A method for preparing a nucleoside derivative by selective acylation catalyzed by a nitrogen heterocyclic carbene and use thereof

Abstract

The present application relates to the preparation method and good biological activity of the selective acylation nucleoside derivative catalyzed by azaheterocyclic carbene organic small molecule, and structural general formula is as follows: wherein R is the substituent of aromatic aldehyde, and N-heterocycle is the substituent of base.The present application discloses the selective acylation nucleoside derivative synthesized by azaheterocyclic carbene organic small molecule catalysis, the derivative thereof is good in universality, has excellent yield (up to 82 %), regioselectivity (> 20:1) and good biological activity.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for the preparation of and use of aza-catalyzed selective acylation of nucleoside derivatives BACKGROUND

[0002] Nucleosides and nucleotides are important components of life molecules, which are essential for the genetic and energy supply of organisms. Nucleoside analogues as effective drugs have played a key role in the treatment of various diseases. Despite the great success in the development of nucleoside drugs, their clinical application is often limited by low bioavailability, undesirable pharmacokinetic properties, and dangerous side effects at high doses. One of the effective strategies to optimize the efficiency of nucleoside drugs is to chemically modify the structure of these biologically active nucleosides to achieve prodrugs with improved bioavailability and pharmacokinetic properties. The selective esterification of OH groups in nucleoside drug molecules is one of the most effective strategies for drug optimization (Chem. Rev. 100, 4319-4348 (2000); Bioorg. Med. Chem. 8, 2681-2687 (2000); J. Am. Chem. Soc. 110, 7200-7205 (2002)).

[0003] Traditionally, the regioselective monofunctionalization of hydroxyl groups on nucleoside molecules requires a pre-protection / de-protection procedure. For example, the monofunctionalization of the 5'-OH group of the sugar moiety in ribavirin requires the pre-protection of the 2'-OH and 3'-OH groups by forming acetal structures with equivalent carbonyl compounds, and after the 5'-OH functionalization and de-protection of the 2'-OH and 3'-OH groups, the 5'-OH monofunctionalization product can be obtained (J. Med. Chem. 60, 1648-1661 (2017)). Similarly, ribavirin 2'-OH functionalization usually involves the pre-protection of the 3'-OH and 5'-OH groups by dichlorosilane reagents and a de-protection step after the target transformation (J. Med. Chem. 43, 1019-1028 (2000)). Enzyme-catalyzed methods can directly obtain 5'-O-acylated ribavirin derivatives regioselectively, but site-selective functionalization of other OH groups of ribavirin and its analogues has not been achieved. To our knowledge, a simple and regioselective method for ribavirin 3'-OH monofunctionalization has not been reported, although enzyme-catalyzed and cross-metal catalysis can produce several 3'-OH monofunctionalized nucleosides other than ribavirin (J. Org. Chem. 39, 24-30 (1974); Biotechnol. Tech. 13, 563-566 (1999)). Therefore, it is very meaningful to develop programmable, economical, simple and non-toxic methods for the regioselective functionalization of nucleoside molecules. SUMMARY

[0004] The present application aims to design novel structure, good substrate versatility and high regioselectivity of monoacylated nucleoside derivatives, and further explore its use in biological activity.

[0005] The selective acylation of nucleoside derivatives of the present application, such as the following general formula (1) represents:

[0006]

[0007] Wherein R is phenyl, substituted phenyl, furan, thiophene, naphthyl, alkenyl benzene, citral, vanillin, propyl sulfonamide, tometin acid, 2-methyl propylene or isopropyl;

[0008] N-heterocyclic ring is purine, pyrimidine base, 5-methyl uridine, adenosine or 8-bromo adenosine.

[0009] The substituted phenyl atom is halogen atom, trifluoromethyl, methyl, methoxy.

[0010] The halogen atom is fluorine, chlorine or bromine.

[0011] The reaction formula and process are as follows:

[0012]

[0013] The synthesized derivatives are as follows:

[0014] Substrate Scope for the 5'-OH Acylation Reaction of Nucleosides a

[0015]

[0016] a Reaction conditions: nucleoside (0.10 mmol), RCHO (0.20 mmol), NHC C (0.01 mmol), DBU (0.02 mmol), DQ (0.10 mmol), boric acid (0.10 mmol), DMF (1.0 Ml), reaction at 30℃ for 12h. b Reaction for 18 hours. The yield is the total yield of 2+3+4. The r.r. is the regioselectivity.

[0017] Substrate Scope for the 3'-OH Acylation Reaction of Nucleosides a

[0018]

[0019] a Reaction conditions: nucleoside (0.10 mmol), RCHO (0.20 mmol), NHC E (0.01 mmol), Na2CO3 (0.02 mmol), DQ (0.10 mmol), DMF / MeCN (1.0 mL), reaction at 50 °C for 2 h. b Reaction 3 h. Overall yield of 2+3+4. r.r. is regioselectivity.

[0020] The method for synthesizing the oral anti-COVID-19 drug is as follows:

[0021]

[0022] The present application has the following advantages: nucleoside compounds with different biological activities can be effectively prepared into 5'-O-acylated nucleoside derivatives and 3'-O-acylated nucleoside derivatives and other prodrug molecules under the catalysis of azacyclic carbene, and have the advantages of good substrate universality (62 compounds), excellent yield and high regioselectivity (the highest yield is 82%, and the regioselectivity is > 20:1). The developed organic catalytic method for nucleoside regioselective monoesterification can be used as a key step for efficiently synthesizing drugs important for the treatment of the new coronavirus infection. The obtained nucleoside monoester products also show good antiviral activity against plant viruses, and provide key information for the future development of antiviral pesticides.

[0023] Specific preparation embodiments

[0024] The following introduces the examples of the present application, introducing 62 preparation examples

[0025] Preparation Example 1

[0026] Preparation of ((2R, 3S, 4R, 5R)-5-(3-carbamoyl-1H-1, 2, 4-triazol-1-yl)-3, 4-dihydroxytetrahydrofuran-2-yl) methyl benzoate (2):

[0027]

[0028] The preparation method and conditions are as follows:

[0029] In a glove box, NHC catalyst C (0.01 mmol, 10 mol%, 3.6 mg), DBU (0.02 mmol, 20 mol%, 3.0 μL), DQ (0.10 mmol, 100 mol%, 40.8 mg), BA-3 (0.10 mmol, 100 mol%, 12.2 mg), ribavirin (0.10 mmol) and aromatic aldehyde (0.20 mmol) were weighed into a 4.0 mL reaction vial with a magnetic stir bar, 1.0 mL DMF was added, the reaction vial was shaken gently to mix well, and the reaction was stirred at 30 °C for 12 h. After the reaction was completed by TLC monitoring, it was dried, dried and loaded onto the column, separated by column chromatography (eluent polarity dichloromethane:methanol = 100:5), and the target compound 2 was obtained. The yield was calculated after weighing, and the compound was characterized by nuclear magnetic resonance instrument NMR and high resolution mass spectrometer HRMS.

[0030] 2H), 7.85 (s, 1H), 7.67 (s, 1H), 7.66-7.62 (m, 1H), 7.53 (t, J = 7.61 Hz, 2H), 5.96 (d, J = 2.67 Hz, 1H), 5.71 (d, J = 5.03 Hz, 1H), 5.44 (d, J = 5.98 Hz, 1H), 4.53-4.47 (m, 2H), 4.44-4.41 (m, 1H), 4.41-4.36 (m, 1H), 4.29-4.24 (m, 1H).

[0031] 13 C NMR (101 MHz, DMSO) δ 166.1, 160.8, 158.2, 146.2, 133.9, 129.8, 129.8, 129.3, 91.7, 81.8, 74.7, 70.7, 64.6.

[0032] HRMS (ESI, m / z) calcd for C 15 H 16 N4O6Na + : 371.0962, found: 371.0960.

[0033] Preparation Example 2

[0034] (2R,3S,4R,5R)-5-(3-carbamoyl-1H-1,2,4-triazol-1-yl)-4-hydroxy-2- (hydroxymethyl)tetrahydrofuran-3-yl benzoate (3)

[0035]

[0036] The preparation method and conditions are as follows:

[0037] In a glove box, NHC catalyst E (0.01 mmol, 10 mol%, 2.9 mg), Na2C03(0.02 mmol, 20 mol%, 2.1 mg), DQ (0.10 mmol, 100 mol%, 40.8 mg), ribavirin (0.10 mmol) and aromatic aldehyde (0.20 mmol) were weighed into a 4.0 mL reaction vial with a magnetic stir bar, 1.0 mL DMF:MeCN = 1:1 solution was added, the reaction vial was shaken gently to mix well, and the reaction was stirred at 50 °C for 2 h. After the reaction was completed by TLC monitoring, it was dried, dried and loaded onto the column, separated by column chromatography (eluent polarity dichloromethane:methanol = 100:5) to obtain the target compound 3, and the corresponding yield was calculated after weighing. The compound was characterized by nuclear magnetic resonance instrument NMR and high resolution mass spectrometer HRMS.

[0038]

[0039] White solid, 70% yield, 24.3 mg; 5:1 (regioselective ratio);

[0040] 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.09-8.05 (m, 2H), 7.88 (s, 1H), 7.73-7.69 (m, 1H), 7.68 (s, 1H), 7.60-7.56 (m, 2H), 6.05 (d, J = 6.02 Hz, 1H), 6.01 (d, J = 5.09 Hz, 1H), 5.49 (dd, J = 5.14, 3.87 Hz, 1H), 5.13 (t, J = 5.66 Hz, 1H), 4.83 (q, J = 5.41 Hz, 1H), 4.33 (q, J = 4.44 Hz, 1H), 3.72-3.62 (m, 2H).

[0041] 13 C NMR (101 MHz, DMSO) δ 165.5, 160.8, 158.0, 146.0, 134.0, 130.0, 129.9, 129.2, 91.8, 83.8, 74.1, 73.3, 61.7.

[0042] HRMS (ESI, m / z) calcd for C 15 H 16 N4O6Na + : 371.0962, found: 371.0961.

[0043] Preparation Example 3

[0044] Substituent R is 4-CH3-Ph, prepared according to the procedure described in Preparation Example 1 ;

[0045]

[0046] White solid, 72% yield, 27.4 mg; 19: 1 (regioselective ratio);

[0047] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.86 (d, J = 8.02 Hz, 2H), 7.84 - 7.82 (m, 1H), 7.69 (s, 1H), 7.33 (d, J = 7.88 Hz, 2H), 5.95 (d, J = 2.65 Hz, 1H), 5.70 (d, J = 5.02 Hz, 1H), 5.43 (d, J = 5.95 Hz, 1H), 4.52 - 4.44 (m, 2H), 4.41 (td, J = 4.83, 2.67 Hz, 1H), 4.37 (dd, J = 12.16, 5.13 Hz, 1H), 4.28 - 4.23 (m, 1H), 2.37 (s, 3H).

[0048] 13 C NMR (101 MHz, DMSO) δ 166.1, 160.8, 158.2, 146.2, 144.1, 129.9, 129.8, 127.1, 91.7, 81.8, 74.7, 70.7, 64.4, 21.7.

[0049] HRMS (ESI, m / z) calcd. for C 16 H 18 N4O6Na + : 385.1119, found: 385.1114.

[0050] Preparation Example 4

[0051] Substituent R is 4-CH3-Ph, prepared according to the procedure described in Preparation Example 1 ;

[0052]

[0053] White solid, 72% yield, 27.4 mg; 19: 1 (regioselective ratio);

[0054] 1 H NMR(400 MHz, DMSO) δ 8.85 (d, J = 1.38 Hz, 1H), 7.92 (d, J = 8.53 Hz, 2H), 7.86 (s, 1H), 7.70 (s, 1H), 7.05 (d, J = 8.49 Hz, 2H), 5.95 (d, J = 2.60 Hz, 1H), 5.70 (d, J = 4.95 Hz, 1H), 5.42 (d, J = 5.97 Hz, 1H), 4.49 (d, J = 5.91 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.35 (dd, J = 12.26, 4.89 Hz, 1H), 4.25 (dt, J = 9.37, 3.68 Hz, 1H), 3.83 (s, 3H).

[0055] 13 C NMR (101 MHz, DMSO) δ 165.8, 163.7, 160.9, 158.2, 146.2, 131.9, 122.0, 114.6, 91.6, 81.9, 74.6, 70.6, 64.1, 55.9.

[0056] HRMS (ESI, m / z) calcd. for C 16 H 18 N4O7Na + : 401.1068, found: 401.1059.

[0057] Preparation Example 5

[0058] Substituent R is 4-CF3-Ph, and the preparation method and conditions are the same as those in Preparation Example 1;

[0059] ratio);

[0060] 1 H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.23 (d, J = 8.10 Hz, 2H), 7.93 (d, J = 8.19 Hz, 2H), 7.90 (s, 1H), 7.75 (s, 1H), 5.97 (d, J = 2.82 Hz, 1H), 5.70 (d, J = 5.03 Hz, 1H), 5.44 (d, J = 5.84 Hz, 1H), 4.59 - 4.47 (m, 3H), 4.47 - 4.40 (m, 1H), 4.32 - 4.25 (m, 1H).

[0061] 13 C NMR(101 MHz, DMSO) δ 165.1, 160.9, 158.3, 146.4, 133.6, 133.4 (d, J = 31.8 Hz), 130.8, 126.4 (d, J = 4.0 Hz), 124.2 (d, J = 273.2 Hz), 91.5, 81.7, 74.7, 70.6, 64.8.

[0062] 19 F NMR (377 MHz, DMSO) δ -61.62.

[0063] HRMS (ESI, m / z) calcd for C 16 H 15 F3N4O6Na + : 439.0836, found: 439.0825.

[0064] Preparation Example 6

[0065] Substituent R is 4-F-Ph, the preparation implementation method and condition are same as preparation example 1;

[0066]

[0067] 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.11 - 8.04 (m, 2H), 7.89 (s, 1H), 7.72 (s, 1H), 7.40 - 7.32 (m, 2H), 5.96 (d, J = 2.61 Hz, 1H), 5.70 (d, J = 5.00 Hz, 1H), 5.43 (d, J = 5.97 Hz, 1H), 4.55 - 4.46 (m, 2H), 4.44 - 4.37 (m, 2H), 4.29 - 4.23 (m, 1H).

[0068] 13 C NMR (101 MHz, DMSO) δ 165.6 (d, J = 251.2 Hz), 165.2, 160.9, 158.2, 146.3, 132.8 (d, J = 9.8 Hz), 126.5 (d, J = 2.9 Hz), 116.4 (d, J = 22.3 Hz), 91.5, 81.7, 74.7, 70.5, 64.4.

[0069] 19 F NMR (377 MHz, DMSO) δ -105.87.

[0070] HRMS (ESI, m / z) calcd for C 15 H 15 FN4O6Na+ : 389.0868, found: 389.0861.

[0071] Preparation Example 7

[0072] The substituent R is 4-Cl-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 1.

[0073] ratio);

[0074] 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.05 - 8.00 (m, 2H), 7.90 (s, 1H), 7.74 (s, 1H), 7.64 - 7.59 (m, 2H), 5.96 (d, J = 2.69 Hz, 1H), 5.70 (d, J = 5.00 Hz, 1H), 5.43 (d, J = 6.00 Hz, 1H), 4.55 - 4.50 (m, 1H), 4.48 (dd, J = 12.10, 2.85 Hz, 1H), 4.44 - 4.38 (m, 2H), 4.29 - 4.23 (m, 1H).

[0075] 13 C NMR (101 MHz, DMSO) δ 165.4, 160.9, 158.2, 146.3, 138.8, 131.8, 129.5, 128.7, 91.5, 81.7, 74.7, 70.5, 64.5.

[0076] HRMS (ESI, m / z) calcd. for C 15 H 15 ClN4O6Na + : 405.0572 found: 405.0563.

[0077] Preparation Example 8

[0078] The substituent R is 4-Br-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 1.

[0079] ratio);

[0080] 1 H NMR(400 MHz, DMSO) δ 8.87 (s, 1H), 7.97 - 7.92 (m, 2H), 7.90 (s, 1H), 7.78 - 7.73 (m, 3H), 5.96 (d, J = 2.69 Hz, 1H), 5.70 (d, J = 5.02 Hz, 1H), 5.43 (d, J = 5.95 Hz, 1H), 4.54 - 4.50 (m, 1H), 4.49 - 4.45 (m, 1H), 4.44 - 4.39 (m, 2H), 4.28 - 4.23 (m, 1H).

[0081] 13 C NMR (101 MHz, DMSO) δ 165.5, 160.9, 158.2, 146.4, 132.5, 131.9, 129.0, 128.0, 91.5, 81.7, 74.7, 70.5, 64.5.

[0082] HRMS (ESI, m / z) calcd. for C 15 H 15 BrN4O6Na + : 449.0067, found: 449.0060.

[0083] Preparation Example 9

[0084] Substituent R is 3-OCH3-Ph, and the preparation method and conditions are the same as those in Preparation Example 1;

[0085] ratio);

[0086] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.57 (dt, J = 7.71, 1.24 Hz, 1H), 7.45 (t, J = 7.94 Hz, 1H), 7.42 (dd, J = 2.69, 1.51 Hz, 1H), 7.25 - 7.20 (m, 1H), 5.95 (d, J = 2.70 Hz, 1H), 5.72 (d, J = 4.92 Hz, 1H), 5.44 (d, J = 5.72 Hz, 1H), 4.51 (dd, J = 12.11, 3.28 Hz, 1H), 4.47 - 4.41 (m, 2H), 4.41 - 4.36 (m, 1H), 4.27 (td, J = 5.78, 3.24 Hz, 1H), 3.80 (s, 3H).

[0087] 13 C NMR(101 MHz, DMSO) δ 165.9, 160.8, 159.7, 158.1, 146.1, 131.2, 130.6, 122.1, 119.9, 114.3, 91.8, 81.9, 74.7, 70.9, 65.1, 55.8.

[0088] HRMS (ESI, m / z) calcd for C 16 H 18 N4O7Na + : 401.1068, found: 401.1061.

[0089] Preparation Example 10

[0090] Substituent R is 3-F-Ph, and the preparation method and conditions are the same as those in Preparation Example 1.

[0091]

[0092] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 7.87 - 7.81 (m, 2H), 7.65 (pd, J = 3.74, 3.07, 1.80 Hz, 2H), 7.62 - 7.56 (m, 1H), 7.56 - 7.49 (m, 1H), 5.95 (d, J = 2.74 Hz, 1H), 5.72 (d, J = 5.06 Hz, 1H), 5.44 (d, J = 5.97 Hz, 1H), 4.53 (dd, J = 12.06, 3.27 Hz, 1H), 4.50 - 4.45 (m, 1H), 4.41 (dt, J = 7.78, 5.18 Hz, 2H), 4.27 (td, J = 5.75, 3.16 Hz, 1H).

[0093] 13 C NMR (101 MHz, DMSO) δ 165.0, 162.4 (d, J = 245.2 Hz), 160.8, 158.2, 146.2, 132.1 (d, J = 7.4 Hz), 131.7 (d, J = 8.0 Hz), 126.1 (d, J = 2.9 Hz), 120.9 (d, J = 20.9 Hz), 116.2 (d, J = 22.7 Hz), 91.7, 81.8, 74.7, 70.8, 65.2.

[0094] 19 F NMR (377 MHz, DMSO) δ -112.11.

[0095] HRMS (ESI, m / z) calcd for C 15 H15 FN4O6Na + :389.0868, found:389.0857.

[0096] Preparation Example 11

[0097] Substituent R is 3-Cl-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 1;

[0098]

[0099] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 7.96 (dt, J = 7.79, 1.33 Hz, 1H), 7.88 (t, J = 1.88 Hz, 1H), 7.84 (s, 1H), 7.76 - 7.72 (m, 1H), 7.65 (s, 1H), 7.58 (t, J = 7.93 Hz, 1H), 5.95 (d, J = 2.71 Hz, 1H), 5.71 (d, J = 5.04 Hz, 1H), 5.45 (d, J = 6.00 Hz, 1H), 4.53 (dd, J = 12.09, 3.30 Hz, 1H), 4.47 (td, J = 6.21, 4.80 Hz, 1H), 4.44 - 4.37 (m, 2H), 4.27 (td, J = 5.88, 3.22 Hz, 1H).

[0100] 13 C NMR (101 MHz, DMSO) δ 164.9, 160.8, 158.2, 146.2, 133.9, 133.7, 131.9, 131.5, 129.2, 128.5, 91.8, 81.7, 74.7, 70.8, 65.3.

[0101] HRMS (ESI, m / z) calcd for C 15 H 15 ClN4O6Na + :405.0572, found:405.0560.

[0102] Preparation Example 12

[0103] Substituent R is 3-Br-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 1;

[0104]

[0105] White solid, 62% yield, 26.5 mg; 20:1 (regioselective ratio);

[0106] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.05 - 7.98 (m, 2H), 7.90 - 7.86 (m, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 7.52 (t, J = 7.89 Hz, 1H), 5.95 (d, J = 2.73 Hz, 1H), 5.71 (d, J = 5.05 Hz, 1H), 5.45 (d, J = 5.94 Hz, 1H), 4.53 (dd, J = 12.08, 3.30 Hz, 1H), 4.50 - 4.44 (m, 1H), 4.44 - 4.37 (m, 2H), 4.30 - 4.24 (m, 1H).

[0107] 13 C NMR (101 MHz, DMSO) δ 164.8, 160.8, 158.2, 146.2, 136.6, 132.1, 131.7, 128.9, 122.3, 91.8, 81.7, 74.7, 70.8, 65.4.

[0108] HRMS (ESI, m / z) calcd. for C 15 H 15 BrN4O6Na + : 449.0067, found: 449.0061.

[0109] Preparation Example 13

[0110] The substituent R is 2-CH3-Ph, and the preparation method and conditions are the same as those in Preparation Example 1.

[0111]

[0112] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.84 (d, J = 1.59 Hz, 1H), 7.83 - 7.81 (m, 1H), 7.65 (s, 1H), 7.47 (td, J = 7.51, 1.47 Hz, 1H), 7.32 (t, J = 8.12 Hz, 2H), 5.94 (d, J = 2.48 Hz, 1H), 5.71 (d, J = 4.72 Hz, 1H), 5.44 (d, J = 5.50 Hz, 1H), 4.51 (dd, J = 11.98, 3.32 Hz, 1H), 4.45 - 4.38 (m, 2H), 4.34 (dd, J = 12.00, 5.98 Hz, 1H), 4.26 (td, J = 5.85, 3.25 Hz, 1H), 2.49 (s, 3H).

[0113] 13 C NMR (101 MHz, DMSO) δ 167.0, 160.8, 158.1, 146.1, 139.8, 132.7, 132.1, 130.8, 129.4, 126.6, 91.8, 81.9, 74.6, 70.9, 64.8, 21.5.

[0114] HRMS (ESI, m / z) calcd for C 16 H 18 N4O6Na + : 385.1119, found: 385.1110.

[0115] Preparation Example 14

[0116] Substituent R is 2-F-Ph, and the preparation method and conditions are the same as those in Preparation Example 1.

[0117]

[0118] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.92 (td, J = 7.79, 1.92 Hz, 1H), 7.84 (s, 1H), 7.72 - 7.67 (m, 1H), 7.66 (d, J = 1.87 Hz, 1H), 7.39 - 7.30 (m, 2H), 5.95 (d, J = 2.66 Hz, 1H), 5.73 (d, J = 4.87 Hz, 1H), 5.45 (d, J = 5.64 Hz, 1H), 4.55 (dd, J = 12.10, 3.18 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.40 - 4.36 (m, 1H), 4.26 (td, J = 5.81, 3.11 Hz, 1H).

[0119] 13 C NMR (101 MHz, DMSO) δ 163.5 (d, J = 3.6 Hz), 161.5 (d, J = 257.9 Hz), 160.8, 158.1, 146.0, 135.8 (d, J = 9.3 Hz), 132.4, 125.3 (d, J = 3.9 Hz), 118.3 (d, J = 9.4 Hz), 117.5 (d, J = 21.8 Hz), 91.8, 81.8, 74.6, 70.8, 65.1.

[0120] 19 F NMR (377 MHz, DMSO) δ -110.72.

[0121] HRMS (ESI, m / z) calcd for C15 H 15 FN4O6Na + :389.0869,found:389.0862.

[0122] Preparation Example 15

[0123] Substituent R is 2-Cl-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 1;

[0124]

[0125] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.87 (d, J = 1.42 Hz, 1H), 7.86-7.84 (m, 1H), 7.66 (s, 1H), 7.60-7.55 (m, 2H), 7.51-7.46 (m, 1H), 5.94 (d, J = 2.58 Hz, 1H), 5.71 (d, J = 4.76 Hz, 1H), 5.45 (d, J = 5.43 Hz, 1H), 4.57 (dd, J = 12.05, 3.28 Hz, 1H), 4.45-4.39 (m, 2H), 4.39-4.34 (m, 1H), 4.26 (td, J = 5.76, 3.17 Hz, 1H).

[0126] 13 C NMR (101 MHz, DMSO) δ 165.1, 160.8, 158.2, 146.1, 133.8, 132.5, 131.8, 131.3, 129.9, 128.0, 91.8, 81.8, 74.6, 70.9, 65.4.

[0127] HRMS (ESI, m / z) calcd for C 15 H 15 ClN4O6Na + :405.0572,found:405.0564.

[0128] Preparation Example 16

[0129] Substituent R is 2-Br-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 1;

[0130]

[0131] 1 H NMR(400 MHz, DMSO) δ 8.84 (s, 1H), 7.88 - 7.84 (m, 1H), 7.82 (dd, J = 7.50, 1.97 Hz, 1H), 7.75 (dd, J = 7.74, 1.49 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.46 (m, 2H), 5.94 (d, J = 2.58 Hz, 1H), 5.71 (d, J = 4.83 Hz, 1H), 5.46 (d, J = 5.42 Hz, 1H), 4.57 (dd, J = 12.00, 3.27 Hz, 1H), 4.45 - 4.39 (m, 2H), 4.36 (dd, J = 11.96, 5.90 Hz, 1H), 4.26 (td, J = 5.79, 3.20 Hz, 1H).

[0132] 13 C NMR (101 MHz, DMSO) δ 165.7, 160.8, 158.2, 146.1, 134.5, 133.8, 132.1, 131.7, 128.5, 120.8, 91.8, 81.9, 74.6, 70.9, 65.6.

[0133] HRMS (ESI, m / z) calcd for C 15 H 15 BrN4O6Na + : 449.0067, found: 449.0059.

[0134] Preparation Example 17

[0135] The substituent R is naphthyl, and the preparation method and conditions are the same as those in Preparation Example 1;

[0136] ratio);

[0137] 1 H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.60 (s, 1H), 8.16 (d, J = 8.10 Hz, 1H), 8.07 - 7.98 (m, 3H), 7.87 (s, 1H), 7.71 - 7.65 (m, 2H), 7.65 - 7.59 (m, 1H), 5.98 (d, J = 2.68 Hz, 1H), 5.74 (d, J = 5.01 Hz, 1H), 5.48 (d, J = 5.90 Hz, 1H), 4.60 (dd, J = 12.12, 3.19 Hz, 1H), 4.53 - 4.46 (m, 2H), 4.46 - 4.43 (m, 1H), 4.36 - 4.30 (m, 1H).

[0138] 13 C NMR (101 MHz, DMSO) δ 166.2, 160.9, 158.2, 146.1, 135.6, 132.5, 131.1, 129.9, 129.1, 129.0, 128.1, 127.4, 127.2, 125.4, 91.9, 82.0, 74.7, 70.9, 65.3.

[0139] HRMS (ESI, m / z) calcd for C 19 H 18 N4O6Na + : 421.1119, found: 421.1115.

[0140] Preparation Example 18

[0141] The substituent R is furan, and the preparation method and conditions are the same as those in Preparation Example 1.

[0142]

[0143] 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 7.99-7.95 (m, 1H), 7.87-7.82 (m, 1H), 7.69-7.63 (m, 1H), 7.40 (dd, J = 3.54, 0.87 Hz, 1H), 6.67 (dd, J = 3.54, 1.72 Hz, 1H), 5.95 (d, J = 2.21 Hz, 1H), 5.76 (s, 1H), 5.49 (d, J = 5.08 Hz, 1H), 4.50 (dd, J = 12.03, 3.08 Hz, 1H), 4.43-4.39 (m, 2H), 4.36 (dd, J = 12.09, 5.79 Hz, 1H), 4.27-4.22 (m, 1H).

[0144] 13 C NMR (101 MHz, DMSO) δ 160.9, 158.1, 158.1, 148.3, 146.0, 143.9, 119.5, 112.9, 91.9, 82.0, 74.7, 70.8, 64.7.

[0145] HRMS (ESI, m / z) calcd for C 13 H 14 N4O7Na + : 361.0755, found: 361.0749.

[0146] Preparation Example 19

[0147] The substituent R is thiophene, the preparation implementation method and condition are same with preparation example 1;

[0148]

[0149] 1 H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.95 (dd, J = 4.99, 1.30 Hz, 1H), 7.87 (dd, J = 3.75, 1.34 Hz, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.20 (dd, J = 4.96, 3.73 Hz, 1H), 5.94 (d, J = 2.60 Hz, 1H), 5.71 (d, J = 4.92 Hz, 1H), 5.44 (d, J = 5.71 Hz, 1H), 4.50 (dd, J = 12.08, 3.09 Hz, 1H), 4.46 - 4.38 (m, 2H), 4.38 - 4.33 (m, 1H), 4.27 - 4.21 (m, 1H).

[0150] 13 C NMR (101 MHz, DMSO) δ 161.8, 160.8, 158.1, 146.0, 134.8, 134.6, 133.0, 129.0, 91.8, 81.9, 74.7, 70.8, 65.0.

[0151] HRMS (ESI, m / z) calcd for C 13 H 14 N4O6SNa + : 377.0526, found: 377.0516.

[0152] Preparation Example 20

[0153] The substituent R is alkenyl benzene, the preparation implementation method and condition are same with preparation example 1;

[0154]

[0155] ratio);

[0156] 1 H NMR(400 MHz, DMSO) δ 8.85 (s, 1H), 7.87 (s, 1H), 7.76 - 7.70 (m, 2H), 7.64 (d, J = 15.24 Hz, 2H), 7.44 (q, J = 3.73 Hz, 3H), 6.62 (d, J = 16.08 Hz, 1H), 5.93 (d, J = 2.37 Hz, 1H), 5.70 (d, J = 4.54 Hz, 1H), 5.43 (d, J = 5.15 Hz, 1H), 4.48 - 4.37 (m, 3H), 4.28 - 4.17 (m, 2H).

[0157] 13 C NMR (101 MHz, DMSO) δ 166.5, 160.8, 158.0, 146.0, 145.4, 134.4, 131.0, 129.4, 128.9, 118.1, 92.0, 82.2, 74.7, 71.0, 64.7.

[0158] HRMS (ESI, m / z) calcd for C 17 H 18 N4O6Na + : 397.1119, found: 397.1113.

[0159] Preparation Example 21

[0160] Substituent R is pyridine, preparation method and conditions are the same as those in Preparation Example 1;

[0161]

[0162] White solid, 68% yield, 23.7 mg; 16:1 (regioselective ratio);

[0163] 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.83 - 8.79 (m, 2H), 7.91 - 7.85 (m, 3H), 7.71 (s, 1H), 5.97 (d, J = 2.60 Hz, 1H), 5.73 (s, 1H), 5.45 (s, 1H), 4.57 - 4.51 (m, 2H), 4.47 - 4.39 (m, 2H), 4.30 - 4.25 (m, 1H).

[0164] 13 C NMR (101 MHz, DMSO) δ 165.1, 160.9, 158.3, 151.4, 146.3, 137.0, 123.1, 91.5, 81.5, 74.7, 70.5, 64.9.

[0165] HRMS (ESI, m / z) calcd for C 14 H 15 N5O6Na + : 372.0915, found: 372.0910.

[0166] Preparation Example 22

[0167] Substituent R is vanillin skeleton, preparation implementation method and condition are same with preparation example 1;

[0168]

[0169] White solid, 42% yield, 16.4 mg; 10:1 (regioselective ratio);

[0170] 1 H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 8.84 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.49 (dd, J = 8.26, 2.02 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H), 6.88 (d, J = 8.29 Hz, 1H), 5.93 (d, J = 2.24 Hz, 1H), 5.72 (d, J = 4.53 Hz, 1H), 5.45 (d, J = 5.22 Hz, 1H), 4.47 - 4.43 (m, 1H), 4.42 - 4.38 (m, 2H), 4.34 (dd, J = 12.05, 5.79 Hz, 1H), 4.27 - 4.22 (m, 1H), 3.80 (s, 3H).

[0171] 13 CNMR (101 MHz, DMSO) δ 166.0, 160.8, 158.1, 152.1, 147.8, 146.1, 124.2, 120.5, 115.8, 112.9, 91.8, 82.1, 74.7, 70.9, 64.7, 56.0.

[0172] HRMS (ESI, m / z) calcd for C 16 H 18 N4O8Na + : 417.1017, found: 417.1012.

[0173] Preparation Example 23

[0174] The substituent R is a propofol skeleton, and the preparation method and conditions are the same as those in Preparation Example 1.

[0175] (regioselective ratio);

[0176] 1 H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.21 (d, J = 8.29 Hz, 2H), 7.97 (d, J = 8.20 Hz, 2H), 7.92 (s, 1H), 7.73 (s, 1H), 5.97 (d, J = 2.77 Hz, 1H), 5.73 (d, J = 5.04 Hz, 1H), 5.47 (d, J = 5.91 Hz, 1H), 4.50 (td, J = 14.07, 13.05, 5.24 Hz, 3H), 4.43 - 4.39 (m, 1H), 4.27 (dt, J = 6.54, 3.79 Hz, 1H), 3.05 (dd, J = 8.72, 6.32 Hz, 4H), 1.49 - 1.43 (m, 4H), 0.80 (t, J = 7.34 Hz, 6H).

[0177] 13 C NMR (101 MHz, DMSO) δ 165.1, 160.9, 158.3, 146.4, 144.1, 133.2, 130.9, 127.8, 91.5, 81.7, 74.7, 70.6, 65.0, 50.0, 22.0, 11.4.

[0178] HRMS (ESI, m / z) calcd. for C 21 H 29 N5O8SNa + : 534.1629, found: 534.1623.

[0179] Preparation Example 24

[0180] The substituent R is a propofol skeleton, and the preparation method and conditions are the same as those in Preparation Example 1;

[0181]

[0182] ratio);

[0183] 1 H NMR(400 MHz, DMSO) δ 9.21 (s, 1H), 8.86 (s, 1H), 7.90 (dd, J = 8.07, 1.69 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.66 (s, 1H), 7.41 - 7.35 (m, 1H), 7.31 - 7.21 (m, 3H), 6.85 - 6.75 (m, 2H), 5.96 (d, J = 2.67 Hz, 1H), 5.73 (d, J = 5.07 Hz, 1H), 5.45 (d, J = 6.00 Hz, 1H), 4.57 - 4.47 (m, 2H), 4.45 - 4.37 (m, 2H), 4.32 - 4.26 (m, 1H), 2.23 (s, 3H).

[0184] 13 C NMR (101 MHz, DMSO) δ 168.1, 160.8, 158.2, 147.9, 146.2, 140.8, 135.2, 134.9, 132.0, 130.8, 128.1, 125.8, 123.2, 118.2, 114.2, 111.6, 91.7, 81.8, 74.7, 70.8, 64.7, 15.2.

[0185] HRMS (ESI, m / z) calcd for C 22 H 22 ClN5O6Na + : 510.1151, found: 510.1146.

[0186] Preparation Example 25

[0187] N-hybrid substituent is adenosine, the preparation method and conditions are the same as those in Preparation Example 1;

[0188] ratio);

[0189] 1 H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.11 (s, 1H), 7.94 (dd, J = 8.06, 1.41 Hz, 2H), 7.67 (t, J = 7.55 Hz, 1H), 7.52 (t, J = 7.64 Hz, 2H), 7.30 (s, 2H), 5.94 (d, J = 4.70 Hz, 1H), 5.59 (d, J = 5.67 Hz, 1H), 5.42 (d, J = 5.53 Hz, 1H), 4.81 - 4.74 (m, 1H), 4.60 (dd, J = 12.07, 3.70 Hz, 1H), 4.45 (dt, J = 10.09, 5.23 Hz, 2H), 4.26 - 4.20 (m, 1H).

[0190] 13 C NMR (101 MHz, DMSO) δ 166.1, 156.6, 153.1, 149.8, 140.4, 133.9, 129.9, 129.7, 129.2, 119.7, 88.6, 81.9, 73.3, 70.6, 64.8.

[0191] HRMS (ESI, m / z) calcd. for C 17 H 17 N5O5H + : 372.1302, found: 372.1302.

[0192] Preparation Example 26

[0193] The N-hybrid substituent is 8-bromoadenosine, and the preparation method and conditions are the same as those in Preparation Example 1 ;

[0194]

[0195] White solid, 58% yield, 26.1 mg; >20:1 (regioselective ratio);

[0196] 1 H NMR (400 MHz, DMSO) δ 8.03 (s, 1 H), 7.86 (dd, J = 8.26, 1.40 Hz, 2H), 7.67 - 7.61 (m, 1 H), 7.52 - 7.44 (m, 4H), 5.85 (d, J = 4.50 Hz, 1 H), 5.59 (d, J = 5.59 Hz, 1 H), 5.43 (d, J = 5.71 Hz, 1 H), 5.26 (q, J = 5.22 Hz, 1 H), 4.66 - 4.58 (m, 2H), 4.43 (dd, J = 12.08, 5.02 Hz, 1 H), 4.21 (td, J = 5.05, 3.48 Hz, 1 H).

[0197] 13 C NMR (101 MHz, DMSO) δ 166.0, 155.5, 153.2, 150.7, 133.8, 129.9, 129.6, 129.1, 127.7, 120.0, 91.1, 82.1, 71.3, 70.3, 64.2.

[0198] HRMS (ESI, m / z) calcd. for C 17 H 16 BrN5O5H +: 450.0408, found: 450.0399.

[0199] Preparation Example 27

[0200] The N-hybrid substituent is guanosine, and the preparation method and conditions are the same as those in Preparation Example 1;

[0201]

[0202] White solid, 67% yield, 25.8 mg; 15: 1 (regioselective ratio);

[0203] 1 H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 7.99 - 7.94 (m, 2H), 7.85 (s, 1H), 7.68 (t, J = 7.35 Hz, 1H), 7.54 (t, J = 7.67 Hz, 2H), 6.52 (s, 2H), 5.75 (d, J = 5.10 Hz, 1H), 5.59 (d, J = 5.75 Hz, 1H), 5.36 (d, J = 5.41 Hz, 1H), 4.60 - 4.50 (m, 2H), 4.44 (dd, J = 11.95, 5.95 Hz, 1H), 4.33 - 4.28 (m, 1H), 4.20 - 4.14 (m, 1H).

[0204] 13 C NMR (101 MHz, DMSO) δ 166.1, 157.2, 154.2, 151.8, 135.9, 134.0, 129.9, 129.7, 129.3, 117.3, 87.4, 81.8, 73.6, 70.8, 65.0.

[0205] HRMS (ESI, m / z) calcd. for C 17 H 17 N5O6Na + : 410.1071, found: 410.1063.

[0206] Preparation Example 28

[0207] The N-hybrid substituent is cytidine, and the preparation method and conditions are the same as those in Preparation Example 1;

[0208]

[0209] White solid, 54% yield, 18.7 mg; 19: 1 (regioselective ratio);

[0210] 1 H NMR (400 MHz, DMSO) δ 8.02 - 7.97 (m, 2H), 7.72 - 7.67 (m, 1H), 7.60 - 7.54 (m, 3H), 7.20 (d, J = 26.93 Hz, 2H), 5.79 (d, J = 3.44 Hz, 1H), 5.62 (d, J = 7.38 Hz, 1H), 5.44 (d, J = 5.00 Hz, 1H), 5.26 (d, J = 5.69 Hz, 1H), 4.58 (dd, J = 12.15, 3.07 Hz, 1H), 4.44 (dd, J = 12.15, 5.32 Hz, 1H), 4.12 (td, J = 5.67, 3.07 Hz, 1H), 4.09 - 4.01 (m, 2H).

[0211] 13 C NMR (101 MHz, DMSO) δ 166.1, 166.0, 155.5, 141.7, 134.0, 129.9, 129.7, 129.3, 94.6, 90.8, 80.9, 74.0, 70.1, 64.7.

[0212] HRMS (ESI, m / z) calcd. for C 16 H 17 N3O6Na + : 370.1009, found: 370.1005.

[0213] Preparation Example 29

[0214] N-hybrid substituent is benzoyl cytidine, preparation method and conditions are the same as those in Preparation Example 1;

[0215]

[0216] White solid, 46% yield, 20.6 mg; >20: 1 (regioselective ratio);

[0217] 1 H NMR(400 MHz, DMSO) δ 11.27 (s, 1H), 8.18 (d, J = 7.53 Hz, 1H), 8.05 - 7.99 (m, 4H), 7.71 (t, J = 7.48 Hz, 1H), 7.63 (t, J = 7.41 Hz, 1H), 7.57 (t, J = 7.72 Hz, 2H), 7.52 (t, J = 7.61 Hz, 2H), 7.29 (d, J = 7.50 Hz, 1H), 5.83 (d, J = 2.44 Hz, 1H), 5.66 (d, J = 4.64 Hz, 1H), 5.35 (d, J = 6.00 Hz, 1H), 4.65 (dd, J = 12.40, 2.92 Hz, 1H), 4.55 (dd, J = 12.37, 5.36 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.16 - 4.08 (m, 2H).

[0218] 13 C NMR (101 MHz, DMSO) δ 167.8, 166.1, 163.7, 154.9, 151.8, 145.6, 134.1, 133.6, 133.2, 129.9, 129.7, 129.3, 128.9, 96.7, 91.9, 81.2, 74.3, 69.7, 64.5.

[0219] HRMS (ESI, m / z) calcd for C 23 H 21 N3O7Na + : 474.1272, found: 474.1266.

[0220] Preparation Example 30

[0221] N-hybrid substituent is 5-methyluridine, preparation method and conditions are the same as those in Preparation Example 1;

[0222]

[0223] White solid, 51% yield, 18.3 mg; >20: 1 (regioselective ratio);

[0224] 1 H NMR(400 MHz, DMSO) δ 11.36 (s, 1H), 8.03 - 7.98 (m, 2H), 7.69 (t, J = 7.42 Hz, 1H), 7.56 (t, J = 7.64 Hz, 2H), 7.37 (s, 1H), 5.81 (d, J = 4.33 Hz, 1H), 5.48 (d, J = 4.61 Hz, 1H), 5.34 (d, J = 4.03 Hz, 1H), 4.59 (dd, J = 12.06, 3.06 Hz, 1H), 4.43 (dd, J = 12.06, 4.77 Hz, 1H), 4.18 - 4.11 (m, 3H), 1.60 (s, 3H).

[0225] 13 C NMR (101 MHz, DMSO) δ 166.1, 164.1, 151.2, 136.5, 134.1, 129.9, 129.7, 129.4, 110.3, 88.7, 81.5, 73.1, 70.3, 64.8, 12.3.

[0226] HRMS (ESI, m / z) calcd for C 17 H 18 N2O7Na + : 385.1006, found: 385.1002.

[0227] Preparation Example 31

[0228] Substituent R is 4-CH3-Ph, and the preparation method and conditions are the same as those in Preparation Example 2;

[0229]

[0230] White solid, 66% yield, 23.7 mg; 4: 1 (regioselective ratio);

[0231] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 7.95 (d, J = 8.05 Hz, 2H), 7.87 (s, 1H), 7.67 (s, 1H), 7.39 - 7.36 (m, 2H), 6.01 (dd, J = 9.31, 5.55 Hz, 2H), 5.46 (t, J = 4.49 Hz, 1H), 5.12 (t, J = 5.64 Hz, 1H), 4.81 (q, J = 5.41 Hz, 1H), 4.31 (q, J = 4.45 Hz, 1H), 3.72 - 3.61 (m, 2H), 2.41 (s, 3H).

[0232] 13 C NMR (101 MHz, DMSO) δ 165.5, 160.8, 158.0, 146.0, 144.4, 130.0, 129.8, 127.3, 91.9, 83.9, 73.9, 73.3, 61.7, 21.7.

[0233] HRMS (ESI, m / z) calcd for C 16 H 18 N4O6Na + : 385.1118, found: 385.1114.

[0234] Preparation Example 32

[0235] Substituent R is 4-OCH3-Ph, and the preparation method and conditions are the same as those in Preparation Example 2.

[0236]

[0237] White solid, 40% yield, 15.3 mg; 4: 1 (regioselective ratio);

[0238] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.05-8.00 (m, 2H), 7.87 (s, 1H), 7.67 (s, 1H), 7.10-7.07 (m, 2H), 6.00 (t, J = 5.67 Hz, 2H), 5.44 (t, J = 4.56 Hz, 1H), 5.11 (t, J = 5.62 Hz, 1H), 4.80 (q, J = 5.43 Hz, 1H), 4.30 (q, J = 4.42 Hz, 1H), 3.86 (s, 3H), 3.65 (dt, J = 14.21, 5.50 Hz, 2H).

[0239] 13 C NMR (101 MHz, DMSO) δ 165.2, 163.8, 160.8, 158.0, 146.0, 132.1, 122.2, 114.5, 91.9, 84.0, 73.7, 73.3, 61.7, 56.1.

[0240] HRMS (ESI, m / z) calcd for C 16 H 18 N4O7Na + : 401.1068, found: 401.1062.

[0241] Preparation Example 33

[0242] Substituent R is 4-F-Ph, prepared according to the procedure described in Preparation Example 2;

[0243]

[0244] White solid, 69% yield, 25.3 mg; 5:1 (regioselective ratio);

[0245] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.16 - 8.11 (m, 2H), 7.89 - 7.86 (m, 1H), 7.68 (s, 1H), 7.44 - 7.39 (m, 2H), 6.05 (d, J = 6.10 Hz, 1H), 6.01 (d, J = 5.13 Hz, 1H), 5.48 (dd, J = 5.13, 3.84 Hz, 1H), 5.13 (t, J = 5.65 Hz, 1H), 4.82 (q, J = 5.44 Hz, 1H), 4.33 (q, J = 4.41 Hz, 1H), 3.71 - 3.61 (m, 2H).

[0246] 13 C NMR (101 MHz, DMSO) δ 167.0, 164.6, 159.4 (d, J = 278.9 Hz), 149.6, 145.9, 132.9 (d, J = 9.5 Hz), 126.6 (d, J = 2.8 Hz), 116.3 (d, J = 22.3 Hz), 91.9, 83.9, 74.3, 73.4, 61.7.

[0247] 19 F NMR (377 MHz, DMSO) δ -105.58.

[0248] HRMS (ESI, m / z) calcd. for C 15 H 15 FN4O6Na + : 389.0868, found: 389.0864.

[0249] Preparation Example 34

[0250] Substituent R is 4-F-Ph, prepared according to the procedure described in Preparation Example 2;

[0251]

[0252] White solid, 61% yield, 23.5 mg; 4: 1 (regioselective ratio);

[0253] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.06 (d, J = 8.58 Hz, 2H), 7.87 (s, 1H), 7.67 (s, 1H), 7.66 - 7.64 (m, 2H), 6.06 (d, J = 6.04 Hz, 1H), 6.01 (d, J = 5.10 Hz, 1H), 5.49 (dd, J = 5.15, 3.85 Hz, 1H), 5.12 (t, J = 5.67 Hz, 1H), 4.82 (q, J = 5.44 Hz, 1H), 4.33 (q, J = 4.44 Hz, 1H), 3.71 - 3.61 (m, 2H).

[0254] 13 C NMR (101 MHz, DMSO) δ 164.7, 160.8, 158.0, 146.0, 139.0, 131.8, 129.4, 128.8, 91.8, 83.8, 74.4, 73.3, 61.6.

[0255] HRMS (ESI, m / z) calcd. for C 15 H 15 ClN4O6Na + : 405.0572, found: 405.0567.

[0256] Preparation Example 35

[0257] Substituent R is 4-Br-Ph, and the preparation method and conditions are the same as those in Preparation Example 2;

[0258]

[0259] White solid, 60% yield, 25.8 mg; 4: 1 (regioselective ratio);

[0260] 1 H NMR(400 MHz, DMSO) δ 8.93 (s, 1H), 8.00 - 7.97 (m, 2H), 7.87 (s, 1H), 7.81 - 7.78 (m, 2H), 7.67 (s, 1H), 6.06 (d, J = 6.01 Hz, 1H), 6.00 (d, J = 5.11 Hz, 1H), 5.48 (dd, J = 5.11, 3.86 Hz, 1H), 5.13 (t, J = 5.65 Hz, 1H), 4.82 (q, J = 5.37 Hz, 1H), 4.33 (q, J = 4.43 Hz, 1H), 3.71 - 3.60 (m, 2H).

[0261] 13 C NMR (101 MHz, DMSO) δ 164.9, 160.8, 158.0, 146.0, 132.4, 131.9, 129.2, 128.1, 91.8, 83.8, 74.4, 73.3, 61.6.

[0262] HRMS (ESI, m / z) calcd for C 15 H 15 BrN4O6Na + : 449.0067, found: 449.0063.

[0263] Preparation Example 36

[0264] Substituent R is 3-CH3-Ph, and the preparation method and conditions are the same as those in Preparation Example 2;

[0265]

[0266] White solid, 71% yield, 25.7 mg; 4: 1 (regioselective ratio);

[0267] 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.88 (s, 1H), 7.86 (d, J = 7.09 Hz, 2H), 7.68 (s, 1H), 7.51 (d, J = 7.63 Hz, 1H), 7.46 (dd, J = 7.61, 2.71 Hz, 1H), 6.03 (dd, J = 10.71, 5.58 Hz, 2H), 5.48 (t, J = 4.49 Hz, 1H), 5.13 (t, J = 5.65 Hz, 1H), 4.82 (q, J = 5.43 Hz, 1H), 4.32 (q, J = 4.41 Hz, 1H), 3.72 - 3.62 (m, 2H), 2.41 (s, 3H).

[0268] 13 C NMR (101MHz, DMSO) δ165.6,160.8,158.0,146.0,138.6,134.6,130.3,129.9,129.1,127.2,91.8,83.9,74.0,73.3,61.7,21.3.

[0269] HRMS (ESI,m / z)calcd.for C 16 H 18 N4O6Na + :385.1118,found:385.1112.

[0270] Preparation Example 37

[0271] The substituent R is 3-OCH3-Ph, and the preparation method and conditions are the same as in Preparation Example 2;

[0272]

[0273] White solid,70% yield,26.5mg; 4:1(regioselective ratio);

[0274] 1 H NMR (400MHz, DMSO) δ8.94(s,1H),7.88(s,1H),7.69–7.64(m,2H),7.54(d,J=1.12H z,1H),7.51–7.47(m,1H),7.28(dd,J=8.23,2.70Hz,1H),6.04(d,J=6.09Hz,1H) ,6.01(d,J=5.15Hz,1H),5.48(dd,J=5.17,3.80Hz,1H),5.12(t,J=5.66Hz,1H), 4.82(q,J=5.46Hz,1H),4.32(q,J=4.42Hz,1H),3.84(s,3H),3.71–3.62(m,2H).

[0275] 13 C NMR (101MHz, DMSO) δ165.4,160.8,159.8,158.0,146.0,131.3,130.4,122.2,119.7,114.9,91.8,83.8,74.2,73.3,61.7,55.9.

[0276] HRMS (ESI,m / z)calcd.for C 16 H 18 N4O7Na+ 401.1068, found: 401.1065.

[0277] Preparation Example 38

[0278] Substituent R is 3-F-Ph, and the preparation method and conditions are the same as those in Preparation Example 2;

[0279]

[0280] White solid, 75% yield, 27.5 mg; 5: 1 (regioselective ratio);

[0281] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 7.92-7.89 (m, 1H), 7.87 (s, 1H), 7.83 (dt, J = 9.44, 2.10 Hz, 1H), 7.68 (s, 1H), 7.64-7.57 (m, 2H), 6.06 (d, J = 6.16 Hz, 1H), 6.03 (d, J = 5.21 Hz, 1H), 5.50 (dd, J = 5.14, 3.71 Hz, 1H), 5.13 (t, J = 5.66 Hz, 1H), 4.83 (q, J = 5.49 Hz, 1H), 4.34 (q, J = 4.39 Hz, 1H), 3.72-3.61 (m, 2H).

[0282] 13 C NMR (101 MHz, DMSO) δ 164.5, 162.5 (d, J = 244.88 Hz), 160.8, 158.0, 146.0, 132.3 (d, J = 7.5 Hz), 131.6, 126.2 (d, J = 2.6 Hz), 121.1 (d, J = 20.9 Hz), 116.5 (d, J = 22.8 Hz), 91.7, 83.7, 74.7, 73.3, 61.6.

[0283] 19 F NMR (377 MHz, DMSO) δ -112.31.

[0284] HRMS (ESI, m / z) calcd. for C 15 H 15 FN4O6Na + :389.0868, found:389.0863.

[0285] Preparation Example 39

[0286] Substituent R is 3-Cl-Ph, prepared according to the procedure described in Preparation Example 2;

[0287]

[0288] White solid, 66% yield, 25.2 mg; 5:1 (regioselective ratio);

[0289] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.06 (q, J = 2.90, 2.38 Hz, 1H), 8.02 (dt, J = 7.72, 1.36 Hz, 1H), 7.88 (s, 1H), 7.81 - 7.78 (m, 1H), 7.68 (s, 1H), 7.62 (t, J = 7.89 Hz, 1H), 6.07 (d, J = 6.16 Hz, 1H), 6.03 (d, J = 5.20 Hz, 1H), 5.50 (dd, J = 5.17, 3.73 Hz, 1H), 5.12 (t, J = 5.67 Hz, 1H), 4.83 (q, J = 5.52 Hz, 1H), 4.34 (q, J = 4.38 Hz, 1H), 3.72 - 3.63 (m, 2H).

[0290] 13 C NMR (101 MHz, DMSO) δ 164.4, 160.8, 158.0, 146.1, 134.0, 133.9, 132.0, 131.3, 129.5, 128.7, 91.7, 83.7, 74.6, 73.3, 61.7.

[0291] HRMS (ESI, m / z) calcd. for C 15 H 15 ClN4O6Na + : 405.0572, found: 405.0570.

[0292] Preparation Example 40

[0293] Substituent R is 3-Br-Ph, prepared according to the procedure described in Preparation Example 2;

[0294]

[0295] ratio);

[0296] 1 H NMR(400 MHz, DMSO) δ 8.93 (s, 1H), 8.19 (t, J = 1.94 Hz, 1H), 8.05 (d, J = 7.77 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.67 (s, 1H), 7.55 (t, J = 7.91 Hz, 1H), 6.07 (d, J = 6.18 Hz, 1H), 6.03 (d, J = 5.22 Hz, 1H), 5.52 - 5.47 (m, 1H), 5.12 (t, J = 5.66 Hz, 1H), 4.82 (q, J = 5.52 Hz, 1H), 4.34 (q, J = 4.33 Hz, 1H), 3.71 - 3.62 (m, 2H).

[0297] 13 C NMR (101 MHz, DMSO) δ 164.3, 160.8, 158.0, 146.1, 136.8, 132.3, 132.2, 131.5, 129.0, 122.3, 91.7, 83.7, 74.6, 73.3, 61.7.

[0298] HRMS (ESI, m / z) calcd for C 15 H 15 BrN4O6Na + : 449.0067, found: 449.0065.

[0299] Preparation Example 41

[0300] Substituent R is 2-CH3-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 2;

[0301]

[0302] White solid, 46% yield, 16.8 mg; 4: 1 (regioselective ratio);

[0303] 1 H NMR(400 MHz, DMSO) δ 8.93 (s, 1H), 7.95 (d, J = 7.43 Hz, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.52 (t, J = 7.48 Hz, 1H), 7.36 (d, J = 7.39 Hz, 2H), 6.07 (d, J = 5.87 Hz, 1H), 5.98 (d, J = 4.94 Hz, 1H), 5.48 (t, J = 4.63 Hz, 1H), 5.13 (t, J = 5.69 Hz, 1H), 4.83 (q, J = 5.38 Hz, 1H), 4.32 (d, J = 4.41 Hz, 1H), 3.73 - 3.62 (m, 2H), 2.57 (s, 3H).

[0304] 13 C NMR (101 MHz, DMSO) δ 166.6, 160.8, 158.0, 146.0, 139.8, 132.9, 132.1, 131.0, 129.7, 126.4, 92.0, 83.9, 74.0, 73.3, 61.7, 21.6.

[0305] HRMS (ESI, m / z) calcd. for C 16 H 18 N4O6Na + : 385.1118, found: 385.1114.

[0306] Preparation Example 42

[0307] Substituent R is 2-OCH3-Ph, the preparation implementation method and condition are same with preparation example 2;

[0308]

[0309] White solid, 75% yield, 28.4 mg; 3: 1 (regioselective ratio);

[0310] 1 H NMR(400 MHz, DMSO) δ 8.93 (s, 1H), 7.88 (s, 1H), 7.80 (dd, J = 7.68, 1.96 Hz, 1H), 7.67 (s, 1H), 7.61 - 7.57 (m, 1H), 7.20 - 7.17 (m, 1H), 7.08 - 7.04 (m, 1H), 6.02 (d, J = 5.88 Hz, 1H), 5.95 (d, J = 5.08 Hz, 1H), 5.44 (dd, J = 5.10, 3.85 Hz, 1H), 5.13 (t, J = 5.64 Hz, 1H), 4.81 (q, J = 5.38 Hz, 1H), 4.27 (q, J = 4.41 Hz, 1H), 3.85 (s, 3H), 3.71 - 3.61 (m, 2H).

[0311] 13 C NMR (101 MHz, DMSO) δ 164.8, 160.8, 159.1, 158.0, 146.0, 134.4, 131.7, 120.5, 120.0, 113.1, 91.9, 83.9, 73.6, 73.3, 61.6, 56.3.

[0312] HRMS (ESI, m / z) calcd for C 16 H 18 N4O7Na + : 401.1068, found: 401.1069.

[0313] Preparation Example 43

[0314] Substituent R is 2-F-Ph, the preparation implementation method and condition are same with preparation example 2;

[0315]

[0316] White solid, 62% yield, 20.4 mg; 4: 1 (regioselective ratio);

[0317] 1 H NMR(400 MHz, DMSO) δ 8.93 (s, 1H), 8.00 (t, J = 7.59 Hz, 1H), 7.88 (s, 1H), 7.72 (d, J = 6.79 Hz, 1H), 7.67 (s, 1H), 7.41 - 7.36 (m, 2H), 6.07 (d, J = 5.89 Hz, 1H), 5.96 (d, J = 5.10 Hz, 1H), 5.50 (t, J = 4.52 Hz, 1H), 5.13 (t, J = 5.68 Hz, 1H), 4.83 (q, J = 5.46 Hz, 1H), 3.72 - 3.62 (m, 2H).

[0318] 13 C NMR (101 MHz, DMSO) δ 163.0, 161.7 (d, J = 260.0 Hz), 160.8, 158.0, 146.0, 136.0 (d, J = 9.1 Hz), 132.5, 125.1 (d, J = 3.8 Hz), 118.5 (d, J = 9.5 Hz), 117.6 (d, J = 21.8 Hz), 91.8, 83.7, 74.4, 73.2, 61.6.

[0319] 19 F NMR (377 MHz, DMSO) δ -110.27.

[0320] HRMS (ESI, m / z) calcd. for C 15 H 15 FN4O6Na + : 389.0868, found: 389.0868.

[0321] Preparation Example 44

[0322] Substituent R is 2-Cl-Ph, the preparation implementation method and condition are same with preparation example 2;

[0323]

[0324] White solid, 71% yield, 27.3 mg; 7: 1 (regioselective ratio);

[0325] 1 H NMR(400 MHz, DMSO) δ 8.93 (s, 1H), 7.99 - 7.96 (m, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.64 - 7.61 (m, 2H), 7.54 - 7.50 (m, 1H), 6.11 (d, J = 5.89 Hz, 1H), 5.98 (d, J = 5.22 Hz, 1H), 5.52 (dd, J = 5.12, 3.66 Hz, 1H), 5.14 (t, J = 5.67 Hz, 1H), 4.85 (q, J = 5.43 Hz, 1H), 4.32 (q, J = 4.45 Hz, 1H), 3.73 - 3.62 (m, 2H).

[0326] 13 CNMR (101 MHz, DMSO) δ 164.4, 160.8, 158.0, 146.1, 134.1, 132.8, 132.2, 131.4, 129.9, 127.9, 91.8, 83.7, 74.7, 73.2, 61.6.

[0327] HRMS (ESI, m / z) calcd for C 15 H 15 ClN4O6Na + : 405.0572, found: 405.0570.

[0328] Preparation Example 45

[0329] Substituent R is 2-Br-Ph, the preparation implementation method and condition are same with preparation example 2;

[0330]

[0331] White solid, 77% yield, 32.9 mg; 10: 1 (regioselective ratio);

[0332] 1 H NMR(400 MHz, DMSO) δ 8.92 (s, 1H), 7.96 - 7.92 (m, 1H), 7.88 (s, 1H), 7.80 (dd, J = 7.10, 2.00 Hz, 1H), 7.67 (s, 1H), 7.57 - 7.52 (m, 2H), 6.11 (d, J = 5.90 Hz, 1H), 5.98 (d, J = 5.25 Hz, 1H), 5.51 (dd, J = 5.13, 3.63 Hz, 1H), 5.14 (t, J = 5.62 Hz, 1H), 4.85 (q, J = 5.37 Hz, 1H), 4.33 (q, J = 4.47 Hz, 1H), 3.71 - 3.61 (m, 2H).

[0333] 13 CNMR (101 MHz, DMSO) δ 165.1, 160.8, 158.0, 146.0, 134.6, 134.0, 132.1, 132.0, 128.3, 121.1, 91.9, 83.8, 74.8, 73.3, 61.7.

[0334] HRMS (ESI, m / z) calcd. for C 15 H 15 BrN4O6Na + : 449.0067, found: 449.0066.

[0335] Preparation Example 46

[0336] Substituent R is 2,6-Cl-Ph, and the preparation implementation method and conditions are the same as those in Preparation Example 2;

[0337]

[0338] White solid, 67% yield, 28.0 mg; 7: 1 (regioselective ratio);

[0339] 1 H NMR(400 MHz, DMSO) δ 8.91 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.65 - 7.58 (m, 3H), 6.09 (d, J = 6.25 Hz, 1H), 5.93 (d, J = 5.62 Hz, 1H), 5.55 (dd, J = 5.21, 3.24 Hz, 1H), 5.16 (t, J = 5.66 Hz, 1H), 4.90 (q, J = 5.71 Hz, 1H), 4.29 (q, J = 4.34 Hz, 1H), 3.71 (dt, J = 12.11, 5.04 Hz, 1H), 3.63 (dt, J = 11.70, 5.38 Hz, 1H).

[0340] 13 CNMR (101 MHz, DMSO) δ 163.8, 160.8, 158.1, 146.3, 133.1, 132.7, 131.4, 129.0, 91.4, 84.0, 75.6, 72.8, 61.7.

[0341] HRMS (ESI, m / z) calcd for C 15 H 14 Cl2N4O6Na + : 439.0183, found: 439.0178.

[0342] Preparation Example 47

[0343] Substituent R is 2,4,6-F-Ph, and the preparation method and conditions are the same as those in Preparation Example 2;

[0344]

[0345] White solid, 74% yield, 23.8 mg; 4: 1 (regioselective ratio);

[0346] 1 H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.42 (t, J = 9.10 Hz, 2H), 6.10 (d, J = 5.88 Hz, 1H), 5.89 (d, J = 5.32 Hz, 1H), 5.54 (dd, J = 5.07, 3.47 Hz, 1H), 5.15 (t, J = 5.69 Hz, 1H), 4.86 (q, J = 5.37 Hz, 1H), 4.25 (q, J = 4.46 Hz, 1H), 3.71 - 3.59 (m, 2H).

[0347] 13 CNMR(101 MHz, DMSO) δ 160.8, 159.6 (d, J = 23.2 Hz), 158.0, 146.1, 133.1, 102.7 (d, J = 3.8 Hz), 102.4 (d, J = 3.6 Hz), 102.2 (d, J = 3.5 Hz), 91.8, 83.8, 75.3, 73.0, 61.6.

[0348] 19 F NMR (377 MHz, DMSO) δ -101.13 (t, J = 9.67 Hz), -106.01 (d, J = 9.99 Hz).

[0349] HRMS (ESI, m / z) calcd. for C 15 H 13 F3N4O6Na + : 425.0679, found: 425.0677.

[0350] Preparation Example 48

[0351] Substituent R is furan, preparation method and conditions are the same as those in Preparation Example 2;

[0352]

[0353] White solid, 65% yield, 22.0 mg; 10:1 (regioselective ratio);

[0354] 1 H NMR (400 MHz, DMSO) δ 8.92 (s, 1 H), 8.02 (dd, J = 1.74, 0.84 Hz, 1 H), 7.87 (s, 1 H), 7.67 (s, 1 H), 7.42 (dd, J = 3.52, 0.91 Hz, 1 H), 6.74 (dd, J = 3.52, 1.75 Hz, 1 H), 6.05 (d, J = 5.91 Hz, 1 H), 5.95 (d, J = 5.1 1 Hz, 1 H), 5.44 (dd, J = 5.1 1, 3.79 Hz, 1 H), 5.12 (t, J = 5.64 Hz, 1 H), 4.80 (q, J = 5.39 Hz, 1 H), 4.28 (q, J = 4.41 Hz, 1 H), 3.70 - 3.59 (m, 2H).

[0355] 13 C NMR (101 MHz, DMSO) δ 160.8, 158.0, 157.6, 148.4, 146.0, 144.0, 119.6, 112.9, 91.8, 83.7, 73.9, 73.2, 61.6.

[0356] HRMS (ESI, m / z) calcd for C 13 H 14 FN4O7Na + : 361.0755, found: 361.0757.

[0357] Preparation Example 49

[0358] The substituent R is thiophene, and the preparation method and conditions are the same as those in Preparation Example 2;

[0359]

[0360] White solid, 71% yield, 25.2 mg; 5:1 (regioselective ratio);

[0361] 1 H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.01 (d, J = 4.80 Hz, 1H), 7.91 (dd, J = 3.83, 1.36 Hz, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 7.26 (dd, J = 4.95, 3.70 Hz, 1H), 6.06 (d, J = 5.88 Hz, 1H), 5.95 (d, J = 5.18 Hz, 1H), 5.47 - 5.41 (m, 1H), 5.15 (d, J = 23.19 Hz, 1H), 4.80 (t, J = 5.19 Hz, 1H), 4.29 (q, J = 4.41 Hz, 1H), 3.71 - 3.59 (m, 2H).

[0362] 13 CNMR (101 MHz, DMSO) δ 161.2, 160.8, 158.0, 145.9, 134.8, 134.7, 133.2, 128.8, 91.9, 83.8, 74.3, 73.3, 61.6.

[0363] HRMS (ESI, m / z) calcd for C 13 H 14 N4O6SNa + : 377.0526, found: 377.0524.

[0364] Preparation Example 50

[0365] The substituent R is naphthyl, and the preparation method and conditions are the same as those in Preparation Example 2;

[0366]

[0367] White solid, 61% yield, 24.4 mg; 5:1 (regioselective ratio);

[0368] 1 H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.74 (s, 1H), 8.18 (d, J = 7.88 Hz, 1H), 8.09 - 8.04 (m, 3H), 7.89 (s, 1H), 7.71 - 7.64 (m, 3H), 6.08 (t, J = 6.08 Hz, 2H), 5.56 (t, J = 4.49 Hz, 1H), 5.16 (q, J = 5.87, 4.63 Hz, 1H), 4.87 (q, J = 5.40 Hz, 1H), 4.40 (q, J = 4.45 Hz, 1H), 3.76 - 3.65 (m, 2H).

[0369] 13 CNMR (101 MHz, DMSO) δ 165.7, 160.8, 158.0, 146.0, 135.7, 132.5, 131.4, 129.8, 129.2, 128.9, 128.3, 127.6, 127.3, 125.5, 91.9, 83.9, 74.2, 73.4, 61.7.

[0370] HRMS (ESI, m / z) calcd for C 19 H 18 N4O6Na + : 421.1118, found: 421.1114.

[0371] Preparation Example 51

[0372] Substituent R is alkenyl benzene, preparation method and conditions are same as preparation example 2;

[0373]

[0374] White solid, 50% yield, 18.9 mg; 4:1 (regioselective ratio);

[0375] 1 H NMR(400 MHz, DMSO) δ 8.92 (s, 1H), 7.87 (s, 1H), 7.76 (q, J = 3.55, 3.11 Hz, 3H), 7.67 (s, 1H), 7.47 - 7.44 (m, 3H), 6.72 (d, J = 16.10 Hz, 1H), 6.01 (d, J = 6.02 Hz, 1H), 5.95 (d, J = 4.88 Hz, 1H), 5.37 (t, J = 4.65 Hz, 1H), 5.18 - 4.99 (m, 1H), 4.76 (t, J = 5.13 Hz, 1H), 4.25 (q, J = 4.42 Hz, 1H), 3.69 - 3.58 (m, 2H).

[0376] 13 C NMR (101 MHz, DMSO) δ 165.9, 160.8, 158.0, 145.8, 145.6, 134.5, 131.1, 129.5, 128.9, 128.9, 118.3, 92.1, 83.9, 73.4, 61.6.

[0377] HRMS (ESI, m / z) calcd for C 17 H 18 N4O6Na + : 397.1118, found: 397.1118.

[0378] Preparation Example 52

[0379] Substituent R is citral skeleton, preparation implementation method and condition are same with preparation example 2;

[0380]

[0381] White solid, 62% yield, 24.4 mg; 3: 1 (regioselective ratio);

[0382] 1 H NMR(400 MHz, DMSO) δ 8.91 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 5.95 (dd, J = 5.93, 4.60 Hz, 1H), 5.87 (t, J = 5.19 Hz, 1H), 5.76 (dt, J = 3.04, 1.60 Hz, 1H), 5.25 (t, J = 4.70 Hz, 1H), 5.09 (td, J = 5.70, 2.02 Hz, 2H), 4.70 (q, J = 5.29 Hz, 1H), 4.15 (q, J = 4.42 Hz, 1H), 3.63 (dd, J = 11.29, 6.19 Hz, 1H), 3.58 - 3.52 (m, 1H), 2.62 - 2.55 (m, 1H), 2.19 - 2.15 (m, 2H), 2.13 (s, 3H), 1.92 (s, 1H), 1.65 (d, J = 5.16 Hz, 3H), 1.59 (s, 3H).

[0383] 13 C NMR (101 MHz, DMSO) δ 165.4, 160.8, 158.0, 145.9, 132.2, 124.0, 123.6, 115.3, 92.0, 83.9, 73.2, 72.4, 61.6, 26.0, 26.0, 25.3, 19.0, 18.1.

[0384] HRMS (ESI, m / z) calcd for C 18 H 26 N4O6Na + : 417.1745, found: 417.1746.

[0385] Preparation Example 53

[0386] Substituent R is vanillin skeleton, preparation method and conditions are same as preparation example 2;

[0387]

[0388] White solid, 48% yield, 18.8 mg; 2.4: 1.0 (regioselective ratio);

[0389] 1 H NMR(400 MHz, DMSO) δ 10.02 (s, 1H), 8.93 (s, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 7.58 (dd, J = 8.28, 2.01 Hz, 1H), 7.51 (d, J = 1.99 Hz, 1H), 6.90 (d, J = 8.25 Hz, 1H), 6.04 - 5.95 (m, 2H), 5.42 (dd, J = 5.20, 3.93 Hz, 1H), 5.11 (t, J = 5.64 Hz, 1H), 4.82 - 4.75 (m, 1H), 4.29 (q, J = 4.39 Hz, 1H), 3.84 (s, 3H), 3.72 - 3.58 (m, 2H).

[0390] 13 C NMR (101 MHz, DMSO) δ 165.4, 160.8, 158.0, 152.3, 147.9, 145.9, 124.4, 120.7, 115.6, 113.4, 91.9, 84.0, 73.6, 73.4, 61.7, 56.2.

[0391] HRMS (ESI, m / z) calcd for C 16 H 18 N4O8Na + : 417.1017, found: 417.1016.

[0392] Preparation Example 54

[0393] Substituent R is propofol skeleton, preparation implementation method and condition are same with preparation example 2;

[0394]

[0395] White solid, 62% yield, 31.6 mg; 1.2:1.0 (regioselective ratio);

[0396] 1 H NMR(400 MHz, DMSO) δ 8.94 (s, 1H), 8.24 (d, J = 8.27 Hz, 2H), 7.98 (s, 2H), 7.89 (s, 1H), 7.68 (s, 1H), 6.02 (d, J = 5.03 Hz, 1H), 5.77 - 5.69 (m, 1H), 5.53 (t, J = 4.52 Hz, 1H), 5.14 (t, J = 5.74 Hz, 1H), 4.84 (q, J = 5.24 Hz, 1H), 4.36 (q, J = 4.45 Hz, 1H), 3.74 - 3.63 (m, 2H), 3.08 - 3.06 (m, 4H), 1.49 - 1.46 (m, 4H), 0.81 (d, J = 4.31 Hz, 6H).

[0397] 13 C NMR (101 MHz, DMSO) δ 164.5, 160.8, 158.0, 146.0, 144.2, 133.4, 130.9, 127.6, 91.8, 83.7, 74.8, 73.3, 61.6, 50.0, 22.0, 11.4.

[0398] HRMS (ESI, m / z) calcd for C 21 H 29 N5O8SNa + : 534.1629, found: 534.1631.

[0399] Preparation Example 55

[0400] Substituent R is tometate skeleton, preparation implementation method and condition are same with preparation example 2;

[0401]

[0402] e (58):

[0403] White solid, 54% yield, 26.5 mg; 1.0:1.0 (regioselective ratio);

[0404] 1 H NMR(400 MHz, DMSO) δ 9.16 (s, 1H), 8.94 (s, 1H), 8.06 (dd, J = 7.94, 1.66 Hz, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.41 (dd, J = 7.01, 1.77 Hz, 1H), 7.29 - 7.27 (m, 3H), 6.85 - 6.81 (m, 2H), 6.13 (d, J = 5.88 Hz, 1H), 6.03 (d, J = 4.80 Hz, 1H), 5.51 (t, J = 4.66 Hz, 1H), 5.13 (t, J = 5.64 Hz, 1H), 4.84 (q, J = 5.21 Hz, 1H), 4.38 - 4.35 (m, 1H), 3.73 - 3.64 (m, 2H), 2.26 (s, 3H).

[0405] 13 C NMR (101 MHz, DMSO) δ 167.4, 160.8, 158.0, 148.0, 146.0, 140.7, 135.3, 135.0, 132.3, 130.9, 128.1, 125.8, 123.3, 117.9, 114.3, 111.6, 92.0, 83.8, 73.3, 70.8, 56.5, 19.0.

[0406] HRMS (ESI, m / z) calcd for C 22 H 22 ClN5O6Na + : 510.1151, found: 510.1149.

[0407] Preparation Example 56

[0408] N-hybrid substituent is 5-methyluridine, preparation method and conditions are the same as those in Preparation Example 2;

[0409]

[0410] White solid, 78% yield, 28.2 mg; 3: 1 (regioselective ratio);

[0411] 1 H NMR(400 MHz, DMSO) δ 11.38 (s, 1H), 8.08 - 8.02 (m, 2H), 7.78 (d, J = 1.50 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.57 (t, J = 7.75 Hz, 2H), 5.93 (d, J = 6.94 Hz, 1H), 5.81 (d, J = 6.13 Hz, 1H), 5.38 (dd, J = 5.55, 2.67 Hz, 1H), 5.34 (t, J = 5.40 Hz, 1H), 4.41 (q, J = 6.23 Hz, 1H), 4.20 (q, J = 3.10 Hz, 1H), 3.72 - 3.66 (m, 2H), 1.81 (d, J = 1.11 Hz, 3H).

[0412] 13 C NMR (101 MHz, DMSO) δ 165.6, 164.1, 151.4, 136.6, 133.9, 130.0, 129.9, 129.2, 110.3, 87.7, 83.0, 74.0, 72.1, 61.6, 12.6.

[0413] HRMS (ESI, m / z) calcd for C 17 H 18 N2O7Na + : 385.1006, found: 385.1000.

[0414] Preparation Example 57

[0415] N-hybrid substituent is adenosine, and the preparation method and conditions are the same as those in Preparation Example 2;

[0416]

[0417] 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.17 (s, 1H), 8.11 - 8.07 (m, 2H), 7.74 - 7.68 (m, 1H), 7.59 (t, J = 7.70 Hz, 2H), 7.41 (s, 2H), 6.03 (d, J = 7.22 Hz, 1H), 5.91 (d, J = 6.24 Hz, 1H), 5.76 - 5.71 (m, 1H), 5.55 (dd, J = 5.29, 1.98 Hz, 1H), 5.06 - 5.00 (m, 1H), 4.32 (q, J = 2.99 Hz, 1H), 3.80 - 3.65 (m, 2H).

[0418] 13 C NMR(101 MHz, DMSO) δ 165.6, 156.8, 156.7, 153.0, 140.4, 134.0, 130.2, 129.9, 129.2, 120.1, 88.3, 84.1, 74.7, 72.4, 62.1.

[0419] HRMS (ESI, m / z) calcd for C 17 H 17 N5O5Na + : 394.1122, found: 394.1117.

[0420] Preparation Example 58

[0421] The N-hybrid substituent is 8-bromoadenosine, and the preparation method and conditions are the same as those in Preparation Example 2;

[0422]

[0423] White solid, 82% yield, 36.9 mg; 8: 1 (regioselective ratio);

[0424] 1 H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 8.11-8.06 (m, 2H), 7.71 (t, J = 7.46 Hz, 1H), 7.64 (s, 1H), 7.59 (t, J = 7.65 Hz, 3H), 5.95 (d, J = 6.54 Hz, 2H), 5.76-5.72 (m, 1H), 5.61 (dd, J = 5.67, 2.37 Hz, 1H), 5.42 (q, J = 6.17 Hz, 1H), 4.36 (q, J = 3.38 Hz, 1H), 3.78 (dt, J = 12.34, 4.06 Hz, 1H), 3.72-3.64 (m, 1H).

[0425] 13 C NMR (101 MHz, DMSO) δ 165.6, 156.8, 156.7, 153.0, 140.4, 134.0, 130.2, 129.9, 129.2, 120.1, 88.3, 84.1, 74.7, 72.4, 62.1.

[0426] HRMS (ESI, m / z) calcd for C 17 H 16 BrN5O5Na + : 472.0227, found: 472.0220.

[0427] Preparation Example 59

[0428] Substituent R is 2-methylpropenyl, and the preparation method and conditions are the same as those in Preparation Example 1;

[0429]

[0430] White solid, 41% yield, 12.7 mg; 10:1 (regioselective ratio);

[0431] 1 H NMR (400 MHz, MeOD) δ 7.71 (d, J = 7.50 Hz, 1H), 6.13 (t, J = 1.26 Hz, 1H), 5.87 (d, J = 7.52 Hz, 1H), 5.81 (d, J = 2.87 Hz, 1H), 5.69 (q, J = 1.62 Hz, 1H), 4.51 (dd, J = 12.42, 2.89 Hz, 1H), 4.42 (dd, J = 12.45, 4.65 Hz, 1H), 4.25 - 4.20 (m, 1H), 4.16 - 4.09 (m, 2H), 1.97 (t, J = 1.34 Hz, 3H).

[0432] 13 C NMR (101 MHz, MeOD) δ 166.9, 166.2, 156.8, 140.9, 136.2, 125.3, 94.6, 91.6, 81.1, 74.5, 69.6, 63.3, 17.2.

[0433] HRMS (ESI, m / z) calcd. for C 13 H 17 N3O6Na + : 334.1010, found: 334.1007.

[0434] Preparation Example 60

[0435] Substituent R is isopropyl;

[0436]

[0437] White solid, 86% yield, 28.3 mg; 10:1 (regioselective ratio);

[0438] 1 H NMR(400 MHz, DMSO) δ 10.01 (s, 1H), 9.54 (d, J = 2.29 Hz, 1H), 6.83 (d, J = 8.25 Hz, 1H), 5.71 (d, J = 5.47 Hz, 1H), 5.58 (dd, J = 8.25, 2.11 Hz, 1H), 5.37 (d, J = 5.75 Hz, 1H), 5.22 (d, J = 5.00 Hz, 1H), 4.25 - 4.11 (m, 2H), 4.00 (q, J = 5.45 Hz, 1H), 3.95 - 3.88 (m, 2H), 2.62 - 2.54 (m, 1H), 1.11 (s, 3H), 1.09 (s, 3H).

[0439] 13 C NMR (101 MHz, MeOD) δ 176.9, 150.1, 144.8, 130.4, 98.1, 89.0, 81.2, 73.0, 70.1, 63.5, 33.8, 18.0, 17.9.

[0440] HRMS (ESI, m / z) calcd for C 13 H 19 N3O7Na + : 352.1115, found: 352.1109.

[0441] Preparation Example 61

[0442] Substituent R is 2-methylpropenyl, and the preparation method and conditions are the same as those in Preparation Example 1;

[0443]

[0444] White solid, 50% yield, 18.1 mg; 9: 1 (regioselective ratio);

[0445] 1 H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 6.86 (q, J = 4.59 Hz, 2H), 6.05 (t, J = 1.33 Hz, 1H), 5.63 - 5.59 (m, 1H), 4.88 (s, 1H), 4.54 (dd, J = 12.01, 2.88 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.35 (dd, J = 12.01, 4.76 Hz, 1H), 4.20 (dd, J = 6.40, 5.26 Hz, 1H), 1.89 (t, J = 1.31 Hz, 3H).

[0446] 13 C NMR(101 MHz, MeOD) δ 166.9, 155.8, 146.9, 136.0, 125.3, 124.2, 116.6, 116.2, 110.7, 101.1, 81.9, 80.0, 74.1, 70.5, 62.9, 17.1.

[0447] HRMS (ESI, m / z) calcd for C 16 H 17 N5O5Na + : 382.1122, found: 382.1119.

[0448] Preparation Example 62

[0449] The substituent R is isopropyl;

[0450]

[0451] White solid, 91% yield, 32.9 mg; 9: 1 (regioselective ratio);

[0452] 1 H NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.91 - 6.85 (m, 2H), 4.87 (d, J = 6.15 Hz, 1H), 4.44 - 4.39 (m, 1H), 4.38 - 4.34 (m, 1H), 4.29 (dd, J = 11.61, 4.78 Hz, 1H), 4.14 (t, J = 5.72 Hz, 1H), 2.58 - 2.50 (m, 1H), 1.11 (dd, J = 6.98, 4.10 Hz, 6H).

[0453] 13 C NMR (101 MHz, MeOD) δ 146.9, 144.5, 124.3, 116.6, 116.2, 110.7, 101.1, 98.7, 82.0, 80.0, 74.2, 70.6, 62.9, 33.7, 17.9, 17.8.

[0454] HRMS (ESI, m / z) calcd for C 16 H 19 N5O5Na + : 384.1278, found: 384.1279.

[0455] The following provides the antiviral activity test of 58 preparation examples of 5'-O-acylated nucleoside derivatives and 3'-O-acylated nucleoside derivatives synthesized by the present application:

[0456] 1. Test method

[0457] Tobacco mosaic virus (TMV) and potato virus Y (PVY) were obtained from infected Nicotiana tabacum leaves according to the method reported (J. Virol. Methods 1997, 69, 137.; Phytopathology 1967, 57, 1285.). The antiviral activity of the selective acylated nucleoside derivatives against TMV and PVY was tested using the half-leaf mottle method. The specific inhibition rate was calculated as follows:

[0458]

[0459] 1.1 Therapeutic activity of the selective acylated nucleoside derivatives against TMV

[0460] Uniformly developed 5-6 leaf stage heart leaves of N. tabacum were inoculated with virus juice by rubbing with a brush on carborundum dusted leaves. After 30 minutes of virus inoculation, the leaves were washed with water. After the leaves dried, the right half of the leaves was treated with the test agent, and the left half of the leaves was treated with the corresponding amount of solvent as control. The leaves were then incubated in a light incubator, and the number of mottles was observed and recorded after 1.5-2.0 days.

[0461] 1.2 Protective activity of the selective acylated nucleoside derivatives against TMV

[0462] Uniformly developed 5-6 leaf stage heart leaves of N. tabacum were treated with the test agent by gently rubbing with a brush on the right half of the leaves, and the left half of the leaves was treated with the corresponding amount of solvent as control. After 24 hours of incubation in a light incubator, the leaves were inoculated with virus juice by rubbing with a brush on carborundum dusted leaves. After 30 minutes of virus inoculation, the leaves were washed with water. The leaves were then incubated in a light incubator, and the number of mottles was observed and recorded after 1.5-2.0 days.

[0463] 1.3 Therapeutic activity of the selective acylated nucleoside derivatives against PVY

[0464] Uniformly developed 5-6 leaf stage heart leaves of N. tabacum were inoculated with virus juice by rubbing with a brush on carborundum dusted leaves. After 60 minutes of virus inoculation, the leaves were washed with water. After the leaves dried, the right half of the leaves was treated with the test agent, and the left half of the leaves was treated with the corresponding amount of solvent as control. The leaves were then incubated in a light incubator, and the number of mottles was observed and recorded after 3-4 days.

[0465] 1.4 Protective activity of the selective acylated nucleoside derivatives against PVY

[0466] The 5-6 leaf stage of Amaranthus retroflexus L. with uniform growth was selected, and the right half of the leaf was lightly coated with the agent using a brush, and the left half of the leaf was coated with the solvent as a control. After 24 hours of culture in a light incubator, the virus juice was rubbed on the leaf blade coated with corundum using a brush, and the leaf blade was washed with water 60 minutes after inoculation of the virus. The leaf blade was cultured in a light incubator, and the number of dry spots was observed and recorded after 3-4 days.

[0467] 2. Anti-plant virus biological activity test results

[0468] Table 1 Anti-TMV activity of the mono-esterified nucleoside compounds prepared in Examples 1-58

[0469]

[0470]

[0471] The anti-TMV activity of the mono-esterified nucleoside compounds was tested by the half-leaf dry spot method at a concentration of 500 μg / mL, using the commercial drugs Virazole and Ningnanmycin as control drugs, and the experimental results are shown in Table 1. The biological activity test results show that compounds 9, 27, 28, 29 and 46 exhibit better anti-TMV virus activity than the control drug Ningnanmycin, and can be used as potential plant virus inhibitors, and have good application prospects.

[0472] Table 2 Anti-PVY activity of the mono-esterified nucleoside compounds prepared in Examples 1-58

[0473]

[0474]

[0475] The anti-PVY activity of the mono-esterified nucleoside compounds was tested by the half-leaf dry spot method at a concentration of 500 μg / mL, using the commercial drugs Virazole and Ningnanmycin as control drugs, and the experimental results are shown in Table 2. The biological activity test results show that compounds 9, 29, 42 and 49 exhibit better anti-PVY virus activity than the control drug Ningnanmycin, and can be used as potential plant virus inhibitors, and have good application prospects.

[0476] In summary, the above is only a preferred embodiment of the present application, and does not limit the present application in any form. Any simple modification, equivalent change and modification of the above embodiment according to the technical essence of the present application, without departing from the technical solution content of the present application, still belongs to the scope of the technical solution of the present application.

Claims

1. A method for preparing selectively acylated nucleoside derivatives catalyzed by nitrogen-heterocyclic carbene, characterized in that, The general reaction formula and process are as follows: The structure of the derivative is as follows:

2. A method for preparing an oral anti-COVID-19 drug, characterized in that, The steps are as follows: in,

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