Heteroaromatic amide compound and preparation method and application thereof

Abstract

The invention discloses a heteroaromatic amide compound and a preparation method and application thereof. According to the heteroaryl amide compound provided by the invention, a preliminary activity research shows that the compound has selectivity to STAT3 and also has very strong tumor cell proliferation inhibition activity; the compound can be used as a series of novel STAT3 inhibitors and can be used for preparing drugs for treating corresponding diseases. The compound has obvious killing effect on human cancer cells, especially human breast cancer cell line MDA-MB-231, human prostate cancer cell line PC-3 and human prostate cancer cell line DU-145, has the potential of being prepared into novel antitumor drugs, and has better market prospect.

Description

technical field

[0001] The invention relates to a heteroarylamide compound, its preparation method and application. Background technique

[0002] Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT transcription factor family, exists in the cytoplasm, and plays an important role in transmitting signals from cell surface receptors to the nucleus. In normal cells, STAT3 is strictly regulated, and the continuous activation of STAT3 is often related to tumorigenesis, proliferation, promotion of angiogenesis and inhibition of apoptosis, and is also related to oncogenic functions such as inhibition of anti-tumor immune response. Therefore, the treatment of human cancer and other human diseases by directly targeting the abnormally activated STAT3 signaling pathway has attracted the attention of medical workers.

[0003] It is generally believed that the tyrosine phosphorylation at position 705 of STAT3 activates STAT3, and the two phosphorylated STAT...

Examples

Embodiment 1

[0241] Synthesis of Example 1 Compound 2-(4-(2-formyl-3-methylcyclopent-1-en-1-yl)benzamido)thiophene-3-carboxamide (ST-013)

[0242] Preparation of Intermediates Synthesis of Compound 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carbaldehyde(3)

[0243]

[0244] Measure DMF (2.37mL, 30.6mmol) and dissolve it in anhydrous dichloromethane (35mL). When the ice bath drops to 0°C, add PBr dropwise 3 (2.42mL, 25.5mmol), kept stirring at 0°C for 1 hour. Subsequently, compound 1 (1.0 g, 10.2 mmol) was dissolved in anhydrous dichloromethane (15 mL), and slowly added dropwise to the above reaction solution. After the reaction was dropped, it was slowly raised to room temperature and stirred for 12 hours. When the reaction solution was cooled to 0 °C, water (50 mL) was added to the reaction solution to quench, and the reaction solution was dissolved with NaHCO 3 The solid neutralized the solution, extracted with dichloromethane (3×50 mL), and the organi...

Embodiment 2

[0251] Synthesis of Example 2 Compound (R)-2-(4-(2-formyl-3-methylcyclopent-1-en-1-yl)benzamido)thiophene-3-carboxam-ide (ST-022)

[0252] Synthesis of compound 3a

[0253]

[0254] Compound 3a was synthesized the same as compound 3, and the purchased starting materials were replaced with 1a.

[0255]

[0256] Weigh compound 3a (100mg, 0.53mmol), compound 50 (0.26mmol), Pd(dppf)Cl 2 (19mg, 0.026mmol) and anhydrous sodium carbonate (55mg, 0.52mmol) were dissolved in tetrahydrofuran (10mL) and water (1mL). Under the protection of argon, the temperature of the reaction solution was raised to 75°C and stirred for 1 hour. The above reaction solution was concentrated to obtain a crude product, which was purified by flash column chromatography (PE / EtOAc=2 / 1) to obtain ST-022 (21 mg, 23%) as a yellow solid.

[0257] 1 HNMR (500MHz, Chloroform-d) δ12.98(s,1H),9.82(s,1H),8.06(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),7.13– 6.98(m,1H),6.87(s,1H),5.86(d,J=106.6Hz,2H),3.19–2.95(m,2H),2.74...

Embodiment 3

[0258] Synthesis of Example 3 Compound 2-(4-(pyrimidin-5-yl)benzamido)thiophene-3-carboxamide (ST-024)

[0259]

[0260] Weigh compound 89 (66mg, 0.53mmol), compound 50 (84mg, 0.26mmol), Pd(dppf)Cl 2 (19mg, 0.026mmol) and anhydrous sodium carbonate (55mg, 0.52mmol) were dissolved in tetrahydrofuran (10mL) and water (1mL), and the reaction solution was heated to 85°C under the protection of argon, and stirred for 1 hour. After the reaction solution was concentrated to dryness, it was purified by flash column chromatography (PE / EtOAc=1 / 3) to obtain ST-024 (30 mg, 36%) as a yellow solid. 1 HNMR (500MHz, DMSO-d 6 )δ9.24(s,3H),8.13(s,1H),8.06(q,J=8.1Hz,4H),7.67(s,1H),7.57–7.49(m,1H),7.05(d,J =5.8Hz,1H); 13 CNMR (125MHz, DMSO-d 6 )δ167.82,162.34,158.34,155.51,146.51,138.26,132.70,132.55,128.31,128.21,123.76,117.07,116.28; HRMS(ESI):m / z calcd for C 16 h13 N 4 o 2 S[M+H] + :325.0754, found 325.0750.

technical field

[0001] The invention relates to a heteroarylamide compound, its preparation method and application. Background technique

[0002] Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT transcription factor family, exists in the cytoplasm, and plays an important role in transmitting signals from cell surface receptors to the nucleus. In normal cells, STAT3 is strictly regulated, and the continuous activation of STAT3 is often related to tumorigenesis, proliferation, promotion of angiogenesis and inhibition of apoptosis, and is also related to oncogenic functions such as inhibition of anti-tumor immune response. Therefore, the treatment of human cancer and other human diseases by directly targeting the abnormally activated STAT3 signaling pathway has attracted the attention of medical workers.

[0003] It is generally believed that the tyrosine phosphorylation at position 705 of STAT3 activates STAT3, and the two phosphorylated STAT...

Examples

Embodiment 1

[0241] Synthesis of Example 1 Compound 2-(4-(2-formyl-3-methylcyclopent-1-en-1-yl)benzamido)thiophene-3-carboxamide (ST-013)

[0242] Preparation of Intermediates Synthesis of Compound 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carbaldehyde(3)

[0243]

[0244] Measure DMF (2.37mL, 30.6mmol) and dissolve it in anhydrous dichloromethane (35mL). When the ice bath drops to 0°C, add PBr dropwise 3 (2.42mL, 25.5mmol), kept stirring at 0°C for 1 hour. Subsequently, compound 1 (1.0 g, 10.2 mmol) was dissolved in anhydrous dichloromethane (15 mL), and slowly added dropwise to the above reaction solution. After the reaction was dropped, it was slowly raised to room temperature and stirred for 12 hours. When the reaction solution was cooled to 0 °C, water (50 mL) was added to the reaction solution to quench, and the reaction solution was dissolved with NaHCO 3 The solid neutralized the solution, extracted with dichloromethane (3×50 mL), and the organi...

Embodiment 2

[0251] Synthesis of Example 2 Compound (R)-2-(4-(2-formyl-3-methylcyclopent-1-en-1-yl)benzamido)thiophene-3-carboxam-ide (ST-022)

[0252] Synthesis of compound 3a

[0253]

[0254] Compound 3a was synthesized the same as compound 3, and the purchased starting materials were replaced with 1a.

[0255]

[0256] Weigh compound 3a (100mg, 0.53mmol), compound 50 (0.26mmol), Pd(dppf)Cl 2 (19mg, 0.026mmol) and anhydrous sodium carbonate (55mg, 0.52mmol) were dissolved in tetrahydrofuran (10mL) and water (1mL). Under the protection of argon, the temperature of the reaction solution was raised to 75°C and stirred for 1 hour. The above reaction solution was concentrated to obtain a crude product, which was purified by flash column chromatography (PE / EtOAc=2 / 1) to obtain ST-022 (21 mg, 23%) as a yellow solid.

[0257] 1 HNMR (500MHz, Chloroform-d) δ12.98(s,1H),9.82(s,1H),8.06(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),7.13– 6.98(m,1H),6.87(s,1H),5.86(d,J=106.6Hz,2H),3.19–2.95(m,2H),2.74...

Embodiment 3

[0258] Synthesis of Example 3 Compound 2-(4-(pyrimidin-5-yl)benzamido)thiophene-3-carboxamide (ST-024)

[0259]

[0260] Weigh compound 89 (66mg, 0.53mmol), compound 50 (84mg, 0.26mmol), Pd(dppf)Cl 2 (19mg, 0.026mmol) and anhydrous sodium carbonate (55mg, 0.52mmol) were dissolved in tetrahydrofuran (10mL) and water (1mL), and the reaction solution was heated to 85°C under the protection of argon, and stirred for 1 hour. After the reaction solution was concentrated to dryness, it was purified by flash column chromatography (PE / EtOAc=1 / 3) to obtain ST-024 (30 mg, 36%) as a yellow solid. 1 HNMR (500MHz, DMSO-d 6 )δ9.24(s,3H),8.13(s,1H),8.06(q,J=8.1Hz,4H),7.67(s,1H),7.57–7.49(m,1H),7.05(d,J =5.8Hz,1H); 13 CNMR (125MHz, DMSO-d 6 )δ167.82,162.34,158.34,155.51,146.51,138.26,132.70,132.55,128.31,128.21,123.76,117.07,116.28; HRMS(ESI):m / z calcd for C 16 h13 N 4 o 2 S[M+H] + :325.0754, found 325.0750.

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