Compounds for treating or preventing respiratory syncytial virus diseases

Abstract

Provided are compounds for treating or preventing respiratory syncytial virus diseases. Provided are compounds represented by the following formulas (I-1) and (I-2), and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotope forms thereof. The compounds have antiviral activity and can be used in the preparation of a drug for treating or preventing viral infection in a subject susceptible to viral infection or experiencing viral infection; compared with ziresovir, the compounds have an equivalent or better inhibitory effect on RSV at the in-vitro cell level and better liver microsome metabolic stability; and the compounds are suitable for administration by inhalation.

Description

Compounds for treating or preventing respiratory syncytial virus disease TECHNICAL FIELD

[0001] The present application relates to the field of anti-infective drugs, in particular to a compound for treating or preventing respiratory syncytial virus disease, and further relates to pharmaceutical compositions comprising these compounds. BACKGROUND

[0002] Respiratory syncytial virus (RSV) belongs to the family of paramyxoviridae, subfamily of pneumovirinae. Human respiratory syncytial virus (HRSV) is the only virus that infects humans in the genus of pneumovirus in the family of pneumoviridae, and is therefore also called human pneumovirus. RSV is highly contagious and can cause outbreaks of epidemic anywhere in the world, and can occur throughout the year. Human natural immunity against RSV is incomplete, and human RSV is the main cause of acute upper and lower respiratory tract infections in infants and children. Almost all children are infected with RSV at least once before the age of three. In normal adults and older children, RSV infection is mainly associated with upper respiratory tract symptoms. Most people only show mild symptoms (upper respiratory tract infection) after RSV infection, and can recover within 1-2 weeks, while some groups may be affected by multiple factors such as external and internal causes, and progress to more severe RSV infection. The high-risk groups of severe RSV infection mainly include premature infants, infants under 6 months old, infants with congenital heart disease and other underlying diseases, immunodeficient groups, adult patients with chronic heart or lung disease, and people aged 65 and above.

[0003] There is no specific anti-RSV treatment for RSV infection. Therefore, the standard treatment for children with RSV infection at this stage is limited to supportive care and adjuvant therapy, such as oxygen, nasal congestion relievers, nutrition and water supplementation, and the use of bronchodilators; the main antiviral treatment is ribavirin (a small molecule broad-spectrum antiviral drug of nucleoside, which mimics the mechanism of nucleoside to interfere with the expression of viral genetic information from multiple aspects to inhibit viral replication). However, due to the limited use of ribavirin, the treatment of children with RSV infection in clinical practice is still mainly symptomatic and supportive treatment. The treatment of adult RSV infection is mainly limited to supportive treatment such as bronchodilators, oxygen, intravenous infusion and antipyretics. Therefore, the clinical needs for RSV infection are far from being met. SUMMARY

[0004] There is an urgent need for safe and effective therapeutic drugs for RSV diseases, and therefore the present application provides a compound having antiviral activity, in particular inhibitory activity on the replication of respiratory syncytial virus, which can be used for preparing a drug for treating or preventing viral infection in a patient susceptible to viral infection or experiencing viral infection. The compound provided by the present application has an inhibitory effect on RSV virus at a cell level in vitro, which is comparable to or better than that of zanamivir, has better liver microsomal metabolic stability than zanamivir, and is suitable for inhalation administration.

[0005] To achieve the object of the present application, the present application provides a compound as shown in the following formula (I-1) and (I-2) and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof:

[0006] Wherein:

[0007] R0 is -C 1-3 alkyl-O-prodrug group, -O-prodrug group or -C(=O)-O-prodrug group;

[0008] R1 is absent or hydrogen, deuterium, halogen, cyano, C 0-6 silyl, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy or NHR3;

[0009] R2 is hydrogen, deuterium, halogen, cyano, C 0-6 silyl, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy or NHR3;

[0010] R3 is hydrogen, deuterium, amino, hydroxyl, -O-, cyano, halogen, alkyl, silyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclyl; wherein the amino, hydroxyl, -O-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl each independently optionally has one or more substituents of substituted or unsubstituted alkyl, halogenated alkyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, nitro, cyano, hydroxyl, oxygen atom, substituted or unsubstituted alkoxy, halogenated alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl;

[0011] R4, R5, R6, R7, R8are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, morpholinyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 0-6 silyl, C 1-6 alkylaminocarbonyl, di-C 1-6 alkylaminocarbonyl, C 1-6 alkylsulfonyl, phenoxy, 4-C 0-6 alkylpiperazin-1-yl or hydroxy(CH2) 2-6 -O-;

[0012] R9is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 0-6 silyl or =0;

[0013] R 10 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 0-6 silyl or =0, and R9and R 10 are not simultaneously =0;

[0014] X is -CH2-, -0-, -NH-, -CF2-, -C(C 1-6 alkyl)(OH)-, -S-, -Se-, -C(=0)-, -C(=NOC 0-6 alkyl)-, -S(=0)-, -Se(=0)-, -S(O2)-, -Se(O2)-;

[0015] Y1, Y2are each independently selected from -CH-, nitrogen, or -C-R 12 , wherein R 12 is halogen, -C 1-6 alkyl, -C 1-6 alkylamino, C 0-6 silyl, cycloalkyl, C 1-6 alkoxy, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, pyridyloxy, C 1-6 alkoxy(CH2) 1-6 -O-, cyano, nitro, amino, C 1-6 alkenyl, C 1-6 alkynyl, aminocarbonyl, hydroxy(CH2) 2-6 -O-, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, hydroxy(CH2) 1-6 , carboxyl, C1-6 Alkoxycarbonyl, hydroxyl, -CH(hydroxy)C 1-6 Alkyl or C 1-6 Alkyl thioalkyl.

[0016] In a preferred embodiment of the present invention, the present invention provides compounds of formulas (II-1) and (II-2) and their pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof:

[0017] in:

[0018] R0 is -C 1-3 Alkyl-O-prodrug group, -O-prodrug group, or -C(=O)-O-prodrug group;

[0019] R1 is absent or is hydrogen, deuterium, halogen, cyano, or C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -C 1-6 Alkylamino or NHR3;

[0020] R2 can be hydrogen, deuterium, halogen, cyano, or C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1- 6-alkoxy, -C 1-6 Alkylamino or NHR3;

[0021] R3 can be hydrogen, deuterium, halogen, hydroxyl, cyano, or C. 1-6 Alkyl, C 1-6 cycloalkyl, C 1-6 Alkyl or (NH) n R 11 (NH) n -C 1- 3alkyl-R 11 -OR 11 Where n is 0-1, R 11 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Cycloalkyl, azirrobutyl, oxocyclobutyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazacycloheptyl, or oxopyrrolidinyl ring; wherein C 1-6 Alkyl, C 1-6cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl, oxopyrrolidinyl ring optionally substituted with one or more groups selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NH-C(=O)-C 1-6 alkyl, -NH-C(=O)-O-C 1-6 alkyl, -NH-C(=O)-haloC 1-6 alkyl, -NH-C(=O)-O-haloC 1-6 alkyl, -NH-C(=O)-O-C 1-3 alkyl-O-C(=O)-C 1-6 alkyl, gem-dimethyl, amino, C 1-6 alkanoylamino, aminocarbonyl, hydroxy, oxetanyl amino, C 1-6 alkylpiperazinyl and aminoC 1-6 alkyl;

[0022] Y1, Y2are each independently selected from -CH-, nitrogen;

[0023] X is as defined in the foregoing of the present application.

[0024] Further, in some embodiments of the present application, said Y1is -CH-.

[0025] Further, in some embodiments of the present application, said R0is a -CH2-O- prodrug group or a -C(=O)-O-prodrug group, said prodrug group being alkyl, -C(=O)-C 1-12 alkyl, -C(=O)-C 1-12 alkyl-COOH, -C 1-3 alkyl-O-C(=O)-O-C 1-6 alkyl, -C 1-3 alkyl-O-C(=O)-C 1-6 alkyl, -C(=O)-O-C 1-3 alkyl-O-C 1-3 alkyl, Preferably, said R0is a -C 1-3 alkyl-O-C(=O)-C 1-6 alkyl.

[0026] Further, in some embodiments of the present application, said R1is absent or is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, -C 1-6 alkylamino, deuterated C 1-6 alkyl or haloC 1-6 alkyl.

[0027] Further, in some embodiments of the application, R1is absent or is hydrogen, deuterium, halogen, cyano, C 1-2 alkyl, deuterated C 1-2 alkyl or fluorinated C 1-2 alkyl.

[0028] Further, in some embodiments of the application, R1is hydrogen, methyl, deuterated methyl or fluorinated methyl.

[0029] Further, in some embodiments of the application, R2is hydrogen, deuterium, halogen.

[0030] Further, in some embodiments of the application, R2is hydrogen.

[0031] Further, in some embodiments of the application, X is -S(O2)-.

[0032] Further, in some embodiments of the application, R3is hydroxyl, cyano, -(NH) n R 11 , (NH) n -C 1-3 alkyl-R 11 or -O-R 11 wherein n is 0-1 and R 11 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl or oxopyrrolidinyl ring; said C 1-6 alkyl, C 1-6 cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl, oxopyrrolidinyl ring is optionally substituted with one or more groups selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NH-C(=O)-C 1-6 alkyl, -NH-C(=O)-O-C 1-6 alkyl, -NH-C(=O)-halogenated C 1-6 alkyl, -NH-C(=O)-O-halogenated C 1-6 alkyl, -NH-C(=O)-O-C 1-3 alkyl-O-C(=O)-C 1-6 alkyl, gem-dimethyl, amino, C 1-6 alkanoyl amino, aminocarbonyl, hydroxyl, oxetanyl amino, C 1-6 alkyl piperazinyl and amino C1-6 alkyl.

[0033] Furthermore, in some embodiments of the present invention, R3 is -NH-C 1-3 Alkyl, -NH-C 1-3 Alkylamino,

[0034] Furthermore, in some embodiments of the present invention, the Y2 is nitrogen.

[0035] Furthermore, in some embodiments of the present invention, Y2 is -CH-.

[0036] In some embodiments of the present invention, the present invention provides the following compounds and their pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms:

[0037] The present invention further relates to a pharmaceutical composition comprising a compound having the structure shown in formula (I-1), (I-2), (II-1) or (II-2), a pharmaceutically acceptable salt, ester, prodrug, solvate, isomer, or isotopic form thereof, and a pharmaceutically acceptable carrier or excipient.

[0038] In a preferred embodiment of the present invention, the pharmaceutical composition is an oral administration formulation, a parenteral administration formulation (such as a subcutaneous administration formulation or an intravenous injection formulation), or an inhaled spray formulation.

[0039] The present invention further provides the use of compounds of the structure shown in formula (I-1), (I-2), (II-1) or (II-2), pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, isotopic forms, or pharmaceutical compositions comprising thereof in the preparation of medicaments for treating or preventing viral infection in a host susceptible to or undergoing viral infection, wherein the viral infection is respiratory syncytial virus infection.

[0040] The present invention further provides the use of the compounds represented by formula (I-1), (I-2), (II-1) or (II-2), pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, isotopic forms, or compositions comprising thereof in the preparation of a medicament for treating a respiratory disease in patients, said respiratory disease being respiratory syncytial virus infection.

[0041] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0042] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group having one or more ring atoms selected from S, O, and N; and the remaining ring atoms are carbon, wherein any N or S contained in the ring can optionally be oxidized. Heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl.

[0043] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ringed hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more are heteroatoms selected from N, O, or S(O)n(where n is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, 5 to 10 ring atoms are contained, of which 1 to 3 are heteroatoms; most preferably, 5 to 6 ring atoms are contained, of which 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include piperidinyl, pyrrolidinyl, pyranyl, morpholinyl, and the like. Non-limiting examples of polycyclic heterocyclyl groups include spiro, fused, and bridged ring heterocyclyl groups.

[0044] The term "substituted" means that 1, 2, or 3 or more hydrogen atoms thereon are independently replaced with the following substituents, including but not limited to: -F, -Cl, -Br, -I, -OH, C 1- C 12 -alkyl; C2-C 12 -alkenyl, C2-C 12 -alkynyl, -C3-C 12 -cycloalkyl, protected hydroxyl, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NHC 1- C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C 1- C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C 1- C 12 -alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C 12- alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 - cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 - cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 - cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 - cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 - cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 - cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 - alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12- alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 1- C 12 - alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 - cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(O)-C 1- C 12 - alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 - cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(O)-C 1- C 12 - alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 - cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(O)-C 1- C 12 - alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 - cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(O)-C 1- C 12 - alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 - cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(O)-C 1- C 12 - alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 - cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(O)-C 1- C 12-alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkynyl, -NHSO2-C3-C 12 -cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C 1- C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylsulfanyl-methyl. In certain embodiments, the substituents are independently of each other selected from the group consisting of halogen, preferably Cl and F; C 1- C4-alkyl, preferably methyl and ethyl; halo-C 1- C4-alkyl, e.g. fluoromethyl, difluoromethyl and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, e.g. cyclopropyl; C 1- C4-alkoxy, e.g. methoxy and ethoxy; halo-C 1- C4-alkoxy, e.g. fluoromethoxy, difluoromethoxy and trifluoromethoxy; acyl; -CN; -OH; NH2; C 1- C4-alkylamino; di(C 1- C4-alkyl)amino; and NO2. It will be appreciated that aryl, heteroaryl, alkyl, etc. can be further substituted. In some cases, each substituent of a substituted moiety is additionally optionally substituted with one or more groups, each independently selected from C 1- C4-alkyl; -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2.

[0045] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. The term "optionally substituted" means that the group in question can or can not be substituted.

[0046] Isomers of the compounds according to the application are encompassed, including, for example, stereoisomeric forms (enantiomers, diastereomers, cis-trans isomers). The present application thus relates to enantiomeric or diastereomeric forms and to mixtures thereof, respectively. Stereochemically pure components can be isolated in known manner from mixtures of such enantiomeric and / or diastereomeric forms. When the compounds according to the application can exist in optically isomeric forms, the compositions provided according to the application generally comprise substantially pure optical isomers.

[0047] The term "prodrug" encompasses compounds which can be biologically active or inactive themselves, but which are converted (for example by metabolism or hydrolysis) into a compound according to the application during their residence time in the body.

[0048] Solvates are those forms of the compounds according to the application which form a complex with solvent molecules by coordination in the solid or liquid state. Hydrates are a particular form of solvates in which water is coordinated. Within the scope of the present application, preference is given to hydrates as solvates.

[0049] The present application also includes all suitable isotopic variations of the compounds described herein. An isotopic variation of a compound according to the application is defined as one in which at least one atom has been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be present in the compounds described herein include isotopes of hydrogen, deuterium, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I. Isotopic replacement of deuterium can be preferred in some cases. DETAILED DESCRIPTION

[0050] In order to make the purposes, technical solutions and advantages of the present application more clear, the present application is further described in detail below with examples. The additional aspects and advantages of the present application will be partly given in the following description, partly will become obvious from the following description, or will be understood by the practice of the present application. It should be understood that the following description is only used to explain the present application, and is not used to limit the present application. Any technology achieved based on the above description of the present application belongs to the scope of the present application. The compounds or reagents used in the following examples can be purchased by commercial way, or prepared by conventional methods known to those skilled in the art; the experimental instruments used can be purchased by commercial way.

[0051] The compound C0-001 in the present application is Ziresovir (AK0529), which can be obtained by referring to the preparation method disclosed in patent CN103717589.

[0052] Some of the compounds listed in the present application can be prepared by the following synthesis method and selecting appropriate raw materials:

[0053] In an organic solvent, 1a and 1b are reacted to prepare compound 2a, compound 2a is reacted with compound 2b to prepare compound 3a, and compound 3a is deprotected to obtain a compound for treating or preventing respiratory syncytial virus disease 。

[0054] In some preparation of the compounds for treating or preventing respiratory syncytial virus disease, there is a protecting group on the amino group of compound 2a, for example, the protecting group SEM, which is removed after the reaction of compound 2a with compound 2b.

[0055] By the above similar method, the compounds described in the present application can be prepared by selecting appropriate raw materials. In the operation steps of the embodiments of the present application, 1a, 2a, 3a, 1A, 2A, 3A, 1b, 2b, 3b, 1B, 2B, 3B, etc. are only used to refer to a certain compound in a specific synthesis process route, unless otherwise specified, the compounds referred to by 1a, 2a, 1A, 2A, 1b, 2b, 1B, 2B, etc. in different embodiments are not necessarily the same or different.

[0056] Example 1

[0057] The synthesis process route of compound C2-037 is shown below:

[0058] 1a and 1b are dissolved in methanol at room temperature, DIPEA is added, and the reaction is stirred at room temperature. After the reaction is completed, citric acid solution is added to the reaction system, EA is extracted, anhydrous sodium sulfate is dried, and the organic phase is concentrated to obtain 2a. LCMS (ESI+): m / z = 352.3 [M+1]+ . At room temperature, 2a, 2b and ammonium chloride were added into n-butanol, the reaction was stirred at 120 °C under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated and directly purified by column chromatography to obtain 3a. LCMS (ESI+): m / z = 513.4 [M+1] + . At room temperature, 3a was dissolved in dichloromethane, HCl was slowly added, and the reaction was stirred at room temperature. After the reaction was completed, sodium bicarbonate solution was added to the reaction system, dried with anhydrous sodium sulfate, and the combined organic phase was concentrated to obtain C2-037. LCMS (ESI+): m / z = 413.5 [M+1] + . 1 H NMR (600 MHz, DMSO-d6) δ 10.27 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 7.8, 1.3 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.59 (td, J = 7.6, 1.3 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 5.79 (d, J = 1.6 Hz, 1H), 4.98 (s, 2H), 4.33 (s, 1H), 3.83 (td, J = 13.0, 10.4, 6.8 Hz, 2H), 3.70 (dd, J = 10.6, 5.5 Hz, 1H), 3.57 (p, J = 5.5 Hz, 1H), 3.51 (t, J = 5.1 Hz, 2H), 3.40 (s, 4H), 2.28 (s, 3H), 2.04 (dd, J = 12.7, 6.7 Hz, 1H), 1.73 (dt, J = 12.3, 6.2 Hz, 1H).

[0059] Example 2

[0060] The synthetic process route of compound C2-043 is shown below:

[0061] The specific preparation process was similar to Example 1. LCMS (ESI + ): m / z = 424.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 7.8, 1.3 Hz, 1H), 7.72 (dd, J = 7.5, 1.3 Hz, 1H), 7.62 (td, J = 7.5, 1.3 Hz, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 6.75 (s, 1H), 5.01 (s, 2H), 4.35 (s, 2H), 4.00 - 3.80 (m, 3H), 3.74 - 3.62 (m, 3H), 3.60 - 3.50 (m, 4H), 2.15 - 2.10 (m, 1H), 1.90 - 1.80 (m, 1H).

[0062] Example 3

[0063] The synthetic route of compound C2-044 is shown below:

[0064] The specific preparation process is similar to Example 1. LCMS (ESI+): m / z = 417.50 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 7.8, 1.3 Hz, 1H), 7.72 (dd, J = 7.5, 1.3 Hz, 1H), 7.62 (td, J = 7.5, 1.3 Hz, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 6.75 (s, 1H), 5.01 (s, 2H), 4.35 (s, 2H), 4.00 - 3.80 (m, 3H), 3.74 - 3.62 (m, 3H), 3.60 - 3.50 (m, 4H), 2.15 - 2.10 (m, 1H), 1.90 - 1.80 (m, 1H).

[0065] Example 4

[0066] The synthetic route of compound C2-044 is shown below:

[0067] 1a, 1b, Pd2(dba)3, XantPhos and cesium carbonate were dissolved in 1,4-dioxane at room temperature, and the reaction was stirred at 100 °C. After the reaction was completed, the reaction solution was concentrated and directly subjected to column chromatography to obtain 2a. LCMS (ESI + ): m / z = 628.8 [M+H] +. 2a was dissolved in THF at room temperature, then TBAF was added. The reaction was stirred at room temperature. After the reaction was completed, saturated sodium chloride solution was added to the reaction system, dichloromethane was extracted, anhydrous sodium sulfate was dried, and the organic phase was concentrated to obtain 3a. LCMS (ESI + ): m / z = 498.5 [M+H] + . 3a was dissolved in DCM at room temperature, then TFA was added, and the reaction was stirred at room temperature. After the reaction was completed, saturated sodium chloride solution was added to the reaction system, dichloromethane was extracted, anhydrous sodium sulfate was dried, and the organic phase was concentrated to obtain C2-048 by thin layer chromatography. LCMS (ESI + ): m / z = 398.4 [M+H] + .

[0068] Example 5

[0069] The synthetic process route of compound C3-003 is as shown below:

[0070] The specific preparation process was similar to that of Example 1. LCMS (ESI+): m / z = 385.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 13.2 (s, 2H), 12.2 (s, 1H), 8.95 (s, 2H), 8.1 (m, 1H), 7.7 (m, 1H), 7.55-7.45 (m, 2H), 7.35-7.22 (m, 2H), 5.2 (s, 2H), 4.7-4.52 (m, 2H), 4.36-4.25 (m, 2H), 4.16-4.08 (m, 2H), 3.82 (m, 1H).

[0071] Example 6

[0072] The synthetic process route of compound C3-013 is as shown below:

[0073] 1a and 1b were dissolved in methanol at room temperature, and Et3N was added. The reaction was stirred at room temperature. After the reaction was completed, the reaction liquid was concentrated and directly subjected to column chromatography to obtain 2a. LCMS (ESI+): m / z = 324.3 [M+H] + . 2a, 2b and ammonium chloride were added to n-butanol at room temperature, and the reaction was stirred at 120°C. After the reaction was completed, the reaction liquid was concentrated to obtain 3a. LCMS (ESI+): m / z = 485.4 [M+H] +C3-013. LCMS (ESI+): m / z = 385.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 2.7 Hz, 1H), 5.98 (d, J = 3.2 Hz, 1H), 4.94 (s, 2+1H), 4.30 (s, 2H), 4.02 (t, J = 8.4 Hz, 2H), 3.67 (dd, J = 9.3, 7.1 Hz, 2H), 3.48 (t, J = 5.0 Hz, 3H).

[0074] Example 7

[0075] The synthetic route of compound C3-021 is shown below:

[0076] The specific preparation process is similar to Example 1. LCMS (ESI+): m / z = 399.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 2.7 Hz, 1H), 5.98 (d, J = 3.2 Hz, 1H), 4.94 (s, 2+1H), 4.30 (s, 2H), 4.02 (t, J = 8.4 Hz, 2H), 3.67 (dd, J = 9.3, 7.1 Hz, 2H), 3.48 (t, J = 5.0 Hz, 3H).

[0077] Example 8

[0078] The synthetic route of compound C3-027 is shown below:

[0079] 1a and 1b were dissolved in methanol, then TEA was added, and the reaction was carried out at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to remove methanol, then water was added, and the organic phase was extracted with ethyl acetate three times, washed with saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2a. LCMS (ESI + ): m / z = 339.3 [M+H] + . In the reaction vessel, 2a and 2b were dissolved in n-butanol, and ammonium chloride was added. Then the reaction was carried out at 120°C. After the reaction was completed, the reaction solution was concentrated to remove n-butanol, then water was added, and the organic phase was extracted with ethyl acetate three times, washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3a. LCMS (ESI + ): m / z = 500.5 [M+H] + . In the reaction vessel, 3a was dissolved in methanol. Then HCl / EA was added at 0°C in an ice bath. The reaction was carried out at room temperature. After the reaction was completed, C3-027 was obtained by concentrating under reduced pressure. LCMS (ESI + ): m / z = 400.3 [M+H] + .

[0080] Example 9

[0081] The synthetic process route of compound C3-037 is shown below:

[0082] The specific preparation process was similar to that of Example 6. LCMS (ESI + ): m / z = 399.4 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H), 7.07 (s, 1H), 6.04 (d, J = 2.9 Hz, 1H), 5.02 (s, 2H), 4.37 (s, 2H), 4.10 - 4.04 (m, 1H), 3.70 - 3.60 (m, 2H), 3.60 - 3.50 (m, 4H), 3.30 - 3.28 (m, 1H), 2.30 - 2.25 (m, 1H), 2.11 - 2.03 (m, 1H).

[0083] Example 10

[0084] The synthetic process route of compound C3-039 is shown below:

[0085] The specific preparation process is similar to Example 1. LCMS (ESI+): m / z = 415.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.83 - 7.78 (m, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 2.7 Hz, 1H), 6.22 (s, 2H), 6.03 (d, J = 2.9 Hz, 1H), 4.93 (s, 2H), 4.30 - 4.20 (m, 2+2H), 4.02 (d, J = 9.1 Hz, 2H), 3.46 (t, J = 4.9 Hz, 3H), 2.95 (s, 2H).

[0086] Example 11

[0087] The synthetic route of compound C3-040 is shown below:

[0088] The specific preparation process is similar to Example 6. LCMS (ESI + ): m / z = 415.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (t, J = 2.5 Hz, 1H), 7.82 (dd, J = 7.8, 1.4 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 6.3 Hz, 1H), 7.57 (td, J = 7.5, 1.4 Hz, 1H), 7.41 (td, J = 7.7, 1.3 Hz, 1H), 7.19 (t, J = 2.9 Hz, 1H), 5.98 (dd, J = 2.9, 1.9 Hz, 1H), 5.53 (s, 1H), 4.99 (s, 2H), 4.42 (s, 2H), 4.20 (d, J = 3.9 Hz, 1H), 3.60 - 3.40 (m, 4H), 3.29 (dd, J = 12.1, 4.2 Hz, 2H), 3.05 - 2.93 (m, 2H).

[0089] Example 12

[0090] The synthetic route of compound C3-040 is shown below:

[0091] The specific preparation process is similar to Example 6. LCMS (ESI +): m / z = 415.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 10.0 - 9.0 (m, 3H), 7.84 (d, J = 7.8 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.29 (s, 1H), 6.07 (s, 1H), 5.82 (d, J = 3.9 Hz, 1H), 5.03 (s, 2H), 4.79 (s, 1H), 4.46 - 4.17 (m, 3H), 3.68 - 3.41 (m, 4H), 3.21 (d, J = 12.3 Hz, 1H), 3.00 (t, J = 10.4 Hz, 1H).

[0092] Example 13

[0093] The synthetic route of compound C3-044 is shown below:

[0094] The specific preparation process is similar to Example 6. LCMS (ESI+): m / z = 413.50 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.87 (dd, J = 7.9, 1.3 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.60 (td, J = 7.5, 1.3 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 2.9 Hz, 1H), 7.14 (s, 1H), 6.04 (d, J = 2.9 Hz, 1H), 5.02 (s, 2H), 4.37 (s, 2H), 3.68 (q, J = 8.1, 7.4 Hz, 1H), 3.55 (q, J = 6.2, 5.1 Hz, 4H), 3.39 - 3.25 (m, 2H), 3.15 - 2.94 (m, 1H), 2.00 (q, J = 11.6, 9.2 Hz, 1H), 1.82 (ddt, J = 19.9, 12.9, 7.0 Hz, 2H), 1.61 (dt, J = 13.2, 7.4 Hz, 1H).

[0095] Example 14

[0096] The synthetic route of compound C3-044 is shown below:

[0097] The specific preparation process is similar to Example 6. LCMS (ESI+): m / z = 413.50 [M+1]+ . 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (d, J = 223.6 Hz, 1H), 9.23 (d, J = 59.4 Hz, 1H), 7.94 (t, J = 8.4 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.56 (dd, J = 15.6, 8.0 Hz, 2H), 7.36 - 6.90 (m, 2H), 6.27 (s, 1H), 5.18 (s, 2H), 4.87 (s, 1H), 4.38 (d, J = 40.1 Hz, 2H), 3.81 (s, 2H), 3.71 - 3.61 (m, 1H), 3.44 (d, J = 28.6 Hz, 2H), 3.22 (s, 1H), 2.33 (dq, J = 14.9, 7.5 Hz, 1H), 2.10 (dq, J = 12.7, 6.1 Hz, 1H).

[0098] Example 15

[0099] The synthetic route of compound C3-046 is shown below:

[0100] The specific preparation process is similar to Example 1. LCMS (ESI+): m / z = 413.17 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 6.06 (d, J = 2.9 Hz, 1H), 5.00 (s, 2H), 4.35 (s, 2H), 3.94 - 3.81 (m, 2H), 3.68 (q, J = 8.5 Hz, 1H), 3.53 (d, J = 5.0 Hz, 2H), 3.50 - 3.45 (m, 1H), 2.81 - 2.64 (m, 2H), 2.38 (h, J = 7.6 Hz, 1H), 2.10 (tt, J = 12.1, 5.5 Hz, 1H), 1.73 (dq, J = 12.1, 8.1 Hz, 1H).

[0101] Example 16

[0102] The synthetic route of compound C3-046 is shown below:

[0103] Dissolve 1a in methanol, add 1b, react at 60°C for 24h, concentrate, and purify by column chromatography to obtain 2a. At room temperature, add 2a, 2b and ammonium chloride to n-butanol, and stir the reaction under nitrogen atmosphere at 120°C. After the reaction is completed, concentrate the reaction solution and directly purify by column chromatography to obtain 3a. At room temperature, dissolve 3a in dichloromethane, slowly add HCl, and stir the reaction at room temperature. After the reaction is completed, add sodium bicarbonate solution to the reaction system, dry with anhydrous sodium sulfate, combine the organic phases, and concentrate to obtain C3-047. LCMS (ESI+): m / z = 399.50 [M+1] + .

[0104] Example 17

[0105] The synthetic process route of compound C3-052 is shown below:

[0106] The specific preparation process is similar to that of Example 6. LCMS (ESI+): m / z = 370.62 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.94-7.79 (m, 2H), 7.63 (td, J = 7.5, 1.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 6.11 (s, 1H), 5.09 (s, 2H), 4.38 (s, 2H), 3.65 (s, 2H), 3.07 (s, 1H), 0.97-0.83 (m, 2H), 0.58 (p, J = 4.7 Hz, 2H).

[0107] Example 18

[0108] The synthetic process route of compound C3-053 is shown below:

[0109] The specific preparation process is similar to that of Example 6. LCMS (ESI+): m / z = 499.62 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 9.56 (d, J = 6.9 Hz, 1H), 7.92 (dd, J = 7.8, 1.4 Hz, 2H), 7.69 (td, J = 7.5, 1.3 Hz, 1H), 7.54 (td, J = 7.7, 1.2 Hz, 1H), 7.47 (t, J = 2.9 Hz, 1H), 6.24 (t, J = 2.4 Hz, 1H), 5.15 (s, 2H), 4.70 (q, J = 7.8 Hz, 1H), 4.33 (s, 2H), 3.80 (t, J = 5.1 Hz, 2H), 2.43 - 2.32 (m, 2H), 2.08 (qd, J = 9.2, 2.6 Hz, 2H), 1.89 - 1.75 (m, 2H).

[0110] Example 19

[0111] The synthetic route of compound C3-055 is shown below:

[0112] Dissolve 1a in acetonitrile, add 1b and DIPEA, react at 60°C for 24h, concentrate and purify by column chromatography to obtain 2a. At room temperature, add 2a, 2b and ammonium chloride into n-butanol, stir and react at 120°C under nitrogen atmosphere. After the reaction is completed, concentrate the reaction solution and directly purify by column chromatography to obtain C3-055. LCMS (ESI+): m / z = 344.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 12.17 (s, 1H), 9.31 (s, 1H), 7.94 (dd, J = 7.9, 1.4 Hz, 2H), 7.69 (td, J = 7.5, 1.3 Hz, 1H), 7.56 (td, J = 7.7, 1.2 Hz, 1H), 7.47 (t, J = 2.9 Hz, 1H), 6.27 (t, J = 2.4 Hz, 1H), 5.31 - 5.11 (m, 2H), 4.38 (s, 2H), 3.82 (t, J = 5.1 Hz, 2H), 3.10 (d, J = 4.6 Hz, 3H).

[0113] Example 20

[0114] The synthetic route of compound C7-001 is shown below:

[0115] The specific preparation process is similar to that of Example 6. LCMS (ESI + ): m / z = 399.4 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 5.77 (d, J = 2.0 Hz, 1H), 4.98 (s, 3H), 4.33 (s, 2H), 3.82 (s, 2H), 3.51 (t, J = 5.0 Hz, 2H), 3.46 - 3.40 (m, 3H), 2.28 (s, 3H).

[0116] Example 21

[0117] The synthetic route of compound C7-002 is shown below:

[0118] The specific preparation process is similar to Example 6. LCMS (ESI+): m / z = 429.2 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.90 - 7.81 (m, 2H), 7.65 - 7.57 (m, 1H), 7.43 (t, J = 7.7 Hz, 1H), 5.73 (d, J = 1.9 Hz, 1H), 5.53 (s, 1H), 5.00 (s, 2H), 4.37 (s, 2H), 4.06 (s, 1H), 3.75 (s, 1H), 3.51 (q, J = 4.7 Hz, 4H), 2.24 (s, 3H).

[0119] Example 22

[0120] The synthetic route of compound C7-004 is shown below:

[0121] 1a, 1b and TEA were dissolved in MeCN at room temperature, the reaction was stirred at 60°C, after the reaction was completed by LCMS, water was added to the reaction system, extracted with ethyl acetate, and purified by column to obtain compound C7-004. LCMS (ESI + ): m / z = 429.4 [M+H] +1H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.14 (s, 1H), 5.83 (s, 1H), 5.03 (s, 2H), 4.56 (s, 4H), 4.05 - 3.88 (m, 2H), 3.54 (t, J = 5.0 Hz, 3H), 2.30 (s, 3H).

[0122] Example 23

[0123] The synthetic route of compound C7-006 is shown below:

[0124] The specific preparation process is similar to Example 6. LCMS (ESI + ): m / z = 413.5 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 0.5H), 12.38 (s, 0.5H), 9.47 (s, 1H), 9.00 - 8.90 (m, 1.5H), 8.00 - 7.90 (m, 2H), 7.79 - 7.68 (m, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 50.9 Hz, 0.5H), 6.09 (s, 1H), 5.20 (s, 2H), 4.37 (s, 2H), 4.02 (s, 2H), 3.92 - 3.74 (m, 5H), 3.15 - 3.00 (m, 1H), 2.34 (s, 3H).

[0125] Example 24

[0126] The synthetic route of compound C7-006 is shown below:

[0127] The specific preparation process is similar to Example 6. LCMS (ESI + ): m / z = 429.4 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 5.79 (s, 1H), 5.10 (s, 1H), 4.98 (s, 2H), 4.34 (s, 2H), 3.94 (s, 2H), 3.90 - 3.80 (m, 1H), 3.60 - 3.40 (m, 5H), 2.28 (s, 3H).

[0128] Example 25

[0129] The synthetic route of compound C7-010 is shown below:

[0130] The specific preparation process is similar to Example 6. LCMS (ESI+): m / z = 413.52 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.26 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 7.9, 1.3 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz, 1H), 7.46 (td, J = 7.7, 1.3 Hz, 1H), 6.83 (d, J = 6.7 Hz, 1H), 5.78 (d, J = 2.0 Hz, 1H), 4.99 (s, 2H), 4.72 (s, 1H), 4.35 (s, 2H), 3.64 (td, J = 7.7, 3.9 Hz, 1H), 3.51 (t, J = 5.0 Hz, 2H), 2.29 (s, 3H), 2.21 - 2.13 (m, 2H).

[0131] Example 26

[0132] The synthetic route of compound C7-011 is shown below:

[0133] The specific preparation process is similar to Example 16. LCMS (ESI+): m / z = 431.52 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 5.81 (s, 1H), 5.27 (d, J = 50.7 Hz, 1H), 4.91 (d, J = 80.3 Hz, 2H), 4.36 (s, 2H), 2.27 (s, 3H).

[0134] Example 27

[0135] The synthetic route of compound C7-012 is shown below:

[0136] The specific preparation process is similar to Example 16. LCMS (ESI+): m / z = 431.52 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 5.81 (s, 1H), 5.27 (d, J = 50.7 Hz, 1H), 4.91 (d, J = 80.3 Hz, 2H), 4.36 (s, 2H), 2.27 (s, 3H).

[0137] Example 28

[0138] The synthetic route of compound C7-012 is shown below:

[0139] Compound C2-037 was dissolved in MeCN, TEA was added, 1b was added at room temperature, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was combined and concentrated, and compound C7-016 was obtained by column chromatography. LCMS (ESI+): m / z = 571.2 [M+1] + . 1H NMR (600 MHz, DMSO-d6) δ 10.51 (s, -1H), 7.87 (d, J=7.7 Hz, 1H), 7.74 (s, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.48 (dt, J=15.3, 7.2 Hz, 2H), 5.88 (s, 0H), 5.10 - 4.94 (m, 2H), 4.34 (s, 1H), 4.20 (q, J=6.0 Hz, 1H), 3.96 (q, J=6.0, 5.5 Hz, 2H), 3.89 (dq, J=37.7, 7.5 Hz, 2H), 3.77 (s, 1H), 3.68 - 3.52 (m, 3H), 2.31 (s, 3H), 2.17 (dq, J=13.6, 7.1 Hz, 1H), 1.95 (dq, J=12.7, 6.4 Hz, 1H), 1.55 (q, J=7.0 Hz, 2H), 1.34 - 1.29 (m, 2H), 1.27 (p, J=4.2 Hz, 4H), 0.86 (t, J=6.7 Hz, 3H).

[0140] Example 29

[0141] The synthetic process route of compound C7-027 is shown below:

[0142] 1a, 1b, TEA and BOP were dissolved in DMAc at room temperature, and the reaction was stirred at 50°C for 14h. After the reaction was completed, water was added to quench the reaction, and EA was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column separation to obtain 2a. LCMS (ESI + ): m / z = 499.5 [M+H] + 3a was dissolved in DCM at room temperature, and TFA was slowly added. The reaction was stirred at room temperature for 2h. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to 8-9, and EA was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column separation to obtain compound C7-027. LCMS (ESI + ): m / z = 399.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.85 (dd, J = 7.8, 1.3 Hz, 1H), 7.70 (dd, J = 7.6, 1.3 Hz, 1H), 7.60 (td, J = 7.5, 1.4 Hz, 1H), 7.45 (td, J = 7.7, 1.3 Hz, 1H), 5.80 (dd, J = 1.9, 0.9 Hz, 1H), 4.96 (s, 2H), 4.45 - 4.30 (m, 4H), 3.90 - 3.70 (m, 3H), 3.49 (t, J = 4.9 Hz, 2H), 2.28 (s, 3H).

[0143] Example 30

[0144] The synthetic route of compound C7-028 is shown below:

[0145] Dissolve 1b in THF, add NaH, add 1a at room temperature, stir the reaction at 50°C, monitor the reaction by LCMS until completion. Quench the reaction with saturated ammonium chloride, extract with ethyl acetate, combine the organic phase and concentrate, purify by column chromatography to get 2a. Dissolve 2a in THF, add NaH, add SEMCl at room temperature, stir the reaction at room temperature, monitor the reaction by TLC until completion. Quench the reaction with saturated ammonium chloride, extract with ethyl acetate, combine the organic phase and concentrate, purify by column chromatography to get 3a. Dissolve 3a, 2b in 1,4-dioxane, add cesium carbonate, Xantphos and Pd2(dba)3, react at 100°C under nitrogen protection, monitor the reaction by LCMS until completion, add silica gel to the reaction mixture, purify by column chromatography to get 4a. Dissolve 4a in TFA, react at room temperature, monitor the reaction by LCMS until completion. Concentrate the reaction mixture to get 5a. Dissolve 5a in aqueous ammonia solution, stir at room temperature, monitor the reaction by LCMS until completion, collect the solid precipitated by filtration to get 6a. Dissolve 6a in MeCN, add 6b, triethylamine, BOP, react at 50°C, monitor the reaction by LCMS until completion, pour the reaction mixture into water, extract with ethyl acetate, combine the organic phase and concentrate, purify by column chromatography to get compound C7-028. LCMS (ESI+): m / z = 431.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 7.8, 1.3 Hz, 1H), 7.76 (dd, J = 7.5, 1.2 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.51 (td, J = 7.7, 1.3 Hz, 1H), 5.86 (d, J = 1.8 Hz, 1H), 5.02 (s, 2H), 4.46 (t, J = 7.4 Hz, 4H), 3.89 (dq, J = 24.0, 6.2 Hz, 3H), 3.55 (t, J = 5.0 Hz, 2H).

[0146] Example 31

[0147] The synthetic route of compound C7-046 is shown below:

[0148] The specific preparation process is similar to Example 1. LCMS (ESI + ): m / z = 402.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 7.8, 1.3 Hz, 1H), 7.76 (dd, J = 7.5, 1.2 Hz, 1H), 7.66 (td, J = 7.5, 1.4 Hz, 1H), 7.51 (td, J = 7.7, 1.3 Hz, 1H), 5.86 (d, J = 1.8 Hz, 1H), 5.02 (s, 2H), 4.46 (t, J = 7.4 Hz, 4H), 3.89 (dq, J = 24.0, 6.2 Hz, 3H), 3.55 (t, J = 5.0 Hz, 2H).

[0149] Example 32

[0150] The synthetic route of compound C7-050 is shown below:

[0151] The specific preparation process is similar to Example 1. LCMS (ESI + ): m / z = 400.4 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.88 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 4.0 Hz, 1H), 5.75 (s, 1H), 4.75 (s, 2H), 4.35 (d, J = 8.0 Hz, 2H), 4.11-4.09 (m, 2H), 3.83-3.79 (m, 1H), 3.76-3.72 (m, 2H), 2.47 (t, J = 4.0 Hz, 2H), 2.39-2.29 (m, 2H), 2.25 (s, 3H).

[0152] Example 33

[0153] The synthetic process route of compound C7-051 is shown below:

[0154] At room temperature, 1a, 1b and TEA were dissolved in MeOH, and the reaction was stirred at 60°C. After the reaction was completed by TLC monitoring, water was added to the reaction system to precipitate the solid. After filtration, solid 2a was obtained. LCMS (ESI + ): m / z = 352 [M+H] + At room temperature, 2a was dissolved in DCM, and TFA was slowly added. The reaction was stirred at room temperature for 2h. After the reaction was completed by LCMS monitoring, saturated sodium bicarbonate aqueous solution was added to the reaction system to adjust pH = 8-9, and DCM was added for extraction. After drying over anhydrous sodium sulfate, the organic phases were combined and concentrated to obtain solid 3a. LCMS (ESI + ): m / z = 251.8 [M+H] + At room temperature, 3a and 3b were dissolved in n-BuOH, and NH4Cl was added. The reaction was stirred at 120°C under nitrogen atmosphere. After the reaction was completed by TLC monitoring, water was added to the reaction liquid to precipitate the solid. The obtained solid was washed with EA, and then filtered to obtain compound C7-051. LCMS (ESI + ): m / z = 207.0 [M / 2+H] + .

[0155] Example 34

[0156] The synthetic process route of compound C7-052 is shown below:

[0157] The specific preparation process was similar to that of Example 1. LCMS (ESI + ): m / z = 413.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 5.78 (s, 1H), 4.93 (s, 2H), 4.31 (s, 2H), 4.04 (d, J = 8.0 Hz, 2H), 3.93 (d, J = 8.1 Hz, 2H), 3.46 (t, J = 5.0 Hz, 3H), 2.25 (s, 3H), 1.41 (s, 3H).

[0158] Example 35

[0159] The synthetic route of compound C1-037 is shown below:

[0160] The starting material 1A (299.02 mg, 1.48 mmol), starting material 1B (330.78 mg, 1.78 mmol) were dissolved in methanol (5 mL), sodium bicarbonate (126.82 mg, 1.51 mmol) was added, and stirring was performed at 50 °C overnight. After the reaction was completed by LCMS monitoring, the reaction solution was rotary dried, slurried with 1 mL water and 3 mL methanol, and filtered to obtain the product 2A. LCMS (ESI+): m / z = 352.3 [M+H] + The starting material 2A (211.10 mg, 0.60 mmol), DMAP (7.33 mg, 0.06 mmol) were dissolved in acetonitrile (10 mL), triethylamine (182.14 mg, 1.80 mmol) and Boc20 (392.85 mg, 1.80 mmol) were added, and stirring was performed at 30 °C for 4 h. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated and separated by column chromatography to obtain the product 3A. LCMS (ESI+): m / z = 452.4 [M+H] + The starting material 3A (148.88 mg, 0.28 mmol), starting material 3B (82.85 mg, 0.42 mmol), cesium carbonate (182.46 mg, 0.56 mmol), P(tBu)3PdG4 (32.82 mg, 0.06 mmol) were added to 1,4-dioxane (2 mL), and after nitrogen replacement, stirring was performed at 80 °C for 3 h by microwave heating. After the reaction was completed, the reaction solution was filtered, and the filtrate was separated by column chromatography to obtain 4A. LCMS (ESI+): m / z = 513.3 [M+H] +To a solution of starting material 4A (120.00 mg, 0.20 mmol) in DCM (2 mL) was added trifluoroacetic acid (1.37 g, 12.00 mmol) and stirred at room temperature for 1 h. After the reaction was monitored to be completed by LCMS, the solvent and trifluoroacetic acid were removed by rotary evaporation, and the residue was separated by column chromatography. The product was added to water (10 mL) and acetonitrile (1 mL), and then freeze-dried after ultrasonic treatment to obtain the final product C1-037. LCMS (ESI+): m / z = 207.3 [M / 2+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.19 (s, 2H), 7.88 (dd, J = 7.8, 1.3 Hz, 1H), 7.73 (dd, J = 7.6, 1.3 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz, 1H), 7.48 (td, J = 7.6, 1.3 Hz, 1H), 5.99 (s, 1H), 5.00 (s, 2H), 4.34 (s, 2H), 3.93 (s, 2H), 3.85 (d, J = 8.7 Hz, 1H), 3.78 (d, J = 9.5 Hz, 2H), 3.56 (t, J = 5.0 Hz, 2H), 2.37 - 2.26 (m, 1H), 2.18 (s, 3H), 2.09 (s, 1H).

[0161] Example 36

[0162] The synthetic process route of compound C1-038 is shown below:

[0163] To a solution of starting material 1A (400.04 mg, 1.98 mmol), starting material 1B (387.21 mg, 2.08 mmol) in methanol (3 mL) was added triethylamine (220.39 mg, 2.18 mmol) and stirred at room temperature for 4 h. After the reaction was monitored to be completed by LCMS, the reaction solution was concentrated and separated by column chromatography to obtain the product 2A. LCMS (ESI+): m / z = 352.2 [M+H] + To a solution of starting material 2A (686.07 mg, 1.95 mmol), starting material 2B (461.56 mg, 2.34 mmol), ammonium chloride (20.86 mg, 0.39 mmol) in n-butanol (10 mL) was stirred at 115 °C overnight. After the reaction was monitored to be completed by LCMS, the reaction solution was concentrated and extracted with water / DCM three times. The organic phase was combined and rotary evaporated to obtain 3A. LCMS (ESI+): m / z = 513.4 [M+H] +To a solution of 3A (917.59 mg, 1.79 mmol) in DCM (15 mL) was added trifluoroacetic acid (10.20 g, 89.50 mmol) and stirred at room temperature for 1.5 h. After the reaction was completed, the solvent and trifluoroacetic acid were removed by rotary evaporation, the residue was separated by column chromatography, the product was added to water (20 mL) and acetonitrile (2 mL), and then freeze-dried after ultrasonic treatment to obtain the final product C1-038. LCMS (ESI+): m / z = 413.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 7.94 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 6.3 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 6.30 (s, 1H), 5.13 (s, 2H), 4.35 (s, 2H), 4.16 - 4.02 (m, 2H), 3.96 (d, J = 7.5 Hz, 1H), 3.89 (s, 5H), 3.79 (s, 2H), 2.28 (dq, J = 13.7, 7.6 Hz, 1H), 2.11 (p, J = 8.6, 7.3 Hz, 1H).

[0164] Example 37

[0165] The synthesis process route of compound C3-023 is shown below:

[0166] Dissolve 1a (300 mg, 1.59 mmol, 1 equivalent) and 2b (296 mg, 1.59 mmol, 1 equivalent) in methanol (10 ml), then add triethylamine (TEA, 0.32 g, 3.18 mmol, 2 equivalents). The reaction was stirred at 25°C for 2 hours. The target molecular weight was detected by LCMS. The reaction mixture was poured into water (100 ml), extracted with ethyl acetate (100 ml), washed with brine (100 ml), and dried over sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 2a. LCMS (ESI+): m / z = 339.3 / 341.3 [M+1] +In 1,4-dioxane (10 ml) was dissolved 2a (300 mg, 0.89 mmol, 1 eq), 2b (0.26 g, 1.33 mmol, 1.5 eq), Pd2(dba)3(0.081 g, 0.089 mmol, 0.1 eq) and Xantphos (0.1 g, 0.18 mmol, 0.1 eq), then cesium carbonate (0.72 g, 2.23 mmol, 2.5 eq) was added. The reaction was stirred at 110 °C for 12 h. The target molecular weight was detected by LCMS. The reaction was filtered and concentrated, and the residue was purified by column chromatography to give 3a. LCMS (ESI+): m / z = 500.5 [M+1] + In dichloromethane (3 ml) was dissolved 3a (100 mg, 0.2 mmol, 1 eq), then trifluoroacetic acid (TFA, 1 ml) was added. The reaction was stirred at 25 °C for 1 h. The target molecular weight was detected by LCMS. The reaction mixture was concentrated to give 4a. LCMS (ESI+): m / z = 400.4 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 3H), 8.19 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 7.8, 1.4 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (td, J = 7.5, 1.4 Hz, 1H), 7.53 (td, J = 7.6, 1.3 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 5.08 (s, 2H), 4.39 (d, J = 13.9 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 2.44 - 2.27 (m, 1H), 2.12 (d, J = 30.0 Hz, 1H).

[0167] Example 38

[0168] The synthetic process route of compound C3-059 is shown below:

[0169] The specific preparation process was similar to Example 6. LCMS (ESI + ): m / z = 373.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.80 (dd, J = 7.8, 1.3 Hz, 1H), 7.71 - 7.65 (m, 1H), 7.54 (ddd, J = 7.5, 5.6, 1.4 Hz, 1H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 6.94 (t, J = 5.7 Hz, 1H), 5.96 (d, J = 2.9 Hz, 1H), 4.95 (s, 2H), 4.30 (s, 2H), 3.60 - 3.41 (m, 4H), 2.75 (t, J = 6.3 Hz, 2H).

[0170] Example 39

[0171] The synthetic route of compound C7-044 is shown below:

[0172] NaH (296.4 mg, 7.41 mmol) was added to a solution of 1a (610 mg, 1.73 mmol), 1b (0.38 g, 1.9 mmol) and NH4Cl (9.3 mg, 0.17 mmol) in THF (10 mL) at 0 °C. The reaction was stirred at 60 °C for 14 h. After the reaction was completed, the reaction was quenched by adding water, extracted with EA (20 mL*3), dried over anhydrous sodium sulfate, the organic phases were combined and concentrated, purified by column separation (PE / EA (v / v)=3 / 1, Rf=0.3) to give 2a. LCMS (ESI + ): m / z = 399.3 [M+H] + A mixture of 2a (0.8 g, 2.36 mmol), 2b (0.51 g, 2.60 mmol) and NH4Cl (13 mg, 0.24 mmol) was dissolved in n-BuOH (10 mL) at room temperature. The reaction was stirred at 120 °C for 14 h under nitrogen atmosphere. After the reaction was completed, the reaction was concentrated and directly purified by column chromatography (PE / EA (v / v)=3 / 1, Rf=0.3) to give 3a. LCMS (ESI + ): m / z = 500.3 [M+H] + A mixture of 3a (0.24 g, 0.48 mmol) was dissolved in DCM (2 mL) at room temperature. TFA (1 mL) was added slowly. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was adjusted to pH = 8-9 by adding saturated sodium bicarbonate solution. The reaction was extracted with EA (20 mL*3), dried over anhydrous sodium sulfate, the organic phases were combined and concentrated, purified by plate separation (DCM:MeOH (v / v)=8:1, Rf=0.2) to give C7-044. LCMS (ESI + ): m / z = 400.4 [M+H]+ .

[0173] Test Example 1: Biological activity test

[0174] Evaluation of the inhibitory effect of the test compound on the virus at the in vitro cell level (RSV A2 strain)

[0175] 1. Experimental materials

[0176] Cells: Hep-2 cells

[0177] Strain: RSV-RFP (Lot: 20231121, 3 x 10 6 PFU / mL)

[0178] 2. Experimental procedure:

[0179] 1) Hep-2 cells were plated in a 96-well plate at 20000 cells / well and adherently cultured overnight.

[0180] 2) RSV-RFP virus was infected at an MOI of 0.2 (about 5000 PFU / well), and the diluted virus was mixed with different concentrations of drugs, respectively. The original culture medium of the cells was discarded and replaced with the virus-drug mixture, and cultured for 24H, 48H, respectively. The fluorescent spots in each well were read by cello (drug group). The group with only virus without drug was used as the positive group, and the group without virus and drug was used as the negative group.

[0181] 3. Data analysis:

[0182] 1) The virus inhibition rate of different concentrations of drugs was calculated by the number of fluorescent spots in each well, and the calculation formula was as follows:

[0183] Inhibition rate (%) = (number of fluorescent spots in positive group - number of fluorescent spots in drug group) / (number of fluorescent spots in positive group - number of fluorescent spots in negative group) x 100%

[0184] 2) The Graphpad Prism software was used to analyze the inhibition rate data (inhibition rate %) of the drug at different concentrations by log(inhibitor) vs. response-Variable slope(four parameters) nonlinear fitting analysis, and the EC 50 value of the compound to RSV A2 strain virus was obtained, and the results are shown in Table 1.

[0185] Table 1 Inhibitory effect of the test compound on the virus at the in vitro cell level (RSV A2 strain)

[0186] Test Example 2: Liver microsomal stability

[0187] The liver microsomal metabolic stability investigation is the ease of compound metabolism and the size of in vitro clearance rate, commonly used in vitro metabolic half-life (T 1 / 2 ) and intrinsic clearance (CL int ) are expressed. Generally calculated by quantitative determination of the clearance of the target compound in enzyme incubation system.

[0188] Incubation system: the total volume of each incubation system is 500 μL, the system includes 0.1M PBS buffer (pH = 7.4) 479.75 μL, 20 mg / ml liver microsomes 18.75 μL, 0.5 mM drug DMSO solution 1.5 μL. Precise 30 μL of system solution, preheat in 37℃ incubator for 5 min; add 6 mM NADPH initiator liquid 15 μL, mix gently, incubate in 37℃ incubator, set 0 min, 10 min, 30 min, 45 min, 4 time points to collect samples. After the reaction is completed, add 150 μL of ice methanol-acetonitrile (1:1) solution containing internal standard to terminate the reaction.

[0189] Calculation: the concentration of the test compound at 0 min incubation time is taken as 100%, the concentration at other incubation time points is converted to the percentage of residual amount, the natural logarithm of the percentage of residual amount at each time point is linearly regressed with the incubation time, and the slope k is calculated. The in vitro half-life can be calculated according to the formula T 1 / 2 = -0.693 / k. The results are shown in Table 2.

[0190] Table 2 Investigation results of liver microsomal metabolic stability of test compounds

[0191] Test example 3: in vivo pharmacokinetic test

[0192] 18 6-9 week old female Balbc mice, after isoflurane anesthesia, 5 mg / kg C7-027 (ultrapure water preparation, concentration 5 mg / mL) was given by nasal drops, 10 min, 30 min, 1 h, 3 h, 8 h, 24 h after administration, 3 animals at each time point, 100 ul of ocular fundus venous blood was collected, and the animals were immediately sacrificed, the lung tissue was separated and placed on wet ice. The whole blood was centrifuged within 2 hours after collection, the centrifugation conditions were 6800g, 2-8℃, 6 minutes, and the lung tissue was homogenized according to the ratio of 1 g tissue: 3 mL PBS (pH 7.4) buffer.

[0193] The protein precipitation method was used for pretreatment of plasma and tissue homogenate, LC-MS / MS was used for detection of sample concentration, and Phoenix 7.0 software non-compartment model statistical moment method was used to calculate the following main pharmacokinetic parameters, and the test results are shown in Table 3.

[0194] Table 3 PK parameters of C7-027 in various tissues

[0195] Test Example 4: In vivo pharmacodynamic test

[0196] The compound of the present application is dissolved in a suitable solvent to form a clear solution for nasal instillation.

[0197] Animals: BALB / c mice, 6 weeks old, female.

[0198] Preparation of in vivo RSV virus infection model: On experimental days -6 and -1, the immunosuppressant was injected intraperitoneally. On experimental day 0, the RSV virus solution was inoculated intranasally, 2 x 10 5 PFU.

[0199] Animal grouping: The animals were divided into a solvent control group and a drug administration group. There were 6 animals in each group.

[0200] Administration method and dosage: The compound of the present application was administered intranasally at 5 mg / kg or the solvent used for the administration of the compound of the present application was administered intranasally at a volume of 1 mL / kg. The control compound CO-001 was administered orally at 50 mg / kg at a volume of 10 mL / kg.

[0201] Experimental procedure: The mice were transferred to the ABSL-2 laboratory in advance and acclimated. On experimental days -6 and -1, the immunosuppressant cyclophosphamide was injected intraperitoneally at a dose of 100 mg / kg and a volume of 10 mL / kg. On experimental day 0, the mice were anesthetized using isoflurane, and then inoculated intranasally with the RSV virus solution at 2 x 10 5 PFU per mouse. The compound of the present application was administered continuously for 4 days from day 0 to day 3 at a dose of 5 mg / kg once a day by intranasal administration at a volume of 1 mL / kg, with the first administration at 1 hour after virus inoculation. The control compound CO-001 was also administered continuously for 4 days at a dose of 50 mg / kg twice a day by oral administration at a volume of 10 mL / kg, with the first administration at 1 hour after virus inoculation. The mice were euthanized on day 4, and lung tissue samples were collected. The animals were observed daily from day 0 to day 4, and the body weight, health, and survival were recorded.

[0202] Sample processing: The lung tissue of the mice was taken, and homogenized at 4°C after adding DMEM medium containing 1% double-antibiotic (penicillin-streptomycin), and the supernatant was used for the detection of viral load by plaque assay after centrifugation.

[0203] Sample detection: The viral load in the lung tissue was detected by plaque assay.

[0204] Experimental results: the virus load in the lung tissue of the compound of the present application is lower than that of the control compound C0-001 on the 4th day after administration, and the administration frequency is less than that of the control compound C0-001, and the compound of the present application has good in vivo antiviral effect. The exemplary compounds are shown in Table 4 below.

[0205] Table 4 Change of lung RSV virus load of mice after administration

[0206] Note: a: BID means twice a day administration, b: QD means once a day administration.

[0207] Those skilled in the art will readily understand that the above description is only an example of the present application and is not intended to limit the present application, and any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. Compounds of formulas (I-1) and (I-2), and their pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof: wherein: R0is -C 1-3 alkyl-O-prodrug group, -O-prodrug group, or -C(=O)-O-prodrug group; R1is absent or hydrogen, deuterium, halogen, cyano, C 0-6 silyl, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy or NHR3; R2is hydrogen, deuterium, halogen, cyano, C 0-6 silyl, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy or NHR3; R3 is hydrogen, deuterium, amino, hydroxyl, -O-, cyano, halogen, alkyl, silyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; wherein each of said amino, hydroxyl, -O-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl independently optionally has one or more substituents of substituted or unsubstituted alkyl, haloalkyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, nitro, cyano, hydroxyl, oxygen atom, substituted or unsubstituted alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl; R4, R5, R6, R7, R8are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, morpholinyl, C 1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkyl, halogen-C 1-6 alkoxy, C 0-6 silyl, C 1-6 alkylaminocarbonyl, di-C 1-6 alkylaminocarbonyl, C 1-6 alkylsulfonyl, phenoxy, 4-C 0-6 alkylpiperazin-1-yl or hydroxy(CH2) 2-6 -O-; R9is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 0-6 silyl, or =0; R 10 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 0-6 silyl or =0, and R9and R 10 are not simultaneously =0; X is -CH2-, -0-, -NH-, -CF2-, -C(C 1-6 alkyl)(OH)-, -S-, -Se-, -C(=0)-, -C(=NOC 0-6 alkyl)-, -S(=0)-, -Se(=0)-, -S(02)-, -Se(02)-, -S(=0)(NH)-, or -Se(=0)(NH)-; Y1, Y2are each independently selected from -CH-, nitrogen, or -C-R 12 wherein R 12 is halogen, -C 1-6 alkyl, -C 1-6 alkylamino, C 0-6 silyl, cycloalkyl, C 1-6 alkoxy, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, pyridyloxy, C 1-6 alkoxy (CH2) 1-6 -O-, cyano, nitro, amino, C 1-6 alkenyl, C 1-6 alkynyl, aminocarbonyl, hydroxy (CH2) 2-6 -O-, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, hydroxy (CH2) 1-6 , carboxy, C 1-6 alkoxycarbonyl, hydroxyl, -CH(hydroxy)C 1-6 alkyl or C 1-6 alkylsulfanyl.

2. A compound represented by Formula (II-1), (II-2) and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof: wherein: R0is -C 1-3 alkyl-O-prodrug group, -O-prodrug group, or -C(=O)-O-prodrug group; R1is absent or hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -C 1-6 alkylamino or NHR3; R2is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1- 6alkoxy, -C 1-6 alkylamino or NHR3; R3is hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 alkoxy, or (NH) n R 11 , (NH) n -C 1- 3alkyl-R 11 , -O-R 11 wherein n is 0-1 and R 11 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl, or oxopyrrolidinyl ring; said C 1-6 alkyl, C 1-6 cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl, oxopyrrolidinyl ring is optionally substituted with one or more groups selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NH-C(=O)-C 1-6 alkyl, -NH-C(=O)-O-C 1-6 alkyl, -NH-C(=O)-haloC 1-6 alkyl, -NH-C(=O)-O-haloC 1-6 alkyl, -NH-C(=O)-O-C 1-3 alkyl-O-C(=O)-C 1-6 alkyl, gem-dimethyl, amino, C 1-6 alkanoyl, aminocarbonyl, hydroxyl, oxetanyl, C 1-6 alkylpiperazinyl, and aminoC 1-6 alkyl; X is -CH2-, -0-, -NH-, -CF2-, -C(C 1-6 alkyl)(OH)-, -S-, -Se-, -C(=0)-, -C(=NOC 0-6 alkyl)-, -S(=0)-, -Se(=0)-, -S(O2)-, -Se(O2)-; Y1, Y2 are each independently selected from -CH-, nitrogen.

3. The compound of claim 1 or 2, and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof, characterized in that, R0is a -CH2-O-prodrug group or a -C(=O)-O-prodrug group, said prodrug group being an alkyl, -C(=O)-C 1-12 alkyl, -C(=O)-C 1-12 alkyl-COOH, -C 1-3 alkyl-O-C(=O)-O-C 1-6 alkyl, -C 1-3 alkyl-O-C(=O)-C 1-6 alkyl, -C(=O)-O-C 1-3 alkyl-O-C 1-6 alkyl, Preferably, said R0is a -C 1-3 alkyl-O-C(=O)-C 1-6 alkyl.

4. The compound of any one of claims 1-3, and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof, characterized in that, R1is absent or hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, -C 1-6 alkylamino, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl; preferably, R1is absent or hydrogen, deuterium, halogen, cyano, C 1-2 alkyl, deuterated C 1-2 alkyl or fluorinated C 1-2 alkyl; preferably, R1is hydrogen, methyl or deuterated methyl.

5. The compound of any one of claims 1-4, and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof, characterized in that, said R2 is hydrogen, deuterium, halogen; preferably, said R2 is hydrogen; preferably, said X is -S(O2)-; preferably, said Y1 is -CH-; preferably, said Y2 is nitrogen or -CH-, more preferably nitrogen.

6. The compound of any one of claims 1-5, and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof, characterized in that, said R3is hydroxyl, cyano, -(NH) n R 11 , (NH) n -C 1-3 alkyl-R 11 or -O-R 11 wherein n is 0-1, R 11 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl or oxopyrrolidinyl ring; said C 1-6 alkyl, C 1-6 cycloalkyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, diazepanyl, oxopyrrolidinyl ring is optionally substituted with one or more groups selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NH-C(=O)-C 1-6 alkyl, -NH-C(=O)-O-C 1-6 alkyl, -NH-C(=O)-haloC 1-6 alkyl, -NH-C(=O)-O-haloC 1- 6alkyl, -NH-C(=O)-O-C 1-3 alkyl-O-C(=O)-C 1-6 alkyl, gem-dimethyl, amino, C 1-6 alkanoyl amino, aminocarbonyl, hydroxyl, oxetanyl amino, C 1-6 alkyl piperazinyl and amino C 1-6 alkyl; preferably said R3is hydroxyl, -NH-C 1-3 alkyl, -NH-C 1-3 alkyl amino, More preferably, said R3is 7. A compound as shown below: and pharmaceutically acceptable salts, esters, prodrugs, solvates, isomers, or isotopic forms thereof.

8. A pharmaceutical composition, characterized by, said pharmaceutical composition comprises a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, an isomer, or an isotopic form thereof, and a pharmaceutically acceptable carrier or excipient; preferably, said pharmaceutical composition is an oral administration formulation, a parenteral administration formulation, or an inhalation spray formulation.

9. Use of a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, an isomer, or an isotopic form thereof, or a composition of claim 8, for the manufacture of a medicament for treating or preventing viral infection in a subject susceptible to or experiencing viral infection, said virus being respiratory syncytial virus.

10. Use of a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, an isomer, or an isotopic form thereof, or a composition of claim 8, for the manufacture of a medicament for treating a respiratory disease in a patient; preferably, said respiratory disease is respiratory syncytial virus infection.

Images