Diaminopyrimidine compounds and uses thereof

Abstract

The invention provides a diaminopyrimidine compound with a structure as shown in a 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, and an application of the diaminopyrimidine compound, or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the prodrug molecule thereof, or the deuteride thereof, or the tritium thereof. The diaminopyrimidine compound provided by the invention has obvious inhibitory activity on RSV virus, has a chemical structure type completely different from that of the existing anti-RSV drug ribavirin and the like, is expected to be developed into a novel anti-RSV drug, is used for inhibiting replication or reproduction of the RSV virus, and has broad application prospects. The pharmaceutical composition can be used for preventing, relieving and / or treating respiratory syncytial virus infection and cytopathic effects caused by the respiratory syncytial virus infection, and can be used for treating bronchitis or pneumonia and other diseases caused by the respiratory syncytial virus infection.

Description

[0001] Related Applications

[0002] The present application claims priority to the Chinese patent application No. 2024104294188, filed on April 10, 2024, entitled "Diaminopyrimidine Compounds and Uses Thereof", the contents of which are incorporated herein by reference in its 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 life and health 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, vaccines 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, which has good anti-RSV viral activity.

[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]

[0011] 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 together form a fused ring;

[0012] ring B is selected from: 1 or more R-substituted or unsubstituted 9-12 membered nitrogen-containing fused bicyclic rings;

[0013] each R1is independently selected from: hydrogen, 1 or more R4-substituted or unsubstituted C1-C6alkyl, 1 or more R4-substituted or unsubstituted C1-C6alkoxy, 1 or more R4-substituted or unsubstituted C1-C6alkylthio, halogen, cyano, nitro, hydroxyl, thiol, amino, 1 or more R4-substituted or unsubstituted C3-C8cycloalkyl, 1 or more R4-substituted or unsubstituted 3-8 membered heterocyclyl, C1-C6alkylacyl, or 2 R1together with the atom to which they are attached form 1 or more R4-substituted or unsubstituted C3-C8cycloalkyl or 3-8 membered heterocyclyl, or 2 R1on the same carbon together with the carbon atom to which they are attached form C=O;

[0014] R2, R3are independently selected from: 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;

[0015] each R4is independently selected from: hydrogen, phenyl, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, amino, hydroxyl;

[0016] each R5is 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-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;

[0017] each R6is independently selected from: hydrogen, C1-C6alkyl;

[0018] each R is independently selected from the group consisting of hydrogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkylthio, halogen, cyano, nitro, hydroxy, mercapto, amino;

[0019] n is selected from the group consisting of 0, 1, 2, 3, 4.

[0020] In some embodiments, when ring A is phenyl, ring B is not R-substituted or unsubstituted 11-membered nitrogen-containing bicyclic ring.

[0021] In some embodiments, ring A is selected from the group consisting of phenyl, C5-C8cycloalkyl, 5-8 membered heterocyclyl.

[0022] In some embodiments, ring A is selected from the group consisting of phenyl, C5-C6cycloalkyl, 5-6 membered heterocyclyl having one or two nitrogen atoms as heteroatoms.

[0023] In some embodiments, ring A is selected from the group consisting of 5-6 membered heterocyclyl having one or two nitrogen atoms as heteroatoms, the hydrogens on the nitrogen atoms being unsubstituted by R1.

[0024] In some embodiments, each R1is independently selected from the group consisting of hydrogen, 1 or more R4-substituted or unsubstituted C1-C3alkyl, 1 or more R4-substituted or unsubstituted C1-C3alkoxy, 1 or more R4-substituted or unsubstituted C1-C3alkylthio, halogen, cyano, nitro, hydroxy, mercapto, amino, 1 or more R4-substituted or unsubstituted C3-C6cycloalkyl, 1 or more R4-substituted or unsubstituted 4-6 membered heterocyclyl, C1-C3alkylacyl, or 2 R1together with the atom to which they are attached form 1 or more R4-substituted or unsubstituted C3-C6cycloalkyl or 4-6 membered heterocyclyl, or 2 R1on the same carbon together with the carbon atom to which they are attached form C=O.

[0025] 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 2 R1together with the atom to which they are attached form R4-substituted or unsubstituted C3-C6cycloalkyl or 4-6 membered heterocyclyl, or 2 R1on the same carbon together with the carbon atom to which they are attached form C=O;

[0026] wherein R4is selected from the group consisting of hydrogen, halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylthio, amino, hydroxy.

[0027] 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.

[0028] In some embodiments, ring A and the pyrimidine ring to which it is attached together form the following structure:

[0029]

[0030] In some embodiments, ring B is selected from: 1 or more R substituted or unsubstituted 10-11 membered benzo nitrogen-containing heterocycle.

[0031] In some embodiments, ring B is selected from:

[0032]

[0033] X is selected from: -C(R7)2-, -O-, -S-, -Se-, -S(=O)-, -S(=O)2-, -NR8-;

[0034] Q is selected from: -C(R7)2-, -O-, -S-, -NR8-;

[0035] Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8are each independently selected from: CR, N;

[0036] R7is selected from: hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio;

[0037] R8is selected from: hydrogen, C1-C6 alkyl.

[0038] In some embodiments, ring B is selected from:

[0039]

[0040] X is selected from: -C(R7)2-, -O-, -S-, -Se-, -S(=O)-, -S(=O)2-, -NR8-;

[0041] R7is selected from: hydrogen, fluorine, chlorine, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio;

[0042] R8is selected from: hydrogen, C1-C3 alkyl;

[0043] m is selected from: 0, 1, 2, 3, 4.

[0044] In some embodiments, each R is independently selected from the group consisting of hydrogen, C1-C3 alkyl, one or more fluoro-substituted C1-C3 alkyl, C1-C3 alkoxy, one or more fluoro-substituted C1-C3 alkylthio, C1-C3 alkylthio, fluoro, chloro, bromo, cyano.

[0045] In some embodiments, ring B is selected from the group consisting of:

[0046]

[0047] wherein each R is independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, cyano.

[0048] In some embodiments, R2and R3are each independently selected from the group consisting of hydrogen, one or more R5-substituted or unsubstituted C1-C4 alkyl, one or more R4-substituted or unsubstituted C3-C8 cycloalkyl, one or more R4-substituted or unsubstituted 3-8 membered heterocyclyl, or R2and R3together with the nitrogen atom to which they are attached form one or more R4-substituted or unsubstituted 3-8 membered heterocyclyl;

[0049] each R5is independently selected from the group consisting of hydrogen, amino, hydroxyl, 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 R5on the same carbon 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.

[0050] In some embodiments, each R4is independently selected from the group consisting of hydrogen, phenyl, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino, hydroxyl;

[0051] each R6is independently selected from the group consisting of hydrogen, C1-C3 alkyl.

[0052] In some embodiments, only one of R2and R3is hydrogen.

[0053] In some embodiments, R2and R3together with the nitrogen or oxygen atom to which they are attached form a group selected from the group consisting of:

[0054]

[0055]

[0056] In some embodiments, the diaminopyrimidine compound is selected from the following compounds:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067] The present 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:

[0068] 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 a disease caused by respiratory syncytial virus infection.

[0069] 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 a disease caused by respiratory syncytial virus infection.

[0070] In some embodiments, the disease caused by respiratory syncytial virus infection is bronchitis, pneumonia, asthma or chronic obstructive pulmonary disease.

[0071] The present application also provides an anti-respiratory syncytial virus drug, which comprises an active ingredient and a pharmaceutically acceptable adjuvant, wherein 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.

[0072] The diaminopyrimidine compound provided by the application has significant inhibitory activity on 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 for inhibiting the replication or propagation of RSV virus, preventing, alleviating and / or treating respiratory syncytial virus infection and the cytopathic effect caused thereby, and can be used for treating diseases such as bronchitis or pneumonia caused by respiratory syncytial virus infection. BRIEF DESCRIPTION OF DRAWINGS

[0073] Figure 1 Distribution concentration of compound Z-04 in each tissue of mice after oral administration.

[0074] Figure 2 Body weight change of each group of mice after RSV infection.

[0075] Figure 3 Lung index of each group of mice after RSV infection.

[0076] Figure 4 Virus titer of each group of mice after RSV infection.

[0077] Figure 5 RSV-F copy number of each group of mice after RSV infection.

[0078] Figure 6 TNF-α gene expression of each group of mice after RSV infection.

[0079] Figure 7 IL-1β gene expression of each group of mice after RSV infection.

[0080] Figure 8 IL-6 gene expression of each group of mice after RSV infection. DETAILED DESCRIPTION

[0081] In order to facilitate the understanding of the present application, the present application will be described more fully below. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided so that the disclosure of the present application can be more thorough and complete.

[0082] The experimental methods in the following examples not specifically indicated are generally carried out according to the conventional conditions or according to the conditions recommended by the manufacturers. The various common chemical reagents used in the examples are commercially available products.

[0083] 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. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0084] Also, as used herein, the term "or" is the inclusive "or" and not the

[0085] In the compounds of the present application, when any variable (e.g., R 4 , R 5 , etc.) occurs more than one time in any constituent, its meaning independent of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in chemically stable compounds. A dashed line extending from a ring system indicates that the bond can be attached to any available carbon atom of the ring system. 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 compounds which are chemically stable and which can be easily synthesized from readily available starting materials by the methods described and hereafter presented. 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.

[0086] In the present application, a dotted line "— " or a wavy line "— " in a chemical group or chemical structure represents the position of bond connection.

[0087] 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 definition of "C1-C6" in "C1-C6 alkyl" includes groups with 1, 2, 3, 4, 5, or 6 carbon atoms in linear or branched arrangements. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl.

[0088] As used herein, the term "cycloalkyl" refers to saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon groups having ring atoms consisting of carbon atoms, bicyclic or polycyclic rings include fused, spiro, and bridged rings. For example, "cycloalkyl" includes, but is not limited to, the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0089] As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, and the like.

[0090] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituents in which one or more ring atoms are selected from the group consisting of 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, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotirazolyl, dihydroazetidinyl, tetrahydrofuran, tetrahydrothiophenyl, and N-oxides thereof. The attachment of the heterocyclic substituent can be through a carbon atom or through a heteroatom.

[0091] 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, for example 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 groups. The attachment of the heteroaryl group can be through a carbon atom or through a heteroatom.

[0092] As used herein, "halo" or "halogen" means chlorine, fluorine, bromine, and iodine, as understood by those skilled in the art.

[0093] ​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 of the present application are amines in the non-salt form, i.e., the "free form." 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 reacting the free base with the desired salt former in a suitable solvent or a combination of solvents. Similarly, the salts of the acidic compounds are prepared by reacting the free acid with the desired salt former in a suitable solvent or a combination of solvents.

[0094] 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.

[0095] If the compounds of the present application are 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 their formation 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.

[0096] The preparation of the above-mentioned pharmaceutically acceptable salts from the respective compounds of the present application is appropriately described in the literature, for example, in "Pharmaceutical Salts," by S. Berge et al., J. Pharm. Sci. 1977:66:1-19, and in other standard pharmaceutical texts.

[0097] The stereoisomers according to the invention, 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 invention in the form of pure stereoisomers or in the form of any mixture of stereoisomers, in the latter case preferably as racemates.

[0098] Metabolites of the compounds according to the invention and pharmaceutically acceptable salts thereof, as well as those metabolites which can be formed in vivo and have the same physiological effect as the compounds according to the invention and their salts, are also included within the scope of the present invention.

[0099] The present invention also provides a pharmaceutical composition for the treatment of RSV virus, which comprises a safe and effective amount of the active ingredient, and pharmaceutically acceptable adjuvants.

[0100] The "active ingredient" according to the present invention means the compound of the formula I according to the present invention, 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.

[0101] A "safe and effective amount" means an amount of the active ingredient sufficient to significantly improve the condition, but low enough to avoid serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the active ingredient per dose, more preferably 10-200 mg of the active ingredient per dose. Preferably, the "dose" is a tablet.

[0102] The pharmaceutical composition is used by applying a safe and effective amount of the compound according to the present invention to a mammal (e.g. human) in need of treatment, wherein the dose is administered in a pharmaceutically effective amount, typically 1-2000 mg, preferably 20-500 mg per day for a 60 kg body weight. The exact amount will, of course, depend on the route of administration, the health condition of the patient, etc., and will be within the discretion of the attending physician.

[0103] The "pharmaceutically acceptable adjuvants" means one or more compatible solid or liquid filler or gel materials, which are suitable for use in humans and must be of sufficient purity and sufficiently low toxicity.

[0104] "Compatibility" means here that the components of the composition are able to be blended with the active ingredient according to the invention and among themselves without significantly reducing the efficacy of the active ingredient.

[0105] Examples of pharmaceutically acceptable adjuvants include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween ), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0106] 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-covalent interaction. In another preferred embodiment, the compound of formula I of the present application can also be linked to a macromolecular compound or polymer through a chemical bond as a small molecule. The macromolecular compound can be a biological macromolecule such as a polysaccharide, a protein, a nucleic acid, a polypeptide, etc.

[0107] The mode of administration of the active ingredient or pharmaceutical composition of the present application is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), etc.

[0108] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0109] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with the following ingredients:

[0110] (a) a filler or bulking agent, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid;

[0111] (b) a binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia;

[0112] (c) a humectant, such as glycerol;

[0113] (d) a disintegrant, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0114] (e) a slow-release agent, such as paraffin;

[0115] (f) an absorption accelerator, such as a quaternary ammonium compound;

[0116] (g) a wetting agent, such as cetyl alcohol and glycerol monostearate;

[0117] (h) an adsorbent, such as kaolin; and

[0118] (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, dosage forms can also comprise buffering agents.

[0119] Solid dosage forms can also be prepared with coatings and shells, e.g., 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.

[0120] Liquid dosage forms for oral administration 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

[0121] Suspensions, in addition to the active ingredient, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, as well as mixtures thereof.

[0122] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0123] The compounds of the present application can be administered alone, or in combination with known treatments or other drugs used to treat or improve the same condition. When administered in combination, the previously known drugs are administered at their usual dose, while the compound of Formula I is administered simultaneously or sequentially. When the compound of Formula I is administered simultaneously with the other drug(s), a pharmaceutical composition containing both the known drug(s) and the compound of Formula I is preferred. The combination of drugs also includes administration of the compound of Formula I and the other drug(s) within a time period that will allow the combination to have a therapeutic effect. When the compound of Formula I is administered in combination with the other drug(s), the dosage of the compound of Formula I or the known drug(s) can be lower than when they are administered alone.

[0124] The application will be further described in conjunction with specific examples. It should be understood, however, that these examples are intended to illustrate the application and not to limit the scope of the application. The experimental procedures in the following examples, unless otherwise indicated, were carried out in accordance with conventional procedures or as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight.

[0125] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs. Also, any methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials are presented by way of example only.

[0126] The starting materials in the following examples can be obtained commercially, or prepared by known methods in the art, or prepared according to the methods described herein.

[0127] Example 1

[0128]

[0129] In a round bottom flask containing 3 mL of dry methanol, 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) were added, stirred at room temperature and triethylamine (102.9 mg, 1.02 mM) was added, the reaction was refluxed and monitored, after the reaction was completed, MeOH was removed by rotary evaporation and dissolved in appropriate amount of DCM, washed with saturated brine and water for three times, the organic layer was collected, dried over Mg2SO4, filtered and the organic solution was concentrated, the sample was mixed with silica gel and column chromatography was performed (DCM:MeOH=90:1), the target product Z-01-1 (204.2 mg, Yield: 75.12%) was collected and dried.

[0130] In a round bottom flask containing 3 mL of dry methanol, 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) were added, stirred at room temperature and triethylamine (102.9 mg, 1.02 mM) was added, the reaction was refluxed and monitored, after the reaction was completed, MeOH was removed by rotary evaporation and dissolved in appropriate amount of DCM, washed with saturated brine and water for three times, the organic layer was collected, dried over Mg2SO4, filtered and the organic solution was concentrated, the sample was mixed with silica gel and column chromatography was performed (DCM:MeOH=90:1), the target product Z-01-1 (204.2 mg, Yield: 75.12%) was collected and dried.

[0131] Dry compound Z-01-2 (100 mg, xxmM) was dissolved in DCM (5 mL), TFA (1.0 mL) was added, and the reaction was allowed to proceed at room temperature overnight. After monitoring the reaction, the reaction was terminated, and the pH was adjusted to 9-10 with an aqueous NaOH 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-01 (30.6 mg, Yield: 37.76%) was collected and dried.

[0132] Z-01: 1 H 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] + .

[0133] Example 2

[0134]

[0135] The target product Z-02 was synthesized step by step according to Example 1 using 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline and N-tert-butoxycarbonyl-1,2-ethanediamine as starting materials.

[0136] Z-02: 1H 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] + .

[0137] Example 3

[0138]

[0139] 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.

[0140] 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] + .

[0141] Example 4

[0142]

[0143] The target product Z-04 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, tert-butyl N-[3- (aminomethyl)oxetan-3-yl]carbamate according to Reference Example 1.

[0144] 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] + .

[0145] Example 5

[0146]

[0147] The target product Z-05 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, 1-aminomethyl-1- (BOC-amino)cyclopropane according to Reference Example 1.

[0148] Z-05: 1 H 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] + .

[0149] Example 6

[0150]

[0151] The target product Z-06 was synthesized step by step with the starting material 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, tert-butyl 1-(aminomethyl)cyclobutylcarbamate according to Example 1.

[0152] 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] + .

[0153] Example 7

[0154]

[0155] The target product Z-16 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, tert-butoxycarbonyl-3-aminocyclobutylamine according to Example 1.

[0156] Z-16: 1 H 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] + .

[0157] Example 8

[0158]

[0159] 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.

[0160] 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] + .

[0161] Example 9

[0162]

[0163] The target product Z-51 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, tert-butyl (2-amino-isopropyl)carbamate according to Example 1.

[0164] Z-51: 1 H NMR (600 MHz, CDCl3+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] + .

[0165] Example 10

[0166]

[0167] The target product Z-60 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, N,N-dimethylethylenediamine in reference to Example 1.

[0168] 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] + .

[0169] Example 11

[0170]

[0171] The target product Z-62 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline, 2-(methylsulfonyl)ethanamine in reference to Example 1.

[0172] Z-62: 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] + .

[0173] Example 12

[0174]

[0175] 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.

[0176] Z-70: 1 H NMR (600 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 54.4 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 6.58 (t, J = 5.6 Hz, 1H), 4.96 (s, 2H), 4.31 (s, 2H), 3.77 (d, J = 5.7 Hz, 2H), 3.51 (s, 4H), 2.91 (s, 2H), 2.45 (s, 2H). LCMS (ESI): m / z 390 [M+1] + .

[0177] Example 13

[0178]

[0179] 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.

[0180] Z-71: 1 H NMR (600 MHz, CDCl3+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] + .

[0181] Example 14

[0182]

[0183] The target product Z-72 was synthesized stepwise using the starting materials N-BOC-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-D]pyrimidine and N-tert-butyloxycarbonyl-1,2-ethylenediamine according to Example 1.

[0184] Z-72: 1 H NMR(600MHz,DMSO-d6)δ7.90-7.85(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 = 40.4Hz, 6H), 2.32 (s, 1H). LCMS (ESI): m / z 389[M+1] + .

[0185] Example 15

[0186]

[0187] According to a similar method to Example 1, 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-D]pyrimidine and N-tert-butoxycarbonyl-1,2-ethylenediamine were used to synthesize intermediate Z-73-1 under the catalysis of triethylamine. Intermediate Z-73-1 was heated with 2,3,4,5-tetrahydrobenzo[1,4]thiazepine-1,1-dioxide and ammonium chloride in anhydrous ethanol to generate Z-73-2. The target product Z-73 was obtained after purification by removing the Boc group with trifluoroacetic acid.

[0188] Z-73:1H NMR(600MHz,DMSO-d6)δ7.87(dd,J=7.7,1.3Hz,1H),7.62-7.56(m,1H),7.47(t ,J=7.6Hz,1H),7.35-7.28(m,5H),7.27(d,J=6.3Hz,1H),6.46(t,J=5.7Hz,1H), 4.92(s,2H),4.29(s,2H),3.57(s,2H),3.44(q,J=6.7Hz,4H),3.11(s,2H),2.6 8(t,J=7.1Hz,2H),2.60(t,J=5.9Hz,2H),2.24(t,J=5.9Hz,2H).LCMS(ESI):m / z 479[M+1] + .

[0189] Example 16

[0190]

[0191] 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.

[0192] Z-74: 1 H NMR (600 MHz, CDC13+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] + .

[0193] Example 17

[0194]

[0195] 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.

[0196] Z-75: 1 H NMR (600 MHz, CDC13) δ 8.04 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 5.13 (s, 2H), 4.77 (s, 2H), 4.66 (t, J = 5.6 Hz, 1H), 4.56 - 4.36 (m, 5H), 3.82 (s, 2H), 3.41 (t, J = 5.1 Hz, 2H), 1.71 (s, 8H), 1.36 (s, 6H). LCMS (ESI): m / z 446 [M+1] + .

[0197] Example 18

[0198]

[0199] 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 under ice bath, sodium methoxide (7.04 g, 130.4 mM) was added slowly in batches, stirred for 30 min, then transferred to room temperature and heated to reflux. A large amount of white solid was precipitated as the reaction proceeded. After the reaction was completed, the reaction solution was cooled to room temperature and stirred in an ice bath for 1 h, then filtered and washed with ice methanol. The white solid was collected and dried, dissolved in an appropriate amount of water, and the pH value was adjusted to 7 with 1M HCl. Solid was precipitated, filtered, washed with water, and the solid was collected and dried to obtain intermediate Z-77-2 (7.6 g, Yield: 97.12%).

[0200] 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 under ice bath, sodium methoxide (7.04 g, 130.4 mM) was added slowly in batches, stirred for 30 min, then transferred to room temperature and heated to reflux. A large amount of white solid was precipitated as the reaction proceeded. After the reaction was completed, the reaction solution was cooled to room temperature and stirred in an ice bath for 1 h, then filtered and washed with ice methanol. The white solid was collected and dried, dissolved in an appropriate amount of water, and the pH value was adjusted to 7 with 1M HCl. Solid was precipitated, filtered, washed with water, and the solid was collected and dried to obtain intermediate Z-77-2 (7.6 g, Yield: 97.12%).

[0201] In a round-bottom flask, intermediate Z-77-2 (7.4 g, 41.09 mM) was added slowly in batches with phosphorus oxychloride as the solvent, heated to reflux, and after the reaction was completed, the reaction bottle was cooled to room temperature. Excess phosphorus oxychloride was removed by distillation under reduced pressure. After the reaction bottle was cooled to room temperature, ice water was added, and the pH value was adjusted to 9 with 1M NaOH (aq) under ice bath. Brown solid was precipitated, filtered, washed with water, and the solid was collected and dried. Then it was separated by silica gel column chromatography (PE:DCM = 1:2) to obtain intermediate Z-77-3 (6.5 g, Yield: 71.3%).

[0202] 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. Stirring was carried out at room temperature and triethylamine (211.0 mg, 2.22 mM) was added. The reaction was refluxed and monitored. After the reaction was completed, MeOH 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. The organic layer was collected, dried over Mg2SO4, filtered, and the organic solution was concentrated. Silica gel was added to the sample for column chromatography (DCM:MeOH = 100:1). The target product Z-77-4 (398.0 mg, Yield: 70.3%) was collected and dried.

[0203] To dry compound Z-77-4 (220.0 mg, 0.58 mM), 2,3,4,5-tetrahydrobenzo[l,4]thiazepine-l,l-dioxide (170.15 mg, 0.87 mM) and NH4CI (46.2 mg, 0.87 mM) were dissolved in a heated synthesis tube containing absolute ethanol. After heating to 85 °C in a heating synthesizer for 12 h and monitoring the reaction, 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 solution was washed with saturated brine and water three times each, the organic layer was collected, dried over Mg2S04, filtered and the organic solution was concentrated. The sample was mixed with silica gel and column chromatography was performed (DCM:MeOH = 70: 1). The target product Z-77-5 (165.0 mg, Yield: 52.76%) was collected and dried.

[0204] 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 and confirming that the reaction was complete, the pH was adjusted to 9-10 using an aqueous NaOH solution (1 mol), the solution was washed with saturated brine and water three times each, the organic layer was collected, dried over Mg2S04, filtered and the organic solution was concentrated. The sample was mixed with silica gel and column chromatography was performed (DCM:MeOH = 25: 1). The target product Z-77 (80 mg, Yield: 65.38%) was collected and dried.

[0205] Z-77: 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] + .

[0206] Example 19

[0207]

[0208] The target product Z-78 was synthesized step by step according to Example 18 using 2-methylcyclohexanone and diethyl carbonate as starting materials.

[0209] Z-78:1 H NMR (600 MHz, CDC13) 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] + .

[0210] Example 20

[0211]

[0212] The target product Z-79 was stepwise synthesized with reference to Example 18 using the starting material 4,4-dimethylcyclohexanone and diethyl carbonate.

[0213] Z-79: 1 H NMR (600 MHz, CDC13) 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] + .

[0214] Example 21

[0215]

[0216] The target product Z-80 was synthesized step by step from the starting material 2',4'-dichloro-7',8'-EQ-5'H-spiro[cyclopropane-l,6'-quinazoline, tert-butyl N-[3- (aminomethyl)oxetan-3-yl]carbamate according to Reference Example 18.

[0217] 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] + .

[0218] Example 22

[0219]

[0220] The target product Z-158 was synthesized step by step from the starting material 4-trifluoromethylcyclohexan-l-one, diethyl carbonate according to Reference Example 18.

[0221] Z-158: 1 H NMR (600 MHz, CDC13 + MeOD-d4) 1 H NMR (600 MHz, CDC13) δ 8.01 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 5.09 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.52 (d, J = 6.5 Hz, 2H), 4.01 - 3.81 (m, 2H), 3.43 (d, J = 5.3 Hz, 2H), 2.70 - 2.51 (m, 3H), 2.40 (s, 1H), 2.29 (t, J = 13.4 Hz, 1H), 2.14 (d, J = 12.7 Hz, 1H).. LCMS (ESI): m / z 498 [M+1] + .

[0222] Example 23

[0223]

[0224] The target product Z-184 was synthesized step by step from the starting material 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-D]pyrimidine, tert-butyl N-[3- (aminomethyl)oxetan-3-yl]carbamate according to Reference Example 1.

[0225] Z-184: 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 432 [M+1] + .

[0226] Example 24

[0227]

[0228] 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 Reference Example 1. 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] + .

[0229] Example 25

[0230]

[0231] According to the similar method of example 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 under catalysis of triethylamine, intermediate Z-187-1 was generated by heating intermediate Z-187-1 with 2,3,4,5-tetrahydrobenzo[l,4]thiazepine-l,l-dioxide and ammonium chloride in anhydrous ethanol, and the target product Z-187 was obtained after purification of Boc group by trifluoroacetic acid.

[0232] 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] + .

[0233] Example 26

[0234]

[0235] According to the similar method of example 1 and 2, tert-butyl 2,4-dichloro-5,6- dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylate, tert-butyl N-[3-(aminomethyl)oxetan-3- yl]carbamate was synthesized under catalysis of triethylamine, intermediate Z-188-1 was generated by heating intermediate Z-188-1 with 2,3,4,5-tetrahydrobenzo[l,4]thiazepine-l,l- dioxide and ammonium chloride in anhydrous ethanol, and the target product Z-188 was obtained after purification of Boc group by trifluoroacetic acid.

[0236] Z-188: 1H 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] + .

[0237] Example 27

[0238]

[0239] Intermediate Z-187-2, formic acid and formaldehyde were heated to synthesize intermediate Z-191-1 under ice-bath condition. Intermediate Z-191-1 was dissolved in methanol and hydrogen gas was removed under catalysis of palladium hydroxide and trifluoroacetic acid to synthesize target compound Z-191.

[0240] Z-191: 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] + .

[0241] Example 28

[0242]

[0243] Intermediate Z-187-2, acetyl chloride was under triethylamine to synthesize intermediate Z-192-1 under ice-bath condition. Intermediate Z-192-1 was dissolved in methanol and hydrogen gas was removed under catalysis of palladium hydroxide and trifluoroacetic acid to synthesize target compound Z-192.

[0244] Z-192: 1H 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+l] + .

[0245] Example 29

[0246]

[0247] The target product Z-196 was synthesized step by step with reference to Example 18 using the starting material 4-ethylcycloheptanone and diethyl carbonate.

[0248] 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+l] + .

[0249] Example 30

[0250]

[0251] 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.

[0252] 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] + .

[0253] Example 31

[0254]

[0255] The target product Z-199 was synthesized step by step according to example 16 from starting material 4-ethylcyclohexanone and diethyl carbonate.

[0256] Z-199: 1H 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), 7.49 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (td, J = 7.7, 1.3 Hz, 1H), 5.10 (s, 2H), 4.88 (t, J = 5.6 Hz, 1H), 4.53 (dd, J = 6.5, 3.4 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 3.85 (d, J = 16.2 Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H), 2.53 (ddd, J = 17.9, 13.4, 9.0 Hz, 2H), 2.26 (dd, J = 15.1, 5.3 Hz, 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, 5.0 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z 458 [M+1] + .

[0257] Example 32

[0258]

[0259] The target product Z-200 was synthesized step by step with reference to Example 16 using the starting material 4,4-dimethylcyclohexanone and diethyl carbonate.

[0260] Z-200: 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), 7.49 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (td, J = 7.7, 1.3 Hz, 1H), 5.10 (s, 2H), 4.88 (t, J = 5.6 Hz, 1H), 4.53 (dd, J = 6.5, 3.4 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 3.85 (d, J = 16.2 Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H), 2.53 (ddd, J = 17.9, 13.4, 9.0 Hz, 2H), 2.26 (dd, J = 15.1, 5.3 Hz, 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, 5.0 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z 458 [M+1] + .

[0261] Example 33

[0262]

[0263] The target product Z-205 was synthesized step by step with the starting material 2,4-dichloro-6-ethyl-5,6,7,8-tetrahydroquinazoline, 1-tert-butoxycarbonyl-3- aminocyclobutylamine according to Example 1.

[0264] Z-205: 1 H NMR (600 MHz, DMSO-d6) δ 7.87 (d, J = 8.0 Hz, 1H), 7.76-7.57 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H), 6.75 (d, J = 6.2 Hz, 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, 3.1 Hz, 2H), 1.26-1.18 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z 428 [M+1] + .

[0265] Example 34

[0266]

[0267] The target product Z-208 was synthesized step by step with the starting material N-BOC-2,4-dichloro-5,7,8-trihydropyrido[4,3-D]pyrimidine, 2-(methylsulfonyl)ethylamine according to Example 1.

[0268] Z-208: 1 H NMR (600 MHz, DMSO-d6) δ 7.89 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 66.1 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 36.1 Hz, 1H), 4.98 (s, 2H), 4.36 (s, 2H), 3.87 (s, 1H), 3.72 (s, 2H), 3.53 (t, J = 5.2 Hz, 4H), 3.26 (s, 3H), 3.04 (d, J = 61.1 Hz, 4H), 2.65 (d, J = 13.0 Hz, 2H).

[0269] Example 35

[0270]

[0271] The target product Z-209 was synthesized step by step with the starting material 2,4-dichloro-6-methyl-5,6,7,8-tetrahydroquinazoline and (3-amino-2-hydroxypropyl) tert-butyl carbamate according to Reference Example 1.

[0272] Z-209: 1 H 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).

[0273] Example 36

[0274]

[0275] The target product Z-210 was synthesized step by step with the starting material 4-isopropylcyclohexanone and diethyl carbonate according to Reference Example 16.

[0276] 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).

[0277] Example 37 Testing of the activity of the compound against RSV

[0278] Ziresovir (AK0529, CAS 1422500-60-4) as a positive control, the activity of the target compounds against RSV was tested by cultivating RSV-A2 strain on Hep-2 cells. The specific steps are as follows:

[0279] On the first day, 1x10 5 cells / mL, 100 μL / well of cells were passaged and then cultured at 37°C, 5% CO2 overnight. On the second day, samples including positive controls and target compounds were diluted by DMEM medium containing 2% FBS by eight concentrations. At the same time, the medium in the 96-well cell culture plate was discarded, and the plate was washed once with PBS 100 μL / well. After the liquid in the 96-well cell culture plate was discarded, the gradient-diluted samples were added at a specification of 200 μL per well, and each concentration had four duplicate wells (two wells for cytotoxicity and two wells for drug efficacy), and then cultured at 37°C, 5% CO2 overnight. On the third day, samples (drugs) were diluted by DMEM medium containing 2% FBS by eight concentrations. At the same time, the liquid in the 96-well cell culture plate was discarded, and the plate was washed once with PBS 100 μL / well. The RSV virus was taken out from the -80°C refrigerator, and then diluted to 100 TCID 50 per 100 μL with serum-free DMEM medium, and then added to the drug efficacy wells at a specification of 100 μL, and 100 μL 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 a specification of 200 μL per well, and then cultured at 35°C, 5% CO2 for 48-72 h, and the CPE was observed and recorded. The inhibition rate and IC 50 were calculated by CPE.

[0280] The test results (IC 50 ) of the inhibition of RSV virus activity of each compound are shown in Table 1 below. The results show that the diaminopyrimidine 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 better than 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.

[0281] Table 1 IC 50 values of each compound against RSV

[0282]

[0283]

[0284] Pharmacokinetic test of the compound of Example 38

[0285] 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.

[0286] 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%.

[0287] Water solubility test of the compound of Example 39

[0288] The test compound and the control compound were prepared as DMSO stock solutions at a concentration of 10 mM. 30 μL of the stock solution was taken from 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 an oscillator and shaken at 25°C for 2 hours. After 2 hours, all samples were filtered. The sample was taken from the filtrate and diluted into H2O and acetonitrile solution (1:1, volume ratio). 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 values ​​of the test compound and the control compound were calculated based on the standard curve. The test results showed that compound Z-04 had good water solubility, and its water solubility was 0.2 mg / mL.

[0289] Example 40 Distribution test of compound Z-04 in various tissues of mice after oral administration

[0290] Four-week-old C57BL / 6 female mice (n=4) were used, and the compound group was dosed at 50 mg / kg. The administration method was gavage, twice a day, 200 μl each time. The mice were fasted the day before administration and gavage was performed the next day. The administration was continued for 3 consecutive days, and the changes in the weight of the mice were observed and recorded every day. The mice were killed immediately 2 hours after the last gavage. The heart, liver, lung, kidney, stomach, small intestine and brain tissues were collected, washed twice in PBS, and immediately stored in liquid nitrogen. The mouse eyeball blood was collected, kept at room temperature for 2 hours, centrifuged at 12000 r / min for 20 minutes at 4°C, and the supernatant was transferred to a clean EP tube and stored at -80°. The tissue samples were homogenized separately, and the concentration of the key metabolite Z-04 in plasma and tissue homogenate was analyzed by LC-MS / MS.

[0291] result( Figure 1 ) showed that after 3 days of continuous oral administration, the concentration of compound Z-04 in the lung tissue of mice was about 6×10 4 (ng / g or ng / mL), while the concentration of compound Z-04 in plasma was only 6×10 2 (ng / g or ng / mL), the concentration of compound Z-04 in lung tissue is about 100 times that of compound Z-04 in plasma. According to the results of drug tissue distribution, the drug is targeted and enriched in the lungs, thereby inhibiting RSV activity.

[0292] Example 41 Anti-RSV Activity Test of Compounds in Mouse Model

[0293] Ziresovir (AK0529, CAS 1422500-60-4) was used as a positive control drug, and an RSV-A2 infection model was established in C57BL / 6 mice to test the anti-RSV activity of the target compound. The specific steps are as follows:

[0294] Four-week-old C57BL / 6 female mice were used and divided into groups including normal control group, RSV infection model group, AK0529 group (50 mg / kg), and compound group (compound Z-04, including two dose groups of 12.5 mg / kg and 50 mg / kg respectively), with 6 mice in each group. The administration method was gavage treatment, and the control group was gavaged with PBS twice a day, 200 μl each time. The mice were fasted the day before infection, and the mice were infected with RSV the next day. Except for the control group, the mice in the other groups were treated with 100 μl of RSV-A2 virus solution by nasal drops. After 2 hours of nasal drops, the mice were given gavage treatment with different concentrations of drugs according to the group. The drug was administered continuously for 3 days, and the changes in the weight of the mice were observed and recorded every day. The mice were killed on the 4th day. The right lung of the mouse was homogenized and centrifuged at 12000 r / min at 4°C for 10 minutes. The supernatant was taken and TCID 50 Virus titer was measured by RNA extraction from lung sediment and RSV-F gene was quantitatively analyzed.

[0295] result( Figure 2 ) showed that after 24 hours of RSV infection, the weight of mice gradually decreased, the weight of mice in the drug group gradually recovered after 48 hours, and the weight of mice in the drug group was close to that of the control group after 72 hours. According to the results of mouse lung index ( Figure 3 ) showed that the lung index of the drug group was significantly lower than that of the virus infection group, and the compound group and the positive control drug group had similar effects. 50 The titer of RSV virus in lung tissue of each group was detected. Figure 4 ) showed that the virus titer of the drug group was lower than that of the virus infection group, and the virus titer of the compound 50mg / kg dose group was lower than that of the positive control drug group with the same dose. Figure 5 ) showed that the RSV-F copy number in the drug group was significantly lower than that in the virus-infected group, and the compound group had comparable effects to the positive control group. The above in vivo results all demonstrated that the compound has a good effect in terms of anti-RSV viral activity.

[0296] 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 the drug groups were significantly reduced, and the effect of the compound 50 mg / kg dose group was better than that of the positive control drug group with the same dose.

[0297] Any combination of the technical features in the above-described embodiments can be made, and for the sake of brevity, not all possible combinations are described in the following embodiments, however, as long as the combination of the technical features does not exist contradictory, it should be considered as the scope of the description.

[0298] The above-described embodiments only express several implementation manners of the present application, the description is more specific and detailed, but it cannot be understood as the limitation of the patent scope of the present application. It should be pointed out that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which belong to the protection scope of the present application. Therefore, the protection scope of the patent 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, characterized in that: 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 its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, characterized in that: Ring A is selected from: phenyl, C5-C8 cycloalkyl, 5-8 membered heterocyclic group; 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, characterized in that: Ring A is selected from a 5-6 membered heterocyclic group wherein the heteroatom is one or two nitrogen atoms, and the hydrogen on the nitrogen atom is not replaced by R1.

5. 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, characterized in that: 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, characterized in that: 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 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, characterized in that: 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 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: Ring A and the pyrimidine ring connected thereto together form the following structure:

9. 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, characterized in that: 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 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: 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, characterized in that: 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, characterized in that: 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, characterized in that: 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 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, characterized in that: 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, characterized in that: 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 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated compound, or its tritiated compound, characterized in that: 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, characterized in that The related diseases caused by the respiratory syncytial virus infection are bronchitis, pneumonia, asthma or chronic obstructive pulmonary disease.

22. A pharmaceutical composition for resisting respiratory syncytial virus, characterized in that: The invention comprises 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 substance thereof, or a tritiated substance thereof.

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