Imidazo [4, 5-b] pyridine compound and application thereof in preparation of antitumor drugs for blocking mRNA translation of tumor cells

Abstract

The invention discloses an imidazo [4, 5-b] pyridine compound capable of blocking mRNA translation of tumor cells and an application of the imidazo [4, 5-b] pyridine compound in preparation of antitumor drugs for blocking mRNA translation of tumor cells, and the imidazo [4, 5-b] pyridine compound has a structure shown in a formula (I) or a pharmaceutically acceptable salt of the imidazo [4, 5-b] pyridine compound. The mRNA translation of cancer promoting protein is crucial to the occurrence and development of malignant tumors, but a small molecular compound for targeted inhibition of mRNA translation is lacked clinically at present. The invention provides an imidazo [4, 5-b] pyridine compound, which can be combined with a translation initiation factor eIF4A and inhibit the ATP-dependent RNA helicase function of the translation initiation factor eIF4A so as to block the translation of mRNA and present proliferation inhibition and apoptosis promotion functions in various tumor cells. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and relates to an imidazo[4,5-b]pyridine compound and its application in blocking mRNA translation of tumor cells, specifically its application in the preparation of anti-tumor drugs, especially its application in the preparation of eIF4A inhibitors. Background Art

[0002] Cellular mRNA translation is the process of synthesizing proteins from mRNA, which is the final step of gene expression and one of the biological processes that consume the most ATP in cells. Translation initiation is the rate-limiting step of mRNA translation, which is mediated by the translation initiation complex composed of the cap-binding protein eIF4E, the scaffold protein eIF4G, and the ATP-dependent RNA helicase eIF4A. The mRNAs of oncoproteins (such as c-Myc, etc.) have longer and more complex secondary structure 5' untranslated regions (5' UTRs). The unwinding of their secondary structure is a prerequisite for their translation. Therefore, malignant tumors usually overexpress factors such as eIF4A to achieve the massive synthesis of oncoproteins, while maintaining the growth needs of tumors, significantly improving the adaptability to the complex and variable tumor microenvironment, resulting in the occurrence, development, and drug resistance of tumors.

[0003] eIF4A has two functional pockets for small molecule intervention - the ATP-binding and RNA-binding pockets. Currently, a variety of natural products (such as Rocaglamides, Pateamine A, etc.) have been reported to act on the RNA-binding domain of eIF4A to block the function of eIF4A, mRNA translation, and tumor progression in an ATP-independent manner; while there is no report on compounds that directly block the RNA helicase function of the ATP-binding site of eIF4A. Summary of the Invention

[0004] The purpose of the present invention is to provide an imidazo[4,5-b]pyridine compound and its application in the preparation of anti-tumor drugs for blocking mRNA translation of tumor cells.

[0005] An imidazo[4,5-b]pyridine compound with the ability to block mRNA translation of tumor cells has the structure shown in formula (I),

[0006]

[0007] or a pharmaceutically acceptable salt thereof;

[0008] Wherein:

[0009] R1 is selected from -NR 11 R 12 ; R 11 、R 12Each independently selected from H, C1-C5 alkyl, 5-8 membered aryl; the alkyl and aryl may be further substituted by C1-C3 alkyl, phenyl, halogen substituted phenyl, 5-10 membered heteroaryl; or R1 and R2 together with the N atom to which they are attached form a 4-8 membered heterocyclic group, and the heterocyclic group may be further substituted by C1-C3 alkyl;

[0010] R2 is selected from 5-8 membered aryl, 5-10 membered heteroaryl, C1-C5 alkyl, and the aryl, heteroaryl and alkyl may be further substituted by one or more, independently of each other, C1-C3 alkoxy, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkylsulfonyl;

[0011] Further, R1 is selected from -NR 11 R 12 ; R 11 、R 12 Each independently selected from H, C1-C3 alkyl, phenyl; the alkyl and phenyl may be further substituted by C1-C3 alkyl, phenyl, halogen substituted phenyl, 5-10 membered heteroaryl; or R1 and R2 together with the N atom to which they are attached form a 5-7 membered heterocyclic group, and the heterocyclic group may be further substituted by C1-C3 alkyl; R2 is selected from phenyl, 5-10 membered heteroaryl, C1-C4 alkyl, and the phenyl, heteroaryl and alkyl may be further substituted by one or more, independently of each other, C1-C3 alkoxy, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkylsulfonyl;

[0012] Further, R1 is selected from -NR 11 R 12 ; R 11 、R 12 Each independently selected from H, C1-C3 alkyl, phenyl; the alkyl and phenyl may be further substituted by methyl, phenyl, halogen substituted phenyl, indolyl; or R1 and R2 together with the N atom to which they are attached form a morpholine ring, a piperazine ring, and the morpholine ring and piperazine ring may be further substituted by methyl; R2 is selected from phenyl, furyl, indolyl, pyridyl, pyrrolyl, isopropyl, and the phenyl and indolyl may be further substituted by one or more, independently of each other, methoxy, halogen, hydroxy, methyl, methylsulfonyl;

[0013] Further, R1 is selected from N-methylpiperazinyl, morpholinyl, p-chlorobenzylamine, p-fluorobenzylamine, p-methylaniline, tryptamine; R2 is selected from phenyl, 4-methoxyphenyl, 2-bromophenyl, 4-bromophenyl, 3,4-dimethoxyphenyl, 3-fluorophenyl, 4-hydroxyphenyl, methylsulfonylphenyl, indole ring, methyl substituted indole ring, pyridine ring, furan ring, pyrrole ring, isopropyl.

[0014] Further, selected from the following compounds:

[0015] 2-(3,4-Dimethoxyphenyl)-5-[(4-fluorobenzyl)amino]-3-propyl-3H-imidazo[4,5-b]pyridine

[0016] 2-(4-Methoxyphenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine

[0017] 2-(4-Bromophenyl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine

[0018] 2-Phenyl-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine

[0019] 2-(Furan-2-yl)-3-propyl-5-[(2-(1H-indol-3-yl)ethyl)amino]-3H-imidazo[4,5-b]pyridine

[0020] 2-(3-Fluorophenyl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine

[0021] 2-Isopropyl-3-propyl-5-[(4-methylphenyl)amino]-3H-imidazo[4,5-b]pyridine

[0022] 2-(2-Methyl-1H-indol-3-yl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine

[0023] 2-(4-Hydroxyphenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine

[0024] 2-(2-Fluorophenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine

[0025] 2-(2-Fluorophenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine

[0026] 2-(3,4-Dimethoxyphenyl)-3-propyl-5-[(2-(1H-indol-3-yl)ethyl)amino]-3H-imidazo[4,5-b]pyridine

[0027] 2-(Furan-2-yl)-3-propyl-5-[(4-chlorobenzyl)amino]-3H-imidazo[4,5-b]pyridine

[0028] 2-(2-Methyl-1H-indol-3-yl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine

[0029] 2-(Pyridin-3-yl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine

[0030] 2-(Pyrrol-2-yl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine

[0031] 2-Phenyl-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine

[0032] 2-(Furan-2-yl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine

[0033] 2-(4-Methylsulfonylphenyl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine.

[0034] Further, it is selected from the following compounds:

[0035]

[0036]

[0037] The present invention also provides the use of the compound according to any one of the above technical solutions in the preparation of an anti-tumor drug.

[0038] Further, the anti-tumor drug is a tumor drug having the activity of inhibiting the RNA helicase activity of eIF4A.

[0039] Further, the anti-tumor drug is an anti-tumor drug that inhibits the helicase activity of eIF4A by competing for the ATP binding site.

[0040] Further, the anti-tumor drug is an anti-tumor drug that increases the level of p-eIF2α and induces endoplasmic reticulum stress.

[0041] Further, the tumor drug is a drug that inhibits one or more of the following cancers: breast cancer, colon cancer.

[0042] An imidazo[4,5-b]pyridine compound having the ability to block mRNA translation of tumor cells, having the structure shown in formula (I),

[0043]

[0044] Wherein

[0045] R1 is selected from alkylamines and arylamines,

[0046] (1) The alkylamines are selected from linear alkylamines and cyclic alkylamines, preferably cyclic alkylamines, among which the cyclic alkylamines are preferably N-methylpiperazine and morpholine;

[0047] (2) The arylamines are selected from substituted benzylamines and heteroarylamines. The substituted benzylamines are preferably p-chlorobenzylamine, p-fluorobenzylamine, and p-methylaniline, and the heteroarylamines are preferably tryptamine.

[0048] R2 is selected from aryl and alkyl,

[0049] (1) The aryl is selected from benzene ring, substituted benzene ring or heteroaryl ring;

[0050] (2) The substituted benzene rings are selected from 4-methoxyphenyl, 2-bromophenyl, 4-bromophenyl, 3,4-dimethoxyphenyl, 3-fluorophenyl, 4-hydroxyphenyl, and phenylmethanesulfonyl;

[0051] (3) The heteroaryl rings are preferably indole ring, pyridine ring, furan ring, and pyrrole ring;

[0052] (4) The alkyl is selected from linear alkyl, branched alkyl, and cycloalkyl, preferably isopropyl.

[0053] Another object of the present invention is to provide that the imidazo[4,5-b]pyridine compounds can block the translation of protein mRNA in tumor cells and promote tumor cell apoptosis by inhibiting the RNA helicase activity of eIF4A.

[0054] Advantages of the present invention: The translation of mRNA of oncoproteins is crucial for the occurrence and development of malignant tumors, but currently there is a lack of small molecule compounds that target and inhibit mRNA translation in clinical practice. The present invention provides an imidazo[4,5-b]pyridine compound, which can bind to the translation initiation factor eIF4A and inhibit its ATP-dependent RNA helicase function, thereby blocking the translation of mRNA, and showing proliferation inhibition and apoptosis-promoting functions in various tumor cells. Brief Description of the Drawings

[0055] Figure 1 Inhibitory effects of 19-1 to 19-18 on the overall mRNA translation of tumor cells;

[0056] Figure 2 19-3 inhibits the mRNA translation in tumor cells in a dose-dependent manner;

[0057] Figure 3 19-3 inhibits the helicase activity of eIF4A by competing for the ATP binding site;

[0058] Figure 419-3 induces endoplasmic reticulum stress in tumor cells;

[0059] Figure 5 The proliferation inhibitory activity of 19-3 against various tumor cells;

[0060] Figure 6 19-3 induces apoptosis in tumor cells. Specific implementation manners

[0061] The present invention will be further described in conjunction with the accompanying drawings and embodiments.

[0062] Example 1. Synthesis of 2-(3,4-dimethoxyphenyl)-5-[(4-fluorobenzyl)amino]-3-propyl-3H-imidazo[4,5-b]pyridine (No. 19-3)

[0063]

[0064] Step 1: Synthesis of compound 19-3-2

[0065] Under an ice bath, DIPEA (3.1 g, 27 mmol) was added to a solution of compound 19-3-1 (4.94 g, 26 mmol) in DCM (60 mL), and then n-propylamine (1.53 g, 26 mmol) was added dropwise with stirring. After the addition was completed, the reaction was carried out at 0 °C for 5 h. After the reaction was completed, the organic phase was washed with 1N hydrochloric acid (60 mL) and dried by rotary evaporation to obtain the crude product of compound 19-3-2, which was directly used for the subsequent reaction. HRMS (ESI): m / z calcd for C8H 11 ClN3O2 + [M+H] + : 216.0534, found: 216.0525.

[0066] Step 2: Synthesis of compound 19-3-3

[0067] To a solution of compound 19-3-2 (1.25 g, 5.8 mmol) in acetonitrile (10 mL), 4-fluorobenzylamine (0.75 g, 6 mmol) and triethylamine (0.75 g, 7.4 mmol) were successively added. The mixture was heated to reflux for 4 h. After the reaction was completed, the reaction solution was restored to room temperature, and acetonitrile was removed by rotary evaporation. Ethyl acetate (50 mL) and 1N hydrochloric acid (50 mL) were added, and the organic phase was separated. The organic phase was washed successively with water (2×50 mL) and saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered to obtain the crude product of compound 19-3-3. HRMS (ESI): m / z calcd for C 15 H 18 FN4O2 + [M+H]+ : 305.1408, found: 305.1400.

[0068] Step 3: Synthesis of Compound 19-3

[0069] Dissolve Compound 19-3-3 (304 mg, 1 mmol) and 3,4-dimethoxybenzaldehyde (166 mg, 1 mmol) in a mixed solution of 8 mL of ethanol and 2 mL of water. Add 50% sodium dithionite (1.4 g, 4 mmol), seal the tube and heat to 110 °C for reaction for 5 h. After the reaction is completed, rotary evaporate to remove ethanol in the reaction solution, dilute with water (20 mL), extract with ethyl acetate (3 × 20 mL), combine the organic phases, wash the organic phase successively with water (1 × 60 mL) and saturated brine (1 × 60 mL), dry over anhydrous sodium sulfate, filter, rotary dry, and purify the obtained crude product by silica gel column chromatography to obtain Compound 19-3. Pale yellow powder, 1 H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.0, 2.5 Hz, 1H), 7.03 - 6.96 (m, 3H), 6.38 (d, J = 8.5 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.58 (d, J = 5.0 Hz, 2H), 4.19 (t, J = 8.0 Hz, 2H), 3.94 (d, J = 1.5 Hz, 6H), 1.84 - 1.76 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl3) δ 162.1 (d, J = 242.5 Hz), 155.3, 150.6, 150.1, 149.3, 147.8, 135.8 (d, J = 2.5 Hz), 129.3 (d, J = 7.5 Hz), 128.9, 128.0, 123.9, 121.3, 115.4 (d, J = 21.3 Hz), 112.3, 111.2, 104.3, 56.2, 56.1, 46.0, 45.2, 23.1, 11.4. HRMS (ESI): m / z calcd for C 24 H 26 FN4O2 + [M + H] + : 421.2034, found: 421.2041.

[0070] Example 2. Synthesis of 2-(4-methoxyphenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-1)

[0071] Using 4-methoxybenzaldehyde instead of 3,4-dimethoxybenzaldehyde, with the molar amount unchanged, and the rest the same as in Example 1, 19-1 was obtained.

[0072] Pale yellow powder, 1 H NMR(500MHz,CDCl3)δ7.75(d,J=8.5Hz,1H),7.66–7.61(m,2H),7.39–7.33(m,2H),7.03–6.97(m,4H),6.36(d,J=8.5Hz,1H),4.92(t,J=5.9Hz,1H),4.57(d,J=5.8Hz,2H),4.17(t,J=8.0Hz,1H),3.87(s,3H),1.78(m,2H),0.83(t,J=7.4Hz,3H). 13 C NMR(125MHz,CDCl3)δ161.1(d,J=243.8Hz),160.5,155.2,150.6,147.7,135.9(d,J=2.5Hz),130.3,129.3(d,J=8.5Hz),128.9,128.1,123.7,115.3(d,J=21.3Hz),114.2,104.2,55.5,47.0,45.0,23.1,11.4.HRMS(ESI):m / z calcd forC 23 H 24 FN4O + [M+H] + :391.1929,found:391.1924.

[0073] Example 3. Synthesis of 2-(4-bromophenyl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine (No. 19-2)

[0074] Using morpholine instead of 4-fluorobenzylamine, and 4-bromobenzaldehyde instead of 3,4-dimethoxybenzaldehyde, with the molar amount unchanged, and the rest the same as in Example 1, 19-2 was obtained.

[0075] Pale yellow powder, 1 H NMR(500MHz,CDCl3)δ7.87(d,J=8.9Hz,1H),7.65–7.58(m,4H),6.66(d,J=8.8Hz,1H),4.22(t,J=7.5Hz,2H),3.87(t,J=5Hz,4H),3.57(t,J=5Hz,4H),1.83(m,2H),0.86(t,J=7.4Hz,3H). 13CNMR(125MHz,CDCl3)δ156.9,150.4,147.6,132.1,130.4,130.2,129.1,128.6,124.0,103.8,66.9,46.6,45.1,23.1,11.4.HRMS(ESI):m / zcalcd forC 19 H 22 BrN4O + [M+H] + :401.0972,found:401.0963.

[0076] Example4.Synthesis of2-phenyl-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine(No.19-4)

[0077] Using benzaldehyde instead of4-bromobenzaldehyde,with the same molar amount,and the rest the same as in Example3,19-4was obtained.

[0078] Brown viscous semi-solid 1 H NMR(500MHz,CDCl3)δ7.85(d,J=8.9Hz,1H),7.71(dd,J=7.9,1.7Hz,2H),7.52–7.43(m,3H),6.67(d,J=8.7Hz,1H),4.24(t,J=7.5Hz,2H),3.64(t,J=5.0Hz,4H),2.58(t,J=5.0Hz,4H),1.84(m,2H),0.85(t,J=7.4Hz,3H). 13 C NMR(125MHz,CDCl3)δ156.7,151.4,147.6,131.3,129.5,129.0,128.9,128.8,128.3,103.8,55.1,46.2,45.1,23.1,11.4.HRMS(ESI):m / z calcd for C 19 H 23 N4O + [M+H] + :323.1866,found:323.1865.

[0079] Example5.Synthesis of2-(furan-2-yl)-3-propyl-5-[(2-(1H-indol-3-yl)ethyl)amino]-3H-imidazo[4,5-b]pyridine(No.19-5)

[0080] Using tryptamine instead of4-fluorobenzylamine,and2-furaldehyde instead of3,4-dimethoxybenzaldehyde,with the same molar amount,and the rest the same as in Example1,19-5was obtained.

[0081] Pale yellow solid, 1 H NMR(500MHz,CDCl3)δ8.12(s,1H),7.73(d,J=8.5Hz,1H),7.68(d,J=8.0Hz,1H),7.58(dd,J=6.5,1.0Hz,1H),7.39(d,J=8.0Hz,1H),7.24-7.20(m,1H),7.17-7.12(m,1H),7.07(d,J=2.5Hz,1H),7.04(q,J=3.5,0.5Hz,1H),6.58(dd,J=1.5Hz,1H),6.33(d,J=9.0Hz,1H),4.63(s,1H),4.46(t,J=7.5Hz,2H),3.78–3.74(m,2H),3.15(t,J=7.0Hz,2H),1.93-1.86(m,2H),0.97(t,J=7.5Hz,3H). 13 C NMR(125MHz,CDCl3)δ156.1,147.4,146.4,143.3,141.0,136.6,128.9,127.8,127.7,122.3,122.2,119.6,119.1,113.8,112.0,111.4,110.8,105.1,45.1,42.8,25.6,23.6,10.7.HRMS(ESI):m / zcalcd for C 23 H 24 N5O + [M+H] + :386.1975,found:386.1979.

[0082] Example 6. Synthesis of 2-(3-fluorophenyl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine (No. 19-6)

[0083] Using N-methylpiperazine to replace 4-fluorobenzylamine and 3-fluorobenzaldehyde to replace 3,4-dimethoxybenzaldehyde, with the molar amounts unchanged, and the rest the same as in Example 1, 19-6 was obtained.

[0084] Red powder, 1 H NMR(500MHz,CDCl3)δ 11H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.8 Hz, 1H), 7.53–7.37 (m, 3H), 7.16 (tdd, J = 8.3, 2.6, 1.3 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 4.24 (t, J = 7.5 Hz, 2H), 3.64 (t, J = 5.0 Hz, 4H), 2.57 (t, J = 5.0 Hz, 4H), 2.36 (s, 3H), 1.83 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H). 13 13C NMR (125 MHz, CDCl3) δ 162.9 (d, J = 245.0 Hz), 156.8, 149.8 (d, J = 2.5 Hz), 147.6, 133.3 (d, J = 7.5 Hz), 130.5 (d, J = 8.8 Hz), 129.1, 128.1, 124.6 (d, J = 3.8 Hz), 116.4 (d, J = 21.3 Hz), 116.1 (d, J = 22.5 Hz), 115.9, 104.1, 55.0, 46.3, 46.1, 45.0, 23.1, 11.4. HRMS (ESI): m / z calcd for C 20 H 25 FN5 + [M + H] + : 354.2089, found: 354.2087.

[0085] Example 7. Synthesis of 2-Isopropyl-3-propyl-5-[(4-methylphenyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-7)

[0086] Using 4-methylaniline instead of 4-fluorobenzylamine and isobutyraldehyde instead of 3,4-dimethoxybenzaldehyde, with the same molar amounts, and the rest the same as in Example 1, 19-7 was obtained.

[0087] Purple-black powder, 1 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 8.5 Hz, 1H), 6.53 (s, 1H), 4.12 (t, J = 7.5 Hz, 2H), 3.16 (m, 1H), 2.32 (s, 3H), 1.90 (m, 2H), 1.43 (d, J = 6.5 Hz, 6H), 1.00 (t, J = 7.5 Hz, 3H). 13CNMR(125MHz,CDCl3)δ157.9,152.1,146.7,138.9,131.5,129.7,128.4,128.2,119.5,104.8,43.9,26.8,23.5,21.8,20.9,11.5.HRMS(ESI):m / z calcd for C 19 H 25 N4 + [M+H] + :309.2074,found:309.2066.

[0088] Example 8. Synthesis of 2-(2-methyl-1H-indol-3-yl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-8)

[0089] Using 2-methyl-1H-indole-3-carbaldehyde instead of 3,4-dimethoxybenzaldehyde, with the same molar amount, and the rest the same as in Example 1, 19-8 was obtained.

[0090] Yellow powder 1 H NMR(500MHz,CDCl3)δ10.97(s,1H),7.80(d,J=8.5Hz,1H),7.42-7.35(m,3H),7.20-7.18(m,1H),7.08-7.00(m,4H),6.39(d,J=8.5Hz,1H),4.91(t,J=6.0Hz,1H),4.60(d,J=5.0Hz,2H),4.12(t,J=7.0Hz,2H),2.07(s,3H),1.64(m,2H),0.60(t,J=7.5Hz,3H). 13 C NMR(125MHz,CDCl3)δ162.6(d,J=243.4Hz),155.1,147.6,147.3,137.7,135.9(d,J=3.1Hz),135.7,129.3(d,J=7.8Hz),128.3,128.2,127.8,121.3,120.1,118.4,115.4(d,J=21.3Hz),111.2,103.7,102.8,46.1,45.0,22.5,11.9,11.1.HRMS(ESI):m / z calcd for C 25 H 25 FN5 + [M+H] + :414.2089,found:414.2082.

[0091] Synthesis of Example 9. 2-(4-Hydroxyphenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-9)

[0092] Using 4-hydroxybenzaldehyde instead of 3,4-dimethoxybenzaldehyde, with the same molar amount, and the rest the same as in Example 1, 19-9 was obtained.

[0093] Pale yellow powder 1 H NMR(500MHz,DMSO-d6)δ9.87(s,1H),7.63(d,J=8.5Hz,1H),7.53(d,J=8.5Hz,2H),7.45–7.39(m,2H),7.23(t,J=6.0Hz,1H),7.11(t,J=8.5Hz,2H),6.90(d,J=9.0Hz,2H),6.46(d,J=8.5Hz,1H),4.50(d,J=6.0Hz,2H),4.11(t,J=7.4Hz,2H),1.60(m 2H),0.69(t,J=7.4Hz,3H). 13 C NMR(125MHz,DMSO-d6)δ160.9(d,J=240.1Hz),158.3,155.2,149.0,147.2,137.2(d,J=3.1Hz),129.9,129.3(d,J=7.6Hz),129.3,128.9,126.4,121.8,115.5,114.7(d,J=20.8Hz),104.8,44.1,44.0,22.3,11.0.HRMS(ESI):m / z calcd for C 22 H 22 FN4O + [M+H] + :377.1772,found:377.1762.

[0094] Synthesis of Example 10. 2-(2-Bromophenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-10)

[0095] Using 2-bromobenzaldehyde instead of 3,4-dimethoxybenzaldehyde, with the same molar amount, and the rest the same as in Example 1, 19-10 was obtained.

[0096] Pale yellow powder 11H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.7 Hz, 1H), 7.70 (dd, J = 8.0, 1.0 Hz, 1H), 7.48 (dd, J = 7.5, 1.5 Hz, 1H), 7.43 (td, J = 7.4, 1.0 Hz, 1H), 7.40–7.34 (m, 3H), 7.04–6.99 (m, 2H), 6.40 (d, J = 8.5 Hz, 1H), 4.94 (t, J = 6.0 Hz, 1H), 4.58 (d, J = 6.5 Hz, 2H), 3.98 (t, J = 7.5 Hz, 2H), 1.67 (m, 2H), 0.73 (t, J = 7.5 Hz, 3H). 13 13C NMR (125 MHz, CDCl3) δ 162.0 (d, J = 243.4 Hz), 155.6, 149.2, 146.8, 135.8 (d, J = 3.1 Hz), 133.0, 132.9, 132.5, 131.3, 129.5, 129.3 (d, J = 7.6 Hz), 127.9, 127.5, 124.2, 115.4 (d, J = 21.3 Hz), 104.5 45.9, 44.9, 22.8, 11.4. HRMS (ESI): m / z calcd for C 22 H 21 BrFN4 + [M + H] + : 439.0928, found: 439.0928.

[0097] Example 11. Synthesis of 2-(3,4-dimethoxyphenyl)-3-propyl-5-[(2-(1H-indol-3-yl)ethyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-11)

[0098] Using 3,4-dimethoxybenzaldehyde instead of 2-formylfuran, with the same molar amount, and the rest the same as in Example 5, 19-11 was obtained.

[0099] Pale yellow powder, 11H NMR (500 MHz, CDCl3) δ 10.82 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.0, 2.0 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.11 c, 7.09–7.06 (m, 1H), 7.01–6.98 (m, 1H), 6.84 (t, J = 5.5 Hz, 1H), 6.46 (d, J = 9.0 Hz, 1H), 4.28 (t, J = 7.5 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.63 - 3.59 (m, 2H), 3.02 (t, J = 7.0 Hz, 2H), 1.81–1.73 (m, 2H), 0.78 (t, J = 7.5 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 156.3, 150.0, 149.1, 148.8, 148.0, 136.8, 128.5, 127.9, 126.5, 124.1, 123.2, 121.3, 121.3, 118.8, 118.6, 112.9, 112.5, 112.1, 111.9, 105.6, 56.0, 55.4, 44.7, 42.7, 25.7, 23.0, 11.6. HRMS (ESI): m / z calcd for C 27 H 30 N5O2 + [M + H] + : 456.2394, found: 456.2389.

[0100] Example 12. Synthesis of 2-(furan-2-yl)-3-propyl-5-[(4-chlorobenzyl)amino]-3H-imidazo[4,5-b]pyridine (No. 19-12)

[0101] Using 4-chlorobenzylamine instead of tryptamine in the same molar amount and following the same procedure as in Example 5, 19-12 was obtained.

[0102] Yellow powder 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.30–7.26 (m, 2H), 7.03 (d, J = 2.7 Hz, 1H), 6.56 (dd, J = 3.4, 1.8 Hz, 1H), 6.37 (d, J = 8.7 Hz, 1H), 4.95 (s, 1H), 4.58 (s, 2H), 4.40 (t, J = 7.0 Hz, 1H), 1.84–1.79 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13 13C NMR (125 MHz, CDCl3) δ 155.5, 147.2, 146.2, 143.4, 141.4, 138.6, 132.8, 129.1, 129.0, 128.7, 128.1, 112.0, 110.9, 104.9, 45.9, 44.8, 23.5, 11.4. HRMS (ESI): m / z calcd for C 20 H 20 ClN4O + [M + H] + : 367.1320, found: 367.1311.

[0103] Example 13. Synthesis of 2-(2-methyl-1H-indol-3-yl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine (No. 19-13)

[0104] Using morpholine instead of 4-fluorobenzylamine with the same molar amount, and the rest the same as in Example 8, 19-13 was obtained.

[0105] Pale yellow powder, 1 1H NMR (500 MHz, CDCl3) δ 11.24 (s, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.09–7.01 (m, 2H), 6.67 (d, J = 8.9 Hz, 1H), 4.18 (t, J = 7.0 Hz, 2H), 3.91 (t, J = 5.0 Hz, 4H) 3.59 (t, J = 5.0 Hz, 4H), 2.03 (s, 3H), 1.71 (m, 2H), 0.63 (t, J = 7.5 Hz, 3H). 13CNMR(125MHz,CDCl3)δ156.5,148.9,147.2,137.9,135.8,128.8,128.0,127.8,121.3,120.1,118.3,111.2,103.0,102.6,67.0,46.9,44.98,22.5,11.9,11.2.HRMS(ESI):m / z calcd for C 22 H 26 N5O + [M+H] + :376.2132,found:376.2123.

[0106] Example 14. Synthesis of 5-(4-methylpiperazin-1-yl)-3-propyl-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridine (No. 19-14)

[0107] Using 3-pyridinecarboxaldehyde instead of 3-fluorobenzaldehyde, with the same molar amount, and the rest the same as in Example 6, 19-14 was obtained.

[0108] Pale yellow powder, 1 H NMR(500MHz,CDCl3)δ8.96(dd,J=2.3,1.1Hz,1H),8.69(dd,J=4.9,1.7Hz,1H),8.07(dt,J=7.9,2.0Hz,1H),7.85(d,J=8.9Hz,1H),7.43(ddd,J=7.9,4.9,1.0Hz,1H),6.69(d,J=8.9Hz,1H),4.24(t,J=7.5Hz,2H),3.63(t,J=5.0Hz,4H),2.56(t,J=5.0Hz,4H),2.35(s,3H),1.85(m,2H),0.86(t,J=7.4Hz,3H). 13 C NMR(125MHz,CDCl3)δ156.9,150.3,149.4,148.0,147.6,136.4,129.2,128.3,127.6,123.7,104.2,55.0,46.3,46.1,45.1,23.2,11.4.HRMS(ESI):m / z calcd for C 19 H 25 N6 + [M+H] + :337.2135,found:337.2127.

[0109] Synthesis of Example 15. 2-(Pyrrol-2-yl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine (No. 19-15)

[0110] Using 2-formylpyrrole instead of 4-bromobenzaldehyde with the same molar amount, and the rest the same as in Example 3, 19-15 was obtained.

[0111] Pale yellow powder, 1 H NMR(500MHz,CDCl3)δ11.11(s,1H),7.76(d,J=9.0Hz,1H),6.95(s,1H),6.69(s,1H),6.60(d,J=9.0Hz,1H),6.35(s,1H),4.40(t,J=7.5Hz,2H),3.88(t,J=5.0Hz,4H),3.55(t,J=5.0Hz,4H),2.01–1.93(m,2H),4.40(t,J=7.5Hz,3H). 13 C NMR(125MHz,CDCl3)δ156.5,147.5,145.3,128.1,127.5,122.3,121.0,110.1,109.1,103.2,67.0,46.8,44.5,22.9,11.6.HRMS(ESI):m / z calcd for C 17 H 22 N5O + [M+H] + :312.1819,found:312.1813.

[0112] Synthesis of Example 16. 2-Phenyl-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine (No. 19-16)

[0113] Using benzaldehyde instead of 3-fluorobenzaldehyde with the same molar amount, and the rest the same as in Example 6, 19-16 was obtained.

[0114] Yellow powder, 1 H NMR(500MHz,CDCl3)δ7.90(d,J=8.9Hz,1H),7.74–7.69(m,2H),7.52–7.46(m,3H),6.66(d,J=8.9Hz,1H),4.24(t,J=7.5Hz,2H),3.88(t,J=5.0Hz,4H),3.57(t,J=5.0Hz,4H),2.67(s,3H),1.87–1.82(m,2H),0.85(t,J=7.4Hz,3H). 1313C NMR (125 MHz, CDCl3) δ 156.7, 151.5, 147.4, 130.9, 129.5, 128.9, 128.9, 128.7, 128.3, 103.5, 66.8, 66.6, 46.6, 45.0, 23.0, 11.3. HRMS (ESI): m / z calcd for C 20 H 26 N5 + [M + H] + : 336.2183, found: 336.2174.

[0115] Example 17. Synthesis of 2-(furan-2-yl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine (No. 19-17)

[0116] Using 2-formylfuran instead of 3-fluorobenzaldehyde with the same molar amount, and the rest the same as in Example 6, 19-17 was obtained.

[0117] Yellow solid 1 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 3.5 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H), 6.57 (dd, J = 3.5, 1.7 Hz, 1H), 4.44 (t, J = 7.2 Hz, 2H), 3.69 (t, J = 5.5 Hz, 4H), 2.68 (t, J = 5.5 Hz, 4H), 2.44 (s, 3H), 1.86 (m 2H), 0.94 (t, J = 7.5 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 156.5, 147.1, 146.2, 143.6, 142.3, 128.8, 128.3, 112.0, 111.2, 104.1, 54.8, 46.0, 45.7, 44.8, 23.5, 11.5. HRMS (ESI): m / z calcd for C 18 H 24 N5O + [M + H] + : 326.1975, found: 326.1984.

[0118] Example 18. Synthesis of 2-(4-methylsulfonylphenyl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine (No. 19-18)

[0119] Using 4-(methylsulfonyl)benzaldehyde instead of 4-bromobenzaldehyde, with the molar amount unchanged, and the rest the same as in Example 3, 19-18 was obtained.

[0120] Yellow powder, 1 H NMR(500MHz,CDCl3)δ8.07(d,J=8.5Hz,2H),7.95(d,J=8.5Hz,2H),7.89(d,J=8.9Hz,1H),6.69(d,J=8.9Hz,1H),4.27(t,J=7.5Hz,2H),3.87(t,J=5.0Hz,4H),3.59(t,J=5.0Hz,4H),3.11(s,3H),1.86–1.80(m,2H),0.87(t,J=7.5Hz,3H). 13 C NMR(125MHz,CDCl3)δ157.1,148.9,147.7,141.0,136.5,129.7,129.5,128.5,127.9,104.3,66.9,46.4,45.3,44.6,23.2,11.4.HRMS(ESI):m / z calcd for C 20 H 25 N4O3S + [M+H] + :401.1642,found:401.1632.

[0121] Example 19. Evaluation of the inhibitory activity of 19-1 to 19-18 on the overall mRNA translation function of tumor cells

[0122] The compounds described in Examples 1 to 18 were co-incubated with breast cancer cells 4T1 for 4 h, 10 μg / mL puromycin was added, and after culturing at 37 °C for 15 min, the cells in the 6-well plate were scraped off, the cell pellet was collected by centrifugation at 800 g for 3 min, an appropriate amount of RIPA lysis buffer was then added, and the cells were lysed on ice for 30 min, centrifuged at 16000 g at 4 °C for 10 min, the supernatant was taken, and the protein was quantified by BCA. Protein samples with the same concentration were prepared according to the protein concentration. Then Western Blot was performed. The gel was run at a constant voltage of 80 V until the protein marker was separated, and then run to the end at a constant voltage of 140 V. After activating the PVDF membrane with methanol, the membrane was transferred at a constant current of 300 mA on ice for 75 min, blocked with 5% milk prepared with PBST at room temperature for 1 h, washed with 5% PBST 3 times, 5 min each time, and then incubated with the corresponding primary antibodies (puromycin, β-actin), incubated on a shaker at 4 °C overnight, washed the membrane the next day and then added the secondary antibody of the corresponding mouse species, incubated at room temperature for 1 h, washed with 5% PBST 3 times, 5 min each time, and dropped 1:1 prepared ECL developing solution for exposure. Gray scale analysis was performed and the changes in translation activity were statistically analyzed.

[0123] The results are as Figure 1 shown. The results indicate that all 18 compounds from Compound 19-1 to Compound 19-18 can inhibit the mRNA translation level in 4T1 cells, among which Compound 19-1, Compound 19-3, Compound 19-8 and Compound 19-11 have the strongest effects.

[0124] Example 20. Evaluation of the dose-effect relationship of Compound 19-3 in inhibiting mRNA translation

[0125] Digest and passage 4T1 cells in the logarithmic growth phase, plate them in a 6-well plate at 200,000 cells / well. Wait until the cell confluence reaches about 80%, then add Compound 19-3 at gradients of 0, 5, 10, 15, 20, 30 μM. After 4 hours of treatment, add 10 μg / mL puromycin, and the rest is the same as in Example 19.

[0126] The results are as Figure 2 shown. The results indicate that in 4T1 cells, Compound 19-3 exhibits a dose-dependent function in inhibiting mRNA translation.

[0127] Example 21. Cloning, expression and purification of eIF4A protein and RNA helicase enzyme activity experiment

[0128] The human eIF4A (NM_001416.4) and eIF4B (NM_001417.7) were cloned into the pCoofy plasmid and transfected into Escherichia coli BL21. BL21 was cultured in a 300 mL conical flask with shaking until the OD value reached between 0.6 and 0.8. IPTG at a concentration of 0.5 mM was added at a ratio of 1:1000, and eIF4A and eIF4B protein expression was induced at 18 °C, 220 rpm for 16 h. Then, the bacteria were collected by centrifugation at 4 °C, 4000 g for 20 min. Lysis buffer (50 mM NaH2PO4, 300 mM NaCl, 10 mM imidazole, pH adjusted to 8.0) was added to the bacterial cells, and PMSF and leupeptin were supplemented. After lysis on ice for 30 min, the cells were sonicated and centrifuged at 4 °C, 12000 g for 30 min. The supernatant was collected and added to Ni-NTA beads, and incubated with rotation at 4 °C for 4 h. The protein was purified through the 10xHis tag. After incubation, the supernatant was discarded, and the beads were washed 5 times with Wash buffer (50 mM NaH2PO4, 300 mM NaCl, 20 mM imidazole, pH adjusted to 8.0), and then eluted with Elution buffer (50 mM NaH2PO4, 300 mM NaCl, 250 mM imizazole, pH adjusted to 8.0) to obtain the protein solution. The buffer system of the protein solution was replaced by dialysis against PBS overnight to remove imidazole and obtain purified eIF4A and eIF4B proteins.

[0129] The 32 nt (5′–Cy5-CGAGGUCCCAAGGGUUGGGCUGUUCGCCCAUU-3′) and 9 nt RNA (5′–UUGGGACCU-Cy3–3′) fluorescently labeled RNAs were successively placed at 96 °C for 2 min, room temperature for 1 h, and on ice for 15 min to prepare 25 μM RNA duplex (25 mM Hepes / KOH, pH 7.4). A helicase reaction system (500 nM duplex RNA, 5 μM unlabeled complementary strand RNA (5′–AGGUCCCAA–3’), 5 μM purified eIF4A and eIF4B proteins, 30 mM Hepes / KOH pH 7.4, 100 mM KOAc, 3 mM Mg(OAc)2, 2 mM DTT) was configured. 0.3 mM or 3 mM ATP and different concentrations of the compound were added to a 384-well black square-bottom round plate (corning 4514) for reaction. Based on the FRET principle, Cy3 was excited at 554 nm, and then the fluorescence value change was detected at 666 nm. The detection was performed once every 10 s for a total of 30 min.

[0130] The results are as Figure 3As shown, 19-3 can dose-dependently inhibit the helicase activity of eIF4A, and its inhibitory efficiency is more significant at low concentrations of ATP, suggesting that 19-3 is an ATP-competitive inhibitor of eIF4A helicase activity.

[0131] Example 22. Detection of 19-3-mediated endoplasmic reticulum stress in tumor cells

[0132] Digest and passage MDA-MB-231 and 4T1 cells in the logarithmic growth phase, plate them in a 6-well plate at 200,000 cells / well. When the cells grow to an appropriate density, collect samples 4 hours after administration according to the concentration gradient of compound 19-3: 0, 5, 10, 15, 20, 30 μM. Select p-eIF2αSer51 and β-actin as the primary antibodies, and the rest is the same as in Example 19.

[0133] The experimental results are shown in Figure 4 , and the results show that compound 19-3 can dose-dependently increase the level of p-eIF2α and induce endoplasmic reticulum stress.

[0134] Example 23. Detection of the inhibitory effect of 19-3 on tumor cell proliferation

[0135] 150 μL (a total of 4000 - 10000) cells ( Figure 5 as shown) were seeded in a 96-well plate. After 24 hours, compound 19-3 was added at concentrations of 0, 5, 10, 15, 20, 25, 30 μM and the cells were treated for 48 hours. 150 μL of pre-cooled 10% trichloroacetic acid (TCA) solution was added to each well to fix the cells, and then 100 μL of 0.2% SRB solution (prepared with 1% glacial acetic acid) was added, and the cells were stained on a shaker at room temperature for 30 minutes. After staining, the wells were rinsed with freshly prepared 1% glacial acetic acid until there was no excess SRB staining solution in the well plate, and then dried in an oven. The dye was dissolved with 100 μL of 10 mM Tris-HCl pH 10.5 solution per well, shaken on a shaker at room temperature for 5 minutes, and the absorbance was measured at 515 nm.

[0136] The experimental results are shown in Figure 5 , and the results show that compound 19-3 has an inhibitory effect on the proliferation of different tumor cells.

[0137] Example 24. Detection of compound 19-3-mediated apoptosis in tumor cells

[0138] Add 30 μM of Compound 19-3 or DMSO control to 4T1 cells and treat for 24 h. When collecting samples, collect all the culture medium, washed PBS, and digested cell suspension into one centrifuge tube. After centrifuging at 800 g for 3 min, wash the cells twice with pre-cooled 1x PBS. Then resuspend the cell pellet with 100 μL of 1x PBS, add 5 μL of Annexin V-FITC and 5 μL of PI dye, mix well by pipetting, and incubate in the dark at room temperature for 10 min. Then resuspend with 400 μL of Binding Buffer and perform flow cytometry within 1 h after staining. Set the FITC and PE channels to detect the proportion of apoptotic cells.

[0139] The results are shown in Figure 6 , indicating that Compound 19-3 can significantly induce apoptosis of tumor cells.

Claims

1. An imidazo[4,5-b]pyridine compound, characterized in that, Having the structure shown in formula (I), or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from -NR 11 R 12 ; R 11 , R 12 are each independently selected from H, C1-C5 alkyl, 5-8 membered aryl; the alkyl and aryl may be further substituted by C1-C3 alkyl, phenyl, halogen-substituted phenyl, 5-10 membered heteroaryl; or R1 and the N atom to which it is attached form a 4-8 membered heterocyclic group, and the heterocyclic group may be further substituted by C1-C3 alkyl; R2 is selected from 5- to 8-membered aryl, 5- to 10-membered heteroaryl, C1-C5 alkyl, and the aryl, heteroaryl and alkyl may be further substituted by one or more C1-C3 alkoxy groups, halogens, hydroxyl groups, C1-C3 alkyl groups, C1-C3 alkylsulfonyl groups independently of each other.

2. The imidazo[4,5-b]pyridine compound according to claim 1, wherein The R1 is selected from -NR 11 R 12 ; R 11 , R 12 are each independently selected from H, C1-C3 alkyl, phenyl; the alkyl and phenyl may be further substituted by C1-C3 alkyl, phenyl, halogen-substituted phenyl, 5-10 membered heteroaryl; or R1 and the N atom to which it is attached form a 5-7 membered heterocyclic group, and the heterocyclic group may be further substituted by C1-C3 alkyl; R2 is selected from phenyl, 5-10 membered heteroaryl, C1-C4 alkyl, and the phenyl, heteroaryl and alkyl may be further substituted by one or more, independently of each other, C1-C3 alkoxy, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkylsulfonyl.

3. The imidazo[4,5-b]pyridine compound according to claim 1, wherein The R1 is selected from -NR 11 R 12 ; R 11 and R 12 are each independently selected from H, an alkyl group having 1 to 3 carbon atoms, and phenyl; the alkyl group and the phenyl group may be further substituted by methyl, phenyl, halogen-substituted phenyl, or indolyl; or R1 and the N atom to which they are attached form a morpholine ring or a piperazine ring, and the morpholine ring and the piperazine ring may be further substituted by methyl; R2 is selected from phenyl, furyl, indolyl, pyridyl, pyrrolyl, and isopropyl, and the phenyl group and the indolyl group may be further substituted by one or more independently selected methoxy groups, halogens, hydroxyl groups, C-methyl groups, and methylsulfonyl groups.

4. The imidazo[4,5-b]pyridine compound according to claim 1, wherein R1 is selected from N-methylpiperazinyl, morpholinyl, p-chlorobenzylamine, p-fluorobenzylamine, p-methylaniline, tryptamine; R2 is selected from phenyl, 4-methoxyphenyl, 2-bromophenyl, 4-bromophenyl, 3,4-dimethoxyphenyl, 3-fluorophenyl, 4-hydroxyphenyl, methylsulfonylphenyl, indole ring, methyl-substituted indole group, pyridine ring, furan ring, pyrrole ring, isopropyl.

5. The imidazo[4,5-b]pyridine compound according to claim 1, characterized in that, Selected from the following compounds: 2-(3,4-Dimethoxyphenyl)-5-[(4-fluorobenzyl)amino]-3-propyl-3H-imidazo[4,5-b]pyridine 2-(4-Methoxyphenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine 2-(4-Bromophenyl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine 2-Phenyl-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine 2-(Furan-2-yl)-3-propyl-5-[(2-(1H-indol-3-yl)ethyl)amino]-3H-imidazo[4,5-b]pyridine 2-(3-Fluorophenyl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine 2-Isopropyl-3-propyl-5-[(4-methylphenyl)amino]-3H-imidazo[4,5-b]pyridine 2-(2-Methyl-1H-indol-3-yl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine 2-(4-Hydroxyphenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine 2-(2-Fluorophenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine 2-(2-Bromophenyl)-3-propyl-5-[(4-fluorobenzyl)amino]-3H-imidazo[4,5-b]pyridine 2-(3,4-Dimethoxyphenyl)-3-propyl-5-[(2-(1H-indol-3-yl)ethyl)amino]-3H-imidazo[4,5-b]pyridine 2-(Furan-2-yl)-3-propyl-5-[(4-chlorobenzyl)amino]-3H-imidazo[4,5-b]pyridine 2-(2-Methyl-1H-indol-3-yl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine 2-(Pyridin-3-yl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine 2-(Pyrrol-2-yl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine 2-Phenyl-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine 2-(Furan-2-yl)-3-propyl-5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine 2-(4-Methylsulfonylphenyl)-3-propyl-5-(morpholin-4-yl)-3H-imidazo[4,5-b]pyridine.

6. Use of a compound according to any one of claims 1 to 5 in the preparation of an anti-tumor drug.

7. The application according to claim 6, wherein The anti-tumor drug is a tumor drug having inhibitory activity against the RNA helicase activity of eIF4A.

8. The application according to claim 6, wherein The anti-tumor drug is an anti-tumor drug that inhibits the helicase activity of eIF4A by competing for the ATP binding site.

9. The application according to claim 6, wherein The anti-tumor drug is an anti-tumor drug that increases the level of p-eIF2α and induces endoplasmic reticulum stress.

10. The application according to claim 6, wherein The tumor drug is a drug that inhibits one or more of the following cancers: breast cancer, colon cancer.

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