Thiochromone compounds, intermediates for preparing such compounds, their preparation methods and applications

Abstract

The present invention discloses a class of thiochromone compounds, belonging to the technical field of chemical synthesis. The thiochromone compounds have the structure shown in general formula (4). The present invention also discloses a preparation method of the above compounds, which is prepared by a dearomatization [4+2] cycloaddition / elimination / oxidation cascade reaction using nitrobenzheterocycle as a substrate. The present invention also discloses the use of the above compounds in the preparation of drugs for treating tumor diseases; it has important application value for drug screening and the pharmaceutical industry. The operation of the present invention is simple and easy, the raw materials are cheap and easily available, the product has good air stability, can be carried out in various organic solvents, has good compatibility with various substituents, and has a wide applicability.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a thiochromone compound, an intermediate for preparing such a compound, a preparation method thereof and an application thereof. Background Art

[0002] Thiochromone derivatives are an important class of structural units, commonly found in natural products and active molecules with anti-inflammatory, anti-cancer and antibacterial activities, etc. Clinical studies have shown that drugs containing related structures can prevent and treat diseases caused by steroid sulfatase deficiency, adrenaline imbalance, abnormal uric acid excretion, etc. In view of the wide range of physiological activities of thiochromone derivatives and their importance in the field of medicinal chemistry, it is of great significance to develop more synthetic routes for such compounds. At present, many methods for synthesizing thiochromone derivatives have been reported, among which the most common are intramolecular cyclization of molecules containing a thiochromone skeleton and cycloaddition reactions of aryl mercapto reagents with unsaturated electrophilic reagents.

[0003] Although the currently reported methods can effectively synthesize thiochromone derivatives, there are still some inevitable disadvantages: most reactions involve the use of expensive metal or organic catalysts; the steps are cumbersome, and the initial substrates need to be prepared through multiple steps; the reactions require relatively harsh conditions, posing challenges to the tolerance of product functional groups; the reaction yields are relatively low, which is not conducive to industrialization. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a new class of thiochromone compounds to solve the above problems.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows: a thiochromone compound, the compound has a structure shown in the general formula (4):

[0006] Wherein, R 1 is selected from H, alkyl, halogen, aryl.

[0007] Another purpose of the present invention is to provide a preparation method of the above-mentioned thiochromone compound. The technical solution adopted is as follows: including the following steps:

[0008] (a) Using R 1 -substituted 2-nitrobenzofuran (1) and o-mercaptobenzaldehyde (2) as raw materials, dissolving them in a reaction solvent, and adding 0.05 - 0.15 times the molar equivalent of base A, reacting for 8 - 20 min, monitoring the reaction until it is complete, to obtain compound (3);

[0009] (b) Then adding 2.5 - 3.5 times the molar equivalent of base B, reacting for more than 20 h, monitoring the reaction until it is complete, concentrating, separating and purifying to obtain the product compound (4). The reaction route is as follows:

[0010]

[0011] In the present invention, the "molar equivalent", unless otherwise specified, is based on R 1 -substituted 2-nitrobenzofuran (1), that is, in step (a), the molar ratio of base A to R 1 -substituted 2-nitrobenzofuran is (0.05 - 0.15):1, and so on.

[0012] Currently, there are reports on the synthesis methods of similar compounds, but the yields are generally low, and the highest yield is less than 70%. In the present invention, by adding materials in two steps, first adding the preliminary reaction raw materials and an appropriate and proper amount (0.05 - 0.15 molar equivalent) of base A, an intermediate compound (3) is formed within a short time, that is, the intermediate compound 3 can be obtained by reacting with a small amount of base for a short time; then a larger amount of base B is added and the reaction is carried out for a long time to finally obtain the target compound (4).

[0013] The mechanism is as follows: The corresponding 2-nitro-substituted benzofuran (1) and o-mercaptobenzaldehyde (2) first undergo a Michael addition reaction under specific conditions (controlling the type, amount and reaction time of the added base), triggering an intramolecular dearomatization cycloaddition to obtain a [4 + 2] cyclized product (3); then the cyclized product 3 is triggered by the subsequently added specific base (DBU or Barton, a larger addition amount) to undergo a nitrous acid elimination reaction to obtain an intermediate (3-1), and the intermediate (3-1) is easily oxidized by the oxygen in the air to obtain the final product (4) of benzofuran thiochromone. By using the above method, the yield can be increased to more than 90%, and the independently obtained intermediate has high diastereoselectivity.

[0014] As a preferred technical solution, in step (a), the reaction solvent is selected from one of DCE, THF, Toluene, DCM, EtOH, CH3CN, MTBE.

[0015] As a further preferred technical solution, in step (a), the reaction solvent is selected from one of DCE, THF, Toluene.

[0016] Because compared with other solvents, the dr value of product 3 is greater than 20:1; more preferably, the solvent is Toluene. Using Toluene as the solvent can obtain the intermediate compound 3 in a short time (10 min) with a high yield (>99% yield) and high diastereoselectivity (>20:1 dr).

[0017] As a preferred technical solution, in step (a), the base A is selected from one of DIPEA, DMAP, DABCO, Et3N, DBU, and Na2CO3. The molar ratio of the o-mercaptobenzaldehyde to the 2-nitroheteroarene is preferably 1:1.2. The raw materials with this reactant ratio are fully utilized and the yield is relatively high.

[0018] As a further preferred technical solution, the base A is selected from one of DIPEA, DMAP, DABCO, Et3N, and DBU.

[0019] Because compared with inorganic bases, the yield of the reaction with organic bases participating is relatively high and the reaction time is shorter; more preferably, the base A is DABCO, because compared with other organic bases, DABCO can achieve a high yield of the target product 3 in a shorter time.

[0020] As a preferred technical solution: in step (b), the base B is selected from DBU or Barton.

[0021] The inventors have tried other bases, such as DABCO, DIPEA, DMAP, Cs2CO3, etc., and the results show that the yield is higher when using DBU or Barton.

[0022] As a preferred technical solution: in step (a), the addition amount of the base A is 0.1 times the molar equivalent; in step (b), the addition amount of the base B is 3 times the molar equivalent.

[0023] In step (b), when the amount of the base used is appropriately increased, the yield gradually increases with the increase of the usage amount.

[0024] As a preferred technical solution: in step (a), the reaction time is 10 min; in step (b), the reaction time is 24 h.

[0025] The third object of the present invention is to provide the use of the above compound in the preparation of a drug for treating human prostate cancer and / or human lung cancer.

[0026] Compared with the prior art, the advantages of the present invention are as follows: The present invention uses various substituted 2-nitroheteroarenes and o-mercaptobenzaldehyde as raw materials, and through a two-step feeding method, a tandem dearomatization [4+2] cycloaddition / elimination / oxidation process is carried out to obtain a series of benzofuro[3,2-c]chromone compounds with potential biological activities. During the synthesis of such compounds, the intermediate products can also be independently obtained as active intermediates in a short time with high yield and high diastereoselectivity. The present invention not only provides new ideas for the synthesis of benzofuro[3,2-c]chromone compounds, but also the active intermediates have research value. Through preliminary cell activity studies, it is shown that such compounds have good inhibitory effects on human prostate (PC-3) tumor cells and human lung cancer cells (A549), and are expected to become lead compounds for anti-tumor drugs, providing a rich source of compounds for biological activity screening, and having important application value for drug screening and the pharmaceutical industry; the operation of the present invention is simple and easy, the raw materials are cheap and easy to synthesize, and it also has good air stability, wide applicability, and good compatibility with various substituents. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1-2 1H NMR and 13C NMR spectra of compound 3a of the embodiment of the present invention;

[0028] Figure 3-4 1H NMR and 13C NMR spectra of compound 3a' of the embodiment of the present invention;

[0029] Figure 5-6 1H NMR and 13C NMR spectra of compound 4a of the embodiment of the present invention;

[0030] Figure 7 X-ray single crystal diffraction pattern of compound 3a of the present invention;

[0031] Figure 8 X-ray single crystal diffraction pattern of compound 4a of the present invention. EMBODIMENTS

[0032] The present invention will be further described below with reference to the accompanying drawings. EXAMPLES

[0033] Preparation of Compound 3

[0034] 2-Nitrobenzofuran 1a (0.1 mmol) and base DABCO (1 mg, 0.01 mmol) were successively added to a reaction tube, and then o-mercaptobenzaldehyde 2a (0.12 mmol) was added. Using toluene (1 mL) as a solvent, the mixture was stirred at room temperature for 10 min. After TLC detection showed that the reaction was basically complete, the product was concentrated, dissolved in a small amount of dichloromethane, and loaded onto a silica gel column chromatography (eluent: V (petroleum ether): V(Ethyl acetate)= 10:1) Compound 3a was purified as a white solid, melting point: 175.0 - 175.5 o °C; yield 99%; >20:1 dr. Nuclear magnetic resonance (as Figure 1 and 2 shown) and high-resolution mass spectrometry test results are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.66 (d, J J = 7.7 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.26 - 7.11 (m, 3H), 7.00 (t, 1H), 6.77 (d, J J = 8.1 Hz, 1H), 5.75 (d, J J = 9.6 Hz, 1H), 5.18(s, 1H), 2.95 (d, J J = 9.7 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 156.8, 135.8, 130.3, 129.9, 129.3, 128.4, 128.1, 125.9, 125.1, 124.9, 123.8, 121.1, 110.4, 73.3, 52.9; HRMS (ESI) Calcd. for C 15 H 11 NO4S [M + Na] + : 324.0301; found: 324.0297. The X-ray single crystal diffraction pattern is shown in Figure 7 .

[0035] Comparative examples:

[0036] (1) Based on the above preparation of 3a, DBU was used as the base, with the same addition amount, and the other conditions remained unchanged. The yield was 64% and the dr value was 1.6:1;

[0037] (2) Based on the above preparation of 3a, Na2CO3 was used as the base, with the same addition amount, and the other conditions remained unchanged. The yield was 68% and the dr value was 1:1;

[0038] (3) Based on the above preparation of 3a, CH3CN was used as the solvent, with an addition amount of 1 mL, and the other conditions remained unchanged. The yield was 97% and the dr value was 5:1;

[0039] (4) Based on the above preparation of 3a, EtOH was used as the solvent, with an addition amount of 1 mL, and the other conditions remained unchanged. The yield was 88% and the dr value was 8:1;

[0040] (5) This comparative example is based on the above preparation of 3a. The solvent used is DCE, and the addition amount is 1 mL. Other conditions remain unchanged. The yield is 92%, and the dr value > 20:1.

[0041] The preparation methods of compounds 3b - 3u, 3a' - 3h' are the same as that of compound 3a, and the feeding ratio is the same as that of compound 3a. The results of reaction yields and diastereoselectivity of the products are as follows. It should be emphasized that the examples are intended to illustrate rather than limit the scope of the present invention. The compounds of the present invention are not limited to the following structures.

[0042] Structure of the dearomatized [4 + 2] cycloaddition product of 2 - nitroheteroarene and o - mercaptobenzaldehyde:

[0043] Structure of the dearomatized cycloaddition product of 2 - nitroheteroarene and mercaptoacetaldehyde:

[0044] ;

[0045] In this example, compound 3b was prepared: white solid, melting point: 156.2 - 156.7 ºC; yield 97%; > 20:1 dr. The results of nuclear magnetic resonance and high - resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO - d 6) δ 7.62 (d, J J = 7.6 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.30 - 7.25 (m, 1H), 7.25 - 7.14 (m, 2H), 7.05 - 6.94 (m, 2H), 6.94 - 6.86 (m, 1H), 5.74 (s, 1H), 5.56 (d, J J = 7.2 Hz, 1H); 13 CNMR (75 MHz, DMSO - d 6) δ 158.2 ( J J = 237.2 Hz), 152.7, 137.1, 129.3, 129.2, 128.7 ( J= 9.3 Hz), 128.1, 127.8, 125.7, 122.3, 116.8 ( J = 24.6 Hz), 112.3 ( J = 25.5 Hz), 111.0 ( J = 9.0 Hz), 72.1, 52.3; HRMS (ESI) Calcd. for C 15 H 10 FNO4S[M + Na] + : 342.0207; found: 342.0213.

[0046] In this example, compound 3c was prepared: white solid, melting point: 166.2 - 166.6 ºC; yield 94%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.66 (d, J =7.7 Hz, 1H), 7.42-7.32 (m, 1H), 7.30-7.15 (m, 3H), 7.15-7.06 (m, 2H), 7.06-6.98 (m, 1H), 5.86 (s, 1H), 5.60 (d, J = 7.2 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ 145.3 ( J = 245.3 Hz), 143.0 ( J = 11.3 Hz), 136.9, 130.6, 129.4, 129.3,128.2, 127.9, 125.7, 124.7 ( J = 5.3 Hz), 122.3, 121.2 ( J = 3.8 Hz), 117.0 ( J = 15.8 Hz), 72.1, 52.6; HRMS (ESI) Calcd. for C 15 H 10 FNO4S [M + Na] + : 342.0207;found: 342.0216.

[0047] This example prepares compound 3d: white solid, melting point: 164.9 - 165.5 ºC; yield 97%; 10:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.66 (d, J =7.7 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.32 - 7.25 (m, 1H), 7.20 (t, J = 8.1 Hz, 2H),7.08 (t, J = 7.0 Hz, 2H), 6.89 (d, J = 8.1 Hz, 1H), 5.80 (s, 1H), 5.63 (d, J = 7.2 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ 157.6, 137.2, 131.8, 130.0, 129.4,129.0, 128.2, 127.9, 125.7, 124.4, 123.9, 121.2, 109.1, 71.9, 51.8; HRMS(ESI) Calcd. for C 15 H 10 ClNO4S [M + Na] + : 357.9911; found: 357.9916.

[0048] This example prepares compound 3e: white solid, melting point: 176.8 - 177.4 ºC; yield 97%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.62 (d, J =7.7 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.31 - 7.26 (m, 1H), 7.25 - 7.15 (m, 2H), 7.02(d, J = 7.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.75 (s, 1H), 5.56 (d, J = 7.2Hz, 1H);13 C NMR (75 MHz, DMSO- d 6) δ 155.4, 137.0, 130.0, 129.4, 129.3, 129.2, 128.2, 127.9, 127.0, 125.7, 125.2, 122.0, 111.6, 72.0, 52.1; HRMS (ESI) Calcd. for C 15 H 10 ClNO4S [M + Na] + : 357.9911; found: 357.9914.

[0049] Compound 3f was prepared in this example : White solid, melting point: 183.6 - 184.3 ºC; yield 91%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.64 (d, J J =7.7 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.41 - 7.25 (m, 3H), 7.20 (t, J J = 7.4 Hz, 1H),7.06 (d, J J = 7.2 Hz, 1H), 6.87 (d, J J = 8.6 Hz, 1H), 5.75 (s, 1H), 5.58 (d, J J = 7.1 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ 155.9, 137.0, 132.8, 129.8, 129.4, 129.2, 128.2, 128.1, 127.9, 125.7, 122.0, 114.7, 112.1, 72.1, 52.0; HRMS(ESI) Calcd. for C 15 H 10 BrNO4S [M + Na] + : 401.9406; found: 401.9409.

[0050] Compound 3g was prepared in this example: white solid, melting point: 194.2 - 194.8 ºC; yield 90%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.64 (d, J J =7.6 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.32 - 7.27 (m, 1H), 7.27 - 7.15 (m, 4H), 7.06(d, J J = 7.1 Hz, 1H), 5.73 (s, 1H), 5.59 (d, J J = 7.1 Hz, 1H); 13 C NMR (75 MHz,DMSO- d 6) δ 157.5, 137.0, 129.4, 129.3, 128.2, 127.8, 127.0, 126.7, 126.6,125.7, 122.2, 122.1, 113.2, 72.0, 52.0; HRMS (ESI) Calcd. for C 15 H 10 BrNO4S [M +Na] + : 401.9406; found: 401.9416.

[0051] Compound 3h was prepared in this example: white solid, melting point: 190.6 - 191.3 ºC; yield 93%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.65 (d, J J =7.7 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.29 - 7.17 (m, 2H), 7.07 (d, J J = 6.7 Hz, 1H),6.96 (t, J J = 7.8 Hz, 1H), 5.87 (s, 1H), 5.60 (d, J J = 6.7 Hz, 1H); 13 C NMR (75MHz, DMSO- d6) δ 154.0, 136.9, 132.8, 129.3, 128.6, 128.2, 127.9, 125.7, 125.2, 124.8, 121.3, 121.2, 101.4, 71.9, 53.1; HRMS (ESI) Calcd. for C 15 H 10 BrNO4S [M + Na] + : 401.9406; found: 401.9417.

[0052] This example prepares compound 3i: a white solid, melting point: 180.9 - 181.8 ºC; yield 92%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.65 (d, J J =7.7 Hz, 1H), 7.63 - 7.60 (m, 1H), 7.53 - 7.49 (m, 1H), 7.43 - 7.34 (m, 1H), 7.29(d, J J = 6.5 Hz, 1H), 7.22 (t, J J = 7.2 Hz, 1H), 7.13 (d, J J = 6.7 Hz, 1H), 5.87(s, 1H), 5.58 (d, J J = 6.7 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ 153.6, 136.7, 134.7, 130.8, 129.4, 128.9, 128.4, 128.1, 127.5, 125.8, 121.5, 115.1, 102.8, 71.9, 52.9; HRMS (ESI) Calcd. for C 15 H9Br2NO4S [M + Na] + : 479.8511; found: 479.8517.

[0053] This example prepares compound 3j: A white solid, melting point: 185.3 - 186.0 ºC; yield 98%; 6.8:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO-d 6) δ 8.24 - 8.18 (m, 1H), 8.09 (dd, J J = 9.1, 2.3 Hz, 1H), 7.64 (d, J J = 7.6 Hz, 1H), 7.43 - 7.32 (m, 1H), 7.32 - 7.26 (m, 1H), 7.26 - 7.18 (m, 1H), 7.18 - 7.12 (m, 2H), 5.88 (s, 1H), 5.61 (d, J J = 7.0 Hz, 1H); 13 C NMR (75 MHz, DMSO - d 6) δ 161.1, 143.7, 136.6, 129.5, 129.2, 129.0, 128.3, 128.1, 127.0, 125.8, 122.6, 121.5, 110.7, 72.0, 51.5; HRMS (ESI) Calcd. for C 15 H 10 N2O6S [M + Na] + : 369.0152; found: 369.0153.

[0054] Compound 3k was prepared in this example: white solid, melting point: 157.3 - 157.8 ºC; yield 98%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO - d 6) δ 7.63 (d, J J = 7.6 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.28 - 7.15 (m, 2H), 7.14 (s, 1H), 7.01 - 6.90 (m, 2H), 6.74 (d, J J = 8.3 Hz, 1H), 5.67 (s, 1H), 5.57 (d, J J = 7.3 Hz, 1H), 2.20 (s, 3H); 13 C NMR (75 MHz, DMSO - d6) δ 154.7, 137.2, 132.6, 130.5, 129.6, 129.3, 128.0, 127.6, 126.8, 125.6, 125.5, 122.0, 109.6, 72.1, 52.4, 20.3; HRMS (ESI) Calcd. for C 16 H 13 NO4S [M + Na] + : 338.0457; found: 338.0442.

[0055] Compound 3l was prepared in this example : White solid, melting point: 174.2 - 174.8 ºC; yield 94%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.62 (d, J J =7.7 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.28 - 7.12 (m, 3H), 6.98 (d, J J = 7.3 Hz, 1H), 6.81 (d, J J = 7.7 Hz, 1H), 6.68 (s, 1H), 5.67 (s, 1H), 5.56 (d, J J = 7.3 Hz,1H), 2.18 (s, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 156.9, 140.3, 137.2, 129.7, 129.3, 128.0, 127.6, 125.6, 125.0, 124.3, 123.8, 122.1, 110.4, 72.2, 52.3, 21.0; HRMS (ESI) Calcd. for C 16 H 13 NO4S [M + Na] + : 338.0457; found: 338.0461.

[0056] Compound 3m was prepared in this example: White solid, melting point: 162.1 - 162.7 ºC; yield 97%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 11H NMR (300 MHz, CDCl3) δ 7.65 (d, J J =7.7 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.26 - 7.14 (m, 3H), 6.68 (d, J J = 8.6 Hz, 1H),5.72 (d, J J = 9.8 Hz, 1H), 5.16 (s, 1H), 3.00 (d, J J = 9.7 Hz, 1H), 1.25 (s,9H); 13 13C NMR (75 MHz, CDCl3) δ 154.6, 147.1, 135.9, 129.8, 129.5, 128.4,127.9, 127.4, 125.5, 125.0, 121.6, 121.5, 109.6, 73.3, 53.1, 34.5, 31.5; HRMS(ESI) Calcd. for C 19 H 19 NO4S [M + Na] + : 380.0927; found: 380.0930.

[0057] Compound 3n was prepared in this example: white solid, melting point: 151.1 - 151.8 ºC; yield 96%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 1H NMR (300 MHz, DMSO - d 6) δ 7.62 (d, J J =7.6 Hz, 1H), 7.42 - 7.30 (m, 1H), 7.30 - 7.16 (m, 2H), 6.95 (d, J J = 7.3 Hz, 1H),6.89 (d, J J = 2.1 Hz, 1H), 6.78 (d, J J = 8.8 Hz, 1H), 6.75 - 6.66 (m, 1H), 5.66(s, 1H), 5.54 (d, J J = 7.3 Hz, 1H), 3.67 (s, 3H); 13 13C NMR (75 MHz, DMSO - d6) δ 155.6, 150.5, 137.2, 129.5, 129.3, 128.0, 127.8, 127.6, 125.6, 122.3, 115.7, 110.4, 110.3, 72.1, 55.7, 52.7; HRMS (ESI) Calcd. for C 16 H 13 NO5S [M + Na] + : 354.0407; found: 354.0411.

[0058] This example prepares compound 3o: white solid, melting point: 157.6 - 158.2 ºC; yield 96%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.62 (d, J J = 7.6 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.28 - 7.15 (m, 3H), 6.96 (d, J J = 7.1 Hz, 1H), 6.57 (dd, J J = 8.4, 2.3 Hz, 1H), 6.49 (d, J J = 2.2 Hz, 1H), 5.63 (s, 1H), 5.55 (d, J J = 7.1 Hz, 1H), 3.65 (s, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 161.2, 158.1, 137.2, 129.8, 129.3, 128.0, 127.6, 125.7, 125.6, 122.6, 118.2, 109.9, 95.9, 72.1, 55.5, 52.3; HRMS (ESI) Calcd. for C 16 H 13 NO5S [M + Na] + : 354.0407; found: 354.0392.

[0059] This example prepares compound 3p: white solid, melting point: 170.5 - 171.3 ºC; yield 98%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 11H NMR (300 MHz, DMSO- d 6) δ 7.63 (d, J J =7.6 Hz, 1H), 7.39-7.30 (m, 1H), 7.28-7.15 (m, 2H), 7.02-6.88 (m, 3H), 6.84(d, J J = 7.6 Hz, 1H), 5.72 (s, 1H), 5.56 (d, J J = 7.3 Hz, 1H), 3.69 (s, 3H); 13 13C NMR (75 MHz, DMSO- d 6) δ 144.9, 143.3, 137.1, 129.6, 129.2, 128.1, 128.0,127.7, 125.7, 124.3, 122.0, 116.7, 113.2, 72.1, 55.6, 52.8; HRMS (ESI) Calcd.for C 16 14 13 H + 15

[0060] This example prepared compound 3q: yellow solid, melting point: 169.8-170.4 ºC; yield 93%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 1H NMR (300 MHz, DMSO- d 6) δ 7.65 (d, J J =7.6 Hz, 1H), 7.34 (t, J J = 7.4 Hz, 1H), 7.27-7.14 (m, 2H), 7.04 (d, J J = 7.1Hz, 1H), 6.98-6.87 (m, 2H), 6.84-6.74 (m, 1H), 5.72 (s, 1H), 5.59 (d, J J = 7.2Hz, 1H), 4.02-3.86 (m, 2H), 1.21 (t, J J = 6.9 Hz, 3H); 13 13C NMR (75 MHz, DMSO- d 6) δ 145.1, 142.6, 137.2, 129.6, 129.1, 128.1, 128.0, 127.7, 125.7, 124.3, 122.1, 116.8, 114.6, 72.1, 64.2, 52.7, 14.5; HRMS (ESI) Calcd. for C 17 H 15 NO5S[M + Na] + : 368.0563; found: 368.0566.

[0061] This example prepares compound 3r: white solid, melting point: 116.7 - 117.3 ºC; yield 94%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.65 (d, J J =7.7 Hz, 1H), 7.40 - 7.30 (m, 1H), 7.27 - 7.21 (m, 2H), 7.04 - 6.98 (m, 1H), 6.81(d, J J = 1.5 Hz, 1H), 5.70 (d, J J = 10.0 Hz, 1H), 5.15 (s, 1H), 3.75 (s, 3H), 3.19 (d, J J = 10.3 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 144.5, 135.6, 129.9, 128.8, 128.7, 128.5, 128.3, 125.2, 121.2, 119.3, 116.7, 116.0, 76.6, 73.2, 56.4, 52.9; HRMS (ESI) Calcd. for C 16 H 12 BrNO5S [M + Na] + : 431.9512; found: 431.9527.

[0062] This example prepares compound 3s: yellow solid, melting point: 208.8 - 209.8 ºC; yield 97%; 11.6:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 8.02 (d, J J =8.3 Hz, 1H), 7.91 (d, 11.6:1 J J = 8.3 Hz, 1H), 7.82 (d, J J = 8.9 Hz, 1H), 7.67(d, J J = 7.8 Hz, 1H), 7.64-7.58 (m, 1H), 7.44 (t, J J = 7.3 Hz, 1H), 7.39-7.31(m, 1H), 7.18 (d, J J = 8.9 Hz, 1H), 7.12 (d, J J = 3.9 Hz, 2H), 7.07 (d, J J = 7.2Hz, 1H), 6.24 (s, 1H), 5.68 (d, J J = 7.3 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ154.4, 137.3, 131.7, 130.2, 129.6, 129.4, 128.9, 128.5, 127.9, 127.6, 127.5,125.5, 124.5, 123.3, 122.4, 118.1, 111.3, 72.2, 52.5; HRMS (ESI) Calcd. forC 19 H 13 NO4S [M + Na] + : 374.0457; found: 374.0466.

[0063] This example prepared compound 3t: white solid, melting point: 148.3-149.0 ºC; yield 98%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.63 (d, J J =7.7 Hz, 1H), 7.41 (d, J J = 7.5 Hz, 1H), 7.38-7.30 (m, 1H), 7.21-7.08 (m, 3H),7.05 (d, J J = 7.2 Hz, 1H), 6.99 (t, J= 7.5 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.68 (d, J = 7.2 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ 155.7, 137.7, 130.9, 130.3, 129.6, 128.7, 128.1, 128.0, 125.9, 125.6, 123.9, 123.5, 109.7, 72.0, 59.6, 24.2; HRMS (ESI) Calcd. for C 16 H 13 NO4S [M + Na] + : 338.0457; found: 338.0462.

[0064] In this example, compound 3u was prepared: a white solid, melting point: 162.3 - 162.9 ºC; yield 96%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.67 (d, J = 7.6 Hz, 1H), 7.49 - 7.31 (m, 5H), 7.24 - 7.11 (m, 4H), 7.08 - 6.97 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 5.91 (d, J = 7.3 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ 157.1, 137.4, 136.5, 130.6, 129.7, 129.6, 129.5, 129.2, 128.8, 128.4, 128.2, 128.2, 126.7, 126.0, 125.8, 123.5, 109.7, 72.3, 69.9; HRMS (ESI) Calcd. for C 21 H 15 NO4S [M + Na] + : 400.0614; found: 400.0602.

[0065] Compound 3a’ was prepared in this example: white solid, melting point: 153.8 - 154.5 ºC; yield 95%; 3.4:1 dr. The results of nuclear magnetic resonance (as Figure 3 and Figure 4 shown) and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.32 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 8.1 Hz, 1H), 7.09 (m, J = 7.3Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 5.41 (s, 1H), 5.26 - 5.12 (m, 1H), 3.16 (dd, J = 11.1, 6.1 Hz, 1H), 2.86 (t, J = 11.0 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ157.0, 129.8, 128.8, 125.0, 123.7, 121.9, 110.4, 79.1, 51.9, 33.9; HRMS (ESI)Calcd. for C 10 H9NO4S [M + Na] + : 262.0144; found: 262.0155.

[0066] Compound 3b’ was prepared in this example: white solid, melting point: 111.8 - 112.5 ºC; yield 93%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.15 - 7.00 (m,3H), 5.38 - 5.26 (m, 1H), 5.18 (s, 1H), 3.25 (dd, J = 11.3, 6.0 Hz, 1H), 3.04(t, J = 11.0 Hz, 1H), 2.85 (d, J = 10.6 Hz, 1H); 13 C NMR (75 MHz, CDCl3)δ146.7 ( J= 249.8 Hz), 143.5 ( J = 11.3 Hz), 131.2, 125.3 ( J = 5.3 Hz), 121.0,119.8 ( J = 3.8 Hz), 117.4 ( J = 16.5 Hz), 79.6, 52.9, 35.3; HRMS (ESI) Calcd.for C 10 H8FNO4S [M + Na] + : 280.0050; found: 280.0044.

[0067] In this example, compound 3c’ was prepared: white solid, melting point: 113.8 - 114.2 ºC; yield 94%; 1:1 dr; The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.32 - 7.20 (m,2H), 7.03 (d, J = 8.1 Hz, 1H), 5.40 - 5.28 (m, 1H), 5.18 (s, 1H), 3.23 (dd, J =11.4, 6.0 Hz, 1H), 3.19 - 3.08 (m, 1H), 2.79 (d, J = 9.8 Hz, 1H); 13 C NMR (75MHz, CDCl3) δ 157.3, 131.4, 130.7, 126.4, 124.4, 120.3, 109.3, 79.5, 52.3,34.9; HRMS (ESI) Calcd. for C 10 H8ClNO4S [M + Na] + : 295.9755; found: 295.9748.

[0068] In this example, compound 3d’ was prepared: white solid, melting point: 151.8 - 152.2 ºC; yield 96%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.26 - 7.22 (m,1H), 7.16 (d, J= 7.5 Hz, 2H), 5.56 (s, 1H), 4.89 - 4.81 (m, 1H), 3.31 (dd, J = 12.7, 3.3 Hz, 1H), 3.11 (dd, J = 12.7, 2.4 Hz, 1H), 3.05 (d, J = 10.4 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 156.9, 127.4, 127.0, 126.0, 123.3, 114.3, 78.3, 51.7, 38.8, 38.6; HRMS (ESI) Calcd. for C 10 H8BrNO4S [M + Na] + : 339.9250; found: 339.9236.

[0069] This example prepares compound 3e’: a white solid, melting point: 150.3 - 150.9 ºC; yield 93%; 1.2:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.16 (d, J = 7.7 Hz, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 5.58 (s, 1H), 4.87 - 4.78 (m, 1H), 3.30 (dd, J = 12.7, 3.3 Hz, 1H), 3.20 - 3.14 (m, 1H), 3.09 (dd, J = 12.8, 2.4 Hz, 1H), 2.35 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 156.6, 140.9, 127.0, 124.9, 124.4, 123.6, 111.1, 78.4, 52.0, 38.7, 21.6; HRMS (ESI) Calcd. for C 11 H 11 NO4S[M + Na] + : 276.0301; found: 276.0291.

[0070] This example prepares compound 3f’: white solid, melting point: 127.8 - 128.6 ºC; yield 92%; 10:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.02 (t, J =7.8 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 5.38 - 5.23(m, 1H), 5.15 (s, 1H), 4.30 - 4.10 (m, 2H), 3.21 (dd, J = 11.3, 6.0 Hz, 1H),3.09 - 2.94 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 145.4,143.7, 129.2, 125.1, 120.7, 116.0, 114.8, 79.8, 65.1, 53.3, 35.3, 14.8; HRMS(ESI) Calcd. for C 12 H 13 NO5S [M + Na] + : 306.0407; found: 306.0397.

[0071] This example prepares compound 3g’: white solid, melting point: 182.6 - 183.0 ºC; yield 96%; 4.3:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.23 - 7.16(m, 2H), 6.70 (d, J = 5.3 Hz, 1H), 5.73 (s, 1H), 4.78 - 4.69 (m, 1H), 3.85 (s,3H), 3.27 (dd, J = 12.2, 4.3 Hz, 1H), 3.08 (dd, J = 12.2, 4.8 Hz, 1H); 13 C NMR(75 MHz, DMSO- d6) δ 144.6, 130.5, 127.5, 122.1, 119.3, 116.2, 115.3, 78.5, 56.4, 52.0, 38.1; HRMS (ESI) Calcd. for C 11 H 10 BrNO5S [M + Na] + : 369.9355; found: 369.9337.

[0072] This example prepares compound 3h’: white solid, melting point: 188.0 - 188.6 ºC; yield 92%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 7.99 (d, J =8.7 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.53 - 7.42 (m, 2H), 6.56 (d, J = 7.3 Hz, 1H), 5.94 (s, 1H), 5.39 - 5.20 (m, 1H), 3.21 (dd, J =11.1, 5.9 Hz, 1H), 2.91 (t, J = 11.1 Hz, 1H); 13 C NMR (75 MHz, DMSO- d 6) δ154.7, 131.3, 130.3, 129.0, 128.4, 127.8, 124.7, 123.1, 122.5, 120.7, 111.7, 79.6, 51.8, 33.9; HRMS (ESI) Calcd. for C 14 H 11 NO4S [M + Na] + : 312.0301; found: 312.0289. Example

[0073] Preparation of compound 4:

[0074] 2-Nitrobenzofuran 1a (0.1 mmol) and DABCO (1 mg, 0.01 mmol) (as base A) were successively added to a reaction tube, followed by the addition of o-mercaptobenzaldehyde 2a (0.12 mmol). Using toluene (1 mL) as the solvent, the mixture was stirred at room temperature for 10 min. After the reaction was complete, DBU (45.9 mg, 0.3 mmol) (as base B) was added and the reaction was carried out at room temperature for 24 h. After TLC detection showed that the reaction was basically complete, the product was concentrated, dissolved in a small amount of dichloromethane, and then loaded onto a silica gel column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 10:1) to obtain compound 4a as a white solid, melting point: 219.5 - 220.3 o °C; yield 92%. The results of nuclear magnetic resonance (as shown in Figure 5 and 6 ) and high-resolution mass spectrometry tests are as follows: 1 1H NMR (300 MHz, CDCl3) δ 8.75 (dd, J J = 8.1, 1.4 Hz, 1H), 7.80 (d, J J = 7.9 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.69 - 7.54 (m, 3H), 7.45 - 7.38 (m, 1H); 13 13C NMR (75 MHz, CDCl3) δ 170.1, 155.2, 144.6, 135.6, 133.2, 131.4, 130.1, 129.2, 127.0, 126.8, 125.5, 124.4, 124.0, 121.2, 113.2; HRMS (ESI) Calcd. for C 15 18H8O2S [M + Na] + : 275.0137; found: 275.0136. The X-ray single crystal diffraction pattern is shown in Figure 8 .

[0075] Comparative example:

[0076] (1) Based on the above preparation of 4a, in this comparative example, DABCO (11.2 mg, 0.1 mmol) was selected as base B, and DABCO was added at the beginning of the reaction together with the other raw materials, and the other conditions remained unchanged. The yield was 0;

[0077] (2) This comparative example is based on the above Preparation 4a. Base B is selected as DBU (15.2 mg, 0.1 mmol), and DBU is added at once with the remaining raw materials at the beginning of the reaction, and the other conditions remain unchanged. The yield is 35%;

[0078] (3) This comparative example is based on the above Preparation 4a. Base B is selected as DBU (30.4 mg, 0.2 mmol), and DBU is added at once with the remaining raw materials at the beginning of the reaction, and the other conditions remain unchanged. The yield is 52%;

[0079] (4) This comparative example is based on the above Preparation 4a. Base B is selected as DBU (30.4 mg, 0.2 mmol), and DBU is added at once with the remaining raw materials at the beginning of the reaction. The reaction time is 12 h, and the other conditions remain unchanged. The yield is 52%.

[0080] (5) This comparative example is based on the above Preparation 4a. DBU (7.6 mg, 0.05 mmol) is added (as Base B), and the other conditions remain unchanged. The yield is 52%;

[0081] (6) This comparative example is based on the above Preparation 4a. DBU (30.4 mg, 0.2 mmol) is added as Base B), and the other conditions remain unchanged. The yield is 83%;

[0082] The preparation methods of compounds 4b - 4r are the same as that of compound 4a. The feeding ratio is the same as that of compound 4a. The reaction time and yield results are as follows:

[0083]

[0084]

[0085] In this example, compound 4b was prepared: white solid, melting point: 289.7 - 290.5 ºC; yield 89%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3)δ 8.77 (dd, J = 8.0, 1.6 Hz,1H), 7.80 (d, J = 7.4 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.66 - 7.58 (m, 1H), 7.49(dd, J = 7.7, 2.6 Hz, 1H), 7.41 - 7.32 (m, 1H); 13 C NMR (75 MHz, CDCl3)13 13C NMR (75 MHz, CDCl3) δ 170.2, 159.4 ( J J = 241.5 Hz), 151.5, 145.9, 135.5, 133.1, 131.7, 129.3, 127.1, 127.0, 125.2, 125.0, 118.3 ( J J = 26.3 Hz), 114.4 ( J J = 9.0 Hz), 106.8 ( J J = 25.5 Hz); HRMS (ESI) Calcd. for C 15 H7FO2S [M + Na] + : 293.0043; found: 293.0035.

[0086] Compound 4c was prepared in this example: white solid, melting point: 259.6 - 260.2 ºC; yield 93%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 1H NMR (600 MHz, CDCl3) δ 8.82 - 8.73 (m, 1H), 7.79 (d, J J = 8.1 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.66 - 7.58 (m, 2H), 7.42 - 7.32 (m, 2H); 13 13C NMR (151 MHz, CDCl3) δ 170.4, 149.0 ( J J = 255.2 Hz), 145.5, 143.2 ( J J = 13.6 Hz), 135.8, 133.6, 132.0, 129.7, 128.1, 127.4 ( J J = 3.0 Hz), 125.9, 125.8, 125.2 ( J J = 4.5 Hz), 117.1 ( J J = 4.5 Hz), 116.4 ( J J = 15.1 Hz); HRMS (ESI) Calcd. for C 15 H7FO2S [M + Na] + : 293.0043; found: 293.0053.

[0087] Compound 4d was prepared in this example: white solid, melting point: 272.4 - 272.9 ºC; yield 92%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.81 - 8.75 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.68 - 7.60 (m, 2H), 7.55 (t, J = 8.1 Hz,1H), 7.41 (d, J = 7.8 Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 170.5, 156.1, 145.3,136.9, 133.2, 131.9, 130.7, 129.3, 128.7, 127.5, 127.4, 125.5, 124.6, 123.9,112.1; HRMS (ESI) Calcd. for C 15 H7ClO2S [M + Na] + : 308.9747; found: 308.9746.

[0088] Compound 4e was prepared in this example: white solid, melting point: 277.2 - 280.0 ºC; yield 90%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.77 (d, J = 8.1 Hz, 1H),7.85 - 7.77 (m, 2H), 7.73 - 7.67 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.58 (d, J =8.7 Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 170.5, 154.0, 145.9, 135.9, 133.5,132.1, 130.8, 130.2, 129.7, 127.49, 127.5, 126.1, 124.9, 121.1, 114.8; HRMS(ESI) Calcd. for C 15 H7ClO2S [M + Na] +: 308.9747; found: 308.9760.

[0089] In this example, compound 4f was prepared: white solid, melting point: 267.2 - 267.9 ºC; yield 92%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.77 (dd, J J = 8.1, 1.2 Hz, 1H), 7.97 (d, J J = 1.6 Hz, 1H), 7.79 (d, J J = 7.9 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.67 - 7.58 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 170.14, 154.00, 145.36, 135.48, 133.13, 133.06, 131.70, 129.30, 127.12, 126.69, 126.29, 124.39, 123.87, 117.09, 114.80; HRMS (ESI) Calcd. for C 15 H7BrO2S [M + Na] + : 352.9242; found: 352.9244.

[0090] In this example, compound 4g was prepared: white solid, melting point: 276.8 - 277.3 ºC; yield 89%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.77 (dd, J J = 7.9, 1.3 Hz, 1H), 7.92 (d, J J = 1.2 Hz, 1H), 7.79 (d, J J = 8.1 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.66 - 7.54 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 170.1, 155.4, 144.9, 137.1, 135.4, 133.2, 131.6, 129.3, 127.8, 127.1, 125.3, 123.9, 123.5, 122.1, 116.7; HRMS (ESI) Calcd. for C 15H7BrO2S [M + Na] + : 352.9242; found: 352.9248.

[0091] This example prepared compound 4h: a white solid, melting point: 228.2 - 228.8 ºC; yield 87%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.79 - 8.70 (m, 1H), 7.84 - 7.71 (m, 3H), 7.71 - 7.64 (m, 1H), 7.63 - 7.54 (m, 1H), 7.30 (t, J = 7.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 169.8, 152.6, 144.8, 135.4, 133.3, 132.9, 131.6,129.3, 127.1, 125.7, 125.6, 125.2, 120.2, 106.0; HRMS (ESI) Calcd. forC 15 H7BrO2S [M + Na] + : 352.9242; found: 352.9241.

[0092] This example prepared compound 4j: a yellow solid, melting point: 297.3 - 297.8 ºC; yield 91%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (600 MHz, CDCl3)δ 8.86 - 8.74 (m, 2H), 8.55 (dd, J = 9.2, 2.3 Hz, 1H), 7.92 - 7.82 (m, 2H), 7.78 - 7.73 (m, 1H), 7.67 (t, J = 7.5Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 170.4, 158.1, 147.1, 145.0, 135.6, 133.5,132.5, 129.8, 127.9, 127.65, 126.0, 125.5, 125.4, 118.5, 114.3 ; HRMS (ESI)Calcd. for C 15 H7NO4S [M + Na] +: 319.9988; found: 319.9993.

[0093] This example prepares compound 4k: a white solid, melting point: 223.7 - 224.5 ºC; yield 83%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.73 (dd, J J =8.0, 1.2 Hz, 1H), 7.78 - 7.68 (m, 1H), 7.67 - 7.60 (m, 1H), 7.60 - 7.50 (m, 3H),7.41 - 7.33 (m, 1H); 13 C NMR (75 MHz, CDCl3) δ 170.0, 153.6, 144.6, 135.6,133.8, 133.1, 131.6, 131.2, 129.1, 127.0, 126.7, 125.2, 124.3, 120.6, 112.7,21.3; HRMS (ESI) Calcd. for C 16 H 10 O2S [M + Na] + : 289.0294; found: 289.0289.

[0094] This example prepares compound 4l: a white solid, melting point: 269.7 - 270.3 ºC; yield 80%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3)δ 8.76 (d, J J = 7.9 Hz, 1H),7.76 (d, J J = 7.5 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.62 - 7.54 (m, 1H), 7.52 (s, 1H),7.25 (d, J J = 3.5 Hz, 1H), 2.55 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 170.0,155.8, 144.3, 141.4, 135.6, 133.2, 131.2, 129.1, 127.0, 126.8, 125.8, 125.7,121.9, 120.6, 113.1, 22.3; HRMS (ESI) Calcd. for C16 H 10 O2S [M + Na] + : 289.0294; found: 289.0296.

[0095] This example prepares compound 4m: white solid, melting point: 176.8 - 177.2 ºC; yield 82%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.83 - 8.72 (m, 1H), 7.84 - 7.73 (m, 2H), 7.73 - 7.62 (m, 3H), 7.62 - 7.54 (m, 1H), 1.43 (s, 9H); 13 C NMR (75MHz, CDCl3) δ 170.1, 153.6, 147.5, 144.8, 135.6, 133.2, 131.3, 129.1, 128.6,127.0, 126.8, 125.8, 124.1, 116.9, 112.6, 35.0, 31.6; HRMS (ESI) Calcd. forC 19 H 16 O2S [M + Na] + : 331.0763; found: 331.0762

[0096] This example prepares compound 4n: white solid, melting point: 198.8 - 199.3 ºC; yield 88%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.75 (d, J =7.9 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 - 7.53 (m, 3H), 7.24 - 7.15 (m, 1H),7.13 (d, J = 2.6 Hz, 1H), 3.90 (s, 3H); 1313C NMR (75 MHz, CDCl3) δ 170.1, 156.7, 150.3, 145.2, 135.6, 133.2, 131.3, 129.2, 127.0, 126.8, 125.2, 124.8, 120.0, 114.0, 102.1, 56.0; HRMS (ESI) Calcd. for C 16 H 10 O3S [M + Na] + : 305.0209; found: 305.0200.

[0097] Compound 4o was prepared in this example: white solid, melting point: 208.8 - 209.8 ºC; yield 97%; >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 1H NMR (300 MHz, CDCl3) δ 8.73 (dd, J J = 8.1, 1.3 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.66 - 7.58 (m, 1H), 7.57 - 7.50 (m, 1H), 7.32 - 7.26 (m, 2H), 7.03 (dd, J J = 6.6, 2.4 Hz, 1H), 4.04 (s, 3H); 13 13C NMR (75 MHz, CDCl3) δ 169.8, 146.4, 145.0, 144.5, 135.5, 133.2, 131.2, 129.1, 126.9, 126.7, 125.8, 125.5, 124.8, 112.5, 111.5, 56.3; HRMS (ESI) Calcd. for C 22 H 19 N2O6 [M + Na] + : 407.1238; found: 407.1228.

[0098] Compound 4p was prepared in this example: white solid, melting point: 185.8 - 186.4 ºC; yield 93%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 1H NMR (300 MHz, CDCl3) δ 8.76 (dd, J= 8.1, 1.2 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.69 - 7.61 (m, 1H), 7.60 - 7.52 (m, 1H), 7.33 - 7.25 (m, 2H), 7.05 (dd, J = 7.2, 1.8 Hz, 1H), 4.31 (q, J = 7.0 Hz, 2H), 1.54 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 169.9, 145.8, 145.2, 144.5, 135.6, 133.2, 131.3, 129.2, 127.0, 126.7, 125.9, 125.7, 124.8, 112.6, 112.4, 65.0, 14.8; HRMS (ESI) Calcd. for C 17 H 12 O3S [M + Na] + : 319.0399; found: 319.0407.

[0099] This example prepares compound 4q: white solid, melting point: 279.8 - 280.2 ºC; yield 88%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.77 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.18 (d, J = 1.4 Hz, 1H), 4.07 (s, 3H); 13 C NMR (151 MHz, CDCl3 + CD3OD) δ 170.5, 147.2, 145.4, 144.5, 136.0, 133.3, 132.1, 129.5, 127.5, 127.3, 125.5, 117.7, 115.6, 115.5, 56.9; HRMS (ESI) Calcd. for C16 H9BrO3S [M + Na] + : 382.9348; found: 382.9348.

[0100] In this example, compound 4r was prepared: a white solid, melting point: 283.3 - 283.8 ºC; yield 76%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, CDCl3) δ 8.79 (d, J J = 8.1 Hz, 1H), 8.30 (d, J J = 8.3 Hz, 1H), 8.01 (d, J J = 8.7 Hz, 2H), 7.82 (d, J J = 7.5 Hz, 2H), 7.78 - 7.67 (m, 2H), 7.65 - 7.56 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 169.5, 154.4, 136.0, 132.9, 131.9, 131.4, 130.6, 129.5, 129.1, 128.2, 127.8, 126.9, 126.9, 126.0, 125.7, 123.4, 118.8, 113.1; HRMS (ESI) Calcd. for C 19 H 10 O2S [M + Na] + : 325.0294; found: 325.0300.

[0101] The thiochromone compounds of formula (1) of the present invention have important biological activities. In vitro cytotoxicity tests on two tumor cell lines show that: the thiochromone compounds with the structure shown in formula (1) of this type have an inhibitory effect on the growth of tumor cells, have a good killing effect on human prostate (PC-3) tumor cells and human lung cancer cells A549, and may be developed into new anti-tumor drugs or intermediates for anti-tumor drugs. It must be noted that the pharmacological examples of the present invention are used to illustrate the present invention rather than limit the present invention. Simple improvements made according to the essence of the present invention all fall within the scope claimed by the present invention.

[0102] Pharmacological Example 1: Cytotoxicity of Compounds 4b, 4d, 4f, 4k, 4m, 4o, 4q and 4r against PC-3 Cells

[0103] PC-3 (human prostate cancer) cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 U / mL streptomycin. The cells were seeded into 96-well plates at a density of 4000 cells per well and cultured in a humidified incubator at 37 o °C with 5% CO2 for 24 hours.

[0104] Cell viability was determined by the modified MTT assay. After 24 hours of incubation, DMSO solutions of newly prepared compounds 4b, 4d, 4f, 4k, 4m, 4o, 4q, and 4r were added to each well at a series of concentration gradients, resulting in final compound concentrations of 6.25 μmol / L, 12.5 μmol / L, 25 μmol / L, 50 μmol / L, and 100 μmol / L. After 48 hours, 10 μL of MTT (5 mg / mL) in phosphate buffer was added to each well, and the plates were further incubated at 37 o °C for 4 hours. The plates were then centrifuged for 5 minutes to remove unreacted MTT, and 150 μL of DMSO was added to each well to dissolve the reduced MTT crystal formazan. The absorbance was measured at 490 nm using a microplate reader. The half-maximal inhibitory concentration (IC 50 50) values of compounds 4b, 4d, 4f, 4k, 4m, 4o, 4q, and 4r against A549 cells were analyzed using SPSS software. The IC 50 50 value of compound 4b against PC-3 tumor cells was 11.17 μmol / L; the IC 50 50 value of compound 4d against PC-3 tumor cells was 9.43 μmol / L; the IC 50 50 value of compound 4f against PC-3 tumor cells was 28.58 μmol / L; the IC 50 50 value of compound 4k against PC-3 tumor cells was 7.94 μmol / L; the IC 50 50 value of compound 4m against PC-3 tumor cells was 27.68 μmol / L; the IC 50 50 value of compound 4o against PC-3 tumor cells was 25.05 μmol / L; the IC 50 50 value of compound 4q against PC-3 tumor cells was 27.39 μmol / L; the IC 50 50 value of compound 4r against PC-3 tumor cells was 32.20 μmol / L; while the IC 50 50 value of the positive control cisplatin against PC-3 tumor cells was 25.37 μmol / L.

[0105] Experimental conclusion: PC-3 cells are an effective tool and evaluation index for testing the cytotoxicity of compounds against tumor cells. This experiment shows that the thiochromone compounds represented by formula (1) have strong cytotoxicity against PC-3 cells, which is at the same order of magnitude as cisplatin, the first-line drug for tumor treatment, or has better activity than cisplatin, and may be developed into new anti-tumor drugs.

[0106] Pharmacological Example 2: Cytotoxicity of Compounds 4b, 4d, 4f, 4k, 4m, 4o, 4q and 4r against A549 Cells

[0107] A549 (human non-small cell lung cancer) cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 U / mL streptomycin. The cells were seeded into 96-well plates at a concentration of 4000 cells per well and cultured in an incubator with 5% CO2 humidified air at 37 °C for 24 hours.

[0108] The cell viability was determined by the modified MTT method. The specific method was referred to Pharmacological Example 1. The IC 50 of compound 4b against A549 tumor cells was 17.52 μmol / L; the IC 50 of compound 4d against A549 tumor cells was 12.33 μmol / L; the IC 50 of compound 4f against A549 tumor cells was 28.68 μmol / L; the IC 50 of compound 4k against A549 tumor cells was 9.52 μmol / L; the IC 50 of compound 4m against A549 tumor cells was 15.65 μmol / L; the IC 50 of compound 4o against A549 tumor cells was 8.59 μmol / L; the IC 50 of compound 4q against A549 tumor cells was 22.36 μmol / L; the IC 50 of compound 4r against A549 tumor cells was 32.73 μmol / L; while the IC 50 of the positive control cisplatin against A549 tumor cells was 23.35 μmol / L.

[0109] Experimental conclusion: A549 cells are an effective tool and evaluation index for testing the cytotoxicity of compounds against tumor cells. This experiment shows that the thiochromone compounds represented by formula (1) have strong cytotoxicity against A549 cells, which is at the same order of magnitude as cisplatin, the first-line drug for tumor treatment, or has better activity than cisplatin, and may be developed into new anti-tumor drugs.

[0110] As can be seen from the above pharmacological examples, these thiochromone compounds show certain cytotoxicity against these two tumor cell lines. It can be seen that these compounds have the potential to be developed into anti-tumor drugs or intermediates for the prevention and treatment of tumor drugs, and are worthy of in-depth study.

[0111] Derivatization of the product of the dearomatization [4+2] cycloaddition / elimination / oxidation cascade reaction of nitroheteroarenes with o-mercaptobenzaldehyde.

[0112] The preparation method, reaction yield, etc. of compound 5a are shown in Table 4. However, it should be emphasized that the examples are intended to illustrate rather than limit the scope of the present invention. The compounds of the present invention are not limited to the content shown in Table 4.

[0113] In this example, compound 5a was prepared as follows: m-chloroperbenzoic acid (0.30 mmol), compound 4a (0.1 mmol), and dichloromethane solution (1.0 mL) were successively added to a reaction tube, and the mixture was stirred at room temperature for 8 h. TLC detection showed that the reaction was basically complete. After concentrating the reaction solution, it was loaded onto a column chromatography (eluent: V (petroleum ether): V (ethyl acetate) = 5:1~1:1) for purification to obtain compound 5a as a white solid, melting point: 265.3-265.7 o °C; yield 91%. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (300 MHz, DMSO- d 6) δ 9.58 (d, J J = 7.9 Hz, 1H), 8.61 (d, J J = 7.9 Hz, 1H), 8.53 (d, J J = 8.8 Hz, 1H), 8.03 (d, J J = 6.5 Hz, 1H), 7.92-7.79 (m, 2H), 7.71-7.61 (m, 3H), 7.53 (t, J J = 7.6 Hz, 1H), 7.00 (s, 2H). 13 C NMR (75 MHz, DMSO- d 6) δ155.9, 142.4, 141.7, 132.4, 129.0, 128.3, 127.9, 126.7, 126.1, 125.4, 124.2, 123.8, 123.7, 123.4, 122.2, 122.0, 120.2, 119.3, 112.3, 83.8; HRMS (ESI-TOF) calcd. for C 15H8O4S [M + H] + 284.2850; found: 284.2034.

[0114] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of thiochromone compounds in the preparation of a medicament for treating human prostate cancer and / or human lung cancer, characterized in that: The thiochromone compounds have structures shown in the following formulas 4k, 4m, 4o, 4q, and 4r: 。

Images