A pyridoimidazole nitrogen fused ring compound and its preparation method and application

Abstract

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a pyridoimidazole nitrogen condensed ring compound, comprising: using a substituted chromone and a substituted 2-aminopyridine as raw materials, adding an oxidant and a catalyst, and reacting in a solvent to obtain a pyridoimidazole nitrogen condensed ring compound; the substituted 2-aminopyridine contains a group R 1 , substituted chromones contain a group R 2 , R 1 is selected from one of an alkyl group, a hydrogen group, a halogen group, an ester group, a methanol group, a trifluoromethyl group and a cyano group, R 2 is selected from one of alkyl, hydrogen, methoxy and halogen, R 1 and R 2 The substitution modes are all single substitution or multiple substitution. The preparation method of the present invention is simple and safe to operate, the cost of raw materials is low, and the scope of application is wide. In addition, the pyridine imidazole nitrogen fused ring compound of the present invention has a novel structure, has anti-MV4-11 cell proliferation activity, and can be used in the preparation of leukemia drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a pyridine imidazole nitrogen condensed ring compound and a preparation method and application thereof. Background Art

[0002] Pyridimidazole is an important nitrogen-containing fused ring compound skeleton in medicinal chemistry, with a wide range of biological activities such as anticancer, antibacterial, central nervous system regulation, and kinase inhibition. In particular, some clinically used drugs, such as zolpidem, oprinone, and pyrimidine, have imidazole [1,2-a] pyridine fragments. Therefore, the development of synthetic methods for preparing pyridimidazoles is extremely important for the construction of various bioactive drug molecules.

[0003] In recent years, people have been committed to developing new strategies for constructing pyridoimidazoles. Generally speaking, the reaction of acetophenone, ethylbenzene, styrene or phenylacetylene with 2-aminopyridine to prepare pyridoimidazole compounds is a common strategy. In addition, three-component reactions of aldehydes, 2-aminopyridine and alkynes / isocyanides are also included. Although these excellent works have improved the efficiency of synthesizing pyridoimidazoles, there has been little exploration of the preparation of imidazo[1,2-a]pyridines from simple and readily available raw materials, especially the synthesis of C3-carbonylated imidazo[1,2-a]pyridines. In our previous work, indolizine compounds with two acyl motifs at the C1 and C3 positions can be synthesized from chromones and pyridinium salts through a sequence of 1,3-dipolar cycloaddition, ring opening and aromatization. Therefore, we want to prepare pyridoimidazole compounds using chromones and 2-aminopyridine as raw materials, in order to prepare imidazo[1,2-a]pyridine compounds from simple and readily available raw materials, thereby reducing the difficulty of synthesizing imidazo[1,2-a]pyridine compounds. Summary of the invention

[0004] The present invention aims to provide a method for preparing a pyridine imidazole nitrogen condensed ring compound, in order to obtain a new method for synthesizing a pyridine imidazole nitrogen condensed ring compound.

[0005] In order to achieve the above-mentioned object, the scheme of the present invention is: a method for preparing a pyridoimidazole nitrogen condensed ring compound, comprising the steps of: using a substituted chromone as shown in formula (1) and a substituted 2-aminopyridine as shown in formula (2) as raw materials, adding an oxidant and a catalyst, and reacting in a solvent to obtain a pyridoimidazole nitrogen condensed ring compound as shown in formula (3);

[0006]

[0007] Among them, R 1 is selected from one of an alkyl group, a hydrogen group, a halogen group, an ester group, a methanol group, a trifluoromethyl group and a cyano group, R 1 The substitution mode is single substitution or multiple substitution, R 1The substitution position is any position on the pyridine ring;

[0008] R 2 is selected from one of alkyl, hydrogen, methoxy and halogen, R 2 The substitution mode is single substitution or multiple substitution, R 2 The substitution position is any position on the benzene ring;

[0009] The oxidant is DTBP or TBHP or H 2 O 2 The catalyst is iodine or NIS, and the solvent is one of toluene, chlorobenzene, p-xylene, p-dichlorobenzene, and a mixed solvent of toluene and chlorobenzene.

[0010] The working principle and beneficial effect of this scheme are as follows: iodine element / NIS first generates butyl hypoiodite under the action of DTBP (oxidant), and then reacts with chromone to generate iodonium ion intermediate A, and then 2-aminopyridine reacts with intermediate A to obtain intermediate B, and further obtains the target compound 3a through intramolecular cyclization and aromatization, and the reaction process is shown in formula (I) / formula (II). This reaction principle is different from the traditional free radical mechanism, and the prepared pyridoimidazole nitrogen fused ring compound is a brand-new structure.

[0011]

[0012]

[0013] In the prior art scheme, it is also impossible to directly synthesize the nitrogen fused ring compound of pyridoimidazole from chromone and 2-aminopyridine. Although acetophenone, DMSO and 2-aminopyridine are used in the prior art to prepare similar compounds in this scheme, there are significant differences in the selection of raw materials and reaction conditions. The intermediates A, B, C and D involved in this scheme are extremely unstable and cannot be separated and obtained. They are only captured based on LC-MC to be present, thereby inferring the possible mechanism of the reaction. The synthetic method of the present invention is simple and safe to operate, has low raw material cost, and is widely applicable, and is an economical and efficient synthetic method.

[0014] Optionally, the molar ratio of the substituted chromone of formula (1) to the substituted 2-aminopyridine of formula (2) is 1:1 to 3, preferably 1:2.

[0015] Optionally, the molar ratio of the substituted chromone represented by formula (1) to the oxidant is 1:1 to 3, preferably 1:2.5.

[0016] Optionally, the molar ratio of the substituted chromone represented by formula (1) to the catalyst is 1:0.2 to 2, preferably 1:0.4.

[0017] Optionally, the reaction time of the synthesis step is 8 to 24 hours, preferably 24 hours.

[0018] Optionally, the reaction temperature of the synthesis step is 80-120°C, preferably 110°C.

[0019] Optionally, the volume ratio of the solvent to the amount of the substituted chromone substance represented by formula (1) is 4 mL:1 mmol.

[0020] Optionally, the solvent is a mixed solvent of toluene and chlorobenzene, and the volume ratio of toluene to chlorobenzene is 3:1.

[0021] Optionally, the molar ratio of the substituted chromone shown in formula (1) to the substituted 2-aminopyridine shown in formula (2) is 1:2; the molar ratio of the substituted chromone shown in formula (1) to the oxidant is 1:2.5, and the oxidant is DTBP; the molar ratio of the substituted chromone shown in formula (1) to the catalyst is 1:0.4, and the catalyst is elemental iodine; the solvent is a mixed solvent of toluene and chlorobenzene in a volume ratio of 3:1; the reaction temperature of the synthesis step is 110°C, and the reaction time of the synthesis step is 24h.

[0022] Optionally, the synthesis step further includes a purification step: in the synthesis step, a mixed solution containing a pyridine imidazole nitrogen fused ring compound as shown in formula (3) is obtained, and the mixed solution is evaporated and concentrated to obtain a crude product; the crude product is purified by silica gel column chromatography to obtain a pure product.

[0023] Optionally, the step of purifying the crude product using silica gel column chromatography includes: dissolving the crude product using dichloromethane, then loading the crude product-dichloromethane solution into a silica gel column, eluting the silica gel column using an eluent, collecting the eluate, and concentrating the eluate under reduced pressure to obtain a pure product; wherein the ratio of the volume of the dichloromethane to the mass of the crude product is 5mL:1g.

[0024] Optionally, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 4:1.

[0025] The present invention also intends to provide a pyridoimidazole nitrogen-fused ring compound obtained according to the above preparation method.

[0026] The present invention also intends to provide the use of the above pyridoimidazole nitrogen fused ring compound in the preparation of leukemia drugs. DETAILED DESCRIPTION

[0027] The following is further described in detail through specific implementation methods:

[0028] Example 1

[0029] Synthesis of Compound 3a——(2-Hydroxyphenyl)(Imidazol[1,2-a]pyridin-3-yl)methanone

[0030]

[0031] The preparation method of compound 3a comprises the following steps:

[0032] S1. Synthesis steps: In a 10 mL threaded high pressure reaction tube, chromone (1a, 146 mg, 1 mmol), 2-aminopyridine (2a, 188 mg, 2 mmol), I 2 (40mol%, I 2 The amount of substance is 40% of the amount of substance of chromone), 1 mL of chlorobenzene, 3 mL of toluene and DTBP (2.5 mmol, 366 mg), placed in an oil bath at 110° C. for reaction for 24 hours to obtain a mixed solution containing compound 3a.

[0033] S2. Purification step: dissolve the mixed solution containing compound 3a with dichloromethane, and concentrate and remove the solvent with a rotary evaporator to obtain a crude product; purify with 200-300 mesh silica gel column chromatography. Specifically, dissolve the crude product with dichloromethane (the ratio of the volume of dichloromethane to the mass of the crude product is 5 mL:1 g), then load the crude product-dichloromethane solution into a 30 cm long silica gel column, and elute with a mixed solvent of petroleum ether:ethyl acetate = 3:1 (volume ratio) as an eluent, collect the eluate, and concentrate the eluate under reduced pressure to obtain 183 mg of compound 3a (pure product) as a yellow solid with a yield of 77%. 1 H NMR (400 MHz, CDCl 3 )δ11.43(s,1H),9.52(dt,J=6.9,1.1Hz,1H),8.32(s,1H),7.91(dd,J=8.0,1.6Hz,1H),7.81(dt,J=9.0,1.1Hz ,1H),7.58–7.47(m,2H),7.14(td,J=6.9,1.1Hz,1H),7.06(dd,J=8.4,1.0Hz,1H),6.99(td,J=7.8,1.1Hz,1H). 13 C NMR (101 MHz, CDCl 3 )δ186.62,161.75,149.23,145.43,135.33,130.94,129.63,128.95,122.76,120.41,119.25,118.35,117.94,115.21.HRMS(ESI+)[M+H] + calculated for 14 H11 N 2 O 2 ] + :239.0815,found:239.0817.

[0034] Example 2

[0035] The difference between this embodiment and embodiment 1 is that in the synthesis step, the catalyst is 1 2 (5 mol%), i.e., I 2 The amount of substance is 5% of the amount of substance of chromone, the solvent is 4 mL of chlorobenzene, the oil bath temperature is 100° C., and the rest is the same as Example 1.

[0036] In this example, 69 mg of compound 3a was obtained as a yellow solid with a yield of 29%.

[0037] Example 3

[0038] The difference between this embodiment and embodiment 1 is that in the synthesis step, the catalyst is 1 2 (5 mol%), i.e., I 2 The amount of substance is 5% of the amount of substance of chromone, the solvent is 4 mL of chlorobenzene, the oxidant is TBHP (2.5 mmol, 366 mg), the oil bath temperature is 100° C., and the rest is the same as Example 1.

[0039] In this example, 55 mg of compound 3a was obtained as a yellow solid with a yield of 23%.

[0040] Example 4

[0041] The difference between this embodiment and embodiment 1 is that in the synthesis step, the catalyst is 1 2 (5 mol%), i.e., I 2 The amount of substance is 5% of the amount of substance of chromone, the solvent is 4 mL chlorobenzene, and the oxidant is H 2 O 2 (2.5mmol, 366mg), the oil bath temperature is 100°C, and the rest is the same as Example 1.

[0042] In this example, 24 mg of compound 3a was obtained as a yellow solid with a yield of 10%.

[0043] Example 5

[0044] The difference between this embodiment and embodiment 1 is that in the synthesis step, the catalyst is NIS (40 mol%), that is, the amount of NIS is 40% of the amount of chromone, and the rest is the same as embodiment 1.

[0045] In this example, 131 mg of compound 3a was obtained as a yellow solid with a yield of 55%.

[0046] Example 6

[0047] Synthesis of Compound 3b——(8-fluoroimidazole[1,2-a]pyridin-3-yl)(2-hydroxyphenyl)methanone

[0048]

[0049] The preparation method of compound 3b comprises the following steps:

[0050] S1. Synthesis steps: In a 10 mL threaded high pressure reaction tube, chromone (1a, 146 mg, 1 mmol), 3-fluoro-2-aminopyridine (2b, 224 mg, 2 mmol), I 2 (40 mol%), 1 mL of chlorobenzene, 3 mL of toluene and DTBP (2.5 mmol, 366 mg) were placed in an oil bath at 110° C. for reaction for 24 hours to obtain a mixed solution containing compound 3b.

[0051] S2. Purification step: dissolving the mixed solution containing compound 3b with dichloromethane, and concentrating and removing the solvent with a rotary evaporator to obtain a crude product; purifying with 200-300 mesh silica gel column chromatography, specifically, dissolving the crude product with dichloromethane (the ratio of the volume of dichloromethane to the mass of the crude product is 5 mL:1 g), then loading the crude product-dichloromethane solution into a 30 cm long silica gel column, eluting with a mixed solvent of petroleum ether:ethyl acetate = 3:1 (volume ratio) as an eluent, collecting the eluate, and concentrating the eluate under reduced pressure to obtain 248 mg of compound 3b as a yellow solid, with a yield of 97%. 1 H NMR (400 MHz, CDCl 3 )δ11.34(s,1H),9.31(d,J=7.0Hz,1H),8.31(s,1H),7.91(dd,J=8.0,1.4Hz,1H),7.53 (ddd,J=8.5,7.3,1.6Hz,1H),7.29–7.25(m,1H),7.10–7.04(m,2H),7.03–6.98(m,1H). 13 C NMR(101MHz,dmso)δ184.93,156.26,151.99,149.50,145.43,140.66(d,J=27.5Hz),133.11,130.14,12 6.19,125.47–125.16(m),119.49,117.24,115.57(d,J=6.7Hz),113.33(d,J=15.6Hz).HRMS(ESI+)[M+H] +calculated for 14 H 10 FN 2 O 2 ] + :257.0721,found:257.0716.

[0052] Example 7

[0053] Synthesis of Compound 3c——(2-Hydroxyphenyl)(8-methylimidazo[1,2-a]pyridin-3-yl)methanone

[0054]

[0055] The preparation method of compound 3c comprises the following steps:

[0056] S1. Synthesis steps: In a 10 mL threaded high pressure reaction tube, add chromone (1a, 146 mg, 1 mmol), 3-methyl-2-aminopyridine (2c, 216 mg, 2 mmol), I 2 (40 mol%), 1 mL of chlorobenzene, 3 mL of toluene and DTBP (2.5 mmol, 366 mg) were placed in an oil bath at 110° C. for reaction for 24 hours to obtain a mixed solution containing compound 3c.

[0057] S2. Purification step: using dichloromethane to dissolve the mixed solution containing compound 3c, and concentrating and removing the solvent by a rotary evaporator to obtain a crude product; using 200-300 mesh silica gel column chromatography for purification, specifically, using dichloromethane to dissolve the crude product (the ratio of the volume of dichloromethane to the mass of the crude product is 5 mL: 1 g), and then loading the crude product-dichloromethane solution into a 30 cm long silica gel column, using a mixed solvent of petroleum ether: ethyl acetate = 3: 1 (volume ratio) as an eluent for elution, collecting the eluate, and concentrating the eluate under reduced pressure to obtain 219 mg of compound 3c as a yellow solid, with a yield of 87%. 1 H NMR (400 MHz, CDCl 3 )δ11.44(s,1H),9.44–9.31(m,1H),8.28(s,1H),7.89(dd,J=7.9,1.5Hz,1H),7.5 0(ddd,J=8.4,7.3,1.6Hz,1H),7.38–7.30(m,1H),7.09–6.95(m,3H),2.68(s,3H). 13 C NMR (101 MHz, CDCl 3)δ186.70,161.77,149.36,144.72,135.22,130.95,128.63,127.82,126.65,123.16,120.54,119.19,118.32,115.21,16.94.HRMS(ESI+)[M+H] + calculated for 15 H 13 N 2 O 2 ] + :253.0972,found:253.0975.

[0058] Example 8

[0059] Synthesis of Compound 3d——(2-Hydroxyphenyl)(8-methoxyimidazole[1,2-a]pyridin-3-yl)methanone

[0060]

[0061] The preparation method of compound 3d comprises the following steps:

[0062] S1. Synthesis steps: In a 10 mL threaded high pressure reaction tube, chromone (1a, 146 mg, 1 mmol), 3-methoxy-2-aminopyridine (2d, 248 mg, 2 mmol), I 2 (40 mol%), 1 mL of chlorobenzene, 3 mL of toluene and DTBP (2.5 mmol, 366 mg) were placed in an oil bath at 110° C. for reaction for 24 hours to obtain a mixed solution containing compound 3d.

[0063] S2. Purification step: using dichloromethane to dissolve the mixed solution containing compound 3d, and concentrating and removing the solvent using a rotary evaporator to obtain a crude product; using 200-300 mesh silica gel column chromatography for purification, specifically, using dichloromethane to dissolve the crude product (the ratio of the volume of dichloromethane to the mass of the crude product is 5 mL: 1 g), and then loading the crude product-dichloromethane solution into a 30 cm long silica gel column, using a mixed solvent of petroleum ether: ethyl acetate = 3: 1 (volume ratio) as an eluent for elution, collecting the eluate, and concentrating the eluate under reduced pressure to obtain 121 mg of compound 3d as a yellow solid, with a yield of 45%. 1 H NMR (400 MHz, CDCl 3)δ11.42(s,1H),9.10(dd,J=6.9,0.9Hz,1H),8.23(s,1H),7.91(dd,J=8.0,1.4Hz,1H),7.50(ddd ,J=8.5,7.3,1.6Hz,1H),7.02(ddd,J=15.7,8.7,0.9Hz,3H),6.83(d,J=7.8Hz,1H),4.06(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ186.91,161.82,148.92,144.05,143.27,135.39,131.01,123.74,121.36,120.45,119.23,118.33,115.12,105.98,56.19.HRMS(ESI+)[M+H] + calculated for 15 H 13 N 2 O 3 ] + :269.0921,found:269.0926.

[0064] Example 9

[0065] Synthesis of Compound 3e——(8-Hydroxymethylimidazole[1,2-a]pyridin-3-yl)(2-hydroxyphenyl)methanone

[0066]

[0067] The preparation method of compound 3e is similar to the preparation method of compound 3a in Example 1, except that: in this example, the substituted 2-aminopyridine in the raw material is specifically 3-methanol-2-aminopyridine (2e, 248 mg, 2 mmol), and the rest is the same.

[0068] In this example, 46 mg of compound 3e was obtained as a yellow solid with a yield of 17%. 1 H NMR(400MHz,dmso)δ10.14(s,1H),9.47(d,J=6.7Hz,1H),7.97(s,1H),7.66(dd,J=7.1,1.2Hz,1H),7.45(dd,J=7. 6,1.6Hz,1H),7.41–7.29(m,2H),6.93(ddd,J=10.2,8.3,4.6Hz,2H),5.52(t,J=5.7Hz,1H),4.89(d,J=5.6Hz,2H). 13C NMR(101MHz,dmso)δ184.71,156.26,146.63,145.44,132.83,131.96,130.08,12 6.73,126.41,125.82,124.31,119.44,117.18,116.02,58.54.HRMS(ESI+)[M+Na] + calculated for 15 H 12 N 2 NaO 3 ] + :291.0740,found:291.0744.

[0069] Example 10

[0070] Synthesis of Compound 3f——Ethyl 3-(2-hydroxyphenyl)imidazole[1,2-a]pyridine-8-carboxylate

[0071]

[0072] The preparation method of compound 3f is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 2-aminonicotinic acid ethyl ester (2f, 332 mg, 2 mmol), and the rest is the same.

[0073] In this example, 99 mg of compound 3f was obtained as a yellow solid with a yield of 32%. 1 H NMR (400 MHz, CDCl 3 )δ12.20(s,1H),9.66(dd,J=6.9,1.3Hz,1H),8.40(s,1H),8.27(dd,J=7.3,1.3Hz,1H),8.01(dd,J=7.8,1.4Hz,1H),7.88(dd, J=7.9,1.5Hz,1H),7.27–7.25(m,1H),7.23–7.20(m,1H),6.80(t,J=7.8Hz,1H),4.53(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ186.25,163.52,160.49,146.34,145.02,135.76,133.28,132.95,132.39,13 1.17,121.01,120.34,119.39,118.48,114.44,62.14,14.34.HRMS(ESI+)[M+Na]+ calculated for 17 H 14 N 2 NaO 4 ] + :333.0846,found:333.0840.

[0074] Embodiment 11

[0075] Compound 3h——Synthesis of ethyl 3-(2-hydroxyphenyl)imidazole[1,2-a]pyridine-7-carboxylate

[0076]

[0077] The preparation method of compound 3h is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 2-aminoisonicotinate (2h, 332 mg, 2 mmol), and the rest is the same.

[0078] In this example, 294 mg of compound 3h was obtained as a yellow solid with a yield of 95%. 1 H NMR(400MHz,dmso)δ10.19(s,1H),9.63(dd,J=7.2,0.8Hz,1H),8.30(d,J=0.7Hz,1H),8.16(s,1H),7.68( dd,J=7.2,1.6Hz,1H),7.48–7.33(m,2H),7.00–6.86(m,2H),4.36(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H). 13 CNMR(101MHz,dmso)δ185.05,164.39,156.31,147.64,146.91,133.21,130.32,130.21,1 28.86,126.14,124.87,119.54,119.19,117.27,114.51,62.18,14.48.HRMS(ESI+)[M+Na] + calculated for 17 H 14 N 2 NaO 4 ] + :333.0846,found:333.0843.

[0079] Example 12

[0080] Compound 3i——Synthesis of 3-(2-hydroxyphenyl)imidazole[1,2-a]pyridine-7-carbonitrile

[0081]

[0082] The preparation method of compound 3i is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 2-aminoisonicotinonitrile (2i, 238 mg, 2 mmol), and the rest is the same.

[0083] In this example, 250 mg of compound 3i was obtained as a yellow solid with a yield of 95%. 1 H NMR(400MHz,dmso)δ10.20(s,1H),9.63(dd,J=7.2,0.9Hz,1H),8.61(dd,J=1.6,0.9Hz,1H),8. 21(s,1H),7.59(dd,J=7.2,1.6Hz,1H),7.49–7.35(m,2H),6.94(ddd,J=10.4,8.3,4.6Hz,2H). 13 C NMR(101MHz,dmso)δ185.20,156.32,146.89,146.62,133.40,130.28,129.46,12 6.02,125.09,124.20,119.59,117.67,117.31,116.21,111.31.HRMS(ESI+)[M+H] + calculated for 15 H 10 N 3 O 2 ] + :264.0768,found:264.0770.

[0084] Embodiment 13

[0085] Synthesis of Compound 3j——(2-Hydroxyphenyl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone

[0086]

[0087] The preparation method of compound 3j is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 4-trifluoromethyl-2-aminopyridine (2j, 324 mg, 2 mmol), and the rest is the same.

[0088] In this example, 263 mg of compound 3j was obtained as a yellow solid, with a yield of 86%. 1H NMR(400MHz,dmso)δ10.19(s,1H),9.71(d,J=7.2Hz,1H),8.36(s,1H),8.19(s,1H),7.57(dd,J=7. 3,1.7Hz,1H),7.47(dd,J=7.6,1.5Hz,1H),7.44–7.37(m,1H),6.95(ddd,J=10.6,8.2,4.5Hz,2H). 13 C NMR(101MHz,dmso)δ185.18,156.33,146.92,146.75,133.31,130.26,130.03,129.24(d,J=33.7Hz),12 6.05,124.92,122.15,119.56,117.30,116.09–115.89(m),111.32(dd,J=6.5,3.6Hz).HRMS(ESI+)[M+H] + calculated for 15 H 10 F 3 N 2 O 2 ] + :307.0689,found:307.0692.

[0089] Embodiment 14

[0090] Synthesis of Compound 3k——(2-Hydroxyphenyl)(7-methoxyimidazole[1,2-a]pyridin-3-yl)methanone

[0091]

[0092] The preparation method of compound 3k is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 4-methoxy-2-aminopyridine (2k, 248 mg, 2 mmol), and the rest is the same.

[0093] In this example, 96 mg of compound 3k was obtained as a yellow solid with a yield of 36%. 1 H NMR (400 MHz, CDCl 3 )δ11.43(s,1H),9.35(d,J=7.6Hz,1H),8.22(s,1H),7.88(dd,J=7.9,1.5Hz,1H),7.52–7. 43(m,1H),7.08–7.01(m,2H),7.00–6.92(m,1H),6.80(dd,J=7.6,2.5Hz,1H),3.93(s,3H).13 CNMR (101MHz, CDCl 3 )δ185.79,161.55,161.17,151.54,146.23,134.99,130.69,129.51,122.39,120.48,119.12,118.25,109.23,95.88,55.86.HRMS(ESI+)[M+H] + calculated for 15 H 13 N 2 O 3 ] + :269.0921,found:269.0925.

[0094] Embodiment 15

[0095] Compound 3l——Synthesis of (2-hydroxyphenyl)(6-methoxyimidazole[1,2-a]pyridin-3-yl)methanone

[0096]

[0097] The preparation method of compound 31 is similar to the preparation method of compound ab in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 5-methoxy-2-aminopyridine (21, 248 mg, 2 mmol), and the rest is the same.

[0098] In this example, 177 mg of compound 31 was obtained as a yellow solid with a yield of 66%. 1 H NMR(400MHz,dmso)δ10.14(s,1H),9.26(s,1H),7.95(s,1H),7.79(d,J=9.6Hz,1 H),7.46(t,J=9.0Hz,2H),7.38(t,J=7.2Hz,1H),6.99–6.84(m,2H),3.88(s,3H). 13 C NMR(101MHz,dmso)δ184.59,156.22,151.08,145.74,145.44,132.77,129.99,126.44, 124.58,124.05,119.42,118.06,117.15,110.72,56.64(d,J=8.3Hz).HRMS(ESI+)[M+H] + calculated for 15 H 13 N 2 O 3 ] +:269.0921,found:269.0918.

[0099] Example 16

[0100] Synthesis of Compound 3m——(6-Fluoroimidazol[1,2-a]pyridin-3-yl)(2-hydroxyphenyl)methanone

[0101]

[0102] The preparation method of compound 3m is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 5-fluoro-2-aminopyridine (2m, 224 mg, 2 mmol), and the rest is the same.

[0103] In this example, 212 mg of compound 3m was obtained as a yellow solid, with a yield of 83%. 1 H NMR(400MHz,dmso)δ10.17(s,1H),9.61(dd,J=4.5,2.3Hz,1H),8.08(s,1H),7.94(dd,J=9.8,4. 9Hz,1H),7.83–7.73(m,1H),7.45(dd,J=7.6,1.5Hz,1H),7.42–7.34(m,1H),7.00–6.87(m,2H). 13 CNMR(101MHz,dmso)δ184.74,156.30,153.40,146.54–146.27(m),133.09,130.13,126.05,124.9 8,121.51(d,J=25.1Hz),119.50,118.71(d,J=9.2Hz),117.24,115.91,115.48.HRMS(ESI+)[M+H] + calculated for 14 H 10 FN 2 O 2 ] + :257.0721,found:257.0728.

[0104] Embodiment 17

[0105] Synthesis of Compound 3n——(6-chloroimidazole[1,2-a]pyridin-3-yl)(2-hydroxyphenyl)methanone

[0106]

[0107] The preparation method of compound 3n is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 5-chloro-2-aminopyridine (2n, 256 mg, 2 mmol), and the rest is the same.

[0108] In this example, 177 mg of compound 3n was obtained as a yellow solid, with a yield of 65%. 1 H NMR(400MHz,dmso)δ10.17(s,1H),9.64(d,J=1.3Hz,1H),8.08(s,1H),7.90(d,J=9.5Hz,1H),7 .75(dd,J=9.5,2.1Hz,1H),7.45(dd,J=7.6,1.4Hz,1H),7.42–7.34(m,1H),6.99–6.88(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ186.66,161.90,147.44,145.35,135.67,130.81,130.75,126.94,123.58,122.97,120.15,119.34,118.51,118.13.HRMS(ESI+)[M+H] + calculated for 14 H 10 C1N 2 O 2 ] + :273.0425,found:273.0431.

[0109] Embodiment 18

[0110] Synthesis of Compound 3o——(2-Hydroxyphenyl)(6-iodoimidazole[1,2-a]pyridin-3-yl)methanone

[0111]

[0112] The preparation method of compound 3o is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 5-iodo-2-aminopyridine (2o, 440 mg, 2 mmol), and the rest is the same.

[0113] In this example, 317 mg of compound 3o was obtained as a yellow solid with a yield of 87%. 1H NMR(400MHz,dmso)δ10.19(s,1H),9.80(d,J=0.8Hz,1H),7.97(s,1H),7.87(dd,J=9.3,1.7Hz, 1H),7.69(d,J=9.3Hz,1H),7.47–7.42(m,1H),7.42–7.34(m,1H),6.93(dd,J=17.1,8.0Hz,1H). 13 C NMR (101MHz, cdcl 3 )δ186.63,161.90,147.75,144.91,137.50,135.65,133.77,130.82,122.49,120.17,119.32,118.83,118.50,78.64.HRMS(ESI+)[M+Na] + calculated for 14 H 9 IN 2 NaO 2 ] + :386.9601,found:386.9597.

[0114] Embodiment 19

[0115] Compound 3p——Synthesis of 3-(2-hydroxyphenyl)imidazole[1,2-a]pyridine-6-carbonitrile

[0116]

[0117] The preparation method of compound 3p is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 5-nitrile-2-aminopyridine (2p, 238 mg, 2 mmol), and the rest is the same.

[0118] In this example, 142 mg of compound 3p was obtained as a yellow solid, with a yield of 54%. 1 H NMR(400MHz,dmso)δ10.23(s,1H),10.03(d,J=1.0Hz,1H),8.20(s,1H),8.00(dd,J=9.3,0.8Hz,1H ),7.93(dd,J=9.3,1.6Hz,1H),7.47(dd,J=7.6,1.5Hz,1H),7.44–7.36(m,1H),7.02–6.89(m,2H). 13CNMR(101MHz,dmso)δ184.95,156.49,147.98,147.00,135.01,133.46,130.30,13 0.11,125.67,124.64,119.56,118.90,117.34,116.94,100.88.HRMS(ESI+)[M+H] + calculated for [C 15 H 10 N 3 O 2 ] + :264.0768,found:264.0774.

[0119] Embodiment 20

[0120] Compound 3q——Synthesis of 3-(2-hydroxyphenyl)imidazole[1,2-a]pyridine-6-carbonitrile

[0121]

[0122] The preparation method of compound 3q is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 6-methyl-2-aminopyridine (2q, 216 mg, 2 mmol), and the rest is the same.

[0123] In this example, 101 mg of compound 3q was obtained as a yellow solid with a yield of 40%. 1 H NMR(400MHz,dmso)δ11.10(s,1H),8.01(s,1H),7.79(d,J=7.7Hz,1H),7.72(d,J=8.8Hz,1H),7.63(d d,J=8.8,7.1Hz,1H),7.56–7.47(m,1H),7.14(d,J=7.0Hz,1H),7.04–6.95(m,1H),2.50–2.43(m,3H). 13 C NMR(101MHz,dmso)δ184.71,160.15,150.48,145.97,139.88,135.41,132.83,13 0.22,125.45,122.99,119.62,117.76,116.61,115.37,22.21.HRMS(ESI+)[M+H] + calculated for 15 H 13 N 2 O 2 ] +:253.0972,found:253.0976.

[0124] Embodiment 21

[0125] Compound 3s——Synthesis of 3-(2-hydroxyphenyl)imidazole[1,2-a]pyridine-5-carbonitrile

[0126]

[0127] The preparation method of compound 3s is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted 2-aminopyridine in the raw material is specifically 6-nitrile-2-aminopyridine (2s, 238 mg, 2 mmol), and the rest is the same.

[0128] In this example, 95 mg of compound 3s was obtained as a yellow solid with a yield of 36%. 1 H NMR (400 MHz, CDCl 3 )δ11.59(s,1H),8.21(s,1H),8.08(dd,J=9.0,1.2Hz,1H),7.94(dd,J=8.0,1.5Hz,1H),7.6 7(dd,J=7.1,1.0Hz,1H),7.61–7.52(m,2H),7.09(dd,J=8.4,0.7Hz,1H),7.04–6.96(m,1H). 13 C NMR (101 MHz, CDCl 3 )δ185.50,163.09,148.77,144.36,136.82,131.76,127.13,125.42,125 .16,123.43,119.40,119.24,118.72,112.82,112.06.HRMS(ESI+)[M+H] + calculated for 15 H 10 N 3 O 2 ] + :264.0768,found:264.0765.

[0129] Embodiment 22

[0130] Synthesis of Compound 3u——(6-bromo-7-methylimidazo[1,2-a]pyridin-3-yl)(2-hydroxyphenyl)methanone

[0131]

[0132] The preparation method of compound 3u is similar to the preparation method of compound 3a in Example 1, except that: in this example, the substituted 2-aminopyridine in the raw material is specifically 5-bromo-4-methyl-2-aminopyridine (2u, 374 mg, 2 mmol), and the rest is the same.

[0133] In this example, 241 mg of compound 3u was obtained as a yellow solid with a yield of 73%. 1 H NMR (400MHz, dmso) δ10.18(s,1H),9.72(s,1H),8.02(s,1H),7.88(s,1H),7.50–7.35(m,2H),6.93(ddd,J=9.9,8.3,4.6Hz,2H),2.47(s,3H). 13 C NMR(101MHz,dmso)δ184.45,156.40,147.94,146.23,140.62,133.08,130.15,12 8.20,125.90,123.63,119.48,117.44,117.26,113.85,22.71.HRMS(ESI+)[M+H] + calculated for 15 H 12 Bn 2 O 2 ] + :331.0077,found:331.0072.

[0134] Embodiment 23

[0135] Compound 4a——Synthesis of (2-hydroxy-4-methoxyphenyl)(imidazole[1,2-a]pyridin-3-yl)methanone

[0136]

[0137] The preparation method of compound 4a is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 7-methoxychromone (1b, 176 mg, 1 mmol), and the rest is the same.

[0138] In this example, 209 mg of compound 4a was obtained as a yellow solid, with a yield of 78%. 1H NMR(400MHz,dmso)δ11.26(s,1H),9.46(d,J=7.0Hz,1H),8.22(s,1H),7.85(d,J=9.1Hz,1H),7.7 0(d,J=8.6Hz,1H),7.65(t,J=7.9Hz,1H),7.28(t,J=6.9Hz,1H),6.58–6.49(m,2H),3.80(s,3H). 13 C NMR(101MHz,dmso)δ184.59,164.43,161.49,148.68,145.15,132.93,130.15,12 8.93,123.32,117.90,116.67,115.83,106.91,101.97,55.93.HRMS(ESI+)[M+H] + calculated for [C 15 H 13 N 2 O 3 ] + :269.0921,found:269.0915.

[0139] Embodiment 24

[0140] Compound 4b: Synthesis of (2-hydroxy-4-propargylphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone

[0141]

[0142] The preparation method of compound 4b is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 7-propynyloxychromone (1c, 200 mg, 1 mmol), and the rest is the same.

[0143] In this example, 29 mg of compound 4b was obtained as a yellow solid with a yield of 10%. 1 H NMR(400MHz,dmso)δ11.13(s,1H),9.49(d,J=7.1Hz,1H),8.20(s,1H),7.85(d,J=8.7Hz,1H),7.6 6(dd,J=13.2,8.9Hz,2H),7.29(t,J=6.8Hz,1H),6.59(d,J=5.1Hz,2H),4.86(s,2H),3.65(s,1H). 13C NMR(101MHz,dmso)δ184.43,162.07,160.82,148.71,145.34,132.70(d,J=5.1Hz),130.21,128.91,123.41,1 17.90,117.64,115.89,107.34(d,J=5.2Hz),102.91(d,J=7.0Hz),79.37–79.06(m),56.15.HRMS(ESI+)[M+Na] + calculated for 17 H 12 N 2 NaO 3 ] + :315.0740,found:315.0744.

[0144] Embodiment 25

[0145] Synthesis of Compound 4d——(4-bromo-2-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone

[0146]

[0147] The preparation method of compound 4d is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 7-bromochromone (1d, 225 mg, 1 mmol), and the rest is the same.

[0148] In this example, 268 mg of compound 4d was obtained as a yellow solid, with a yield of 85%. 1 H NMR(400MHz,dmso)δ10.54(s,1H),9.59(d,J=6.8Hz,1H),8.05(s,1H),7.85(d,J=8.9Hz,1H),7.68(t,J =7.9Hz,1H),7.38(d,J=8.1Hz,1H),7.33(t,J=6.9Hz,1H),7.15(d,J=1.4Hz,1H),7.11(d,J=8.2Hz,1H). 13 C NMR(101MHz,dmso)δ183.26,156.89,148.86,146.38,131.66,130.57,128.67 ,126.23,125.00,123.95,122.35,119.71,117.95,116.31.HRMS(ESI+)[M+H] + calculated for 14 H 10 Bn2 O 2 ] + :316.9920,found:316.9926.

[0149] Embodiment 26

[0150] Synthesis of Compound 4e——(4-fluoro-2-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone

[0151]

[0152] The preparation method of compound 4e is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 7-fluorochromone (1e, 164 mg, 1 mmol), and the rest is the same.

[0153] In this example, 213 mg of compound 4e was obtained as a yellow solid with a yield of 83%. 1 H NMR(400MHz,dmso)δ10.69(s,1H),9.58(d,J=6.7Hz,1H),8.07(s,1H),7.86(d,J=8.9Hz, 1H),7.73–7.64(m,1H),7.58–7.50(m,1H),7.32(t,J=7.0Hz,1H),6.76(d,J=9.8Hz,2H). 13 C NMR(101MHz,dmso)δ183.46,164.62(d,J=247.8Hz),158.41(d,J=12.2Hz),148.81,146.14,132.25,130.4 6,128.70,123.95,123.26,117.93,116.20,106.63(d,J=20.5Hz),104.05(d,J=22.7Hz).HRMS(ESI+)[M+H] + calculated for 14 H 10 FN 2 O 2 ] + :257.0721,found:257.0717.

[0154] Embodiment 27

[0155] Synthesis of Compound 4f——(5-chloro-2-hydroxyphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone

[0156]

[0157] The preparation method of compound 4f is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 8-chlorochromone (1f, 180 mg, 1 mmol), and the rest is the same.

[0158] In this example, 169 mg of compound 4f was obtained as a yellow solid, with a yield of 62%. 1 H NMR (400 MHz, CDCl 3 )δ11.25(s,1H),9.50(d,J=6.9Hz,1H),8.34(s,1H),7.89–7.80(m,2H),7.61–7. 51(m,1H),7.44(dd,J=8.9,2.6Hz,1H),7.19–7.13(m,1H),7.01(d,J=8.9Hz,1H). 13 C NMR (101 MHz, CDCl 3 )δ185.18,160.11,149.49,145.63,135.02,130.03,128.97,124.02,122.49,119.89,118.03,115.49.HRMS(ESI+)[M+H] + calculated for 14 H 10 C1N 2 O 2 ] + :273.0425,found:273.0429.

[0159] Embodiment 28

[0160] Compound 4g - Synthesis of (5-bromo-2-hydroxyphenyl)(imidazole[1,2-a]pyridin-3-yl)methanone

[0161]

[0162] The preparation method of compound 4g is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 8-bromochromone (1 g, 225 mg, 1 mmol), and the rest is the same.

[0163] In this example, 123 mg of compound 4g was obtained as a yellow solid, with a yield of 39%. 1 H NMR (400 MHz, CDCl 3)δ11.27(s,1H),9.52–9.48(d,1H),8.34(s,1H),8.01(d,J=2.4Hz,1H),7.83(d,J=9.0Hz,1H) ,7.59–7.57(d,1H),7.56(d,J=2.4Hz,1H),7.16(dd,J=6.9,1.0Hz,1H),6.96(d,J=8.9Hz,1H). 13 C NMR (101 MHz, CDCl 3 )δ185.09,160.59,149.52,145.70,137.83,133.01,130.05,128.96,122.49,121.78,120.29,118.05,115.50,110.90.HRMS(ESI+)[M+H] + calculated for 14 H 10 Bn 2 O 2 ] + :316.9920,found:316.9923.

[0164] Embodiment 29

[0165] Synthesis of Compound 4h——(2-Hydroxy-5-methylphenyl)(Imidazol[1,2-a]pyridin-3-yl)methanone

[0166]

[0167] The preparation method of compound 4h is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 8-methylchromone (1h, 160 mg, 1 mmol), and the rest is the same.

[0168] In this example, 156 mg of compound 4h was obtained as a yellow solid, with a yield of 62%. 1 H NMR (400 MHz, CDCl 3 )δ11.18(s,1H),9.50(d,J=6.9Hz,1H),8.30(d,J=6.1Hz,1H),7.80(d,J=9.0Hz,1H),7.68(d,J=1.1Hz,1H),7.58–7 .48(m,1H),7.31(dd,J=8.4,1.7Hz,1H),7.12(td,J=6.9,1.0Hz,1H),6.96(d,J=8.4Hz,1H),2.32(d,J=6.8Hz,3H). 13C NMR (101 MHz, CDCl 3 )δ186.66,159.59,149.15,145.28,136.26,130.84,129.51,128.90,128.38,122.79,120.17,118.07,117.87,115.12,20.62.HRMS(ESI+)[M+H] + calculated for 15 H 13 N 2 O 2 ] + :253.0972,found:253.0968.

[0169] Embodiment 30

[0170] Compound 4i——Synthesis of (2-hydroxy-5-methylphenyl)(imidazo[1,2-a]pyridin-3-yl)methanone

[0171]

[0172] The preparation method of compound 4i is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 7,8-dimethylchromone (1i, 174 mg, 1 mmol), and the rest is the same.

[0173] In this example, 160 mg of compound 4i was obtained as a yellow solid with a yield of 60%. 1 H NMR (400 MHz, CDCl 3 )δ11.35(s,1H),9.48(d,J=6.9Hz,1H),8.31(s,1H),7.79(d,J=9.0Hz,1H),7.65(s,1H) ,7.57–7.44(m,1H),7.11(dd,J=7.4,6.5Hz,1H),6.86(s,1H),2.29(s,3H),2.24(s,3H). 13 CNMR(101MHz,dmso)δ184.84,155.54,148.65,145.81,142.75,130.97(d,J=3.0Hz),130.20 ,128.76,127.32,123.76,122.56,118.35,117.87,115.97,20.17,18.75.HRMS(ESI+)[M+H] + calculated for 16 H 15 N 2O 2 ] + :267.1128,found:267.1120.

[0174] Embodiment 31

[0175] Synthesis of Compound 4j——(2-Hydroxy-5-methylphenyl)(Imidazol[1,2-a]pyridin-3-yl)methanone

[0176]

[0177] The preparation method of compound 4j is similar to the preparation method of compound 3a in Example 1, except that in this example, the substituted chromone in the raw material is specifically 7,8-dimethoxychromone (1j, 206 mg, 1 mmol), and the rest is the same.

[0178] In this example, 200 mg of compound 4i was obtained as a yellow solid with a yield of 67%. 1 H NMR(400MHz,dmso)δ11.22(s,1H),9.42(d,J=6.9Hz,1H),8.37(s,1H),7.84(d,J=8.9Hz,1H),7. 64(t,J=7.7Hz,1H),7.27(t,J=6.8Hz,1H),7.23(s,1H),6.61(s,1H),3.82(s,3H),3.74(s,3H). 13 CNMR(101MHz,dmso)δ184.53,156.32,155.05,148.64,144.85,142.23,130.07,128.94,123 .24,117.88,115.73,113.65,113.13,101.36(d,J=5.8Hz),56.32,56.24.HRMS(ESI+)[M+H] + calculated for 16 H 15 N 2 O 4 ] + :299.1026,found:299.1018.

[0179] Experimental example

[0180] The pyridoimidazole nitrogen fused ring compounds obtained in Examples 1 and 6 to 31 were screened for anti-MV4-11 cell proliferation activity. In order to evaluate the inhibitory activity of pyridoimidazole nitrogen fused ring compounds on MV4-11, CCK8 assay was used: the compound was dissolved in DMSO and diluted with culture medium. MV4-11 cells were inoculated in 96-well plates (cell density 1.5×10 5 Up to 3.0×10 5 cells / well) and cultured for 24 h (5% CO 2 , 37°C). The cells were treated with the diluted compounds and cultured for 24 hours (5% CO 2 , 37°C), add 10 μL Cell-Counting-Kit-8 (CCK-8) to each well, and incubate the plate for 3-5 hours (5% CO 2 The absorbance was measured at 450 nm, and three replicate wells were set up for each sample for analysis. The inhibitory concentration of 50% (IC 50 ). Inhibition rate = [(Ac-As) / (Ac-Ab)] × 100%, As: absorbance of experimental wells (containing cells, culture medium, CCK-8 solution and drug solution); Ac: absorbance of control wells (containing cells, culture medium, CCK-8 solution, no drug); Ab: absorbance of blank wells (containing culture medium, CCK-8 solution, no cells, no drug). The results are shown in Table 1 ("ND" means no detection).

[0181] Table 1 IC of pyridoimidazole nitrogen fused ring compounds against MV4-11 cell proliferation 50

[0182]

[0183]

[0184]

[0185] As shown in Table 1, the pyridine imidazole nitrogen fused ring compounds of the present invention have an inhibitory effect on the proliferation of MV4-11 cells, especially compound 4b has the best activity. Therefore, the pyridine imidazole nitrogen fused ring compounds of the present invention can be used as a single drug or a compound preparation in the preparation of leukemia drugs.

[0186] The above are only embodiments of the present invention. The invention is not limited to the fields involved in this implementation case. The common sense such as the known specific structures and characteristics in the scheme is not described in detail here. The ordinary technicians in the relevant field know all the common technical knowledge in the technical field to which the invention belongs before the application date or priority date, can obtain all the existing technologies in the field, and have the ability to apply the conventional experimental means before that date. The ordinary technicians in the relevant field can improve and implement this scheme in combination with their own abilities under the enlightenment given by this application. Some typical known structures or known methods should not become obstacles for ordinary technicians in the relevant field to implement this application. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the protection scope of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the present invention. The protection scope required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to explain the content of the claims.

Claims

1. A method for preparing a pyridoimidazole nitrogen fused ring compound, characterized in that: The method comprises the following steps: using a substituted chromone as shown in formula (1) and a substituted 2-aminopyridine as shown in formula (2) as raw materials, adding an oxidant and a catalyst, and reacting in a solvent to obtain a pyridine imidazole nitrogen condensed ring compound as shown in formula (3); Among them, R 1 is selected from one of an alkyl group, a hydrogen group, a halogen group, an ester group, a methanol group, a trifluoromethyl group and a cyano group, R 1 The substitution mode is single substitution or multiple substitution, R 1 The substitution position is any position on the pyridine ring; R 2 is selected from one of alkyl, hydrogen, methoxy and halogen, R 2 The substitution mode is single substitution or multiple substitution, R 2 The substitution position is any position on the benzene ring; The oxidant is DTBP, the catalyst is elemental iodine, the solvent is a mixed solvent of toluene and chlorobenzene, and the volume ratio of toluene to chlorobenzene is 3:1; The molar ratio of the substituted chromone shown in formula (1) to the substituted 2-aminopyridine shown in formula (2) is 1:2; the molar ratio of the substituted chromone shown in formula (1) to the oxidant is 1:2.5; the molar ratio of the substituted chromone shown in formula (1) to the catalyst is 1:0.4; the reaction time of the synthesis step is 8 to 24 hours; the reaction temperature of the synthesis step is 80 to 120°C.

2. The method for preparing the pyridoimidazole nitrogen fused ring compound according to claim 1, characterized in that: The volume ratio of the solvent to the amount of the substituted 2-aminopyridine substance represented by formula (2) is 4 mL:1 mmol.

3. The method for preparing the pyridoimidazole nitrogen fused ring compound according to claim 1, characterized in that: The synthesis step further includes a purification step: a mixed solution containing the pyridoimidazole nitrogen fused ring compound as shown in formula (3) is obtained in the synthesis step, and the mixed solution is evaporated and concentrated to obtain a crude product; The crude product was purified by silica gel column chromatography to obtain a pure product.

4. The method for preparing the pyridoimidazole nitrogen fused ring compound according to claim 3, characterized in that: The step of purifying the crude product by silica gel column chromatography comprises: dissolving the crude product by dichloromethane, then loading the crude product-dichloromethane solution into a silica gel column, eluting the silica gel column by an eluent, collecting the eluate, and concentrating the eluate under reduced pressure to obtain a pure product; wherein, the ratio of the volume of the dichloromethane to the mass of the crude product is 5mL:1g, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 4:

1.

5. A pyridoimidazole nitrogen-fused ring compound, characterized in that: The pyridoimidazole nitrogen fused ring compound is one of the following compounds:

6. Use of the pyridoimidazole nitrogen fused ring compound as claimed in claim 5 in the preparation of leukemia drugs.

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