N-Aryl-polycyclo[C]-2-pyridone derivatives, synthesis methods and their applications

Abstract

The present invention discloses a class of N-aryl-polycyclic-fused-[c]-2-pyridone derivatives, a synthesis method thereof and an application thereof. The present invention provides a class of novel compounds with anti-fibrotic biological activity, namely N-aryl-polycyclic-fused-[c]-2-pyridone derivatives. The compounds have novel structures, simple and easy synthetic operations, inexpensive and easily available raw materials, mild reaction conditions, and good compatibility with various substituents. At the same time, the anti-fibrotic biological activity of the N-aryl-polycyclic-fused-[c]-2-pyridone derivative compounds is determined by the MTT method, with pirfenidone as a positive control. The results show that the vast majority of such compounds have better anti-fibrotic activity than pirfenidone.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis and preparation of organic compounds, and particularly relates to N-aryl-polycyclo[C]-2-pyridone derivatives, a synthesis method thereof, and applications thereof. Background Art

[0002] Fibrotic diseases are diseases that can occur in multiple organs. The pathogenesis thereof has not been known to scientists yet. However, in the process of the occurrence of fibrotic reactions in the whole organ, the main manifestations are: necrosis of parenchymal cells of tissues caused by factors such as inflammation and repeated injuries, excessive accumulation of extracellular matrix (ECM), resulting in the generation of permanent scars and organ failure, and ultimately leading to death. It is common in organ diseases such as liver cancer, kidney disease, idiopathic pulmonary fibrosis, and heart failure. At present, the incidence of this disease shows an increasing trend year by year, and it has a great impact on the quality of life of patients. Pirfenidone is an orally administered small molecule drug of pyridone derivative type, and is approved by the European Union and the US FDA for the treatment of mild to moderate idiopathic fibrotic diseases. It has anti-inflammatory, antioxidant, and broad-spectrum anti-fibrotic effects. Its defect is that the drug efficacy is low, high doses need to be taken, and it is prone to cause adverse reactions in the gastrointestinal tract and skin, with large side effects, and still cannot meet the needs of curing patients. Based on this, by modifying and improving the structure of pirfenidone, new derivative compounds that are more effective for fibrotic diseases are prepared, which have potential practical application value. Summary of the Invention

[0003] In order to solve the above technical problems, the present invention provides N-aryl-polycyclo[C]-2-pyridone derivatives, a synthesis method thereof, and applications thereof. The present invention modifies the ethyl group at the 5th position on the pyridine ring, and introduces groups such as cyano group, carboxyl group, ester group, amide group, etc., so that this type of compound has better anti-fibrotic biological activity than similar compounds.

[0004] The specific technical solution of the present invention is as follows:

[0005] The N-aryl-polycyclo[C]-2-pyridone derivative has the following general chemical formula as shown in the following general formula (Ⅲ):

[0006]

[0007] Among them, ring A is selected from one of a five-membered ring, a six-membered ring, and a seven-membered ring; R 1 is -CN or R x ; R 2 is selected from one of methoxy group, halogen atom, methyl group, halomethyl group, and hydrogen; R x is selected from -CONHR 3 , -COOR 3 ; R 3Selected from one of phenyl, mono-substituted aryl, multi-substituted aryl, and hydrogen.

[0008] As a preference of the above technical solution of the present invention, the said R 3 group is selected from one of hydrogen, p-chlorobenzyl, phenyl, and o-iodophenyl.

[0009] As a preference of the above technical solution of the present invention, the said halomethyl is trifluoromethyl, and the said halogen atom is chlorine.

[0010] When R 1 is -CN, the synthesis method of the N-aryl-polycyclo[C]-2-pyridone derivative comprises the following steps:

[0011] Dissolve the compound of formula (I), a cyanating reagent, and an additive in a first organic solvent to form a first reaction system, and react to obtain the target compound of formula (III 1 ); the said additive is a Lewis base;

[0012]

[0013] wherein, X is a halogen atom.

[0014] In the above technical solution, usually after the reaction is completed, it also includes the post-treatment of the reaction solution, including the following steps: rotary evaporation and concentration of the reaction solution to remove most of the first organic solvent, adding an aqueous NaOH solution at room temperature to remove hydrocyanic acid generated by the reaction of the excessive cyanating reagent with water, extracting with CH2Cl2 for multiple times, then washing with saturated brine in sequence, drying with anhydrous magnesium sulfate, and subjecting to silica gel column chromatography, the developing agent is: V(petroleum ether)∶V(ethyl acetate)=2∶1, collecting the eluate containing the target compound, rotary evaporation and concentration to remove the solvent and drying, thus obtaining the product.

[0015] As a preference of the above technical solution of the present invention, the said cyanating reagent is trimethylsilyl cyanide (TMSCN).

[0016] As a preference of the above technical solution of the present invention, the said first organic solvent is selected from one of acetonitrile, acetone, tetrahydrofuran, and dimethyl sulfoxide; as a preference, the said first organic solvent is acetonitrile.

[0017] As a preference of the above technical solution, the said additive is selected from one of cesium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and lithium hydroxide monohydrate; as a preference, potassium carbonate is selected.

[0018] As a preference of the above technical solution, the reaction is carried out at the reflux temperature, and the reaction time is 10 - 24 h.

[0019] When R 1 is R x , and Rx When R is -COOH, the synthesis method of N-aryl-polycyclo[C]-2-pyridone derivatives comprises the following steps:

[0020] Adding a 5-(N-aryl-polycyclo[C]-2-pyridone) propionitrile derivative of formula (III 1 ) and a strong alkaline aqueous solution into a second organic solvent to form a second reaction system, and reacting to obtain a 5-(N-aryl-polycyclo[C]-2-pyridone) propionic acid derivative of formula (III 2 );

[0021]

[0022] As a preference of the above technical solution of the present invention, the second organic solvent is miscible with water; preferably ethanol.

[0023] As a preference of the above technical solution of the present invention, the strong alkaline aqueous solution is selected from the aqueous solutions of one or more of sodium hydroxide and potassium hydroxide.

[0024] When R 1 is R x , and R x is not -COOH, the synthesis method of N-aryl-polycyclo[C]-2-pyridone derivatives comprises the following steps:

[0025] Reacting a 5-(N-aryl-polycyclo[C]-2-pyridone) propionic acid derivative of formula (III 2 ) and an amine or alcohol compound in a basic third reaction system, and reacting to obtain an N-aryl-polycyclo[C]-2-pyridone derivative of formula (III 3 );

[0026]

[0027] As a preference of the above technical solution of the present invention, the third reaction system at least comprises a Lewis base, an organic solvent, a carbonyl activating reagent and a condensation reagent.

[0028] In the above technical solution, the organic solvent is preferably dichloromethane, the second Lewis base is selected from organic amine compounds such as DIPEA, the carbonyl activating reagent is preferably EDCI, and the condensation reagent is preferably HOBT.

[0029] The present invention also provides the application of N-aryl-polycyclo[C]-2-pyridone derivatives in the preparation of drugs for treating fibrotic diseases.

[0030] Determining the IC of N-aryl-polycyclo[C]-2-pyridone derivatives by MTT method 50Values, with pirfenidone as the positive control, the results showed that this class of compounds had better anti-fibrotic bioactivity than pirfenidone. Thus, it can be seen that the N-aryl-polycyclic-fused[C]-2-pyridone derivatives provided by the present invention have a broader application prospect in anti-fibrosis.

[0031] In summary, the beneficial effects of the present invention are as follows:

[0032] The present invention provides a new N-aryl-polycyclic-fused[C]-2-pyridone derivative, which has higher physiological activity against fibrotic lesions than existing drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 1H spectrum of Compound A1 1 1H spectrum;

[0034] Figure 2 13C spectrum of Compound A1 13 13C spectrum;

[0035] Figure 3 1H spectrum of Compound A3 1 1H spectrum;

[0036] Figure 4 13C spectrum of Compound A3 13 13C spectrum;

[0037] Figure 5 1H spectrum of Compound A9 1 1H spectrum;

[0038] Figure 6 13C spectrum of Compound A9 13 13C spectrum;

[0039] Figure 7 1H spectrum of Compound A 13 of 1 1H spectrum;

[0040] Figure 8 13C spectrum of Compound A 13 of 13 13C spectrum;

[0041] Figure 9 1H spectrum of Compound A 15 of 1 1H spectrum;

[0042] Figure 10 13C spectrum of Compound A 15 of 13 13C spectrum;

[0043] Figure 11 1H spectrum of Compound A 16 of 1 1H spectrum;

[0044] Figure 12 is compound A 16 of 13 C spectrum Detailed implementation mode

[0045] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0046] Example 1

[0047] In a 25 ml single-necked round-bottom flask, add substrate a (0.11 g, 0.3 mmol), TMSCN (1.8 equiv, 0.54 mmol), anhydrous acetonitrile (5 ml), potassium carbonate (1.8 equiv, 0.54 mmol), and stir at reflux temperature. Monitor the reaction process by thin layer chromatography (TLC). When the spot of substrate a disappears, the reaction is complete. After the reaction, rotary evaporate to remove the solvent anhydrous acetonitrile, wash with sodium hydroxide aqueous solution to remove potassium carbonate, extract with dichloromethane, wash with saturated brine, dry over anhydrous Mg2SO4, concentrate, and perform silica gel column chromatography. The eluent is: V(petroleum ether)∶V(ethyl acetate)=2∶1, to obtain yellow oil A1 with a yield of 73%. The 1 H spectrum 13 C spectrum is shown in Appendix Figure 1 、 2 , and the high-resolution data are as follows:

[0048] (A1) 1 H NMR(500MHz, CDCl3): δ7.54 - 7.52(m, 1H), 7.38 - 7.33(m, 3H), 6.93(s, 1H), 2.79 - 2.68(m, 2H), 2.59 - 2.53(m, 6H), 1.82 - 1.75(m, 4H);

[0049] 13 C NMR(125MHz, CDCl3): δ160.95, 146.19, 138.41, 132.02, 131.70, 130.33, 129.98, 129.30, 129.23, 127.75, 118.53, 114.95, 26.29, 25.10, 23.99, 21.71, 21.50, 18.16; HRMS(ESI+) calculated for C 18 H 17 ClN2O[M + Na] + 335.0922, found 335.0930.

[0050] Example 2:

[0051] The experimental operation process of this example is the same as that of Example 1, and the only difference is that the chlorine atom attached to the N-aryl of the selected substrate a is in the meta position. A white solid A2 was obtained by the reaction, with a yield of 72%. The 1 H, 13 high-resolution data of the C spectrum are as follows:

[0052] (A2) 1 H NMR(500MHz, CDCl3): δ7.43 - 7.37(m, 3H), 7.30 - 7.28(m, 1H), 7.08(s, 1H), 2.74(t, J = 7.20Hz, 2H), 2.60 - 2.51(m, 6H), 1.81 - 1.77(m, 4H);

[0053] 13 C NMR(125MHz, CDCl3): δ161.18, 146.03, 141.87, 134.63, 131.96, 130.16, 129.35, 128.43, 127.11, 124.90, 118.58, 115.23, 26.32, 25.18, 24.16, 21.75, 21.59, 18.34; HRMS(ESI+) calculated for C 18 H 17 ClN2O[M + Na] + 335.0922, found 335.0933.

[0054] Example 3:

[0055] The experimental operation process of this example is the same as that of Example 1, and the only difference is that the chlorine atom attached to the N-aryl of the selected substrate a is in the para position. A white solid A3 was obtained by the reaction, with a yield of 70%. The 1 H spectrum, 13 C spectrum are shown in Appendices Figure 3 、 4 , and the high-resolution data are as follows:

[0056] (A3) 1 H NMR(500MHz, CDCl3): δ7.44(d, J = 8.63Hz, 2H), 7.35(d, J = 8.67Hz, 2H), 7.09(s, 1H), 2.75(t, J = 7.10Hz, 2H), 2.61 - 2.57(m, 4H), 2.55 - 2.52(m, 2H), 1.82 - 1.78(m, 4H); 1313C NMR (125 MHz, CDCl3): δ 161.32, 145.94, 139.42, 134.03, 132.15, 129.38, 128.34, 127.97, 118.60, 115.15, 26.35, 25.21, 24.21, 21.79, 21.66, 18.43; HRMS (ESI+) calculated for C 18 H 17 ClN2O [M+Na] + 335.0922, found 335.0936.

[0057] Example 4:

[0058] The experimental operation process of this example is the same as that of Example 1, and the only difference is that the group connected to the N-aryl of the selected substrate a is a meta-methyl group. A white solid A4 was obtained by the reaction, and the yield was 80%. The 1 H, 13 high-resolution data of the 13C spectrum are as follows:

[0059] (A4) 1 1H NMR (500 MHz, CDCl3): δ 7.35 (t, J = 7.92 Hz, 1H), 7.21 - 7.15 (m, 3H), 7.10 (s, 1H), 2.74 (t, J = 7.13 Hz, 2H), 2.61 - 2.52 (m, 6H), 2.39 (s, 3H), 1.81 - 1.77 (m, 4H);

[0060] 13 13C NMR (125 MHz, CDCl3): δ 161.52, 145.64, 140.97, 139.21, 132.62, 129.20, 129.04, 129.00, 127.28, 123.55, 118.65, 114.75, 26.34, 25.28, 24.21, 21.86, 21.72, 21.29, 18.38; HRMS (ESI+) calculated for C 19 H 20 N2O [M+Na] + 315.1468, found 315.1480.

[0061] Example 5:

[0062] The experimental operation process of this example is the same as that of Example 1, and the only difference is that the group connected to the N-aryl of the selected substrate a is an ortho-methyl group. A light yellow solid A5 was obtained by the reaction, and the yield was 75%. The 1 H, 13The high-resolution data of the C spectrum are as follows:

[0063] (A5) 1 H NMR (500 MHz, CDCl3): δ 7.32 - 7.27 (m, 3H), 7.15 (d, J = 7.46 Hz, 1H), 6.96 (s, 1H), 2.74 - 2.65 (m, 2H), 2.60 - 2.53 (m, 6H), 2.14 (s, 3H), 1.81 - 1.75 (m, 4H);

[0064] 13 C NMR (125 MHz, CDCl3): δ 161.10, 145.73, 140.20, 135.13, 132.45, 130.86, 129.00, 128.70, 127.13, 126.85, 118.55, 114.61, 26.19, 25.05, 24.02, 21.73, 21.56, 18.17, 17.60; HRMS (ESI+) calculated for C 19 H 20 N2O [M+Na] + 315.1468, found 315.1482.

[0065] Example 6:

[0066] The experimental operation process of this example is the same as that of Example 5, and the only difference is that the polycyclic ring of the selected substrate a is a seven-membered ring. A white solid A6 was obtained by the reaction, and the yield was 50%. The 1 H, 13 The high-resolution data of the C spectrum are as follows:

[0067] (A6) 1 H NMR (500 MHz, CDCl3): δ 7.33 - 7.28 (m, 3H), 7.18 (d, J = 7.57 Hz, 1H), 6.97 (s, 1H), 3.02 - 2.88 (m, 2H), 2.79 - 2.68 (m, 4H), 2.57 - 2.47 (m, 2H), 2.15 (s, 3H), 1.94 - 1.88 (m, 2H), 1.69 - 1.59 (m, 4H);

[0068] 1313C NMR (125 MHz, CDCl3): δ 161.32, 152.35, 140.57, 135.08, 134.66, 133.62, 130.94, 128.77, 127.08, 126.92, 118.39, 114.13, 32.46, 29.85, 26.71, 26.26, 26.02, 26.01, 19.06, 17.59; HRMS (ESI+) calculated for C 20 H 22 N2O [M+Na] + 329.1624, found 329.1634.

[0069] Example 7:

[0070] The experimental operation process of this example is the same as that of Example 5, and the only difference is that the polycyclic ring of the selected substrate a is a five-membered ring. A brown solid A7 was obtained by the reaction, with a yield of 73%. The 1 H, 13 high-resolution data of the 13C spectrum are as follows:

[0071] (A7) 1 1H NMR (500 MHz, CDCl3): δ 7.33 - 7.27 (m, 3H), 7.17 (d, J = 7.19 Hz, 1H), 7.02 (s, 1H), 2.92 - 2.87 (m, 4H), 2.73 - 2.70 (m, 2H), 2.58 - 2.56 (m, 2H), 2.17 - 2.15 (m, 5H);

[0072] 13 13C NMR (125 MHz, CDCl3): δ 159.76, 154.03, 140.10, 135.25, 135.03, 133.64, 130.98, 128.87, 127.28, 126.95, 118.51, 113.37, 32.63, 30.45, 25.98, 23.18, 18.29, 17.64; HRMS (ESI+) calculated for C 18 H 18 N2O [M+Na] + 301.1311, found 301.1326.

[0073] Example 8:

[0074] The experimental operation process of this example is the same as that of Example 1, and the only difference is that the group attached to the N-aryl of the selected substrate a is a para-trifluoromethyl group. A white solid A8 was obtained by the reaction, with a yield of 85%. The 1 H,13 The high-resolution data of the C spectrum are as follows:

[0075] (A8) 1 H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.40 Hz, 2H), 7.56 (d, J = 8.30 Hz, 2H), 7.12 (s, 1H), 2.75 (t, J = 7.02 Hz, 2H), 2.61 - 2.52 (m, 6H), 1.82 - 1.78 (m, 4H);

[0076] 13 C NMR (125 MHz, CDCl3): δ 161.14, 146.16, 143.84, 131.75, 130.24 (q, J = 32.88 Hz), 129.51, 127.14, 126.33 (q, J = 3.54 Hz), 123.64 (q, J = 272.05 Hz), 118.58, 115.43, 26.34, 25.17, 24.18, 21.74, 21.58, 18.40; HRMS (ESI+) calculated for C 19 H 17 F3N2O [M+Na] + 369.1185, found 369.1202.

[0077] Example 9:

[0078] The experimental operation process of this example is the same as that of Example 1. The only difference is that the group connected to the N-aryl of the selected substrate a is a para-methoxy group. A yellow solid A9 was obtained by the reaction with a yield of 83%. The 1H spectrum and 13C spectrum of the product are shown in the appendix Figure 5 、 6 , and the high-resolution data are as follows:

[0079] (A9) 1 H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 8.85 Hz, 2H), 7.10 (s, 1H), 6.97 (d, J = 8.91 Hz, 2H), 3.84 (s, 3H), 2.74 (t, J = 6.85 Hz, 2H), 2.61 - 2.52 (m, 6H), 1.81 - 1.77 (m, 4H);

[0080] 1313C NMR (125 MHz, CDCl3): δ 161.48, 158.96, 145.55, 133.79, 132.72, 128.73, 127.46, 118.63, 114.62, 114.15, 55.37, 26.11, 24.97, 24.08, 21.66, 21.54, 18.14; HRMS (ESI+) calculated for C 19 H 20 N2O2 [M+Na] + 331.1417, found 331.1427.

[0081] Example 10:

[0082] The experimental operation process of this example is the same as that of Example 1, and the only difference is that there is no substituent on the N-aryl of the selected substrate a. A white solid A was obtained 10 , with a yield of 78%. The 1 H, 13 high-resolution data of the 13C spectrum are as follows:

[0083] (A 10 ) 1 1H NMR (500 MHz, CDCl3): δ 8.57 (dd, J1 = 1.34 Hz, J2 = 8.44 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.60 - 7.57 (m, 2H), 7.53 - 7.42 (m, 5H), 7.21 (s, 1H), 3.08 (t, J = 7.13 Hz, 2H), 2.74 (t, J = 7.50 Hz, 2H);

[0084] 13 13C NMR (125 MHz, CDCl3): δ 161.48, 140.95, 135.38, 132.84, 131.47, 129.32, 129.30, 128.17, 127.38, 126.75, 121.74, 118.70, 112.07, 25.59, 18.06; HRMS (ESI+) calculated for C 18 H 14 N2O [M+Na] + 297.0998, found 297.1008.

[0085] The substrates and product molecular formulas of Examples 1 - 10 are shown in the following table:

[0086]

[0087]

[0088]

[0089] Synthesis method of N-aryl-polycyclo[C]-2-pyridone derivatives of carboxylic acids, esters and amides, comprising the following steps:

[0090] (1) Reacting a 5-(N-aryl-polycyclo[C]-2-pyridone) propionitrile derivative of formula III 1 with an aqueous sodium hydroxide solution in a second organic solvent at reflux temperature for 3 to 5 hours to obtain a 5-(N-aryl-polycyclo[C]-2-pyridone) propionic acid derivative of formula (III 2 ), and terminating at this step to obtain the product of carboxylic acids;

[0091] (2) Reacting a 5-(N-aryl-polycyclo[C]-2-pyridone) propionic acid derivative of formula (III 2 ) with an amine or alcohol compound in a third organic solvent under basic conditions and at a certain temperature to obtain an N-aryl-polycyclo[C]-2-pyridone derivative of formula (III 3 ).

[0092]

[0093] In the above molecular formulas, ring A can be a five-membered ring, a six-membered ring or a seven-membered ring; R 1 can be -CONHR 3 or -COOR 3 ; R 2 can be methoxy, a halogen atom, methyl, halomethyl or hydrogen; R 3 can be phenyl, a mono-substituted aryl, a multi-substituted aryl, hydrogen.

[0094] The reaction substances in step (1) are: sodium hydroxide, ethanol, water.

[0095] The reaction substances in step (2) are: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), N,N-diisopropylethylamine (DIPEA), dichloromethane. The above reaction is carried out at 0 °C to room temperature, and the reaction time is 3 h to 12 h.

[0096] Generally, the post-treatment method in step (2) is as follows: after the reaction is completed, water is added for quenching, and it is extracted with CH2Cl2 for multiple times. The organic phase is washed with 5% HCl solution and 5% NaOH solution respectively, then washed with saturated brine in sequence, dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography. The developing agent is: V(petroleum ether)∶V(ethyl acetate) = 2∶1. The eluate containing the target compound is collected, concentrated by rotary evaporation to remove the solvent and dried to obtain the product.

[0097] Example 11

[0098] In a 25 ml single-necked round-bottom flask, compound A3 (0.13 g, 0.4 mmol), NaOH (3.0 equiv, 1.2 mmol), ethanol (5 ml), and H2O (1 ml) were added, and stirred at reflux temperature. After monitoring the reaction by TLC until completion, the solvent was removed by rotary evaporation, water and dichloromethane were added for washing, the aqueous phase was adjusted to acidic with hydrochloric acid, and after the solid was completely precipitated, it was filtered, washed with water, and dried in vacuo at 50 °C for 5 h to obtain white solid A 11 , with a yield of 95%. The 1 1H spectrum, 13 and high-resolution data of 13C spectrum are as follows:

[0099] (A 11 ) 1 1H NMR (500 MHz, DMSO): δ 12.18 (br, 1H), 7.56 (d, J = 8.71 Hz, 2H), 7.42 (d, J = 8.70 Hz, 2H), 7.21 (s, 1H), 2.61 (t, J = 7.19 Hz, 2H), 2.57 - 2.54 (m, 2H), 2.46 (t, J = 7.16 Hz, 2H), 2.41 - 2.38 (m, 2H), 1.71 - 1.67 (m, 4H); 13 13C NMR (125 MHz, DMSO): δ 173.71, 160.14, 147.15, 139.90, 132.17, 131.60, 128.79, 128.59, 126.63, 117.09, 33.65, 25.52, 24.01, 23.60, 21.44, 21.34; HRMS (ESI+) calculated for C 18 H 18 ClNO3 [M + Na] + 354.0867, found 354.0879.

[0100] Example 12:

[0101] The experimental operation process of this example is the same as that of Example 11, and the only difference is that the substrate selected is A1. A pale yellow solid A was obtained after the reaction.12 , with a yield of 93%. The 1 H, 13 high-resolution data of the

[0102] (A 12 ) 1 H NMR(500MHz, CDCl3): δ7.53 - 7.51(m, 1H), 7.39 - 7.31(m, 3H), 6.86(s, 1H), 2.72(t, J = 7.35Hz, 2H), 2.61 - 2.53(m, 6H), 1.83 - 1.76(m, 4H); 13 C NMR(125MHz, CDCl3): δ176.35, 161.28, 147.72, 138.67, 131.79, 131.25, 130.43, 129.99, 129.47, 128.75, 127.74, 117.67, 33.77, 26.47, 24.14, 24.09, 21.87, 21.69; HRMS(ESI+) calculated for C 18 H 18 ClNO3[M + Na] + 354.0867, found 354.0881.

[0103] Example 13:

[0104] The experimental operation process of this example is the same as that of Example 11, and the only difference is that the selected substrate is A2. The reaction obtained white solid A 13 , with a yield of 90%. The 1 H spectrum, 13 C spectrum are shown in Appendix Figure 7 、 8 , and the high-resolution data are as follows:

[0105] (A 13 ) 1 H NMR(500MHz, CDCl3): δ7.39 - 7.37(m, 3H), 7.28 - 7.25(m, 1H), 7.01(s, 1H), 2.74(t, J = 7.35Hz, 2H), 2.60 - 2.55(m, 6H), 1.80 - 1.77(m, 4H); 1313C NMR (125 MHz, CDCl3): δ 176.45, 161.41, 147.55, 142.11, 134.64, 131.17, 130.09, 128.76, 128.40, 127.15, 125.05, 117.98, 33.75, 26.44, 24.19, 24.16, 21.84, 21.72; HRMS (ESI+) calculated for C 18 H 18 ClNO3 [M+Na] + 354.0867, found 354.0880.

[0106] Example 14:

[0107] The experimental operation process of this example is the same as that of Example 11, and the only difference is that the selected substrate is A 10 . A white solid A was obtained by the reaction 14 , with a yield of 96%. The 1 H, 13 high-resolution data of the 13C spectrum are as follows:

[0108] (A 14 ) 1 1H NMR (500 MHz, DMSO): δ 12.21 (br, 1H), 8.32 (dd, J1 = 0.60 Hz, J2 = 7.65 Hz, 1H), 7.85 - 7.80 (m 2H), 7.61 - 7.53 (m, 3H), 7.48 - 7.44 (m, 3H), 7.29 (s, 1H), 2.97 (t, J = 7.47 Hz, 2H), 2.59 (t, J = 7.43 Hz, 2H); 13 13C NMR (125 MHz, DMSO): δ 173.70, 160.37, 141.11, 136.14, 132.85, 130.80, 129.01, 127.99, 127.78, 126.93, 126.90, 125.82, 122.99, 114.01, 33.65, 23.85; HRMS (ESI+) calculated for C 18 H 15 NO3 [M+Na] + 316.0944, found 316.0956.

[0109] Example 15:

[0110] Under the condition of an ice-water bath, substrate A was added to a 25 ml single-necked flask 12(0.10 g, 0.3 mmol), EDCI (1.2 equiv, 0.36 mmol), HOBT (1.0 equiv, 0.3 mmol), DIPEA (1.5 equiv, 0.45 mmol), CH2Cl2 (5 ml), stirred for 30 min, p-chlorobenzyl alcohol (1.3 equiv, 0.39 mmol) was added, the ice bath was removed and the mixture was stirred at room temperature for 6 h. After monitoring the reaction by TLC and completion, water (20 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 20 ml). The organic phase was washed with 5% HCl solution (30 ml) and 5% NaOH solution (30 ml) respectively, and saturated sodium chloride solution (30 ml), dried over anhydrous magnesium sulfate, and purified by column chromatography. The eluent was: V(petroleum ether)∶V(ethyl acetate)=3∶1, and a pale yellow oil A was obtained. 15 , with a yield of 77%. The 1 1H NMR, 13 13C NMR spectra are shown in Appendices Figure 9 and 10 . The high-resolution data are as follows:

[0111] (A 15 ) 1 1H NMR (500 MHz, CDCl3): δ 7.53 - 7.51 (m, 1H), 7.38 - 7.34 (m, 2H), 7.30 - 7.27 (m, 3H), 7.23 (d, J = 8.44 Hz, 2H), 6.82 (s, 1H), 5.06 (s, 2H), 2.75 - 2.72 (m, 2H), 2.61 - 2.55 (m, 6H), 1.79 - 1.74 (m, 4H);

[0112] 13 13C NMR (125 MHz, CDCl3): δ 172.00, 160.95, 147.04, 138.67, 134.12, 131.68, 131.07, 130.30, 129.79, 129.52, 129.31, 128.66, 127.64, 116.97, 65.51, 33.97, 26.31, 24.10, 23.99, 21.79, 21.60; HRMS(ESI+) calculated for C 25 H 23 Cl2NO3 [M + H] + 456.1128, found 456.1121.

[0113] Example 16:

[0114] The experimental procedure of this example is the same as that of Example 15, the only difference is that the substrate used is A 13。A white solid A was obtained by the reaction 16 , with a yield of 77%. The 1H and 13C spectra of the product are shown in the appendix Figure 11 . The high-resolution data of the 1H and 13C spectra are as follows:

[0115] (A 16 ) 1 1H NMR (500 MHz, CDCl3): δ 7.38 - 7.35 (m, 3H), 7.30 - 7.28 (m, 2H), 7.24 - 7.21 (m, 3H), 6.96 (s, 1H), 5.07 (s, 2H), 2.73 (t, J = 7.27 Hz, 2H), 2.61 - 2.53 (m, 6H), 1.78 - 1.75 (m, 4H);

[0116] 13 13C NMR (125 MHz, CDCl3): δ 172.01, 161.12, 146.90, 142.11, 134.50, 134.19, 134.11, 130.97, 129.99, 129.52, 128.70, 128.66, 128.17, 127.00, 124.85, 117.34, 65.56, 33.96, 26.30, 24.17, 24.13, 21.79, 21.66; HRMS (ESI+) calculated for C 25 H 23 Cl2NO3 [M + H] + 456.1128, found 456.1120.

[0117] Example 17

[0118] The experimental procedure of this example was the same as that of Example 15, except that the selected substrates were A 12 and o-iodoaniline. A white solid A was obtained by the reaction 17 , with a yield of 63%. The 1 1H, 13 13C spectra of the product have the following high-resolution data: (A 17 ) 11H NMR (500 MHz, CDCl3): δ 8.14 (d, J = 7.63 Hz, 1H), 7.76 (d, J = 7.76 Hz, 1H), 7.49 (dd, J1 = 1.49 Hz, J2 = 7.49 Hz, 1H), 7.44 (br, 1H), 7.36 - 7.30 (m, 3H), 7.23 (dd, J1 = 1.54 Hz, J2 = 7.45 Hz, 1H), 6.89 (s, 1H), 6.86 (t, J = 7.44 Hz, 1H), 2.85 (t, J = 7.37 Hz, 2H), 2.65 - 2.60 (m, 6H), 1.81 - 1.75 (m, 4H);

[0119] 13 13C NMR (125 MHz, CDCl3): δ 169.81, 161.12, 147.17, 138.82, 138.70, 137.93, 131.82, 131.41, 130.38, 129.88, 129.44, 129.27, 128.92, 127.69, 126.23, 122.24, 117.15, 90.35, 37.70, 26.54, 24.77, 24.14, 21.94, 21.76; HRMS (ESI+) calculated for C 24 H 22 ClIN2O2 [M + H] + 533.0487, found 533.0479.

[0120] Example 18

[0121] The experimental operation process of this example is the same as that of Example 15, and the only difference is that the substrate selected is A 12 and aniline. A white solid A 18 was obtained by the reaction, 1 with a yield of 78%. The high-resolution data of the 13 1H and 18 13C spectra of the product are as follows: (A 1 ) 1313C NMR (125 MHz, CDCl3): δ 169.93, 161.15, 147.58, 138.74, 137.92, 131.79, 131.41, 130.36, 129.93, 129.38, 128.89, 128.57, 127.73, 124.20, 119.85, 117.82, 37.41, 26.51, 24.67, 24.19, 21.92, 21.73; HRMS (ESI+) calculated for C 24 H 23 ClN2O2 [M+H] + 407.1521, found 407.1519.

[0122] Example 19

[0123] The experimental operation process of this example is the same as that of Example 15, and the only difference is that the selected substrate is A 14 and p-chlorobenzyl alcohol. A pale yellow solid A 19 was obtained by the reaction, with a yield of 77%. The 1 H, 13 high-resolution data of the 13C spectrum are as follows:

[0124] (A 19 ) 1 1H NMR (500 MHz, CDCl3): δ 8.56 (d, J = 7.72 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.67 (d, J = 8.04 Hz, 1H), 7.56 (t, J = 7.40 Hz, 1H), 7.51 (t, J = 7.51 Hz, 2H), 7.44 - 7.39 (m, 3H), 7.29 (t, J = 8.40 Hz, 2H), 7.23 (d, J = 8.40 Hz, 2H), 7.09 (s, 1H), 5.09 (s, 2H), 3.09 (t, J = 7.36 Hz, 2H), 2.77 (t, J = 7.56 Hz, 2H);

[0125] 13 13C NMR (125 MHz, CDCl3): δ 172.26, 161.57, 141.25, 136.17, 134.24, 134.20, 132.62, 130.51, 129.56, 129.25, 129.07, 128.77, 128.03, 127.10, 126.74, 126.70, 122.40, 114.23, 65.63, 34.01, 24.59; HRMS (ESI+) calculated for C 25 H 20ClNO3[M+Na] + 440.1024, found 440.1025.

[0126] Example 20

[0127] The experimental operation process of this example is the same as that of Example 15, and the only difference is that the selected substrate is A 11 and p-chlorobenzyl alcohol. A yellow solid A was obtained by reaction 20 , with a yield of 78%. The 1 H, 13 high-resolution data of the C spectrum are as follows:

[0128] (A 20 ) 1 H NMR(500MHz, CDCl3): δ7.40(d, J = 8.68Hz, 2H), 7.29(d, J = 8.33Hz, 2H), 7.26(d, J = 8.66Hz, 2H), 7.23(d, J = 8.37Hz, 2H), 6.95(s, 1H), 5.06(s, 2H), 2.73(t, J = 7.29Hz, 2H), 2.60 - 2.53(m, 6H), 1.78 - 1.74(m, 4H);

[0129] 13 C NMR(125MHz, CDCl3): δ171.97, 161.14, 146.81, 139.56, 134.12, 134.08, 133.61, 131.05, 129.47, 129.08, 128.64, 128.53, 127.80, 117.26, 65.49, 33.88, 26.25, 24.12, 24.10, 21.75, 21.62; HRMS(ESI+) calculated for C 25 H 23 Cl2NO3[M+H] + 456.1128, found 456.1124.

[0130] Example 21:

[0131] The experimental operation process of this example is the same as that of Example 15, and the only difference is that the selected substrate is A 14 and aniline. A yellow solid A was obtained by reaction 21 , with a yield of 70%. The 1 H, 13 high-resolution data of the C spectrum are as follows: (A 21 ) 11H NMR (500 MHz, CDCl3): δ 8.43 (d, J = 7.87 Hz, 1H), 8.31 (br, 1H), 7.67 - 7.60 (m, 2H), 7.45 - 7.42 (m, 3H), 7.35 - 7.21 (m, 7H), 7.06 (t, J = 7.40 Hz, 1H), 7.02 (s, 1H), 3.07 (t, J = 7.32 Hz, 2H), 2.59 (t, J = 7.74 Hz, 2H);

[0132] 13 13C NMR (125 MHz, CDCl3): δ 170.32, 161.66, 141.01, 138.06, 136.30, 132.67, 130.30, 129.17, 128.80, 128.72, 128.07, 127.04, 126.65, 126.33, 124.05, 122.68, 119.82, 115.16, 36.95, 24.97; HRMS (ESI+) calculated for C 24 H 20 N2O2 [M + H] + 369.1598, found 369.1592.

[0133] The molecular formulas of the substrates and products of Examples 11 - 21 are as follows in the table:

[0134]

[0135]

[0136] Determination of the anti - fibrotic bioactivity of N - aryl - polycyclic - fused[C] - 2 - pyridone derivatives

[0137] The method for determining the anti - fibrotic bioactivity of N - aryl - polycyclic - fused[C] - 2 - pyridone derivatives is as follows: Select mouse embryonic fibroblast NIH3T3 as the research object, use pirfenidone as the positive control, and adopt the MTT method to investigate the inhibitory effect intensity of the synthesized N - aryl - polycyclic - fused[C] - 2 - pyridone derivatives on the proliferation of NIH3T3 cells. Compare the bioactivity differences between pirfenidone and this series of compounds through the IC 50 value.

[0138] The specific operation steps are as follows:

[0139] Using the MTT colorimetric method, mouse embryonic fibroblasts were cultured in DMEM medium containing 10% fetal bovine serum at 37 °C in a humidified cell culture incubator containing 5% CO2. NIH3T3 cells were seeded in a 96-well plate at 10,000 cells per well and cultured for an additional 12 h. After the cells adhered, the medium was replaced with a medium containing 10% fetal bovine serum and the products (A1 - A 22 ) of Examples 1 - 21 of N-aryl-polycyclo[C]-2-pyridone derivatives and pirfenidone (as shown in Formula x), and 5 replicates were set for each concentration. After culturing for 48 h, 10% MTT solution (20 μL) was added to each well. After 4 h, the MTT was aspirated, and 100 μL of MTT solubilization solution DMSO was added to each well until the MTT was completely dissolved. After 15 min, the OD value was measured at 570 nm using an enzyme-linked immunosorbent assay reader, and the data was processed using GraphPad Prism 8.0 software to obtain the IC 50 values of pirfenidone and N-aryl-polycyclo[C]-2-pyridone derivatives.

[0140]

[0141] The results are shown in the following table:

[0142]

[0143]

[0144] From the above table, it can be concluded that the N-aryl-polycyclo[C]-2-pyridone derivatives prepared in the examples of the present invention have anti-fibrotic biological activity:

[0145] (1) The activity of most compounds in this series is superior to that of the positive control pirfenidone, and there is no situation where the compound is insoluble and cannot be tested, indicating that this series of compounds helps to improve anti-fibrotic biological activity.

[0146] (2) Generally speaking, the substituents of compound R 2 have a certain promoting effect on biological activity. From the comparison of the activities of substituents at the ortho, meta, or para positions of R 2 , it can be seen that the meta-substituent is superior to the ortho and para positions. Among them, the activities of compounds A2 and A 16 are 33 and 95 times that of pirfenidone, respectively.

[0147] (3) The activity of the compound with R 1 being an amide or ester group is superior to that of a cyano or carboxyl group. Among them, the activities of A 16 and A 21 are 95 times and 85 times that of pirfenidone, respectively, indicating that the introduction of an amide or ester group increases the hydration of the compound, which is beneficial to drug transport and improves the activity of the compound.

[0148] (4) In the compound containing a six-membered ring (A 17 -A 18 ), R 2 are all o-chloroaniline. It can be seen that when R 1 is a single substituent and is an iodine atom-containing aromatic amide, its activity is superior to that of aromatic amide.

[0149] The present invention is not limited to the above specific embodiments, and the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made to the above embodiments based on the technical essence of the present invention shall be included within the protection scope of the present invention.

Claims

1. N-aryl polycyclo[C]-2-pyridone derivatives, characterized in that, Its chemical structural formula is as follows:

2. Use of the N-aryl-polycyclo[C]-2-pyridone derivative according to claim 1 in the preparation of a medicament for treating fibrotic diseases.

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