25 mL×3). The organic phase after extraction was dried over anhydrous magnesium sulfate, concentrated, and separated and purified by column chromatography to obtain intermediate 6r. The yield was 45.0%.

[0205] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=8.2Hz,1H),7.90(d,J=5.1Hz,2H),7.65–7.61(m,1H),7.15(d,J=9.0Hz,2H),6.79(d,J=9.0Hz,2H),2.99(s,6H). 13C NMR (100MHz, CDCl3) δ168.37,156.22,152.74,148.86,142.79,134.88,127.49,127.07,124.07,121.77,115.05,113.12,40.91.

[0206] (2) The intermediate 6a in step (3) of Example 6 was replaced by 6r, and phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid, and the rest was the same as Example 6. Compound 37 was prepared with a yield of 61.8%.

[0207] 1 H NMR(400MHz,DMSO-d6)δ8.43(dd,J=18.9,8.3Hz,3H),8.11–8.03(m,4H),(dd,J=15.2,7.5Hz,4H ),7.79(t,J=7.9Hz,1H),7.28(d,J=8.9Hz,2H),6.86(d,J=9.0Hz,2H),3.24(s,3H),2.97(s,6H). 13 C NMR(100MHz,DMSO-d6)δ167.10,157.40,151.55,148.38,142.59,142.36,141.70,134.93,128 .54,128.25,127.90,127.30,123.59,122.04,114.81,112.74,43.37,40.45.HRMS(ESI)calcd for C 23 H 21 N3O3S[M+H] + ,420.1377;found,420.1379.

[0208] Embodiment 38

[0209] Preparation of compound 38: R1=H, R2=H, X=NH,

[0210] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by N5,N5-dimethylpyridine-2,5-diamine, and the rest was the same as step (2) of Example 6. Intermediate 6b was prepared with a yield of 28.6%.

[0211] 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.67(d,J=8.3Hz,1H),7.98–7.92(m,2H),7.87(t,J=7.6 Hz,1H),7.70(d,J=8.3Hz,1H),7.60(t,J=7.6Hz,1H),7.32(dd,J=9.1,3.0Hz,1H),2.96(s,6H). 13 C NMR (100MHz, DMSO-d6) δ158.93,156.18,150.81,144.16,140.88,133.99,131.85,126.75,126.58,123.66,121.03,118.02,113.61.

[0212] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6b, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 38 was prepared with a yield of 50.8%.

[0213] 1 H NMR (400MHz, CDCl3) δ8.75(d,J=8.1Hz,2H),8.60(d,J=9.4Hz,1H),8.17(s,1H),8.09(d,J=8.3Hz,2H),7.99(t,J=7.8Hz,2H) ,7.91(d,J=3.0Hz,1H),7.84(t,J=8.0Hz,1H),7.59(t,J=7.6Hz,1H),7.29(dd,J=9.1,2.9Hz,1H),3.11(s,3H),3.03(s,6H). 13 C NMR (100MHz, CDCl3) δ158.45,156.61,150.63,144.19,143.81,142.70,142.28,141.40,133.19, 132.30,129.33,129.28,127.47,127.03,121.86,120.74,115.52,44.61,40.64.HRMS(ESI)calcd for C 22 H 21 N5O2S[M+H] + ,420.1489;found,420.1490.

[0214] Embodiment 39

[0215] Preparation of compound 39: R1=H, R2=H, X=NH,

[0216] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by 4-dimethylaminobenzylamine, and the rest was the same as step (2) of Example 6. Intermediate 6c was prepared with a yield of 49.9%.

[0217] 1 H NMR (400MHz, DMSO-d6) δ9.18(t,J=5.5Hz,1H),8.32(d,J=8.2Hz,1H),7.79(t,J=7.6Hz,1H),7.64(d,J=8.3Hz ,1H),7.53(t,J=7.6Hz,1H),7.24(d,J=8.5Hz,2H),6.69(d,J=8.5Hz,2H),4.65(d,J=5.7Hz,2H),2.85(s,6H). 13 C NMR (100MHz, DMSO-d6) δ160.87,157.00,150.36,149.71,133.52,128.57,126.59,126.00,125.80,123.08,113.54,112.31,43.57.

[0218] (2) The intermediate 6a in step (3) of Example 6 was replaced by 6c, and phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 39 was prepared with a yield of 67.2%.

[0219] 1 H NMR (400MHz, DMSO-d6) δ8.94(t,J=5.7Hz,1H),8.72(d,J=8.3Hz,2H),8.33(d,J=8.3Hz,1H),8.06(d,J=8.4Hz,2H),7.81(d,J= 3.1Hz,2H),7.61–7.49(m,1H),7.32(d,J=8.5Hz,2H),6.69(d,J=8.5Hz,2H),4.81(d,J=5.6Hz,2H),3.27(s,3H),2.83(s,6H). 13 CNMR(100MHz,DMSO-d6)δ159.57,157.75,149.69,149.62,143.35,141.72,132.94,128 .53,127.97,127.03,126.97,126.01,122.75,114.03,112.37,43.53.HRMS(ESI)calcd forC 24 H24 N4O2S[M+H] + ,433.1693;found,433.1696.

[0220] Embodiment 40

[0221] Preparation of compound 40: R1 = H, R2 = H, X=NH,

[0222] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by 4-amino-N,N-dimethylbenzamide, and the rest was the same as step (2) of Example 6. Intermediate 6d was prepared with a yield of 44.8%.

[0223] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.61(d,J=8.3Hz,1H),7.91(d,J=8.3Hz,3H),7.80–7.62(m,2H),7.50(d,J=8.4Hz,2H),3.00(s,6H). 13 C NMR (100MHz, DMSO-d6) δ169.71,159.21,155.99,150.88,139.23,134.21,132.19,127.69,126.95,126.73,123.50,121.89,113.79.

[0224] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6d, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 40 was prepared with a yield of 43.5%.

[0225] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.65(dd,J=12.5,8.4Hz,3H),8.08(dd,J=13.7,8.4Hz,4 H),8.01–7.90(m,2H),7.70(t,J=8.2Hz,1H),7.56(d,J=8.5Hz,2H),3.28(s,3H),3.03(s,6H). 13C NMR(100MHz,DMSO-d6)δ169.90,157.96,157.52,150.30,142.82,141.97,140.17,133.62,131.25 ,128.60,128.34,127.81,127.25,126.79,123.15,121.38,114.22,54.88,43.48.HRMS(ESI)calcd for C 24 H 22 N4O3S[M+H] + ,447.1486;found,447.1499.

[0226] Embodiment 41

[0227] Preparation of compound 41: R1 = H, R2 = H, X=NH,

[0228] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by 4-amino-N-methylacetanilide, and the rest was the same as step (2) of Example 6. Intermediate 6e was prepared with a yield of 43.9%.

[0229] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.59(d,J=8.2Hz,1H),7.91(t,J=7.7Hz,3H),7.74 (d,J=8.3Hz,1H),7.68(t,J=7.6Hz,1H),7.41(d,J=8.2Hz,2H),3.18(s,3H),1.83(s,3H). 13 C NMR (100MHz, DMSO-d6) δ169.11,159.20,156.07,150.85,140.51,137.24,134.16,127.28,126.93,126.68,123.43,123.37,113.76,36.49,22.24.

[0230] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6e, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 41 was prepared with a yield of 40.2%.

[0231] 1H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.97(d,J=7.9Hz,1H),8.56(d,J=7.8Hz,2H),8.30(d,J=7.7Hz,1H),8.09(d,J=7.9Hz, 2H),8.02(t,J=7.2Hz,1H),7.93(s,2H),7.76(t,J=7.1Hz,1H),7.42(d,J=7.6Hz,2H),3.27(s,3H),3.16(s,3H),1.81(s,3H). 13 C NMR (100MHz, DMSO-d6) δ169.10,158.79,156.17,143.82,141.68,135.60,129.95,128. 19,127.33,124.88,124.60,122.16,113.15,43.22,36.59,22.32.HRMS(ESI)calcdfor C 24 H 22 N4O3S[M+H] + ,447.1486;found,447.1478.

[0232] Embodiment 42

[0233] Preparation of compound 42: R1=H, R2=H, X=NH,

[0234] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by aniline, and the rest was the same as step (2) of Example 6. Intermediate 6f was prepared with a yield of 76.1%.

[0235] 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.58(d,J=8.3Hz,1H),7.90(t,J=7.7Hz,1H),7.79(d,J=8.3 Hz,2H),7.73(d,J=8.3Hz,1H),7.66(t,J=7.7Hz,1H),7.45(t,J=8.0Hz,2H),7.22(t,J=7.4Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ159.39,156.21,150.84,138.15,134.06,128.61,126.89,126.59,124.73,123.44,122.97,113.74.

[0236] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6f, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 42 was prepared with a yield of 45.6%.

[0237] 1 H NMR(400MHz, DMSO-d6)δ9.99(s,1H),8.64(t,J=8.3Hz,3H),8.08(d,J=8.3Hz,2H),8.01–7.95(m,2H ),7.94–7.88(m,2H),7.72–7.64(m,1H),7.49(t,J=7.8Hz,2H),7.21(t,J=7.4Hz,1H),3.28(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.07,157.57,150.24,142.96,141.93,139.03,133.47,128.55, 128.28,127.18,126.64,123.89,123.12,122.38,122.27,114.18,43.47.HRMS(ESI)calcd for C 21 H 17 N3O2S[M+H] + ,376.1114;found,376.1118.

[0238] Embodiment 43

[0239] Preparation of compound 43: R1=H, R2=H, X=NH,

[0240] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by p-phenylenediamine, and the rest was the same as step (2) of Example 6. 6 g of the intermediate was prepared with a yield of 70.9%.

[0241] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),8.52(d,J=8.2Hz,1H),7.84(t,J=7.3Hz,1H),7.66(d,J =8.2Hz,1H),7.59(t,J=7.6Hz,1H),7.35(d,J=8.4Hz,2H),6.67(d,J=8.3Hz,2H),5.76(s,2H). 13C NMR (100MHz, DMSO-d6) δ159.87,152.27,139.82,134.08,133.85,126.40,125.88,124.81,124.73,124.46,117.48,110.59.

[0242] (2) The intermediate 6a in step (3) of Example 6 was replaced by 6g, and phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 43 was prepared with a yield of 70.3%.

[0243] 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.60(d,J=8.4Hz,2H),8.53(d,J=8.2Hz,1H),8.05(d,J=8.4Hz,2H),7. 87(d,J=3.8Hz,2H),7.61(dt,J=8.2,3.9Hz,1H),7.53(d,J=8.6Hz,2H),6.72(d,J=8.6Hz,2H),3.26(s,3H). 13 C NMR(100MHz,DMSO-d6)δ158.60,158.23,150.50,145.22,143.69,142.29,133.62, 128.96,128.54,127.54,126.80,124.83,123.43,114.65,43.97.HRMS(ESI)calcd for C 21 H 18 N4O2S[M+H] + ,391.1223;found,391.1226.

[0244] Embodiment 44

[0245] Preparation of compound 44: R1 = H, R2 = H, X=NH,

[0246] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by N,N-diethyl-p-phenylenediamine, and the rest was the same as step (2) of Example 6. Intermediate 6h was prepared with a yield of 60.4%.

[0247] 1H NMR(400MHz, CDCl3)δ7.81–7.77(m,2H),7.76–7.71(m,1H),7.52(s,1H),7.50–7 .44(m,3H),6.68(d,J=9.0Hz,2H),3.35(q,J=7.1Hz,4H),1.16(t,J=7.1Hz,6H). 13 C NMR (101MHz, CDCl3) δ158.80,157.69,151.31,145.89,133.43,128.02,126.31,125.56,123.94,120.80,113.55,112.06,44.53,12.60.

[0248] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6h, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 44 was prepared with a yield of 43.4%.

[0249] 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.64(d,J=8.4Hz,2H),8.56(d,J=8.3Hz,1H),8.07(d,J=8.4Hz,2H),7.87(d,J=2.8Hz,2H ),7.70(d,J=8.9Hz,2H),7.64–7.60(m,1H),6.78(d,J=9.0Hz,2H),3.38(q,J=7.0Hz,4H),3.27(s,3H),1.14(t,J=7.0Hz,6H). 13 CNMR(100MHz, CDCl3)δ158.70,150.74,144.24,141.19,132.90,129.34,127.30,126.54,123.80,120.43,114.10,112.12,44.61,12.65.HRMS(ESI)calcd for C 25 H 26 N4O2S[M+H] + ,447.1849;found,447.1855.

[0250] Embodiment 45

[0251] Preparation of compound 45: R1=H, R2=H, X=NH,

[0252] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by N,N-diethyl-1,4-cyclohexanediamine, and the rest was the same as step (2) of Example 6. Intermediate 6i was prepared with a yield of 58.3%.

[0253] 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=8.3Hz,1H),8.24(d,J=6.4Hz,1H),7.79(t,J=7.6Hz,1H),7.60(d,J=8.3Hz,1H) ,7.51(t,J=7.6Hz,1H),4.24(s,1H),3.31(s,1H),2.60(s,4H),1.88(s,4H),1.56(d,J=48.2Hz,4H),0.96(s,6H). 13 C NMR (100MHz, DMSO-d6) δ160.42,156.94,150.33,133.48,126.48,125.75,123.66,113.55,54.46,48.63,42.12,26.97,26.12,11.81.

[0254] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6i, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 45 was prepared with a yield of 47.3%.

[0255] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=8.4Hz,2H),8.51(d,J=8.3Hz,1H),8.06(d,J= 8.4Hz,2H),7.91(d,J=6.5Hz,1H),7.81(d,J=3.8Hz,2H),7.53(dt,J=8.2,4.1Hz, 1H),4.48(d,J=6.6Hz,1H),3.27(s,3H),2.60(q,J=6.9Hz,5H),2.12–1.96(m,2H) ,1.93–1.83(m,2H),1.81–1.66(m,2H),1.65–1.52(m,2H),0.97(t,J=7.0Hz,6H). 13C NMR(100MHz,DMSO-d6)δ159.22,157.69,149.72,143.44,141.69,132.83,128.45,127.87,127.0 3,125.72,123.33,114.06,55.36,48.26,43.54,42.28,27.39,25.88,12.32.HRMS(ESI)calcdfor C 25 H 32 N4O2S[M+H] + ,453.2319;found,453.2320.

[0256] Embodiment 46

[0257] Preparation of compound 46: R1=H, R2=H, X=NH,

[0258] (1) The N,N-dimethyl-p-phenylenediamine in step (2) of Example 6 was replaced by 3-diethylaminopropylamine, and the rest was the same as step (2) of Example 6. Intermediate 6j was prepared with a yield of 58.3%.

[0259] H NMR (400MHz, DMSO-d6) δ8.86 (s, 1H), 8.22 (d, J = 8.2Hz, 1H), 7.79 (t, J = 7.6Hz, 1H),

[0260] 7.61(d,J=8.3Hz,1H),7.53(t,J=7.6Hz,1H),3.53(t,J=6.7Hz,2H),2.54( d,J=3.9Hz,4H),1.91(s,2H),1.79(p,J=7.0Hz,2H),0.97(t,J=7.1Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ160.98,157.05,150.18,133.48,126.62,125.98,122.94,113.54,50.01,46.18,25.35,21.15,11.35.

[0261] (2) In step (3) of Example 6, the intermediate 6a was replaced by 6j, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 46 was prepared with a yield of 50.3%.

[0262] 1H NMR (400MHz, DMSO-d6) δ8.73(d,J=8.4Hz,2H),8.67(s,1H),8.31(d,J=7.8Hz,1H),8.06(d,J=8.4Hz,2H),7.83(d,J= 3.6Hz,2H),7.56(dt,J=8.1,3.7Hz,1H),3.77(d,J=5.1Hz,2H),3.28(s,4H),2.93(s,5H),2.05(s,2H),1.12(s,6H). 13 C NMR(100MHz,DMSO-d6)δ160.36,158.28,150.11,143.84,142.28,138.80,133.48,129 .38,129.05,128.51,127.48,126.52,123.28,114.54,46.68,44.06.HRMS(ESI)calcd for C 22 H 28 N4O2S[M+H] + ,413.2006;found,413.2015.

[0263] Embodiment 47

[0264] Preparation of compound 47: R1 = CH3O, R2 = CH3O, X=NH,

[0265] (1) In step (1) of Example 6, 3a was replaced by 3b, 4a was replaced by 4b, and the rest was the same as step (1) of Example 6. Compound 5b was prepared with a yield of 43.9%.

[0266] 1 H NMR (400MHz, DMSO-d6) δ7.40(s,1H),7.32(s,1H),3.99(s,6H).

[0267] (2) In step (2) of Example 6, 5a was replaced by 5b, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 6k was prepared with a yield of 84.4%.

[0268] 1H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 7.83 (s, 1H), 7.40 (d, J = 8.7Hz, 2H), 7.12 (s, 1H) ),6.72(d,J=8.7Hz,2H),3.92(d,J=5.9Hz,6H),3.38(s,4H),1.11(t,J=6.9Hz,6H). 13 CNMR(100MHz,DMSO-d6)δ158.26,154.81,154.55,148.70,147.73,144.97,1 26.27,124.96,111.42,107.09,106.59,102.32,56.21,55.90,43.71,12.45.

[0269] (3) In step (3) of Example 6, the intermediate 6a was replaced by 6k, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 47 was prepared with a yield of 84.7%.

[0270] 1 H NMR (400MHz, DMSO-d6) δ9.46(s,1H),8.60(d,J=8.2Hz,2H),8.04(d,J=8.4Hz,2H),7.89(s,1H),7.63(d,J=8.7Hz,2H ),7.29(s,1H),6.79(d,J=8.8Hz,2H),3.97(d,J=2.1Hz,6H),3.41–3.36(m,4H),3.26(s,3H),1.14(t,J=6.9Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ156.68,156.16,154.18,149.03,147.05,144.37,143.57,141.30,128.08,1 27.54,127.05,124.11,111.54,107.82,102.14,56.24,55.76,43.76,43.52,12.48.HRMS(ESI)calcd for C 27 H 30 N4O4S[M+H] + ,507.2061;found,507.2062.

[0271] Embodiment 48

[0272] Preparation of compound 48: R1 = CH3O, R2 = H, X=NH,

[0273] (1) In step (1) of Example 6, 3a was replaced by 3c, 4a was replaced by 4c, and the rest was the same as step (1) of Example 6. Compound 5c was prepared with a yield of 40.8%.

[0274] 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, J=9.2Hz, 1H), 7.81 (dd, J=9.2, 2.8Hz, 1H), 7.47 (s, 1H), 4.00 (s, 3H).

[0275] (2) In step (2) of Example 6, 5a was replaced by 5c, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 61 was prepared with a yield of 60.8%.

[0276] 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 7.91 (d, J = 2.2Hz, 1H), 7.61 (d, J = 9.1Hz, 1H), 7.53–7. 39(m,3H),6.73(d,J=8.9Hz,2H),3.93(s,3H),3.38(d,J=6.9Hz,4H),1.12(t,J=6.9Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ158.73,157.40,154.47,145.82,145.12,128.25,126.02,124.96,124.44,114.32,111.38,102.88,55.99,43.71,12.45.

[0277] (3) In step (3) of Example 6, the intermediate 6a was replaced by 61, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 48 was prepared with a yield of 80.4%.

[0278] 1H NMR (400MHz, DMSO-d6) δ9.61(s,1H),8.60(d,J=8.4Hz,2H),8.04(d,J=8.4Hz,2H),7.96(s,1H),7.81(d,J=9.1Hz,1H),7.67(d,J= 8.9Hz,2H),7.50(d,J=11.5Hz,1H),6.79(d,J=8.9Hz,2H),3.97(s,3H),3.38(q,J=6.9Hz,4H),3.26(s,3H),1.14(t,J=6.9Hz,6H). 13 CNMR(100MHz,DMSO-d6)δ157.62,157.16,155.76,145.32,144.52,143.41,141.38,129.75,128.16,1 27.30,127.07,124.16,123.99,114.76,111.49,102.55,56.05,43.76,43.53,12.49.HRMS(ESI)calcd for C 26 H 28 N4O3S[M+H] + ,477.1955;found,477.1954.

[0279] Embodiment 49

[0280] Preparation of compound 49: R1 = H, R2 = CH3O, X=NH,

[0281] (1) In step (1) of Example 6, 3a was replaced by 3d, 4a was replaced by 4d, and the rest was the same as step (1) of Example 6. Compound 5d was prepared with a yield of 44.9%.

[0282] 1 H NMR (400MHz, CDCl3) δ8.04 (d, J = 9.2Hz, 1H), 7.26–7.22 (m, 1H), 7.20–7.19 (m, 1H), 3.92 (s, 3H). 13 C NMR (100MHz, CDCl3) δ165.94,162.55,155.88,155.08,127.36,122.41,117.42,105.90,56.20.

[0283] (2) In step (2) of Example 6, 5a was replaced by 5d, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 6m was prepared with a yield of 37.2%.

[0284] 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.40(d,J=9.2Hz,1H),7.44(d,J=9.0Hz,2H),7.19(dd,J=9.1,2.5Hz ,1H),7.10(d,J=2.5Hz,1H),6.70(d,J=9.0Hz,2H),3.91(s,3H),3.40–3.33(m,4H),1.11(t,J=7.0Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ163.26,158.93,157.17,153.14,145.02,126.22,124.79,117.11,111.42,107.71,106.61,55.72,43.72,12.43.

[0285] (3) In step (3) of Example 6, the intermediate 6a was replaced by 6m, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 49 was prepared with a yield of 85.8%.

[0286] 1 H NMR (400MHz, CDCl3) δ8.68(d,J=8.6Hz,2H),8.01(d,J=8.6Hz,2H),7.74(d,J=9.1Hz,1H),7.57(d,J=9.0Hz,2H),7.30(d,J=2.5Hz ,1H),7.12(dd,J=9.0,2.5Hz,1H),6.77(d,J=9.0Hz,2H),3.97(s,3H),3.40(q,J=7.1Hz,4H),3.07(s,3H),1.21(t,J=7.1Hz,6H). 13 C NMR (100MHz, CDCl3) δ163.26,159.28,157.60,153.10,145.43,144.30,141.13,129.29,127.27, 126.76,123.91,121.97,118.52,112.19,108.28,107.84,55.73,44.60,12.63.HRMS(ESI)calcd for C 26 H28 N4O3S[M+H] + ,477.1955;found,477.1960.

[0287] Embodiment 50

[0288] Preparation of compound 50: R1 = H, R2 = CH3, X=NH,

[0289] (1) In step (1) of Example 6, 3a was replaced by 3e, 4a was replaced by 4e, and the rest was the same as step (1) of Example 6. Compound 5e was prepared with a yield of 40.7%.

[0290] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.5Hz,1H),7.83(s,1H),7.74(d,J=8.6Hz,1H),2.60(s,3H).

[0291] (2) In step (2) of Example 6, 5a was replaced by 5e, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 6n was prepared with a yield of 39.3%.

[0292] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.4Hz,1H),7.57(s,1H),7.48(d,J=9.0Hz,2H),7.40(s,1H),7.30 (d,J=9.4Hz,1H),6.70(d,J=9.0Hz,2H),3.36(q,J=7.1Hz,4H),2.51(s,3H),1.17(t,J=7.1Hz,6H). 13 C NMR (100MHz, CDCl3) δ158.66,157.68,151.57,145.80,144.39,128.18,127.34,125.75,123.87,120.51,112.12,111.33,44.54,21.87,12.58.

[0293] (3) In step (3) of Example 6, the intermediate 6a was replaced by 6n, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 50 was prepared with a yield of 71.9%.

[0294] 1H NMR (400MHz, CDCl3) δ8.68(d,J=8.4Hz,2H),8.01(d,J=8.4Hz,2H),7.74(d,J=9.1Hz,1H),7.57(d,J=8.8Hz,2H),7.30(s ,1H),7.15–7.10(m,1H),6.77(d,J=8.5Hz,1H),3.97(s,3H),3.40(q,J=7.0Hz,4H),3.07(s,3H),1.21(t,J=7.0Hz,6H). 13 C NMR (100MHz, CDCl3) δ163.26,159.26,157.59,153.07,144.28,141.13,129.29,127.26,1 23.89,122.00,118.52,112.22,108.27,107.83,55.67,44.60,12.62.HRMS(ESI)calcdfor C 26 H 28 N4O2S[M+H] + ,461.2006;found,461.2010.

[0295] Embodiment 51

[0296] Preparation of compound 51: R1 = H, R2 = F, X=NH,

[0297] (1) In step (1) of Example 6, 3a was replaced by 3f, 4a was replaced by 4f, and the rest was the same as step (1) of Example 6. Compound 5f was prepared with a yield of 43.1%.

[0298] 1 H NMR (400MHz, DMSO-d6) δ8.42(dd,J=9.2,5.8Hz,1H),7.94(d,J=12.0Hz,1H),7.84(t,J=10.1Hz,1H).

[0299] (2) In step (2) of Example 6, 5a was replaced by 5f, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 6o was prepared with a yield of 37.8%.

[0300] 1H NMR(400MHz, DMSO-d6)δ10.07(s,1H),8.59(dd,J=9.2,6.0Hz,1H),7.55–7.49(m,1H) ,7.47–7.42(m,3H),6.72(d,J=9.0Hz,2H),3.39–3.34(m,4H),1.11(t,J=7.0Hz,6H). 13 CNMR(100MHz,DMSO-d6)δ166.19,163.69,158.91,157.90,152.78,152.65,145.23 ,126.50,126.39,125.75,124.87,115.55,115.31,111.33,110.90,43.71,12.41.

[0301] (3) In step (3) of Example 6, the intermediate 6a was replaced by 6o, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 51 was prepared with a yield of 63.1%.

[0302] 1 H NMR (400MHz, DMSO-d6) δ9.86(s,1H),8.65(dd,J=9.1,6.1Hz,1H),8.61(d,J=8.5Hz,2H),8.06(d,J=8.5Hz,2H),7.67(d,J=9.0Hz, 2H),7.59(d,J=10.2Hz,1H),7.52(t,J=10.1Hz,1H),6.78(d,J=9.1Hz,2H),3.44–3.35(m,4H),3.27(s,3H),1.14(t,J=7.0Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ163.45,158.95,157.67,152.28,152.15,144.68,142.88,142.00 ,128.63,127.11,126.95,124.19,111.45,111.34,43.75,43.48,12.48.HRMS(ESI)calcd for C 25 H 25 FN4O2S[M+H] + ,465.1760;found,465.1760.

[0303] Embodiment 52

[0304] Preparation of compound 52: R1 = H, R2 = Cl, X=NH,

[0305] (1) In step (1) of Example 6, 3a was replaced by 3g, 4a was replaced by 4g, and the rest was the same as step (1) of Example 6. Compound 5g was prepared with a yield of 42.9%.

[0306] 1 H NMR (400MHz, CDCl3) δ8.14 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.9, 2.0 Hz, 1H).

[0307] (2) In step (2) of Example 6, 5a was replaced by 5g, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 6p was prepared with a yield of 36.0%.

[0308] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.53(d,J=8.9Hz,1H),7.72(d,J=2.0Hz,1H),7.65(dd,J=8.8,2 .0Hz,1H),7.47(d,J=8.9Hz,2H),6.71(d,J=8.9Hz,2H),3.35(d,J=10.1Hz,4H),1.11(t,J=7.0Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ158.93,157.87,151.63,145.24,138.29,126.55,125.72,125.58,125.43,124.77,112.60,111.30,43.70,12.43.

[0309] (3) In step (3) of Example 6, the intermediate 6a was replaced by 6p, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 52 was prepared with a yield of 57.1%.

[0310] 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),8.59(t,J=8.9Hz,3H),8.06(d,J=8.4Hz,2H),7.88(d,J=2.0Hz,1H) ,7.67(t,J=7.7Hz,3H),6.78(d,J=9.0Hz,2H),3.38(q,J=7.0Hz,4H),3.27(s,3H),1.14(t,J=7.0Hz,6H).13 C NMR(100MHz,DMSO-d6)δ158.98,157.66,151.20,144.70,142.82,142.05,137.67,128.64,127.13 ,126.88,126.78,126.48,125.21,124.11,112.94,111.43,43.75,43.48,12.47.HRMS(ESI)calcd for C 25 H 25 ClN4O2S[M+H] + ,481.1460;found,481.1464.

[0311] Embodiment 53

[0312] Preparation of compound 53: R1 = H, R2 = CF3, X=NH,

[0313] (1) In step (1) of Example 6, 3a was replaced by 3h, 4a was replaced by 4h, and the rest was the same as step (1) of Example 6. Compound 5h was prepared with a yield of 45.4%.

[0314] 1 H NMR (400MHz, DMSO-d6) δ8.55–8.47(m,1H),8.22(dd,J=41.4,8.5Hz,1H),7.98–7.80(m,1H).

[0315] (2) In step (2) of Example 6, 5a was replaced by 5h, and N,N-dimethyl-p-phenylenediamine was replaced by N,N-diethyl-p-phenylenediamine. The rest was the same as step (2) of Example 6. Intermediate 6q was prepared with a yield of 35.6%.

[0316] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.74(d,J=8.6Hz,1H),7.99(s,1H),7.91(d,J=8.6Hz,1 H),7.50(d,J=9.0Hz,2H),6.73(d,J=9.1Hz,2H),3.36(q,J=7.1Hz,5H),1.11(t,J=7.0Hz,7H). 13C NMR (100MHz, DMSO-d6) δ158.84,158.15,150.38,145.35,133.45,133.13,125.58,125.37,124.76,123.96,121.70,116.34,111.28,43.70,12.43.

[0317] (3) In step (3) of Example 6, the intermediate 6a was replaced by 6q, and the phenylboronic acid was replaced by 4-(methylsulfonyl)phenylboronic acid. The rest was the same as step (3) of Example 6. Compound 53 was prepared with a yield of 81.8%.

[0318] 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),8.77(d,J=8.6Hz,1H),8.62(d,J=8.4Hz,2H),8.14(s,1H),8.08(d,J=8.4Hz,2H),7.9 0(d,J=8.7Hz,1H),7.70(d,J=8.9Hz,2H),6.79(d,J=9.0Hz,2H),3.39(q,J=6.9Hz,5H),3.27(s,3H),1.14(t,J=6.9Hz,7H). 13 CNMR(100MHz,DMSO-d6)δ159.23,157.58,149.84,144.82,142.63,142.18,128.70,127.17, 126.70,125.25,125.07,124.15,116.55,111.38,43.75,43.46,12.48.HRMS(ESI)calcdfor C 26 H 25 F3N4O2S[M+H] + ,515.1723;found,515.1728.

[0319] Experimental Example 1

[0320] LSD1 inhibitory activity assay:

[0321] The test sample for LSD1 inhibitory activity is obtained by purifying the compound prepared in Examples 1 to 53. The preparation process of the sample stock solution is as follows: weigh 1 to 2 mg of the sample and place it in a 1.5 mL EP tube, prepare it into a solution with a concentration of 20 mM with DMSO, store it at 4 ° C for use, and dilute it with DMSO according to the required concentration during the experiment. After incubating the sample to be tested with LSD1 protein at room temperature, add the LSD1 substrate H3K4me2 and incubate the reaction. Finally, add the fluorescent dye Amplex and horseradish peroxidase HRP and incubate at room temperature. The fluorescence value is detected on the microplate reader with excitation light of 530 nm and emission light of 590 nm. The calculation formula of the inhibition rate is as follows. The experimental results are calculated using SPSS software IC 50 The results are shown in Table 1.

[0322]

[0323] Table 1

[0324]

[0325]

[0326] As shown in Table 1, a quinazoline compound provided by the present invention has a certain inhibitory activity against LSD1. When the concentration of the compound is 10 μM, compounds 2, 4, 6-11, 13-17, 19-20, 22-34, 37-38, 43-44, 49-51, etc. have good inhibitory activity, and the inhibitory activity against LSD1 is relatively high, all reaching more than 80%. When compounds 4, 6, 10, 12-17, 19-20, 22-37, 43-44, 49-51, etc. play a role, their IC 50 The values ​​were low, all below 1 μM, and had low biological toxicity.

[0327] In summary, the quinazoline compounds provided by the present invention have good inhibitory activity against LSD1, showing good development potential, opening up an effective way for the development of new anti-tumor drugs, combination drugs and new LSD1 inhibitor drugs, and have good market application prospects.

[0328] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A quinazoline compound, characterized in that A compound having the general structural formula I, or a pharmaceutically acceptable salt of the compound shown in the general structural formula I: Wherein, R1, R2, X, R3, and R4 are selected from the following groups:

2. Use of the quinazoline compound according to claim 1 in the preparation of an anti-tumor drug targeting LSD1.

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