A cyclopropanediamide compound containing an imidazo[1,2-a]pyridine skeleton and its preparation method and use

Abstract

The present invention belongs to the technical field of drug synthesis, and specifically relates to a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, wherein the compound has a structure as shown in formula (I): The compound provided by the present invention shows excellent inhibitory activity and kinase selectivity to tyrosine kinase, can exert good anti-tumor efficacy, and can be used for the treatment of various malignant tumor diseases such as liver cancer, lung cancer and leukemia.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, a preparation method and use thereof. Background Art

[0002] In the past decade, many breakthroughs have been made in targeted tumor therapy. Among them, various targeted inhibitors designed based on tyrosine kinase (TKs) have shown outstanding therapeutic effects on a variety of malignant tumors. TKs are a type of tyrosine-specific protein kinase that catalyzes the transfer of the phosphate group of adenosine triphosphate (ATP) to the tyrosine residue of downstream proteins for phosphorylation. Currently, more than 90 TKs have been discovered, which can be divided into receptor tyrosine kinases (RTKs), cytoplasmic tyrosine kinases and nuclear tyrosine kinases, among which RTKs are the most widely studied.

[0003] RTKs usually consist of three parts: ① an extracellular domain containing a ligand binding site, ② a single-transmembrane hydrophobic α-helix region, and ③ an intracellular domain containing tyrosine protein kinase activity. RTKs have not only been shown to be key regulators of normal cellular processes, but also play a key role in the development and deterioration of many types of cancer. Abnormal expression of RTKs activates a series of downstream signaling pathways, causing cascade reactions, leading to disordered cell proliferation regulation, and ultimately leading to tumor formation. When drugs bind to the intracellular tyrosine kinase domain of RTKs, they can effectively inhibit the activity of RTKs, thereby exerting an anti-tumor effect. Based on this, people have successively developed a variety of RTKs inhibitors, such as sorafenib, gefitinib, crizotinib, gilteritinib, osimertinib, lorlatinib, cabozantinib, etc. The main targets of these RTKs inhibitors include FLT3, AXL, MET, EGFR, FGFR, VEGFR and KIT, and the malignant tumors covered include lung cancer, liver cancer, kidney cancer, pancreatic cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, lymphoma, etc. Therefore, it is very meaningful to continue to study tyrosine kinase inhibitors in order to obtain more compounds with high inhibitory activity against tyrosine kinases, in order to provide more options for the treatment of diseases. Summary of the invention

[0004] The present invention aims to provide a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, in order to obtain more compounds with high inhibitory activity against tyrosine kinase.

[0005] In order to achieve the above object, the present invention provides an imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof having a structure as shown in formula (I):

[0006]

[0007] In formula (I), R 1 and R 2 Each is independently hydrogen, halogen, trifluoromethyl, hydroxyl, hydroxymethyl, trifluoromethoxy, acetyl, or C1-C4 linear or branched alkyl;

[0008] R 3 , R 4 , R 5 and R 6 Each is independently hydrogen, halogen, trifluoromethyl, hydroxyl, cyano, nitro, amino, hydroxymethyl, trifluoromethoxy, carboxyl, mercapto, C1-C12 straight or branched alkyl, C2-C12 straight or branched unsaturated hydrocarbon, C3-C12 cycloalkyl, C3-C12 heterocyclic, -SOR 7 、-SO2R 7 、-COR 7 、-COOR 7 、-CONR 7 R 8 、-SO 2 NR 7 R 8 、-OCOR 7 、-NR 7 R 8 、-OR 7 、-SR 7 ,-SCOR 7 、-N(R 7 )COR 8 、-POR 7 R 8 , -PR 7 R 8 ;

[0009] R 7 and R 8 Each is independently hydrogen, methyl, difluoromethyl, trifluoromethyl, hydroxyl, amino, hydroxymethyl, mercapto, C2-C12 straight or branched alkyl, C2-C12 straight or branched substituted alkyl, C2-C12 straight or branched unsaturated hydrocarbon group, C3-C12 cycloalkyl group, C3-C12 heterocyclic group;

[0010] X is CH 2 , O or C=O.

[0011] The present invention also provides a pharmaceutical composition, which comprises the above-mentioned imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof and at least one of a pharmaceutically acceptable carrier, diluent or excipient. The preparation made from the pharmaceutical composition includes a solid preparation for oral administration, a liquid preparation for oral administration, a preparation for parenteral injection and a preparation for local administration.

[0012] The present invention also provides the use of the above-mentioned imidazo[l,2-a]pyridine compounds or their pharmaceutically acceptable salts in the preparation of drugs for preventing or treating diseases mediated by tyrosine protein kinase, and tyrosine protein kinase-mediated diseases include various malignant tumor diseases such as liver cancer, lung cancer, kidney cancer, colorectal cancer, prostate cancer, breast cancer, ovarian cancer and leukemia.

[0013] Optionally, the imidazo[l,2-a]pyridine compound is one of the following compounds:

[0014]

[0015] Optionally, the pharmaceutically acceptable salt of the imidazo[l,2-a]pyridine compound is an inorganic salt or an organic salt, the inorganic salt being hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt being formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.

[0016] The present invention is an innovative structural modification based on existing tyrosine kinase inhibitors. A series of compounds designed and synthesized have high inhibitory activity on tyrosine kinases and outstanding anti-proliferative activity on different malignant tumor cell lines. They can be particularly used to prevent or treat diseases that can be regulated by inhibiting tyrosine kinases, such as liver cancer, lung cancer, kidney cancer, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, leukemia and other malignant tumor diseases. Specifically, the compounds of the present invention show anti-cancer activity by regulating the activity of protein kinases. Among the kinases whose activity is sought to be regulated, FLT3 and mutants of FLT3 protein are preferred. DETAILED DESCRIPTION

[0017] The following is further described in detail by specific embodiments. It should be understood that the method described in the embodiments of the present invention is only used to illustrate the present invention, rather than to limit the present invention, and simple improvements to the preparation method of the present invention under the premise of the concept of the present invention belong to the scope of protection claimed in the present invention. All raw materials and solvents used in the embodiments are commercially available analytically pure.

[0018] Example 1

[0019] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is nitrogen-(4-fluorophenyl)-nitrogen(4-(imidazole[1,2-a]pyridine-8-yloxy)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-1.

[0020] The preparation method of compound A-1-1 is as follows:

[0021]

[0022] Step A: Preparation of imidazo[1,2-a]pyridin-8-ol

[0023] 2-Amino-3-hydroxypyridine (2.2 g, 20 mmol) was dissolved in 50 mL of ethanol, and 10 mL of 40% aqueous chloroacetaldehyde solution was added dropwise. After the addition was complete, the mixture was refluxed for 12 hours. After the reaction was complete, the ethanol was dried, 50 mL of saturated NaCl was added and heated to dissolve, and NaOH (20%) aqueous solution was added to adjust the pH to 8. The solid was precipitated, filtered, and dried to obtain 2 g of a light yellow solid product with a yield of 75%.

[0024] Step B: Preparation of 8-(4-nitrophenoxy)imidazole[1,2-a]pyridine

[0025] Dissolve imidazo[1,2-a]pyridine-8-ol (300 mg, 2.238 mmol) in 4 mL DMF, add 1-fluoro-4-nitrobenzene (315.67 mg, 2.238 mmol) and potassium carbonate (328.98 mg, 3.357 mmol) in turn, and react at 60°C for 6 h. After the reaction is complete, add saturated ammonium chloride to quench, extract with ethyl acetate (20 mL × 3), combine the organic layers, wash with 30 mL saturated NaCl, and then wash with anhydrous Na 2 SO 4 The crude product was purified by column chromatography using PE:EA=2:1 as eluent to obtain 253 mg of a light yellow solid product with a yield of 44.3%. 1 H NMR (400 MHz, DMSO-d 6)δ8.52(d,J=6.8Hz,1H),8.19(d,J=9.1Hz,2H),8.04(s,1H),7.49(s,1H),7.17–7.10(m,3H),6.93(t,J=7.1Hz,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ162.77,142.81,142.35,139.50,133.46,126.34,125.37,117.45,115.17,114.91,112.01.HRMS(ESI+)[M+H] + calculated for 13 H 10 N 3 O 3 ] + :256.0717,found:256.0715.

[0026] Step C: Preparation of 8-(4-aminophenoxy)imidazo[1,2-a]pyridine

[0027] 8-(4-nitrophenoxy)imidazole[1,2-a]pyridine (200 mg, 0.912 mmol) was dissolved in 10 mL of methanol, and Pd / C (20 mg, 10%, w%) was added. The reaction solution was placed in a hydrogen atmosphere and stirred at room temperature for 4 h. After the reaction was completed, a layer of diatomaceous earth was spread on the suction funnel, and then the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 180 mg of a white solid crude product with a yield of 85%. It was used directly in the next step without further treatment.

[0028] Step D: Preparation of methyl 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate

[0029] 1-(Methoxycarbonyl)cyclopropane-1-carboxylic acid (1.944 g, 13.5 mmol) was dissolved in DCM, and diisopropylethylamine (DIPEA, 3.48 g, 27 mmol) and HATU (6.84 g, 18 mmol) were added in sequence. After stirring at room temperature for 30 min, 4-fluoroaniline (1 g, 9 mmol) was added and reacted at room temperature for 16 h. After the reaction was completed, saturated ammonium chloride solution was added to quench, and ethyl acetate (20 mL × 3) was used for extraction. The organic layers were combined and washed with 30 mL of saturated NaCl, and then washed with anhydrous Na 2 SO 4 The crude product was purified by column chromatography using PE:EA=2:1 as eluent to obtain 1.813 g of a white solid product with a yield of 85%.

[0030] Step E: Preparation of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid

[0031] Methyl 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylate (1 g, 4.21 mmol) was dissolved in a mixed solution of methanol and water (1:1), and then lithium hydroxide (0.811 g, 33.8 mmol) was added and stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was diluted with water and the pH was adjusted to 3 with 1N hydrochloric acid. A white solid was precipitated, filtered, and washed with water to obtain 0.722 g of a white solid with a yield of 77%.

[0032] Step F: Preparation of N-(4-fluorophenyl)-N-(4-(imidazo[1,2-a]pyridin-8-yloxy)phenyl)cyclopropane-1,1-dicarboxamide

[0033] 1-((4-Fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (70 mg, 0.313 mmol) was dissolved in DMF, and DIPEA and HATU were added in sequence. After stirring at room temperature for 30 min, 8-(4-aminophenoxy)imidazole[1,2-a]pyridine (60 mg, 0.235 mmol) was added. After reacting at room temperature for 4 h, saturated ammonium chloride was added to quench, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated NaCl, and anhydrous Na 2 SO 4 The crude product was purified by column chromatography using DCM:MeOH=30:1 as eluent to obtain 73 mg of a light yellow solid product with a yield of 72.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.08(d,J=4.3Hz,2H),8.31(d,J=6.7Hz,1H),7.99(s,1H),7.61(d,J=8.7Hz,4H),7.51(s,1H),7.12( t,J=8.7Hz,2H),7.03(d,J=8.6Hz,2H),6.77(t,J=7.0Hz,1H),6.56(d,J=7.5Hz,1H),1.47–1.38(m,1H). 13 C NMR (101 MHz, DMSO-d 6)δ168.57,168.44,158.64(d,J=239.9Hz),151.85,146.33,139.69,135.64(d,J=2.8Hz),135.46,133.03,122 .79,122.69,122.52,119.39,115.46(d,J=22.2Hz),114.83,112.09,109.31,31.90,15.82.HRMS(ESI+)[M+H] + calculated for 24 H 20 FN 4 O 3 ] + :431.1514,found:431.1516.

[0034] Example 2

[0035] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(imidazole[1,2-a]pyridine-8-yloxy)-2-methoxyphenyl)cyclopropane-1,1-dicarboxamide, named A-1-2.

[0036] The preparation method of compound A-1-2 is as follows:

[0037]

[0038] Step A: Preparation of 8-(3-methoxy-4-nitrophenoxy)imidazo[1,2-a]pyridine

[0039] Dissolve imidazo[1,2-a]pyridine-8-ol (300 mg, 2.238 mmol) in 4 mL DMF, add 5-fluoro-2-nitroanisole (382.6 mg, 2.238 mmol) and potassium carbonate (463.2 mg, 3.357 mmol) in turn, and react at 60°C for 6 h. After the reaction is complete, add saturated ammonium chloride to quench, and extract with ethyl acetate (20 mL × 3), combine the organic layers, wash with 30 mL saturated NaCl, and anhydrous Na 2 SO 4 The crude product was purified by column chromatography using PE:EA=2:1 as the eluent to obtain 306.1 mg of a light yellow solid product with a yield of 48%.

[0040] Step B: Preparation of 4-(imidazole[1,2-a]pyridin-8-yloxy)-2-methoxyaniline

[0041] 8-(3-methoxy-4-nitrophenoxy)imidazole[1,2-a]pyridine (260 mg, 0.912 mmol) was dissolved in 10 mL of methanol, and Pd / C (26 mg, 10%, w%) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 h. After the reaction was completed, the mixture was filtered, the filtrate was collected and concentrated under reduced pressure to obtain 197.6 mg of a white solid crude product with a yield of 85%. The product was used directly in the next step without further purification.

[0042] Step C: Preparation of N-(4-fluorophenyl)-N-(4-(imidazo[1,2-a]pyridin-8-yloxy)-2-methoxyphenyl)cyclopropane-1,1-dicarboxamide

[0043] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (131.1 mg, 0.588 mmol) was dissolved in 3 mL of DMF, and DIPEA (126.4 mg, 0.98 mmol) and HATU (297.9 mg, 0.784 mmol) were added in sequence. The mixture was stirred at room temperature for 30 min, and then 4-(imidazole [1,2-a] pyridin-8-yloxy)-2-methoxyaniline (100 mg, 0.392 mmol) was added and the reaction was continued for 4 h until the reaction was completed. 20 mL of saturated ammonium chloride was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layer was washed with saturated NaCl and anhydrous Na 2 SO 4 The crude product was dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using petroleum ether:ethyl acetate = 2:1 as the eluent to obtain 82.9 mg of a light yellow solid product with a yield of 46%. 1 HNMR (400 MHz, DMSO-d 6 )δ10.46(s,1H),9.83(s,1H),8.31(d,J=6.7Hz,1H),8.09–7.92(m,2H),7.62–7.54(m,2H),7.52(s,1H),7.22 –7.10(m,2H),6.91(s,1H),6.82–6.73(m,1H),6.65–6.52(m,2H),3.77(s,3H),1.62–1.48(d,J=15.7Hz,4H). 13 C NMR (101 MHz, DMSO-d 6)δ170.41,167.97,159.09(d,J=241.0Hz),152.61,150.91,146.30,139.70,134.81(d,J=2.6Hz),133.04,124.00,123.82, 123.74,122.66,122.20,115.73,115.51,114.81,112.08,110.46,109.25,103.69,56.69,30.09,17.11.HRMS(ESI+)[M+H] + calculated for 25 H 22 FN 4 O 4 ] + :461.1620,found:461.1623.

[0044] Example 3

[0045] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(imidazole[1,2-a]pyridine-8-yloxy)-2-methylphenyl)cyclopropane-1,1-dicarboxamide, named A-1-3.

[0046] The preparation method of compound A-1-3 is as follows:

[0047]

[0048] Step A: Preparation of 8-(3-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine

[0049] Dissolve imidazo[1,2-a]pyridine-8-ol (300 mg, 2.238 mmol) in 4 mL DMF, add 5-fluoro-2-nitrotoluene (346.8 mg, 2.238 mmol) and potassium carbonate (463.2 mg, 3.357 mmol) in sequence, and react at 60°C for 6 h. After the reaction is complete, add saturated ammonium chloride to quench, and extract with ethyl acetate (20 mL × 3), combine the organic layers, wash with 30 mL saturated NaCl, and anhydrous Na 2 SO 4 The crude product was purified by column chromatography using PE:EA=2:1 as eluent to obtain 246.8 mg of a light yellow solid product with a yield of 41%.

[0050] Step B: Preparation of 4-(imidazole[1,2-a]pyridin-8-yloxy)-2-methylaniline

[0051] 10 mL of methanol was added to 8-(3-methyl-4-nitrophenoxy)imidazole[1,2-a]pyridine (200 mg, 0.743 mmol), and Pd / C (20 mg, 10%, w%) was added, and the mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. After the reaction, the filtrate was collected and concentrated under reduced pressure to obtain 142 mg of a crude white solid with a yield of 80%, which was directly used in the next step.

[0052] Step C: Preparation of N-(4-fluorophenyl)-N-(4-(imidazo[1,2-a]pyridin-8-yloxy)-2-methylphenyl)cyclopropane-1,1-dicarboxamide

[0053] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (139.8 mg, 0.627 mmol) was dissolved in 3 mL of DMF, and DIPEA (134.8 mg, 1.045 mmol) and HATU (317.6 mg, 0.836 mmol) were added in sequence. The mixture was stirred at room temperature for 30 min, and 4-(imidazole [1,2-a] pyridin-8-yloxy)-2-methylaniline (100 mg, 0.418 mmol) was added and the reaction was continued for 4 h until the reaction was completed. 20 mL of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layer was washed with saturated NaCl and anhydrous Na 2 SO 4 The crude product was dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using petroleum ether:ethyl acetate = 2:1 as the eluent to obtain 79.8 mg of a white solid product with a yield of 43%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.22(s,1H),9.86(s,1H),8.33(d,J=6.6Hz,1H),7.99(s,1H),7.70–7.55(m,2H),7.54–7.45(m,2H),7.13(t,J=8.4H z,2H),6.95(s,1H),6.86(d,J=7.7Hz,1H),6.79(t,J=7.0Hz,1H),6.62(d,J=7.0Hz,1H),2.16(s,3H),1.58–1.44(m,4H). 13 C NMR (101 MHz, DMSO-d 6)δ169.35,169.10,158.78(d,J=236.5Hz),153.51,145.90,139.80,135.32,134.36,133.10,132.49,126.9 4,122.96,120.45,116.41,115.68,115.45,114.83,112.06,110.09,30.31,18.17,16.73.HRMS(ESI+)[M+H] + calculated for 25 H 22 FN 4 O 3 ] + :445.1670,found:445.1674.

[0054] Example 4

[0055] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(3-fluoro-4-(imidazole[1,2-a]pyridin-8-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, named A-1-4.

[0056] The preparation method of compound A-1-4 is as follows:

[0057]

[0058] Step A: Preparation of 8-(2-fluoro-4-nitrophenoxy)imidazo[1,2-a]pyridine

[0059] Dissolve imidazo[1,2-a]pyridine-8-ol (300 mg, 2.238 mmol) in 4 mL DMF, add 3,4-difluoronitrobenzene (355.8 mg, 2.238 mmol) and potassium carbonate (463.2 mg, 3.357 mmol) in turn and react at 60°C for 6 h. After the reaction is complete, add saturated ammonium chloride to quench, extract with ethyl acetate (20 mL × 3), combine the organic layers, wash with 30 mL saturated NaCl, and anhydrous Na 2 SO 4 After drying, filtering and concentrating under reduced pressure, a crude product was obtained. The crude product was purified by column chromatography using PE:EA=2:1 as eluent to obtain 330 mg of a light yellow solid product with a yield of 54.1%.

[0060] Step B: Preparation of 3-fluoro-4-(imidazo[1,2-a]pyridin-8-yloxy)aniline

[0061] 8-(2-Fluoro-4-nitrophenoxy)imidazole[1,2-a]pyridine (200 mg, 0.732 mmol) was added to 5 mL of methanol, and then Pd / C (20 mg, 10%, w%) was added. The reaction solution was stirred at room temperature for 4 h under a hydrogen atmosphere. After the reaction was completed, the filtrate was collected and concentrated under reduced pressure to obtain 146.2 mg of a white solid crude product with a yield of 82.3%, which was directly used in the next step.

[0062] Step C: Preparation of N-(3-fluoro-4-(imidazo[1,2-a]pyridin-8-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0063] 1-((4-Fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (137.4 mg, 0.616 mmol) was dissolved in 3 mL of DMF, and DIPEA (132.5 mg, 1.027 mmol) and HATU (312.3 mg, 0.822 mmol) were added in sequence. The mixture was stirred at room temperature for 30 min, and then 3-fluoro-4-(imidazole [1,2-a] pyridin-8-yloxy) aniline (100 mg, 0.411 mmol) was added and the reaction was continued for 4 h until the reaction was completed. 20 mL of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layer was washed with saturated NaCl and anhydrous Na 2 SO 4 The crude product was purified by column chromatography using petroleum ether:ethyl acetate = 2:1 as eluent to obtain 71.7 mg of a white solid product with a yield of 39%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.28(s,1H),10.01(s,1H),8.30(d,J=6.7Hz,1H),8.00(s,1H),7.81(d,J=13.5Hz,1H),7.61(dd,J=8.8,5.1Hz,2H), 7.53(s,1H),7.37(d,J=8.9Hz,1H),7.21–7.08(m,3H),6.75(t,J=7.2Hz,1H),6.47(d,J=7.5Hz,1H),1.45–1.41(m,4H). 13CNMR (101MHz, DMSO) δ168.60, 168.31, 158.68 (d, J = 240.1Hz), 153.11 (d, J = 244. 5Hz),146.35,139.01,137.73(d,J=11.8Hz),137.20(d,J=9.7Hz),135.63(d,J= 2.5Hz),133.12,122.82(d,J=7.9Hz),122.62,122.47,117.10,115.57,115.35, 114.92,111.95,109.44(d,J=22.9Hz),107.26,32.25,15.75.HRMS(ESI+)[M+H] + calculated for 24 H 19 F 2 N 4 O 3 ] + :449.1420,found:449.1421.

[0064] Example 5

[0065] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(imidazole[1,2-a]pyridine-8-yloxy)-3-methylphenyl)cyclopropane-1,1-dicarboxamide, named A-1-5.

[0066] The preparation method of compound A-1-5 is as follows:

[0067]

[0068] Step A: Preparation of 8-(2-methyl-4-nitrophenoxy)imidazo[1,2-a]pyridine

[0069] Dissolve imidazo[1,2-a]pyridine-8-ol (300 mg, 2.238 mmol) in 4 mL DMF, add 2-fluoro-5-nitrotoluene (346.8 mg, 2.238 mmol) and potassium carbonate (463.2 mg, 3.357 mmol) in turn, and react at 60°C for 6 h. After the reaction is complete, add saturated ammonium chloride to quench, and extract with ethyl acetate (20 mL × 3), combine the organic layers, wash with 30 mL saturated NaCl, and anhydrous Na 2 SO 4 The crude product was purified by column chromatography using PE:EA=2:1 as eluent to obtain 241 mg of a light yellow solid product with a yield of 40%.

[0070] Step B: Preparation of 4-(imidazole[1,2-a]pyridin-8-yloxy)-3-methylaniline

[0071] 8-(2-Methyl-4-nitrophenoxy)imidazole[1,2-a]pyridine (200 mg, 0.743 mmol) was dissolved in 5 mL of methanol, and Pd / C (20 mg, 10%, w%) was added. The reaction solution was stirred at room temperature for 4 h under a hydrogen atmosphere. After the reaction was completed, the filtrate was collected by suction and concentrated under reduced pressure to obtain 150.9 mg of a white solid crude product with a yield of 85%, which was directly used in the next step.

[0072] Step C: Preparation of N-(4-fluorophenyl)-N-(4-(imidazo[1,2-a]pyridin-8-yloxy)-3-methylphenyl)cyclopropane-1,1-dicarboxamide

[0073] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (139.8 mg, 0.627 mmol) was dissolved in 3 mL of DMF, and DIPEA (134.8 mg, 1.045 mmol) and HATU (317.6 mg, 0.836 mmol) were added in sequence. The mixture was stirred at room temperature for 30 min, and then 4-(imidazole [1,2-a] pyridin-8-yloxy)-3-methylaniline (100 mg, 0.418 mmol) was added and the reaction was continued for 4 h until the reaction was completed. 20 mL of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic layer was washed with saturated NaCl and anhydrous Na 2 SO 4 After drying, filtering and concentrating under reduced pressure, a crude product was obtained. The crude product was purified by column chromatography using petroleum ether: ethyl acetate = 2:1 as the eluent to obtain 78 mg of a white solid product with a yield of 42%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.05(d,J=4.8Hz,2H),8.25(d,J=6.7Hz,1H),7.98(s,1H),7.64–7.57(m,3H),7.53(s,1H),7.46(d,J=9.5Hz,1H),7. 12(t,J=8.8Hz,2H),6.93(d,J=8.7Hz,1H),6.72(t,J=7.1Hz,1H),6.26(d,J=7.5Hz,1H),2.13(s,3H),1.47–1.40(m,4H). 13 CNMR (101MHz, DMSO-d 6)δ168.66,168.45,158.68(d,J=239.9Hz),149.12,146.97,139.31,136.01,135.59(d,J=2.5Hz),132.90,129.68,123.83,122. 82(d,J=7.7Hz),121.87,120.44,120.04,115.46(d,J=22.2Hz),114.85,112.12,106.67,31.81,16.25,15.89.HRMS(ESI+)[M+H] + calculated for 25 H 22 FN 4 O 3 ] + :445.1670,found:445.1668.

[0074] Example 6

[0075]

[0076] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(imidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-6.

[0077] The preparation method of compound A-1-6 is as follows:

[0078] Step A: Preparation of (E)-N,N-dimethyl-N'-(pyridin-2-yl)carboximide

[0079] 2-Aminopyridine (1 g, 10.63 mmol) was added to 30 mL of methanol, and DMF-DMA (2.529 g, 21.26 mmol) was added dropwise. After the addition was complete, the reaction was refluxed for 12 hours. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.33 g of a light yellow liquid with a yield of 84%.

[0080] Step B: Preparation of imidazo[1,2-a]pyridin-3-yl(4-nitrophenyl)methanone

[0081] 2-Bromo-4-nitroacetophenone (1.637 g, 6.71 mmol) was dissolved in 50 mL of ethanol, (E)-N,N-dimethyl-N'-(pyridin-2-yl)carboximide (1 g, 6.71 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and the filter cake was washed with ethanol to obtain 758 mg of white solids with a yield of 42.3%.

[0082] Step C: Preparation of (4-aminophenyl)(imidazo[1,2-a]pyridin-3-yl)methanone

[0083] Imidazole [1,2-a] pyridin-3-yl (4-nitrophenyl) ketone (300 mg, 1.123 mmol) was added to 50 mL of ethanol, and ammonium formate (212.2 mg, 3.369 mmol) and Pd / C (30 mg, 10%, w%) were added in sequence. The mixture was reacted at 70 ° C for 5 h until the reaction was completed and filtered. The filtrate was collected and concentrated under reduced pressure to obtain 201 mg of a pale yellow solid crude product with a yield of 76%, which was directly used in the next step. 1 H NMR (400 MHz, DMSO-d 6 )δ9.54(d,J=7.0Hz,1H),8.24(s,1H),7.84(d,J=8.9Hz,1H),7.73(d,J=8.7Hz,2 H),7.65–7.58(m,1H),7.25(t,J=6.8Hz,1H),6.69(d,J=8.8Hz,2H),6.10(s,2H). 13 C NMR (101 MHz, DMSO-d 6 )δ182.39,153.86,148.18,143.34,131.86,129.27,128.67,125.91,123.48,117.79,115.21,113.30.HRMS(ESI+)[M+H] + calculated for 14 H 12 N 3 O] + :238.0975,found:238.0972.

[0084] Step D: Preparation of N-(4-fluorophenyl)-N-(4-(imidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide

[0085] (4-aminophenyl)(imidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.422 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (142.4 mg, 0.591 mmol) and triethylamine (127.8 mg, 1.27 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, and anhydrous Na 2 SO 4 The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 90 mg of solid with a yield of 48.3%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.46(s,1H),9.99(s,1H),9.59(d,J=6.9Hz,1H),8.26(s,1H),7.90–7.81(m,5H) ,7.71–7.57(m,3H),7.30(t,J=6.9Hz,1H),7.12(t,J=8.7Hz,2H),1.51–1.40(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ183.03,168.78,168.48,158.70(d,J=240.1Hz),148.70,145.15,143.14,135.63(d,J=2.5Hz),133.80,130.21,1 28.79,123.31,122.89(d,J=7.9Hz),119.94,117.86,115.89,115.44(d,J=22.2Hz),32.40,15.93.HRMS(ESI+)[M+H] + calculated for 25 H 20 FN 4 O 3 ] + :443.1514,found:443.1516.

[0086] Preparation of the intermediate in step D - 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride

[0087]

[0088] 1-((4-Fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (1 g) was added to 8 mL of dichlorothionyl, and the mixture was heated at 60°C for 2 h to complete the reaction. The mixture was concentrated under reduced pressure to obtain an off-white solid, which was directly used in the next step.

[0089] Example 7

[0090] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(5-methylimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-7.

[0091] The preparation method of compound A-1-7 is as follows:

[0092]

[0093] Step A: Preparation of (E)-N,N-dimethyl-N'-(6-methylpyridin-2-yl)carboximide

[0094] 2-Amino-6-methylpyridine (1 g, 9.26 mmol) was added to 30 mL of methanol, and DMF-DMA (2.203 g, 18.52 mmol) was added dropwise. After the addition was complete, the reaction was refluxed for 12 hours. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl, and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.141 g of a light yellow liquid with a yield of 75.6%.

[0095] Step B: Preparation of (5-methylimidazole[1,2-a]pyridin-3-yl)(4-nitrophenyl)methanone

[0096] Dissolve 2-bromo-4-nitroacetophenone (1.495 g, 6.13 mmol) in 50 mL of ethanol, add (E)-N,N-dimethyl-N'-(6-methylpyridin-2-yl)carboximide (1 g, 6.13 mmol), and reflux for 6 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and solids are precipitated. Filter by suction, and wash the filter cake with ethanol to obtain 524 mg of white solids, with a yield of 30%.

[0097] Step C: Preparation of (4-aminophenyl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone

[0098] (5-Methylimidazole [1,2-a] pyridin-3-yl) (4-nitrophenyl) ketone (300 mg, 1.067 mmol) was added to 50 mL of ethanol, followed by ammonium formate (201.6 mg, 3.201 mmol) and Pd / C (30 mg, 10%, w%), and the mixture was reacted at 70°C for 5 h until the reaction was completed. A layer of diatomaceous earth was spread on the filtration funnel, and the reaction solution was then filtered, the filtrate was collected and concentrated under reduced pressure to obtain 182 mg of a pale yellow solid crude product with a yield of 68%, which was directly reacted in the next step. 1 H NMR (400 MHz, DMSO-d 6 )δ9.38(d,J=6.8Hz,1H),8.18(s,1H),7.70(d,J=8.6Hz,2H),7.42(d,J=7.0Hz ,1H),7.14(t,J=6.9Hz,1H),6.67(d,J=8.7Hz,2H),6.08(s,2H),2.59(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ182.51,153.84,148.33,142.76,131.81,127.86,127.27,126.34,126.01,123.94,115.13,113.27,16.92.HRMS(ESI+)[M+H] + calculated for 15 H 14 N 3 O] + :252.1131,found:252.1129.

[0099] Step D: Preparation of N-(4-fluorophenyl)-N-(4-(5-methylimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide

[0100] (4-aminophenyl)(5-methylimidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.398 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (142.4 mg, 0.591 mmol) and triethylamine (127.8 mg, 1.27 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL×3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, and anhydrous Na 2 SO 4The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 70 mg of solid with a yield of 38%. 1 H NMR (400 MHz, CDCl 3 )δ10.15(s,1H),8.70(s,1H),8.03(s,1H),8.00(d,J=5.7Hz,2H),7.73(d,J=8.4Hz,2H),7.65(d,J=8.9Hz,1H),7.49(d,J=7.0Hz,1H) ,7.44(dd,J=9.2,4.9Hz,2H),7.03(t,J=8.7Hz,2H),6.92(d,J=7.1Hz,1H),2.65(s,3H),1.77(q,J=4.9Hz,2H),1.63(q,J=4.8Hz,2H). 13 C NMR (101 MHz, CDCl 3 )δ181.35,169.65,168.71,159.85(d,J=245.0Hz),150.67,145.71,141.91,139.90,134.22,132.84,131.46,129. 32,125.64,123.01(d,J=7.6Hz),119.71,116.04,115.92,115.70,115.17,29.31,22.51,17.94.HRMS(ESI+)[M+H] + calculated for 26 H 22 FN 4 O 3 ] + :457.1670,found:457.1673.

[0101] Example 8

[0102] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(7-methylimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-8.

[0103] The preparation method of compound A-1-8 is as follows:

[0104]

[0105] Step A: Preparation of (E)-N,N-dimethyl-N'-(4-methylpyridin-2-yl)carboximide

[0106] 2-Amino-4-methylpyridine (1 g, 9.26 mmol) was added to 30 mL of methanol, and DMF-DMA (2.203 g, 18.52 mmol) was added dropwise. After the addition was complete, the reaction was refluxed for 12 hours. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl, and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.296 g of a light yellow liquid with a yield of 82%.

[0107] Step B: Preparation of (7-methylimidazo[1,2-a]pyridin-3-yl)(4-nitrophenyl)methanone

[0108] 2-Bromo-4-nitroacetophenone (1.496 g, 6.134 mmol) was dissolved in 50 mL of ethanol, (E)-N,N-dimethyl-N'-(4-methylpyridin-2-yl)carboximide (1 g, 6.134 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and the filter cake was washed with ethanol to obtain 1120 mg of yellow solids with a yield of 65%. 1 HNMR (400 MHz, DMSO-d 6 )δ9.51(d,J=7.0Hz,1H),8.36(d,J=8.5Hz,2H),8.22(s,1H),8.06(d,J=8.5Hz,2H) ,7.71(s,1H),7.23(d,J=7.1Hz,1H),2.47(s,overlapping,3H).HRMS(ESI+)[M+H] + calculated for 15 H 12 N 3 O 3 ] + :282.0873,found:282.0875.

[0109] Step C: Preparation of (4-aminophenyl)(7-methylimidazo[1,2-a]pyridin-3-yl)methanone

[0110] (7-Methylimidazole [1,2-a] pyridin-3-yl) (4-nitrophenyl) ketone (300 mg, 1.123 mmol) was added to 50 mL of ethanol, followed by ammonium formate (201.6 mg, 3.369 mmol) and Pd / C (30 mg, 10%, w%), and the mixture was reacted at 70°C for 5 h until the reaction was completed. A layer of diatomaceous earth was spread on the filtration funnel, and the reaction solution was then filtered, the filtrate was collected and concentrated under reduced pressure to obtain 193 mg of a pale yellow solid crude product with a yield of 72%, which was directly reacted in the next step.

[0111] Step D: Preparation of N-(4-fluorophenyl)-N-(4-(7-methylimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide

[0112] (4-aminophenyl)(7-methylimidazole[1,2-a]pyridin-3-yl)methanone was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (134.2 mg, 0.557 mmol) and triethylamine (120.6 mg, 1.194 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL×3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, and anhydrous Na 2 SO 4 The crude product was dried and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 78 mg of solid with a yield of 43%. 1 HNMR (400 MHz, DMSO-d 6 )δ10.45(s,1H),9.99(s,1H),9.47(d,J=7.0Hz,1H),8.19(s,1H),7.88–7.77(m,4H) ,7.65(s,1H),7.64–7.57(m,2H),7.17–7.07(m,3H),2.44(s,3H),1.51–1.38(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ182.71,168.76,168.48,158.69(d,J=240.3Hz),149.14,145.40,143.01,141.40,135.64,133.91,130.09,127.93 ,123.05,122.88(d,J=7.6Hz),119.93,118.14,116.40,115.44(d,J=22.Hz),32.39,21.35,15.92.HRMS(ESI+)[M+H]+ calculated for 26 H 22 FN 4 O 3 ] + :457.1670,found:457.1672.

[0113] Example 9

[0114] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(7-methoxyimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-9.

[0115] The preparation method of compound A-1-9 is as follows:

[0116]

[0117] Step A: Preparation of (E)-N'-(4-methoxypyridin-2-yl)-N,N-dimethylformimide

[0118] 4-Methoxypyridin-2-amine (1 g, 8.06 mmol) was added to 30 mL of methanol, and DMF-DMA (1.918 g, 16.12 mmol) was added dropwise. After the addition was complete, the mixture was refluxed for 12 hours. After the reaction was complete, the methanol was concentrated under reduced pressure, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.154 g of a white solid with a yield of 80%.

[0119] Step B: Preparation of (7-methoxyimidazole[1,2-a]pyridin-3-yl)(4-nitrophenyl)methanone

[0120] 2-Bromo-4-nitroacetophenone (1.362 g, 5.586 mmol) was dissolved in 50 mL of ethanol, (E)-N'-(4-methoxypyridin-2-yl)-N,N-dimethylformimide (1 g, 5.586 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and the filter cake was washed with ethanol to obtain 962 mg of yellow solids with a yield of 58%.

[0121] Step C: Preparation of (4-aminophenyl)(7-methoxyimidazo[1,2-a]pyridin-3-yl)methanone

[0122] (7-methoxyimidazole [1,2-a] pyridin-3-yl) (4-nitrophenyl) ketone (300 mg, 1.01 mmol) was added to 50 mL of ethanol, followed by ammonium formate (190.8 mg, 3.03 mmol) and Pd / C (30 mg, 10%, w%), and the mixture was reacted at 70°C for 5 h until the reaction was completed. A layer of diatomaceous earth was spread on the filtration funnel, and the reaction solution was then filtered, the filtrate was collected and concentrated under reduced pressure to obtain 132 mg of a pale yellow solid crude product with a yield of 49%, which was directly reacted in the next step.

[0123] Step D: Preparation of N-(4-fluorophenyl)-N-(4-(7-methoxyimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide

[0124] (4-Aminophenyl)(7-methoxyimidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.374 mmol) was suspended in 3 mL of DCM, and 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (126.2 mg, 0.523 mmol) and triethylamine (113.3 mg, 1.122 mmol) were added in sequence, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL×3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, anhydrous Na 2 SO 4 The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 97 mg of solid with a yield of 55%. 1 H NMR (400 MHz, CDCl 3 )δ9.46(d,J=7.6Hz,1H),8.02(s,1H),7.81(d,J=9.0Hz,2H),7.69(d,J=8.8Hz,2H),7.47–7.41( m,2H),7.04–6.96(m,3H),6.82–6.76(m,1H),3.91(s,3H),1.71–1.65(m,2H),1.65–1.59(m,2H). 13 CNMR (101MHz, DMSO-d 6)δ182.37,168.74,168.45,161.29,158.68(d,J=240.0Hz),150.39,144.57,143.08,135.65,133.71,130. 08,129.62,122.79,119.92,115.45(d,J=23.9Hz),109.69,96.07,56.63,32.44,15.86.HRMS(ESI+)[M+H] + calculated for 26 H 22 FN 4 O 4 ] + :473.1620,found:473.1618.

[0125] Example 10

[0126] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(8-methoxyimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-10.

[0127] The preparation method of compound A-1-10 is as follows:

[0128]

[0129] Step A: Preparation of (E)-N'-(3-methoxypyridin-2-yl)-N,N-dimethylformimide

[0130] 3-Methoxypyridin-2-amine (1 g, 8.06 mmol) was added to 30 mL of methanol, and DMF-DMA (1.918 g, 16.12 mmol) was added dropwise. After the addition was complete, the mixture was refluxed for 12 hours. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.168 g of a light yellow solid with a yield of 81%.

[0131] Step B: Preparation of (8-methoxyimidazole[1,2-a]pyridin-3-yl)(4-nitrophenyl)methanone

[0132] Dissolve 2-bromo-4-nitroacetophenone (1.362 g, 5.586 mmol) in 50 mL of ethanol, add (E)-N'-(3-methoxypyridin-2-yl)-N,N-dimethylformimide (1 g, 5.586 mmol), and reflux for 6 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and solids are precipitated. Filter by suction, and wash the filter cake with ethanol to obtain 928 mg of light yellow solids, with a yield of 54%.

[0133] Step C: Preparation of (4-aminophenyl)(8-methoxyimidazo[1,2-a]pyridin-3-yl)methanone

[0134] Add (8-methoxyimidazole [1,2-a] pyridin-3-yl) (4-nitrophenyl) ketone (300 mg, 1.01 mmol) to 50 mL of ethanol, and then add ammonium formate (190.8 mg, 3.03 mmol) and Pd / C (30 mg, 10%, w%), and react at 70°C for 5 hours until the reaction is complete. Spread a layer of diatomaceous earth on the suction funnel, then filter the reaction solution, collect the filtrate and concentrate under reduced pressure to obtain 137 mg of a pale yellow solid crude product with a yield of 51%, which is directly reacted in the next step. 1 H NMR (400 MHz, CDCl 3 )δ9.23(d,J=6.9Hz,1H),8.11(s,1H),7.78(d,J=8.5Hz,2H),6.97(t,J=7.3Hz,1H),6.81–6.70(m,3H),4.15(s,2H),4.05(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ182.49,153.90,148.85,142.21,142.00,131.88,125.93,124.36,121.01,115.19,113.28,106.37,56.56.HRMS(ESI+)[M+H] + calculated for 15 H 14 N 3 O 2 ] + :268.1081,found:268.1085.

[0135] Step D: Preparation of N-(4-fluorophenyl)-N-(4-(8-methoxyimidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide

[0136] (4-aminophenyl)(8-methoxyimidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.374 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (126.2 mg, 0.523 mmol) and triethylamine (113.3 mg, 1.122 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, anhydrous Na 2 SO 4 The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 93 mg of solid with a yield of 53%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.46(s,1H),9.98(s,1H),9.18(d,J=5.8Hz,1H),8.15(s,1H),7.88–7.80( m,4H),7.66–7.58(m,2H),7.24–7.06(m,4H),3.98(s,3H),1.51–1.41(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ183.19,168.76,168.45,158.68(d,J=240.0Hz),148.79,143.80,143.18,142.63,135.65,133.81,130.22,124.15 ,122.86(d,J=8.3Hz),121.04,119.91,115.94,115.44(d,J=22.1Hz),107.37,56.56,32.42,15.91.HRMS(ESI+)[M+H] + calculated for 26 H 22 FN 4 O 4 ] + :473.1620,found:473.1617.

[0137] Embodiment 11

[0138] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-(7-ethoxyimidazole[1,2-a]pyridine-3-carbonyl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, named A-1-11.

[0139] The preparation method of compound A-1-11 is as follows:

[0140]

[0141] Step A: Preparation of (E)-N'-(4-ethoxypyridin-2-yl)-N,N-dimethylformimide

[0142] 4-Ethoxypyridin-2-amine (1 g, 7.24 mmol) was added to 30 mL of methanol, and DMF-DMA (1.723 g, 14.48 mmol) was added dropwise. After the addition was complete, the mixture was refluxed for 12 h. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.089 g of a light yellow solid with a yield of 78%.

[0143] Step B: Preparation of (7-ethoxyimidazole[1,2-a]pyridin-3-yl)(4-nitrophenyl)methanone

[0144] 2-Bromo-4-nitroacetophenone (1.263 g, 5.18 mmol) was dissolved in 50 mL of ethanol, (E)-N'-(4-ethoxypyridin-2-yl)-N,N-dimethylformimide (1 g, 5.18 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and the filter cake was washed with ethanol to obtain 805 mg of a light yellow solid with a yield of 50%.

[0145] Step C: Preparation of (4-aminophenyl)(7-ethoxyimidazo[1,2-a]pyridin-3-yl)methanone

[0146] Add (7-ethoxyimidazole [1,2-a] pyridin-3-yl) (4-nitrophenyl) ketone (300 mg, 0.964 mmol) to 50 mL of ethanol, and then add ammonium formate (182.2 mg, 2.892 mmol) and Pd / C (30 mg, 10%, w%), and react at 70°C for 5 hours until the reaction is complete. Spread a layer of diatomaceous earth on the suction funnel, then filter the reaction solution, collect the filtrate and concentrate under reduced pressure to obtain 170 mg of a pale yellow solid crude product with a yield of 63%, which is directly reacted in the next step. 1 H NMR (400 MHz, DMSO-d 6)δ9.36(d,J=7.6Hz,1H),8.10(s,1H),7.68(d,J=8.5Hz,2H),7.20(d,J=2.4Hz,1H),6.91(dd,J=7 .6, 2.4Hz, 1H), 6.66 (d, J = 8.5Hz, 2H), 6.01 (s, 2H), 4.19 (q, J = 6.9Hz, 2H), 1.39 (t, J = 6.9Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 )δ181.91,159.50,153.59,150.44 143.99,131.56,129.32,126.11,122.93,113.26,109.10,96.63,64.61,14.69.HRMS(ESI+)[M+H] + calculated for 16 H 16 N 3 O 2 ] + :282.1237,found:282.1235.

[0147] Step D: Preparation of N-(4-(7-ethoxyimidazole[1,2-a]pyridine-3-carbonyl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0148] (4-aminophenyl)(7-ethoxyimidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.356 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (120.1 mg, 0.498 mmol) and triethylamine (107.8 mg, 1.068 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL×3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, and anhydrous Na 2 SO 4 The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 81.3 mg of solid with a yield of 47%. 1 H NMR (400 MHz, DMSO-d 6)δ10.43(s,1H),9.98(s,1H),9.41(d,J=7.6Hz,1H),8.13(s,1H),7.85–7.76(m,1H),7.61(dd,J=8.5,5.1Hz,1H),7.24 (s,1H),7.12(t,J=8.7Hz,1H),6.96(d,J=7.6Hz,1H),4.18(q,J=7.0Hz,1H),1.51–1.40(m,1H),1.37(t,J=6.9Hz,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ182.25,168.76,168.52,160.07,158.70(d,J=240.0Hz),151.07,145.82,142.87,135.62,133.99,129.97,129.39,12 2.91,122.80,119.93,115.44(d,J=29.1Hz),109.53,96.85(d,J=9.7Hz),64.71,32.32,15.96,14.62.HRMS(ESI+)[M+H] + calculated for 27 H 24 FN 4 O 4 ] + :487.1776,found:487.1779.

[0149] Example 12

[0150] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-(6-fluoroimidazole[1,2-a]pyridine-3-carbonyl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, named A-1-12.

[0151] The preparation method of compound A-1-12 is as follows:

[0152]

[0153] Step A: Preparation of (E)-N'-(5-fluoropyridin-2-yl)-N,N-dimethylformimide

[0154] 5-Fluoropyridine-2-amine (1 g, 8.92 mmol) was added to 30 mL of methanol, and DMF-DMA (2.122 g, 17.84 mmol) was added dropwise. After the addition was complete, the mixture was refluxed for 12 h. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl and anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain 1.266 g of off-white solid with a yield of 85%.

[0155] Step B: Preparation of (6-fluoroimidazole[1,2-a]pyridin-3-yl)(4-nitrophenyl)methanone

[0156] 2-Bromo-4-nitroacetophenone (1.459 g, 5.98 mmol) was dissolved in 50 mL of ethanol, (E)-N'-(5-fluoropyridin-2-yl)-N,N-dimethylformimide (1 g, 5.98 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and the filter cake was washed with ethanol to obtain 988 mg of off-white solids with a yield of 58%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.63(s,1H),8.41–8.32(m,3H),8.08(d,J=8.4Hz,2H),8.00(dd,J=9.8,5.2Hz,1H),7.86(t,J=9.0Hz,1H).HRMS(ESI+)[M+H] + calculated for 14 H 9 FN 3 O 3 ] + :286.0622,found:286.0624.

[0157] Step C: Preparation of (4-aminophenyl)(6-fluoroimidazole[1,2-a]pyridin-3-yl)methanone

[0158] Add (6-fluoroimidazole [1,2-a] pyridin-3-yl) (4-nitrophenyl) ketone (300 mg, 1.05 mmol) to 50 mL of ethanol, and then add ammonium formate (198.4 mg, 3.15 mmol) and Pd / C (30 mg, 10%, w%), and react at 70°C for 5 hours until the reaction is complete. Spread a layer of diatomaceous earth on the suction funnel, then filter the reaction solution, collect the filtrate and concentrate under reduced pressure to obtain 128.5 mg of a pale yellow solid crude product with a yield of 48%, which is directly reacted in the next step.

[0159] Step D: Preparation of N-(4-(6-fluoroimidazole[1,2-a]pyridine-3-carbonyl)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0160] (4-aminophenyl)(6-fluoroimidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.392 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (132.2 mg, 0.548 mmol) and triethylamine (118.7 mg, 1.176 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, and anhydrous Na 2 SO 4 The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 79 mg of solid with a yield of 44%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.47(s,1H),9.98(s,1H),9.60(s,1H),8.32(s,1H),7.95(dd,J=9.8,5.3Hz,1H),7.89–7 .82(m,4H),7.81–7.74(m,1H),7.65–7.58(m,2H),7.12(t,J=8.7Hz,2H),1.49–1.41(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ183.03,168.80,168.48,158.70(d,J=240.4Hz),154.39(d,J=235.9Hz),146.31,145.46,143.33,135.60,133.37,130.24,12 4.29,123.04–122.72(m),119.96,118.60,116.01,115.52(d,J=11.6Hz),115.31(d,J=6.6Hz),32.38,15.95.HRMS(ESI+)[M+H] + calculated for 25 H 19 F 2 N 4 O 3 ] + :461.1420,found:461.1424.

[0161] Example 13

[0162] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(7-(trifluoromethyl)imidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide, named A-1-13.

[0163] The preparation method of compound A-1-13 is as follows:

[0164]

[0165] Step A: Preparation of (E)-N,N-dimethyl-N'-(4-(trifluoromethyl)pyridin-2-yl)carboximide

[0166] 4-(Trifluoromethyl)pyridin-2-amine (1 g, 6.172 mmol) was added to 30 mL of methanol, and DMF-DMA (1.468 g, 12.34 mmol) was added dropwise. After the addition was complete, the reaction was refluxed for 12 hours. After the reaction was complete, the methanol was dried, 50 mL of water was added, and the aqueous layer was extracted with DCM (20 mL × 3). The organic layers were combined and washed with 50 mL of saturated NaCl, and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.071 g of an off-white solid with a yield of 80%.

[0167] Step B: Preparation of (4-nitrophenyl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone

[0168] 2-Bromo-4-nitroacetophenone (1.124 g, 4.61 mmol) was dissolved in 50 mL of ethanol, (E)-N,N-dimethyl-N'-(4-(trifluoromethyl)pyridin-2-yl)carboximide (1 g, 4.61 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered and the filter cake was washed with ethanol to obtain 834 mg of white solids with a yield of 54%.

[0169] Step C: Preparation of (4-aminophenyl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone

[0170] (4-Nitrophenyl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone (800 mg, 2.388 mmol) was added to 50 mL of ethanol, followed by ammonium formate (451.3 mg, 7.164 mmol) and Pd / C (80 mg), and the mixture was reacted at 70°C for 6 h until the reaction was completed. The mixture was filtered through diatomaceous earth, the filtrate was collected, and the mixture was concentrated under reduced pressure to obtain 473.4 mg of a pale yellow solid crude product with a yield of 65%, which was used directly in the next step without purification. 1 H NMR (400 MHz, DMSO-d 6 )δ9.62(d,J=7.2Hz,1H),8.40(s,1H),8.34(s,1H),7.75(d,J=8.5Hz,2H),7.50(dd,J=7.3,1.3Hz,1H),6.69(d,J=8.6Hz,2H),6.20(s,2H). 13 C NMR (101 MHz, DMSO-d 6 )δ182.35,154.34,146.26,143.97,132.18,130.10,128.36(d,J=33.7Hz),125.25,12 4.50,123.67(d,J=272.3Hz),115.86(d,J=4.9Hz),113.33,110.29.HRMS(ESI+)[M+H] + calculated for 15 H 11 F 3 N 3 O] + :306.0849,found:306.0852.

[0171] Step D: Preparation of N-(4-fluorophenyl)-N-(4-(7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-dicarboxamide

[0172] (4-aminophenyl)(7-(trifluoromethyl)imidazole[1,2-a]pyridin-3-yl)methanone (100 mg, 0.327 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (110 mg, 0.457 mmol) and triethylamine (99 mg, 0.981 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL×3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, and anhydrous Na 2 SO 4The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 76 mg of solid with a yield of 46%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.50(s,1H),9.98(s,1H),9.69(d,J=7.3Hz,1H),8.43(s,1H),8.39(s,1H),7.88(q,J=8.6Hz, 4H),7.61(dd,J=8.9,5.1Hz,2H),7.56(d,J=7.4Hz,1H),7.12(t,J=8.6Hz,2H),1.50–1.41(m,4H). 13 CNMR (101MHz, DMSO-d 6 )δ183.39,168.81,168.44,158.68(d,J=240.2Hz),146.89,145.74,143.59,135.63(d,J=2.5Hz),133.14,130.48,130.23,129.15(d,J=33. 6Hz),124.22,123.52(d,J=272.9Hz),122.86(d,J=7.8Hz),119.93,115.95,115.43(d,J=22.1Hz),110.97,32.44,15.92.HRMS(ESI+)[M+H] + calculated for 26 H 19 F 4 N 4 O 3 ] + :511.1388,found:511.1390.

[0173] Embodiment 14

[0174] This embodiment provides a cyclopropanediamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is methyl 3-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)benzoyl)imidazole[1,2-a]pyridine-7-carboxylate, named A-1-14.

[0175] The preparation method of compound A-1-14 is as follows:

[0176]

[0177] Step A: Preparation of methyl (E)-6-(((dimethylamino)methylene)amino)nicotinate

[0178] 2-Aminoisonicotinic acid methyl ester (1g, 6.572mmol) was added to 30mL methanol, and DMF-DMA (1.564g, 13.14mmol) was added dropwise. After the addition was complete, the reaction was refluxed for 12 hours. After the reaction was completed, the methanol was dried, 50mL of water was added, and the aqueous layer was extracted with DCM (20mL×3). The organic layers were combined and washed with 50mL of saturated NaCl, and anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain 1.142 g of an off-white solid with a yield of 84%.

[0179] Step B: Preparation of methyl 3-(4-nitrobenzoyl)imidazo[1,2-a]pyridine-7-carboxylate

[0180] 2-Bromo-4-nitroacetophenone (1.178 g, 4.83 mmol) was dissolved in 50 mL of ethanol, and methyl (E)-6-(((dimethylamino)methylene)amino)nicotinate (1 g, 4.83 mmol) was added, and the mixture was refluxed for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, and solids precipitated. The solids were filtered, and the filter cake was washed with ethanol to obtain 769 mg of white solids with a yield of 49%.

[0181] Step C: Preparation of methyl 3-(4-aminobenzoyl)imidazo[1,2-a]pyridine-7-carboxylate

[0182] Methyl 3-(4-nitrobenzoyl)imidazo[1,2-a]pyridine-7-carboxylate (600 mg, 1.864 mmol) was added to 50 mL of ethanol, followed by ammonium formate (348.9 mg, 5.538 mmol) and Pd / C (60 mg), and the mixture was reacted at 70°C for 6 h until the reaction was completed. The mixture was filtered through diatomaceous earth, the filtrate was collected, and the mixture was concentrated under reduced pressure to obtain 324.4 mg of a pale yellow solid crude product with a yield of 59%, which was used directly in the next step without purification.

[0183] Step D: Preparation of methyl 3-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)benzoyl)imidazole[1,2-a]pyridine-7-carboxylate

[0184] Methyl 3-(4-aminobenzoyl) imidazole [1,2-a] pyridine-7-carboxylate (100 mg, 0.338 mmol) was added to 3 mL of DCM, followed by 1-((4-fluorophenyl) carbamoyl) cyclopropane-1-carbonyl chloride (114 mg, 0.473 mmol) and triethylamine (102.4 mg, 1.014 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction, 20 mL of saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with dichloromethane (20 mL × 3), and the organic layers were combined. The organic layer was washed with 20 mL of saturated NaCl, anhydrous Na 2 SO 4 The crude product was separated and purified by column chromatography with the eluent being dichloromethane:ethyl acetate = 4:1 to obtain 81 mg of solid with a yield of 48%. 1 H NMR (400 MHz, CDCl 3 )δ10.52(s,1H),9.62(d,J=6.7Hz,1H),9.44(s,1H),8.38(s,1H),8.21(s,1H),7.81(d,J=7.4Hz,2 H),7.74–7.60(m,3H),7.47–7.34(m,2H),7.03–6.88(m,2H),3.94(s,3H),1.64(d,J=26.7Hz,4H). 13 CNMR (101MHz, CDCl 3 )δ183.97,170.04,169.53,164.88,159.69(d,J=244.4Hz),147.73,145.43,141.85,134.04,133.11,130.52,130.12, 128.45,124.12,123.12(d,J=8.5Hz),120.03,119.40,115.63,115.41,114.28,52.93,29.24,17.57.HRMS(ESI+)[M+H] + calculated for 27 H 22 FN 4 O 5 ] + :501.1569,found:501.1565.

[0185] Embodiment 15

[0186] This embodiment provides a cyclopropane diamide compound containing an imidazo[l,2-a]pyridine skeleton, specifically, the compound is N-(4-fluorophenyl)-N-(4-(7-((2-morpholinoethyl)carboxamide)imidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-diamide, named A-1-15.

[0187] The preparation method of compound A-1-15 is as follows:

[0188]

[0189] Step A: Preparation of 3-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)benzoyl)imidazole[1,2-a]pyridine-7-carboxylic acid

[0190] Methyl 3-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenyl)imidazole[1,2-a]pyridine-7-carboxylate (200 mg, 0.4 mmol) was added to a mixed solvent of methanol (4 mL): water (2 mL), and then LiOH (73.6 mg, 3.2 mmol) was added, and the reaction was carried out at 40°C for 2 h until the reaction was completed. The solvent was dried, diluted with water, and the pH was adjusted to 3-4 with 2N hydrochloric acid. The solid was precipitated, filtered, and the filter cake was washed with a small amount of water and dried to obtain 190 mg of a yellow solid crude product, which was used for the next reaction.

[0191] Step B: Preparation of N-(4-fluorophenyl)-N-(4-(7-((2-morpholinoethyl)carboxamide)imidazole[1,2-a]pyridine-3-carbonyl)phenyl)cyclopropane-1,1-diamide

[0192] 3-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)benzoyl)imidazole[1,2-a]pyridine-7-carboxylic acid (100 mg, 0.205 mmol) was dissolved in 3 mL of DMF, and DIPEA (53 mg, 0.411 mmol) and HATU (104.1 mg, 0.274 mmol) were added in sequence. The mixture was stirred at room temperature for 30 min, and then N-(2-aminoethyl)morpholine (17.8 mg, 0.137 mmol) was added to continue the reaction for 4 h until the reaction was completed. 20 mL of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic layers were combined. The organic layer was washed with saturated NaCl and anhydrous Na 2 SO 4 The crude product was dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using EA:EtOH=5:1 as the eluent to obtain 19 mg of a white solid product with a yield of 23%. 1 H NMR (400 MHz, CDCl 3)δ10.09(s,1H),9.67(d,J=7.1Hz,1H),8.60(s,1H),8.24(s,1H),8.14(s,1H),7 .86(d,J=8.6Hz,2H),7.72(d,J=8.7Hz,2H),7.54(d,J=7.3Hz,1H),7.48–7.43(m ,2H),7.03(t,J=8.4Hz,2H),3.79–3.72(m,4H),3.66–3.58(m,2H),2.73–2.68(m ,2H),2.65–2.54(m,4H),1.81–1.73(m,2H),1.66–1.58(m,2H).HRMS(ESI+)[M+H] + calculated for 32 H 32 FN 6 O 5 ] + :599.2413,found:599.2415.

[0193] Experimental example

[0194] 1. In vitro protein activity assay of compounds

[0195] The compound was dissolved in DMSO to prepare a stock solution with a concentration of 1 mM. The inhibitory activity of the compound on kinase was screened in vitro using Lantha screen Assay, and the compound was tested using Giltertinib as a reference compound.

[0196] 1.1 Preparation of 1X Kinase Buffer

[0197] 1X Kinase Buffer

[0198] 50 mM HEPES, pH 7.5

[0199] 10 mM MgCl 2

[0200] 4mM DTT

[0201] 0.01% Tween-20

[0202] 0.01% BSA

[0203] 1.2 Preparation of compounds

[0204] Dilute compounds to 100x the final desired maximum concentration in the reaction with 100% DMSO. For compounds tested at 1 μM, prepare a 100 μM DMSO solution of compound in this step. Transfer all prepared compounds to one well of a 96-well storage plate, transfer 10 μl to the next 90 μl 100% DMSO well, dilute compounds sequentially, and so on for a total of 5 concentrations. Add 100 μl of 100% DMSO to two empty wells in the same 96-well plate for no compound control and no enzyme control. Label the plate as the source plate. Transfer 40 μl of compound from the source plate to a new 384-well echo plate as an intermediate plate. Transfer 200 nl of each well from the 384-well echo plate to the 384-well assay plate in duplicate. For example, A1 of the 384-well Echo Plate is transferred to A1 and A2 of the 384-well Assay Plate. A2 of the 384-well Echo Plate is transferred to A3 and A4 of the 384-well Assay Plate, and so on.

[0205] 1.3 Kinase reaction

[0206] Prepare 2X kinase solution

[0207] Prepare a solution of FLT3-ITD in 1X kinase buffer at 2x the final concentration of each reagent in the assay. Add 10 μl of kinase solution to each well of the assay plate, except for the control wells without enzyme (add 5 μl of 1X kinase buffer instead), and shake the plate. Incubate at room temperature for 10 minutes.

[0208] Prepare 2X substrate solution

[0209] Prepare a substrate solution containing Fluorescein-Poly GT and ATP in 1X kinase reaction buffer at a concentration of 2 times the final concentration of each reagent required in the assay and start the reaction by adding 10 μl of substrate solution to each well of the assay plate.

[0210] Kinase reaction

[0211] Cover the assay plate and incubate at room temperature for 60 minutes.

[0212] 1.4 Kinase assay

[0213] Prepare detection solution at 2x final concentration in antibody dilution buffer. Add 20 μl detection solution to each well of the assay plate to stop the reaction. Mix briefly by centrifuge and incubate at room temperature for 60 minutes before reading fluorescence.

[0214] 1.5 Data Reading

[0215] Data were collected on an Envision with an excitation wavelength of 340 nm and emission wavelengths of 520 nm and 495 nm.

[0216] 1.6 Curve Fitting

[0217] Copy the RFU value from Envision. Calculate the ratio of RFU 520nm / RFU 495nm to convert the ratio value to a percent inhibition value.

[0218] Inhibition percentage = (max - sample ratio) / (max - min) * 100.

[0219] "Min" refers to the ratio of the no enzyme control group, and "max" refers to the ratio of the DMSO control group. Data were displayed in MS Excel and curves were fitted by XLFit Excel add-in version 5.4.0.8.

[0220] IC 50 The calculation formula is: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X) ^ HillSlope

[0221] The calculation results are shown in Table 1.

[0222] Table 1 Inhibitory effects of compounds on FLT3 and FLT3-ITD

[0223]

[0224] 2. Determination of cell proliferation activity of compounds

[0225] An appropriate amount of cell suspension in logarithmic growth phase was evenly inoculated in a 96-well plate and pre-cultured in an incubator for 24 hours (at 37C, 5% CO2). The compound was dissolved in DMSO, and a 10mM stock solution was prepared, diluted with culture medium, and different concentrations of the compound were added to the culture plate, and culture was continued for 24 hours (at 37C, 5% CO2). 10μL CCK8 solution was added to each well (be careful not to generate bubbles in the well, as they will affect the OD reading), incubated in an incubator for 3-4 hours, and the OD value at 450nm was measured with an enzyme reader. The compound inhibition rate was calculated using the following formula: Cell survival rate = [(As-Ab) / (Ac-Ab)]×100%; 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, but no drug); Ab: absorbance of blank wells (containing culture medium, CCK-8 solution, but no cells or drug). The IC of each compound was calculated using Graphpad Prism software. 50 The calculation results are shown in Table 2.

[0226] Table 2 Proliferation inhibition activity of compounds on different cells

[0227]

[0228]

[0229] As shown in Table 1 and Table 2, most of the compounds A-1-1 to A-1-15 of the present invention have an inhibitory effect on FLT3, especially compound A-1-15 and compound A-1-11; some compounds have an inhibitory effect on FLT3-ITD, especially compound A-1-15. In addition, although some compounds have no significant inhibitory effect on FLT3 and FLT3-ITD, such as compound A-1-3 and compound A-1-4, both compound A-1-3 and compound A-1-4 have a good inhibitory effect on the proliferation of MV4-11 cells and THP-1 cells. Moreover, on the other hand, in terms of cell activity evaluation, compound A-1-5, compound A-1-11 and compound A1-1-14 all have good inhibitory activity against HepG2 cells and A549 cells. These cell types usually have high expression of tyrosine kinases, such as c-Kit, c-MET, VEGFR, PDGFR, EGFR, etc. Therefore, the compounds of the present invention may be potential multi-target tyrosine kinase inhibitors.

[0230] In summary, the compounds of the present invention have high inhibitory activity against tyrosine kinases and outstanding anti-proliferative activity against different malignant tumor cell lines, and can be used to prevent or treat diseases that can be regulated by inhibiting tyrosine kinases, such as liver cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, leukemia and other malignant tumor diseases.

[0231] 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. An imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof, characterized in that: The imidazo[1,2-a]pyridine compound is one of the following compounds:

2. The imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt of the imidazo[l,2-a]pyridine compound is an inorganic salt or an organic salt, wherein the inorganic salt is a hydrochloride, a hydrobromide, a hydroiodide, a perchlorate, a sulfate, a bisulfate, a nitrate, a phosphate, or an acid phosphate; and the organic salt is a formate, an acetate, a trifluoroacetate, a propionate, a pyruvate, a glycolate, an oxalate, a malonate, a succinate, a glutarate, a fumarate, a maleate, a lactate, a malate, a citrate, a tartrate, a methanesulfonate, an ethanesulfonate, a benzenesulfonate, a salicylate, a p-toluenesulfonate, or an ascorbate.

3. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the imidazo[l,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 and at least one of a pharmaceutically acceptable carrier, diluent or excipient.

4. The pharmaceutical composition according to claim 3, characterized in that: The preparations made from the pharmaceutical composition include solid preparations for oral administration, liquid preparations for oral administration, preparations for parenteral injection and preparations for local administration.

5. Use of the imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 in the preparation of a medicament for preventing or treating a disease mediated by tyrosine protein kinase.

6. The use according to claim 5, characterized in that: The tyrosine protein kinase-mediated diseases include liver cancer, lung cancer, kidney cancer, colorectal cancer, prostate cancer, breast cancer, ovarian cancer and leukemia.

7. The method for preparing the imidazo[1,2-a]pyridine compound according to claim 1, characterized in that: When the imidazo[l,2-a]pyridine compound is compound A-1-15, the synthesis route of the imidazo[l,2-a]pyridine compound is as follows:

8. The method for preparing the imidazo[1,2-a]pyridine compound according to claim 1, characterized in that: When the imidazo[l,2-a]pyridine compound is compound A-1-9, the synthetic route of the imidazo[l,2-a]pyridine compound is as follows:

9. The method for preparing the imidazo[1,2-a]pyridine compound according to claim 1, characterized in that: When the imidazo[l,2-a]pyridine compound is compound A-1-8, the synthesis route of the imidazo[l,2-a]pyridine compound is as follows:

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