Synthesis and Use of Respiratory Syncytial Virus Inhibitors

Abstract

The present invention provides the synthesis and use of respiratory syncytial virus inhibitors, which are compounds having the structure of Formula I or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs, or isotopically labeled versions thereof. These compounds have the advantages of higher activity and higher in vivo exposure compared to existing RSV inhibitors.

Description

[Technical Field]

[0001] This invention claims priority to a patent application for invention filed in China on January 22, 2020, entitled "Synthesis and Use of Respiratory Syncytial Virus Inhibitors" and bearing application number 202010075139.8, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of compounds, specifically to a tetrahydrobenzo[1,4]thiazepine-1,1-dioxide compound and a mixture or composition containing a tetrahydrobenzo[1,4]thiazepine-1,1-dioxide compound, and more particularly to a tetrahydrobenzo[1,4]thiazepine-1,1-dioxide compound and a mixture or composition containing a tetrahydrobenzo[1,4]thiazepine-1,1-dioxide compound for the prevention and treatment of respiratory syncytial virus infection. [Background technology]

[0003] Respiratory syncytial virus (RSV) is an enveloped virus belonging to the Pneumococcaceae family. 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 hydrophobin (SH), fusion protein (F), attachment glycoprotein (G), large RNA-dependent RNA polymerase (L), antitermination protein (M2-1), and M2-2 protein. RSV is a leading cause of acute lower respiratory tract infections and hospitalizations in children. Globally, 33.8 million children under the age of 5 become ill with RSV infection each year, of which 3.4 million require hospitalization for acute lower respiratory tract infections (NPL 1). Although extensive research has been conducted into the mechanisms of RSV replication, pathogenesis, and transmission, no vaccine has been approved for commercial sale. Palivizumab and ribavirin are approved as preventive and therapeutic drugs. The administration of these two drugs to high-risk patients for RSV infection is clinically recommended, but their effectiveness remains controversial (Non-Patent Document 2).

[0004] To date, various small molecule inhibitors of RSV have been reported. These inhibitors can be divided into RSV granule inactivators, RSV replication / protein synthesis inhibitors, RSV cell binding inhibitors, RSV cell entry inhibitors, and host cell modulators that induce apoptosis, depending on the mechanism of interaction between the drug and the virus and host. These antiviral agents are in different stages of clinical research (Non-Patent Document 3). For example, ALS-8176, a nucleic acid analog developed by Alios, terminates RNA chain synthesis, inhibits L protein polymerization, and reduces respiratory syncytial virus load in more than 85% of volunteers. Furthermore, oral administration of GS-5806, an RSV fusion inhibitor developed by Gilead, can reduce viral load, mucus weight, and symptom scores. Patent Document 1 reports RSV inhibitors, including a representative compound, Example 61-1, which can inhibit RSV replication by blocking viral entry and cell fusion. Although substantial progress has been made in the development of several RSV replication inhibitors and monoclonal antibodies with different mechanisms of action, the two antiviral drugs currently in clinical use are still insufficient for the prevention and treatment of RSV infection, and no small molecule drugs have been approved for sale. Furthermore, existing clinical drugs have low RSV replication inhibitor activity and low bioavailability. Therefore, RSV inhibitors have great market potential and a broad therapeutic space, so the development of new RSV inhibitors with high activity and high bioavailability is necessary. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. WO2013 / 020993 [Non-patent literature]

[0006] [Non-Patent Document 1] Ramagopal G., et al., Journal of Clinical and Diagnostic Research, 2016, 10(8):SC05-SC08 [Non-patent document 2] Glick AF, et al., Hospital Pediatrics, 2017, 7(5):271-278 [Non-patent document 3] Villenave R. et al. , J. Virol., 2015, 89(24):12309-12318 Summary of the Invention [Problem to be solved by the invention]

[0007] To solve the above problems, the present invention provides an RSV inhibitor that has high activity and high in vivo exposure. [Means for solving the problem]

[0008] In order to solve the above problems, the present invention provides the following configurations.

[0009] Formula I below: [ka] (In the formula, R 1 and R 2 are each independently hydrogen, deuterium, and unsubstituted or R 4 C replaced with 1~6 Alkyl group, C 3~7 cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups, unsubstituted or R 4 C replaced with 1~6 Alkyl group, C3~7 Cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups are preferred, or R 1 and R 2 are linked to form a 3- to 6-membered heterocycloalkyl group, and the 3- to 6-membered heterocycloalkyl group is unsubstituted or 5 and R 6 is replaced by R 3 is a halogen, a carboxyl group, C 1~6 Alkyl group, C 1~6 Alkoxy groups and C 3~7 cycloalkyl groups, wherein C 1~6 Alkyl group, C 1~6 Alkoxy groups and C 3~7 The cycloalkyl group may be unsubstituted or may contain deuterium, halogen, hydroxyl groups and C 1~6 may be substituted with a substituent selected from an alkoxy group, preferably R 3 is a halogen, a carboxyl group, C 1~6 Alkyl groups and C 3~7 cycloalkyl groups, and 1~6 Alkyl groups and C 3~7 The cycloalkyl group may be unsubstituted or may contain deuterium, halogen, hydroxyl groups and C 1~6 substituted with a substituent selected from an alkoxy group; Each R 4 are each independently deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~6 Alkyl group, C 3~7 cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups, 1~6 Alkyl group, C 3~7 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group may be unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen atom, and preferably each R 4 represents deuterium, hydroxyl group, amino group, cyano group, halogen, C 3~7 a cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, and 3~7The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen; Each R 5 and R 6 are each independently hydrogen, deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, or C 1~6 alkyl group, 1~6 the alkyl group is unsubstituted or substituted with a substituent selected from hydroxy, amino, cyano, and halogen; And R 3 is a methyl group, preferably R 1 is hydrogen and R 3 is a methyl group, R 2 is not an unsubstituted azetidine group, and R 2 is a methylene group and R 3 is a methyl group, preferably R 1 is hydrogen and R 2 is a methylene group and R 3 is a methyl group, R 2 R connected to 4 is not an oxetanyl group substituted with an amino group. or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound thereof.

[0010] The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, and use of the above-mentioned compound or pharmaceutical composition for the manufacture of a medicament for preventing and / or treating a disease caused by respiratory syncytial virus infection, or a medicament using the above-mentioned compound or pharmaceutical composition for the prevention and / or treatment of a disease caused by respiratory syncytial virus infection. The present invention also provides a method for preventing and / or treating a disease caused by respiratory syncytial virus infection, comprising the step of administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, or the above-mentioned pharmaceutical composition to a patient in need thereof. [Effects of the Invention]

[0011] The compounds of the present invention have the advantages of higher activity and higher in vivo exposure compared to existing RSV inhibitors. DETAILED DESCRIPTION OF THE INVENTION

[0012] In order to more clearly describe the present invention, the definitions of terms used in this application are explained below.

[0013] "C 1~6 The term "alkyl group", alone or in combination, means a saturated straight or branched alkyl group having 1 to 6, especially 1 to 4, carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like. Preferably, "C 1~6 The "alkyl group" is any one of a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group.

[0014] "C 3~7 The term "cycloalkyl group", alone or in combination, means a saturated cycloalkyl group having 3 to 7, especially 3 to 6, carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Preferably, "C 3~7 The "cycloalkyl group" is any one of a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.

[0015] The term "heterocycloalkyl group," alone or in combination, refers to a saturated or partially unsaturated (containing one or two double bonds) non-aromatic cyclic group consisting of carbon atoms and heteroatoms such as nitrogen, oxygen, or sulfur; such cyclic groups may be monocyclic or bicyclic. In the present invention, heterocycloalkyl groups have 2 to 11 carbon atoms and preferably 1, 2, 3, or 4 heteroatoms, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may be oxidized. The hydrogen atoms in the "heterocycloalkyl group" may be independently substituted with one or more substituents described in the present invention. The "heterocycloalkyl group" may be linked to the parent molecule via any ring atom in the ring. The terms "3- to 6-membered heterocycloalkyl group" and "3- to 7-membered heterocycloalkyl group" refer to saturated or partially unsaturated monocyclic or polycyclic heterocycloalkyl groups containing 3 to 6 and 3 to 7 carbon atoms and heteroatoms or heteroatomic groups, respectively. The heteroatoms or heteroatomic groups may be selected from N, O, S(O), and S(O). m (wherein m is an integer of 0 to 2). For example, an aziridinyl group, an azetidine group, an oxetanyl group, a tetrahydropyrrolyl group, a tetrahydrofuran group, a tetrahydrothienyl group, a piperidine group, a morpholinyl group, a piperazinyl group, a thiomorpholinyl group, a tetrahydropyranyl group, a 1,1-dioxothiomorpholinyl group, and [ka] Examples include:

[0016] "C 1~6 The term "alkoxy group", alone or in combination, refers to 1~6 The alkyl group -O- is used herein. 1~6 "Alkyl group" is as defined above.

[0017] The term "amino group", alone or in combination, refers to a primary amino (-NH), secondary amino (-NH-) or tertiary amino ( [ka] ) means

[0018] The term "hydroxyl group", alone or in combination, means an --OH group.

[0019] The term "halogen", alone or in combination, means fluorine, chlorine, bromine or iodine, and in particular fluorine, chlorine or bromine.

[0020] The term "cyano", alone or in combination, means a -CN radical.

[0021] The term "carboxyl", alone or in combination, means a -COOH group.

[0022] The term "isomer" includes all isomeric forms, such as enantiomers, diastereomers, and geometric isomers, including cis-trans isomers. Thus, all single stereoisomers of the compounds of the present invention, or mixtures of their enantiomers, diastereomers, or geometric isomers (or cis-trans isomers), are within the scope of the present invention.

[0023] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist as pharmaceutically acceptable salts, including acid addition salts and base addition salts. SM Berge et al. describe pharmaceutically acceptable salts in the "Pharmaceutical Salts" section of J. Pharmaceutical Sciences (66:1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt refers to a salt formed by a compound of the present invention with an organic or inorganic acid. Examples of organic or inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including alkali metal salts such as lithium salts, sodium salts, or potassium salts; alkaline earth metal salts such as calcium salts or magnesium salts; ammonium salts formed with N-containing organic bases; + (C 1~6 Pharmaceutically acceptable salts include, but are not limited to, organic base salts such as alkyl group salts. Pharmaceutically acceptable salts can be synthesized by conventional chemical methods.

[0024] The term "ester" refers to an ester formed by a compound of the present invention with one or more protic acids such as carboxylic acids, phosphoric acids, carbonic acids, sulfonic acids, boric acids, etc., via one or more hydroxyl groups in its structure, or an ester formed by a compound of the present invention with an alcohol and / or a phenol, via one or more carboxyl groups in its structure.

[0025] The term "solvate" refers to an association formed by one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0026] The term "hydrate" refers to an association formed between water and a compound of the present invention.

[0027] The term "prodrug" refers to a chemical derivative of a compound of the present invention, which is converted into a compound of general formula I by chemical reaction in vivo.

[0028] The term "isotopic derivative" refers to an isotopic derivative in which one to six hydrogen atoms in general formula I are replaced with deuterium atoms and / or one to three carbon atoms in general formula I are replaced with deuterium atoms. 14 It means an isotopic derivative substituted at the C atom.

[0029] The terms used in the present invention are defined as above. Those skilled in the art can understand the above terms by referring to the prior art. The present invention will be further described below based on the definitions of the terms.

[0030] The present invention relates to a compound of formula I: [ka] (In the formula, R 1 and R 2 are each independently hydrogen, deuterium, and unsubstituted or R 4 C replaced with 1~6 Alkyl group, C 3~7 cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups, unsubstituted or R 4 C replaced with 1~6 Alkyl group, C 3~7 Cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups are preferred, or R 1 and R 2 are linked to form a 3- to 6-membered heterocycloalkyl group, and the 3- to 6-membered heterocycloalkyl group is unsubstituted or 5 and R 6 is substituted with R 5 and R 6 may be the same or different, and R 5 and R 6may be one or more, R 3 is a halogen, a carboxyl group, C 1~6 Alkyl group, C 1~6 Alkoxy groups and C 3~7 cycloalkyl groups, wherein C 1~6 Alkyl group, C 1~6 Alkoxy groups and C 3~7 The cycloalkyl group may be unsubstituted or may contain deuterium, halogen, hydroxyl groups and C 1~6 may be substituted with a substituent selected from an alkoxy group, preferably R 3 is a halogen, a carboxyl group, C 1~6 Alkyl groups and C 3~7 cycloalkyl groups, and 1~6 Alkyl groups and C 3~7 The cycloalkyl group may be unsubstituted or may contain deuterium, halogen, hydroxyl groups and C 1~6 substituted with a substituent selected from an alkoxy group; Each R 4 are each independently deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~6 Alkyl group, C 3~7 cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups, 1~6 Alkyl group, C 3~7 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group may be unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen atom, and preferably each R 4 represents deuterium, hydroxyl group, amino group, cyano group, halogen, C 3~7 a cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, and 3~7 The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group are unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen atom; Each R 5 and R 6are each independently hydrogen, deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, or C 1~6 alkyl group, 1~6 the alkyl group is unsubstituted or substituted with a substituent selected from hydroxy, amino, cyano, and halogen; And R 3 is a methyl group, preferably R 1 is hydrogen and R 3 is a methyl group, R 2 is not an unsubstituted azetidine group, and R 2 is a methylene group and R 3 is a methyl group, preferably R 1 is hydrogen and R 2 is a methylene group and R 3 is a methyl group, R 2 R connected to 4 is not an oxetanyl group substituted with an amino group. or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound thereof.

[0031] In one preferred embodiment, R 1 is selected from hydrogen and deuterium, R 2 is unsubstituted or R 4 methyl group, ethyl group, n-propyl group, isopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, tetrahydrofuran group, tetrahydropyrrolyl group, azetidine group, and [ka] or R 1 and R 2 are linked to form an azetidine group or a tetrahydropyrrolyl group, said azetidine group or tetrahydropyrrolyl group being unsubstituted or 5 and R 6 is replaced by .

[0032] In one preferred embodiment, R 3 is selected from a methyl group, a deuterated methyl group, a cyclopropyl group, a fluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a carboxyl group, a 1-hydroxyethyl group, a 1-ethoxyethyl group, a 2-hydroxy-2-propyl group, and a difluoromethyl group.

[0033] In one preferred embodiment, R 1 and R 2 are each independently hydrogen, deuterium, and unsubstituted or 1 to 2 R 4 C replaced with 1~6 Alkyl group, C 3~7 cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups, preferably unsubstituted or 4 C replaced with 1~6 Alkyl group, C 3~7 cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups, and each R 4 are independently deuterium, halogen, C 1~6 is selected from alkyl, cyano, amino, aminomethyl, hydroxyl, hydroxylmethyl, tetrahydropyrrolyl, oxetane, azetidine and cyclobutane groups, wherein the tetrahydropyrrolyl, oxetane, azetidine and cyclobutane groups may be substituted with a hydroxyl or amino group, and preferably each R 4 is deuterium, halogen, C 1~6 It is selected from an alkyl group, a cyano group, an amino group, an aminomethyl group, a hydroxyl group, a hydroxylmethyl group, a tetrahydropyrrolyl group, an azetidine group and a cyclobutane group, and the tetrahydropyrrolyl group, the azetidine group and the cyclobutane group may be substituted with a hydroxyl group or an amino group.

[0034] In one preferred embodiment, each R 5 and R 6are each independently selected from hydrogen, hydroxyl, amino, cyano, halogen, methyl, ethyl, n-propyl and isopropyl, preferably selected from hydroxyl, amino, cyano, halogen, methyl, ethyl, n-propyl and isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl groups are unsubstituted or substituted with a substituent selected from hydroxyl, amino and halogen.

[0035] In one preferred embodiment, R 1 is selected from hydrogen and deuterium, R 2 is unsubstituted or R 4 methyl group, ethyl group, n-propyl group, isopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, tetrahydrofuran group, tetrahydropyrrolyl group, azetidine group, and [ka] or R 1 and R 2 are linked to form an azetidine group or a tetrahydropyrrolyl group, said azetidine group or tetrahydropyrrolyl group being unsubstituted or R 5 and R 6 is replaced by Each R 4 are each independently deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, and C 3~7 cycloalkyl groups, wherein C 3~7 the cycloalkyl group is unsubstituted or substituted with a substituent selected from a hydroxyl group, an amino group, and a halogen; Each R 5 and R 6are each independently selected from hydrogen, hydroxyl, amino, cyano, halogen, methyl, ethyl, n-propyl and isopropyl, preferably selected from hydroxyl, amino, cyano, halogen, methyl, ethyl, n-propyl and isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl groups are unsubstituted or substituted with a substituent selected from hydroxyl, amino and halogen.

[0036] In one preferred embodiment, R 1 is selected from hydrogen and deuterium, R 2 is unsubstituted or R 4 methyl group, ethyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, tetrahydropyrrolyl group, azetidine group, and [ka] or R 1 and R 2 are linked to form an azetidine group or a tetrahydropyrrolyl group, and the azetidine group or the tetrahydropyrrolyl group is unsubstituted or has 1 to 2 R 5 and R 6 is replaced by Each R 4 are each independently selected from deuterium, hydroxyl, amino, cyano, and cyclobutyl, wherein the cyclobutyl is substituted with an amino group; Each R 5 and R 6 are each independently selected from hydrogen, a hydroxyl group, an amino group, a methyl group, and an ethyl group, and preferably selected from a hydroxyl group, an amino group, a methyl group, and an ethyl group, and the methyl group and the ethyl group are substituted with a substituent selected from a hydroxyl group and an amino group.

[0037] In one preferred embodiment, the compound of formula I has the structure of formula I-1: [ka] (In the formula, R 3 is a methyl group or a difluoromethyl group, and R 5 and R 6 are each independently hydrogen, deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, or C 1~6 alkyl group, 1~6 The alkyl group is unsubstituted or substituted with a substituent selected from deuterium, hydroxyl, amino, cyano, and halogen, and R 5 and R 6 is not simultaneously hydrogen or deuterium.) It has a structure represented by the following formula:

[0038] In one preferred embodiment, R 5 and R 6 are each independently selected from hydrogen, hydroxyl, amino, cyano, methyl, and ethyl groups, the methyl and ethyl groups being substituted with substituents selected from hydroxyl and amino groups, and R 5 and R 6 is not hydrogen at the same time.

[0039] The present invention further provides a compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, which compound is

[0040] [ka] [ka] The compound is any one of the compounds represented by the formula:

[0041] The present invention further provides a pharmaceutical composition comprising any one of the above compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound thereof.

[0042] The present invention further provides use of any one of the above compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound thereof, or the above pharmaceutical composition, for the manufacture of a medicament for preventing and / or treating a disease caused by respiratory syncytial virus infection.

[0043] The present invention further provides any one of the above compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above pharmaceutical composition, for use as a pharmaceutical for preventing and / or treating a disease caused by respiratory syncytial virus infection.

[0044] The present invention further provides a method for preventing and / or treating a disease caused by respiratory syncytial virus infection, comprising the step of administering a therapeutically effective amount of any one of the above compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound thereof, or the above pharmaceutical composition to a patient in need thereof.

[0045] The present invention will be further illustrated below by describing one typical synthetic route for compounds of general formula I. As is apparent from the reaction route shown below, Compound 1 is converted to product 2 in the presence of sodium hydroxide, Product 2 and compound 7 are reacted in the presence of triethylamine to give product 3; Product 3 reacts in the presence of phosphorus oxychloride to give product 4, Product 4 and compound 8 are reacted in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene to give product 5; The product 5 is treated with trifluoroacetic acid to remove the protecting group, to give the product 6.

[0046] [ka]

[0047] As a variation of the typical reaction pathway above, the following alternative reaction pathway is shown: 3When is a difluoromethyl group, the reaction pathways for compounds 9 to 12 refer to the reaction pathways for compounds 1 to 4. Hereinafter, only the reaction pathways for the changes from product 12 onwards will be shown.

[0048] The title compound 13 can be obtained by reacting compound 12 with trifluoroethanol in the presence of potassium tert-butoxide. Product 13 and compound 18 are reacted in the presence of n-butyllithium to give product 14. Product 14 is reacted in the presence of DAST to give product 15. Product 15 and compound 19 are reacted in the presence of triethylamine to give product 16. Product 16 is treated with trifluoroacetic acid to remove the protecting group and give the desired product 17. The reaction pathway is shown below.

[0049] [ka]

[0050] As a variation of the above reaction pathway, an alternative reaction pathway is shown below.

[0051] Compound 19 reacts with NBS in the presence of AIBN to give product 20. Product 20 reacts with compound 26 in the presence of triethylamine to give product 21. Product 21 reacts with silver nitrate to give product 22. Product 22 reacts with DAST to give product 23. Product 23 reacts with compound 7 in the presence of ammonium chloride to give product 24. Product 24 is treated with trifluoroacetic acid to remove the protecting group and give product 25.

[0052] [ka]

[0053] The present invention will now be further described with reference to the following examples, which, however, should not be construed as limiting the scope of the present invention.

[0054] The abbreviations used in this invention are as follows:

[0055] CCl4: carbon tetrachloride CDCl3: deuterated chloroform CC 50 : The compound concentration at which half of the cultured cells became toxic CO2: Carbon dioxide DAST: Diethylaminotrifluorosulfur DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DMF: N,N-dimethylformamide DMSO-d6: Deuterated dimethyl sulfoxide g: grams HCOOH: Formic acid Hz: Hertz h: time I C 50 : Half maximal inhibitory concentration mg: milligram mL: milliliter mmol: millimolar MHz: Megahertz NaHCO3: Sodium bicarbonate NBS: N-bromosuccinimide NMR: nuclear magnetic resonance M: Molar concentration PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TLC: Thin Layer Chromatography uM: micromoles / liter μg: microgram μL: microliter δ: chemical shift

[0056] General test conditions for the examples of the present invention will be explained below.

[0057] First, the reactions in the examples are generally carried out under the protection of nitrogen gas.

[0058] Additionally, intermediates and final products are separated and purified by chromatography columns, preparative TLC plates and ICSO high performance preparative chromatography systems.

[0059] Furthermore, the LC-MS chromatograph mass spectrometer used was an ACQUITY Arc (Waters) equipped with a QDa detector. Mass spectrometry (MS) uses an ESI source and displays only the molecular weight M of the parent molecule, usually [M + H]. + The injection volume is determined by the sample concentration. The flow rate is 0.8 mL / min. The HPLC peaks are read by recording UV-Vis wavelengths at 220 nm and 254 nm. The mobile phases are 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B). The gradient elution conditions are shown in Tables 1 and 2 below.

[0060] [Table 1]

[0061] [Table 2]

[0062] NMR spectra were acquired using a Varian 400 MHz nuclear magnetic resonance spectrometer. Typically, CDCl3 and DMSO-d6 were used as solvents, and chemical shifts are expressed in ppm. The various peaks are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and dd (double doublet). Coupling constants are expressed in Hz. [Example]

[0063] Example 1: 4-(4-(3-aminoazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5 tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0064] [ka]

[0065] Step 1a: Preparation of 2-chloro-6-methylquinazolin-4(3H)-one

[0066] [ka]

[0067] Step 1a is specifically as follows. 2M aqueous sodium hydroxide solution (20 mL) was added to a solution of 2,4-dichloro-6-methylquinazoline (8.0 g, 37.55 mmol) in tetrahydrofuran (80 mL) at room temperature. The mixture was stirred at room temperature for 8 hours. Next, acetic acid (20 mL) was added dropwise to the reaction mixture, which was then suction filtered and the cake washed with ethyl acetate (20 mL). The cake was dried under reduced pressure to give 2-chloro-6-methylquinazolin-4(3H)-one (7.0 g) as a white solid.

[0068] Step 1b: Preparation of 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4(3H)-one

[0069] [ka]

[0070] Step 1b is specifically as follows: To a solution of 2-chloro-6-methylquinazolin-4(3H)-one (7.0 g, 35.97 mmol) in toluene (150 mL) at room temperature, 2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (9.22 g, 46.76 mmol) and triethylamine (10 mL) were added. The mixture was stirred at 130°C for 10 hours. It was then suction filtered, and the cake was washed with ethyl acetate (30 mL). The cake was dried under reduced pressure to give 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4(3H)-one as a white solid (11.5 g).

[0071] Step 1c: Preparation of 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0072] [ka]

[0073] Step 1c is specifically as follows: 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4(3H)-one (1.5 g, 4.22 mmol) was added to phosphorus oxychloride (15 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80°C for 2 hours and then cooled to room temperature. The phosphorus oxychloride was removed by distillation under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (1.58 g) as a yellow solid.

[0074] Step 1d: Preparation of tert-butyl (1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-ylcarbamate

[0075] [ka]

[0076] At room temperature, under the protection of nitrogen gas, a solution of 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (108 mg, 0.29 mmol) and azetidin-3-yl tert-butylcarbamate (100 mg, 0.58 mmol) in anhydrous tetrahydrofuran (10 mL) was added with DBU (48 mg, 0.32 mmol). The mixture was refluxed with stirring for 16 hours, cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography to give tert-butyl (1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin)-4-yl)azetidin-3-ylcarbamate (125 mg) as a white solid.

[0077] Step 1e: Preparation of 4-(4-(3-aminoazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0078] [ka]

[0079] To a solution of tert-butyl (1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin)-4-yl)azetidin-3-ylcarbamate (125 mg, 0.25 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure to remove trifluoroacetic acid, the pH was adjusted to 8 with concentrated aqueous ammonia and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give 4-(4-(3-aminoazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (65 mg) as a white solid. 1 H NMR(400MHz,CD3OD)δ7.95(d,J=7.6Hz,1H),7.83(d,J=7.6Hz,1H),7.58(t,J=7.8Hz,1H),7.48(s,1H),7.42(t,J=7.6Hz,1H),7.38-7.29 (m,2H),5.15(s,2H),4.73(t,J=8.4Hz,2H),4.52(br.s,2H),4.23-4.15(m,2H),4.03-3.94(m,1H),3.49(t,J=10.0Hz,2H),2.35(s,3H). MS actual value (ESI + )[(M+H) + ]:410.

[0080] Example 2: 4-(4-((azetidin-3-ylmethyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0081] [ka]

[0082] Step 2a: Preparation of tert-butyl 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)azetidine-1-carboxylate

[0083] [ka]

[0084] Specifically, Step 2a is as follows: 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (100 mg, 0.27 mmol) and tert-butyl 3-(aminomethyl)azetidine-1-formate (99 mg, 0.53 mmol) were used in the same manner as in Step 1d of Example 1 to give tert-butyl 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)azetidine-1-carboxylate (98 mg) as a white solid.

[0085] Step 2b: Preparation of 4-(4-((azetidin-3-ylmethyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0086] [ka]

[0087] Specifically, Step 2b is as follows: 4-(4-((azetidin-3-ylmethyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (15.4 mg) was obtained as a white solid by preparing the same as in Step 1e of Example 1 using tert-butyl 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)azetidine-1-carboxylate (98 mg, 0.19 mmol). 11H NMR(400MHz,CD3OD)δ8.00 (d,J=7.6Hz,1H),7.82(d,J=7.6Hz,1H),7.71(s,1H),7.62(t,J=7.2Hz,1H),7.49-7.43(m,2H),7.35(t,J=8.4Hz,1H),5.22(br.s,2 H),4.59(s,2H),4.18-4.13(m,2H),4.07-4.03(m,2H),3.89(d,J=6.0Hz,2H),3.57(t,J=5.0Hz,2H),3.47-3.43(m,1H),2.42(s,3H). MS actual value (ESI + )[(M+H) + ]:424.

[0088] Example 3: 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0089] [ka]

[0090] Step 3a: Preparation of tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate

[0091] [ka]

[0092] Specifically, Step 3a is as follows: Using tert-butyl 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (50 mg, 0.13 mmol) and ((3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate hydrochloride (34 mg, 0.13 mmol), preparation was carried out in the same manner as in Step 1d of Example 1 to obtain tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (60 mg) as a white solid.

[0093] Step 3b: Preparation of 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0094] [ka]

[0095] Specifically, Step 3b is as follows: Using tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (30 mg, 0.05 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (14 mg) as a white solid. 1H NMR(400MHz,DMSO-d6)δ7.88(d,J=8.0Hz,1H),7.82-7.73(m,1H),7.68-7.61(m,1H),7.53-7.43(m,2H),7.36(d,J=8.0Hz,1H) ,7.30-7.22(m,1H),6.04(br.s,3H),5.05(br.s,2H),4.53-4.13(m,6H),3.67(s,2H),3.56(s,2H),3.06(s,2H),2.31(s,3H). MS actual value (ESI + )[(M+H) + ]:454.

[0096] Example 4: 4-(4-(3-aminoazetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0097] [ka]

[0098] Step 4a: Preparation of 6-bromo-2-chloroquinazolin-4(3H)-one

[0099] [ka]

[0100] Specifically, Step 4a is as follows: 6-Bromo-2,4-dichloroquinazoline (5.0 g, 18 mmol) was used in the same manner as in Step 1a of Example 1 to give 6-bromo-2-chloroquinazolin-4(3H)-one (4.4 g) as a pale yellow solid.

[0101] Step 4b: Preparation of 6-bromo-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4(3H)-one

[0102] [ka]

[0103] Specifically, Step 4b is as follows: 6-Bromo-2-chloroquinazolin-4(3H)-one (5.1 g, 19.6 mmol) and 2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (5.0 g, 25.6 mmol) were used in the same manner as in Step 1b of Example 1 to give 6-bromo-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4(3H)-one (7.2 g) as a white solid.

[0104] Step 4c: Preparation of 4-(6-bromo-4-chloroquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0105] [ka]

[0106] Specifically, Step 4c is as follows: 6-Bromo-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4(3H)-one (7.2 g, 17.1 mmol) was used in the same manner as in Step 1c of Example 1 to give 4-(6-bromo-4-chloroquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (5.3 g) as a yellow solid.

[0107] Step 4d: Preparation of 4-(6-bromo-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0108] [ka]

[0109] Step 4d is specifically as follows: Under the protection of nitrogen gas, potassium tert-butoxide (2.7 g, 24.1 mmol) was added to a solution of 4-(6-bromo-4-chloroquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (5.3 g, 12.1 mmol) in trifluoroethanol (100 mL). The mixture was stirred at 60 °C for 4 hours, then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to give 4-(6-bromo-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (5.0 g) as a yellow solid.

[0110] Step 4e: Preparation of 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-formaldehyde

[0111] [ka]

[0112] Step 4e is specifically as follows: Under nitrogen gas protection, at −40° C., a solution of 4-(6-bromo-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (2.5 g, 5.0 mmol) and N-formylmorpholine (1.7 g, 14.9 mmol) in anhydrous tetrahydrofuran (30 mL) was slowly added dropwise over 2 hours. The mixture was stirred at −40° C. for 1 hour, then quenched with ammonium chloride (30 mL) at −40° C. and extracted with ethyl acetate (40 mL × 3). The combined organic phase was then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-formaldehyde (600 mg) as a yellow solid.

[0113] Step 4f: Preparation of 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0114] [ka]

[0115] Step 4f is specifically as follows: Under the protection of nitrogen gas, diethylaminotrifluorosulfur (446 mg, 2.8 mmol) was added to a solution of 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-formaldehyde (500 mg, 1.1 mmol) in anhydrous dichloromethane (10 mL). The mixture was stirred at room temperature for 16 hours, and then the reaction was quenched with saturated sodium bicarbonate (20 mL) solution. After extraction with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to give 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (490 mg) as a pale yellow solid.

[0116] Step 4g: Preparation of tert-butyl (1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)azetidin-3-yl)carbamate

[0117] [ka]

[0118] Step 4g is specifically as follows: Under the protection of nitrogen gas, triethylamine (32 mg, 0.32 mmol) was added to a solution of 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (50 mg, 0.10 mmol) and tert-butyl azetidin-3-ylcarbamate (27 mg, 0.16 mmol) in dimethyl sulfoxide (2 mL). The mixture was stirred at 90° C. for 3 hours, then cooled to room temperature, diluted with ethyl acetate (30 mL), and washed with water (10 mL×3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give tert-butyl (1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)azetidin-3-yl)carbamate (35 mg) as a white solid.

[0119] Step 4h: Preparation of 4-(4-(3-aminoazetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0120] [ka]

[0121] Specifically, Step 4h is as follows: Using tert-butyl (1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)azetidin-3-yl)carbamate (35 mg, 0.06 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-aminoazetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (16 mg) as a white solid.1 H NMR(400MHz,CD3OD)δ7.96(d,J=7.6Hz,1H),7.83(s,1H),7.80(d,J=7.6Hz,1H),7.67-7.56(m,2H),7.50-7.40(m,2H),6.76(t, J=56.4Hz,1H),5.18(br.s,2H),4.78(br.s,2H),4.66-4.47(m,2H),4.23(br.s,2H),4.05-3.98(m,1H),3.50(t,J=5.2Hz,2H). MS actual value (ESI + )[(M+H) + ]:446.

[0122] Example 5: 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0123] [ka]

[0124] Step 5a: Preparation of tert-butyl ((1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate

[0125] [ka]

[0126] Specifically, Step 5a is as follows: Using 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (50 mg, 0.10 mmol) and tert-butyl ((3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (27 mg, 0.16 mmol), preparation was carried out in the same manner as in Step 4g of Example 4 to obtain tert-butyl ((1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (35 mg) as a white solid.

[0127] Step 5b: Preparation of 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0128] [ka]

[0129] Specifically, Step 5b is as follows: Using tert-butyl ((1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (35 mg, 0.06 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (15 mg) as a white solid. 1H NMR(400MHz,CD3OD)δ7.96(d,J=7.6Hz,1H),7.86(s,1H),7.81(d,J=7.2Hz,1H),7.65(d,J=8.0Hz,1H),7.60(t,J=7.6Hz,1H),7.49(d,J=8.4 Hz,1H),7.44(t,J=8.0Hz,1H),6.77(t,J=56.4Hz,1H),5.19(br.s,2H),4.68-4.24(m,6H),3.95(s,2H),3.50(t,J=5.0Hz,2H),3.42(s,2H). MS actual value (ESI + )[(M+H) + ]:490.

[0130] Example 6: 4-(4-(azetidin-3-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0131] [ka]

[0132] Step 6a: Preparation of tert-butyl 3-((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)amino)azetidine-1-carboxylate

[0133] [ka]

[0134] Specifically, Step 6a is as follows: Using 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (50 mg, 0.10 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (37 mg, 0.21 mmol), preparation was carried out in the same manner as in Step 4g of Example 4 to give tert-butyl 3-((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)amino)azetidine-1-carboxylate (24 mg) as a white solid.

[0135] Step 6b: Preparation of 4-(4-(azetidin-3-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0136] [ka]

[0137] Specifically, Step 6b is as follows: Using tert-butyl 3-((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)amino)azetidine-1-carboxylate (24 mg, 0.04 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(azetidin-3-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (6.1 mg) as a white solid. 11H NMR(400MHz,CD3OD)δ8.19(s,1H),8.00(d,J=7.6Hz,1H),7.90(d,J=7.6Hz,1H),7.71(d,J=9.2Hz,1H),7.66(s,1H),7.53(d,J=9.2Hz,1H),7.48 (t,J=7.8Hz,1H),6.81(t,J=56.2Hz,1H),5.23(br.s,2H),4.61(br.s,3H),4.48(br.s,2H),4.29-4.21(m,2H),3.52(t,J=4.6Hz,2H).MS actual value (ESI + )[(M+H) + ]:446.

[0138] Example 7: 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0139] [ka]

[0140] Step 7a: Preparation of 2,4-dichloro-6-dibromomethylquinazoline

[0141] [ka]

[0142] Step 7a is specifically as follows: 2,4-Dichloro-6-methyl-quinazoline (10 g, 46.9 mmol) was dissolved in CCl4 (100 M) at room temperature, and NBS (33.4 g, 0.187 mol) and AIBN (1.93 g, 11.7 mmol) were added in batches. The mixture was then heated to 90 °C and reacted for 4 hours, after which the reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature and washed with saturated NaHCO3 solution and saturated brine. After concentration, the crude product was separated and purified by flash column chromatography to obtain 2,4-dichloro-6-dibromomethylquinazoline (12 g) as a yellow solid.

[0143] Step 7b: Preparation of 4-methoxybenzyl (3-(((2-chloro-6-(dibromomethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate

[0144] [ka]

[0145] Specifically, Step 7b is as follows: To a solution of 2,4-dichloro-6-dibromomethylquinazoline (5.8 g, 15.6 mmol) in anhydrous tetrahydrofuran (150 mL) was added (3-(aminomethyl)oxetan-3-yl)carbamic acid p-methoxybenzyl p-chlorobenzoate (7.2 g, 17.2 mmol) and triethylamine (3.9 g, 39.0 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (200 mL), washed with water (150 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give 4-methoxybenzyl (3-(((2-chloro-6-(dibromomethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (8.2 g) as a yellow solid.

[0146] Step 7c: Preparation of 4-methoxybenzyl (3-(((2-chloro-6-formylquinazolin-4-yl)amino)oxetan-3-yl))carbamate

[0147] [ka]

[0148] Step 7c is specifically as follows. At room temperature, 4-methoxybenzyl 3-(((2-chloro-6-(dibromomethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (4 g, 6.66 mmol) was dissolved in acetonitrile and water (50 mL, v:v=4:1), and silver nitrate (2.83 g, 16.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by TLC and then filtered. The cake was washed several times with ethyl acetate, and the filtrate was combined. The filtrate was washed with saturated brine and concentrated to obtain the crude product. The crude product was separated and purified by flash column chromatography to obtain 4-methoxybenzyl (3-(((2-chloro-6-formylquinazolin-4-yl)amino)oxetan-3-yl))carbamate (1.2 g) as a white solid.

[0149] Step 7d: Preparation of 4-methoxybenzyl (3-(((2-chloro-6-(difluoromethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl))carbamate

[0150] [ka]

[0151] Step 7d is specifically as follows: 4-Methoxybenzyl (3-(((2-chloro-6-formylquinazolin-4-yl)amino)oxetan-3-yl))carbamate (570 mg, 1.25 mmol) was dissolved in anhydrous dichloromethane (5 mL) at 0°C, and DAST reagent (1.01 g, 6.24 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was confirmed to be complete by TLC, the reaction solution was poured into a saturated NaHCO3 solution on ice and extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, and concentrated to obtain the crude product. The crude product was separated and purified by flash column chromatography to obtain 4-methoxybenzyl (3-(((2-chloro-6-(difluoromethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl))carbamate (60 mg) as a white solid.

[0152] Step 7e: Preparation of 4-methoxybenzyl (3-(((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate

[0153] [ka]

[0154] Step 7e is specifically as follows: To a solution of 4-methoxybenzyl (3-(((2-chloro-6-(difluoromethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl))carbamate (60 mg, 0.12 mmol) in ethanol (5 mL) were added 2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (26 mg, 0.13 mmol) and ammonium chloride (3 mg, 0.06 mmol). The mixture was heated to 80° C. and stirred at 80° C. for 8 hours. The mixture was concentrated to give the crude product. The crude product was dissolved in water (20 mL) and then extracted with ethyl acetate (20 mL×3). The organic phases were combined and concentrated to give the crude product, which was separated and purified by flash column chromatography to give 4-methoxybenzyl (3-(((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (50 mg) as a white solid.

[0155] Step 7f: Preparation of 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0156] [ka]

[0157] Specifically, Step 7f is as follows: Using 4-methoxybenzyl (3-(((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (50 mg, 0.078 mmol), preparation was carried out in the same manner as in Step 1h of Example 1 to give 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (23.6 mg) as a white solid. 1 HNMR(400MHz,CD3OD)δ8.14(s,1H),7.98(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7. 52(d,J=8.0Hz,1H),7.45(t,J=8.0Hz,1H),6.79(t,J=56.0Hz,1H),5.25(br.s,2H),4.82-4.69(m,6H),4.27(s,2H),3.53(s,2H). MS actual value (ESI + )[(M+H) + ]:476.

[0158] Example 8: 4-(4-(((3-hydroxyazetidin-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0159] [ka]

[0160] Step 8a: Preparation of tert-butyl 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)-3-hydroxylazetidine-1-carboxylate

[0161] [ka]

[0162] Specifically, Step 8a is as follows: 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (100 mg, 0.27 mmol) and tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate (162 mg, 0.80 mmol) were used in the same manner as in Step 1d of Example 1 to obtain tert-butyl 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)-3-hydroxyazetidine-1-carboxylate (135 mg) as a white solid. Actual MS data (ESI + )[(M+H) + ]:540.

[0163] Step 8b: Preparation of 4-(4-(((3-hydroxyazetidin-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0164] [ka] Specifically, Step 8b is as follows: Using tert-butyl 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)-3-hydroxyazetidine-1-carboxylate (80 mg, 0.15 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(((3-hydroxyazetidin-3-yl)methyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (21.9 mg) as a white solid. 1H NMR(400MHz,CD3OD)δ7.95(d,J=8.0Hz,1H),7.83(d,J=7.6Hz,1H),7.70(s,1H),7.58(td,J=7.6,1.2Hz,1H),7.44-7.39(m,2H),7.3 5(d,J=8.8Hz,1H),5.16(br.s,2H),4.54(br.s,2H),4.28(d,J=12.4Hz,2H),3.98-3.87(m,4H),3.94(t,J=5.2Hz,2H),2.39(s,3H). MS actual value (ESI + )[(M+H) + ]:440.

[0165] Example 9: 4-(4-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0166] [ka] Step 9a: Preparation of tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxypyrrol-3-yl)methyl)carbamate

[0167] [ka]

[0168] Step 9a is specifically as follows. Under the protection of nitrogen gas, 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (500 mg, 1.41 mmol) and tert-butyl ((3-hydroxypyrrol-3-yl)methyl)carbamate (338 mg, 1.69 mmol) were dissolved in 5 mL of DMF, and PyBOP and DBU were added at room temperature. The mixture was heated to 60°C and stirred for 3–4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxypyrrol-3-yl)methyl)carbamate (127 mg) as a yellow solid.

[0169] Step 9b: Preparation of 4-(4-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0170] [ka]

[0171] Specifically, Step 9b is as follows: Using tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepine-4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxypyrrolidin-3-yl)methyl)carbamate (127 mg, 0.24 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (24.2 mg) as a white powder. 1H NMR(400MHz,CD3OD)δ7.95(d,J=8.0Hz,1H),7.83-7.76(m,2H),7.58(t,J=7.8Hz,1H),7.45-7.41(m,1H),7.34(s,2H),5.17(br.s,2H),4 .54(br.s,2H),4.25-4.19(m,1H),4.05-3.92(m,2H),3.85-3.80(m,1H),3.55-3.48(m,2H),2.91(s,2H),2.37(s,3H),2.07-2.02(m,2H). MS actual value (ESI + )[(M+H) + ]:453.

[0172] Example 10: 4-(4-(3-(aminomethyl)-3-hydroxyazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0173] [ka]

[0174] Step 10a: Preparation of tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxyazetidin-3-yl)methyl)carbamate

[0175] [ka]

[0176] Specifically, Step 10a is as follows: Using 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (444 mg, 1.19 mmol) and tert-butyl ((3-hydroxyazetidin-3-yl)methyl)carbamate (150 mg, 0.74 mmol), preparation was carried out in the same manner as in Step 1d of Example 1 to give tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxyazetidin-3-yl)methyl)carbamate (320 mg) as a white solid.

[0177] Step 10b: Preparation of 4-(4-(3-(aminomethyl)-3-hydroxyazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0178] [ka]

[0179] Specifically, Step 10b is as follows: Using tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxyazetidin-3-yl)methyl)carbamate (80 mg, 0.15 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-aminomethyl-3-hydroxyazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (21.9 mg) as a white powder. 1H NMR(400MHz,CD3OD)δ7.96(d,J=7.6Hz,1H),7.79(d,J=7.2Hz,1H),7.60(t,J=8.0Hz,1H),7.49(s,1H),7.45(d,J=7.6Hz,1H),7.41(dd,J=8.0,1.6Hz, 1H),7.37(d,J=8.4Hz,1H),5.18(s,2H),4.63(d,J=9.6Hz,2H),4.55(s,2H) ),4.42(d,J=10.0Hz,2H),3.51(t,J=5.0Hz,2H),3.37(s,2H),2.36(s,3H). MS actual value (ESI + )[(M+H) + ]:440.

[0180] Example 11: 4-(4-(3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0181] [ka]

[0182] Step 11a: Preparation of tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-yl)methyl)carbamate

[0183] [ka]

[0184] Specifically, Step 11a is as follows: Using 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (80 mg, 0.21 mmol) and tert-butyl (azetidin-3-ylmethyl)carbamate (48 mg, 0.26 mmol), preparation was carried out in the same manner as in Step 1d of Example 1 to give tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-yl)methyl)carbamate (66 mg) as a white solid.

[0185] Step 11b: Preparation of 4-(4-(3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0186] [ka]

[0187] Specifically, Step 11b is as follows: Using tert-butyl ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-yl)methyl)carbamate (66 mg, 0.13 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (18.3 mg) as a white powder. 1H NMR(400MHz,CD3OD)δ7.95(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.60-7.56(m,1H),7.50(s,1H),7.44-7.40(m,1H),7.36-7.30(m, 2H),5.15(br.s,2H),4.61-4.38(m,4H),4.23-4.20(m,2H),3.32-3.30(m,2H),2.98(d,J=9.6Hz,2H),2.91-2.84(m,1H),2.34(s,3H). MS actual value (ESI + )[(M+H) + ]:424.

[0188] Example 12: 4-(4-((3-aminocyclobutylamino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0189] [ka]

[0190] Step 12a: Preparation of tert-butyl (3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)cyclobutyl)carbamate

[0191] [ka]

[0192] Specifically, Step 12a is as follows: Using 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (180 mg, 0.48 mmol) and tert-butyl (3-aminocyclobutyl)carbamate (98 mg, 0.53 mmol), preparation was carried out in the same manner as in Step 1d of Example 1 to give tert-butyl (3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)cyclobutyl)carbamate (105 mg) as a white solid.

[0193] Step 12b: Preparation of 4-(4-(3-aminocyclobutyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0194] [ka]

[0195] Specifically, Step 12b is as follows: Using tert-butyl (3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)cyclobutyl)carbamate (105 mg, 0.20 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-(3-(aminocyclobutyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (40.4 mg) as a white powder. 1H NMR(400MHz,CD3OD)δ7.95(d,J=8.0Hz,1H),7.85-7.79(m,1H),7.72-7.66(m ,1H),7.60-7.55(m,1H),7.43-7.39(m,1H),7.37-7.34(m,1H),7.30-7.28(m ,1H),5.17(br.s,2H),4.54-4.41(m,3H),3.77-3.71(m,1H),3.49(t,J=8.0H z,2H),2.88-2.82(m,1H),2.51-2.44(m,2H),2.37(s,3H)1.93-1.85(m,1H). MS actual value (ESI + )[(M+H) + ]:424.

[0196] Example 13: 4-(4-(3-amino-3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0197] [ka]

[0198] Step 13a: Preparation of tert-butyl 3-(bis(4-methoxybenzyl)amino)-3-cyanoazetidine-1-carboxylate

[0199] [ka]

[0200] Step 13a is specifically as follows. At room temperature, tert-butyl 3-oxoazetidine-1-carboxylate (1.00 g, 5.84 mmol) and bis(4-methoxybenzyl)amine (3.76 g, 14.6 mmol) were dissolved in 20 mL of glacial acetic acid, and trimethylsilylnitrile (724 mg, 7.30 mmol) was added. The reaction solution was heated to 80 °C for 4 hours, cooled, and concentrated to remove acetic acid. The residue was dissolved in ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (10 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain tert-butyl 3-(bis(4-methoxybenzyl)amino)-3-cyanoazetidine-1-carboxylate (1.75 g) as a colorless oil.

[0201] Step 13b: Preparation of 3-(bis(4-methoxybenzyl)amino)azetidine-3-nitrile

[0202] [ka]

[0203] Step 13b is specifically as follows. Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 3-(bis(4-methoxybenzyl)amino)-3-cyanoazetidine-1-carboxylate (910 mg, 2.08 mmol) in dichloromethane (3 mL) at room temperature. After stirring the mixture at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), and washed with saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with a 10% methanol in dichloromethane solution (15 mL × 2), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to obtain 3-(bis(4-methoxybenzyl)amino)azetidine-3-nitrile (267 mg) as a colorless oil.

[0204] Step 13c: Preparation of 3-(bis(4-methoxybenzyl)amino)-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-nitrile

[0205] [ka]

[0206] Specifically, Step 13c is as follows: Using 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (296 mg, 0.79 mmol) and 3-(bis(4-methoxybenzyl)amino)azetidine-3-nitrile (267 mg, 0.79 mmol), preparation was carried out in the same manner as in Step 1d of Example 1 to give 3-(bis(4-methoxybenzyl)amino)-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-nitrile (340 mg) as a white solid.

[0207] Step 13d: Preparation of 3-amino-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-nitrile

[0208] [ka]

[0209] Step 13d is specifically as follows: 3-(bis(4-methoxybenzyl)amino)-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-nitrile (340 mg, 0.50 mmol) was dissolved in trifluoroacetic acid (3 mL). After stirring the mixture at 60° C. for 2 hours, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), and washed with saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with a 10% methanol in dichloromethane solution (15 mL×2), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give 3-amino-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-nitrile (130 mg) as a white solid.

[0210] Step 13e: Preparation of 4-(4-(3-amino-3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0211] [ka]

[0212] Step 13e is specifically as follows: Under ice-water bath conditions, nickel chloride hexahydrate (233 mg, 0.98 mmol) and sodium borohydride (37 mg, 0.98 mmol) were added to a solution of 3-amino-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-nitrile (130 mg, 0.30 mmol) in methanol (3 mL). The mixture was subsequently stirred at room temperature for 2 hours. Water (10 mL) was added to quench the reaction, and the mixture was filtered. The mother liquor was extracted with a 10% solution of methanol in dichloromethane (15 mL × 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give 4-(4-(3-amino-3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (16.2 mg) as a white solid. 1 H NMR(400MHz,CD3OD)δ7.94(d,J=7.6Hz,1H),7.79(d,J=7.6Hz,1H),7.58(t,J=7.2Hz,1H),7.50(s,1H),7.41(t,J=8.0Hz,1H),7.37(dd,J=8.0,1.4Hz,1H ),7.33(d,J=8.4Hz,1H),5.16(br.s,2H),4.55(br.s,2H),4.47(d,J=9.6Hz, 2H), 4.23(d,J=9.2Hz,2H),3.49(t,J=4.8Hz,2H),3.10(s,2H),2.35(s,3H). MS actual value (ESI + )[(M+H) + ]:439.

[0213] Example 14: 4-(4-(((3S,4S)-4-hydroxypyrrolidin-3-yl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0214] [ka]

[0215] Step 14a: Preparation of tert-butyl (3S,4S)-3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)-4-hydroxypyrrolidine-1-carboxylate

[0216] [ka]

[0217] Specifically, Step 14a is as follows: 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (93.5 mg, 0.25 mmol) and tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (50 mg, 0.25 mmol) were used in the same manner as in Step 1d of Example 1 to give tert-butyl (3S,4S)-3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)-4-hydroxypyrrolidine-1-carboxylate (118 mg) as a white solid.

[0218] Step 14b: Preparation of 4-(4-(((3S,4S)-4-hydroxypyrrolidin-3-yl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0219] [ka]

[0220] Specifically, Step 14b is as follows: tert-butyl (3S,4S)-3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)-4-hydroxypyrrolidine-1-carboxylate (118 mg, 0.22 mmol) was used in a similar manner to Step 1e of Example 1 to give 4-(4-(((3S,4S)-4-hydroxypyrrolidin-3-yl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (62.6 mg) as a white solid. 1 H NMR(400MHz,CD3OD)δ7.91(d,J=7.6Hz,1H),7.89(d,J=7.2Hz,1H),7.75(s, 1H),7.57(t,J=7.2Hz,1H),7.42-7.34(m,2H),7.31(d,J=8.0Hz,1H),5.17(b r.s,2H),4.72(br.s,2H),4.52(br.s,2H),3.78(dd,J=12.4,5.6Hz,1H),3.5 4-3.43(m,3H),3.39(d,J=12.0Hz,1H),3.23(d,J=12.0Hz,1H),2.36(s,3H). MS actual value (ESI + )[(M+H) + ]:440.

[0221] Example 15: 4-(4-((2-azaspiro[3.3]heptan-6-yl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0222] [ka]

[0223] Step 15a: Preparation of tert-butyl 6-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0224] [ka]

[0225] Specifically, Step 15a is as follows: 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (120 mg, 0.32 mmol) and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (68 mg, 0.32 mmol) were used in the same manner as in Step 1d of Example 1 to obtain tert-butyl 6-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg) as a white solid.

[0226] Step 15b: Preparation of 4-(4-((2-azaspiro[3.3]heptan-6-yl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0227] [ka]

[0228] Specifically, Step 15b is as follows: Using tert-butyl 6-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 0.27 mmol), preparation was carried out in the same manner as in Step 1e of Example 1 to give 4-(4-((2-azaspiro[3.3]heptan-6-yl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (108.5 mg) as a white solid. 1H NMR(400MHz,CD3OD)δ7.93(d,J=7.6Hz,1H),7.76(d,J=7.2Hz,1H),7.65(s,1H) ,7.56(t,J=7.6Hz,1H),7.38(t,J=7.6Hz,1H),7.33(d,J=8.8Hz,1H),7.26(d,J= 8.4Hz,1H),5.14(br.s,2H),4.65-4.40(br.s,3H),3.93(s,2H),3.74(s,2H),3. 49(t,J=4.6Hz,2H),2.76(t,J=9.6Hz,2H),2.35(s,3H),2.29(t,J=10.0Hz,2H). MS actual value (ESI + )[(M+H) + ]:450.

[0229] In the following, biological performance data will be specifically described to further explain the solution of the present invention.

[0230] Materials and Methods RSV cell line: HEp-2 cells (ATCC CCL-23, human laryngeal carcinoma epithelial cells) were purchased from the American Type Culture Collection. They were cultured in DMEM medium containing 10% fetal bovine serum (FBS) and 1% double antibody. The cells were placed in a 5% CO2 incubator at 37°C.

[0231] Cytopathic Effect (CPE) Assay: To measure the anti-RSV activity of compounds, 5 x 10 cells were cultured per well in Hyclone™ DMEM containing 10% fetal bovine serum (FBS). 3 Cells were seeded into 96-well plates. The next day, cells were infected with RSV Long strain (ATCC) at 0.5 MOI in the presence of serial 3-fold diluted compounds, so that each well had a total volume of 100 μL after 4 days. Cell viability was measured after 4 days using the CellTiter-Glo Reagent cell counting kit. Fluorescence signals were read using a multifunctional microplate reader, and the 50% effective concentration (EC) was calculated based on the fluorescence values. 50 ) was decided.

[0232] Measurement results The RSV inhibitory activity of the compounds of Examples 1 to 15 of the present invention was measured by the above method, and the results are shown in Table 3.

[0233] [Table 3]

[0234] Furthermore, the pharmacokinetics of Examples 4 and 7 of the present invention were compared with those of Example 61-1 (Control 1) of Patent WO2013020993 in ICR mice, using a single intravenous injection (2 mg / kg) and a single oral administration (10 mg / kg), respectively. Blood was collected at the following times: before administration, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. The pharmacokinetic parameters of Examples 4 and 7 in mouse plasma are shown in Table 5 below. The pharmacokinetics of the above Control 1 in ICR mice was investigated in a similar manner, using a single intravenous injection (2 mg / kg) and a single oral administration (10 mg / kg), respectively. The pharmacokinetic parameters of Control 1 in mouse plasma and liver are shown in Table 4 below.

[0235] [Table 4]

[0236] As is clear from Table 4, the average blood concentrations of the example compounds of the present invention after intravenous injection and oral administration in mice were clearly higher than those of Control 1. It was found that the compounds of the present invention have a higher internal exposure and can contribute more to the treatment of RSV infection.

[0237] Furthermore, as will be understood by those skilled in the art, the compounds represented by the general formula I, the different embodiments of the compounds represented by the general formula I, and the compounds described in the specific examples of the compounds represented by the general formula I can all be prepared into their corresponding isomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts. Preferably, the compounds are prepared into pharmaceutically acceptable derivatives. The derivatives are any one of prodrugs, salts, esters, amides, ester-based salts, amide-based salts, and metabolites.

[0238] Furthermore, pharmaceutically acceptable salts include conventional non-toxic salts obtained by forming a salt of any compound according to the present invention using inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, or phosphoric acid, etc.) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.). For reviews of suitable pharmaceutically acceptable salts, see Berge SM et al., J.Pharm.Sci. 1977, 66, 1-19; Gould PL Int. J.Pharm 1986, 33, 201-277 and Bighley et al., Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc., New York 1996, Vol. 13, pp. 453-497.

[0239] Furthermore, a stable isotope derivative can be used to introduce an isotope into any compound according to the present invention. 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 It may also be Cl, and specific isotopic derivatives may be prepared by conventional techniques.

[0240] Furthermore, the actual product may be one of tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, and washcloths.

[0241] Furthermore, in addition to the above, a mixture can also be formed with any one of a pharmaceutically acceptable carrier, adjuvant, or excipient.

[0242] All compounds according to the present invention, as well as mixtures, compositions, etc. containing the compounds of the present invention, can be administered to a living body by any route of administration, including oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, buccal inhalation, ocular instillation, and local or systemic transdermal administration.

[0243] All compounds according to the present invention, as well as mixtures and compositions containing the compounds of the present invention, can be prepared into single-dose formulations containing the active compound of the present invention and carriers, excipients, etc. Dosage forms may include tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, and cleansers. These dosage forms may contain ingredients commonly used in pharmaceutical formulations, such as diluents, absorbents, lubricants, binders, disintegrants, colorants, pH adjusters, antioxidants, bacteriostatic agents, isotonicity adjusters, and anti-adherents.

[0244] Formulations suitable for the various dosage forms described above are publicly available, for example, from Remington: The Science and Practice of Pharmacy 21st Edition, Lippincott Williams & Wilkins, 2006; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005, and therefore can be easily prepared by those skilled in the art.

[0245] Different dosages can be selected depending on factors such as the nature and severity of the disease suffered by the individual, the age, sex, and weight of the patient, the route of administration, etc. The dosage of the compound of the present invention may be 0.01 to 500 mg / kg per day, preferably 1 to 100 mg / kg per day, and can be administered in a single or multiple doses.

[0246] Those skilled in the art will understand that a typical use of all compounds according to the present invention and mixtures and compositions containing the compounds of the present invention is medical use, particularly for the prevention or treatment of respiratory syncytial virus infection. Specific indications are as follows:

[0247] The novel compounds capable of inhibiting the production or secretion of respiratory syncytial virus (RSV) can be used to treat and prevent RSV infection. Specific examples of the present invention have been described above. It should be noted that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various changes and modifications within the scope of the claims, without affecting the essential content of the present invention.

Claims

1. Formula I below: 【Chemical 1】 (In the formula, R １ are each independently hydrogen or deuterium; R ２ is unsubstituted or 1 to 2 R ４ C substituted with １～６ selected from an alkyl group or an azetidine group; R ４ are each independently deuterium or an oxetane group, and the oxetane group may be substituted with an amino group; R ３ is a difluoromethyl group) or a pharmaceutically acceptable salt, solvate, or isotopically labeled compound thereof.

2. The following formula I-1: 【Chemistry 2】 (In the formula, R ３ is a difluoromethyl group, R ５ and R ６ are each independently hydrogen, deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, or C １～６ alkyl group, １～６ The alkyl group is unsubstituted or substituted with deuterium, hydroxyl, amino, cyano, and halogen, and R ５ and R ６ is not simultaneously hydrogen or deuterium, preferably R ５ and R ６ are each independently selected from hydrogen, hydroxyl, amino, cyano, methyl, and ethyl groups, the methyl and ethyl groups being substituted with hydroxyl or amino groups, and R ５ and R ６ is not hydrogen at the same time) or a pharmaceutically acceptable salt, solvate, or isotopically labeled compound thereof.

3. The following formula: 【Chemistry 3】 3. The compound according to claim 1 or 2, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt, solvate, or isotope-labeled compound thereof.

4. below: 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate, or isotope-labeled compound thereof.

5. The following formula: 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 or a pharmaceutically acceptable salt, solvate, or isotope-labeled compound thereof.

6. A method for preparing a compound represented by Compound 6, comprising the steps of: 【Chemistry 8】 (In the formula, R １ and R ２ are each independently hydrogen, deuterium, and unsubstituted or R ４ C substituted with １～６ Alkyl group, C ３～７ cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups, ４ C substituted with １～６ Alkyl group, C ３～７ Cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups are preferred, or R １ and R ２ are linked to form a 3- to 6-membered heterocycloalkyl group, said 3- to 6-membered heterocycloalkyl group being unsubstituted or ５ and R ６ is substituted with; Each R ４ are each independently a deuterium atom, a hydroxyl group, an amino group, a cyano group, a halogen atom, or C １～６ Alkyl group, C ３～７ cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups, １～６ Alkyl group, C ３～７ The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group may be unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen, and preferably each R ４ represents deuterium, hydroxyl group, amino group, cyano group, halogen, C ３～７ is selected from a cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, and ３～７ The cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups are unsubstituted or substituted with substituents selected from hydroxy groups, amino groups, cyano groups, and halogens; Each R ５ and R ６ are each independently hydrogen, deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, or C １～６ alkyl group, １～６ The alkyl group is unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen. reacting compound 4 with compound 8 in the presence of DBU to obtain a compound represented by compound 5; removing the protecting group from compound 5 in the presence of trifluoroacetic acid to obtain compound 6; A method comprising:

7. A method for preparing a compound represented by Compound 17, comprising the steps of: 【Chemistry 9】 (In the formula, R １ and R ２ are each independently hydrogen, deuterium, and unsubstituted or R ４ C substituted with １～６ Alkyl group, C ３～７ cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups, ４ C substituted with １～６ Alkyl group, C ３～７ Cycloalkyl groups and 3- to 7-membered heterocycloalkyl groups are preferred, or R １ and R ２ are linked to form a 3- to 6-membered heterocycloalkyl group, said 3- to 6-membered heterocycloalkyl group being unsubstituted or ５ and R ６ is replaced by Each R ４ are each independently a deuterium atom, a hydroxyl group, an amino group, a cyano group, a halogen atom, or C １～６ Alkyl group, C ３～７ cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups, １～６ Alkyl group, C ３～７ The cycloalkyl group and the 3- to 6-membered heterocycloalkyl group may be unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen, and preferably each R ４ represents deuterium, hydroxyl group, amino group, cyano group, halogen, C ３～７ is selected from a cycloalkyl group and a 3- to 6-membered heterocycloalkyl group, and ３～７ The cycloalkyl groups and 3- to 6-membered heterocycloalkyl groups are unsubstituted or substituted with substituents selected from hydroxy, amino, cyano, and halogen; and Each R ５ and R ６ are each independently hydrogen, deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, or C １～６ alkyl group, １～６ The alkyl group is unsubstituted or substituted with a substituent selected from a hydroxy group, an amino group, a cyano group, and a halogen. reacting compound 15 with compound 8 in the presence of triethylamine to obtain a compound having a structure represented by compound 16; removing the protecting group from a compound having a structure represented by compound 16 in the presence of trifluoroacetic acid to obtain a compound having a structure represented by compound 17; A method comprising:

8. A pharmaceutical composition comprising the compound of claim 1 or 5, or a pharmaceutically acceptable salt, solvate, or isotopically labeled compound thereof.

9. 10. A compound according to claim 1 or 5, or a pharmaceutically acceptable salt, solvate, or isotopically labeled compound thereof, or a pharmaceutical composition according to claim 8, for use as a pharmaceutical.

10. A compound according to claim 1 or 5, or a pharmaceutically acceptable salt, solvate, or isotopically labeled compound thereof, or a pharmaceutical composition according to claim 8, for use in preventing and / or treating a disease caused by respiratory syncytial virus infection.

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