Synthesis and Use of a Class of Respiratory Syncytial Virus Inhibitors

Abstract

The present invention provides the synthesis and use of a class of respiratory syncytial virus inhibitors, and the inhibitors are compounds having the structure of formula I or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope-labeled substances thereof. Compared with existing RSV inhibitors, the compounds have the advantages of strong activity and higher in vivo exposure.

Description

[0001] Citation of Related Applications

[0002] This invention claims the priority of the invention patent application titled "Synthesis and Use of a Class of Respiratory Syncytial Virus Inhibitors", with the application number 202010075139.8, which was filed in China on January 22, 2020. The entire content of this patent application is incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of compounds, and specifically relates to tetrahydrobenzo[1,4]thiazepine -1,1-dioxide compounds and mixtures or compositions containing tetrahydrobenzo[1,4]thiazepine -1,1-dioxide compounds, especially tetrahydrobenzo[1,4]thiazepine -1,1-dioxide compounds and mixtures or compositions containing tetrahydrobenzo[1,4]thiazepine -1,1-dioxide compounds for preventing and treating respiratory syncytial virus infections. Background Art

[0004] Respiratory syncytial virus (RSV) is an enveloped virus belonging to the family Pneumoviridae. The RSV genome consists of 10 genes encoding 11 proteins: non-structural proteins 1 and 2 (NS1 and NS2), nucleoprotein (N), phosphoprotein (P), matrix protein (M), small hydrophobic protein (SH), fusion protein (F), attachment glycoprotein (G), large RNA-dependent RNA polymerase (L), and transcriptional antitermination protein (M2-1) and M2-2 proteins. RSV is a major cause of acute lower respiratory tract diseases and hospitalizations in young children. Worldwide, RSV causes 33.8 million cases of illness in children under 5 years old each year, and 3.4 million children with acute lower respiratory tract diseases require hospitalization (Ramagopal G., et al., Journal of Clinical and Diagnostic Research, 2016, 10(8): SC05-SC08).

[0005] Despite in-depth research on RSV replication, pathogenesis, and transmission, no vaccine has been approved for market yet. The drugs approved for prevention and treatment are palivizumab and ribavirin, and these two drugs are clinically recommended for high-risk patients with RSV infection, but their effectiveness is controversial (Glick A.F., et al., Hospital Pediatrics, 2017, 7(5): 271-278).

[0006] Currently, a variety of small molecule inhibitors against RSV have been reported. According to the different mechanisms of drug interaction with the virus and the host, these inhibitors can be classified into RSV virion inactivators, RSV replication / protein synthesis inhibitors, RSV cell binding inhibitors, RSV cell entry inhibitors, and host cell regulators of apoptosis, etc. These antiviral drugs are in different clinical research stages (Villenave R.et al., J.Virol., 2015, 89(24):12309-12318). For example, the nucleic acid analogue ALS-8176 of Alios can terminate RNA chain synthesis, inhibit L protein polymerization, and can reduce the respiratory syncytial virus load in more than 85% of volunteers; the RSV fusion inhibitor GS-5806 of Gilead can reduce the virus load, mucus quality, and symptom score, etc. WO2013020993 reported a class of RSV inhibitors, and the representative compound 61-1 can inhibit the replication of RSV by blocking virus entry and cell fusion.

[0007] Although several drugs and monoclonal antibodies that inhibit RSV replication with different mechanisms of action have made substantial progress, the two antiviral drugs currently in clinical use are still insufficient to prevent and treat RSV infection, and no small molecule drugs have been approved for marketing. Moreover, the drugs currently in the clinical stage have weak activity in inhibiting RSV replication and low in vivo exposure. Therefore, the market prospect of RSV inhibitors is broad, with a huge treatment space, and there is still a need to develop new RSV inhibitors with strong activity and high in vivo exposure. Summary of the Invention

[0008] Problems to be Solved by the Invention

[0009] To solve the above technical problems, the present invention provides an RSV inhibitor with strong activity and high in vivo exposure.

[0010] Solutions for Solving the Problems

[0011] To solve the above technical problems, the present invention provides the following technical solutions:

[0012] A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof:

[0013]

[0014] Wherein, R 1 and R 2 each independently selected from hydrogen, deuterium, and unsubstituted or R 4 substituted C 1-6 alkyl, C 3-7Cycloalkyl and 3- to 7-membered heteroalkyl, preferably unsubstituted or substituted by R 4 substituted C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heteroalkyl; or R 1 and R 2 are linked to form a 3- to 6-membered heteroalkyl, the 3- to 6-membered heteroalkyl being unsubstituted or substituted by R 5 and R 6 ;

[0015] R 3 is selected from halogen, carboxyl, C 1-6 alkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy and C 3-7 cycloalkyl being unsubstituted or substituted by substituents selected from deuterium, halogen, hydroxyl and C 1-6 alkoxy, preferably halogen, carboxyl, C 1-6 alkyl and C 3-7 cycloalkyl, the C 1-6 alkyl and C 3-7 cycloalkyl being unsubstituted or substituted by substituents selected from deuterium, halogen, hydroxyl and C 1-6 alkoxy;

[0016] Each R 4 is independently selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 6-membered heteroalkyl, the C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 6-membered heteroalkyl being unsubstituted or substituted by substituents selected from hydroxyl, amino, cyano and halogen, preferably deuterium, hydroxyl, amino, cyano, halogen, C 3-7 cycloalkyl and 3- to 6-membered heteroalkyl, the C 3-7 cycloalkyl and 3- to 6-membered heteroalkyl being unsubstituted or substituted by substituents selected from hydroxyl, amino, cyano and halogen;

[0017] Each R 5 and R 6 are independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen and C 1-6 alkyl, the C 1-6 alkyl being unsubstituted or substituted by substituents selected from hydroxyl, amino, cyano and halogen;

[0018] And when R 3 is methyl, preferably when R 1 is hydrogen, R 3 is methyl, R2 is not an unsubstituted azetidinyl; and when R 2 is methylene and R 3 is methyl, preferably when R 1 is hydrogen, R 2 is methylene, R 3 is methyl, the R 2 connected to R 4 is not an amino-substituted oxetanyl.

[0019] In addition, the present invention also provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, and the use of the above compound and pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases caused by respiratory syncytial virus infection, or the above compound and pharmaceutical composition as a drug for preventing and / or treating diseases caused by respiratory syncytial virus infection. Moreover, the present invention also provides a method for preventing and / or treating diseases caused by respiratory syncytial virus infection, which comprises the following steps: administering a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above pharmaceutical composition to a patient in need thereof.

[0020] Effects of the Invention

[0021] The compounds of the present invention have the advantages of strong activity and higher in vivo exposure compared with existing RSV inhibitors. Detailed embodiments

[0022] For a clearer description of the content of the present invention, the terms involved in this application are defined as follows:

[0023] The term "C 1-6 alkyl" alone or in combination represents a saturated straight-chain or branched-chain alkyl containing 1-6, especially 1-4 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, etc. Preferably, "C 1-6 alkyl" is any one of methyl, ethyl, isopropyl, and tert-butyl.

[0024] The term "C 3-7"Cycloalkyl" alone or in combination represents 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 cycloalkyl" is any one of cyclopropyl, cyclopentyl, and cyclohexyl.

[0025] The term "heterocycloalkyl" alone or in combination represents a saturated or partially unsaturated (including 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms such as nitrogen, oxygen, or sulfur. This cyclic group can be a monocyclic or bicyclic group. In the present invention, the number of carbon atoms in the heterocycloalkyl is 2 to 11, the number of heteroatoms is preferably 1, 2, 3, or 4, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl can be optionally oxidized. The hydrogen atoms on the "heterocycloalkyl" are independently optionally substituted by one or more substituents described in the present invention. "Heterocycloalkyl" can be linked to the parent molecule through any ring atom on the ring. The terms "3- to 6-membered heterocycloalkyl" and "3- to 7-membered heterocycloalkyl" respectively refer to saturated or partially unsaturated monocyclic or polycyclic heterocycloalkyl groups containing 3 to 6 and 3 to 7 carbon atoms and heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are selected from N, O, S(O) m (where m is an integer from 0 to 2); for example, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, and etc.

[0026] The term "C 1-6 alkoxy" alone or in combination represents the group C 1-6 alkyl-O-, where "C 1-6 alkyl" is as defined above.

[0027] The term "amino" alone or in combination represents a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group

[0028] The term "hydroxy" alone or in combination represents the group -OH.

[0029] The term "halogen" alone or in combination represents fluorine, chlorine, bromine, or iodine. Particularly, fluorine, chlorine, or bromine.

[0030] The term "cyano" alone or in combination represents the group -CN.

[0031] The term "carboxy" alone or in combination represents the group -COOH.

[0032] The term "isomer" encompasses all isomeric forms including enantiomers, diastereomers and geometric isomers including cis-trans isomers. Accordingly, the individual stereochemical isomers of the compounds involved in the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or cis-trans isomers) are within the scope of the present invention.

[0033] The term "pharmaceutically acceptable salts" means that the compounds of the present invention exist in the form of their medicinal salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in the section "pharmaceutically salts" by S.M. Berge et al. in J. Pharmaceutical Sciences (Volume 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts mean salts formed by the compounds of the present invention with organic or inorganic acids, and the 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 mean salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts formed by reacting with organic bases containing N groups or N + (C 1-6 (alkyl)4 salts. "Pharmaceutically acceptable salts" can be synthesized by general chemical methods.

[0034] The term "ester" means esters formed by one or more hydroxyl groups in the structure of the compounds of the present invention with any one or more of proton acids such as carboxylic acids, phosphoric acid, carbonic acid, sulfonic acid, boric acid, etc., or esters formed by one or more carboxyl groups in the structure of the compounds of the present invention with alcohols and / or phenols.

[0035] The term "solvate" means an association formed by one or more solvent molecules with the compounds of the present invention. The solvents forming solvates include but are not limited to water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0036] The term "hydrate" refers to an association formed by water with the compounds of the present invention.

[0037] The term "prodrug" means a chemical derivative of the compounds of the present invention, which is converted in vivo by a chemical reaction into the compounds represented by general formula I.

[0038] The term "isotope derivative" refers to an isotope derivative obtained by replacing the hydrogen atoms in general formula I with 1 to 6 deuterium atoms and / or an isotope derivative obtained by replacing the carbon atoms in general formula I with 1 to 3 14 C atoms.

[0039] The above terms related to the present invention are defined. Those skilled in the art can also understand the above terms in combination with the prior art. The following further describes the content of the present invention based on the term definitions.

[0040] The present invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof:

[0041]

[0042] wherein, R 1 and R 2 each independently selected from hydrogen, deuterium, and unsubstituted or R 4 substituted C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocycloalkyl, preferably unsubstituted or R 4 substituted C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocycloalkyl; or R 1 and R 2 are linked to form a 3- to 6-membered heterocycloalkyl, which is unsubstituted or substituted by R 5 and R 6 ; R 5 and R 6 can be different or the same, R 5 and R 6 can each be one or more.

[0043] R 3 is selected from halogen, carboxyl, C 1-6 alkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy and C 3-7 cycloalkyl are unsubstituted or substituted by substituents selected from deuterium, halogen, hydroxyl and C 1-6 alkoxy, preferably halogen, carboxyl, C 1-6 alkyl and C 3-7 cycloalkyl, and the C 1-6 alkyl and C 3-7 cycloalkyl are unsubstituted or substituted by substituents selected from deuterium, halogen, hydroxyl and C 1-6 alkoxy;

[0044] Each R 4 is independently selected from deuterium, hydroxy, amino, cyano, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, and 3-6 membered heterocycloalkyl are unsubstituted or substituted with substituents selected from hydroxy, amino, cyano, and halogen, preferably deuterium, hydroxy, amino, cyano, halogen, C 3-7 cycloalkyl, and 3-6 membered heterocycloalkyl, wherein the C 3-7 cycloalkyl, and 3-6 membered heterocycloalkyl are unsubstituted or substituted with substituents selected from hydroxy, amino, cyano, and halogen;

[0045] Each R 5 and R 6 are independently selected from hydrogen, deuterium, hydroxy, amino, cyano, halogen, and C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with substituents selected from hydroxy, amino, cyano, and halogen;

[0046] And when R 3 is methyl, preferably when R 1 is hydrogen, R 3 is methyl, R 2 is not unsubstituted azetidinyl; and when R 2 is methylene, R 3 is methyl, preferably when R 1 is hydrogen, R 2 is methylene, R 3 is methyl, the R 2 linked to R 4 is not amino-substituted oxetanyl.

[0047] In a preferred embodiment, R 1 is selected from hydrogen and deuterium, R 2 is selected from unsubstituted or R 4 substituted methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, azetidinyl, and or R 1 and R 2 are linked to form azetidinyl or tetrahydropyrrolyl, wherein the azetidinyl or tetrahydropyrrolyl is unsubstituted or substituted with R 5 and R 6 ;

[0048] In a preferred embodiment, R 3Selected from methyl, deuterated methyl, cyclopropyl, fluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, carboxyl, 1-hydroxyethyl, 1-ethoxyethyl, 2-hydroxy-2-propyl, and difluoromethyl.

[0049] In a preferred embodiment, R 1 and R 2 are each independently selected from hydrogen, deuterium, and unsubstituted or 1-2 R 4 substituted C 1-6 alkyl, C 3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, preferably unsubstituted or 1-2 R 4 substituted C 1-6 alkyl, C 3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, each R 4 is independently selected from deuterium, halogen, C 1-6 alkyl, cyano, amino, aminomethyl, hydroxy, hydroxymethyl, pyrrolidinyl, oxetanyl, azetidinyl, and cyclobutyl, where the pyrrolidinyl, oxetanyl, azetidinyl, and cyclobutyl are optionally substituted with hydroxy or amino, preferably deuterium, halogen, C 1-6 alkyl, cyano, amino, aminomethyl, hydroxy, hydroxymethyl, pyrrolidinyl, azetidinyl, and cyclobutyl, where the pyrrolidinyl, azetidinyl, and cyclobutyl are optionally substituted with hydroxy or amino.

[0050] In a preferred embodiment, each R 5 and R 6 are each independently selected from hydrogen, hydroxy, amino, cyano, halogen, methyl, ethyl, n-propyl, and isopropyl, preferably hydroxy, amino, cyano, halogen, methyl, ethyl, n-propyl, and isopropyl, where the methyl, ethyl, n-propyl, and isopropyl are unsubstituted or substituted with substituents selected from hydroxy, amino, and halogen.

[0051] In a preferred embodiment, R 1 is selected from hydrogen and deuterium, R 2 is selected from unsubstituted or R 4 substituted methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl, and or R 1 and R 2 are linked to form azetidinyl or pyrrolidinyl, where the azetidinyl or pyrrolidinyl is unsubstituted or substituted with R 5 and R 6 ;

[0052] Each R 4 is independently selected from deuterium, hydroxy, amino, cyano, halogen, and C 3-7Cycloalkyl, wherein the C 3-7 The cycloalkyl is unsubstituted or substituted with substituents selected from hydroxy, amino, and halogen;

[0053] Each R 5 and R 6 are each independently selected from hydrogen, hydroxy, amino, cyano, halogen, methyl, ethyl, n-propyl, and isopropyl, preferably hydroxy, amino, cyano, halogen, methyl, ethyl, n-propyl, and isopropyl, and the methyl, ethyl, n-propyl, and isopropyl are unsubstituted or substituted with substituents selected from hydroxy, amino, and halogen.

[0054] In a preferred embodiment, R 1 is selected from hydrogen and deuterium, R 2 is selected from unsubstituted or R 4 substituted methyl, ethyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, azetidinyl, and or R 1 and R 2 are linked to form azetidinyl or pyrrolidinyl, and the azetidinyl or pyrrolidinyl is unsubstituted or substituted with 1-2 R 5 and R 6 ;

[0055] Each R 4 is independently selected from deuterium, hydroxy, amino, cyano, and cyclobutyl, and the cyclobutyl is substituted with amino;

[0056] Each R 5 and R 6 are each independently selected from hydrogen, hydroxy, amino, methyl, and ethyl, preferably hydroxy, amino, methyl, and ethyl, and the methyl and ethyl are substituted with substituents selected from hydroxy and amino.

[0057] In a preferred embodiment, the compound of formula I has the structure shown in formula I-1:

[0058]

[0059] Wherein,

[0060] R 3 is methyl or difluoromethyl, R 5 and R 6 are each independently selected from hydrogen, deuterium, hydroxy, amino, cyano, halogen, and C 1-6 alkyl, the C 1-6 alkyl is unsubstituted or substituted with substituents selected from deuterium, hydroxy, amino, cyano, and halogen, and R 5 and R 6 are not simultaneously hydrogen or deuterium.

[0061] In a preferred embodiment, R 5 and R 6 are each independently selected from hydrogen, hydroxy, amino, cyano, methyl and ethyl, wherein the methyl and ethyl are substituted with substituents selected from hydroxy and amino, and R 5 and R 6 are not simultaneously hydrogen.

[0062] The present invention also provides a compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, wherein the compound is any one of the following:

[0063]

[0064]

[0065] The present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof.

[0066] The present invention also provides the use of any one of the above-mentioned compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above-mentioned pharmaceutical composition, in the preparation of a drug for preventing and / or treating a disease caused by respiratory syncytial virus infection.

[0067] The present invention also provides any one of the above-mentioned compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above-mentioned pharmaceutical composition, which is used as a drug for preventing and / or treating a disease caused by respiratory syncytial virus infection.

[0068] The present invention also provides a method for preventing and / or treating a disease caused by respiratory syncytial virus infection, which comprises the following steps: administering a therapeutically effective amount of any one of the above-mentioned compounds or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above-mentioned pharmaceutical composition, to a patient in need thereof.

[0069] The following further describes the technical solution of the present invention by describing a typical synthesis route of the compound represented by the general formula I. Specifically, it can be seen from the following reaction route shown:

[0070] Compound 1 gives product 2 in the presence of sodium hydroxide;

[0071] Product 2 reacts with compound 7 in the presence of triethylamine to give product 3;

[0072] Product 3 reacts in the presence of phosphorus oxychloride to give product 4;

[0073] Product 4 reacts with compound 8 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene to give product 5;

[0074] Product 5 is treated with trifluoroacetic acid to remove the protecting group to give product 6.

[0075]

[0076] As a variation of the above typical reaction route, another reaction route is shown below: When R 3 is difluoromethyl, the reaction route of compounds 9 to 12 follows the reaction route of compounds 1 to 4, and only the partial reaction route after product 12 is shown below.

[0077] The target compound 13 can be obtained by reacting compound 12 with trifluoroethanol in the presence of potassium tert-butoxide; product 13 reacts with compound 18 in the presence of n-butyllithium to give product 14; product 14 reacts in the presence of DAST to give product 15; product 15 reacts with compound 8 in the presence of triethylamine to give product 16; product 16 is treated with trifluoroacetic acid to remove the protecting group to give the target product 17. The reaction route is shown below:

[0078]

[0079] As a variation of the above reaction route, another reaction route is shown below:

[0080] Compound 19 reacts with NBS in the presence of AIBN to give product 20; product 20 and compound 26 react 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 to give product 25.

[0081]

[0082] The following examples can further describe the present invention. However, these examples should not be construed as limiting the scope of the present invention.

[0083] The abbreviations used in the present invention are as follows:

[0084] CCl4: carbon tetrachloride

[0085] CDCl3: deuterated chloroform

[0086] CC 50 : the concentration of the compound when it is toxic to half of the cultured cells

[0087] CO2: Carbon dioxide

[0088] DAST: Diethylaminosulfur trifluoride

[0089] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0090] DMF: N,N-Dimethylformamide

[0091] DMSO-d6: Deuterated dimethyl sulfoxide

[0092] g: Gram

[0093] HCOOH: Formic acid

[0094] Hz: Hertz

[0095] h: Hour

[0096] IC 50 : Half maximal inhibitory concentration

[0097] mg: Milligram

[0098] mL: Milliliter

[0099] mmol: Millimole

[0100] MHz: Megahertz

[0101] NaHCO3: Sodium bicarbonate

[0102] NBS: N-Bromosuccinimide

[0103] NMR: Nuclear magnetic resonance

[0104] M: Molar concentration

[0105] PyBOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0106] TLC: Thin layer chromatography

[0107] uM: Micromole per liter

[0108] μg: Microgram

[0109] μL: Microliter

[0110] δ: Chemical shift

[0111] The following describes the general test conditions in the embodiments of the present invention:

[0112] First, the reactions in the embodiments are generally carried out under nitrogen protection.

[0113] Furthermore, the intermediates and final products are separated and purified by a chromatographic column, a preparative chromatographic plate, and an ICSO rapid preparative chromatography system.

[0114] Further, the LC-MS liquid chromatography-mass spectrometry instrument uses a Waters ACQUITY Arc equipped with a QDa Detector. For mass spectrometry (MS), the ESI source is used, which only indicates the molecular weight M of the parent molecule and usually reports [M+H]. + . The injection volume is determined by the sample concentration; the flow rate is 0.8 mL / min; the HPLC peaks are recorded and read at UV-Vis wavelengths of 220 nm and 254 nm. The mobile phase is an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and an acetonitrile solution of 0.01% formic acid (mobile phase B). The gradient elution conditions are shown in Tables 1 and 2 below:

[0115] Table 1: Gradient Elution Conditions 1

[0116] Time (min) <![CDATA[A(H2O, 0.01% HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.0-0.3 95-85 5-15 0.3-3.2 85-20 15-80 3.2-3.8 20-5 80-95 3.8-3.81 5-95 95-5 3.81-4.0 95 5

[0117] Table 2: Gradient Elution Conditions 2

[0118] Time (min) <![CDATA[A(H2O, 0.01% HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.00-5.90 95-5 5-95 5.90-5.91 5-95 95-5 5.91-6.00 95 5

[0119] Further, the NMR spectra are obtained using a Varian 400 MHz nuclear magnetic resonance spectrometer. CDCl3 and DMSO-d6 are often used as solvents, and the chemical shifts are reported in ppm. The descriptions of various peaks are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doubledoublet). The coupling constants are expressed in Hz.

[0120] Example 1: 4-(4-(3-Aminoazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazine -1,1-dioxide

[0121]

[0122] Step 1a: Preparation of 2-chloro-6-methylquinazolin-4(3H)-one

[0123]

[0124] Specific method of Step 1a: At room temperature, 2 M 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). The mixture was stirred at room temperature for 8 hours. Then acetic acid (20 mL) was added dropwise to the reaction mixture, followed by suction filtration, and the filter cake was washed with ethyl acetate (20 mL). The filter cake was dried under reduced pressure to obtain white solid 2-chloro-6-methylquinazolin-4(3H)-one (7.0 g).

[0125] Step 1b: Preparation of 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4(3H)-one

[0126]

[0127] Specific method of Step 1b: At room temperature, to a toluene (150 mL) solution of 2-chloro-6-methylquinazolin-4(3H)-one (7.0 g, 35.97 mmol) was added 2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide (9.22 g, 46.76 mmol) and triethylamine (10 mL). The mixture was stirred at 130 °C for 10 hours. Then, it was filtered by suction, and the filter cake was washed with ethyl acetate (30 mL). The filter cake was dried under reduced pressure to obtain the white solid 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4(3H)-one (11.5 g).

[0128] Step 1c: Preparation of 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide

[0129]

[0130] Specific method of Step 1c: At room temperature, under a nitrogen atmosphere, 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). The mixture was stirred at 80 °C for 2 hours, and then cooled to room temperature. Phosphorus oxychloride was removed by distillation under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the yellow solid 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide (1.58 g).

[0131] 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

[0132]

[0133] At room temperature, under nitrogen protection, to 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 tert-butyl azetidin-3-ylcarbamate (100 mg, 0.58 mmol) in anhydrous tetrahydrofuran (10 mL) was added DBU (48 mg, 0.32 mmol). The mixture was stirred under reflux for 16 h and then 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 phases were 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 give a white solid (tert-butyl (1-(2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-ylcarbamate (125 mg).

[0134] 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

[0135]

[0136] At room temperature, trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (1-(2-(1,1-dioxido-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). The mixture was stirred at room temperature for 2 h. Trifluoroacetic acid was removed by concentration under reduced pressure, then the pH was adjusted to 8 with concentrated ammonia, and the mixture was concentrated under reduced pressure to obtain the crude product, which was further purified by flash column chromatography to give a white solid 4-(4-(3-aminoazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide (65 mg). 11H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.38 - 7.29 (m, 2H), 5.15 (s, 2H), 4.73 (t, J = 8.4 Hz, 2H), 4.52 (br.s, 2H), 4.23 - 4.15 (m, 2H), 4.03 - 3.94 (m, 1H), 3.49 (t, J = 10.0 Hz, 2H), 2.35 (s, 3H). MS found (ESI + ) [(M + H) + : 410.

[0137] Example 2: 4-(4-((Azetidin-3-ylmethyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide

[0138]

[0139] Step 2a: Preparation of tert-butyl 3-(((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)azetidine-1-carboxylate

[0140]

[0141] Specific method of Step 2a: 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-carboxylate (99 mg, 0.53 mmol) were prepared according to the method similar to Step 1d of Example 1 to obtain white solid tert-butyl 3-(((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)azetidine-1-carboxylate (98 mg).

[0142] 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

[0143]

[0144] Specific method of step 2b: 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)azetidine-1-carboxylic acid tert-butyl ester (98 mg, 0.19 mmol) was prepared into a white solid 4-(4-((azetidin-3-ylmethyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (15.4 mg) according to the method similar to step 1e of Example 1. 1 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 5.22 (br.s, 2H), 4.59 (s, 2H), 4.18 - 4.13 (m, 2H), 4.07 - 4.03 (m, 2H), 3.89 (d, J = 6.0 Hz, 2H), 3.57 (t, J = 5.0 Hz, 2H), 3.47 - 3.43 (m, 1H), 2.42 (s, 3H). MS measured value (ESI + ) [(M + H) + : 424.

[0145] Example 3: 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0146]

[0147] Step 3a: Preparation of ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamic acid tert-butyl ester

[0148]

[0149] Specific method of step 3a: 4-(4-chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (50 mg, 0.13 mmol) and ((3-(hydroxymethyl)azetidin-3-yl)methyl)carbamic acid tert-butyl ester hydrochloride (34 mg, 0.13 mmol) were prepared into the white solid ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamic acid tert-butyl ester (60 mg) according to the method of Step 1d in Example 1

[0150] Step 3b: Preparation of 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0151]

[0152] Specific method of Step 3b: ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol) was prepared into the white solid 4-(4-(3-(aminomethyl)-3-(hydroxymethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (14 mg) according to the method of Step 1e in Example 1 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.0 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.68 - 7.61 (m, 1H), 7.53 - 7.43 (m, 2H), 7.36 (d, J = 8.0 Hz, 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 found (ESI + ) [(M + H) + : 454

[0153] Example 4: 4-(4-(3-Azetidin-1-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0154]

[0155] Step 4a: Preparation of 6-bromo-2-chloroquinazolin-4(3H)-one

[0156]

[0157] Specific method of Step 4a: 6-Bromo-2-chloroquinazolin-4(3H)-one (4.4 g) as a pale yellow solid was obtained by preparing 6-bromo-2,4-dichloroquinazoline (5.0 g, 18 mmol) according to the method of Step 1a in Example 1.

[0158] Step 4b: Preparation of 6-bromo-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)quinazolin-4(3H)-one

[0159]

[0160] Specific method of Step 4b: 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 was obtained by preparing 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) according to the method of Step 1b in Example 1.

[0161] Step 4c: Preparation of 4-(6-bromo-4-chloroquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide

[0162]

[0163] Specific method of Step 4c: 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 was obtained by preparing 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) according to the method of Step 1c in Example 1.

[0164] 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

[0165]

[0166] Specific method of Step 4d: Under nitrogen protection, 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 and then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (50 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 the yellow solid 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).

[0167] Step 4e: Preparation of 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-carbaldehyde -4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-carbaldehyde

[0168]

[0169] Specific method of Step 4e: Under nitrogen protection, at -40 °C, a solution of n-butyllithium (2.5 M, 4 mL, 10 mmol) was slowly added dropwise over 2 hours to 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). The mixture was stirred at -40 °C for an additional 1 hour, then the reaction was quenched with ammonium chloride (30 mL) solution at -40 °C and extracted with ethyl acetate (40 mL × 3). The combined organic phases were 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 obtain the yellow solid 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-carbaldehyde -4(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-carbaldehyde (600 mg).

[0170] 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

[0171]

[0172] The specific method of step 4f is as follows: under nitrogen protection, 2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepine To a solution of 6-(5H)-yl)-4-(2,2,2-trifluoroethoxy)quinazoline-6-carboxaldehyde (500 mg, 1.1 mmol) in anhydrous dichloromethane (10 mL) was added diethylaminosulfur trifluoride (446 mg, 2.8 mmol). The mixture was stirred at room temperature for 16 hours, then the reaction was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL×3), and then the combined organic phase was washed with saturated brine (20 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 a light yellow solid 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazoline-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide (490 mg).

[0173] Step 4g: Preparation of (1-(6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepine -tert-Butyl (4(5H)-quinazolin-4-yl)azetidin-3-yl)carbamate

[0174]

[0175] The specific method of step 4g is as follows: under nitrogen protection, 4-(6-(difluoromethyl)-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine A solution of -1,1-dioxide (50 mg, 0.10 mmol) and tert-butyl azetidin-3-ylcarbamate (27 mg, 0.16 mmol) in dimethyl sulfoxide (2 mL) was added with triethylamine (32 mg, 0.32 mmol). The mixture was stirred at 90 °C for 3 hours and 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 obtain a white solid (tert-butyl (1-(6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)quinazolin-4-yl)azetidin-3-yl)carbamate (35 mg).

[0176] Step 4h: Preparation of 4-(4-(3-aminoazetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0177]

[0178] Specific method of Step 4h: (tert-Butyl (1-(6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)quinazolin-4-yl)azetidin-3-yl)carbamate (35 mg, 0.06 mmol) was prepared into a white solid 4-(4-(3-aminoazetidin-1-yl)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (16 mg) according to the method of Step 1e in Example 1. 1 H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.50 - 7.40 (m, 2H), 6.76 (t, J = 56.4 Hz, 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 = 5.2 Hz, 2H). MS found (ESI + ) [(M + H) + : 446.

[0179] 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

[0180]

[0181] Step 5a: Preparation of tert-butyl ((1-(6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate -4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate

[0182]

[0183] Specific method of Step 5a: 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) were prepared into white solid tert-butyl ((1-(6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (35 mg) according to the method similar to Step 4g of Example 4. -4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate (35 mg).

[0184] 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

[0185]

[0186] Specific method of Step 5b: ((1-(6-(Difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)carbamate -4(5H)-yl)quinazolin-4-yl)-3-(hydroxymethyl)azetidin-3-yl)methyl)tert-butyl carbamate (35 mg, 0.06 mmol) was prepared as a white solid 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) according to the method of Step 1e of Example 1. 1 H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 6.77 (t, J = 56.4 Hz, 1H), 5.19 (br.s, 2H), 4.68 - 4.24 (m, 6H), 3.95 (s, 2H), 3.50 (t, J = 5.0 Hz, 2H), 3.42 (s, 2H). MS found (ESI + ) [(M + H) + : 490.

[0187] Example 6: 4-(4-(Azetidin-3-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide

[0188]

[0189] 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

[0190]

[0191] Specific method of Step 6a: 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) were prepared into white solid tert-butyl 3-((6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)quinazolin-4-yl)amino)azetidine-1-carboxylate (24 mg) according to the method of Step 4g in Example 4.

[0192] Step 6b: Preparation of 4-(4-(azetidin-3-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0193]

[0194] Specific method of Step 6b: tert-Butyl 3-((6-(difluoromethyl)-2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)quinazolin-4-yl)amino)azetidine-1-carboxylate (24 mg, 0.04 mmol) was prepared into white solid 4-(4-(azetidin-3-ylamino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (6.1 mg) according to the method of Step 1e in Example 1. 1 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 6.81 (t, J = 56.2 Hz, 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 = 4.6 Hz, 2H). MS found (ESI + ) [(M + H) + : 446.

[0195] Example 7: 4-(4-(((3-aminooxetane-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0196]

[0197] Step 7a: Prepare 2,4-dichloro-6-dibromomethylquinazoline

[0198]

[0199] Specific method of step 7a: At room temperature, dissolve 2,4-dichloro-6-methylquinazoline (10 g, 46.9 mmol) in CCl4 (100 M), and add NBS (33.4 g, 0.187 mol) and AIBN (1.93 g, 11.7 mmol) in batches. Subsequently, heat the mixture to 90 °C and react for 4 hours. Detect the completion of the reaction by TLC. Cool the reaction solution to room temperature and wash it with saturated NaHCO3 solution and saturated brine. After concentration, the crude product is separated and purified by flash column chromatography to obtain yellow solid 2,4-dichloro-6-dibromomethylquinazoline (12 g).

[0200] Step 7b: Prepare 4-methoxybenzyl (3-(((2-chloro-6-(dibromomethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate

[0201]

[0202] Specific method of step 7b: Add 4-methoxybenzyl (3-(aminomethyl)oxetan-3-yl)carbamate p-chlorobenzoate (7.2 g, 17.2 mmol) and triethylamine (3.9 g, 39.0 mmol) to a solution of 2,4-dichloro-6-dibromomethylquinazoline (5.8 g, 15.6 mmol) in anhydrous tetrahydrofuran (150 mL). Stir the mixture at room temperature for 16 hours. Dilute the mixture with ethyl acetate (200 mL), then wash it with water (150 mL) and saturated brine (100 mL), then dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by flash column chromatography to obtain yellow solid 4-methoxybenzyl (3-(((2-chloro-6-(dibromomethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamate (8.2 g).

[0203] Step 7c: Prepare 4-methoxybenzyl (3-(((2-chloro-6-formylquinazolin-4-yl)amino)oxetan-3-yl))carbamate

[0204]

[0205] Specific method for step 7c: At room temperature, dissolve (3-(((2-chloro-6-(dibromomethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamic acid 4-methoxybenzyl ester (4 g, 6.66 mmol) in acetonitrile and water (50 mL, v:v = 4:1), and add silver nitrate (2.83 g, 16.6 mmol). Stir the mixture at room temperature for 2 hours. Detect the completion of the reaction by TLC, and then filter. Wash the filter cake with ethyl acetate several times and combine the filtrates. Wash the combined filtrates with saturated brine and then concentrate to obtain the crude product. The crude product is separated and purified by flash column chromatography to obtain the white solid 4-methoxybenzyl ((3-(((2-chloro-6-formylquinazolin-4-yl)amino)oxetan-3-yl))carbamate (1.2 g).

[0206] Step 7d: Prepare (3-(((2-chloro-6-(difluoromethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl))carbamic acid 4-methoxybenzyl ester

[0207]

[0208] Specific method for step 7d: At 0 °C, dissolve 4-methoxybenzyl ((3-(((2-chloro-6-formylquinazolin-4-yl)amino)oxetan-3-yl))carbamate (570 mg, 1.25 mmol) in anhydrous dichloromethane (5 mL), add DAST reagent (1.01 g, 6.24 mmol), and stir the mixture at room temperature for 4 hours. Detect the completion of the reaction by TLC, pour the reaction solution into ice-cold saturated NaHCO3 solution, and extract with dichloromethane three times. Combine the organic phases, wash with saturated brine, concentrate to obtain the crude product, and separate and purify by flash column chromatography to obtain the white solid (3-(((2-chloro-6-(difluoromethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl))carbamic acid 4-methoxybenzyl ester (60 mg).

[0209] Step 7e: Prepare (3-(((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazin -4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)carbamic acid 4-methoxybenzyl ester

[0210]

[0211] Specific method of step 7e: Add 2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide (26 mg, 0.13 mmol) and ammonium chloride (3 mg, 0.06 mmol) to a solution of (3-(((2-chloro-6-(difluoromethyl)quinazolin-4-yl)amino)methyl)oxetan-3-yl))4-methoxybenzyl carbamate (60 mg, 0.12 mmol) in ethanol (5 mL). Heat the mixture to 80 °C and stir at 80 °C for 8 hours. Concentrate the mixture to obtain a crude product. Dissolve the crude product in water (20 mL), and then extract with ethyl acetate (20 mL × 3). Combine the organic phases, concentrate to obtain a crude product, and purify the crude product by flash column chromatography to obtain a white solid (3-(((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepine -4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)4-methoxybenzyl carbamate (50 mg).

[0212] Step 7f: Prepare 4-(4-(((3-aminooxetan-3-yl)methyl)amino)-6-(difluoromethyl)quinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine -1,1-dioxide

[0213]

[0214] Specific method of step 7f: Prepare the white solid 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) from (3-(((6-(difluoromethyl)-2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepine -4(5H)-yl)quinazolin-4-yl)amino)methyl)oxetan-3-yl)4-methoxybenzyl carbamate (50 mg, 0.078 mmol) according to the method similar to step 1h of Example 1. 1HNMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 6.79 (t, J = 56.0 Hz, 1H), 5.25 (br.s, 2H), 4.82–4.69 (m, 6H), 4.27 (s, 2H), 3.53 (s, 2H). MS found (ESI + ) [(M + H) + : 476.

[0215] 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

[0216]

[0217] Step 8a: Preparation of tert-butyl 3-(((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)-3-hydroxyazetidine-1-carboxylate

[0218]

[0219] Specific method of Step 8a: 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 prepared into white solid tert-butyl 3-(((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)-3-hydroxyazetidine-1-carboxylate (135 mg) according to the method similar to Step 1d of Example 1. MS found (ESI + ) [(M + H) + : 540.

[0220] 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

[0221]

[0222] Specific method of Step 8b: 3-(((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (80 mg, 0.15 mmol) was prepared into white solid 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) according to the method of Step 1e in Example 1. 1 H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.58 (td, J = 7.6, 1.2 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 5.16 (br.s, 2H), 4.54 (br.s, 2H), 4.28 (d, J = 12.4 Hz, 2H), 3.98 - 3.87 (m, 4H), 3.94 (t, J = 5.2 Hz, 2H), 2.39 (s, 3H). MS measured value (ESI + ) [(M + H) + : 440.

[0223] 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

[0224]

[0225] Step 9a: Preparation of ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxypyrrolidin-3-yl)methyl)carbamic acid tert-butyl ester

[0226]

[0227] Specific method of Step 9a: Under nitrogen protection, 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-hydroxypyrrolidin-3-yl)methyl)carbamate (338 mg, 1.69 mmol) were dissolved in 5 mL of DMF. PyBOP and DBU were added at room temperature, and the mixture was heated to 60 °C and stirred for 3 - 4 hours. The reaction was diluted with water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a yellow solid ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxypyrrolidin-3-yl)methyl)carbamate tert-butyl ester (127 mg).

[0228] 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

[0229]

[0230] Specific method of Step 9b: ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxypyrrolidin-3-yl)methyl)carbamate tert-butyl ester (127 mg, 0.24 mmol) was prepared into a white powder 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) according to the method similar to Step 1e of Example 1. 1HNMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.0 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.58 (t, J = 7.8 Hz, 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 found (ESI + ) [(M + H) + : 453.

[0231] 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

[0232]

[0233] 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

[0234]

[0235] Specific method of Step 10a: 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) were prepared into white solid 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) according to the method similar to Step 1d of Example 1.

[0236] 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

[0237]

[0238] Specific method of Step 10b: ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)-3-hydroxyazetidin-3-yl)methyl)tert-butyl carbamate (80 mg, 0.15 mmol) was prepared into white powder 4-(4-(3-(aminomethyl)-3-hydroxyazetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (21.9 mg) according to the method in Step 1e of Example 1. 1 H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.18 (s, 2H), 4.63 (d, J = 9.6 Hz, 2H), 4.55 (s, 2H), 4.42 (d, J = 10.0 Hz, 2H), 3.51 (t, J = 5.0 Hz, 2H), 3.37 (s, 2H), 2.36 (s, 3H). MS found (ESI + ) [(M+H) + : 440.

[0239] Example 11: 4-(4-(3-(Aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0240]

[0241] Step 11a: Prepare ((1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-yl)methyl)tert-butyl carbamate

[0242]

[0243] Specific method of Step 11a: 4-(4-Chloro-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (80 mg, 0.21 mmol) and tert-butyl ((azetidin-3-ylmethyl)carbamate) (48 mg, 0.26 mmol) were prepared into a white solid ((1-(2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-yl)methyl)carbamate (66 mg) according to the method of Step 1d in Example 1.

[0244] Step 11b: Preparation of 4-(4-(3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0245]

[0246] Specific method of Step 11b: ((1-(2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)azetidin-3-yl)methyl)carbamate (66 mg, 0.13 mmol) was prepared into a white powder 4-(4-(3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (18.3 mg) according to the method of Step 1e in Example 1. 1 H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 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 = 9.6 Hz, 2H), 2.91 - 2.84 (m, 1H), 2.34 (s, 3H). MS found (ESI + ) [(M + H) + : 424.

[0247] Example 12: 4-(4-((3-aminocyclobutyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0248]

[0249] Step 12a: Prepare tert-butyl (3-((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)cyclobutyl)carbamate

[0250]

[0251] Specific method of Step 12a: 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) were prepared into white solid tert-butyl (3-((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)cyclobutyl)carbamate (105 mg) according to the method of Step 1d in Example 1.

[0252] Step 12b: Prepare 4-(4-((3-aminocyclobutyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide

[0253]

[0254] Specific method of Step 12b: tert-butyl (3-((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)cyclobutyl)carbamate (105 mg, 0.20 mmol) was prepared into white powder 4-(4-((3-aminocyclobutyl)amino)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (40.4 mg) according to the method of Step 1e in Example 1. 1 ​​​​​​1H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.0 Hz, 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 = 8.0 Hz, 2H), 2.88 - 2.82 (m, 1H), 2.51 - 2.44 (m, 2H), 2.37 (s, 3H) 1.93 - 1.85 (m, 1H). MS found (ESI + ) [(M + H) + : 424.

[0255] 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

[0256]

[0257] Step 13a: Preparation of tert-butyl 3-(bis(4-methoxybenzyl)amino)-3-cyanoazetidine-1-carboxylate

[0258]

[0259] Specific method of Step 13a: 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 trimethylsilyl cyanide (724 mg, 7.30 mmol) was added. The reaction solution was heated to 80 °C and reacted for 4 hours. After cooling, acetic acid was removed by concentration. The residue was dissolved in ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (10 mL × 3), then 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.

[0260] Step 13b: Preparation of 3-(bis(4-methoxybenzyl)amino)azetidine-3-carbonitrile

[0261]

[0262] Specific method for Step 13b: At room temperature, 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). The mixture was stirred at room temperature for 1 hour, then 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 dichloromethane solution containing 10% methanol (15 mL × 2), then the combined organic phases were 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-carbonitrile (267 mg) as a colorless oil.

[0263] 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-carbonitrile

[0264]

[0265] Specific method for Step 13c: 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-carbonitrile (267 mg, 0.79 mmol) were prepared to obtain 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-carbonitrile (340 mg) as a white solid according to the method in Step 1d of Example 1.

[0266] 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-carbonitrile

[0267]

[0268] Specific method for Step 13d: 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-carbonitrile (340 mg, 0.50 mmol) was dissolved in trifluoroacetic acid (3 mL). The mixture was stirred at 60 °C for 2 hours, then 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 dichloromethane solution of 10% methanol (15 mL × 2). Then the combined organic phases were 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 a white solid 3-amino-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-carbonitrile (130 mg).

[0269] Step 13e: Preparation of 4-(4-(3-amino-3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide

[0270]

[0271] Specific method of Step 13e: Under ice-water bath conditions, nickel(II) chloride hexahydrate (233 mg, 0.98 mmol) and sodium borohydride (37 mg, 0.98 mmol) were added to a methanol (3 mL) solution of 3-amino-1-(2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)azetidine-3-carbonitrile (130 mg, 0.30 mmol). The mixture was continuously stirred at room temperature for 2 hours. The reaction was quenched by adding water (10 mL), filtered, and the mother liquor was extracted with dichloromethane solution of 10% methanol (15 mL × 2). Then the combined organic phases were 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 a white solid 4-(4-(3-amino-3-(aminomethyl)azetidin-1-yl)-6-methylquinazolin-2-yl)-2,3,4,5-tetrahydrobenzo[1,4]thiazepin -1,1-dioxide (16.2 mg). 11H NMR (400 MHz, CD3OD) δ 7.94 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.50 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.0, 1.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 5.16 (br.s, 2H), 4.55 (br.s, 2H), 4.47 (d, J = 9.6 Hz, 2H), 4.23 (d, J = 9.2 Hz, 2H), 3.49 (t, J = 4.8 Hz, 2H), 3.10 (s, 2H), 2.35 (s, 3H). MS found (ESI + ) [(M + H) + : 439.

[0272] 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

[0273]

[0274] Step 14a: Preparation of tert-butyl (3S,4S)-3-((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)-4-hydroxypyrrolidine-1-carboxylate

[0275]

[0276] Specific method of Step 14a: 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 prepared according to the method of Step 1d of Example 1 to obtain a white solid, tert-butyl (3S,4S)-3-((2-(1,1-dioxido-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)-4-hydroxypyrrolidine-1-carboxylate (118 mg).

[0277] 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

[0278]

[0279] Specific method of Step 14b: (3S,4S)-3-((2-(1,1-dioxo-2,3-dihydrobenzo[1,4]thiazepin -4(5H)-yl)-6-methylquinazolin-4-yl)amino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (118 mg, 0.22 mmol) was prepared into a white solid 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) in the same manner as in Step 1e of Example 1. 1 H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 5.17 (br.s, 2H), 4.72 (br.s, 2H), 4.52 (br.s, 2H), 3.78 (dd, J = 12.4, 5.6 Hz, 1H), 3.54 - 3.43 (m, 3H), 3.39 (d, J = 12.0 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H), 2.36 (s, 3H). MS found (ESI + ) [(M + H) + : 440.

[0280] 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

[0281]

[0282] Step 15a: Preparation of 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-carboxylic acid tert-butyl ester

[0283]

[0284] Specific method of step 15a: 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 prepared into white solid 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) according to the method of step 1d in Example 1.

[0285] Step 15b: Prepare 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

[0286]

[0287] Specific method of step 15b: 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) was prepared into white solid 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) according to the method of step 1e in Example 1. 11H NMR (400 MHz, CD3OD) δ 7.93 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.65 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 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 = 4.6 Hz, 2H), 2.76 (t, J = 9.6 Hz, 2H), 2.35 (s, 3H), 2.29 (t, J = 10.0 Hz, 2H). MS found (ESI + ) [(M + H) + : 450.

[0288] The following specifically describes the biological implementation data to further elaborate on the technical solution of the present invention.

[0289] Materials and Methods

[0290] RSV cell line:

[0291] HEp-2 cells (ATCC CCL-23, human laryngeal carcinoma epithelial cells) were purchased from American Type Culture Collection. The culture conditions were as follows: 1% double antibody was added to DMEM medium containing 10% fetal bovine serum (FBS), and the cells were placed in a 5% CO2 incubator at 37 °C for culture.

[0292] Viral cytopathic effect (CPE) experiment:

[0293] To determine the anti-RSV activity of the compound, 96-well plates were inoculated at a density of 5 × 10 3 cells per well, and the cells were in HycloneTM DMEM containing 10% fetal bovine serum (FBS). The next day, in the presence of serially 3-fold diluted compounds, the cells were infected with 0.5 MOI of RSV Long strain (ATCC) so that after 4 days, the total volume per well was 100 μL. After 4 days, the cell viability was determined using the CellTiter-Glo Reagent cell counting kit, and the fluorescence signal was read on a multifunctional microplate reader. The 50% effective concentration EC 50 .

[0294] Detection Results

[0295] The activities of the compounds involved in Examples 1 to 15 of the present invention for inhibiting RSV were determined by the above method, and the results are summarized in Table 3.

[0296] Table 3: Activity data of the example compounds

[0297] Embodiment <![CDATA[IC 50 (nM)]]> Embodiment <![CDATA[IC 50 (nM)]]> 1 4.4 2 6.3 3 5.0 4 7.0 5 7.9 6 4.9 7 4.1 8 2.9 9 0.9 10 3.3 11 1.2 12 1.7 13 9.6 14 1.3 15 3.7

[0298] Furthermore, the pharmacokinetics of Example 4 and Example 7 in the present invention and Example 61-1 (Control 1) in Patent WO2013020993 were further compared in ICR mice. Single intravenous injection (dose 2 mg / kg) and single oral administration (dose 10 mg / kg) were used respectively. Blood sampling points: before dosing, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h after dosing. The pharmacokinetic parameters of Example 4 and Example 7 in mouse plasma are shown in Table 5 below. The pharmacokinetics of the above Control 1 in ICR mice were studied using the same method, and single intravenous injection (dose 2 mg / kg) and single oral administration (dose 10 mg / kg) were used respectively. The pharmacokinetic parameters of Control 1 in mouse plasma and liver are shown in Table 4 below:

[0299] Table 4: Plasma drug concentration in mice

[0300]

[0301] NA: Not detected; ND: Not detected.

[0302] As can be seen from Table 4, the average concentrations of the example compounds in the present invention in mouse plasma after intravenous injection and oral administration are significantly higher than those of Control 1, indicating that the compounds involved in the present invention have a higher in vivo exposure and are more beneficial for the treatment of RSV diseases.

[0303] Furthermore, those skilled in the art understand that all the compounds involved in the aforementioned general formula I compounds, different implementation manners of the general formula I compounds, and specific examples of the general formula I compounds can be made into corresponding isomers, solvates, hydrates, prodrugs, stable isotope derivatives, and pharmaceutically acceptable salts. Preferably, the compound is made into a pharmaceutically acceptable derivative, and the derivative is any one of a prodrug, a salt, an ester, an amide, a salt of an ester, a salt of an amide, and a metabolite.

[0304] Further, pharmaceutically acceptable salts include conventional non-toxic salts obtained by salifying any of the compounds involved in the present invention with an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid or phosphoric acid, etc.) or with an organic acid (such as 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 a review of suitable pharmaceutical salts, reference can be made to Berge S.M et al., J. Pharm. Sci. 1977, 66, 1-19; Gould P.L., Int. J. Pharm 1986, 33, 201-277 and Bighley et al., Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, pages 453-497.

[0305] Further, for stable isotope derivatives, isotopes can be introduced into any of the compounds involved in the present invention, and the introduced isotopes can be 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and specific isotope derivatives can be prepared by conventional techniques.

[0306] Further, as an actual product, it can also be made into any one of tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions.

[0307] Further, on the above basis, it can also form a mixture with any of the following substances: pharmaceutically acceptable carriers or adjuvants or excipients.

[0308] All compounds involved in the present invention and mixtures, compositions, etc. containing the compounds of the present invention can be administered into a living body through any administration route. The administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or topical or systemic transdermal administration.

[0309] All compounds involved in the present invention, as well as mixtures, compositions, etc. containing the compounds of the present invention, can be formulated into single doses, which contain the active compounds of the present invention as well as carriers, excipients, etc. The dosage forms for administration can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. These dosage forms can contain common components used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostatic agents, isotonicity regulators, anti-adhesion agents, etc.

[0310] Suitable formulations for the above-mentioned various dosage forms can be obtained from public sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, published by Lippincott Williams & Wilkins in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in 2005. Therefore, those skilled in the art can easily prepare them.

[0311] According to factors such as the nature and intensity of the diseases suffered by different individuals, the age, gender, and weight of the patients, and the administration route, different administration doses can be selected. The administration dose of the compounds of the present invention can be 0.01 to 500 mg / kg per day, preferably the daily dose is 1 - 100 mg / kg, and can be administered once or multiple times.

[0312] Those skilled in the art understand that all compounds involved in the present invention, as well as mixtures, compositions, etc. containing the compounds of the present invention, their typical application is medical application, especially for preventing or treating respiratory syncytial virus infection. The specific indications are as follows:

[0313] It can inhibit the production or secretion of respiratory syncytial virus (RSV). This novel compound can be used for the treatment and prevention of RSV infection. The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various deformations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A compound having the structure of Formula I or a pharmaceutically acceptable salt or isotope-labeled compound thereof: Among them, R 1 selected from hydrogen and deuterium, R 2 is unsubstituted azetidinyl or methyl substituted by R 4 ; or R 1 and R 2 are linked to form an azetidinyl group, and the azetidinyl group is substituted by R 5 and R 6 ; R 3 is difluoromethyl; R 4 is an oxetanyl group, and the oxetanyl group is substituted by an amino group; R 5 and R 6 each independently selected from hydrogen, amino or methyl, the methyl being substituted by hydroxyl or amino, and R 5 and R 6 are not simultaneously hydrogen.

2. The compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof according to claim 1, wherein R 1 is hydrogen, and R 2 is methyl substituted by R 4 groups.

3. The compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof according to claim 1, wherein R 5 and R 6 each independently selected from amino or methyl, said methyl being substituted by hydroxy or amino.

4. The compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof according to claim 1, wherein R 5 and R 6 are each independently an amino group.

5. The compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof according to claim 1, wherein R 5 and R 6 are each independently selected from hydrogen or amino, and R 5 and R 6 are not both hydrogen at the same time.

6. The following compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof:

7. A method for preparing the compound shown in Formula 17, the method comprising: reacting the compound shown in Formula 15 with the compound shown in Formula 8 in the presence of triethylamine to obtain the compound shown in Formula 16; treating the compound shown in Formula 16 with trifluoroacetic acid to remove the protecting group to obtain the compound shown in Formula 17; In the compound shown in Formula 8, R 1 is hydrogen, R 2 is unsubstituted azetidinyl; or R 1 and R 2 are linked to form azetidinyl, and the azetidinyl is substituted by R 5 and R 6 ; R 5 and R 6 are each independently selected from hydrogen, amino or methyl, and the methyl is substituted by hydroxy or amino, and R 5 and R 6 are not both hydrogen at the same time.

8. A method for preparing the compound shown in Formula 25, the method comprising: reacting the compound shown in Formula 23 with the compound shown in Formula 7 in the presence of ammonium chloride and ethanol to obtain the compound shown in Formula 24; treating the compound shown in Formula 24 with trifluoroacetic acid and dichloromethane to remove the protecting group to obtain the compound shown in Formula 25.

9. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof according to any one of claims 1 to 6.

10. Use of the compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a drug for preventing and / or treating diseases caused by respiratory syncytial virus infection.

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