Nitro-containing diphenyl ether compound, application thereof and coronavirus HCoV-OC43 inhibitor

Abstract

The invention relates to the technical field of biology, and discloses a nitro-containing diphenyl ether compound, application of the nitro-containing diphenyl ether compound and a coronavirus HCoV-OC43 inhibitor. The nitryl-containing diphenyl ether compound has a structure as shown in a formula (I), has a good inhibition effect on coronavirus HCoV-OC43, and can overcome the problem of cross drug resistance. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of biotechnology, and specifically relates to nitro-containing diphenyl ether compounds and their applications, and coronavirus HCoV-OC43 inhibitors. Background Art

[0002] Coronaviruses are a group of RNA viruses with envelopes and linear single-stranded positive-sense genomes. Currently, seven human coronaviruses have been identified, and they all belong to groups α and β: HCoV-NL63, HCoV-229E, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV, SARS-CoV-2. Coronaviruses can spread rapidly between people, resulting in high morbidity and mortality.

[0003] Among them, HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1 usually cause mild respiratory diseases in immunocompetent populations. In some cases, severe respiratory infections occur in children, the elderly, and immunosuppressed patients. The other three species, respectively, have caused three worldwide infectious disease pandemics. In particular, the global pandemic caused by SARS-CoV-2 has brought catastrophic damage to the health and economy of the global human population.

[0004] Unfortunately, the current antiviral drugs in clinical practice are not sufficient to combat these infections. Currently, a large number of anti-coronavirus drugs have been approved for marketing, but most of these drugs are single-target drugs and the action targets are very limited. At the same time, the existing anti-coronavirus drugs still have the problem of poor antiviral efficacy.

[0005] Therefore, there is an urgent need to develop anti-coronavirus drugs with new structures to provide new solutions and methods for the above key problems. Summary of the Invention

[0006] The purpose of the present invention is to provide a new class of antiviral drugs.

[0007] To achieve the above purpose, in the first aspect of the present invention, a nitro-containing diphenyl ether compound is provided, and this compound has the structure shown in formula (I),

[0008]

[0009] Wherein, in formula (I),

[0010] m is 0 or 1;

[0011] R is selected from one of -NH-(CH2) n -L1-R1, -NH-R2, and -O-R3;

[0012] In -NH-(CH2) n -L1-R1, n is an integer from 0 to 6, and R1 is selected from C1-C 10 alkyl, C1-C 10 alkoxy, C2-C8 alkynyl, halogen, cyano, benzaldehyde group, phenoxy group, triazole group, morpholine group, and phenyl substituted by at least one halogen;

[0013] In -NH-R2, R2 is selected from C3-C 10 cycloalkyl, C2-C 10 alkynyl, -CH(Ph)2, pyridyl substituted by at least one halogen, pyridyl substituted by at least one C1-C6 alkyl;

[0014] In -O-R3, R3 is selected from C1-C 10 alkyl;

[0015] L and L1 are each independently a linking group provided by removing any two H atoms from benzene.

[0016] The second aspect of the present invention provides the use of the compound described in the first aspect as a coronavirus HCoV-OC43 inhibitor.

[0017] The third aspect of the present invention provides a coronavirus HCoV-OC43 inhibitor, which comprises an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient is the compound described in the first aspect.

[0018] The nitro-containing diphenyl ether compound provided by the present invention is introduced as an antiviral active ingredient into the HCoV-OC43 coronavirus inhibitor, and can effectively inhibit the HCoV-OC43 virus.

[0019] The present invention has at least the following specific advantages compared with the prior art:

[0020] The nitro-containing diphenyl ether compound prepared by the technical solution provided by the present invention has a good inhibitory effect on the coronavirus HCoV-OC43, and has high safety while ensuring excellent inhibitory effect. Detailed implementation manners

[0021] In the ranges disclosed herein, the endpoints and any values are not limited to the exact range or value, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and a single point value, and between single point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0022] As used in the present invention, "n is an integer from 0 to 6", for example, n can be 0, 1, 2, 3, 4, 5, or 6.

[0023] As used in the present invention, "C 1-10 alkyl" means an alkyl group having a total of 1 to 10 carbon atoms (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), including a straight-chain group or a branched-chain group.

[0024] As used in the present invention, "C 1-10 alkoxy" means an alkoxy group having a total of 1 to 10 carbon atoms (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), including a straight-chain group or a branched-chain group.

[0025] As used in the present invention, "C 2-8 alkynyl" means an alkynyl group having a total of 2 to 8 carbon atoms (for example, 1, 2, 3, 4, 5, 6, 7, 8), which can be a straight-chain alkynyl group or a branched-chain alkynyl group, and contains at least one triple bond, and there is no special requirement for the position of the triple bond.

[0026] As used in the present invention, "phenyl substituted by at least one halogen", for example, the halogen can be located at any one or more than two positions among the 1, 2, 3, 4, 5 positions on the phenyl group.

[0027] As used in the present invention, "C 3-10 cycloalkyl" means a cycloalkyl group having a total of 3 to 10 carbon atoms, and the number of ring-forming carbon atoms is any one of 3 to 10, for example, 3, 4, 5, 6, 7, 8, 9, 10, and for example, it can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl.

[0028] As used in the present invention, Ph in "-CH(Ph)2" represents a phenyl group.

[0029] As used in the present invention, "pyridyl substituted by at least one halogen", for example, the halogen can be located at any one or more than two positions among the 1, 2, 3, 4, 5 positions on the pyridyl group.

[0030] As used in the present invention, "pyridyl substituted by at least one of C1-C3 alkyl", for example, an alkyl group having a total of 1 to 3 carbon atoms (for example, 1, 2, 3) (including a straight-chain group or a branched-chain group) can be located at any one or more than two positions among the 1, 2, 3, 4, 5 positions on the pyridyl group.

[0031] As used in the present invention, "L and L1 are each independently a linking group provided by removing any two H atoms from benzene", for example, it can be para-disubstitution of benzene, ortho-disubstitution of benzene, or meta-disubstitution of benzene.

[0032] For the remaining substituents, they have similar definitions as above, except for the different number of carbon atoms, which will not be elaborated herein in the present invention.

[0033] As described above, the first aspect of the present invention provides a nitro-containing diphenyl ether compound, which has the structure shown in formula (I).

[0034]

[0035] Wherein, in formula (I),

[0036] m is 0 or 1;

[0037] R is selected from one of -NH-(CH2) n -L1-R1, -NH-R2 and -O-R3;

[0038] In -NH-(CH2) n -L1-R1, n is an integer from 0 to 6, and R1 is selected from C1-C 10 alkyl, C1-C 10 alkoxy, C2-C8 alkynyl, halogen, cyano, benzaldehyde group, phenoxy, triazolyl, morpholinyl and phenyl substituted by at least one halogen;

[0039] In -NH-R2, R2 is selected from C3-C 10 cycloalkyl, C2-C 10 alkynyl, -CH(Ph)2, pyridyl substituted by at least one halogen, pyridyl substituted by at least one of C1-C6 alkyl;

[0040] In -O-R3, R3 is selected from C1-C 10 alkyl;

[0041] L and L1 are each independently a linking group provided by removing any two H atoms from benzene.

[0042] According to a preferred specific embodiment 1:

[0043] In formula (I),

[0044] m is 0 or 1;

[0045] R is selected from one of -NH-(CH2) n -L1-R1, -NH-R2 and -O-R3;

[0046] In -NH-(CH2) nIn -NH-(CH2)n-L1-R1, n is an integer from 0 to 4, and R1 is selected from one of C1-C8 alkyl, C1-C8 alkoxy, C2-C6 alkynyl, halogen, cyano, benzaldehyde group, phenoxy, triazole group, morpholine group, and phenyl substituted by at least one halogen;

[0047] In -NH-R2, R2 is selected from one of C3-C8 cycloalkyl, C2-C8 alkynyl, -CH(Ph)2, pyridyl substituted by at least one halogen, and pyridyl substituted by at least one of C1-C3 alkyl;

[0048] In -O-R3, R3 is selected from C1-C8 alkyl;

[0049] L and L1 are each independently a linking group provided by removing any two H atoms from benzene;

[0050] The halogen is selected from at least one of chlorine, bromine, and iodine.

[0051] According to a preferred specific embodiment 2:

[0052] In formula (I),

[0053] m is 0 or 1;

[0054] R is selected from -NH-(CH2) n -L1-R1, -NH-R2, and -O-R3;

[0055] In -NH-(CH2) n -L1-R1, n is 0 or 1, and R1 is selected from one of methyl, ethyl, methoxy, ethynyl, halogen, cyano, benzaldehyde group, phenoxy, triazole group, morpholine group, and phenyl substituted by at least one halogen;

[0056] In -NH-R2, R2 is selected from one of cyclopropyl, cyclohexyl, propynyl, -CH(Ph)2, pyridyl substituted by at least one halogen, and pyridyl substituted by at least one methyl;

[0057] In -O-R3, R3 is selected from methyl and ethyl;

[0058] L and L1 are each independently a linking group provided by removing any two H atoms from benzene;

[0059] The halogen is selected from at least one of chlorine, bromine, and iodine.

[0060] Particularly preferably, the organic compound represented by formula (I) is selected from any one of the following:

[0061]

[0062]

[0063] According to a particularly preferred specific embodiment, the organic compound represented by formula (I) is selected from any one of the following:

[0064]

[0065] The present invention does not particularly limit the specific method for preparing the foregoing compounds. Those skilled in the art can obtain the foregoing compounds of the present invention according to the specific structural formulas provided by the present invention in combination with the known knowledge in the field of organic synthesis. Moreover, several examples are exemplarily listed in the following text of the present invention to illustrate the preparation methods of the compounds of the present invention. Those skilled in the art can also obtain the specific preparation methods of all the remaining compounds by replacing the types of raw materials according to the preparation methods of the compounds in the following text of the present invention. The present invention will not elaborate on the preparation methods of all the compounds, and those skilled in the art should not construe this as a limitation to the present invention.

[0066] As described above, the second aspect of the present invention provides the use of the compound described in the first aspect as a coronavirus HCoV-OC43 inhibitor.

[0067] As described above, the third aspect of the present invention provides a coronavirus HCoV-OC43 inhibitor, which comprises an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient is the compound described in the first aspect.

[0068] Preferably, the pharmaceutically acceptable excipient is selected from at least one of a bulking agent, a diluent, a binder, and a lubricant.

[0069] Preferably, the bulking agent is selected from at least one of calcium carbonate and calcium phosphate.

[0070] Preferably, the diluent is selected from at least one of lactose, cyclodextrin, and calcium sulfate.

[0071] Preferably, the binder is selected from at least one of ethanol, glycerol, propylene glycol, and syrup.

[0072] Preferably, the lubricant is selected from at least one of silica, corn starch, and liquid paraffin.

[0073] More preferably, the content of the active ingredient is 0.01-99.99 wt%.

[0074] Particularly preferably, the content of the active ingredient is 0.1-99.9 wt%.

[0075] More preferably, the content of the active ingredient is 1 wt%, 2 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%, 95 wt%.

[0076] Preferably, the dosage form of the inhibitor is selected from at least one of hydrating agent, powder, emulsion, suspending agent and granule.

[0077] The present invention has no particular requirements on the specific preparation process of the inhibitor, and those skilled in the art can adopt the processes for preparing inhibitors known in the art, and those skilled in the art should not regard it as a limitation of the present invention.

[0078] The present invention will be described in detail below by way of examples. In the following examples, various raw materials used are ordinary commercially available products without special instructions.

[0079] The structural formula of p-ethynylaniline in the present invention is as follows:

[0080]

[0081] The structural formula of p-chloroaniline in the present invention is as follows:

[0082]

[0083] The structural formula of cyclopropylamine in the present invention is as follows:

[0084]

[0085] The structural formula of p-cyanoaniline in the present invention is as follows:

[0086]

[0087] The structural formula of (4-aminophenyl)phenylmethanone in the present invention is as follows:

[0088]

[0089] The structural formula of 4-(phenyloxy)aniline in the present invention is as follows:

[0090]

[0091] The structural formula of 4-(1,2,4-triazol-1-yl)aniline in the present invention is as follows:

[0092]

[0093] Preparation Example 1:

[0094]

[0095] Synthesis of Compound III: Compound II (10 mmol), anhydrous potassium carbonate (14 mmol), and N,N-dimethylformamide (DMF, 30 mL) were mixed and heated at 120 °C for 2 h. Then, the reaction solution was cooled to 90 °C, p-chlorophenol (11 mmol) was added, and the mixture was continuously heated for 5 h. Subsequently, the reaction solution was heated to 120 °C and reacted for 9 h, and the reaction progress was monitored by TLC. After the reaction was completed, hydrochloric acid with pH = 1 was added for acidification, 50 mL of water was added, and the reaction solution was allowed to stand for the solid to precipitate. The reaction solution was filtered to obtain the filter residue, and the filter residue was washed with water, filtered, and dried to obtain Compound III. Compound III was an orange-yellow powder with a yield of 70%.

[0096] Synthesis of Compound IV: Compound III (3 mmol) was dissolved in dichloromethane (DCM, 20 mL), and the mixture was heated to reflux. After Compound III was dissolved, thionyl chloride (6 mmol) was added dropwise to the system, and the reaction continued for 1 h. After the reaction was monitored by TLC and completed, the reaction solution was concentrated by rotary evaporation to obtain Compound IV without further purification.

[0097] Synthesis of Compound 28: p-Ethynylaniline (3 mmol) and triethylamine (15 mmol) were dissolved in dichloromethane (20 mL), and the solution was added dropwise to the dichloromethane solution (10 mL) of Compound IV at 0 °C. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain Compound 28. Compound 28 was a white solid powder with a yield of 55%.

[0098] The 1H NMR and 13C NMR results of Compound 28 are as follows:

[0099] 1 H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.32 (dd, J = 9.2, 2.9 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.57–7.53 (m, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 9.2 Hz, 1H), 4.13 (s, 1H);

[0100] 1313C NMR (101 MHz, DMSO-d6): δ 162.97, 159.69, 153.72, 142.64, 139.63, 132.95, 130.89, 130.10, 128.64, 127.81, 125.86, 122.85, 120.00, 117.97, 117.42, 83.92, 80.75.

[0101] Preparation Example 2:

[0102]

[0103] Synthesis of Compound III: Prepared in the same manner as in Preparation Example 1.

[0104] Synthesis of Compound IV: Prepared in the same manner as in Preparation Example 1.

[0105] Synthesis of Compound 23: Prepared in a manner similar to the synthesis of Compound 28 in Preparation Example 1, except that an equimolar amount of p-chloroaniline was used to replace p-ethynylaniline to obtain Compound 23. Compound 23 is a white solid powder with a yield of 60%.

[0106] The 1H nuclear magnetic resonance and 13C nuclear magnetic resonance of Compound 23 are as follows:

[0107] 1 1H NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.32 (dd, J = 9.2, 2.9 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 9.2 Hz, 1H);

[0108] 13 13C NMR (101 MHz, DMSO-d6): δ 162.89, 159.65, 153.75, 142.65, 138.06, 130.87, 130.07, 129.26, 129.18, 128.64, 128.10, 127.79, 125.85, 122.81, 121.72, 118.03.

[0109] Preparation Example 3:

[0110]

[0111] Synthesis of Compound III: Prepared in the same manner as in Preparation Example 1.

[0112] Synthesis of Compound IV: Prepared by the same method as in Preparation Example 1.

[0113] Synthesis of Compound 25: Prepared by a method similar to the synthesis of Compound 28 in Preparation Example 1, except that equimolar amount of cyclopropylamine was used to replace p-ethynylaniline, to obtain Compound 25. Compound 25 is a white solid powder with a yield of 60%.

[0114] The 1H NMR and 13C NMR of Compound 25 are as follows:

[0115] 1 H NMR(400MHz,DMSO-d6): δ8.55(d,J = 3.9Hz,1H),8.35(d,J = 2.9Hz,1H),8.27(dd,J = 9.1,2.9Hz,1H),7.56–7.52(m,2H),7.23–7.19(m,2H),7.04(d,J = 9.1Hz,1H),2.80(tq,J = 7.8,4.0Hz,1H),0.68(dt,J = 6.9,3.4Hz,2H),0.51–0.46(m,2H);

[0116] 13 C NMR(101MHz,DMSO-d6): δ165.06,159.43,154.03,142.73,130.74,129.71,128.78,127.38,125.76,122.41,118.57,23.33,6.32.

[0117] Preparation Example 4:

[0118]

[0119] Synthesis of Compound III: Prepared by the same method as in Preparation Example 1.

[0120] Synthesis of Compound IV: Prepared by the same method as in Preparation Example 1.

[0121] Synthesis of Compound 21: Prepared by a method similar to the synthesis of Compound 28 in Preparation Example 1, except that equimolar amount of p-cyanoaniline was used to replace p-ethynylaniline, to obtain Compound 21. Compound 21 is a white solid powder with a yield of 60%.

[0122] The 1H NMR and 13C NMR of Compound 21 are as follows:

[0123] 11H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.34 (dd, J = 9.2, 2.8 Hz, 1H), 7.85 (q, J = 8.8 Hz, 4H), 7.55 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 9.2 Hz, 1H);

[0124] 13 13C NMR (101 MHz, DMSO-d6): δ 163.50, 159.69, 153.66, 143.26, 142.63, 133.88, 130.89, 130.14, 128.28, 128.03, 125.92, 122.84, 120.21, 119.43, 117.98, 106.28.

[0125] Preparation Example 5:

[0126]

[0127] Synthesis of Compound III: Prepared by the same method as in Preparation Example 1.

[0128] Synthesis of Compound IV: Prepared by the same method as in Preparation Example 1.

[0129] Synthesis of Compound 17: Prepared by a method similar to the synthesis of Compound 28 in Preparation Example 1, except that equimolar amount of (4-aminophenyl)phenylmethanone was used to replace p-ethynylaniline, to obtain Compound 17. Compound 17 is a white solid powder with a yield of 60%.

[0130] The 1H nuclear magnetic resonance and 13C nuclear magnetic resonance of Compound 17 are as follows:

[0131] 1 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.34 (dd, J = 9.1, 2.7 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 7.3 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.58–7.54 (m, 4H), 7.31 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 9.2 Hz, 1H);

[0132] 1313C NMR (101 MHz, DMSO-d6): δ 195.08, 163.34, 159.72, 153.69, 143.14, 142.63, 137.88, 132.86, 132.58, 131.65, 130.89, 130.13, 129.94, 129.00, 128.51, 127.91, 125.88, 122.86, 119.45, 117.93.

[0133] Preparation Example 6:

[0134]

[0135] Synthesis of Compound III: Prepared in the same manner as in Preparation Example 1.

[0136] Synthesis of Compound IV: Prepared in the same manner as in Preparation Example 1.

[0137] Synthesis of Compound 19: Prepared in a manner similar to the synthesis of Compound 28 in Preparation Example 1, except that equimolar amounts of 4-(phenyloxy)aniline were used instead of 4-ethynylaniline to obtain Compound 19. Compound 19 is a brown solid powder with a yield of 30%.

[0138] 1H NMR and 13C NMR of Compound 19 are as follows:

[0139] 1 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.32 (dd, J = 9.2, 2.9 Hz, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.57–7.53 (m, 2H), 7.40–7.35 (m, 2H), 7.31–7.28 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H);

[0140] 13 13C NMR (101 MHz, DMSO)-d6): δ 162.59, 159.65, 157.75, 153.80, 152.79, 142.66, 135.00, 130.87, 130.47, 130.03, 128.90, 127.65, 125.79, 123.55, 122.81, 121.89, 120.03, 118.38, 118.04.

[0141] Preparation Example 7:

[0142]

[0143] Synthesis of Compound III: Prepared by the same method as in Preparation Example 1.

[0144] Synthesis of Compound IV: Prepared by the same method as in Preparation Example 1.

[0145] Synthesis of Compound 32: Prepared by a method similar to the synthesis of Compound 28 in Preparation Example 1, except that equimolar amounts of 4-(1,2,4-triazol-1-yl)aniline were used to replace p-ethynylaniline, to obtain Compound 32. Compound 32 is a white solid powder with a yield of 50%.

[0146] The 1H NMR and 13C NMR results of Compound 32 are as follows:

[0147] 1 H NMR(400MHz,DMSO-d6): δ10.79(s,1H),9.24(s,1H),8.54(d,J = 2.8Hz,1H),8.34(dd,J = 9.2,2.8Hz,1H),8.22(s,1H),7.86(s,4H),7.56(d,J = 8.8Hz,2H),7.30(d,J = 8.8Hz,2H),7.09(d,J = 9.2Hz,1H);

[0148] 13 C NMR(101MHz,DMSO-d6): δ162.94,159.68,153.77,152.77,142.66,142.52,138.58,133.10,130.87,130.06,128.64,127.82,125.88,122.80,121.03,120.50,118.07.

[0149] Preparation Example 8:

[0150]

[0151] Synthesis of Compound III: Prepared by the same method as in Preparation Example 1.

[0152] Synthesis of Compound IV: Prepared by the same method as in Preparation Example 1.

[0153] Synthesis of Compound VI: p-Aminobenzoic acid (6 mmol) was dissolved in tetrahydrofuran (50 mL). At 0 °C, it was added dropwise to a tetrahydrofuran solution (20 mL) of Compound IV. The reaction progress was monitored by TLC. After the reaction was completed, water was added to the reaction solution until a white solid precipitated. The reaction solution was filtered to obtain the residue, and the residue was dried to obtain Compound VI. Compound VI was a white powder with a yield of 60%.

[0154] Synthesis of Compound 16: Compound VI (3 mmol), anhydrous potassium carbonate (4.2 mmol), and acetonitrile (30 mL) were heated under reflux. Methyl bromide (3 mmol) was added dropwise to the reaction solution. After the reaction was monitored by TLC and completed, the reaction solution was filtered. Subsequently, the filtrate was concentrated under reduced pressure, and the crude product was obtained by column chromatography to obtain Compound 16. Compound 16 was a white solid powder with a yield of 40%.

[0155] The 1H NMR and 13C NMR of Compound 16 were as follows:

[0156] 1 H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.33 (dd, J = 9.2, 2.9 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.2 Hz, 1H), 3.84 (s, 3H);

[0157] 13 C NMR (101 MHz, DMSO-d6): δ 166.23, 163.31, 159.72, 153.68, 143.44, 142.62, 130.89, 130.84, 130.13, 128.48, 127.91, 125.90, 125.17, 122.88, 119.60, 117.92, 52.47.

[0158] Preparation Example 9:

[0159]

[0160] Synthesis of Compound III: Prepared by the same method as in Preparation Example 1.

[0161] Synthesis of Compound IV: Prepared by the same method as in Preparation Example 1.

[0162] Synthesis of Compound VI: Prepared by the same method as in Preparation Example 8.

[0163] Synthesis of Compound VII: Dissolve Compound VI (3 mmol) in dichloromethane (DCM, 30 mL), heat under reflux. After Compound VI is dissolved, add thionyl chloride (6 mmol) dropwise to the reaction solution. After monitoring the reaction by TLC until it is completed, rotary evaporate the reaction solution to obtain Compound VII without further purification.

[0164] Synthesis of Compound 11: Dissolve 4-ethynylaniline (3 mmol) and triethylamine (15 mmol) in dichloromethane (DCM, 20 mL). At 0 °C, dropwise add the solution to the dichloromethane solution (10 mL) of Compound VII. Monitor the reaction process by TLC. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is purified by column chromatography to obtain Compound 11. Compound 11 is a white solid powder with a yield of 20%.

[0165] The 1H NMR and 13C NMR of Compound 11 are as follows:

[0166] 1 H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 10.32 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.34 (dd, J = 9.2, 2.8 Hz, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.83 (t, J = 8.1 Hz, 4H), 7.56 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 9.2 Hz, 1H), 4.10 (s, 1H);

[0167] 13 C NMR (101 MHz, DMSO-d6): δ 164.84, 162.59, 159.13, 153.16, 142.07, 141.61, 139.75, 132.13, 130.31, 129.62, 129.53, 128.72, 127.99, 127.30, 125.34, 122.24, 119.94, 118.85, 117.43, 116.30, 83.52, 79.88.

[0168] Test Example 1:

[0169] It is proved by the test example that the diphenyl ether compounds provided by the present invention have good inhibitory effects on coronavirus HCoV-OC43.

[0170] 1. In vitro antiviral activity experiment:

[0171] Inoculate African green monkey kidney cells (Vero E6) in a 384-well plate (catalog number 781080; Greiner Bio-one) with 10 μL of human coronavirus HCoV-OC43 (800 infectious units [IU]) and 10 μL of compound solutions at different concentration gradients (the concentration range of the compound is 0.15 μM to 80 μM) (add 20 μL of medium containing 7x10 3 cells per well). Incubate the cells at 37 °C for 7 hours. Detect the luciferase activity of the cells 7 hours after infection using the Steady-Glo luciferase system (Promega) kit and a 2030 ARVO X luminometer (Perkinelmer).

[0172] Obtain the EC 50 value of the compound by non-linear regression analysis of the dose-response curve, and the results are shown in Table 1.

[0173] 2. In vitro normal cell cytotoxicity experiment:

[0174] Culture African green monkey kidney cells (Vero E6) (add 20 μL of medium containing 7x10 3 cells per well) in a 384-well plate (catalog number 781080; Greiner Bio-One) at 37 °C, and then add 20 μL of compound solutions at different concentration gradients (the concentration range of the compound is 0.15 μM to 80 μM). Incubate the cells at 37 °C for 2 days, and then determine the cell viability using the CellTiter-Glo luminescent cell viability assay kit (Promega) and a 2030 ARVO X luminometer (Perkelmer) to obtain the CC 50 value, and the results are shown in Table 1.

[0175] Table 1

[0176]

[0177]

[0178] In summary, the compound of the present invention has a good inhibitory effect on human coronavirus HCoV-OC43 and very low toxicity to African green monkey kidney cells. This compound has excellent inhibitory effects on coronavirus HCoV-OC43 and has high safety while ensuring excellent inhibitory effects.

[0179] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including combinations of various specific technical features in any suitable manner. To avoid unnecessary repetition, the present invention will not separately describe various possible combination methods. However, these simple modifications and combinations should also be regarded as the content disclosed by the present invention and all fall within the protection scope of the present invention.

Claims

1. A nitro-containing diphenyl ether compound, characterized in that, The compound has the structure shown in formula (I), wherein, in formula (I), m is 0 or 1; R is selected from -NH-(CH2) n -L1-R1, -NH-R2, and -O-R3; In -NH-(CH2) n -L1-R1, n is an integer from 0 to 6, and R1 is selected from C1-C 10 alkyl, C1-C 10 alkoxy, C2-C8 alkynyl, halogen, cyano, benzaldehyde group, phenoxy group, triazolyl group, morpholinyl group, and phenyl substituted by at least one halogen; In -NH-R2, R2 is selected from a cycloalkyl group having 3 to C 10 carbons, an alkynyl group having 2 to C 10 carbons, -CH(Ph)2, a pyridyl group substituted by at least one halogen, or a pyridyl group substituted by at least one alkyl group having 1 to 6 carbon atoms; In -O-R3, R3 is selected from C1-C 10 alkyl groups; L and L1 are each independently a linking group provided by removing any two H atoms from benzene.

2. The compound according to claim 1, wherein In formula (I), m is 0 or 1; R is selected from -NH-(CH2) n -L1-R1, -NH-R2 and -O-R3; In -NH-(CH2) n -L1-R1, n is an integer from 0 to 4, and R1 is selected from the group consisting of C1-C8 alkyl, C1-C8 alkoxy, C2-C6 alkynyl, halogen, cyano, benzaldehyde group, phenoxy, triazolyl, morpholinyl, and phenyl substituted by at least one halogen; in -NH-R2, R2 is selected from one of cycloalkyl with 3 to 8 carbon atoms, alkynyl with 2 to 8 carbon atoms, -CH(Ph)2, pyridyl substituted by at least one halogen, and pyridyl substituted by at least one alkyl with 1 to 3 carbon atoms; in -O-R3, R3 is selected from alkyl with 1 to 8 carbon atoms; L and L1 are each independently a linking group provided by removing any two H atoms from benzene; the halogen is selected from at least one of chlorine, bromine, and iodine; Preferably, in formula (I), m is 0 or 1; R is selected from one of -NH-(CH2) n -L1-R1, -NH-R2, and -O-R3; In -NH-(CH2) n -L1-R1, n is 0 or 1, and R1 is selected from the group consisting of methyl, ethyl, methoxy, ethynyl, halogen, cyano, benzaldehyde group, phenoxy group, triazolyl group, morpholinyl group, and phenyl substituted by at least one halogen; in -NH-R2, R2 is selected from one of cyclopropyl, cyclohexyl, propynyl, -CH(Ph)2, pyridyl substituted by at least one halogen, and pyridyl substituted by at least one methyl; in -O-R3, R3 is selected from methyl and ethyl; L and L1 are each independently a linking group provided by removing any two H atoms from benzene; the halogen is selected from at least one of chlorine, bromine, and iodine.

3. The compound according to claim 2, wherein The organic compound shown in formula (I) is selected from any one of the following:

4. The compound according to claim 3, wherein The organic compound shown in formula (I) is selected from any one of the following:

5. Use of the compound according to any one of claims 1-4 in an inhibitor of coronavirus HCoV-OC43.

6. A coronavirus HCoV-OC43 inhibitor, characterized in that, The inhibitor comprises an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient is the compound according to any one of claims 1-4.

7. The inhibitor according to claim 6, characterized in that, The pharmaceutically acceptable excipient is selected from at least one of excipients, diluents, binders, and lubricants; and / or, the excipient is selected from at least one of calcium carbonate and calcium phosphate; and / or, the diluent is selected from at least one of lactose, cyclodextrin, and calcium sulfate; and / or, the binder is selected from at least one of ethanol, glycerol, propylene glycol, and syrup; and / or, the lubricant is selected from at least one of silica, corn starch, and liquid paraffin.

8. The inhibitor according to claim 6 or 7, characterized in that, The content of the active ingredient is 0.01-99.99 wt%.

9. The inhibitor according to any one of claims 6-8, wherein The content of the active ingredient is 0.1-99.9 wt%.

10. The inhibitor according to any one of claims 6-9, characterized in that, The dosage form of the inhibitor is selected from at least one of hydrates, powders, emulsions, suspensions, and granules.

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