Amide derivatives with RSV inhibitory activity, their preparation methods and applications

Abstract

The present invention discloses amide derivatives having RSV inhibitory activity, and their preparation methods and applications. The present invention provides an amide derivative having RSV inhibitory activity with the structure shown in formula (I), a pharmaceutical composition and a hydrate containing the derivative of formula (I), as well as isotope derivatives, chiral isomers, allosteric isomers, different salts, prodrugs and preparations of these compounds, etc. The present invention also provides a preparation method of the amide derivative having RSV virus inhibitory activity and the application of these compounds in antiviral treatment.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to an amide derivative having inhibitory activity against Respiratory Syncytial Virus (RSV), and a preparation method and application thereof. Background Art

[0002] Respiratory Syncytial Virus (RSV) is a non-segmented, negative-strand, enveloped RNA virus, belonging to the family Paramyxoviridae, genus Pneumovirus, subfamily Pneumovirinae. Human respiratory syncytial virus is an important pathogen of human respiratory diseases, the main cause of lower respiratory tract diseases and bronchiolitis in children, and also an important cause of morbidity and mortality in the elderly and immunocompromised patients.

[0003] The RSV gene is a single-stranded non-segmented negative RNA molecule, containing 10 genes encoding 11 proteins: NS1, NS2, N, P, M, SH, G, F, M2-1, M2-2, and L (the m gene encodes two proteins - M2-1 and M2-2). The genomic RNA is encapsulated in a nucleocapsid composed of the N protein, RNA polymerase (L protein), its cofactor (P protein), and M2-1 protein. HRSV can be divided into two subtypes, A and B, according to the antigenicity of the G protein. Each subtype is divided into different genotypes according to the nucleotide sequence of the second highly variable region at the C-terminus of the G gene.

[0004] The prevalence of RSV is also associated with the subtypes (A, B) of the virus. Subtype A has high polymorphism, and the virus evolution rate of subtype B is faster than that of subtype A. Overall, the nucleotide metabolism rates of the two subtypes are the same. There are also differences in the prevalence patterns of the two subtypes, and most infection epidemics are mainly dominated by one subtype (subtype A). RSV is mainly transmitted through droplets and close contact in the air, infects through inhalation via the mouth and nose, has an incubation period of 3-7 days in the body, and can survive on the surface of objects for 12-24 hours. During this period, it is also possible to infect the virus through close contact.

[0005] Preventive treatment of RSV still faces huge challenges. Currently, there are two therapies licensed for the treatment of diseases caused by severe RSV infection. Ribavirin is the first licensed therapeutic agent, an antiviral nucleoside analogue, which was recommended for the treatment of severe RSV infection in 1993. However, the clinical trials of this drug had methodological flaws, and the efficacy of Ribavirin was overstated. Subsequent studies found that the benefits of Ribavirin were limited or non-existent. The only currently licensed preventive measure, Palivizumab, a humanized monoclonal antibody against RSV, was licensed for the prevention of RSV infection in 1998. Due to the high cost, limited efficacy, and the need for monthly prophylactic injections of Palivizumab, it is only used for high-risk infants.

[0006] Developing RSV inhibitors with novel structures is of great significance. WO2022 / 092141 discloses an amide derivative I-082 with antiviral activity, and its structure is as follows: I-082 has strong inhibitory activity against the two antigenic subtypes A and B of RSV. However, the synthesis of the hexahydrospiro[indole-3,4'-pyran] moiety in its structure is relatively complex, and this oxygen-containing six-membered heterocycle is easily metabolized by metabolic enzymes, which is not conducive to obtaining good drug properties. Based on this, the present invention has explored many different alternative groups for the "hexahydrospiro[indole-3,4'-pyran] moiety". Summary of the Invention

[0007] The first object of the present invention is to provide a novel amide derivative with RSV inhibitory activity in view of the deficiencies in the prior art such as the complex synthesis of the "hexahydrospiro[indole-3,4'-pyran] moiety" and its easy metabolism by metabolic enzymes.

[0008] An amide derivative having anti-RSV virus inhibitory activity, or its optical isomer, racemate, single enantiomer, possible diastereomer, or its pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate, and the structure of the derivative is shown in formula (I):

[0009]

[0010] Wherein:

[0011] R is a hydrogen atom, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted non-aromatic heteroepoxy group, a substituted or unsubstituted non-aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic carbocyclic epoxy group, a substituted or unsubstituted aromatic heteroepoxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a hydroxyl group, a halogen, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;

[0012] m is any natural number among 0, 1, 2, 3, 4, 5. When m is 0, n is any natural number among 3, 4, 5, 7, 8; when m is 1, 2, 3, 4, 5, n is any natural number among 0, 1, 2, 3, 4, 5;

[0013] L is selected from one of the following structures

[0014] R 1 is a carboxyl group, a cyano group, a substituted or unsubstituted aromatic heterocyclic group, -C(=O)-NR 1B R 1C or -CH=CHC(=O)-OH;

[0015] R 1B and R 1C are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aminosulfonyl group or a substituted or unsubstituted non-aromatic heterocyclic sulfonyl group;

[0016] R 2 is a substituted or unsubstituted alkyl group;

[0017] V is -CR V or -N=, W is =CR W or =N-;

[0018] R V and R W are each independently a hydrogen atom, a cyano group, a halogen-substituted or unsubstituted alkyl group or a substituted or unsubstituted carbamoyl group.

[0019] Preferably, R includes but is not limited to the following structures:

[0020]

[0021] Preferably, L is

[0022] Preferably, R 1 is a carboxyl group.

[0023] Preferably, the chemical structural formula of the amide derivative having anti-RSV virus inhibitory activity is any one of the following formulas 1 to 24:

[0024]

[0025] A method for preparing the above amide derivative having anti-RSV virus inhibitory activity, the synthetic route of the method is shown as follows:

[0026]

[0027] Raw material A1 and A2 undergo a substitution reaction to obtain intermediate A3; A3 and intermediate A4 undergo a substitution reaction to obtain A5; A5 undergoes an ester hydrolysis reaction to obtain carboxylic acid intermediate A6; finally, A6 and A7 undergo acid amide condensation to obtain the compound shown in formula (I).

[0028] The compound shown in formula (I) of the present invention can be prepared by the above method. However, the conditions of this method, such as reactants, solvents, the amounts of compounds used, reaction temperature, reaction time required, etc. are not limited to the above explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthesis methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0029] The third object of the present invention is to provide the application of the amide derivative having anti-RSV virus inhibitory activity, or its optical isomers, racemates, single enantiomers, possible diastereoisomers, or its pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates in the preparation of drugs for treating or preventing viruses.

[0030] The compounds of the present invention have been found to be inhibitors of RSV in biological tests. The compounds are thus therapeutically useful. Accordingly, the present invention further provides compounds, as defined above, which have the structure of formula (I) or its pharmaceutically acceptable salts, for use in a method of treating a human or animal body by treatment. The present invention also provides the compounds of the present invention as defined above, for use in a method of treating or preventing RSV infection. Further still, the present invention provides the use of the compounds of the present invention as defined above in the manufacture of a medicament for treating or preventing RSV infection. Subjects suffering from or susceptible to RSV infection can thus be treated by a method comprising administering to them the compounds of the present invention as defined above. The condition of the subjects can thus be improved or alleviated.

[0031] In one embodiment, the present invention provides the compounds defined above for treating or preventing RSV infection in pediatric patients. Optionally, the infection can be in mature or elderly adults, such as adults over 60 years old, adults over 70 years old, or adults over 80 years old. The present invention further provides compounds for treating or preventing RSV infection in elderly patients.

[0032] The fourth object of the present invention is to provide an antiviral drug containing a safe and effective amount of the above-mentioned amide derivative having anti-RSV virus inhibitory activity, or its optical isomer, racemate, single enantiomer, possible diastereomer, or its pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate.

[0033] Preferably, the antiviral drug may further include a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier.

[0034] Since the compounds of the present invention have the activity of inhibiting RSV virus, therefore, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for treating, preventing, and alleviating various diseases.

[0035] The "safe and effective amount" as used in the present invention means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, contains 5 - 1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0036] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatible" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0037] There are no particular limitations on the mode of administration of the compounds or pharmaceutical compositions of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0038] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or is admixed with the following components: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0039] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings and casings, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released at a certain site in the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0040] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0041] In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0042] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of these substances.

[0043] Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0044] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required, if necessary.

[0045] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0046] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 to 5000 mg, preferably 5 to 2000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0047] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0048] The present invention synthesizes a novel class of amide derivatives with RSV inhibitory activity. The synthesis method is concise and rapid, and the raw materials used can be purchased. It eliminates the difficulty of synthesizing complex structures. The synthesized amide derivatives still maintain their original good biological activity, thus increasing the means to deal with RSV infection. Compared with simple structural modification, it is pioneering. The present invention also provides a preparation method, uses of the amide derivatives with RSV inhibitory activity, and the activity of these compounds in inhibiting RSV genes. The amide derivative compounds in the present invention are expected to become candidate drugs for RSV infection diseases, which has far-reaching significance. Detailed Description of the Invention

[0049] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The operating methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0050] Example 1: Preparation of Compound 1

[0051]

[0052] Step 1: At room temperature, add 1a (2000 mg, 17.5 mmol, 1.0 equiv), 1b (1949 mg, 19.2 mmol, 1.2 equiv), and K2CO3 (7245 mg, 52.5 mmol, 3.0 equiv) to DMF. The mixed solution is reacted at 50 °C for 3 h. After detection by TLC, the reaction is complete. Rotate the reaction solution to dryness, and then quench the reactants by adding 250 mL of water. Extract the obtained solution with 3 × 250 mL of EtOAc. Combine the organic layers and concentrate. Apply the residue to a silica gel column (ethyl acetate: petroleum ether = 4:1). Combine and concentrate the collected eluates to obtain an oily substance. A total of 1c (2500 mg, yield 90%) of the target compound is obtained as a pale yellow oil.

[0053] Step 2: At room temperature, dissolve compound 1c (2500 mg, 13.96 mmol, 1.0 equiv), DMAP (170 mg, 1.39 mmol, 0.1 equiv), and Et3N (11.4 mL, 83.0 mmol, 6.0 equiv) in DCM. Place the mixed solution in an ice bath and add TsCl (6368 mg, 33.5 mmol, 2.4 equiv) dropwise at 0 °C. React at 0 °C for 8 h. After detection by TLC, the reaction is complete. Rotate the reaction solution to dryness, and then add 150 mL of water to the obtained crude product. Extract the obtained solution with 3 × 250 mL of EtOAc. Combine the organic layers and concentrate. Apply the residue to a silica gel column (ethyl acetate: petroleum ether = 4:1). Combine and concentrate the collected eluates to obtain a white solid. 1d (2000 mg, yield 90.0%) is obtained.

[0054] Step 3: Refer to the synthesis procedure of Step 1 in Example 1 to obtain a yellow oily substance 1i (426 mg, yield 61%).

[0055] Step 4: Refer to the synthesis procedure of Step 1 in Example 1 to obtain a yellow oily substance 1m (240 mg, yield 38%).

[0056] Step 5: Add NaOH (184 mg, 1.45 mmol, 10.00 equiv) to a solution of 1m (240 mg, 0.46 mmol, 1.00 equiv) in MeOH (2 mL), THF (1 mL), and H2O (1 mL). Stir the obtained solution at room temperature for 4 h. Then quench the reactants by adding 2 mL (1 M HCl). After detection by TLC, the reaction is complete. Then add 150 mL of water to the obtained crude product. Extract the obtained solution with 3 × 250 mL of EtOAc. Combine the organic layers and concentrate to obtain a white solid product 1n. The crude product is directly used in the next reaction without purification.

[0057] Step 6: At room temperature, compound 1n (116 mg, 0.27 mmol, 1.0 equiv), Et3N (68 mg, 0.675 mmol, 2.5 equiv) were added to DMF (1.5 mL), then HATU (133 mg, 0.35 mmol, 1.3 equiv) was added, and the mixture was stirred for 20 min. Subsequently, 1h (81 mg, 0.324 mmol, 1.2 equiv) was added in portions, and the mixture was stirred for 2 h. After the reaction was complete as detected by TLC, the reaction solution was concentrated in vacuo. Subsequently, 150 mL of water was added to the obtained crude product. The resulting solution was extracted with 3 × 150 mL of EtOAc and the organic layers were combined. The organic layer was washed with 250 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give yellow solid compound 1p (152 mg, yield 86.0%) for the next reaction.

[0058] Step 7: At room temperature, compound 1p (152 mg, 0.234 mmol, 1.0 equiv) was added to DCM (1 mL), then CF3COOH (1 mL) was added, and the mixture was stirred for 1 h. After the reaction was complete as detected by TLC, 150 mL of water was added to the obtained crude product. The resulting solution was extracted with 3 × 150 mL of EtOAc and the organic layers were combined. The organic layer was washed with 250 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was recrystallized from petroleum ether and dichloromethane to give white solid compound 1 (66 mg, yield 47%). 1 HNMR(500MHz,CDCl3)δ8.67(s,1H),8.52(d,J=5.0Hz,2H),7.14(d,J=7.8Hz,1H),6.82(dd,J=8.4,2.5Hz,1H),6.77(d,J=2.5Hz,1H),6.70(t,J=5.0Hz,1H),6.21(s,1H),4.91(s,2H),4.66–4.60(m,1H),4.10(t,J=5.6Hz,2H),4.05(q,J=6.4,6.0Hz,4H),2.93(t,J=6.0Hz,2H),2.64(s,2H),2.19(d,J=13.2Hz,2H),2.05–1.94(m,6H),1.89(s,2H),1.81(s,1H),1.76(q,J=9.1,7.2Hz,5H).

[0059] Example 2: Preparation of Compound 2

[0060]

[0061] Step 1: Referring to the synthesis procedure of Step 1 in Example 1, yellow oil 2i (391 mg, yield 55%) was obtained.

[0062] Step 2: Referring to the synthesis steps of Step 1 in Example 1, a yellow oil 2m (267 mg, yield 37%) was obtained.

[0063] Step 3: Referring to the synthesis steps in Step 5 of Example 1, a white solid compound 2n was obtained. The product was used directly in the next reaction without purification.

[0064] Step 4: Referring to the synthesis steps in Step 6 of Example 1, a yellow oil compound 2m (87 mg, yield 17%) was obtained.

[0065] Step 5: Referring to the synthesis steps in Step 7 of Example 1, a white solid compound 2 (25 mg, yield 23%) was obtained. 1 HNMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 8.45 (d, J = 5.1 Hz, 2H), 7.41 (d, J = 2.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.5 Hz, 1H), 6.63 (s, 1H), 4.51 (tt, J = 6.6, 3.4 Hz, 1H), 4.12–4.01 (m, 4H), 3.89 (dt, J = 12.4, 4.6 Hz, 2H), 2.80 (s, 1H), 2.74 (t, J = 6.6 Hz, 2H), 2.59 (s, 2H), 2.15–2.03 (m, 3H), 2.03–1.97 (m, 4H), 1.97–1.89 (m, 3H), 1.81 (d, J = 14.6 Hz, 2H), 1.70 (d, J = 11.6 Hz, 6H).

[0066] Example 3: Preparation of Compound 3

[0067]

[0068] Step 1: Referring to the synthesis steps of Step 1 in Example 1, a yellow oil 3f (370 mg, yield 52%) was obtained.

[0069] Step 2: Referring to the synthesis steps of Step 1 in Example 1, a yellow oil 3m (280 mg, yield 37%) was obtained.

[0070] Step 3: Referring to the synthesis steps in Step 5 of Example 1, a white solid compound 3n was obtained. The product was used directly in the next reaction without purification.

[0071] Step 4: Referring to the synthesis steps in Step 6 of Example 1, a yellow oil compound 3p (101 mg, yield 23%) was obtained.

[0072] Step 5: Refer to the synthesis step in Step 7 of Example 1 to obtain white solid compound 3 (55 mg, yield 54%). 1 HNMR(500MHz,CDCl3)δ8.71(s,1H),8.48(d,J=4.9Hz,2H),7.72(d,J=8.9Hz,1H),6.82(dd,J=9.0,2.9Hz,1H),6.77(s,1H),6.66(s,1H),6.47(s,1H),4.62(tt,J=6.7,3.4Hz,1H),4.17–4.08(m,4H),3.95(ddd,J=13.6,7.0,3.9Hz,2H),2.82(t,J=6.6Hz,2H),2.65(s,2H),2.30–2.18(m,2H),2.05(td,J=10.8,9.4,4.4Hz,6H),1.97(ddt,J=10.5,6.7,3.6Hz,2H),1.92(p,J=3.2Hz,2H),1.86–1.73(m,6H).

[0073] Example 4: Preparation of Compound 4

[0074]

[0075] Step 1: Refer to the synthesis step in Step 1 of Example 1 to obtain yellow oil 4i (360 mg, yield 55%).

[0076] Step 2: Refer to the synthesis step in Step 1 of Example 1 to obtain yellow oil 4m (280 mg, yield 37%).

[0077] Step 3: Refer to the synthesis step in Step 5 of Example 1 to obtain white solid compound 4n. The product is used directly in the next reaction without purification.

[0078] Step 4: Refer to the synthesis step in Step 6 of Example 1 to obtain yellow oil compound 4p (120 mg, yield 27%).

[0079] Step 5: Refer to the synthesis step in Step 7 of Example 1 to obtain white solid compound 4 (50 mg, yield 53%). 1HNMR(500MHz,CDCl3)δ8.57(s,1H),8.26(d,J=4.8Hz,2H),7.01(d,J=8.3Hz,1H),6.81–6.61(m,2H),6.42(t,J=4.8Hz,1H),6.22(s,1H),4.84(s,2H),4.47(dt,J=7.5,3.7Hz,1H),4.08(ddd,J=13.4,7.5,3.8Hz,2H),4.01(t,J=5.9Hz,2H),3.64(ddd,J=13.1,8.1,3.5Hz,2H),2.80(t,J=5.9Hz,2H),2.52(s,2H),2.17–2.02(m,2H),1.93(tdd,J=13.3,8.6,3.4Hz,4H),1.84–1.71(m,4H),1.71–1.59(m,6H).

[0080] Example 5: Preparation of Compound 5

[0081]

[0082] Step 1: Referring to the synthetic procedure of Step 1 in Example 1, a yellow oil 5i (176 mg, yield 84%) was obtained.

[0083] Step 2: Referring to the synthetic procedure of Step 1 in Example 1, a yellow oil 5m (100 mg, yield 83%) was obtained.

[0084] Step 3: Referring to the synthetic procedure of Step 5 in Example 1, a white solid compound 5n was obtained. The product was directly used in the next step without purification.

[0085] Step 4: Referring to the synthetic procedure of Step 6 in Example 1, a yellow oil compound 5p (50 mg, yield 43%) was obtained.

[0086] Step 5: Referring to the synthetic procedure of Step 7 in Example 1, a white solid compound 5 (20 mg, yield 23%) was obtained. 11H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J = 4.8 Hz, 2H), 7.60 (d, J = 8.9 Hz, 1H), 6.73 (dd, J = 9.0, 2.9 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.45 (s, 1H), 5.82 (s, 1H), 4.49 (s, 1H), 4.09 (td, J = 9.2, 7.7, 4.7 Hz, 2H), 4.01 (t, J = 6.2 Hz, 2H), 3.75 (s, 3H), 2.76–2.69 (m, 3H), 2.49 (s, 2H), 2.11 (d, J = 13.2 Hz, 2H), 1.95 (p, J = 6.4 Hz, 4H), 1.89 (d, J = 13.2 Hz, 3H), 1.80 (s, 5H), 1.73–1.61 (m, 7H), 1.59–1.45 (m, 8H).

[0087] Example 6: Preparation of Compound 6

[0088]

[0089] Step 1: Referring to the synthetic procedure of Step 1 in Example 1, a yellow oil 6i (259 mg, yield 61%) was obtained.[[ID=??]] [[ID=??]]

[0090] Step 2: Compound 6i (250 mg, 0.63 mmol, 1.0 equiv) was dissolved in MeOH (3 mL), and dioxane hydrochloride (1 mL) was added. The reaction was carried out at room temperature for 4 h. After TLC detection, the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain Compound 6g. The crude product was used directly in the next step without purification.

[0091] Step 3: Referring to the synthetic procedure of Step 1 in Example 1, a white solid Compound 6m (170 mg, yield 52%) was obtained.

[0092] Step 4: Referring to the synthetic procedure of Step 5 in Example 1, a white solid Compound 6n was obtained. The crude product was used directly in the next step without purification.

[0093] Step 5: Referring to the synthetic procedure of Step 6 in Example 1, a white solid Compound 6p (79 mg, yield 34%) was obtained.

[0094] Step 6: Referring to the synthetic procedure of Step 7 in Example 1, a white solid Compound 6 (50 mg, yield 69%) was obtained. 1 Note: There seems to be some incorrect line numbering in your original text. I've translated it as accurately as possible based on the content. If you have any further clarification or correction regarding the text, please let me know.1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.38 (s, 1H), 8.32 (d, J = 4.7 Hz, 2H), 7.30 (dd, J = 8.4, 4.0 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.93 (dt, J = 8.3, 2.9 Hz, 1H), 6.57 (t, J = 4.7 Hz, 1H), 4.79 (t, J = 17.9 Hz, 4H), 4.62 (qt, J = 7.9, 3.6 Hz, 1H), 4.26 - 4.10 (m, 2H), 3.57 - 3.44 (m, 2H), 2.46 (p, J = 1.9 Hz, 2H), 2.06 (dd, J = 24.7, 12.7 Hz, 4H), 1.95 (ddt, J = 13.3, 7.0, 3.3 Hz, 2H), 1.81 - 1.71 (m, 2H), 1.70 - 1.60 (m, 4H), 1.55 (ddd, J = 20.4, 14.2, 10.1 Hz, 4H).

[0095] Example 7: Preparation of Compound 7

[0096]

[0097] Step 1: Referring to the synthetic procedure of Step 1 in Example 1, a yellow oil 7i (355 mg, yield 95%) was obtained.

[0098] Step 2: Referring to the synthetic procedure of Step 1 in Example 1, a yellow oil 7m (120 mg, yield 23%) was obtained.

[0099] Step 3: Referring to the synthetic procedure of Step 5 in Example 1, a white solid compound 7n was obtained. The product was directly used in the next reaction without purification.

[0100] Step 4: Referring to the synthetic procedure of Step 6 in Example 1, a yellow oil compound 7p (90 mg, yield 83%) was obtained.

[0101] Step 5: Referring to the synthetic procedure of Step 7 in Example 1, a white solid compound 7 (78 mg, yield 90%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.36 (d, J = 4.7 Hz, 2H), 7.30 (s, 1H), 7.12 - 6.85 (m, 2H), 6.62 (t, J = 4.8 Hz, 1H), 4.81 (d, J = 36.5 Hz, 6H), 4.15 (d, J = 57.1 Hz, 2H), 3.60 (d, J = 57.4 Hz, 2H), 2.62 (s, 2H), 2.19 (s, 2H), 2.03 (d, J = 36.9 Hz, 5H), 1.74 (s, 2H), 1.69 - 1.55 (m, 6H), 1.54 - 1.42 (m, 3H).

[0102] Example 8: Preparation of Compound 8

[0103]

[0104] Step 1: Referring to the synthesis procedure in Step 1 of Example 1, a yellow oil 8i (302 mg, yield 61%) was obtained.

[0105] Step 2: Referring to the synthesis procedure in Step 1 of Example 1, a yellow oil 8m (206 mg, yield 47%) was obtained.

[0106] Step 3: Referring to the synthesis procedure in Step 5 of Example 1, a white solid compound 8n was obtained. The product was directly used in the next step without purification.

[0107] Step 4: Referring to the synthesis procedure in Step 6 of Example 1, a yellow oil compound 8p (160 mg, yield 60%) was obtained.

[0108] Step 5: Referring to the synthesis procedure in Step 7 of Example 1, a white solid compound 8 (36 mg, yield 49%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 2H), 8.33 (d, J = 4.7 Hz, 2H), 7.13 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.58 (t, J = 4.7 Hz, 1H), 4.82 (s, 2H), 4.78 - 4.68 (m, 1H), 4.20 - 3.86 (m, 4H), 3.69 (s, 2H), 2.83 (t, J = 6.1 Hz, 2H), 2.47 (p, J = 1.9 Hz, 3H), 1.97 (d, J = 37.2 Hz, 6H), 1.68 (s, 4H), 1.56 (d, J = 16.1 Hz, 4H), 1.45 (d, J = 12.4 Hz, 2H).

[0109] Example 9: Preparation of Compound 9

[0110]

[0111] Step 1: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oil 9i (302 mg, yield 61%) was obtained.

[0112] Step 2: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oil 9m (206 mg, yield 47%) was obtained.

[0113] Step 3: Referring to the synthesis procedure of Step 5 in Example 1, a white solid compound 9n was obtained. The product was directly used in the next step without purification.

[0114] Step 4: Referring to the synthesis procedure of Step 6 in Example 1, a yellow oil compound 9p (287 mg, yield 78%) was obtained.

[0115] Step 5: Referring to the synthesis procedure of Step 7 in Example 1, a white solid compound 9 (180 mg, yield 85%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.35 (d, J = 4.7 Hz, 3H), 7.16 (t, J = 8.0 Hz, 1H), 7.01 - 6.73 (m, 2H), 6.60 (t, J = 4.9 Hz, 1H), 4.89 (s, 2H), 4.69 (s, 1H), 4.02 (s, 4H), 3.81 - 3.59 (m, 2H), 2.78 (s, 2H), 2.57 (s, 2H), 2.08 (t, J = 17.3 Hz, 4H), 1.93 (t, J = 10.3 Hz, 3H), 1.73 (s, 2H), 1.62 (s, 6H), 1.53 - 1.35 (m, 3H).

[0116] Example 10: Preparation of Compound 10

[0117]

[0118] Step 1: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oil 10i (832 mg, yield 72%) was obtained.

[0119] Step 2: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oil 10m (709 mg, yield 51%) was obtained.

[0120] Step 3: Referring to the synthesis procedure of Step 5 in Example 1, a white solid compound 10n was obtained. The product was directly used in the next step without purification.

[0121] Step 4: Refer to the synthesis step in Step 6 of Example 1 to obtain yellow oily compound 10p (287 mg, yield 78%).

[0122] Step 5: Refer to the synthesis step in Step 7 of Example 1 to obtain white solid compound 10 (168 mg, yield 62%). 1 H NMR (500 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.31 (d, J = 4.7 Hz, 2H), 7.11 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 8.4, 1.3 Hz, 1H), 6.82 (dd, J = 7.6, 1.1 Hz, 1H), 6.57 (t, J = 4.7 Hz, 1H), 4.55 (dt, J = 7.6, 3.9 Hz, 1H), 3.79 (d, J = 15.2 Hz, 4H), 3.51 (ddd, J = 12.6, 8.3, 3.6 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 2.50 (p, J = 1.9 Hz, 2H), 2.06 (t, J = 10.2 Hz, 4H), 1.93 (p, J = 6.8 Hz, 2H), 1.83 - 1.72 (m, 4H), 1.71 - 1.60 (m, 4H), 1.52 (d, J = 12.7 Hz, 2H), 1.35 (d, J = 14.5 Hz, 2H).

[0123] Example 11: Preparation of Compound 11

[0124]

[0125] Step 1: Refer to the synthesis step in Step 1 of Example 1 to obtain yellow oil 11b (530 mg, yield 63%).

[0126] Step 2: Refer to the synthesis step in Step 2 of Example 1 to obtain yellow solid compound 11c (440 mg, yield 87%).

[0127] Step 3: Refer to the synthesis step in Step 1 of Example 1 to obtain yellow oily compound 11i (279 mg, yield 65%).

[0128] Step 4: Refer to the synthesis step in Step 5 of Example 1 to obtain white solid compound 11m. The crude product is used directly in the next reaction without purification.

[0129] Step 5: Refer to the synthesis step in Step 6 of Example 1 to obtain white solid compound 11p (196 mg, yield 60%).

[0130] Step 6: Refer to the synthesis steps in Step 6 of Example 1 to obtain white solid compound 11 (20 mg, yield 32%). 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.37 (d, J = 4.8 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.87 - 6.79 (m, 1H), 6.74 (dd, J = 8.3, 2.7 Hz, 1H), 6.71 (t, J = 4.8 Hz, 1H), 5.20 - 5.09 (m, 1H), 4.90 (s, 2H), 4.62 - 4.41 (m, 2H), 4.02 (d, J = 7.5 Hz, 2H), 3.96 (dd, J = 10.1, 3.9 Hz, 2H), 2.83 (t, J = 5.9 Hz, 2H), 2.50 (p, J = 1.9 Hz, 3H), 2.07 (s, 4H), 1.75 (s, 2H), 1.64 (d, J = 8.9 Hz, 4H), 1.52 (d, J = 12.6 Hz, 2H).

[0131] Example 12: Preparation of Compound 12

[0132]

[0133] Step 1: Refer to the synthesis steps in Step 2 of Example 1 to obtain yellow solid compound 12b (834 mg, yield 97%).

[0134] Step 2: Refer to the synthesis steps in Step 1 of Example 1 to obtain yellow oily compound 12c (463 mg, yield 82%).

[0135] Step 3: Refer to the synthesis steps in Step 2 of Example 6 to obtain white solid compound 12d. The reaction was used directly in the next step without purification.

[0136] Step 4: Refer to the synthesis steps in Step 1 of Example 1 to obtain white solid compound 12e (279 mg, yield 65%).

[0137] Step 5: Refer to the synthesis steps in Step 5 of Example 1 to obtain white solid compound 12f. The crude product was used directly in the next step without purification.

[0138] Step 6: Refer to the synthesis steps in Step 6 of Example 1 to obtain white solid compound 12g (276 mg, yield 95%).

[0139] Step 7: Refer to the synthesis steps in Step 7 of Example 1 to obtain white solid compound 12g (131 mg, yield 51%). 11H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.33 (d, J = 4.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.84 - 6.76 (m, 1H), 6.70 (dd, J = 8.3, 2.6 Hz, 1H), 6.65 (t, J = 4.8 Hz, 1H), 4.87 (s, 2H), 4.67 (p, J = 6.9 Hz, 1H), 4.11 (s, 2H), 4.02 (q, J = 8.5, 7.8 Hz, 4H), 2.88 - 2.73 (m, 4H), 2.51 (q, J = 1.8 Hz, 1H), 2.34 - 2.20 (m, 2H), 2.07 (t, J = 13.8 Hz, 4H), 1.99 (s, 1H), 1.76 (s, 2H), 1.64 (d, J = 8.2 Hz, 4H), 1.56 - 1.47 (m, 2H).

[0140] Example 13: Preparation of Compound 13

[0141]

[0142] Step 1: Referring to the synthesis procedure of Step 2 in Example 1, a yellow solid compound 13b (176 mg, yield 84%) was obtained.

[0143] Step 2: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oily compound 13c (372 mg, yield 72%) was obtained.

[0144] Step 3: Referring to the synthesis procedure of Step 2 in Example 6, a white solid compound 13d was obtained. The reaction was directly used in the next step without purification.

[0145] Step 4: Referring to the synthesis procedure of Step 1 in Example 1, a white solid compound 13e (276 mg, yield 95%) was obtained.

[0146] Step 5: Referring to the synthesis procedure of Step 5 in Example 1, a white solid compound 13f was obtained. The crude product was directly used in the next step without purification.

[0147] Step 6: Referring to the synthesis procedure of Step 6 in Example 1, a white solid compound 13g (120 mg, yield 43%) was obtained.

[0148] Step 7: Referring to the synthesis procedure of Step 7 in Example 1, a white solid compound 13 (47 mg, yield 55%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 2H), 8.32 (d, J = 4.7 Hz, 2H), 7.07 (d, J = 8.5 Hz, 1H), 6.76 (s, 1H), 6.71 - 6.64 (m, 1H), 6.56 (t, J = 4.7 Hz, 1H), 4.80 (d, J = 50.0 Hz, 3H), 4.06 - 3.86 (m, 2H), 3.74 (t, J = 5.5 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.78 (s, 2H), 2.50 (p, J = 1.8 Hz, 3H), 2.45 (d, J = 9.5 Hz, 2H), 2.06 (s, 4H), 1.87 - 1.77 (m, 2H), 1.76 - 1.66 (m, 2H), 1.66 - 1.58 (m, 4H), 1.58 - 1.52 (m, 3H), 1.48 (t, J = 7.7 Hz, 2H).

[0149] Example 14: Preparation of Compound 14

[0150]

[0151] Step 1: To Compound 1a (124 mg, 1.08 mmol), add 4i (200 mg, 0.544 mmol), KOH (60 mg, 1.08 mmol), dibenzo-18-crown (9.8 mg, 0.0272 mmol), PhCH3 (5 mL), and heat to 130 °C with stirring for 4 h. After detecting the completion of the reaction by TLC, quench the reaction with water. After the reaction cools to room temperature, extract with DCM (10 mL × 3), and wash with an aqueous NaCl solution (10 mL). Combine the organic phases, dry over anhydrous Na2SO4. Filter off the desiccant, concentrate the filtrate, and purify the crude product by silica gel column chromatography (eluted with an EtOAc / Petroleum ether system) to obtain yellow solid Compound 14i (94 mg, yield 20%).

[0152] Step 2: Refer to the synthesis procedure of Step 5 in Example 1 to obtain white solid Compound 14m. The crude product is used directly in the next step without purification.

[0153] Step 3: Refer to the synthesis procedure of Step 6 in Example 1 to obtain white solid Compound 14p (78 mg, yield 63%).

[0154] Step 4: Refer to the synthesis procedure of Step 7 in Example 1 to obtain white solid Compound 14 (25 mg, yield 39%). 11H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J = 4.8 Hz, 2H), 8.55 (s, 2H), 7.38 - 7.21 (m, 2H), 7.20 - 7.12 (m, 1H), 7.02 (dd, J = 8.2, 2.5 Hz, 1H), 4.93 (s, 2H), 4.05 (d, J = 7.6 Hz, 2H), 2.92 (t, J = 6.0 Hz, 2H), 2.50 (p, J = 1.8 Hz, 2H), 2.08 (d, J = 14.0 Hz, 4H), 1.76 (s, 2H), 1.63 (d, J = 17.3 Hz, 4H), 1.52 (d, J = 12.6 Hz, 2H).

[0155] Example 15: Preparation of Compound 15

[0156]

[0157] Step 1: Referring to the synthesis procedure of Step 2 in Example 1, a yellow solid compound 15b (600 mg, yield 85%) was obtained.

[0158] Step 2: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oily compound 15i (236 mg, yield 44%) was obtained.

[0159] Step 3: Referring to the synthesis procedure of Step 5 in Example 1, a white solid compound 15m was obtained. The crude product was directly used in the next step without purification.

[0160] Step 4: Referring to the synthesis procedure of Step 6 in Example 1, a white solid compound 15p (236 mg, yield 71%) was obtained.

[0161] Step 5: Referring to the synthesis procedure of Step 7 in Example 1, a white solid compound 15 (68 mg, yield 45%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.39 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 6.82 (dd, J = 8.4, 2.6 Hz, 1H), 4.88 (s, 2H), 4.59 (tt, J = 8.0, 3.7 Hz, 1H), 4.17 - 3.93 (m, 2H), 3.93 - 3.77 (m, 1H), 3.67 (dd, J = 9.3, 5.6 Hz, 1H), 3.32 (ddd, J = 13.1, 8.9, 3.4 Hz, 2H), 3.21 (ddd, J = 12.8, 8.9, 3.6 Hz, 1H), 2.82 (t, J = 5.8 Hz, 2H), 2.50 (p, J = 1.9 Hz, 2H), 2.08 (t, J = 14.0 Hz, 4H), 2.01 (s, 3H), 1.99 - 1.91 (m, 1H), 1.88 (dq, J = 15.0, 6.1, 5.0 Hz, 1H), 1.78 (s, 2H), 1.66 (d, J = 11.4 Hz, 4H).

[0162] Example 16: Preparation of Compound 16

[0163]

[0164] Step 1: Referring to the synthesis procedure of Step 2 in Example 1, a yellow solid compound 16b (176 mg, yield 84%) was obtained.

[0165] Step 2: Referring to the synthesis procedure of Step 1 in Example 1, a yellow oily compound 16i (500 mg, yield 80%) was obtained.

[0166] Step 3: Referring to the synthesis procedure of Step 5 in Example 1, a white solid compound 16m was obtained. The crude product was used directly in the next step without purification.

[0167] Step 4: Referring to the synthesis procedure of Step 6 in Example 1, a white solid compound 16p (150 mg, yield 75%) was obtained.

[0168] Step 5: Referring to the synthesis procedure of Step 7 in Example 1, a white solid compound 16 (38 mg, yield 40%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ 8.52 (d, J = 30.8 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 6.76 (dd, J = 8.3, 2.6 Hz, 1H), 4.82 (s, 2H), 4.53 (tt, J = 7.8, 3.5 Hz, 1H), 3.95 (t, J = 5.7 Hz, 2H), 3.79 (dt, J = 12.8, 4.7 Hz, 1H), 3.61 (dt, J = 13.8, 4.9 Hz, 1H), 3.27 (ddd, J = 13.2, 8.8, 3.4 Hz, 1H), 3.16 (ddt, J = 14.0, 8.6, 4.3 Hz, 1H), 2.76 (t, J = 5.9 Hz, 2H), 2.46 (p, J = 1.9 Hz, 2H), 1.99 (d, J = 25.5 Hz, 7H), 1.93 - 1.79 (m, 2H), 1.74 - 1.64 (m, 2H), 1.62 - 1.50 (m, 5H), 1.50 - 1.38 (m, 3H).

[0169] Example 17: Test for RSV Inhibitory Activity

[0170] 1. Experimental Materials and Instruments

[0171] 2. Experimental Method

[0172] HEp-2 cells were seeded into a microplate at a certain density and cultured overnight in an incubator with 5% CO2 at 37 °C. The next day, the diluted compound and RSV Along virus were added. A cell control (cells, without compound treatment or virus infection) and a virus control (cells infected with the virus, without compound treatment) were set. The final concentration of DMSO in the culture medium was 0.5% respectively. The cells were cultured in an incubator with 5% CO2 at 37 °C for 5 days. The cytotoxicity experiment was carried out under the same conditions as the antiviral experiment, but without virus infection. The cell viability was detected using the CellTiter-Glo® Luminescent Cell Viability Assay Kit. The antiviral activity and cytotoxicity of the compound were represented by the inhibition rate (%) of the compound on the cytopathic effect caused by the virus and the viability (%) of HEp-2 cells at different concentrations respectively. Nonlinear fitting analysis of the inhibition rate and cell viability of the compound was performed using GraphPad Prism to calculate the half-maximal effective concentration (EC 50 ) and the half-maximal cytotoxic concentration (CC 50 ) values.

[0173] 3. Experimental Results

[0174]

[0175]

[0176] Note: I-082 is the RSV inhibitor with the optimal activity shown in patent WO2022092141, and ALS-8112 is a reported highly efficient and selective respiratory syncytial virus (RSV) polymerase inhibitor.

[0177] + indicates that the compound EC 50 > 10000 nM, CC 50 > 10000 nM

[0178] ++ indicates that the compound 10000 nM > EC 50 > 1000 nM, 10000 nM > CC 50 > 1000 nM

[0179] +++ indicates that the compound 1000 nM > EC 50 > 50 nM, 1000 nM > CC 50 > 50 nM,

[0180] ++++ indicates that the compound EC 50 < 50 nM, CC 50 < 50 nM

[0181] Conclusion: Some compounds of the present invention have obvious inhibitory effects on RSV, and their activities are equivalent to those of I-082 and superior to those of the RSV inhibitor ALS-8112. CC 50 The results show that the compounds of the present invention have certain safety.

[0182] Example 18: Pharmacokinetic test of the compound RSV

[0183] 1. Experimental method

[0184] Eighteen ICR (Improved Castle Road) mice, SPF grade, weighing 21.10 - 24.40 g, were purchased from Hunan Slack Jingda Experimental Animal Co., Ltd. They were divided into two groups: Group 1 (intravenous injection group, 9 mice) and Group 2 (oral administration group, 9 mice). They were fasted for 12 h before dosing. Then, ICR mice were administered compounds I - 082, 4, and 6 by intravenous injection (i.v.) at a dose of 1 mg / kg and oral gavage (p.o.) at a dose of 3 mg / kg. Solvent for intravenous injection / oral administration: 5% DMSO + 15% Solutol HS15 + 80% PBS (preheated at 40 °C). Then, 0.1 mL of blood samples were obtained by tail vein blood collection at the following time points. Blood collection time points for intravenous administration: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing; blood collection time points for oral administration: 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing. The obtained blood samples were placed in labeled EDTA - 2K anticoagulant tubes. After gently inverting up and down to fully mix the anticoagulant (EDTA - 2K) with the blood, they were immediately placed on wet ice and centrifuged to separate plasma within 1 h after blood collection. The centrifugation conditions were set at 4 °C, 6800 r, and 6 min. The plasma separated after centrifugation was filled into labeled EP tubes and stored in an ultra - low temperature freezer before analysis. The concentration of the drug in the plasma of the samples was determined by LC - MS, and the relevant pharmacokinetic parameters were calculated using WinkNonlin software.

[0185] 2. Experimental Results

[0186]

[0187] Note: For Cassette PK, mice were used, and each rat was simultaneously gavaged or injected with four to five different compounds.

[0188] For Full PK, ICR mice were used, and each mouse was simultaneously gavaged or injected with one compound. Conclusion: Compounds R - 011 and R - 022 of the present invention have good pharmacokinetic properties. Among them, the absorption and utilization of compound R - 022 is better than that of the positive compound I - 082, and it has certain research value.

Claims

1. An amide derivative having anti-RSV virus inhibitory activity, characterized in that, The structure of the derivative is shown in formula (I): Wherein: R is selected from the following structures: m is any natural number among 1, 2, 3, 4, 5; n is any natural number among 1, 2, 3, 4, 5; L is R 1 is a carboxyl group; R 2 is an unsubstituted alkyl group; V is -CR V or -N=, W is =CR W or =N-; R V and R W each independently represents one of a hydrogen atom, a cyano group, a halogen-substituted alkyl group, an unsubstituted alkyl group, or an unsubstituted carbamoyl group.

2. The amide derivative having anti-RSV virus inhibitory activity as described in claim 1, wherein The chemical structural formula of the amide derivative with anti-RSV virus inhibitory activity is any one of the following formulas:

3. A method for preparing the amide derivative with anti-RSV virus inhibitory activity as claimed in claim 1 or 2, the synthetic route of the method is shown as follows: Raw material A1 and A2 undergo a substitution reaction to obtain intermediate A3; A3 and intermediate A4 undergo a substitution reaction to obtain A5; A5 undergoes an ester hydrolysis reaction to obtain carboxylic acid intermediate A6; finally, A6 and A7 undergo acid-ammonia condensation to obtain the compound shown in formula (I); the definitions of each group in the formula are as claimed in claim 1 or 2.

4. Use of the amide derivative with anti-RSV virus inhibitory activity as claimed in claim 1 or 2 in the preparation of antiviral drugs.

5. An antiviral drug, containing a safe and effective amount of the amide derivative with anti-RSV virus inhibitory activity as claimed in claim 1 or 2.

6. The antiviral drug according to claim 5, characterized in that It also includes a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier.

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