2apos; -substituted-N-isoquinoline nucleoside compound and application thereof in antitumor active drugs

Abstract

The invention discloses a 2 '-substituted-N-isoquinoline nucleoside compound and application of the 2'-substituted-N-isoquinoline nucleoside compound in antitumor active drugs, and belongs to the technical field of medicinal chemistry. The method comprises the following steps: taking 2-deoxy-1-bromo-2-substituted-3, 5-dibenzoyl-alpha-D-arabinofuranose as a glycosyl donor, carrying out nucleophilic substitution on the glycosyl donor and substituted isoquinoline to generate N-isoquinoline nucleoside salt, then carrying out oxidation reaction under the illumination condition by utilizing the photosensitivity of the isoquinoline nucleoside salt, and generating 2 '-substituted-N-isoquinolinone nucleoside. And finally carrying out dehydroxylation protection to obtain the product. The invention solves the problems of difficult post-treatment purification, low reaction yield and low stereoselectivity in the existing method. In tests of tumor cells H1299, HCT116, Siha and 5637, the 6-(2-methoxyphenyl))-N-isoquinoline nucleoside lead compound 16a shows an excellent anti-tumor effect, and a structural reference is provided for anti-tumor candidate drug molecules.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to 2'-substituted-N-isoquinoline nucleoside compounds and their application in anti-tumor active drugs. BACKGROUND

[0002] Nucleoside drugs are an important class of drugs designed by imitating the structure of natural nucleosides. Cancer is still a major threat to human health, and radiotherapy and chemotherapy still play an important role in clinical treatment. In recent years, nucleoside drugs have emerged in the field of cancer treatment due to their unique anti-tumor mechanism. On the other hand, isoquinoline compounds have wide biological activity and pharmaceutical potential. Isoquinoline nucleoside structures can be inserted into DNA or RNA chains, and have application prospects in antiviral and antitumor fields. However, the existing N-glycosylation method has the problems of poor selectivity and low yield in the reaction of isoquinoline ketone and five-carbon sugar, which seriously restricts the further research and application of the compounds.

[0003] At present, the industrial synthesis of nucleoside compounds mainly relies on two technical routes of biological enzyme catalysis and chemical synthesis. Although the biological enzyme catalysis method has relatively mild reaction conditions, due to the insufficient substrate specificity of the enzyme, more by-products are often produced, and the conversion efficiency is generally low, usually difficult to exceed 40%, and the product separation and purification steps are complex, which significantly limits its application in industrial production. In comparison, the chemical synthesis method has improved production efficiency, but still faces many technical challenges, including the lack of selectivity of traditional protection group strategy, the large fluctuation of base conversion reaction yield, and the difficulty in maintaining the stereoselectivity of the product. These technical bottlenecks not only affect the production efficiency and cost control, but also pose a serious challenge to the quality stability of the final product, which needs to be broken through by technological innovation. SUMMARY

[0004] In view of the deficiencies of the existing 2'-substituted-N-isoquinoline nucleoside compound synthesis method, such as harsh reaction conditions, poor yield, and unsatisfactory stereoselectivity, the purpose of the present application is to provide a 2'-substituted-N-isoquinoline nucleoside compound and its activity research, aiming to solve the problems of difficult reaction, low product yield, and difficult accurate control of stereoisomer in the existing synthesis technology.

[0005] The 2'-substituted-N-isoquinoline nucleoside compound provided by the present application has the structural formula:

[0006] X1, X2 are both selected from halogen; R 2 selected from Bz, Ac, Bn.

[0007] This invention also provides a method for synthesizing the above-mentioned 2'-substituted-N-isoquinoline nucleoside compounds, comprising the following steps: using As a glycosyl donor, it first undergoes a nucleophilic substitution reaction with substituted isoquinoline to generate N-isoquinoline nucleoside salt. Then, taking advantage of the photosensitivity of the isoquinoline nucleoside salt itself, it undergoes an oxidation reaction under light to generate the target product, isoquinoline ketone nucleoside.

[0008] Furthermore, the method for synthesizing the 2'-substituted-N-isoquinoline nucleoside compound of the present invention comprises the following steps: S1, using substituted isoquinoline as a raw material, and The reaction is carried out in an organic solvent to obtain;

[0009] S2, compound 1, and triethylenediamine react in an organic solvent via photocatalytic reaction to yield... .

[0011] Furthermore, in step S1 of the above technical solution, the organic solvent is selected from acetonitrile, toluene or acetone, with acetonitrile being the preferred solvent under the preferred conditions, and the reaction time is 10-12 h.

[0012] Furthermore, in step S2 of the above technical solution, the reaction temperature is 15-30 ℃ (preferably 20 ℃), the reaction time is 3-5 h, and the organic solvent is selected from tetrahydrofuran, toluene, or carbon tetrachloride (preferably tetrahydrofuran).

[0013] Furthermore, in step S2 of the above technical solution, the molar ratio of compound 1 to triethylenediamine is 1:2-4 (preferably 1:2).

[0014] Furthermore, under the optimal conditions, the synthesis method of the present invention is represented by the following reaction formula:

[0015] This invention also provides the application of the aforementioned 2'-substituted-N-isoquinoline nucleoside compounds in the preparation of antitumor drugs.

[0016] Furthermore, in the above technical solution, the antitumor activity is anti-H1299, HCT116, Siha, or 5637 activity.

[0017] The present invention also provides an antitumor active drug, characterized in that: its active ingredient includes the aforementioned 2'-substituted-N-isoquinoline nucleoside compounds and their corresponding pharmaceutically acceptable salts.

[0018] Furthermore, in the above technical solution, the pharmaceutically acceptable salt includes the salt formed by the compound with an organic acid or an inorganic acid; the organic acid is selected from one or more of malic acid, lactic acid, camphor sulfonic acid, citric acid, fumaric acid or oxalic acid, and the inorganic acid is selected from one or more of phosphoric acid, hydrohalic acid, sulfuric acid or nitric acid.

[0019] The present invention also provides pharmaceutical compositions containing 2'-substituted-N-isoquinoline nucleoside compounds.

[0020] Beneficial effects of the invention 1. The 2'-substituted-N-isoquinoline nucleoside compounds of this invention have novel structures, significantly expanding the structural diversity of nucleoside molecules, and the raw materials are readily available and the preparation method is simple and feasible.

[0021] 2. The 2'-substituted-N-isoquinoline nucleoside compounds of this invention showed good performance in activity tests of H1299, HCT116, Siha, and 5637 cells. Specifically, they exhibited significant cellular activity against 5637 cancer cells. Specific Implementation

[0022] The present invention will be further illustrated below with specific examples. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0023] Example 1 Experimental procedure for compound 1a: 1.0 mmol of isoquinoline and 2.0 mmol of 2-deoxy-1-bromo-2-fluoro-3,5-dibenzoyl-α-D-arabinofuranose were weighed and added to a 100 mL round-bottom flask equipped with a magnetic stir bar. Then, 10 mL of acetonitrile was added as a solvent, and the mixture was stirred overnight. The reaction progress was monitored by thin-layer chromatography (TLC) until the liquid phase purity of the isoquinoline starting material was less than 1%. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography, finally yielding the target compound 1a in 89% yield.

[0024] 2-((2S,3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-fluorotetrahydrofuran-2-yl)isoquinolin-2-ium bromide

[0025] Pale pink solid; 1H NMR (400 MHz, CD3CN) δ 10.31 (s, 1H), 8.99 (dt, J = 6.9,1.5 Hz, 1H), 8.50-8.42 (m, 2H), 8.32-8.24 (m, 2H), 8.23 ​​-8.19 (m, 2H),8.10-8.05 (m, 2H), 8.03 (ddd, J = 8.3, 6.6, 1.5 Hz, 1H), 7.73-7.67 (m,1H), 7.64-7.59(m, 1H), 7.59-7.52 (m, 2H), 7.49-7.44 (m, 2H), 7.32 (dd, J = 18.1, 3.3 Hz, 1H),5.81 (ddd, J = 16.0, 2.9, 1.3 Hz, 1H), 5.05-4.99 (m, 1H), 4.95-4.83 (m, 2H); 13 CNMR (101 MHz, CD3CN) δ 166.7, 165.7, 148.0, 139.5, 138.8, 134.6, 134.1,132.3, 132.2, 131.7, 129.3, 129.3, 128.1, 127.8, 126.5, 95.0 (d, J C-F = 7.2 Hz), 94.0 (d, J C-F = 170.7 Hz), 84.1, 76.6 (d, J C-F = 29.9 Hz), 63.9; 19 F NMR (377 MHz, CD3CN) δ -201.2; HRMS (ESI-TOF) Calcd for C 28 H 23 FNO5[M-Br] + 472.1555, found 472.1555. Experimental procedure for compound 1b: 0.1 mmol of compound 1a and 0.2 mmol of triethylenediamine were added to a 15 mL quartz reaction tube containing a magnetic magnet. 3 mL of tetrahydrofuran was injected, and the reaction was carried out at room temperature for 0.5 h under blue light irradiation. The tetrahydrofuran solvent was removed by vacuum concentration, and the product was purified by column chromatography to obtain the corresponding pale yellow oil 1b in 85% yield.

[0026] ((2R,3R,4S,5S)-3-(benzoyloxy)-4-fluoro-5-(1-oxoisoquinolin-2(1H)-yl)tetrahydrofuran-2-yl)methyl benzoate

[0027] 1 H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 8.1, 1.2 Hz, 1H), 8.11 (ddt, J =14.4, 7.0, 1.4 Hz, 4H), 7.70-7.62 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.42 (m,7H), 6.73 (dd, J = 22.6, 2.8 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 5.68 (dd, J = 16.9,2.8 Hz, 1H), 5.51 (dd, J = 50.0, 2.7 Hz, 1H), 4.88 -4.78 (m, 2H), 4.58 (td, J =4.4, 2.7 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 166.3, 165.3, 161.8, 137.0, 134.0,133.4, 132.9, 130.0, 129.8, 129.6, 128.7, 128.5, 128.4,127.7, 127.3, 127.3,126.9, 126.1, 125.4, 105.9, 92.4 (d, J C-F = 191.8 Hz), 85.5 (d, J C-F = 16.9 Hz),81.2, 77.1 (d, J C-F = 30.9 Hz), 63.6 ; 19 F NMR (377 MHz, CDCl3) δ -201.6; HRMS(ESI-TOF) Calcd for C 28 H 22FNNaO6 + [M+Na] + 510.1323, found 510.1324. Example 2 Experimental procedure for compound 3a: 1.0 mmol of isoquinoline and 2.0 mmol of 2-deoxy-1-bromo-2-bromo-3,5-dibenzoyl-α-D-arabinofuranose were weighed and added to a 100 mL round-bottom flask equipped with a magnetic stir bar. Then, 10 mL of acetonitrile was added as a solvent, and the mixture was stirred overnight. The reaction progress was monitored by thin-layer chromatography (TLC) until the liquid phase purity of the isoquinoline starting material was less than 1%. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography, finally yielding the target compound 3a in 80% yield.

[0028] 2-((2S,3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-bromotetrahydrofuran-2-yl)isoquinolin-2-ium bromide

[0029] Yellow solid; 1 H NMR (400 MHz, DMSO- d 6) δ 10.25 (s, 1H), 8.95 (dd, J = 7.0, 1.5 Hz, 1H), 8.75 (d, J = 6.9 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.48-8.33 (m,2H), 8.21-8.11 (m, 3H), 8.11-8.04 (m, 2H), 7.82-7.74 (m,1H), 7.74-7.66 (m,1H), 7.59 (ddd, J = 34.0, 11.0, 4.6 Hz, 4H), 7.19 (d, J = 4.4 Hz, 1H), 5.88 (dd, J = 3.7, 2.5 Hz, 1H), 5.65 (dd, J = 4.5, 2.5 Hz, 1H), 5.11 (dt, J = 6.6, 3.9 Hz,1H), 5.04-4.87 (m, 2H); 13C NMR (101 MHz, DMSO- d 6) δ 166.2, 165.2, 147.8,138.8, 138.8, 134.7, 134.2, 132.2, 132.0, 132.0, 130.3,129.9, 129.7, 129.4,129.3, 129.0, 128.0, 127.0, 126.2, 94.4, 82.4, 79.1, 64.4, 61.6; HRMS (ESI-TOF) Calcd for C 28 H 23 Br NO5[M-Br] + 532.0754, found 532.0752. Experimental procedure for compound 3b: 0.1 mmol of compound 3a and 0.2 mmol of triethylenediamine were added to a 15 mL quartz reaction tube containing a magnetic magnet. 3 mL of tetrahydrofuran was injected, and the mixture was reacted at room temperature for 3 h under blue light irradiation. The tetrahydrofuran solvent was removed by vacuum concentration, and the product was purified by column chromatography to obtain the corresponding pale yellow oil 3b in 34% yield.

[0030] ((2R,3R,4S,5S)-3-(benzoyloxy)-4-bromo-5-(1-oxoisoquinolin-2(1H)-yl)tetrahydrofuran-2-yl)methyl benzoate

[0031] 1 H NMR (400 MHz, CDCl3) δ 8.40 (dd, J = 8.0, 1.2 Hz, 1H), 8.12 (ddt, J =18.0, 6.9, 1.4 Hz, 4H), 7.72-7.61 (m, 2H), 7.61-7.42 (m, 8H), 6.64 (d, J = 3.6Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H), 5.70 (d, J = 2.8 Hz, 1H), 5.11 (dd, J = 3.6, 0.9Hz, 1H), 4.89 (d, J = 5.2 Hz, 2H), 4.60 (td, J= 5.1, 2.8 Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 166.3, 165.3, 161.6, 137.1, 134.0,133.3, 132.9, 130.0, 129.9,129.6, 128.7, 128.5, 127.6, 127.1, 126.9, 126.1, 125.2, 105.6, 86.5, 81.6,80.5, 77.2, 63.9, 60.8; HRMS (ESI-TOF) Calcd for C 28 H 22 BrNNaO6 + [M+Na] + 507.0523, found 507.0523. Example 3 Experimental procedure for compound 4a: 1.0 mmol of 5-methoxyisoquinoline and 2.0 mmol of 2-deoxy-1-bromo-2-fluoro-3,5-dibenzoyl-α-D-arabinofuranose were weighed and added to a 100 mL round-bottom flask equipped with a magnetic stir bar. Then, 10 mL of acetonitrile was added as a solvent, and the mixture was stirred overnight. The reaction progress was monitored by thin-layer chromatography (TLC) until the liquid phase purity of the isoquinoline starting material was less than 1%. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography, finally yielding the target compound 4a in 87% yield.

[0032] 2-((2S,3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-fluorotetrahydrofuran-2-yl)-5-methoxyisoquinolin-2-ium bromide

[0033] White solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.90 (d, J = 7.0Hz, 1H), 8.72 (d, J = 7.0 Hz, 1H), 8.17-7.97 (m, 6H), 7.85-7.73 (m, 2H), 7.64(dt, J = 10.1, 7.6 Hz, 3H), 7.48 (t, J= 7.8 Hz, 2H), 7.10 (dd, J = 17.7, 3.4 Hz,1H), 6.02 (ddd, J = 49.6, 3.5, 1.6 Hz, 1H), 5.92-5.82 (m, 1H), 5.11 (q, J = 3.9Hz, 1H), 4.98-4.82 (m, 2H), 4.13 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 167.1,166.1, 165.2, 146.2, 141.9, 134.7, 134.1, 133.8, 132.6, 130.2, 129.8,129.4,129.2, 129.0, 124.8, 123.9, 122.5, 106.6, 93.9 (d, J C-F = 15.4 Hz), 93.7 (d, J C-F =193.1 Hz), 82.2, 76.3 (d, J C-F = 29.2 Hz), 64.1, 57.3; 19 F NMR (377 MHz, DMSO-d6)δ -199.7; HRMS (ESI-TOF) Calcd for C 29 H 25 FNO6[M-Br] + 502.1660 was found to be 502.1661. Experimental procedure for compound 4b: 0.1 mmol of compound 4a and 0.2 mmol of triethylenediamine were added to a 15 mL quartz reaction tube containing a magnetic magnet. 3 mL of tetrahydrofuran was injected, and the reaction was carried out at room temperature for 2.5 h under blue light irradiation. The tetrahydrofuran solvent was removed by vacuum concentration, and the product was purified by column chromatography to obtain the corresponding pale yellow oil 4b in 80% yield.

[0034] ((2R,3R,4S,5S)-3-(benzoyloxy)-4-fluoro-5-(5-methoxy-1-oxoisoquinolin-2(1H)-yl)tetrahydrofuran-2-yl)methyl benzoate

[0035] 1 1H NMR (400 MHz, CDCl3) δ 8.11 (ddt, J J = 14.9, 7.0, 1.4 Hz, 4H), 7.99(d, J J = 8.1 Hz, 1H), 7.69 - 7.55 (m, 2H), 7.55 - 7.38 (m, 6H), 7.09 (dd, J J = 8.0, 1.0Hz, 1H), 6.90 (d, J J = 7.8 Hz, 1H), 6.71 (dd, J J = 22.5, 2.7 Hz, 1H), 5.68 (dd, J J =16.8, 2.8 Hz, 1H), 4.82 (d, J J = 4.5 Hz, 2H), 4.58 (td, J J = 4.5, 2.8 Hz, 1H), 3.94(s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 166.3, 161.5, 154.5, 134.0, 133.3, 130.0,129.8, 129.6, 128.7, 128.5, 128.4, 128.1, 127.2,126.5, 126.4, 119.2, 112.0,100.3, 92.3 (d, J C-F J = 191.9 Hz), 85.6 (d, J C-F J = 17.2 Hz), 81.2, 77.2 (d, J C-F J = 30.8Hz), 63.5, 55.8, 29.7 . 19 19F NMR (377 MHz, CDCl3) δ -201.6; HRMS (ESI - TOF) Calcdfor C 29 19H 24 19FNNaO7+ [M + Na]+ 540.1429, found 540.1430. Example 4 Experimental procedure for compound 5a: 1.0 mmol of 6-methoxy and 2.0 mmol of 2-deoxy-1-bromo-2-fluoro-3,5-dibenzoyl-α-D-arabinofuranose were weighed and added to a 100 mL round-bottom flask equipped with a magnetic stir bar. Then, 10 mL of acetonitrile was added as a solvent, and the mixture was stirred overnight. The reaction progress was monitored by thin-layer chromatography (TLC) until the liquid phase purity of the isoquinoline starting material was less than 1%. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography, finally yielding the target compound 5a in 88% yield.

[0036] 2-((2S,3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-fluorotetrahydrofuran-2-yl)-6-methoxyisoquinolin-2-ium bromide

[0037] White solid; 1 H NMR (400 MHz, CD3CN) δ 10.06 (s, 1H), 8.86 (dt, J = 7.2, 1.5Hz, 1H), 8.30-8.18 (m, 4H), 8.09-8.04 (m, 2H), 7.70 -7.59 (m, 3H), 7.56-7.50(m, 3H), 7.49-7.43 (m, 2H), 7.26 (dd, J = 18.5, 3.2 Hz, 1H), 6.04 (ddd, J = 49.9,3.3, 1.3 Hz, 1H), 5.78 (ddd, J = 16.2, 2.9, 1.3 Hz, 1H), 4.96 (td, J = 4.4, 3.3Hz, 1H), 4.93-4.82 (m, 2H), 4.06 (s, 3H); 13 C NMR (101 MHz, CD3CN) δ 167.7,166.7, 165.7, 146.0, 142.6, 134.5, 134.1, 133.6, 132.5, 130.5, 130.0, 129.3,129.2, 125.1, 124.1, 117.9, 106.6, 94.3 (d, J C-F= 15.9 Hz), 94.1 (d, J C-F = 193.2Hz), 83.7, 76.7 (d, J C-F = 29.9 Hz), 63.9, 57.3; 19 F NMR (377 MHz, CD3CN) δ -199.4; HRMS (ESI-TOF) Calcd for C 29 H 25 FNO6[M-Br] + 502.1660, found 502.1660. Experimental procedure for compound 5b: 0.1 mmol of compound 5a and 0.2 mmol of triethylenediamine were added to a 15 mL quartz reaction tube containing a magnetic magnet. 3 mL of tetrahydrofuran was injected, and the reaction was carried out at room temperature for 2.5 h under blue light irradiation. The tetrahydrofuran solvent was removed by vacuum concentration, and the product was purified by column chromatography to obtain the corresponding pale yellow oily substance 5b in 81% yield.

[0038] ((2R,3R,4S,5S)-3-(benzoyloxy)-4-fluoro-5-(6-methoxy-1-oxoisoquinolin-2(1H)-yl)tetrahydrofuran-2-yl)methyl benzoate 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.9 Hz, 1H), 8.11 (ddt, J = 15.4,7.0, 1.4 Hz, 4H), 7.68-7.62 (m, 1H), 7.61-7.56 (m, 1H), 7.53-7.43 (m,5H),7.06 (dd, J = 8.9, 2.5 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 22.7, 2.8Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 5.67 (dd, J = 17.0, 2.9 Hz, 1H), 5.48 (dd, J=50.0, 2.8 Hz, 1H), 4.88-4.76 (m, 2H), 4.56 (td, J = 4.4, 2.8 Hz, 1H), 3.91 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 166.3, 161.5, 139.2, 134.0, 133.3, 130.0,129.8, 129.8, 129.6, 128.7, 128.5,128.4, 128.1, 119.2, 116.4, 106.9, 105.7,92.4 (d, J C-F = 191.5 Hz), 85.3 (d, J C-F = 16.9 Hz), 81.1, 77.1 (d, J C-F = 30.8 Hz), 63.6, 55.5; 19 F NMR (377 MHz, CDCl3) δ-201.7; HRMS (ESI-TOF) Calcd forC 29 H 24 FNNaO7 + [M+ Na] + 540.1429, found 540.1430. Example 5 Experimental procedure for compound 6a: 1.0 mmol of 7-methoxy and 2.0 mmol of 2-deoxy-1-bromo-2-fluoro-3,5-dibenzoyl-α-D-arabinofuranose were weighed and added to a 100 mL round-bottom flask equipped with a magnetic stir bar. Then, 10 mL of acetonitrile was added as a solvent, and the mixture was stirred overnight. The reaction progress was monitored by thin-layer chromatography (TLC) until the liquid phase purity of the isoquinoline starting material was less than 1%. After the reaction was complete, the reaction solution was concentrated under vacuum and purified by column chromatography, finally yielding the target compound 6a in 89% yield.

[0039] 2-((2S,3S,4R,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3-fluorotetrahydrofuran-2-yl)-7-methoxyisoquinolin-2-ium bromide

[0040] White solid; 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.83 (d, J = 6.8 Hz,1H), 8.65 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.13 (dt, J = 8.3, 1.0 Hz,2H), 8.02-7.94 (m, 3H), 7.89 (d, J = 2.5 Hz, 1H), 7.82-7.73 (m, 1H), 7.63 (td, J = 7.6, 3.8 Hz, 3H), 7.45 (t, J = 7.7 Hz, 2H), 7.08 (dd, J = 17.3, 3.6 Hz, 1H),6.14-5.93 (m, 1H), 5.93-5.84 (m, 1H), 5.12 (q, J = 4.2 Hz, 1H), 4.88 (qd, J =12.2, 4.6 Hz, 2H), 3.94 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 165.2, 145.3,134.7, 134.1, 131.4, 130.8, 130.2, 129.7, 129.7, 129.4, 129.2, 129.0, 125.8,108.5, 94.3 (d, J C-F = 15.8 Hz), 93.8 (d, J C-F = 193.4 Hz), 82.5, 76.4 (d, J C-F = 29.6Hz), 64.2, 56.7; 19 F NMR (377 MHz, DMSO-d6) δ -199.5; HRMS (ESI-TOF) Calcd forC 29 H 25 FNO6[M-Br] + 502.1660, found 502.1661. Experimental procedure for compound 6b: 0.1 mmol of compound 6a and 0.2 mmol of triethylenediamine were added to a 15 mL quartz reaction tube containing a magnetic magnet. 3 mL of tetrahydrofuran was injected, and the reaction was carried out at room temperature for 2.5 h under blue light irradiation. The tetrahydrofuran solvent was removed by vacuum concentration, and the product was purified by column chromatography to obtain the corresponding pale yellow oil 6b in 79% yield.

[0041] ((2R,3R,4S,5S)-3-(benzoyloxy)-4-fluoro-5-(7-methoxy-1-oxoisoquinolin-2(1H)-yl)tetrahydrofuran-2-yl)methyl benzoate

[0042] 1 H NMR (400 MHz, CDCl3) δ 8.11 (ddt, J = 13.1, 7.0, 1.4 Hz, 4H), 7.81(d, J = 2.7 Hz, 1H), 7.67-7.61 (m, 1H), 7.61-7.55 (m, 1H), 7.53-7.42 (m, 5H),7.40(dd, J = 7.6, 1.9 Hz, 1H), 7.32-7.23 (m, 1H), 6.74 (dd, J = 22.4, 2.8 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 5.69 (dd, J = 16.9, 2.9 Hz, 1H), 5.52 (dd, J = 50.1, 2.8 Hz, 1H), 4.83 (dd, J = 4.4, 1.5 Hz, 2H), 4.58 (td, J = 4.4, 2.8 Hz, 1H), 3.92(s, 3H); 13 C NMR (101 MHz, CDCl3) δ 166.3, 165.3, 161.5, 158.8, 134.0, 133.3,131.1, 130.0, 129.8, 129.6, 128.7,128.5, 128.5, 127.7, 126.5, 125.0, 123.4,107.6, 105.8, 92.4 (d,J C-F = 191.9 Hz), 85.6 (d, J C-F = 16.8 Hz), 81.2, 77.1 (d, J C-F = 30.8 Hz), 63.6, 55.6; 19 F NMR (377 MHz, CDCl3) δ -201.6; HRMS (ESI-TOF)Calcd for C 29 H 24 FNNaO7 + [M+Na] + 540.1429, found 540.1428. Example 6 The experimental steps for screening small molecule drugs by median lethal concentration (LD50) are as follows: ① Seed the cell suspension into 96-well plates, typically 100 μL per well (adjust cell density according to cell type, such as 500-10,000 cells / well). Set up experimental groups (drug treatment), control groups (no drug), and blank groups (culture medium only, no cells). Incubate for 24 hours to allow cell adhesion.

[0043] ② After cell adhesion, add the test compound according to a certain concentration gradient, with 3-6 replicates per group. Continue culturing for a certain period of time.

[0044] ③ After culturing for 48 hours, add 70 µL of 10% CCK-8 reagent to each well, shake gently to avoid generating air bubbles, return to the incubator and continue incubation for 1-4 hours, and then use a microplate reader to measure the OD value at 450 nm.

[0045] Table 1 Test Results

[0046]

[0047]

[0048] Table 1 shows that these compounds exhibit strong inhibitory activity against all four tumor cell lines. Among them, the 6-substituted (6-(2-methoxyphenyl))N-isoquinoline nucleoside 16a demonstrates excellent broad-spectrum antitumor effects in all four tumor cell lines: H1299 (non-small cell lung cancer), HCT116 (colon cancer), Siha (cervical cancer), and 5637 (bladder cancer) cells. 50 The values ​​were 1.01 μM, 1.05 μM, 0.69 μM, and 0.62 μM, respectively.

[0049] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A 2'-substituted-N-isoquinoline nucleoside compound, characterized in that, The general formula for the structure is: X1 and X2 are both selected from halogens; R 2 Selected from Bz, Ac, Bn.

2. The method for synthesizing the 2'-substituted-N-isoquinoline nucleoside compound as described in claim 1, characterized in that, Includes the following steps: S1, using substituted isoquinoline as a raw material, and The reaction is carried out in an organic solvent to obtain; S2, compound 1, and triethylenediamine react in an organic solvent via photocatalytic reaction to yield... .

3. The method for synthesizing the 2'-substituted-N-isoquinoline nucleoside compound according to claim 2, characterized in that: In step S1, the organic solvent is selected from acetonitrile, toluene, or acetone, and the reaction time is 10-12 h.

4. The method for synthesizing the 2'-substituted-N-isoquinoline nucleoside compound according to claim 2, characterized in that: In step S2, the reaction temperature is 15-30 ℃, the reaction time is 3-5 h, and the organic solvent is selected from tetrahydrofuran, toluene, or carbon tetrachloride.

5. The method for synthesizing the 2'-substituted-N-isoquinoline nucleoside compound according to claim 2, characterized in that: In step S2, the molar ratio of compound 1 to triethylenediamine is 1:2-4.

6. The use of the 2'-substituted-N-isoquinoline nucleoside compound as described in claim 1 in the preparation of antitumor drugs.

7. The application of the 2'-substituted-N-isoquinoline nucleoside compound according to claim 6 in antitumor drugs, characterized in that: The antitumor activity is anti-H1299, HCT116, Siha, or 5637 activity.

8. An antitumor active drug, characterized in that: Its active ingredients include the compounds of claim 1 and their corresponding pharmaceutically acceptable salts.

9. The antitumor active drug according to claim 8, characterized in that: The pharmaceutically acceptable salt includes salts formed by the compound with an organic or inorganic acid; the organic acid is selected from one or more of malic acid, lactic acid, camphor sulfonic acid, citric acid, fumaric acid, or oxalic acid, and the inorganic acid is selected from one or more of phosphoric acid, hydrohalic acid, sulfuric acid, or nitric acid.

10. A pharmaceutical composition comprising any one of the compounds of claim 1.

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