Diaminopyrimidine compound and use thereof

Abstract

Provided in the present application are a diaminopyrimidine compound having a structure as represented by formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug molecule thereof, a deuterated derivative thereof or a tritiated derivative thereof, and the use thereof.

Description

Diaminopyrimidine compounds and uses thereof

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. 2024104294188, filed on April 10, 2024, entitled “Diaminopyrimidine compounds and uses thereof”, and Chinese Patent Application No. 202510170426X, filed on February 14, 2025, entitled “Diaminopyrimidine compounds and uses thereof”, the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present application relates to the field of medicinal chemistry, in particular to a class of diaminopyrimidine compounds and uses thereof. BACKGROUND

[0004] Respiratory Syncytial virus (RSV) is an infectious virus of respiratory tract disease worldwide. RSV infection can cause patients to develop symptoms such as bronchiolitis and pneumonia, which poses a serious threat to the health and life of children, especially infants under 6 months old, and the elderly (≥65 years old) and immunocompromised individuals. At the same time, there is evidence that RSV infection during childhood can trigger persistent or recurrent wheezing and asthma later in life, and RSV infection in immunocompromised adults or the elderly can lead to the exacerbation of serious conditions such as asthma, chronic obstructive pulmonary disease, congestive heart failure, and even death.

[0005] Although antibodies such as palivizumab and nirsevimab and the Arexvy vaccine have been approved for use in preventing lower respiratory tract disease caused by RSV in infants and the elderly, vaccine and prophylactic antibody drugs can only be used for the prevention of RSV infection, and there is still a lack of clinical treatment drugs when patients have already been infected with RSV. Therefore, there is still an urgent need for small molecule specific antiviral drugs to combat RSV in clinical practice.

[0006] Currently, ribavirin is the only recognized antiviral drug for the treatment of RSV, but its safety and poor efficacy limit its application in practice. Therefore, finding specific and non-specific methods for treating RSV infection is still a problem that needs to be solved at present. SUMMARY

[0007] In view of the above problems, the present application provides a diaminopyrimidine compound.

[0008] The present application includes the following technical solutions.

[0009] A diaminopyrimidine compound having a structure as shown in formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritium thereof,

[0010] wherein, ring A is selected from: C6-C 10 aryl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, and ring A and the pyrimidine ring form a fused ring;

[0011] ring B is selected from: 1 or more R-substituted or unsubstituted 9-12 membered nitrogen-containing fused bicyclic ring;

[0012] each R1 is independently selected from: hydrogen, 1 or more R4-substituted or unsubstituted C1-C6 alkyl, 1 or more R4-substituted or unsubstituted C1-C6 alkoxy, 1 or more R4-substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, nitro, hydroxyl, thiol, amino, 1 or more R4-substituted or unsubstituted C3-C8 cycloalkyl, 1 or more R4-substituted or unsubstituted 3-8 membered heterocyclyl, C1-C6 alkylacyl, or 2 R1s together with the atom to which they are attached form 1 or more R4-substituted or unsubstituted C3-C8 cycloalkyl or 3-8 membered heterocyclyl, or 2 R1s on the same carbon together with the carbon atom to which they are attached form C=O;

[0013] R2 and R3 are independently selected from: hydrogen, 1 or more R5-substituted or unsubstituted C1-C8 alkyl, 1 or more R4-substituted or unsubstituted C3-C 10 cycloalkyl, 1 or more R4-substituted or unsubstituted 3-10 membered heterocyclyl, or R2 and R3 together with the nitrogen atom to which they are attached form 1 or more R4-substituted or unsubstituted 3-10 membered heterocyclyl;

[0014] each R4 is independently selected from: hydrogen, phenyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, amino, hydroxyl;

[0015] each R5 is independently selected from: hydrogen, amino, hydroxyl, 1 or more R4-substituted or unsubstituted C3-C 10 cycloalkyl, 1 or more R4-substituted or unsubstituted 3-10 membered heterocyclyl, C1-C6 alkylamino, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, cyano, halogen, -S(=O)R6, -S(=O)2R6, -S(=O)(=NH)R6, or 2 R5s on the same carbon together with the carbon atom to which they are attached form 1 or more R4-substituted or unsubstituted C3-C 10cycloalkyl or 3-10 membered heterocyclyl;

[0016] each R6is independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0017] each R is independently selected from the group consisting of hydrogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkylthio, halogen, cyano, nitro, hydroxyl, thiol, amino;

[0018] n is selected from 0, 1, 2, 3, 4.

[0019] The application also provides the use of the diaminopyrimidine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, including the following technical solutions:

[0020] The application provides the use of the diaminopyrimidine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof in the preparation of an anti-respiratory syncytial virus drug.

[0021] The application provides the use of the diaminopyrimidine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof in the preparation of a drug for preventing and / or treating diseases related to respiratory syncytial virus infection.

[0022] The application also provides an anti-respiratory syncytial virus drug, which comprises an active ingredient and a pharmaceutically acceptable adjuvant, and the active ingredient comprises the diaminopyrimidine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is the distribution concentration of compound Z-04 in each tissue of mice after oral administration.

[0024] Figure 2 is the body weight change of each group of mice after RSV infection.

[0025] Figure 3 is the lung index of each group of mice after RSV infection.

[0026] Figure 4 is the virus titer of each group of mice after RSV infection.

[0027] Figure 5 is the RSV-F copy number of each group of mice after RSV infection.

[0028] Figure 6 is the TNF-α gene expression of each group of mice after RSV infection.

[0029] Figure 7 is the IL-1β gene expression of each group of mice after RSV infection.

[0030] Figure 8 is the IL-6 gene expression of each group of mice after RSV infection. DETAILED DESCRIPTION

[0031] For the purposes of the present application, a more complete description of the application will be presented. The present application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the present application can be more thoroughly and completely understood.

[0032] The experimental methods in the following examples, unless otherwise specified, are generally performed according to conventional conditions or according to the conditions recommended by the manufacturer. The various common chemical reagents used in the examples are commercially available products.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0034] In addition, as used in this application, the term "or" is the inclusive "or" and not the

[0035] In the compounds described herein, when any variable (e.g., R 4 , R 5 , etc.) occurs more than one time in any constituent, its meaning in each occurrence is independent of its meaning in every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in chemically stable compounds. A line drawn to a ring indicates that the bond can be attached to any available carbon atom of the ring. If the ring system is polycyclic, it means that the bond is attached to any appropriate carbon atom of the adjacent ring. It is understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present application which result in a stable compound that is readily synthesized from readily available materials by techniques known in the art and presented below. If a substituent is itself substituted with more than one group, it is understood that the groups can be on the same carbon atom or on different carbon atoms, as long as the structure is stable.

[0036] In the present application, dotted lines or wavy lines represent bond attachment points.

[0037] The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the designation "C1-C6alkyl" includes groups with 1, 2, 3, 4, 5, or 6 carbon atoms in either a straight or branched arrangement. For example, "C1-C6alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl.

[0038] The term "cycloalkyl" as used herein refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring systems having ring atoms consisting of carbon atoms, bicyclic or polycyclic rings include spiro, fused, and bridged rings. For example, "cycloalkyl" includes, but is not limited to, the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0039] The term "alkoxy" as used herein refers to groups having the structure -O-alkyl, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, and the like.

[0040] The term "heterocycloalkyl" or "heterocyclyl" as used herein refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring systems having one or more ring atoms selected from N, O, Se, or S(O)m(wherein m is an integer from 0 to 2), the remaining ring atoms being carbon, bicyclic or polycyclic rings include annulated, spiro, fused, and bridged rings. For example: oxetanyl, azetidinyl, morpholinyl, piperidinyl, pyrrolinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotirazolyl, dihydroazetidinyl, tetrahydrofuran, tetrahydrothiophenyl, and the like, and N-oxides thereof. Attachment of the heterocyclic substituent can be through a carbon atom or through a heteroatom.

[0041] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S, which aromatic ring can be monocyclic, bicyclic, or polycyclic, including, but not limited to, quinolinyl, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, and the like; "heteroaryl" is also understood to include N-oxide derivatives of any nitrogen-containing heteroaryl group. Attachment of a heteroaryl group can be through a carbon atom or through a heteroatom.

[0042] As used herein, the term "halo" or "halogen" means chlorine, fluorine, bromine, and iodine, as understood by those skilled in the art.

[0043] The present application includes the free form of the compounds of Formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some of the specific exemplary compounds in the present application are amines in the free form, i.e., "free form." The pharmaceutically acceptable salts of the present application can be synthesized from the compounds of the present application that contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared by ion exchange chromatography or by reacting the free base with a chemical equivalent of the desired salt form in a suitable solvent or combination of solvents. Similarly, the salts of the acidic compounds are prepared by reacting the free acid with a suitable inorganic or organic base in a suitable solvent or combination of solvents.

[0044] Thus, pharmaceutically acceptable salts of the compounds of this application include the conventional nontoxic salts of the compounds of the present application as formed by reaction with inorganic or organic acids. For example, conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic, and the like.

[0045] If the compound of the present application is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyldiamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobal, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0046] The preparation of the above-mentioned pharmaceutically acceptable salts of the compounds of the present application and other typical pharmaceutically acceptable salts are described in more detail in Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977: 66: 1-19.

[0047] The present application relates to the stereoisomers of the compounds of the present application, i.e. (depending on their structure) as enantiomers, diastereomers, syn- / anti-isomers, cis- / trans-isomers, epimers, and (E)- / (Z)-isomers. The compounds of the formula I can be used in the context of the present application in the form of pure stereoisomers or in the form of any mixture of stereoisomers, in the latter case preferably as racemates.

[0048] Metabolites of the compounds of the present application and pharmaceutically acceptable salts thereof, and those compounds which can convert to any of the foregoing in vivo, are encompassed by the present application.

[0049] The present application also provides a pharmaceutical composition for the treatment of RSV virus, comprising a safe and effective amount of the active ingredient, and pharmaceutically acceptable adjuvants.

[0050] The "active ingredient" according to the present application refers to the compound of the formula I according to the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof.

[0051] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet.

[0052] When using a pharmaceutical composition, a safe and effective amount of the compound of the present application is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0053] "Pharmaceutically acceptable excipients" refer to: one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0054] “Compatibility” herein refers to the ability of the components in the composition to be compatible with the active ingredient of the present application and with each other without significantly reducing the efficacy of the active ingredient.

[0055] Examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0056] In another preferred embodiment, the compound of formula I of the present application can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula I of the present application, as a small molecule, can also be linked to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0057] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present application. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0058] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0059] In solid dosage forms of the invention, the active drug compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (or both), such as sodium citrate or dicalcium phosphate, or the following:

[0060] (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acids;

[0061] (b) binders, such as, for example, hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia;

[0062] (c) humectants, such as, for example, glycerol;

[0063] (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0064] (e) agents for retarding dissolution, such as paraffin;

[0065] (f) absorption accelerators, such as, for example, quaternary ammonium compounds;

[0066] (g) agents for retarding dissolution, such as paraffin;

[0067] (h) adsorbents, such as, for example, kaolin; and

[0068] (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0069] Solid dosage forms of the invention can also be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0070] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, together with

[0071] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0072] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0073] The compounds of the present invention can be administered alone or in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When the compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of Formula I is preferably used. Combination administration also includes administering the compound of Formula I and one or more other known drugs during overlapping time periods. When the compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when the compound of Formula I or the known drug is administered alone.

[0074] A diaminopyrimidine compound having a structure as shown in formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof,

[0075] Wherein, ring A is selected from: C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, and Ring A and pyrimidine ring form a ring;

[0076] Ring B is selected from: 1 or more R substituted or unsubstituted 9-12 membered nitrogen-containing bicyclic ring;

[0077] Each R1 is independently selected from the group consisting of hydrogen, one or more R4 substituted or unsubstituted C1-C6 alkyl, one or more R4 substituted or unsubstituted C1-C6 alkoxy, one or more R4 substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, nitro, hydroxy, thiol, amino, one or more R4 substituted or unsubstituted C3-C8 cycloalkyl, one or more R4 substituted or unsubstituted 3-8 membered heterocyclyl, C1-C6 alkylacyl, or two R1s together with the atoms to which they are attached form one or more R4 substituted or unsubstituted C3-C8 cycloalkyl or 3-8 membered heterocyclyl, or two R1s on the same carbon atom together with the carbon atom to which they are attached form C=O;

[0078] R2, R3are each independently selected from the group consisting of: hydrogen, 1 or more R5-substituted or unsubstituted C1-C8alkyl, 1 or more R4-substituted or unsubstituted C3-C 10 cycloalkyl, 1 or more R4-substituted or unsubstituted 3-10 membered heterocyclyl, or R2, R3and the nitrogen atom to which they are attached together form 1 or more R4-substituted or unsubstituted 3-10 membered heterocyclyl;

[0079] each R4is independently selected from the group consisting of: hydrogen, phenyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, amino, hydroxyl;

[0080] each R5is independently selected from the group consisting of: hydrogen, amino, hydroxyl, 1 or more R4-substituted or unsubstituted C3-C 10 cycloalkyl, 1 or more R4-substituted or unsubstituted 3-10 membered heterocyclyl, C1-C6alkylamino, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, cyano, halogen, -S(=O)R6, -S(=O)2R6, -S(=O)(=NH)R6, or 2 R5on the same carbon together with the carbon atom to which they are attached form 1 or more R4-substituted or unsubstituted C3-C 10 cycloalkyl or 3-10 membered heterocyclyl;

[0081] each R6is independently selected from the group consisting of: hydrogen, C1-C6alkyl;

[0082] each R is independently selected from the group consisting of: hydrogen, C1-C6alkyl, halo C1-C6alkyl, C1-C6alkoxy, halo C1-C6alkoxy, C1-C6alkylthio, halogen, cyano, nitro, hydroxyl, thiol, amino;

[0083] n is selected from the group consisting of: 0, 1, 2, 3, 4.

[0084] The diaminopyrimidine compound provided in the present application has significant inhibitory activity against RSV virus, has a completely different chemical structure type from existing anti-RSV drugs such as ribavirin, and is expected to develop into a new type of anti-RSV virus drug, which can be used to inhibit the replication or reproduction of RSV virus, prevent, alleviate and / or treat respiratory syncytial virus infection and the cytopathic effect caused thereby, and can be used to treat diseases such as bronchitis or pneumonia caused by respiratory syncytial virus infection.

[0085] In some embodiments, when ring A is phenyl, ring B is not R-substituted or unsubstituted 11-membered nitrogen-containing bicyclic ring.

[0086] In some embodiments, ring A is selected from the group consisting of: phenyl, C5-C8cycloalkyl, 5-8 membered heterocyclyl.

[0087] In some embodiments, ring A is selected from the group consisting of phenyl, C5-C6 cycloalkyl, 5-6 membered heterocyclyl having one or two nitrogen heteroatoms.

[0088] In some embodiments, ring A is selected from the group consisting of 5-6 membered heterocyclyl having one or two nitrogen heteroatoms, the hydrogens on the nitrogen atoms being unsubstituted by R1.

[0089] In some embodiments, each R1is independently selected from the group consisting of hydrogen, C1-C3 alkyl substituted or unsubstituted by one or more R4, C1-C3 alkoxy substituted or unsubstituted by one or more R4, C1-C3 alkylthio substituted or unsubstituted by one or more R4, halogen, cyano, nitro, hydroxyl, thiol, amino, C3-C6 cycloalkyl substituted or unsubstituted by one or more R4, 4-6 membered heterocyclyl substituted or unsubstituted by one or more R4, C1-C3 alkylacyl, or two R1together with the atom to which they are attached form one or more C3-C6 cycloalkyl or 4-6 membered heterocyclyl substituted or unsubstituted by one or more R4, or two R1on the same carbon together with the carbon atom to which they are attached form C=O.

[0090] In some embodiments, each R1is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, halogen, benzyl, phenethyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, fluoromethyl, fluoroethyl, acetyl, propionyl, or two R1together with the atom to which they are attached form R4substituted or unsubstituted C3-C6 cycloalkyl or 4-6 membered heterocyclyl, or two R1on the same carbon together with the carbon atom to which they are attached form C=O;

[0091] wherein R4is selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino, hydroxyl.

[0092] In some embodiments, when ring A is phenyl or C3-C8 cycloalkyl, at least one R1is C1-C6 alkyl, preferably C1-C3 alkyl, more preferably methyl.

[0093] In some embodiments, ring A and the pyrimidine ring to which it is attached together form the following structure:

[0094] In some embodiments, ring B is selected from the group consisting of 10-11 membered benzo-nitrogen-containing heterocycle substituted or unsubstituted by one or more R.

[0095] In some embodiments, ring B is selected from the group consisting of:

[0096] X is selected from the group consisting of -C(R7)2-, -0-, -S-, -Se-, -S(=0)-, -S(=0)2-, -NR8-;

[0097] Q is selected from the group consisting of -C(R7)2-, -0-, -S-, -NR8-;

[0098] Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8are each independently selected from the group consisting of CR, N;

[0099] R7is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio;

[0100] R8is selected from the group consisting of hydrogen, C1-C6alkyl.

[0101] In some embodiments, ring B is selected from the group consisting of:

[0102] X is selected from the group consisting of -C(R7)2-, -0-, -S-, -Se-, -S(=0)-, -S(=0)2-, -NR8-;

[0103] R7is selected from the group consisting of hydrogen, fluorine, chlorine, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylthio;

[0104] R8is selected from the group consisting of hydrogen, C1-C3alkyl;

[0105] m is selected from the group consisting of 0, 1, 2, 3, 4.

[0106] In some embodiments, each R is independently selected from the group consisting of hydrogen, C1-C3alkyl, one or more fluorine-substituted C1-C3alkyl, C1-C3alkoxy, one or more fluorine-substituted C1-C3alkylthio, C1-C3alkylthio, fluorine, chlorine, bromine, cyano.

[0107] In some embodiments, ring B is selected from the group consisting of:

[0108] wherein each R is independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, cyano.

[0109] In some embodiments, R2, R3are each independently selected from the group consisting of hydrogen, 1 or more R5-substituted or unsubstituted C1-C4alkyl, 1 or more R4-substituted or unsubstituted C3-C8cycloalkyl, 1 or more R4-substituted or unsubstituted 3-8 membered heterocyclyl, or R2, R3and the nitrogen atom to which they are attached together form 1 or more R4-substituted or unsubstituted 3-8 membered heterocyclyl;

[0110] each R5is independently selected from the group consisting of hydrogen, amino, hydroxyl, one or more R4-substituted or unsubstituted C3-C8cycloalkyl, one or more R4-substituted or unsubstituted 3-8 membered heterocyclyl, C1-C3alkylamino, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy, C1-C3alkylthio, cyano, halogen, -S(=O)R6, -S(=O)2R6, -S(=O)(=NH)R6, or 2 R5on the same carbon together with the carbon atom to which they are attached form one or more R4-substituted or unsubstituted C3-C8cycloalkyl or 3-8 membered heterocyclyl.

[0111] In some embodiments, each R4is independently selected from the group consisting of hydrogen, phenyl, halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylthio, amino, hydroxyl;

[0112] each R6is independently selected from the group consisting of hydrogen, C1-C3alkyl.

[0113] In some embodiments, only one of R2and R3is hydrogen.

[0114] In some embodiments, R2, R3, and the nitrogen or oxygen atom to which they are attached together form a group:

[0115] In some embodiments, the diamino pyrimidine compound is selected from the group consisting of:

[0116] The present application also provides uses of the diamino pyrimidine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, including the following technical solutions:

[0117] The present application also provides uses of the diamino pyrimidine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, including the following technical solutions:

[0118] The dianinopyrimidine compound described in the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof is used in the prevention and / or treatment of respiratory syncytial virus infection.

[0119] The dianinopyrimidine compound described in the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof is used in the preparation of a drug for preventing and / or treating diseases related to respiratory syncytial virus infection.

[0120] The dianinopyrimidine compound described in the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof is used in the prevention and / or treatment of diseases related to respiratory syncytial virus infection.

[0121] In some embodiments, the diseases related to respiratory syncytial virus infection are bronchitis, pneumonia, asthma or chronic obstructive pulmonary disease.

[0122] The present application also provides an anti-respiratory syncytial virus drug, comprising an active ingredient and a pharmaceutically acceptable adjuvant, wherein the active ingredient comprises the dianinopyrimidine compound described in the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuteride thereof, or a tritide thereof.

[0123] The present application is further described in conjunction with the following specific examples. It should be understood that these examples are merely for illustration and do not limit the scope of the present application. The experimental methods in the following examples, unless otherwise specified, are generally carried out according to conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0124] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The described preferred methods and materials are merely exemplary.

[0125] The starting materials in the following examples can be obtained from commercial sources, or prepared by known methods in the art, or prepared according to the methods described herein.

[0126] Example 1

[0127] In a round bottom flask containing 3 mL of dry methanol, add 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline (146.3 mg, 0.68 mM) and 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (189.1 mg, 1.02 mM), stir at room temperature and add triethylamine (102.9 mg, 1.02 mM), reflux the reaction and monitor, after the reaction is completed, remove MeOH by rotary evaporation and add an appropriate amount of DCM to dissolve, wash with saturated brine and water three times each, collect the organic layer, dry with Mg2SO4, filter and concentrate the organic solution, and perform column chromatography on silica gel (DCM:MeOH = 90:1) on the sample, collect and dry the target product Z-01-1 (204.2 mg, Yield: 75.12%).

[0128] Dissolve dry compound Z-01-1 (140.0 mg, 0.38 mM), 2,3,4,5-tetrahydrobenzo[1,4]thiazine-1,1-dioxide (97.94 mg, 0.49 mM), and NH4Cl (30.68 mg, 0.57 mM) in a heated synthesis tube containing anhydrous ethanol, heat to 85°C in a heating synthesizer, and react for 12 hours and monitor the reaction, after the reaction is completed, transfer the reaction solution to a round bottom flask, remove EtOH by rotary evaporation and add an appropriate amount of DCM to dissolve, wash with saturated brine and water three times each, collect the organic layer, dry with Mg2SO4, filter and concentrate the organic solution, and perform column chromatography on silica gel (DCM:MeOH = 70:1) on the sample, collect and dry the target product Z-01-2 (133.0 mg, Yield: 65.98%).

[0129] Dissolve dry compound Z-01-2 (100 mg, xx mM) in DCM (5 mL), add TFA (1.0 mL), react at room temperature overnight, monitor the reaction, after the reaction is completed, adjust to pH = 9-10 with aqueous sodium hydroxide (1 mol), wash with saturated brine and water three times each, collect the organic layer, dry with Mg2SO4, filter and concentrate the organic solution, and perform column chromatography on silica gel (DCM:MeOH = 25:1) on the sample, collect and dry the target product Z-01 (30.6 mg, Yield: 37.76%).

[0130] Z-01: 1H NMR (600 MHz, CDC13) δ 7.96 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 5.27 (s, 1H), 4.93 (d, J = 121.3 Hz, 3H), 4.45 (s, 2H), 3.61 - 3.50 (m, 2H), 3.45 - 3.28 (m, 4H), 2.51 (d, J = 11.3 Hz, 2H), 2.40 - 2.31 (m, 2H), 2.10 (d, J = 12.3 Hz, 1H), 1.84 - 1.72 (m, 2H), 1.33 - 1.28 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H). LCMS (ESI): m / z 428 [M+1] + .

[0131] Example 2

[0132] The target product Z-02 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, N-tert- butoxycarbonyl-1,2-ethanediamine.

[0133] Z-02: 1 H NMR (600 MHz, CDC13) δ 8.01 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.47 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 5.09 (s, 2H), 3.59 - 3.46 (m, 2H), 3.41 (t, J = 5.1 Hz, 2H), 2.52 (dt, J = 5.6, 3.3 Hz, 2H), 2.28 - 2.22 (m, 1H), 2.07 (td, J = 8.2, 7.8, 3.2 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.78 (dq, J = 9.4, 3.8, 2.6 Hz, 4H), 1.73 (t, J = 9.1 Hz, 1H), 1.05 (d, J = 6.0 Hz, 3H). LCMS (ESI): m / z 402 [M+1] + .

[0134] Example 3

[0135] The target product Z-03 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, tert-butyl 1- (aminomethyl)cyclobutylcarbamate.

[0136] Z-03:1 H NMR (600 MHz, CDC13 + MeOD-d4) δ 8.01 (dd, J = 12.8, 7.8 Hz, 1H), 7.70-7.63 (m, 1H), 7.57-7.50 (m, 1H), 7.44-7.41 (m, 1H), 5.08 (s, 2H), 3.60-3.51 (m, 2H), 3.45 (dt, J = 13.4, 5.1 Hz, 2H), 3.39-3.35 (m, 1H), 2.92 (p, J = 5.8 Hz, 2H), 2.54 (td, J = 8.5, 7.9, 4.1 Hz, 2H), 2.37-2.27 (m, 1H), 1.81 (dd, J = 22.5, 11.4 Hz, 3H), 1.11-1.05 (m, 3H). LCMS (ESI): m / z 442 [M+1] + .

[0137] Example 4

[0138] The target product Z-04 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, tert-butyl N-[3- (aminomethyl)oxetan-3-yl]carbamate.

[0139] Z-04: 1 H NMR (600 MHz, CDC13) δ 8.02 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.98 (d, J = 145.2 Hz, 3H), 4.65-4.39 (m, 5H), 3.85 (d, J = 31.3 Hz, 2H), 3.50-3.33 (m, 2H), 2.62-2.46 (m, 2H), 2.24 (d, J = 10.1 Hz, 1H), 1.90-1.72 (m, 4H), 1.05 (d, J = 5.3 Hz, 3H). LCMS (ESI): m / z 444 [M+1] + .

[0140] Example 5

[0141] The target product Z-05 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, 1-aminomethyl-1- (BOC-amino)cyclopropane.

[0142] Z-05: 1H NMR (600 MHz, CDC13+ MeOD-d4) δ 8.00 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 3.66 (d, J = 9.5 Hz, 2H), 3.44 (t, J = 5.0 Hz, 2H), 3.38-3.36 (m, 2H), 2.61-2.51 (m, 2H), 2.39 (dd, J = 14.9, 4.4 Hz, 1H), 1.84 (d, J = 14.2 Hz, 2H), 1.33 (td, J = 11.1, 7.8 Hz, 1H), 1.09 (d, J = 6.1 Hz, 3H), 0.91-0.88 (m, 2H), 0.84 (d, J = 4.0 Hz, 2H). LCMS (ESI): m / z 428 [M+1] + .

[0143] Example 6

[0144] The target product Z-06 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, tert-butyl 1- (aminomethyl)cyclobutylcarbamate.

[0145] Z-06: 1 H NMR (600 MHz, CDC13+ DMSO-d6) δ 7.93 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 5.67 (s, 1H), 5.03 (s, 2H), 4.45 (s, 2H), 3.63-3.55 (m, 2H), 2.44 (d, J = 6.2 Hz, 2H), 2.20 (t, J = 6.0 Hz, 2H), 2.06 (d, J = 10.3 Hz, 2H), 1.95-1.89 (m, 2H), 1.85-1.66 (m, 6H). LCMS (ESI): m / z 428 [M+1] + .

[0146] Example 7

[0147] The target product Z-16 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, 1-tert- butyloxycarbonyl-3-aminocyclobutylamine.

[0148] Z-16: 1H NMR (600 MHz, CDC13+ MeOD-d4) δ 8.00 (t, J = 8.9 Hz, 1H), 7.70 (t, J = 8.7 Hz, 1H), 7.58 (q, J = 8.4 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 5.13 (d, J = 80.4 Hz, 3H), 4.45 (s, 1H), 4.31 (d, J = 10.6 Hz, 2H), 3.49 - 3.32 (m, 3H), 2.56 (p, J = 8.7, 6.8 Hz, 2H), 2.41 (td, J = 10.0, 4.8 Hz, 1H), 1.92 - 1.71 (m, 3H), 1.38 - 1.25 (m, 2H), 1.09 (dd, J = 10.3, 6.3 Hz, 3H). LCMS (ESI): m / z 414 [M+1] + .

[0149] Example 8

[0150] The target product Z-45 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, N-tert-butoxycarbonyl-1,2-ethanediamine according to Example 1.

[0151] Z-45: 1 H NMR (600 MHz, DMSO-d6) δ 7.87 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.31 (t, J = 5.6 Hz, 1H), 4.94 (s, 2H), 4.31 (s, 2H), 3.40 (s, 2H), 2.70 (d, J = 6.5 Hz, 2H), 2.44 - 2.38 (m, 2H), 2.35 (s, 3H), 2.31 - 2.26 (m, 1H), 1.68 (q, J = 19.5, 14.7 Hz, 3H), 1.23 (dd, J = 11.2, 6.8 Hz, 2H), 0.99 (d, J = 5.7 Hz, 3H). LCMS (ESI): m / z 416 [M+1] + .

[0152] Example 9

[0153] The target product Z-51 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, (2-amino-isopropyl) tert-butyl carbamate according to Example 1.

[0154] Z-51: 1H NMR (600 MHz, CDC13+ MeOD-d4) δ 7.99 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 5.16 - 4.98 (m, 2H), 3.57 (dd, J = 16.0, 10.8 Hz, 1H), 3.44 (t, J = 5.1 Hz, 2H), 3.25 (q, J = 10.9, 10.2 Hz, 2H), 2.54 (dd, J = 8.6, 4.2 Hz, 2H), 2.34 (t, J = 10.0 Hz, 1H), 1.86 - 1.75 (m, 3H), 1.21 (d, J = 5.9 Hz, 3H), 1.08 (d, J = 5.9 Hz, 3H). LCMS (ESI): m / z 416 [M+1] + .

[0155] Example 10

[0156] The target product Z-60 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, N,N- dimethylethylenediamine.

[0157] Z-60: 1 H NMR (600 MHz, CDC13) δ 8.01 (dd, J = 7.8, 1.3 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (td, J = 7.7, 1.3 Hz, 1H), 5.22 - 4.96 (m, 3H), 4.50 (s, 1H), 3.50 (d, J = 5.9 Hz, 2H), 3.40 (t, J = 5.1 Hz, 2H), 2.52 (q, J = 5.4, 4.5 Hz, 4H), 2.27 (s, 6H), 2.25 (d, J = 9.8 Hz, 1H), 1.83 - 1.74 (m, 3H), 1.34 - 1.28 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H). LCMS (ESI): m / z 430 [M+1] + .

[0158] Example 11

[0159] The target product Z-62 was synthesized step by step with reference to Example 1 using the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, 2- (methylsulfonyl)ethanamine.

[0160] Z-62: 1H NMR (600 MHz, DMSO-d6) δ 7.91-7.85 (m, 1H), 7.75 (s, 1H), 7.61 (dd, J = 7.5, 1.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.61 (s, 1H), 4.96 (s, 2H), 4.34 (s, 2H), 3.82 (s, 2H), 3.51 (t, J = 5.0 Hz, 2H), 3.04 (s, 3H), 2.48-2.39 (m, 2H), 2.29 (d, J = 10.7 Hz, 1H), 1.71 (dd, J = 18.7, 6.2 Hz, 3H), 1.00 (d, J = 6.0 Hz, 3H). LCMS (ESI): m / z 465 [M+1] + .

[0161] Example 12

[0162] The target product Z-70 was synthesized step by step with the starting material 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-D]pyrimidine, N-tert-butoxycarbonyl-1,2-ethanediamine according to Example 1.

[0163] Z-70: 1 H NMR (600 MHz, DMSO-d6) δ 7.91-7.85 (m, 1H), 7.75 (s, 1H), 7.61 (dd, J = 7.5, 1.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.61 (s, 1H), 4.96 (s, 2H), 4.34 (s, 2H), 3.82 (s, 2H), 3.51 (t, J = 5.0 Hz, 2H), 3.04 (s, 3H), 2.48-2.39 (m, 2H), 2.29 (d, J = 10.7 Hz, 1H), 1.71 (dd, J = 18.7, 6.2 Hz, 3H), 1.00 (d, J = 6.0 Hz, 3H). LCMS (ESI): m / z 465 [M+1] + .

[0164] Example 13

[0165] The target product Z-71 was synthesized step by step with the starting material 2,4-dichloro-7,7-dimethyl-5,7-dihydrofuro[3,4-D]pyrimidine, N-tert-butoxycarbonyl-1,2-ethanediamine according to Example 1.

[0166] Z-71: 1H NMR (600 MHz, CDC13+ MeOD-d4) δ 8.00 (d, J = 4.1 Hz, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.43 (d, J = 3.5 Hz, 1H), 5.20-5.02 (m, 2H), 4.79 (d, J = 3.5 Hz, 2H), 3.75-3.64 (m, 4H), 3.45 (q, J = 4.6 Hz, 2H), 3.17-3.09 (m, 2H), 1.27 (s, 6H). LCMS (ESI): m / z 404 [M+1] + .

[0167] Example 14

[0168] The target product Z-72 was synthesized step by step according to the reference example 1 with the starting material N-BOC-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-D]pyrimidine, N-tert-butoxycarbonyl-1,2-ethanediamine.

[0169] Z-72: 1 H NMR (600 MHz, DMSO-d6) δ 7.90-7.85 (m, 1H), 7.72-7.44 (m, 4H), 6.42 (s, 1H), 4.95 (s, 2H), 4.33 (s, 1H), 3.36 (s, 6H), 2.76 (d, J = 40.4 Hz, 6H), 2.32 (s, 1H). LCMS (ESI): m / z 389 [M+1] + .

[0170] Example 15

[0171] According to the similar method of example 1, 7-benzyl-2,4-dichloro-5,6,7,8- tetrahydropyrido[3,4-D]pyrimidine, N-tert-butoxycarbonyl-1,2-ethanediamine was synthesized under the catalysis of triethylamine, the intermediate Z-73-1 was heated with 2,3,4,5- tetrahydrobenzo[1,4]thiazine-1,1-dioxide and ammonium chloride in anhydrous ethanol to generate Z-73-2, and the target product Z-73 was obtained after Boc group was removed by trifluoroacetic acid and purified.

[0172] Z-73: ¾ NMR (600 MHz, DMSO-d6) δ 7.87 (dd, J = 7.7, 1.3 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.35 - 7.28 (m, 5H), 7.27 (d, J = 6.3 Hz, 1H), 6.46 (t, J = 5.7 Hz, 1H), 4.92 (s, 2H), 4.29 (s, 2H), 3.57 (s, 2H), 3.44 (q, J = 6.7 Hz, 4H), 3.11 (s, 2H), 2.68 (t, J = 7.1 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.24 (t, J = 5.9 Hz, 2H). LCMS (ESI): m / z 479 [M+1] + .

[0173] Example 16

[0174] The target product Z-74 was synthesized step by step with the starting material 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-D]pyrimidine, N-tert-butoxycarbonyl-1,2-ethanediamine according to Example 1.

[0175] Z-74: 1 H NMR (600 MHz, CDCl3+MeOD-d4) δ 8.01 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 5.10 (s, 2H), 4.58 (d, J = 6.3 Hz, 2H), 4.49 (d, J = 6.3 Hz, 2H), 4.41 (s, 2H), 3.92 (td, J = 5.8, 2.0 Hz, 2H), 3.88 (s, 2H), 3.44 (t, J = 4.8 Hz, 2H), 3.36 (p, J = 1.6 Hz, 2H), 2.61 (t, J = 5.7 Hz, 2H). LCMS (ESI): m / z 432 [M+1] + .

[0176] Example 17

[0177] The target product Z-75 was synthesized step by step with the starting material 2,4-dichloro-7,7-dimethyl-5,7-dihydrofuro[3,4-D]pyrimidine, N-[3- (aminomethyl)oxetan-3-yl]tert-butylcarbamate according to Example 1.

[0178] Z-75: 1H NMR (600MHz, CDCl3) δ8.04(d,J=7.8Hz,1H),7.70(d,J=7.5Hz,1H),7.49(t,J=7.7Hz,1H),7.39(t,J=7.6Hz,1H),5.13(s,2H),4.7 7(s,2H),4.66(t,J=5.6Hz,1H),4.56-4.36(m,5H),3.82(s,2H),3.41(t,J=5.1Hz,2H),1.71(s,8H),1.36(s,6H).LCMS(ESI): m / z 446[M+1] + .

[0179] Example 18

[0180] 3-Methylcyclohexanone (15.0 g, 133.8 mM) and diethyl carbonate (47.39 g, 401.4 mM) were dissolved in 1,4-dioxane under an ice bath. Sodium hydride (16.05 g, 401.4 mM) was slowly added in batches and stirred for 30 min. The mixture was then transferred to room temperature and heated to reflux. After the reaction was completed, the mixture was cooled to room temperature, poured into ice water, and extracted three times with EA. The organic layer was dried over anhydrous sodium sulfate, concentrated, mixed, and separated by silica gel column chromatography (PE:DCM = 15:1) to obtain intermediate Z-77-1 (8.2 g, Yield: 33.28%).

[0181] Under ice bath, the intermediate Z-77-1 (8.0 g, 43.5 mM) and urea (7.83 g, 130.4 mM) were dissolved in a certain amount of methanol. Sodium methoxide (7.04 g, 130.4 mM) was slowly added in batches and stirred for 30 min. The mixture was then transferred to room temperature and heated to reflux. As the reaction proceeded, a large amount of white solid was precipitated. After the reaction was completed, it was cooled to room temperature. The reaction solution was stirred under ice bath for 1 h, filtered and washed with ice methanol. The white solid was collected and dried, dissolved in an appropriate amount of water and adjusted to pH 7 with 1 M HCl. At the same time, solid precipitated. Filter, wash with water, collect the solid and dry it to obtain intermediate Z-77-2 (7.6 g, Yield: 97.12%).

[0182] In a round bottom flask, intermediate Z-77-2 (7.4 g, 41.09 mM) was added slowly as a solvent with phosphorus oxychloride, and the temperature was raised to reflux. After the reaction was completed, the temperature was cooled to room temperature, and excess phosphorus oxychloride was removed by distillation under reduced pressure. After the reaction flask was cooled to room temperature, ice water was added, and the H value was adjusted to 9 with 1M NaOH (aq) while brown solid was precipitated. The solid was filtered, washed with water, collected, and dried, and then separated by column chromatography on a silica gel column (PE:DCM = 1:2) to obtain intermediate Z-77-3 (6.5 g, Yield: 71.3%).

[0183] In a round bottom flask containing 5 mL of dry methanol, 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline (320.0 mg, 1.48 mM) and tert-butyl N-[3-(aminomethyl)oxetan-3-yl]carbamate (299.42 mg, 1.48 mM) were added, stirred at room temperature, and triethylamine (211.0 mg, 2.22 mM) was added. The reaction was refluxed and monitored, and after the reaction was completed, MeOH was removed by rotary evaporation and dissolved in an appropriate amount of DCM. The organic layer was washed with saturated brine and water three times each, dried with Mg2SO4, filtered, and the organic solution was concentrated. Column chromatography was performed on a silica gel sample (DCM:MeOH = 100:1), and the target product Z-77-4 (398.0 mg, Yield: 70.3%) was collected and dried.

[0184] Dry compound Z-77-4 (220.0 mg, 0.58 mM), 2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide (170.15 mg, 0.87 mM), and NH4Cl (46.2 mg, 0.87 mM) were dissolved in a heated synthesis tube containing anhydrous ethanol. After heating to 85°C in a heating synthesizer, the reaction was performed for 12 h and monitored. After the reaction was completed, the reaction solution was transferred to a round bottom flask, EtOH was removed by rotary evaporation, and an appropriate amount of DCM was added for dissolution. The organic layer was washed with saturated brine and water three times each, dried with Mg2SO4, filtered, and the organic solution was concentrated. Column chromatography was performed on a silica gel sample (DCM:MeOH = 70:1), and the target product Z-77-5 (165.0 mg, Yield: 52.76%) was collected and dried.

[0185] Dry compound Z-77-5 (150.0 mg, 0.276 mM) was dissolved in DCM (5 mL), TFA (1.5 mL) was added, and the reaction was allowed to proceed at room temperature overnight. After monitoring the reaction, the reaction was stopped, and the pH was adjusted to 9-10 with aqueous sodium hydroxide solution (1 mol). The reaction mixture was washed with saturated brine and water three times each, and the organic layer was collected, dried over Mg2SO4, filtered, and concentrated. The organic solution was column chromatographed (DCM:MeOH = 25:1) with silica gel. The target product Z-77 (80 mg, Yield: 65.38%) was collected and dried.

[0186] Z-77: 1 H NMR (600 MHz, CDCl3) δ 8.02 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.98 (d, J = 145.2 Hz, 3H), 4.65-4.39 (m, 5H), 3.85 (d, J = 31.3 Hz, 2H), 3.50-3.33 (m, 2H), 2.62-2.46 (m, 2H), 2.24 (d, J = 10.1 Hz, 1H), 1.90-1.72 (m, 4H), 1.05 (d, J = 5.3 Hz, 3H). LCMS (ESI): m / z 444 [M+1] + .

[0187] Example 19

[0188] The target product Z-78 was synthesized step by step according to Example 18 using 2-methylcyclohexanone and diethyl carbonate as starting materials.

[0189] Z-78: 1 H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 4.49-4.42 (m, 2H), 4.38 (d, J = 6.5 Hz, 2H), 3.76 (s, 2H), 3.35 (dt, J = 7.0, 3.6 Hz, 2H), 2.50 (d, J = 6.4 Hz, 1H), 2.09 (t, J = 6.1 Hz, 2H), 1.76 (tt, J = 13.8, 6.4 Hz, 4H), 1.61-.53 (m, 1H), 1.42-1.34 (m, 1H), 1.19 (dq, J = 22.1, 7.2 Hz, 8H). LCMS (ESI): m / z 444 [M+1] + .

[0190] Example 20

[0191] The target product Z-79 was stepwise synthesized with the starting material 4,4- dimethylcyclohexanone, diethyl carbonate, referring to Example 18.

[0192] Z-79: 1 H NMR (600 MHz, CDC13) δ 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.72 (dd, J = 7.6, 1.2 Hz, 1H), 7.50 (td, J = 7.5, 1.4 Hz, 1H), 7.37 (td, J = 7.7, 1.2 Hz, 1H), 5.10 (s, 2H), 4.85 (d, J = 5.7 Hz, 1H), 4.53 (d, J = 6.5 Hz, 2H), 4.47 (d, J = 6.4 Hz, 2H), 3.84 (s, 2H), 3.42 (t, J = 5.1 Hz, 2H), 2.52 (s, 2H), 1.93 (s, 2H), 1.78 (s, 4H), 1.49 (t, J = 6.6 Hz, 2H), 0.97 (s, 6H). LCMS (ESI): m / z 458 [M+1] + .

[0193] Example 21

[0194] The target product Z-80 was stepwise synthesized with the starting material 2',4'- dichloro-7',8'-EQ-5'H-spiro[cyclopropane-l,6'-quinazoline, N-[3- (aminomethyl)oxetan-3-yl]carbamic acid tert-butyl ester, referring to Example 18.

[0195] Z-80: 1 H NMR (600 MHz, CDC13) δ 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.72 (dd, J = 7.5, 1.2 Hz, 1H), 7.50 (td, J = 7.5, 1.3 Hz, 1H), 7.37 (td, J = 7.7, 1.2 Hz, 1H), 5.11 (s, 2H), 4.74 (t, J = 5.5 Hz, 1H), 4.52 (d, J = 6.5 Hz, 2H), 4.45 (d, J = 6.4 Hz, 2H), 3.84 (s, 2H), 3.42 (t, J = 5.0 Hz, 2H), 2.59 (t, J = 6.3 Hz, 2H), 2.03 (s, 2H), 1.76 (s, 4H), 1.50 (t, J = 6.3 Hz, 2H), 0.43 - 0.34 (m, 4H). LCMS (ESI): m / z 456 [M+1] + .

[0196] Example 22

[0197] The target product Z-158 was synthesized stepwise using 4-trifluoromethylcyclohexane-1-one and diethyl carbonate as starting materials according to Example 18.

[0198] Z-158: 1 H NMR (600 MHz, CDCl3+MeOD-d4) 1 H NMR (600MHz, CDCl3) δ8.01(d,J=8.0Hz,1H),7.74(d,J=7.7Hz,1H),7.55(t,J=7.5Hz,1H),7.42(s,1H),5.09(s,2H),4.60(d,J=5.9Hz,2H),4.52(d,J= 6.5Hz,2H),4.01-3.81(m,2H),3.43(d,J=5.3Hz,2H),2.70-2.51(m,3H),2. 40(s,1H),2.29(t,J=13.4Hz,1H),2.14(d,J=12.7Hz,1H)..LCMS(ESI): m / z 498[M+1] + .

[0199] Example 23

[0200] The target product Z-184 was synthesized stepwise using the starting materials 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-D]pyrimidine and tert-butyl N-[3-(aminomethyl)oxetan-3-yl]carbamate as described in Example 1.

[0201] Z-184: 1 H NMR (600MHz, CDCl3+DMSO-d6) δ7.93(d,J=7.8Hz,1H),7.71(d,J=7.4Hz,1H),7.53(t,J=7.5Hz,1H),7.40(t,J=7.7Hz,1H),5.67(s,1H),5.03(s,2H),4.4 5(s,2H),3.63-3.55(m,2H),2.44(d,J=6.2Hz,2H),2.20(t,J=6.0Hz,2H),2 .06(d,J=10.3Hz,2H),1.95-1.89(m,2H),1.85-1.66(m,6H).LCMS(ESI): m / z 432[M+1] + .

[0202] Example 24

[0203] The target product Z-185 was synthesized step by step from the starting material 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (300.0 mg, 1.477 mM) and tert-butyl N-[3- (aminomethyl)oxetan-3-yl]carbamate according to the procedures of Example 1. Z-185: 1 H NMR (600 MHz, CDC13) δ 8.05 - 7.99 (m, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.49 (td, J = 7.5, 1.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 5.10 (s, 2H), 4.87 (t, J = 5.5 Hz, 1H), 4.52 (d, J = 6.4 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 3.84 (s, 2H), 3.41 (t, J = 5.0 Hz, 2H), 2.49 (t, J = 6.1 Hz, 2H), 2.17 (t, J = 6.1 Hz, 2H), 1.74 - 1.71 (m, 4H). LCMS (ESI): m / z 430 [M+1] + .

[0204] Example 25

[0205] According to the similar procedures of Examples 1 and 2, N-BOC-2,4-dichloro-5,7,8- trihydropyrido[4,3-D]pyrimidine, tert-butyl N-[3-(aminomethyl)oxetan-3-yl]carbamate was synthesized in the presence of catalytic triethylamine, intermediate Z-187-1 was generated from intermediate Z-187-1 and 2,3,4,5-tetrahydrobenzo[l,4]thiazine-l,l-dioxide and ammonium chloride in anhydrous ethanol upon heating, and intermediate Z-187-2 was obtained after purification by removing the Boc group with trifluoroacetic acid, and the target product Z-187 was obtained.

[0206] Z-187: 1 H NMR (600 MHz, DMSO-d6) δ 7.88 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 81.9 Hz, 1H), 4.99 (d, J = 45.2 Hz, 1H), 4.63 - 4.26 (m, 4H), 3.85 (s, 4H), 3.27 (s, 6H), 2.78 - 2.61 (m, 2H). LCMS (ESI): m / z 431 [M+1] + .

[0207] Example 26

[0208] According to similar method of example 1 and 2, intermediate Z-188-1 was synthesized from 2,4-dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylic acid tert-butyl ester, N-[3-(aminomethyl)oxetan-3-yl]carbamic acid tert-butyl ester in the presence of catalytic triethylamine, intermediate Z-188-1 was heated with 2,3,4,5-tetrahydrobenzo[l,4]thiazepine-l,l-dioxide and ammonium chloride in anhydrous ethanol to give intermediate Z-188-2, which was purified by removing Boc group with trifluoroacetic acid to give the target compound Z-188.

[0209] Z-188: 1 H NMR (600 MHz, DMSO-d6) δ 7.87 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 6.53 (s, 1H), 4.94 (s, 2H), 4.59 - 4.18 (m, 6H), 3.77 (s, 2H), 3.51 (d, J = 6.0 Hz, 4H), 2.95 (d, J = 6.1 Hz, 2H), 2.24 (d, J = 6.2 Hz, 2H). LCMS (ESI): m / z 431 [M+1] + .

[0210] Example 27

[0211] Intermediate Z-191-1 was synthesized from intermediate Z-187-2, formic acid and formaldehyde under ice bath condition, which was dissolved in methanol and hydrogen gas to remove benzyl group catalyzed by palladium hydroxide and trifluoroacetic acid to give the target compound Z-191.

[0212] Z-191: 1 H NMR (600 MHz, DMSO-d6) δ 7.87 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 6.51 (s, 1H), 4.95 (s, 2H), 4.52 - 4.27 (m, 6H), 3.81 (td, J = 13.3, 6.7 Hz, 3H), 3.60 (t, J = 6.4 Hz, 3H), 3.12 (s, 2H), 2.54 (d, J = 5.2 Hz, 2H), 2.34 (s, 3H). LCMS (ESI): m / z 445 [M+1] + .

[0213] Example 28

[0214] Intermediate Z-187-2, acetyl chloride under triethylamine catalysis to form intermediate Z-192-1, intermediate Z-192-1 was dissolved in methanol and hydrogen under palladium hydroxide, trifluoroacetic acid catalysis to remove the benzyl group to form the target compound Z-192.

[0215] Z-192: 1 H NMR (600 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 2H), 7.62 (q, J = 7.4, 6.0 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 6.70 (d, J = 51.6 Hz, 1H), 4.96 (s, 2H), 4.56 - 4.25 (m, 6H), 4.20 (d, J = 14.1 Hz, 2H), 3.85 (d, J = 29.6 Hz, 2H), 3.59 (d, J = 5.5 Hz, 4H), 2.59 - 2.49 (m, 4H), 2.42 (s, 1H), 2.06 (d, J = 3.2 Hz, 3H). LCMS (ESI): m / z 473 [M+1] + .

[0216] Example 29

[0217] The starting material 4-ethylcycloheptanone, diethyl carbonate was used to synthesize the target product Z-196 step by step according to Example 18.

[0218] Z-196: 1 H NMR (600 MHz, CDCl3) δ 8.05 - 8.01 (m, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.50 (td, J = 7.5, 1.3 Hz, 1H), 7.37 (td, J = 7.7, 1.2 Hz, 1H), 5.18 - 4.99 (m, 3H), 4.53 (d, J = 6.4 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 3.81 (s, 2H), 3.41 (t, J = 5.0 Hz, 2H), 2.72 - 2.61 (m, 2H), 2.39 - 2.29 (m, 2H), 1.77 (q, J = 6.0 Hz, 2H), 1.71 (s, 4H), 1.58 (p, J = 5.8 Hz, 2H), 1.51 (p, J = 5.7 Hz, 2H). LCMS (ESI): m / z 444 [M+1] + .

[0219] Example 30

[0220] According to similar method of example 1 and 2, intermediate Z-197-1 was synthesized from N-BOC-2,4-dichloro-5,7,8-trihydropyrido[4,3-D]pyrimidine, 3-(aminomethyl)-N,N-dibenzooxetan-3-amine in the presence of catalytic triethylamine, intermediate Z-197-1 was reacted with 2,3,4,5-tetrahydrobenzo[l,4]thiazepine-l,l-dioxide and ammonium chloride in anhydrous ethanol to give intermediate Z-197-2, which was purified by removing Boc group with trifluoroacetic acid to give the target product Z-197.

[0221] Z-197: 1 H NMR (600 MHz, CDC13) δ 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.48 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (td, J = 7.7, 1.2 Hz, 1H), 7.28 (d, J = 6.5 Hz, 8H), 7.22 (td, J = 6.1, 2.6 Hz, 2H), 5.11 (s, 1H), 4.79 (t, J = 4.9 Hz, 1H), 4.74 (d, J = 6.6 Hz, 2H), 4.15 - 4.07 (m, 4H), 3.82 (s, 2H), 3.52 (s, 2H), 3.40 (t, J = 5.0 Hz, 2H), 3.07 (t, J = 5.9 Hz, 2H), 2.53 (t, J = 5.9 Hz, 2H), 1.67 (s, 2H), 1.26 (d, J = 3.1 Hz, 2H). LCMS (ESI): m / z 611 [M+1] + .

[0222] Example 31

[0223] The target product Z-199 was synthesized step by step from starting material 4- ethylcyclohexanone, diethyl carbonate according to example 16.

[0224] Z-199: 1H NMR (600MHz, CDCl3) δ8.02(dd,J=7.8,1.3Hz,1H),7.72(dd,J=7.6,1.2Hz,1H),7.49(td,J=7.5,1.4Hz,1H),7.36(t d,J=7.7,1.3Hz,1H),5.10(s,2H),4.88(t,J=5.6Hz,1H),4.53(dd,J=6.5,3.4Hz,2H),4.46(d,J=6.4Hz,2H),3.85(d ,J=16.2Hz,2H),3.41(t,J=5.0Hz,2H),2.53(ddd,J=17.9,13.4,9.0Hz,2H),2.26(dd,J=15.1,5.3Hz,1H),1.92–1. 85(m,1H),1.85–1.73(m,4H),1.58–1.51(m,1H),1.38(td,J=7.2,5.0Hz,2H),0.95(t,J=7.4Hz,3H).LCMS(ESI): m / z 458[M+1] + .

[0225] Example 32

[0226] The target product Z-200 was synthesized stepwise using 4,4-dimethylcyclohexanone and diethyl carbonate as starting materials according to Example 16.

[0227] Z-200: 1 H NMR (600MHz, CDCl3) δ8.02 (dd, J=7.8, 1.3Hz, 1H), 7.75-7.70 (m, 1H), 7.50 (td, J=7.5, 1. 3Hz,1H),7.37(td,J=7.7,1.2Hz,1H),5.10(s,2H),4.87(t,J=5.6Hz,1H),4.53(d,J=6.4 Hz,2H),4.46(d,J=6.4Hz,2H),3.84(d,J=7.3Hz,2H),3.41(t,J=5.1Hz,2H),2.28(s,2H) ,2.19(t,J=6.5Hz,2H),1.74(s,4H),1.51(t,J=6.5Hz,2H),0.94(s,6H).LCMS(ESI): m / z 458[M+1] + .

[0228] Example 33

[0229] The target product Z-205 was synthesized stepwise using the starting materials 2,4-dichloro-6-ethyl-5,6,7,8-tetrahydroquinazoline and 1-tert-butyloxycarbonyl-3-aminocyclobutylamine according to Example 1.

[0230] Z-205: 1 H NMR (600MHz, DMSO-d6) δ7.87 (d, J=8.0Hz, 1H), 7.76-7.57 (m, 2H), 7.48 (t, J= 7.7Hz,1H),6.75(d,J=6.2Hz,1H),4.93(s,2H),4.30(s,2H),3.88-3.59(m,4H ),2.48-2.36(m,3H),1.82-1.66(m,2H),1.49-1.40(m,1H),1.33(td,J=7.0,3 .1Hz,2H),1.26-1.18(m,2H),0.93(t,J=7.4Hz,3H).LCMS(ESI): m / z428[M+1] + .

[0231] Example 34

[0232] The target product Z-208 was synthesized stepwise using the starting materials N-BOC-2,4-dichloro-5,7,8-trihydropyrido[4,3-D]pyrimidine and 2-(methylsulfonyl)ethylamine according to Example 1.

[0233] Z-208: 1 H NMR (600MHz, DMSO-d6) δ7.89(d,J=7.7Hz,1H),7.74(d,J=66.1Hz,1H),7.62(t,J=7.4Hz,1H),7.50(t,J=7.7Hz,1H),7.11(d,J=36.1Hz,1H ),4.98(s,2H),4.36(s,2H),3.87(s,1H),3.72(s,2H),3.53(t,J=5.2Hz,4H),3.26(s,3H),3.04(d,J=61.1Hz,4H),2.65(d,J=13.0Hz,2H).

[0234] Example 35

[0235] The target product Z-209 was synthesized stepwise using 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline and tert-butyl (3-amino-2-hydroxypropyl)carbamate as starting materials according to Example 1.

[0236] Z-209: 1H NMR (600 MHz, DMSO-d6) δ 8.05 (s, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 49.5 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 6.56 (s, 1H), 5.75 (s, 1H), 4.95 (s, 2H), 4.34 (s, 1H), 3.93 (s, 1H), 3.48 (s, 3H), 3.25 (s, 1H), 2.80 (d, J = 132.9 Hz, 2H), 2.42 (s, 2H), 2.37 - 2.29 (m, 1H), 1.72 (d, J = 14.5 Hz, 2H), 1.00 (d, J = 6.1 Hz, 3H).

[0237] Example 36

[0238] The target product Z-210 was synthesized step by step with reference to Example 16, using the starting material 4-isopropylcyclohexanone and diethyl carbonate.

[0239] Z-257: 1 H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 5.11 (s, 2H), 4.62 (d, J = 7.1 Hz, 2H), 4.56 (d, J = 6.8 Hz, 2H), 3.98 (s, 2H), 3.64 (d, J = 17.4 Hz, 2H), 3.45 (d, J = 6.0 Hz, 2H), 3.37 (s, 4H), 2.58 (d, J = 64.8 Hz, 2H), 2.32 - 2.24 (m, 1H), 1.91 (t, J = 12.4 Hz, 2H), 1.47 - 1.38 (m, 1H), 0.96 (t, J = 6.5 Hz, 6H).

[0240] Example 37 Testing of the activity of the compounds against RSV

[0241] The activity of the target compounds against RSV was tested by cultivating RSV-A2 strain on Hep-2 cells, with Ziresovir (AK0529, CAS 1422500-60-4) as the positive control. The specific steps are as follows:

[0242] On the first day, 1 x 105cells were inoculated in 96-well cell culture plates, and the cells were incubated at 37°C in a 5% CO2 incubator for 24 hours. 5cells / mL, 100 μL / well. After the cells were passaged, they were incubated at 37°C, 5% CO2 overnight. The next day, samples including positive control drugs and target compounds were diluted by half in DMEM medium containing 2% FBS, for a total of 8 concentrations. At the same time, the medium in the 96-well cell culture plate was discarded, and the plate was washed once with 100 μL / well of PBS. After the liquid in the 96-well cell culture plate was discarded, the gradient-diluted samples were added at 200 μL / well, with 4 replicate wells for each concentration (2 wells for cytotoxicity and 2 wells for efficacy), and then incubated at 37°C, 5% CO2 overnight. The next day, samples (drugs) were diluted by half in DMEM medium containing 2% FBS, for a total of 8 concentrations. At the same time, the liquid in the 96-well cell culture plate was discarded, and the plate was washed once with 100 μL / well of PBS. The RSV virus was taken out from the -80°C freezer, thawed under running water, and diluted to 100 TCID 50 / well in serum-free DMEM medium, and then added to the efficacy wells at 100 μL / well, and 100 μL / well of serum-free DMEM medium was added to the cell control wells, and then incubated at 37°C, 5% CO2 for 2 h. The liquid in the 96-well cell culture plate was discarded, and the gradient-diluted samples (drugs) were added at 200 μL / well, and then incubated at 35°C, 5% CO2 for 48-72 h, and the CPE was observed and recorded. The inhibition rate and IC 50 .

[0243] The test results (IC 50 ) of the inhibition of RSV virus activity of the compounds are shown in Table 1 below. The results show that the diamino pyrimidine compounds of the present application have good efficacy in inhibiting the replication of RSV virus, and the activity of compounds Z-01, Z-72 and Z-235 is superior to that of the known RSV inhibitor AK0529 (control compound). The compounds do not show cytotoxicity at the tested dose, and exhibit a good therapeutic index.

[0244] Table 1 IC 50 values of the compounds against RSV

[0245] Pharmacokinetic test of the compound of Example 38

[0246] Each group of 3 SD rats (male) was administered orally at a dose of 2 mg / kg and intravenously at a dose of 10 mg / kg. Blood samples of about 0.3 mL were collected at 0.083 h (oral group only), 0.16 h (oral group only), 0.25 h, 0.5 h, 1 h (intravenous group only), 2 h, 4 h, 8 h, 24 h, 48 h after administration into a heparin tube, centrifuged at 4 °C at a speed of 4000 r / min for 10 min, and the upper plasma was transferred and stored temporarily in a freezer (about -20 °C) until determination. 50 μL of the plasma sample was added with 100 μL of 90% methanol aqueous solution, vortexed and mixed; then 350 μL of a mixed solution of methanol and acetonitrile (1:1, V / V) was added, vortexed and mixed; centrifuged at 10000 rpm for 10 min, and the supernatant was filtered through a 0.22 μm filter membrane before sampling and detection. The drug concentration in each sample was determined by high performance liquid chromatography (HPLC) / mass spectrometry (MS). The pharmacokinetic parameters were calculated by DAS (Drug and Statistics) 3.0 software.

[0247] After a single intravenous injection of 2 mg / kg Z-04 and oral administration of 10 mg / kg Z-04 in rats, the main pharmacokinetic parameters of intravenous administration were as follows: C max was 392 ng / mL, T max was 0.0833 h, T 1 / 2 was 0.955 h, AUC 0-T was 310 hr*ng / mL, AUC 0-∞ was 319 hr*ng / mL, Vz was 8732 mL / kg, Cl was 6338 mL / hr / kg, MRT 0-t was 0.919 h, MRT 0-∞ was 1.05 h. The main pharmacokinetic parameters of oral administration were as follows: C max was 22.1 ng / mL, T max was 0.417 h, T 1 / 2 was 4.06 h, AUC 0-t was 44.4 hr*ng / mL, AUC 0-∞ was 82.8 hr*ng / mL, MRT 0-t was 1.87 h, MRT 0-∞ was 5.77 h, and the oral bioavailability was 5.19%.

[0248] Water solubility test of the compound of Example 39

[0249] The test compound and control compound were prepared as a 10 mM DMSO stock solution. 30 μL of the stock solution was taken for each sample and placed in an EP tube, and 970 μL of PBS at pH 7.4 was added. The test sample was placed in a shaker and shaken at 25°C for 2 hours. After 2 hours, all samples were filtered. The sample was taken from the filtrate and diluted in a H2O and acetonitrile solution (1:1, by volume). The dilution factor was adjusted according to the solubility value and LC-MS signal response. The filtrate was analyzed and quantified by LC-MS / MS analysis and quantification. A compound concentration standard curve was configured, and the solubility value of the test compound and control compound was calculated according to the standard curve. The test results showed that compound Z-04 had good water solubility, and the water solubility was 0.2 mg / mL.

[0250] Example 40 Distribution of compound Z-04 in each tissue of mice after oral administration

[0251] A 4-week-old C57BL / 6 female mouse (n = 4) was used, and the compound group was administered at a dose of 50 mg / kg. The administration method was gavage treatment, twice a day, 200 μl each time. The mice were subjected to fasting treatment one day before administration, and the next day the mice were subjected to gavage treatment. The administration was performed continuously for 3 days, and the body weight change of the mice was observed and recorded every day. The mice were sacrificed 2 hours after the last gavage treatment. The heart, liver, lung, kidney, stomach, small intestine, and brain tissues were taken and washed twice in PBS, and immediately placed in liquid nitrogen for storage. The eyeball blood of the mice was taken, and allowed to stand at room temperature for 2 hours. The supernatant was transferred to a clean EP tube after centrifugation at 12000 r / min for 20 min at 4°C and stored at -80°C. The tissue samples were individually homogenized, and the concentration of the key metabolite Z-04 in the plasma and tissue homogenate was analyzed by LC-MS / MS.

[0252] The results (Figure 1) showed that after 3 days of continuous oral administration, the concentration of compound Z-04 in the lung tissue of the mice was about 6 x 10 4 (ng / g or ng / mL), while the concentration of compound Z-04 in the plasma was only 6 x 10 2 (ng / g or ng / mL), and the concentration of compound Z-04 in the lung tissue was about 100 times that in the plasma. According to the results of drug tissue distribution, the drug was enriched in the lung and played a role in inhibiting the activity of RSV.

[0253] Example 41 Test of the anti-RSV activity of the compound in a mouse model

[0254] Ziresovir (AK0529, CAS 1422500-60-4) was used as a positive control drug, and a C57BL / 6 mouse was selected to construct an RSV-A2 infection model to test the anti-RSV activity of the target compound. The specific steps are as follows:

[0255] The 4-week-old C57BL / 6 female mice were divided into groups, including normal control group, RSV infection model group, AK0529 group (50 mg / kg), compound group (compound Z-04, including two dose groups of 12.5 mg / kg and 50 mg / kg, respectively), 6 mice in each group. The administration method was gavage treatment, and the control group was given PBS gavage, 200 μl twice a day. The mice were subjected to fasting treatment one day before infection, and the next day the mice were infected with RSV. Except for the control group, the mice in the other groups were treated with RSV-A2 virus liquid 100 μl by nasal instillation, and 2 hours after nasal instillation, the mice were given different concentrations of drugs by gavage according to the grouping. Continuous administration for 3 days, the body weight change of mice was observed every day and recorded, and the mice were sacrificed on the 4th day. The right lung of the mice was taken for homogenate, centrifuged at 12000 r / min for 10 min at 4°C, and the supernatant was used for virus titer determination by TCID 50 method, and the lung sediment was extracted for RNA, and the RSV-F gene was quantitatively analyzed.

[0256] The results (Figure 2) showed that the body weight of mice gradually decreased after 24 hours of RSV infection, and gradually recovered after 48 hours of drug treatment, and the body weight of drug-treated mice was close to that of the control group after 72 hours. According to the results of lung index (Figure 3), the lung index of drug-treated mice was significantly lower than that of virus-infected mice, and the effect of compound group and positive control drug group was comparable. The RSV virus titer in lung tissue of each group was detected by TCID 50 The results (Figure 4) showed that the virus titer of drug-treated mice was lower than that of virus-infected mice, and the virus titer of compound 50 mg / kg dose group was lower than that of the same dose of positive control drug group. Further detection of RSV-F copy number results (Figure 5) showed that the RSV-F copy number of drug-treated mice was significantly lower than that of virus-infected mice, and the effect of compound group and positive control drug group was comparable. The above in vivo results showed that the compound had good effect on anti-RSV virus activity.

[0257] On the other hand, we detected the gene levels of inflammatory factors TNF-α, IL-1β and IL-6, and the results (Figures 6-8) showed that the levels of inflammatory factors in drug-treated mice were significantly decreased, and the effect of compound 50 mg / kg dose group was better than that of the same dose of positive control drug group.

[0258] The technical features of the above-described embodiments can be combined in any way. In order to make the description concise, not all possible combinations of the technical features in the following embodiments are described, however, as long as the combinations of the technical features do not exist contradictory, they should be considered as the scope of the present disclosure.

[0259] The above-described embodiments are merely illustrative of several embodiments of the present application, and the description is relatively specific and detailed, but should not be understood as a limitation on the scope of the patent. It should be noted that for those skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the scope of the present application. Therefore, the scope of protection of the present application should be subject to the appended claims.

Claims

1. A diaminopyrimidine compound having a structure as represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof, in, Ring A is selected from: C6-C 10 Aryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, and Ring A and pyrimidine ring form a ring; Ring B is selected from: 1 or more R substituted or unsubstituted 9-12 membered nitrogen-containing bicyclic ring; Each R1 is independently selected from the group consisting of hydrogen, one or more R4 substituted or unsubstituted C1-C6 alkyl, one or more R4 substituted or unsubstituted C1-C6 alkoxy, one or more R4 substituted or unsubstituted C1-C6 alkylthio, halogen, cyano, nitro, hydroxy, thiol, amino, one or more R4 substituted or unsubstituted C3-C8 cycloalkyl, one or more R4 substituted or unsubstituted 3-8 membered heterocyclyl, C1-C6 alkylacyl, or two R1s together with the atoms to which they are attached form one or more R4 substituted or unsubstituted C3-C8 cycloalkyl or 3-8 membered heterocyclyl, or two R1s on the same carbon atom together with the carbon atom to which they are attached form C=O; R2 and R3 are independently selected from the group consisting of hydrogen, one or more R5 substituted or unsubstituted C1-C8 alkyl, one or more R4 substituted or unsubstituted C3-C 10 Cycloalkyl, one or more R4-substituted or unsubstituted 3-10 membered heterocyclic groups, or R2, R3 and the nitrogen atom to which they are attached together form one or more R4-substituted or unsubstituted 3-10 membered heterocyclic groups; Each R4 is independently selected from the group consisting of hydrogen, phenyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, amino, and hydroxyl; Each R5 is independently selected from: hydrogen, amino, hydroxyl, one or more R4 substituted or unsubstituted C3-C 10 Cycloalkyl, 1 or more R4 substituted or unsubstituted 3-10 membered heterocyclic group, C1-C6 alkylamino, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, cyano, halogen, -S(=O)R6, -S(=O)2R6, -S(=O)(=NH)R6, or two R5 on the same carbon atom together with the carbon atom to which they are attached form one or more R4 substituted or unsubstituted C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; Each R6 is independently selected from: hydrogen, C1-C6 alkyl; Each R is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, hydroxyl, thiol, and amino; n is selected from: 0, 1, 2, 3, 4.

2. The diaminopyrimidine compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: When ring A is phenyl, ring B is an 11-membered nitrogen-containing bicyclic ring which is not substituted or unsubstituted with R.

3. The diaminopyrimidine compound according to claim 1 or 2, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Ring A is selected from: phenyl, C5-C8 cycloalkyl, 5-8 membered heterocyclyl; Preferably, ring A is selected from: phenyl, C5-C6 cycloalkyl, and a 5-6 membered heterocyclic group wherein the heteroatom is one or two nitrogen atoms.

4. The diaminopyrimidine compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Ring A is selected from a 5-6 membered heterocyclic group wherein the heteroatom is one or two nitrogen atoms, and the hydrogen atoms on the nitrogen atoms are not replaced by R1.

5. The diaminopyrimidine compound according to any one of claims 1 to 4, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Each R1 is independently selected from the group consisting of hydrogen, one or more R4 substituted or unsubstituted C1-C3 alkyl groups, one or more R4 substituted or unsubstituted C1-C3 alkoxy groups, one or more R4 substituted or unsubstituted C1-C3 alkylthio groups, halogen, cyano, nitro, hydroxyl, mercapto, amino, one or more R4 substituted or unsubstituted C3-C6 cycloalkyl groups, one or more R4 substituted or unsubstituted 4-6 membered heterocyclyl groups, C1-C3 alkylacyl groups, or two R1 groups together with the atoms to which they are attached form one or more R4 substituted or unsubstituted C3-C6 cycloalkyl groups or 4-6 membered heterocyclyl groups, or two R1 groups on the same carbon atom together with the carbon atom to which they are attached form C=O.

6. The diaminopyrimidine compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Each R1 is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, propylthio, halogen, benzyl, phenethyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, monofluoromethyl, monofluoroethyl, acetyl, propionyl, or two R1s together with the atom to which they are attached form R4 substituted or unsubstituted C3-C6 cycloalkyl or 4-6 membered heterocyclyl, or two R1s on the same carbon atom together with the carbon atom to which they are attached form C=O; Wherein, R4 is selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino, and hydroxy.

7. The diaminopyrimidine compound according to any one of claims 1 to 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: When ring A is a phenyl group or a C3-C8 cycloalkyl group, at least one R1 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, and more preferably a methyl group.

8. The diaminopyrimidine compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof, wherein: Ring A and the pyrimidine ring connected thereto together form the following structure:

9. The diaminopyrimidine compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof, wherein: Ring B is selected from: 10-11 membered benzonitrogen-containing heterocyclic rings which are substituted or unsubstituted with one or more R groups.

10. The diaminopyrimidine compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof, wherein: Ring B is selected from: wherein X is selected from: -C(R7)2-, -O-, -S-, -Se-, -S(=O)-, -S(=O)2-, -NR8-; Q is selected from: -C(R7)2-, -O-, -S-, -NR8-; Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are independently selected from the group consisting of: CR and N; R7 is selected from the group consisting of: hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio; R8 is selected from the group consisting of: hydrogen, C1-C6 alkyl.

11. The diaminopyrimidine compound according to claim 10, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Ring B is selected from: wherein X is selected from: -C(R7)2-, -O-, -S-, -Se-, -S(=O)-, -S(=O)2-, -NR8-; R7 is selected from the group consisting of hydrogen, fluorine, chlorine, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkylthio; R8 is selected from: hydrogen, C1-C3 alkyl; m is selected from: 0, 1, 2, 3, 4.

12. The diaminopyrimidine compound according to any one of claims 1 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Each R is independently selected from the group consisting of hydrogen, C1-C3 alkyl, one or more fluorine-substituted C1-C3 alkyl, C1-C3 alkoxy, one or more fluorine-substituted C1-C3 alkylthio, C1-C3 alkylthio, fluorine, chlorine, bromine, and cyano.

13. The diaminopyrimidine compound according to claim 12, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Ring B is selected from: Each R is independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, and cyano.

14. The diaminopyrimidine compound according to any one of claims 1 to 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: R2 and R3 are independently selected from the group consisting of hydrogen, one or more R5 substituted or unsubstituted C1-C4 alkyl groups, one or more R4 substituted or unsubstituted C3-C8 cycloalkyl groups, one or more R4 substituted or unsubstituted 3-8 membered heterocyclyl groups, or R2, R3 and the nitrogen atom to which they are attached together form one or more R4 substituted or unsubstituted 3-8 membered heterocyclyl groups; Each R5 is independently selected from the group consisting of hydrogen, amino, hydroxy, one or more R4 substituted or unsubstituted C3-C8 cycloalkyl, one or more R4 substituted or unsubstituted 3-8 membered heterocyclyl, C1-C3 alkylamino, C1-C3 alkyl, halogen substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, cyano, halogen, -S(=O)R6, -S(=O)2R6, -S(=O)(=NH)R6, or two R5 on the same carbon atom together with the carbon atom to which they are attached form one or more R4 substituted or unsubstituted C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

15. The diaminopyrimidine compound according to claim 14, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: Each R4 is independently selected from the group consisting of hydrogen, phenyl, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino, and hydroxyl; Each R6 is independently selected from the group consisting of hydrogen and C1-C3 alkyl.

16. The diaminopyrimidine compound according to any one of claims 1 to 15, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: One and only one of R2 and R3 is hydrogen.

17. The diaminopyrimidine compound according to claim 14, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: R2, R3 and the nitrogen atom connected thereto together form the following group:

18. The diaminopyrimidine compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, wherein: The diaminopyrimidine compound is selected from the following compounds:

19. Use of the diaminopyrimidine compound according to any one of claims 1 to 18, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product in the preparation of a medicament for treating or preventing respiratory syncytial virus infection.

20. Use of the diaminopyrimidine compound according to any one of claims 1 to 18, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated product, or its tritiated product in the preparation of a medicament for preventing and / or treating diseases related to respiratory syncytial virus infection.

21. The use according to claim 20, wherein: The related diseases caused by the respiratory syncytial virus infection are bronchitis, pneumonia, asthma or chronic obstructive pulmonary disease.

22. A pharmaceutical composition for use against respiratory syncytial virus, comprising an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the diaminopyrimidine compound according to any one of claims 1 to 18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, or a deuterated compound thereof, or a tritiated compound thereof.

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