WO2025190151A1 - Benzoselenazole compounds as well as preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to benzoselenazole compounds as well as a preparation method therefor and the use thereof. Specifically disclosed in the present invention are benzoselenazole compounds as represented by formula I or pharmaceutically acceptable salts thereof. The benzoselenazole compounds have good RSV inhibitory activity and good in-vivo and in-vivo pharmacokinetic properties.

Description

A benzoselenaza compound and its preparation method and use

This application claims priority to Chinese Patent Application No. 2024102876682, filed on March 13, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application.

Technical Field

The present invention relates to a benzoselenazepine Compounds and their preparation methods and uses.

Background Art

Respiratory syncytial virus (RSV) is one of the most contagious human respiratory viruses. It's aptly named because RSV-infected cells fuse together, forming large cell structures resembling syncytia. It infects 3-10% of the world's population annually and is the most common cause of acute lower respiratory tract illness in infants and young children. It is also the leading cause of hospitalization for lower respiratory tract infections, bronchiolitis, and even death in children under five years of age. Globally, it causes approximately 34 million cases of lower respiratory tract infections each year, including up to 200,000 deaths in children under five. RSV can also cause severe lung infections and death in the elderly. Other high-risk patient populations for RSV infection include immunocompromised adults and those with chronic lung diseases, congenital heart disease, and chronic obstructive pulmonary disease (COPD), such as chronic bronchitis and emphysema. RSV is an enveloped virus belonging to the family Streptococcus pneumoniae. The RSV genome consists of 10 genes encoding 11 proteins: nonstructural proteins 1 and 2 (NS1 and NS2), nucleoprotein (N), phosphoprotein (P), matrix protein (M), small hydrophobic protein (SH), fusion protein (F), attachment glycoprotein (G), human RNA-dependent RNA polymerase (L), and transcription antibody terminator protein (M2-1) and M2-2 proteins. RSV is a major cause of acute lower respiratory tract illness and hospitalization in young children. Globally, RSV causes 33.8 million children under the age of 5 years old each year, of which 3.4 million children require hospitalization for acute lower respiratory tract illness (Ramagopal G., et al, Journal of Clinical and Diagnostic Research, 2016, 10(8): SC05-SC08).

Despite extensive research into RSV replication, pathogenesis, and transmission, there is no vaccine available to prevent RSV infection, and current clinical treatment options include only symptomatic or supportive care. Approved drugs for prevention and treatment are palivizumab and ribavirin. These two drugs are clinically recommended for patients at high risk of RSV infection, but their effectiveness remains controversial (Glick A.F., et al., Hospital Pediatrics, 2017, 7(5):271-278).

Currently, a variety of small molecule inhibitors for RSV have been reported. According to the different mechanisms of drug interaction with the virus and the host, these inhibitors can be divided into RSV virus particle inactivators, RSV replication/protein synthesis inhibitors, RSV cell binding inhibitors, RSV cell invasion inhibitors and host cell regulators of apoptosis. Among them, only a few have entered Phase I or II clinical trials. Arrow Therapeutics completed a 5-year Phase II clinical trial of the nucleocapsid (N) protein inhibitor RSV-604 in stem cell transplant patients in February 2010 (www.clinicaltriaIs.gov), but has not yet announced the final results. Most other small molecules have suspended their trials for various reasons. Ziresovir (AK0529; RO-0529) is a benzothiazepine It is a small molecule RSV inhibitor that is orally effective and can selectively inhibit the respiratory syncytial virus fusion protein (RSV-F) (EC50=3nM). It has good safety and pharmacokinetics. It is also the first time that an anti-respiratory syncytial virus drug has shown clinical efficacy in infants and naturally acquired RSV disease.

RNAi therapeutics against RSV are also currently under investigation. ALN-RSV01 (AInyIam Pharmaceuticals, MA, LSA) is a siRNA targeting the RSV gene. Administration of ALN-RSV01 as a nasal spray 2 days before and 3 days after RSV inoculation reduced infection rates in adult volunteers (DeVincenzo J. et al., Proc Natl Acad Sci U S A. 2010 May 11;107(19):8800-5). In another Phase II clinical trial in naturally infected lung transplant patients, results were insufficient to conclude on antiviral efficacy, although some product efficacy was observed (Zamora MR et al., Am T Respir Crit Care Med. 2011 Feb 15;183(4):531-8). Another Phase IIb clinical trial of ALN-RSV01 in a similar patient population is ongoing (www.clinicaltrials.gov). For example, Alios's nucleic acid analog ALS-8176 can terminate RNA chain synthesis, inhibit L protein polymerization, and reduce respiratory syncytial virus load in more than 85% of volunteers: Gilead's RSV fusion inhibitor GS-5806 oral treatment can reduce viral load, mucus quality, and symptom scores, etc.

Although substantial progress has been made in the development of several drugs and monoclonal antibodies that inhibit RSV replication with different mechanisms of action, the two antiviral drugs currently in clinical use remain insufficient for the prevention and treatment of RSV infection. No small molecule drugs have been approved for marketing, and existing clinical-stage drugs have weak activity against RSV replication and low in vivo exposure. Regardless, there is an urgent need for safe and effective treatments for RSV disease. Therefore, the market for RSV inhibitors is promising, with enormous therapeutic potential, and the development of new RSV inhibitors with strong activity and high in vivo exposure is still needed.

Summary of the Invention

The technical problem to be solved by the present invention is to overcome the problems of single structure and poor pharmacokinetic properties of RSV inhibitors in the prior art, and to provide a benzoselenazepine Compounds and their preparation methods and uses. These compounds have good RSV inhibitory activity and good in vitro and in vivo pharmacokinetic properties.

The present invention provides a benzoselenazepine as shown in formula I a compound or a pharmaceutically acceptable salt thereof,

in,

A is -Se- or -Se(=O)-;

R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen or deuterium;

R ₅ is hydrogen, halogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more ^Ra ;

R ^a is independently deuterium, halogen or hydroxy;

R ₆ is hydrogen, —C(═O)C _1-6 alkyl, —C(═O)OC _1-6 alkyl, —C(═O)C _1-6 alkyl substituted by 1 to 3 halogens, or —C(═O)OC _1-6 alkyl substituted by 1 to 3 halogens.

In certain preferred embodiments of the present invention, in R ₅ and ^Ra , the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine.

In certain preferred embodiments of the present invention, in R ₅ , the C _1-6 alkyl group and _the C _1-6 alkyl group substituted by one or more ^Ra are independently C _1-4 alkyl groups, such as methyl.

In certain preferred embodiments of the present invention, in _R6 , the -C(=O) _C1-6 alkyl, -C(=O) _OC1-6 alkyl, -C(=O)C1-6 alkyl substituted by 1 to 3 halogens, and the _C1-6 alkyl in -C(=O) _OC1-6 alkyl substituted by 1 to 3 halogens are independently _{C1-4 alkyl} , such as methyl or tert-butyl.

In certain preferred embodiments of the present invention, in R ₆ , the halogen in the -C(═O)C _1-6 alkyl substituted by 1 to 3 halogens and the -C(═O)OC _1-6 alkyl substituted by 1 to 3 halogens is independently fluorine, chlorine, bromine or iodine, such as fluorine.

In certain preferred embodiments of the present invention, R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen.

In certain preferred embodiments of the present invention, R ₅ is C _1-6 alkyl.

In certain preferred embodiments of the present invention, R ₆ is hydrogen, —C(═O)OC _1-6 alkyl, or _—C (═O)C _1-6 alkyl substituted by 1 to 3 halogens.

In certain preferred embodiments of the present invention, R ₅ is hydrogen, halogen, methyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or methyl substituted with 1 to 3 deuteriums.

In certain preferred embodiments of the present invention, _R5 is methyl, _-CD3 , -F, -Cl, -Br, -I, _-CF3 , _-CF2H , or _-CH2OH .

In certain preferred embodiments of the present invention, R ₅ is methyl.

In certain preferred embodiments of the present invention, R ₆ is H, -C(=O)CF ₃ or

In certain preferred embodiments of the present invention, the benzoselenazepine shown in Formula I The compound is any of the following compounds:

The present invention provides a pharmaceutical composition comprising the benzoselenazepine as shown in formula I as described above. A compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

The selection of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and can generally be fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. conventional in the art.

In certain preferred embodiments of the present invention, the pharmaceutical composition is prepared by adding the benzoselenazepine of formula I The compounds are prepared with one or more pharmaceutical excipients into dosage forms suitable for human or animal use, such as tablets, coated tablets, dragees, suppositories, hard and soft gelatin capsules, solutions, emulsions or suspensions.

In certain preferred embodiments of the present invention, the benzoselenazepine shown in Formula I The compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above is administered to the subject by an enteral or parenteral route, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection or rectal administration.

The present invention also provides a benzoselenazepine as shown in formula I Use of a compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a drug for treating or preventing RSV infection.

The present invention also provides a benzoselenazepine as shown in formula I as described above. The preparation method of the compound comprises the following steps: in an organic solvent, in the presence of an acidic reagent, subjecting a compound as shown in Formula II to a substitution reaction as shown below with a benzopyrimidine compound as shown in Formula III to obtain the benzoselenazepine compound as shown in Formula I. Compounds,

wherein R ₆ is hydrogen, -C(═O)C _1-6 alkyl, -C(═O)OC _1-6 alkyl, -C(═O)C _1-6 alkyl substituted by 1 to 3 halogens, or -C(═O)OC _1-6 alkyl substituted by 1 to 3 halogens; and R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above.

The operations and conditions in the method 1 can be conventional operations and conditions in this type of reaction in the art. Specifically, they are as follows:

The substitution reaction can be carried out under gas protection, which can be nitrogen and/or argon.

In the substitution reaction, the organic solvent may be an alcohol solvent, such as ethanol, isopropanol or n-butanol, for example ethanol.

In the substitution reaction, the acidic reagent may be ammonium chloride.

In the substitution reaction, the molar ratio of the benzopyrimidine compound represented by Formula III to the compound represented by Formula II may be 1:(1-2), for example, 1:1.2 or 1:1.3.

In the substitution reaction, the molar ratio of the acidic reagent to the benzopyrimidine compound represented by Formula III may be (0.02-1):1, for example, 0.05:1 or 0.1:1.

The reaction temperature of the substitution reaction may be 50-100°C, for example 80°C.

The progress of the substitution reaction can be monitored by conventional monitoring methods in the art (eg, TLC, HPLC, or NMR). The reaction endpoint is generally taken as the disappearance or no-reaction of the compound III, for example, 12-16 hours.

The present invention provides a compound as shown in Formula II,

wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

In certain preferred embodiments of the present invention, the compound shown in Formula II is

The present invention provides a method for preparing a compound represented by Formula IIa, comprising the following steps:

Step 1 (substitution reaction): In the presence of a base and a catalyst, phenylselenol undergoes a nucleophilic substitution reaction with (2-bromoethyl)benzylcarbamate to produce intermediate II-1;

Step 2 (cyclization reaction): In the presence of an acid, intermediate II-1 undergoes a cyclization reaction with paraformaldehyde to obtain intermediate II-2;

Step 3 (Cbz protection removal): Intermediate II-2 is hydrolyzed with acid or subjected to reductive hydrogenation to remove the Cbz protecting group to obtain benzoselenazepine Intermediate IIa.

The operations and conditions in step 1, step 2 and step 3 may be conventional operations and conditions for such reactions in the art.

In certain preferred embodiments of the present invention, in step 1, the base is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate.

In certain preferred embodiments of the present invention, in step 1, the catalyst is sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, triethylammonium benzyl bromide or a crown ether (such as 18-crown-6), etc., preferably sodium iodide.

In certain preferred embodiments of the present invention, in step 2, the acid is a hydrohalic acid (such as hydrochloric acid), sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, perfluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.

In certain preferred embodiments of the present invention, in step 3, the acid is a hydrohalic acid, preferably a hydrobromic acid-acetic acid solution.

In certain preferred embodiments of the present invention, in step 3, when reductive hydrogenation is used to remove the Cbz protecting group, the catalyst is palladium carbon, palladium hydroxide, platinum carbon or Raney nickel, and preferably 1-5% palladium carbon.

The present invention also provides the following compounds:

Unless otherwise specified, the following terms appearing in the present specification and claims have the following meanings:

The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the prototype of such compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the prototype of such compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pha rmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with one or more points in the biological cascade that leads to or causes the condition, or one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.

On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive progress of the present invention is that compared with the clinically investigated RSV inhibitor ziresovir, the compound of the present invention has stronger inhibitory activity against respiratory syncytial virus (RSV) and better in vitro and in vivo pharmacokinetic properties. Therefore, the present invention has very good prospects for preparing drugs for treating diseases related to respiratory syncytial virus (RSV) infection.

DETAILED DESCRIPTION

The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

Example 1: 2,3,4,5-tetrahydrobenzo[f][1,4]selenazepine Synthesis of (IIa)

Step 1: Benzyl (2-(phenylphenylpropyl)ethyl)carbamate (II-1)

Dissolve phenylselenol (50 g, 318.30 mmol), benzyl (2-bromoethyl)carbamate (90.4 g, 350.13 mmol), sodium iodide (9.5 g, 63.66 mmol), and potassium carbonate (66.0 g, 477.53 mmol) in N,N-dimethylformamide (600 mL). Under nitrogen, heat to 110°C and stir for 24 hours. The reaction mixture is quenched with water and extracted with dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate II-1 (96.5 g), which is used in the next step without further purification. LC-MS (ESI, m/z) 336[M+H] ⁺ ; ¹ H NMR (500MHz, DMSO-d ₆ ) δ7.55–7.44(m,3H),7.40–7.21(m,8H),5.02(s,2H),3.28–3.23(m,2H),2.99(t,2H).

Step 2: Benzyl 2,3-dihydrobenzo[f][1,4]selenazepine-4(5H)-carboxylate (II-2)

Dissolve compound II-1 (60 g, 179.49 mmol) in toluene (500 mL) and add p-toluenesulfonic acid (9.3 g, 53.85 mmol). Heat to 70°C and add paraformaldehyde (53.9 g, 1.79 mol) in portions. Stir and react for 16 hours, then reflux for 1 hour. Cool to room temperature, add 500 mL of water and 500 mL of ethyl acetate to the reaction mixture, stir for 30 minutes, separate the layers, and wash the organic phase with saturated sodium bicarbonate solution and brine. Concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain the title compound II-2 (48.6 g). LC-MS(ESI,m/z)348[M+H] ⁺ ; ¹ H NMR(500MHz,DMSO-d ₆ )δ7.63(dd,1H),7.42–7.14(m,8H),5.01(d,2H),4.57(s,1H),4.54(s,1H),4.11–4.03(m,2H),2.88(dt,2H).

Step 3: 2,3,4,5-Tetrahydrobenzo[f][1,4]selenazepine hydrobromide (IIa)

II-2 (40.0 g, 115.51 mmol) obtained in the previous step was dissolved in hydrobromic acid/acetic acid (33%, 250 mL) and allowed to react at room temperature for 3 hours. The solvent was removed under reduced pressure, and the mixture was neutralized with sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the title compound IIa (20.6 g). LC-MS (ESI, m/z) 214 [M+H] ⁺ ; ¹ H NMR (400 MHz, Chloroform-d) δ 7.65–7.58 (m, 1H), 7.25 (d, 1H), 7.17–7.13 (m, 2H), 7.04 (ddd, 1H), 4.11 (s, 2H), 3.54–3.49 (m, 2H), 2.77–2.72 (m, 2H).

Alternatively, II-2 (20 g, 57.75 mmol) obtained in the previous step and 5% palladium on carbon (6.2 g, 2.89 mmol) were dissolved in tetrahydrofuran (150 mL) and reacted at room temperature under a hydrogen atmosphere for 5 hours. After completion, the reaction was filtered and the filtrate was concentrated under reduced pressure to yield the title compound IIa (11.5 g). LC-MS (ESI, m/z) 214 [M+H] ⁺ ; ¹ H NMR (400 MHz, Chloroform-d) δ 7.65–7.58 (m, 1H), 7.25 (d, 1H), 7.17–7.13 (m, 2H), 7.04 (ddd, 1H), 4.11 (s, 2H), 3.54–3.49 (m, 2H), 2.77–2.72 (m, 2H).

Example 2: Synthesis of N-((3-aminooxetan-3-yl)methyl)-2-chloro-6-methylquinazolin-4-amine (IIIa)

Step 1: 3-(Aminomethyl)oxetan-3-amine (III-1)

To a solution of 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (10 g, 35 mmol) in ethanol (150 mL) was added 10% Pd/C (1.13 g). The reaction mixture was stirred at 80°C under a hydrogen atmosphere for 16 hours. The solution was filtered, the filtrate collected, and concentrated under reduced pressure at 40°C. This afforded the title compound III-1 (3.72 g, yellow oil). LC-MS (ESI): 103 [M+H] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD) δ 4.45 (s, 4H), 2.91 (s, 2H).

Step 2: N-((3-aminooxetan-3-yl)methyl)-2-chloro-6-methylquinazolin-4-amine (IIIa)

2,4-Dichloro-6-methylquinazoline (3.6 g, 17 mmol), compound III-1 (1.90 g, 19 mmol), and triethylamine (0.36 g, 3.5 mmol) were dissolved in methanol (40 mL) and stirred at room temperature for 12 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound IIIa (2.5 g, yellow solid). LC-MS (ESI, m/z) 279 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.22 (s, 1H), 7.67 (dd, 1H), 7.56 (d, 1H), 4.57 (d, 2H), 4.40 (d, 2H), 3.91 (s, 2H), 3.20 (s, 2H), 2.49 (s, 3H).

Example 3: Synthesis of tert-butyl (3-(((2-chloro-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (IIIb)

Dissolve compound IIIa (4.2 g, 15 mmol) in dichloromethane, add triethylamine (2.1 g, 21 mmol) and di-tert-butyl carbonate (3.39 g, 15.5 mmol). Stir the reaction at room temperature for 2 hours. The reaction solution is diluted with dichloromethane (100 mL), washed with saturated ammonium chloride (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to obtain the title compound (4.25 g, white solid). LC-MS (ESI, m/z) 379[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(t,1H),8.06(s,1H),7.65(dd,1H),7.53(d,1H),7.48(br s,1H),4.59-4.58(m,2H),4.55-4.53(m,2H),4.02-4.01(m,2H),2.46(s,3H),1.35(s,9H).

Example 4: Synthesis of N-(3-(((2-chloro-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)-2,2,2-trifluoroacetamide (IIIc)

Dissolve compound IIIa (1.0 g, 3.59 mmol) in dichloromethane (50 mL), add triethylamine (892 mg, 8.81 mmol) and trifluoroacetic anhydride (1.36 g, 6.46 mmol), and stir at room temperature for 2 hours. Pour the reaction solution into water and extract twice with dichloromethane. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain the title compound IIIc (1.2 g, white solid). LC-MS(ESI,m/z)375[M+H] ⁺ ； ¹ HNMR(400MHz,DMSO-d ₆ )δ9.89(s,1H),8.78(t,1H),8.06(s,1H),7.65(d,1H),7.54(d,1H),4.72(d,2H),4.60(d,2H),4.16(d,2H),2.47(s,3H).

Example 5: (3-(((2-(2,3-dihydrobenzo[f][1,4]selenazepine Synthesis of tert-butyl (4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (I-1)

Dissolve compound IIIb (4.2 g, 11.1 mmol) and compound IIa (3.06 g, 14.4 mmol) in ethanol (75 mL) and add ammonium chloride (60 mg, 1.1 mmol). Under nitrogen, heat to 80°C and stir for 16 hours. Cool to room temperature, concentrate under reduced pressure, and purify by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain the title compound (4.7 g, white solid). LC-MS (ESI, m/z) 556 [M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ7.72 (dd, 1H), 7.68 (br s,1H),7.58(dd,1H),7.43(dd,1H),7.38(d,1H),7.22(td,1H),7.07(td,1H),5.04(s,2H),4.80-4.78( m,2H),4.67-4.65(m,2H),4.53-4.51(m,2H),4.20(s,2H),3.03-3.01(m,2H),2.38(s,3H),1.40(s,9H).

Example 6: N-((3-aminooxetan-3-yl)methyl)-2-(2,3-dihydrobenzo[f][1,4]selenazepine -4(5H)-yl)-6-methylquinazoline-4-amino (I-2) and 4-(((2-(2,3-dihydrobenzo[f][1,4]selenazepine Synthesis of 4-(5H)-6-methylquinazolin-4-yl)amino)methyl)-4-(hydroxymethyl)oxazolin-2-one (I-3)

Compound I-1 (4.6 g, 8.3 mmol) was dissolved in trifluoroacetic acid (20 mL), stirred at room temperature for 15 minutes, and then the reaction solution was poured into a saturated aqueous sodium carbonate solution (150 mL), extracted with dichloromethane (50 mL x 5), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography to obtain the title compounds I-2 (1.2 g, white solid) and I-3 (1.2 g, white solid).

I-2: LCMS (ES, m/z) 456 [M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ7.71 (dd, 1H), 7.68 (br s,1H),7.58(dd,1H),7.37(dd,1H),7.32(d,1H),7.20(td,1H),7.05(td,1H),5.02(s,2H), 4.65(d,2H),4.55(d,2H),4.50-4.52(m,2H),4.05(s,2H),3.03-2.97(m,2H),2.38(s,3H).

I-3: LCMS (ES, m/z) 500 [M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD)δ7.69-7.65(m,2H),7.58(d,1H),7.42-7.40(m,1H),7.35(d,1H),7.22(t,1H),7.07(t,1H),5.07-4.97(m,2H),4.5 8-4.54(m,2H),4.34(d,1H),4.27(d,1H),4.05(d,1H),3.83(d,1H),3.70-3.65(m,2H),3.02-3.01(m,2H),2.39(s,3H).

Example 7: N-((3-aminooxetan-3-yl)methyl)-2-(2,3-dihydrobenzo[f][1,4]selenazepine Synthesis of 4-(5H)-yl)-6-methylquinazoline-4-amino (I-2)

Dissolve compound IIIa (2.78 g, 10.0 mmol) and compound IIa (3.06 g, 14.4 mmol) in ethanol (75 mL) and add ammonium chloride (60 mg, 1.1 mmol). Under nitrogen, heat to 80°C and stir for 16 hours. Cool to room temperature, concentrate under reduced pressure, redissolve in dichloromethane, wash with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain the title compound (3.12 g, white solid). LCMS (ES, m/z) 456 [M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ7.71 (dd, 1H), 7.68 (br s,1H),7.58(dd,1H),7.37(dd,1H),7.32(d,1H),7.20(td,1H),7.05(td,1H),5.02(s,2H),4.65(d,2H),4.55(d,2H),4.50 -4.52(m,2H),4.05(s,2H),3.03-2.97(m,2H),2.38(s,3H).

Example 8: N-(3-(((2-(2,3-dihydrobenzo[f][1,4]selenazepine Synthesis of 4-(5H)-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)-2,2,2-trifluoroacetamide (I-4)

Compound IIIc (1.2 g, 3.2 mmol) and compound IIa (810 mg, 3.80 mmol) were dissolved in ethanol (24 mL), heated to 80°C and stirred for 16 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The mixture was purified by silica gel column chromatography (DCM:MeOH = 80:1 to 40:1) to obtain the title compound I-4 (1.3 g, white solid). LCMS(ES,m/z)552[M+H] ⁺ ； ¹ HNMR(400MHz,DMSO-d ₆ )δ10.08(brs,1H),8.10-7.71(m,3H),7.57(s,1H),7.43-7.26(m,3H),7.10(s,1H),4.93( s,2H),4.75-4.60(m,4H),4.49(s,2H),4.29-4.12(s,2H),3.09-2.89(m,2H),2.36(s,3H).

Example 9: 2,2,2-trifluoro-N-(3-(((6-methyl-2-(1-oxido-2,3-dihydrobenzo[f][1,4]selenazepine Synthesis of 4-(5H)-quinazolin-4-yl)amino)methyl)oxetan-3-yl)acetamide (I-5)

Compound I-4 (200 mg, 0.363 mmol) was dissolved in dichloromethane (10 mL), and 3-chloroperoxybenzoic acid (188 mg, 1.09 mmol) was added at 0°C, followed by stirring at 0°C for 2 hours. Saturated aqueous sodium sulfite solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) were added to the reaction, followed by extraction twice with dichloromethane (30 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound I-5 (200 mg, yellow solid). LCMS (ES, m/z) 568 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ )δ10.01(s,1H),8.15(s,1H),7.98-7.89(m,1H),7.82(s,1H),7.74-7.7 2(m,1H),7.68(d,1H),7.44-7.41(m,1H),7.39-7.38(m,1H),7.27(d,1H ),5.07(s,2H),4.75-4.67(m,3H),4.63-4.61(m,2H),4.36-4.21(m,2H) ,4.16-4.09(m,1H),3.46-3.42(m,1H),3.15-3.06(m,1H),2.35(s,3H).

Example 10: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]selenazepine Synthesis of -1-oxide (I-6)

Compound I-5 (200 mg, 0.353 mmol) was dissolved in methanol (4 mL) and water (4 mL). Sodium hydroxide (71 mg, 1.8 mmol) was added at 0°C, followed by stirring at 60°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by C18 column chromatography (methanol:water (0.1% TFA) = 5% to 65%) to obtain the target compound I-6 (45 mg, white solid). LCMS (ES, m/z) 472 [M+H] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD)δ7.84(d,J=9.2Hz,1H),7.74(s,1H),7.68(d,1H),7.55-7.49(m,2H),7.4 7-7.42(m,1H),7.39-7.37(m,1H),5.58-5.54(m,1H),4.99-4.93(m,1H),4.9 2-4.88(m,1H),4.61(d,2H),4.49(d,J＝6.4Hz,1H),4.45(d,1H),4.12-4.07( m,1H),4.06-3.97(m,2H),3.96-3.91(m,1H),3.54-3.49(m,1H),2.41(s,3H).

Effect Example 1: Virus Cytopathic Effect (CPE) Experiment

To determine the anti-RSV activity of the compounds, 96-well plates were seeded at a density of 6×10 ³ cells per well in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS). The next day, cells were infected with sufficient RSV LongStrain (ATCC) to produce approximately 80-90% cytopathic effects after 6 days in the presence of serial half-log dilutions of the compounds in a total volume of 200 μL per well. After 6 days, cell viability was determined using a Cell Counting Kit-8. The absorbance at 450 nm and the reference value at 630 nm were measured to determine the 50% effective concentration (EC ₅₀ ).

Table 1

The experimental results showed that under the same experimental conditions, the compounds of this example had low nanomolar anti-RSV viral activity, among which I-2 and I-6 had slightly better anti-RSV viral activity than the positive control drug Ziresovir.

Effect Example 2: Study on the liver microsome metabolism of some compounds of the present invention

1. Preparation of test compound and control working solutions:

Dissolve the test compound in DMSO to obtain a 10 mM stock solution. Take 5 μL of the compound stock solution (10 mM in DMSO) and dilute it with 495 μL of acetonitrile to obtain a 100 μM intermediate solution with 99% acetonitrile.

2. Preparation of NADPH coenzyme:

1) Raw materials: NADPH·4Na (supplier: BONTAC, Cat. No. BT04)

2) Preparation procedure: Weigh an appropriate amount of NADPH powder and dilute it into 2 mM _MgCl2 solution (working solution concentration: 2 mM; final concentration in the reaction system: 1 mM).

3. Preparation of Liver Microsomes

1) Raw material: Human liver microsomes (supplier: Corning, Cat No. 452117, containing approximately 45 mg of liver microsome protein per gram of liver)

2) Preparation procedure: Prepare liver microsome working solution of appropriate concentration in 100 mM potassium phosphate buffer.

4. Preparation of stopping solution:

Cold (4°C) acetonitrile (ACN) containing 250 nM tolbutamide and 250 nM labetalol as internal standard (IS) was used as the stop solution.

5. Experimental steps:

1) Using an Apricot automated workstation, add 2 μL/well of compound working solution to all 96-well reaction plates, except for the blanks (T0, T60, and NCF60).

2) Add 100 μL/well of microsomal solution to all reaction plates (blank, T0, T60, and NCF60) using an Apricot automated workstation.

3) All reaction plates containing compound and microsome mixtures were pre-incubated at 37°C for 10 minutes.

4) Add 98 μL/well of 100 mM potassium phosphate buffer to the NCF60 reaction plate using an Aprico automated workstation;

5) Incubate the NCF60 reaction plate at 37°C and start timer 1.

Table 2 NCF60 incubation

6) After pre-incubation, 98 μL/well of NADPH was added to each reaction plate except NCF60 (blank, T0, and T60) using an Aprico automated workstation to start the reaction.

Table 3 Final concentration of each component in the culture medium

7) Incubate the reaction plate at 37°C and start Timer 2.

Table 4 Reaction plate incubation

8) Use the Aprico automated workstation to add 600 μL/well of stop solution to each reaction plate at the appropriate endpoint time point to terminate the reaction.

9) Each plate was sealed and shaken for 10 minutes.

10) After shaking, each plate was centrifuged at 4000 rpm and 4°C for 20 minutes.

11) After centrifugation, 300 μL of supernatant from each reaction plate was transferred to eight new 96-well plates using an Aprico automated workstation for liquid chromatography-mass spectrometry analysis.

3. Data Analysis

Phoenix WinNonlin 7.0 was used to calculate the half-life (T _1/2 , unit: h), intrinsic clearance of hepatic microsomes (CL _int(mic) , unit: μL/min/mg), and hepatic clearance (CL _int(liver) , unit: mL/min/kg). The results are shown in Table 5 below.

Table 5

Note: If the coenzyme NADPH is not added (it is replaced by buffer).

The experimental results show that compared with the positive control drug Ziresovir, the compound of this example has a longer hepatic microsome metabolic half-life and a lower metabolic clearance rate.

Effect Example 3 In vivo pharmacokinetic study of some embodiments of the present invention

1. Caco-2 cell culture

Caco-2 cells source: American type culture collection (ATCC).

Culture Procedure: Caco-2 cells were seeded on polycarbonate (PC) membranes with a pore size of 0.4 μm using 96-well Corning plates at a seeding density of 3.5 × 10 ⁴ cells/cm ² . The culture medium was changed every 4–5 days until a dense cell monolayer was formed between days 21 and 28.

2.Transfer method

The transport buffer used in this study was HBSS containing 10.0 mM HEPES, pH 7.40 ± 0.05. Bidirectional transport experiments were performed at a concentration of 2.00 μM for the test compound, with duplicates per group. Digoxin was tested at a concentration of 10.0 μM for bidirectional transport, with duplicates per group. Both propranolol and metoprolol were tested at a concentration of 2.00 μM in the A-to-B direction. The final DMSO concentration was controlled to less than 1%. The samples were incubated for 2 hours in a _CO2 incubator at 37.0°C, 5% _CO2 , and high humidity (no shaking). All samples were mixed with acetonitrile containing an internal standard and centrifuged at 3220 x g for 10 minutes. The concentrations of the test compound and control compound in the starting, donor, and receiver solutions were determined by LC-MS/MS, and quantification was performed using the peak area ratio of the test compound to the internal standard. After the transport experiment, the integrity of the Caco-2 cell monolayer was assessed using a lucifer yellow exclusion assay.

3. Data Analysis

The apparent permeability coefficient (Papp, cm/s) was calculated using the following formula: _Papp = ( _dCr /dt) x _Vr /(A x _C0 )

Where: _dCr /dt represents the cumulative concentration change rate of the receiving side over time; _Vr is the volume of the solution in the receiving chamber (0.0750 mL for the apical side and 0.250 mL for the basolateral side); A is the surface area of transmission (the monolayer cell area is 0.143 ^cm2 ); _C0 is the initial concentration on the administration side.

The efflux ratio (Efflux Ratio) was calculated by the following formula: Efflux Ratio = P _app (BA) / P _app (AB).

The solution recovery rate (% Solution Recovery) was calculated as follows: % Solution Recovery = 100 × [(V _r × C _r ) + (V _d × C _d )] / (V _d × C ₀ );

Wherein: _Vd represents the volume of the solution in the dosing chamber (0.0750 mL on the apical side and 0.250 mL on the basal side); _Cd and _Cr are the concentrations of the compound in the donating chamber (donor) and the receiving chamber (receiver) at the end of the experiment, respectively.

The results are shown in Table 6 below.

Experimental results showed that the P _app (BA) and efflux ratio (Efflux Ratio) of ziresovir were significantly higher than those of compounds I-2 and I-6. This suggests that ziresovir is likely strongly effluxed by certain active efflux transporters (such as P-gp), thus easily affecting the actual net absorption P _app (AB). Compared with ziresovir, compounds I-2 and I-6 both had significantly lower P _app (BA) and efflux ratios. Overall, compounds I-2 and I-6 have the advantage of lower efflux levels and relatively less efflux-induced net transmembrane absorption.

Effect Example 4 In vivo pharmacokinetic study of some embodiments of the present invention

1. Preparation of test samples

Table 7

2. Experimental Animals

Species: Healthy male Sprague Dawley rats (SPF grade), weighing 180-220 g.

Source: Experimental Animal Management Department of Shanghai Institute of Family Planning Sciences. Animals were transferred from the experimental institution animal reserve (999M-017).

Number: 18 males; Animal selection: random grouping, 3 animals per group

3. Dosage method and blood collection time

Weigh the patient before administration and calculate the dosage based on body weight. Administer the drug by intravenous injection or oral gavage.

After intravenous administration (2 mg/kg), 0.2 ml of blood was collected from the rat jugular vein at 0.033 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration, anticoagulated with EDTA-K2, and placed on ice.

After oral gavage administration (10 mg/kg), 0.2 ml of blood was collected from the rat jugular vein at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration, anticoagulated with EDTA-K2, and placed on ice after collection.

4. Plasma sample processing

1) Add 15 μL of unknown sample, calibration standard, quality control and diluted quality control (if any), single blank and double blank samples to a 96-well plate;

2) Each sample (except the double blank) was quenched with 150 μL of IS1 (the double blank sample was quenched with 150 μL of acetonitrile), and the mixture was stirred at 800 rpm for 10 minutes and then centrifuged at 3220 × g and 4°C for 15 minutes;

3) Transfer 55 μL of the supernatant to another clean 96-well plate and centrifuge again at 3220 × g and 4°C for 5 minutes. The supernatant is then directly subjected to LC-MS/MS analysis.

The procedure was performed on wet ice.

5. Sample analysis

1) UPLC-MS/MS analysis method:

Table 8

6. Data processing

The pharmacokinetic parameters were calculated using the non-compartmental model using Phoenix WinNonlin 7.0 software using the plasma drug concentration data at different time points, providing parameters such as AUC _0-int , C _max , T _max , T _1/2 , and oral bioavailability (F%). The results are shown in Table 9 below.

Table 9

The experimental results showed that compared with ziresovir, compound I-2 has better oral bioavailability, with a significantly improved AUC for both injection and oral administration, and has the advantages of lower metabolic clearance and longer mean residence time (MRT). Therefore, the present invention has very good prospects for the preparation of drugs for treating diseases related to respiratory syncytial virus infection.

The above embodiments are provided for illustrative purposes only and are not intended to limit the scope of implementation. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to provide an exhaustive list of all implementations. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims (11)

A benzoselenazepine as shown in formula I a compound or a pharmaceutically acceptable salt thereof,
in, A is -Se- or -Se(=O)-; R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen or deuterium; R ₅ is hydrogen, halogen, C _1-6 alkyl, or C _1-6 alkyl substituted by one or more ^Ra ; R ^a is independently deuterium, halogen or hydroxy; R ₆ is hydrogen, —C(═O)C _1-6 alkyl, —C(═O)OC _1-6 alkyl, —C(═O)C _1-6 alkyl substituted by 1 to 3 halogens, or —C(═O)OC _1-6 alkyl substituted by 1 to 3 halogens. The benzoselenazepine of formula I as claimed in claim 1 A compound or a pharmaceutically acceptable salt thereof, characterized in that the benzoselenazepine shown in formula I The compound or its pharmaceutically acceptable salt satisfies one or more of the following conditions: (1) In R ₅ and ^Ra , the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine; (2) In R ₅ , the C _1-6 alkyl group and _the C _1-6 alkyl group substituted by one or more ^Ra are independently C _1-4 alkyl groups, such as methyl; (3) In R ₆ , the -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, -C(=O)C _1-6 alkyl substituted by 1 to 3 halogens, and the C _1-6 alkyl in -C(=O)OC _1-6 alkyl substituted by 1 to 3 halogens are independently C _1-4 alkyl, such as methyl or tert-butyl; (4) In R ₆ , the halogen in the —C(═O)C _1-6 alkyl substituted by 1 to 3 halogens and the —C(═O)OC _1-6 alkyl substituted by 1 to 3 halogens is independently fluorine, chlorine, bromine or iodine, for example fluorine. The benzoselenazepine of formula I as claimed in claim 1 A compound or a pharmaceutically acceptable salt thereof, characterized in that the benzoselenazepine shown in formula I The compound or its pharmaceutically acceptable salt satisfies one or more of the following conditions: (1) R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen; (2) _R5 is _C1-6 alkyl; (3) R ₆ is hydrogen, -C(=O)OC _1-6 alkyl, or -C(=O)C _1-6 alkyl substituted by 1 to 3 halogens. The benzoselenazepine of formula I as claimed in claim 1 A compound or a pharmaceutically acceptable salt thereof, characterized in that the benzoselenazepine shown in Formula I The compound or its pharmaceutically acceptable salt satisfies one or both of the following conditions: (1) R ₅ is hydrogen, halogen, methyl, difluoromethyl, trifluoromethyl, hydroxymethyl or methyl substituted with 1 to 3 deuteriums, preferably methyl, -CD ₃ , -F, -Cl, -Br, -I, -CF ₃ , -CF ₂ H or -CH ₂ OH; (2) R ₆ is H, -C(=O)CF ₃ or The benzoselenazepine of formula I as claimed in claim 1 The compound or a pharmaceutically acceptable salt thereof is characterized in that the benzoselenazepine shown in formula I The compound is any of the following compounds:

A pharmaceutical composition comprising a benzoselenazepine as shown in formula I according to any one of claims 1 to 5 A compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. A benzoselenazepine as shown in formula I according to any one of claims 1 to 5 Use of a compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating or preventing RSV infection. A benzoselenazepine as shown in formula I according to any one of claims 1 to 5 The preparation method of the compound is characterized in that it comprises the following steps: in an organic solvent, in the presence of an acidic reagent, subjecting the compound represented by formula II to a substitution reaction as shown below with a benzopyrimidine compound represented by formula III to obtain the benzoselenazepine represented by formula I. Compounds,
wherein R ₆ is hydrogen, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, -C(=O)C _1-6 alkyl substituted by 1 to 3 halogens, or -C(=O)OC _1-6 alkyl substituted by 1 to 3 halogens; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in any one of claims 1 to 5; Preferably, the substitution reaction satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent, such as ethanol, isopropanol or n-butanol; (2) The acidic reagent is ammonium chloride; (3) The molar ratio of the benzopyrimidine compound represented by Formula III to the compound represented by Formula II is 1:(1-2); (4) The molar ratio of the acidic reagent to the benzopyrimidine compound represented by Formula III is (0.02-1):1; (5) The reaction temperature of the substitution reaction is 50-100°C. A compound as shown in formula II,
wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1 or 3; Preferably, the compound shown in formula II is A method for preparing a compound as shown in Formula IIa, characterized in that it comprises the following steps:
Step 1: In the presence of a base and a catalyst, phenylselenol reacts with (2-bromoethyl)benzylcarbamate to undergo a nucleophilic substitution reaction to prepare intermediate II-1; Step 2: In the presence of an acid, intermediate II-1 undergoes a cyclization reaction with paraformaldehyde to obtain intermediate II-2; Step 3: Intermediate II-2 is hydrolyzed with acid or subjected to reductive hydrogenation to remove the Cbz protecting group to obtain benzoselenazepine Intermediate IIa; Preferably, the method for preparing the compound of Formula IIa satisfies one or more of the following conditions: (1) In step 1, the base is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate; (2) In step 1, the catalyst is sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, triethylammonium benzyl bromide or a crown ether, preferably sodium iodide; (3) In step 2, the acid is a hydrohalic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, perfluorosulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, preferably p-toluenesulfonic acid; (4) In step 3, the acid is a hydrohalic acid, preferably a hydrobromic acid-acetic acid solution; (5) In step 3, when reductive hydrogenation is used to remove the Cbz protecting group, the catalyst is palladium carbon, palladium hydroxide, platinum carbon or Raney nickel, preferably 1-5% palladium carbon. A compound shown below: