Amine derivatives and their use

Abstract

The application relates to an amine derivative and application thereof. The amine derivative has structural characteristics shown in the following formula (1) or formula (5). The amine derivative has good antiviral activity. (1) (5).

Description

[0001] Related applications

[0002] This application claims priority to Chinese patent application filed on April 14, 2025, with application number 2025104643164 and entitled "Amine Derivatives and Their Applications", the entire contents of which are incorporated herein by reference.

[0003] This application claims priority to Chinese patent application No. 2025117793403, filed on November 28, 2025, entitled "Amine Derivatives and Their Applications", the entire contents of which are incorporated herein by reference. Technical Field

[0004] This application relates to the field of medicinal chemistry, and in particular to an amine derivative and its applications. Background Technology

[0005] Respiratory syncytial virus (RSV) is an RNA virus belonging to the family Pneumoviridae and the genus Orthopneumovirus. It is an infectious respiratory virus that poses a serious threat to the health and lives of children, especially infants under 6 months of age, as well as the elderly (≥65 years of age) and immunocompromised individuals. Furthermore, there is evidence that RSV infection in childhood may trigger persistent or recurrent wheezing and asthma. RSV infection in immunocompromised adults or the elderly may lead to severe exacerbations of conditions such as asthma, chronic obstructive pulmonary disease, congestive heart failure, and even death.

[0006] Existing drugs for combating RSV include antibodies such as palilizumab and nisevizumab, as well as the Arexvy vaccine. However, considering treatment costs, there is still an urgent clinical need for safe, effective, and low-cost small-molecule anti-RSV drugs. Currently, only one small-molecule anti-RSV drug is available on the market—ribavirin. However, it is a nucleoside analogue, which carries the risk of teratogenicity and has relatively weak efficacy. Furthermore, although a number of RSV fusion inhibitors have been disclosed in the literature or patents, they remain unmarketed for various reasons.

[0007] Therefore, it is still necessary to strengthen the development of small molecule drugs against pneumonia viruses (including RSV) to meet urgent clinical needs. Summary of the Invention

[0008] Based on this, this application provides an amine derivative with good antiviral activity and its application.

[0009] A first aspect of this application provides an amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule, wherein the amine derivative has the structural features shown in formula (1) or formula (5):

[0010] (1) (5)

[0011] in,

[0012] X1, X2, X3, and X4 are each independently N or CH;

[0013] R1 and R2 are each independently H, D, halogen, C1~C10 alkyl, C1~C10 alkoxy, C1~C10 alkylthio, or R1 and R2 together with the connected carbon atom to form C3~C10 cycloalkyl or C1~C10 heterocyclic group;

[0014] R3 is a halogen-substituted C1-C10 alkyl, a sulfonyl-substituted C1-C10 alkyl, an ester-substituted C1-C10 alkyl, an amide-substituted C1-C10 alkyl, a heteroatom-substituted C1-C10 alkyl, a heteroatom-substituted fluorinated C1-C10 alkyl, a C3-C10 cycloalkyl-substituted C1-C10 alkyl, a C1-C10 heterocyclic-substituted C1-C10 alkyl, a C1-C10 alkyl, a C3-C10 cycloalkyl, or a C1-C10 heterocyclic group; optionally, R3 is substituted with at least one D or is unsubstituted;

[0015] R4 and R5 can be independently H, D, halogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 alkylthio, or R4 and R5 together with the connected carbon atom can form C3-C10 cycloalkyl or C1-C10 heterocyclic groups.

[0016] R0 is a group represented by formula (2), (3), or (4):

[0017] (2),

[0018] Wherein, ring A2 and ring B2 are each independently substituted or unsubstituted C6~C30 aryl, substituted or unsubstituted C1~C30 heteroaryl, substituted or unsubstituted C1~C30 heterocyclic, or substituted or unsubstituted C3~C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1~C10 alkyl, halogen-substituted C1~C10 alkyl, C1~C10 alkoxy, C1~C10 alkylthio, hydroxyl, C3~C10 cycloalkyl, cyano, and amino.

[0019] (3),

[0020] Wherein, ring A3 and ring B3 are each independently absent, or are substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C1-C30 heteroaryl, substituted or unsubstituted C1-C30 heterocyclic, or substituted or unsubstituted C1-C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; ring A3 and ring B3 are not absent simultaneously;

[0021] Rings A3 and B3 are fused or screwed onto ring Q1;

[0022] Cycle Q1 is a substituted or unsubstituted amide-containing 5-10-membered heteroaryl or 5-10-membered heterocyclic group, wherein each substituent is independently selected from at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; Cycle Q1 may optionally also contain a sulfonyl group;

[0023] (4),

[0024] Wherein, ring A4 and ring B4 are each independently absent, or are substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C1-C30 heteroaryl, substituted or unsubstituted C1-C30 heterocyclic, or substituted or unsubstituted C3-C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; ring A4 and ring B4 are not absent simultaneously;

[0025] Rings A4 and B4 are fused or screwed onto ring Q2;

[0026] Cycle Q2 is a substituted or unsubstituted nitrogen-containing 5-10-membered heteroaryl or 5-10-membered heterocyclic group, wherein each substituent is independently selected from at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; Cycle Q2 may optionally also contain a sulfonyl group;

[0027] R6 is either H or D;

[0028] R7 is a C1~C10 alkyl, C1~C10 deuterated alkyl, or -C(O)OR 71 or -C(O)R 72 ;

[0029] R71 The substituents are C1-C10 alkyl groups, which may be substituted or unsubstituted, and each substituent is an ester-substituted C6-C30 aryl, ester, or C1-C5 alkyl-substituted 5-10 membered heterocyclic group.

[0030] R 72 It is a substituted or unsubstituted C1~C10 alkyl group, and the substituents are each independently an amino group or an amino-substituted amide group.

[0031] A second aspect of this application provides the use of the amine derivatives or their stereoisomers, isotopic derivatives, pharmaceutically acceptable salts, solvates, and prodrug molecules described in the first aspect in the preparation of medicaments for treating and / or preventing viral infections or related diseases caused by viral infections; optionally, the virus includes a pneumonia virus; further optionally, the pneumonia virus includes one or more of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human influenza virus (IV), animal influenza virus (AIV), adenovirus, human parainfluenza virus (HPIVs), mumps virus (MuV), measles virus (HSV), herpesvirus (CMV), and coronavirus; even more optionally, the pneumonia virus includes one or both of respiratory syncytial virus and human metapneumovirus.

[0032] Optionally, the related diseases caused by the viral infection are bronchitis, pneumonia, asthma, or chronic obstructive pulmonary disease.

[0033] A third aspect of this application provides an antiviral pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the amine derivatives or stereoisomers thereof described in the first aspect, isotope derivatives, pharmaceutically acceptable salts, solvates, or prodrug molecules.

[0034] Through rational design of molecular structure, the above-mentioned amine derivatives have been found to effectively inhibit viral proliferation, including the proliferation of respiratory pneumonia virus (respiratory syncytial virus RSV; human metapneumovirus, abbreviated as HMPV), and can exert a good antiviral effect. Detailed Implementation

[0035] The amine derivatives of this application and their applications are further described in detail below with reference to specific embodiments. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0036] 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 herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0037] In this application, terms such as "first aspect," "second aspect," "third aspect," and "fourth aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, terms such as "first," "second," "third," and "fourth" serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0038] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0039] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0040] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0041] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0042] Unless otherwise specified, the temperature parameters in this application may be either constant-temperature processing or processing within a certain temperature range. The constant-temperature processing allows temperature fluctuations within the precision range controlled by the instrument.

[0043] In this application, room temperature generally refers to 4℃~30℃, and preferably 20±5℃.

[0044] In this application, "fusion" means that two rings share at least two ring atoms.

[0045] In this application, "spiking" means that two rings share a single ring atom.

[0046] In this application, "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C1-C10 alkyl," refer to alkyl groups containing 1 to 10 carbon atoms, and each occurrence can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or C10 alkyl. Suitable examples include, but are not limited to: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, octyl, 2-ethylhexyl, isooctyl, tert-octyl, n-nonyl, 2-methyloctyl, 3-methyloctyl, n-decyl, 2-methylnonyl, 3-methylnonyl.

[0047] In this application, "alkoxy" refers to a group with the structure -O-alkyl, that is, an alkyl group as defined above connected to an adjacent group via an oxygen atom. Phrases containing this term, such as "C1-C10 alkoxy," refer to alkyl moieties containing 1 to 10 carbon atoms, i.e., the aforementioned C1-C10 alkyl groups, which, each time appearing, can independently be C1alkoxy, C2alkoxy, C3alkoxy, C4alkoxy, C5alkoxy, C6alkoxy, C7alkoxy, C8alkoxy, C9alkoxy, and C10alkoxy. Suitable examples include, but are not limited to, methoxy, ethoxy, and tert-butoxy.

[0048] In this application, "alkylthio" refers to a group having the structure -S-alkyl, i.e., an alkyl group as defined above is attached to an adjacent group in the parent nucleus structure via a sulfur atom. Phrases containing this term, such as "C1~C10 alkylthio," refer to alkyl moieties containing 1 to 10 carbon atoms, i.e., the aforementioned C1~C10 alkyl groups, which, each time appearing, can independently be C1 alkylthio, C2 alkylthio, C3 alkylthio, C4 alkylthio, C5 alkylthio, C6 alkylthio, C7 thiooxy, C8 alkylthio, C9 alkylthio, and C10 alkylthio. Suitable examples include, but are not limited to: methylthio (-S-CH3 or -SMe), ethylthio (-S-CH2CH3 or -SEt), and tert-butylthio (-SC(CH3)3 or -StBu).

[0049] In this application, "cycloalkyl" refers to a non-aromatic hydrocarbon containing a ring of carbon atoms, which can be a monocycloalkyl, spirocycloalkyl, or bridged cycloalkyl. Phrases containing this term, such as "C3-C10 cycloalkyl," refer to cycloalkyl compounds containing 3 to 10 carbon atoms, and each occurrence can independently be C3, C4, C5, C6, C7, C8, C9, or C10 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Additionally, "cycloalkyl" may also contain one or more double bonds; representative examples of cycloalkyl compounds containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.

[0050] In this application, "heterocyclic group" refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom, which can be an N atom, O atom, S atom, etc., and can be a saturated ring or a partially unsaturated ring. Phrases containing this term, such as "C1-C10 heterocyclic group," refer to heterocyclic groups containing 1 to 10 carbon atoms, and each occurrence can independently be a C1 heteroalkyl, C2 heteroalkyl, C3 heteroalkyl, C4 heteroalkyl, C5 heteroalkyl, C6 heteroalkyl, C7 heteroalkyl, C8 heteroalkyl, C9 heteroalkyl, or C10 heteroalkyl. Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, oxoheterocyclic butyl, azaheterocyclic butyl, thioheterocyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, or tetrahydrothiazolyl.

[0051] In this application, "sulfonyl group" refers to -S(O)2- or -S(O)2R`, depending on its position in the group. For example, when it is at the end, it can be -S(O)2R`, where R` can be a C1~C5 alkyl group.

[0052] In this application, "ester group" refers to -C(O)O-, -C(O)OR` or -OC(O)R`, depending on its position in the group. For example, when it is an end group, it can be -C(O)2R` or -OC(O)R`, where R` can be a C1~C5 alkyl group.

[0053] In this application, "amide group" refers to -C(O)-NH-, -C(O)-NHR` or -NHC(O)R`, depending on its position in the group. For example, when it is at the end, it can be -C(O)-NHR` or -NHC(O)R`, where R` can be a C1~C5 alkyl group.

[0054] In this application, "heteroatom" refers to N atom, O atom or S atom, and heteroatom-substituted C1~C10 alkyl means that a heteroatom, such as -N-, -O- or -S-, is inserted into the chain segment of C1~C10 alkyl.

[0055] In this application, "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom. It can be a monocyclic aryl, a fused-ring aryl, or a polycyclic aryl. For polycyclic rings, at least one is an aromatic ring system. For example, "C6-C30 aryl" refers to an aryl group containing 6 to 30 carbon atoms, and each occurrence can be independently C6, C7, C8, C9, C10, C12, C15, C18, C20, C22, C25, C28, or C30 aryl. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, dinaphthalene, triphenylene, and their derivatives.

[0056] In this application, "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, which can be an N atom, an O atom, an S atom, etc. For example, "C1~C30 heteroaryl" refers to a heteroaryl group containing 1 to 30 carbon atoms, and each occurrence can be independently of each other as C1 heteroaryl, C2 heteroaryl, C3 heteroaryl, C4 heteroaryl, C5 heteroaryl, C6 heteroaryl, C7 heteroaryl, C8 heteroaryl, C9 heteroaryl, C10 heteroaryl, C12 heteroaryl, C15 heteroaryl, C18 heteroaryl, C20 heteroaryl, C22 heteroaryl, C25 heteroaryl, C28 heteroaryl, and C30 heteroaryl. Suitable examples include, but are not limited to: furanyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrroleyl, pyrazolyl, triazolyl, imidazoyl, oxazolyl, oxadiazolyl, thiazoyl, tetrazolyl, indolyl, carbazoyl, pyrroloimidazoyl, pyrrolopyrroleyl, thiophenolopyrroleyl, thiophenolothiophenyl, furanolopyrroleyl, furanolofuranyl, thiophenolofuranyl, benzoisooxazolyl, benzoisothiazoyl, benzoimidazoyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, o-diazanaphthyl, quinoxalinyl, phenanthridine, primidinyl, quinazolinyl, and quinazolinoneyl.

[0057] In this application, "halogen" refers to F, Cl, Br, or I.

[0058] In this application, "pharmaceutically acceptable" means those ligands, materials, compositions, and / or dosage forms that are suitable for administration to patients within the bounds of reasonable medical judgment and that are commensurate with a reasonable benefit / risk ratio.

[0059] In this application, "pharmaceutically acceptable salt" refers to a salt formed by any compound in the indicated structure with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. One type of salt is the salt formed by the compounds of this invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another type of salt is the salt formed by the compounds of the present invention with a base. Suitable bases for forming salts include, but are not limited to: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0060] In this application, "isotope derivatives" can be deuterides or tritides.

[0061] In the application, the wavy line in the group or structure " "Represents the key connection position.

[0062] Some examples of this application provide an amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule having the structural features shown in formula (1) or formula (5) below:

[0063] (1) (5)

[0064] in,

[0065] X1, X2, X3, and X4 are each independently N or CH;

[0066] R1 and R2 are each independently H, D, halogen, C1~C10 alkyl, C1~C10 alkoxy, C1~C10 alkylthio, or R1 and R2 together with the connected carbon atom to form C3~C10 cycloalkyl or C1~C10 heterocyclic group;

[0067] R3 is a halogen-substituted C1-C10 alkyl, a sulfonyl-substituted C1-C10 alkyl, an ester-substituted C1-C10 alkyl, an amide-substituted C1-C10 alkyl, a heteroatom-substituted C1-C10 alkyl, a heteroatom-substituted fluorinated C1-C10 alkyl, a C3-C10 cycloalkyl-substituted C1-C10 alkyl, a C1-C10 heterocyclic-substituted C1-C10 alkyl, a C1-C10 alkyl, a C3-C10 cycloalkyl, or a C1-C10 heterocyclic group; optionally, R3 is substituted with at least one D or is unsubstituted;

[0068] R4 and R5 can be independently H, D, halogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 alkylthio, or R4 and R5 together with the connected carbon atom can form C3-C10 cycloalkyl or C1-C10 heterocyclic groups.

[0069] R0 is a group represented by formula (2), (3), or (4):

[0070] (2),

[0071] Wherein, ring A2 and ring B2 are each independently substituted or unsubstituted C6~C30 aryl, substituted or unsubstituted C1~C30 heteroaryl, substituted or unsubstituted C1~C30 heterocyclic, or substituted or unsubstituted C3~C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1~C10 alkyl, halogen-substituted C1~C10 alkyl, C1~C10 alkoxy, C1~C10 alkylthio, hydroxyl, C3~C10 cycloalkyl, cyano, and amino.

[0072] (3),

[0073] Wherein, ring A3 and ring B3 are each independently absent, or are substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C1-C30 heteroaryl, substituted or unsubstituted C1-C30 heterocyclic, or substituted or unsubstituted C1-C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; ring A3 and ring B3 are not absent simultaneously;

[0074] Rings A3 and B3 are fused or screwed onto ring Q1;

[0075] Cycle Q1 is a substituted or unsubstituted amide-containing 5-10-membered heteroaryl or 5-10-membered heterocyclic group, wherein each substituent is independently selected from at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; Cycle Q1 may optionally also contain a sulfonyl group;

[0076] (4),

[0077] Wherein, ring A4 and ring B4 are each independently absent, or are substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C1-C30 heteroaryl, substituted or unsubstituted C1-C30 heterocyclic, or substituted or unsubstituted C3-C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; ring A4 and ring B4 are not absent simultaneously;

[0078] Rings A4 and B4 are fused or screwed onto ring Q2;

[0079] Cycle Q2 is a substituted or unsubstituted nitrogen-containing 5-10-membered heteroaryl or 5-10-membered heterocyclic group, wherein each substituent is independently selected from at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; Cycle Q2 may optionally also contain a sulfonyl group;

[0080] R6 is either H or D;

[0081] R7 is a C1~C10 alkyl, C1~C10 deuterated alkyl, or -C(O)OR 71 or -C(O)R 72 ;

[0082] R 71 The substituents are C1-C10 alkyl groups, which may be substituted or unsubstituted, and each substituent is an ester-substituted C6-C30 aryl, ester, or C1-C5 alkyl-substituted 5-10 membered heterocyclic group.

[0083] R 72 It is a substituted or unsubstituted C1~C10 alkyl group, and the substituents are each independently an amino group or an amino-substituted amide group.

[0084] Understandably, a compound with the structural features shown in formula (5) can be a prodrug molecule of the compound shown in formula (1), which is metabolized in vivo to the compound shown in formula (1) to exert its pharmacological effect. As an example, pharmacokinetic experiments have confirmed that the compound… It can be metabolized into compounds in the body. It plays a role.

[0085] In some of these examples, X1, X2, and X3 are CH in equation (1).

[0086] In some of these examples, X4 is N in equation (5).

[0087] In some of these examples, in formula (5), R6 is H or D; R7 is a C1-C3 alkyl group, a C1-C3 deuterated alkyl group, or one of the following groups:

[0088] , , , , , , , , .

[0089] In some of these examples, R1 and R2 are independently H, D, halogen, C1-C3 alkyl, or R1 and R2 together with the connected carbon atom to form a C3-C4 cycloalkyl group.

[0090] Without restrictions, for , , , , , , or .

[0091] In some of these examples, R3 is: -(CH2) n1 -CF3, -(CH2) n2 -S(O)2-(CH2) n3 -CH3 or -(CH2) n4 -O-CF3,

[0092] Where n1, n2, and n4 are each an integer from 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7, and 8;

[0093] Each of n3 is an independent integer from 0 to 3, such as 0, 1, 2, 3.

[0094] Optionally, R3 may be substituted by at least one D or may not be substituted.

[0095] Without restriction, R3 is , , , , or .

[0096] In some of these examples, R4 and R5 are each independently H, D, or C1-C3 alkyl groups.

[0097] Furthermore, in some of these examples, formula (2) is selected from one of the following groups:

[0098]

[0099] Where each m is an independent integer from 1 to 5;

[0100] X 22 Each can be either N or CR independently;

[0101] W can be independently O, S, Se, or NR;

[0102] R can be H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano or amino.

[0103] In some of these examples, equation (2) is selected from one of the following groups:

[0104] , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0105] In some of these examples, in formula (2), R is independently H, F, Br, I, methoxy, hydroxy, methyl, cyclopropyl, or cyano; m is 1.

[0106] In some of these examples, in equation (3), ring A3 and ring B3 are each independently substituted or unsubstituted C6~C30 aryl or substituted or unsubstituted C1~C30 heteroaryl fused to ring Q1.

[0107] In some of these examples, in equation (3), one of ring A3 and ring B3 is a substituted or unsubstituted C6~C30 aryl or a substituted or unsubstituted C1~C30 heteroaryl fused to ring Q1, and the other is absent.

[0108] In some of these examples, equation (3) is selected from one of the following groups:

[0109]

[0110]

[0111]

[0112]

[0113] in,

[0114] X 33 Each can be either N or CR independently;

[0115] Y can be independently O, S, Se, or NR;

[0116] Z can be independently O, S, Se, NR or -S(O)2-;

[0117] T can be independently O, S, Se, NR or -C(R)2-;

[0118] R can be H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano or amino.

[0119] In some of these examples, X in equation (3) 33 For CR, Y is independently S or NR; or selected from one of the following groups:

[0120] , , , , , , , , , , .

[0121] In some of these examples, in formula (3), R is independently H, F, methyl, Cl, Br, cyano, methoxy, or trifluoromethyl.

[0122] In some of these examples, in equation (4), ring A4 and ring B4 are each independently substituted or unsubstituted C6~C30 aryl or substituted or unsubstituted C1~C30 heteroaryl fused to ring Q2.

[0123] In some of these examples, in equation (4), one of ring A4 and ring B4 is a substituted or unsubstituted C6~C30 aryl group or a substituted or unsubstituted C1~C30 heteroaryl group fused to ring Q2, and the other is absent.

[0124] In some of these examples, equation (4) is selected from one of the following groups:

[0125]

[0126]

[0127]

[0128]

[0129] in,

[0130] X 44 Each can be either N or CR independently;

[0131] Y can be independently O, S, Se, or NR;

[0132] Z can be independently O, S, Se, NR or -S(O)2-;

[0133] T can be independently O, S, Se, NR or -C(R)2-;

[0134] R can be H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano or amino.

[0135] In some of these examples, equation (4) is selected from one of the following groups:

[0136] , , .

[0137] Without limitation, this application provides one of the following compounds:

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219] Other examples of this application provide the use of amine derivatives or their stereoisomers, isotopic derivatives, pharmaceutically acceptable salts, solvates, and prodrug molecules as described above in the preparation of medicaments for treating and / or preventing viral infections; optionally, the virus includes pneumonia virus; further optionally, the pneumonia virus includes one or more of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human influenza virus (IV), animal influenza virus (AIV), adenovirus, human parainfluenza virus (HPIVs), mumps virus (MuV), measles virus (HSV), herpesvirus (CMV), and coronavirus; even more optionally, the pneumonia virus includes one or both of respiratory syncytial virus and human metapneumovirus.

[0220] Other examples of this application provide the use of amine derivatives or their stereoisomers, isotopic derivatives, pharmaceutically acceptable salts, solvates, and prodrug molecules as described above in the preparation of medicaments for the prevention and / or treatment of diseases caused by viral infections; optionally, the virus includes pneumonia virus; further optionally, the pneumonia virus includes one or more of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human influenza virus (IV), animal influenza virus (AIV), adenovirus, human parainfluenza virus (HPIVs), mumps virus (MuV), measles virus (HSV), herpesvirus (CMV), and coronavirus; even more optionally, the pneumonia virus includes one or both of respiratory syncytial virus and human metapneumovirus.

[0221] Other examples of this application provide an antiviral pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, said active ingredient comprising the amine derivatives or stereoisomers thereof described in the first aspect, isotope derivatives, pharmaceutically acceptable salts, solvates, or prodrug molecules.

[0222] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0223] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0224] Example 1: Synthesis of compound R823

[0225]

[0226] Step 1: Under room temperature water bath conditions, mix raw material A (1.60 g, 9.63 mmol), acetonitrile (6 mL), and 4,4,4-trifluoro-1-butylamine hydrochloride (1.80 g, 11.0 mmol). Add triethylamine (3.00 g, 29.65 mmol) dropwise. After the addition is complete, stir for 5 minutes. First, heat to 50°C in a microwave for 15 minutes, then continue heating to 80°C for another 15 minutes. When thin-layer chromatography detects that raw material A no longer decreases, stop the reaction. Concentrate the reaction solution to remove acetonitrile and excess triethylamine. Add water (20 mL) to disperse the solid. Then, add a solution prepared from NaHCO3 (30 mmol) and water (30 mL). Collect the yellow solid by filtration and wash the filter cake with water four times to obtain yellow solid compound B (2.50 g, yield 95%).

[0227] Step 2: Under room temperature water bath and nitrogen protection, compound B (1.10 g, 4.03 mmol), methanol (70 mL), and ammonium formate (2.0 g, 15.86 mmol) were mixed, and palladium on carbon catalyst (0.20 g) was added. The mixture was stirred at room temperature until the amount of starting material compound B no longer decreased as detected by thin-layer chromatography, at which point the reaction was stopped. The filtrate was collected by suction filtration, and the filter cake was washed with ethanol and water successively. The filtrate was concentrated. The concentrated residue was mixed with petroleum ether, ethyl acetate, and water and stirred to separate the layers. The organic phase was temporarily stored, and the aqueous phase was extracted with a mixture of petroleum ether and ethyl acetate until no product was detected by thin-layer chromatography. All organic phases were combined, washed with water, and concentrated to obtain the crude product, a brownish-brown solid compound C (0.90 g, yield 92%).

[0228] Step 3: Under room temperature water bath and nitrogen protection, compound C (0.90 g, 3.70 mmol), dichloromethane (15 mL), and acetoxyacetyl chloride (0.51 g, 3.70 mmol) were added sequentially to the reaction flask. Triethylamine (0.75 g, 7.40 mmol) was added dropwise. The mixture was stirred at room temperature for 12 h. When thin-layer chromatography showed that compound C no longer decreased, the reaction was stopped. The reaction solution was concentrated to obtain a paste-like residue, crude compound D (theoretical value 1.27 g, yield 100%), which was directly used in the next step of the reaction.

[0229] Step 4: Under nitrogen protection, compound D (theoretical value 1.27 g, 3.70 mmol) was mixed with glacial acetic acid (20 mL), and the mixture was heated in an oil bath at 80°C for 10 hours. The reaction was stopped when thin-layer chromatography showed no further decrease in the amount of starting compound D. The reaction solution was then distilled under reduced pressure to remove the solvent glacial acetic acid. The solution was then mixed with ethyl acetate (20 mL) and a saturated sodium bicarbonate solution (20 mL), and the system was adjusted to a weakly alkaline state with solid sodium bicarbonate. The mixture was separated, the organic phase was temporarily stored, and the aqueous phase was extracted with ethyl acetate. All organic phases were then combined, concentrated, and separated by silica gel column chromatography. The eluent was petroleum ether:ethyl acetate = 1:1. The main product was collected and concentrated to obtain a brown solid compound E (1.20 g, 100% yield).

[0230] Step 5: Under room temperature water bath and nitrogen protection, compound E (4.77 g, 14.64 mmol), methanol (40 mL), and potassium carbonate (6.00 g, 43.41 mmol) were added sequentially to the reaction flask. The mixture was stirred at room temperature until the amount of starting material compound E no longer decreased as detected by thin-layer chromatography, at which point the reaction was stopped. The filtrate was collected by suction filtration, and the filter cake was washed with methanol. The filtrates were combined and concentrated. The crude product was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent. The main product was collected and concentrated to give a light yellow solid compound F (3.80 g, yield 91%).

[0231] Step 6: Prepare a solution of compound F (5.0 g, 17.65 mmol) with methanol (50 mL), tetrahydrofuran (25 mL), and 36% concentrated hydrochloric acid (12 mL). Add 10% palladium hydroxide (1.10 g, containing about 50% water) supported on activated carbon catalyst. Replace the gas in the bottle three times with nitrogen balloons and hydrogen balloons respectively. Stir the reaction at room temperature under a hydrogen atmosphere for 24 hours, then reduce the cyano group with hydrogen. Thin-layer chromatography detects a small amount of raw material remaining, and then stop the reaction. The catalyst was removed by diatomaceous earth filtration. The pH was adjusted to a weakly alkaline state of 7-8 with sodium bicarbonate and a small amount of sodium carbonate solid. The solvent was removed by vacuum distillation. The solid residue was washed repeatedly with anhydrous ethanol by stirring. The solution was collected by filtration, concentrated, and then subjected to silica gel column chromatography. Elution was performed using dichloromethane:methanol:20% ammonia in a ratio of 40:4:1 to 40:8:1. The main product was collected and concentrated to give a gray solid compound G (3.40 g, yield 67%). LC-MS (ESI): m / z 288.0 [M+H] + .

[0232] Step 7: Under water bath and nitrogen protection, the starting compound G (1.50 g, 5.22 mmol) was mixed with dichloromethane (30 mL) and N,N-dimethylformamide (10 mL). Di-tert-butyl dicarbonate (2.00 g, 9.16 mmol) was added in multiple batches. The mixture was stirred at room temperature for 4 hours. The reaction was stopped when thin-layer chromatography showed no further decrease in starting compound A. 30 mL of water was added to the reaction system, and the mixture was stirred and filtered to collect the solid product. The aqueous phase was extracted with dichloromethane. All organic phases were combined and washed with a small amount of water. The organic phase was concentrated and combined with the solid filter cake. Finally, silica gel column chromatography was performed. The eluent was dichloromethane:methanol = 10:1. The main product was collected and concentrated to give a brown solid compound H (1.60 g, yield 79%). LC-MS (ESI): m / z 388.2 [M+H] + .

[0233] Step 8: Under room temperature water bath and nitrogen protection, compound H (0.80 g, 2.07 mmol), tetrahydrofuran (20 mL), and diisopropylethylamine (1.07 g, 8.26 mmol) were added sequentially to the reaction flask. Methanesulfonyl chloride (0.35 g, 3.10 mmol) was added dropwise. The mixture was stirred at room temperature for 12 hours. When the starting compound H was nearly eliminated by thin-layer chromatography, the reaction was stopped. After the reaction was complete, the reaction solution was added dropwise to a mixture of saturated sodium chloride solution (10 mL) and ethyl acetate (10 mL). The pH was adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, the organic phase was temporarily stored, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and then chromatographically analyzed using silica gel column chromatography. The eluent was dichloromethane:methanol = 30:1 to 20:1. The main product was collected and concentrated to give a light brown solid compound I (0.80 g, 95% yield). LC-MS (ESI): m / z 406.10 [M+H] + .

[0234] Step 9: Under oil bath and nitrogen protection, compound I (0.020 g, 0.05 mmol), compound J (0.011 g, 0.06 mmol), and potassium carbonate (0.028 g, 0.20 mmol) were added sequentially to the reaction flask. The mixture was heated in an oil bath at 120°C for 8 hours. The reaction was stopped when thin-layer chromatography showed no further decrease in the amount of starting material compound I. After the reaction was complete, the reaction solution was added dropwise to a mixture of water (10 mL) and ethyl acetate (10 mL). The mixture was stirred and separated. The organic phase was temporarily stored, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried, concentrated, and then chromatographically analyzed using a silica gel plate. The eluent was dichloromethane:ethyl acetate = 2:1. The main product was collected to give a pale yellow solid compound K (0.020 g, yield 73%). LC-MS (ESI): m / z 556.22 [M+H] + .

[0235] Step 10: Under room temperature water bath and nitrogen protection conditions, compound K (0.020 g, 0.036 mmol) and ethanol (1.0 mL) were added sequentially to the reaction flask, followed by the addition of ethyl acetate solution of hydrogen chloride (10.0 mL, 20.00 mmol). The mixture was stirred at room temperature until the reaction of starting compound K no longer decreased as detected by thin-layer chromatography, at which point the reaction was stopped. The pH was adjusted to 7-8 with sodium bicarbonate solution, the solvent was removed by vacuum distillation, and the solid residue was washed with ethanol (10 mL) until no product was detected. The filtrate was collected, concentrated, and chromatographically analyzed using silica gel plates. The eluent was dichloromethane:methanol:20% ammonia water = 40:4:1. The main product (0.006 g, yield 37%) was collected.

[0236]

[0237] Compound R823: 1 H NMR (600 MHz, Chloroform-d) δ 8.42-8.39 (m, 2H), 8.13(d, J = 12.0 Hz, 1H), 7.52 (s, 1H), 7.47 (t, J = 12.0 Hz, 1H), 7.33 (t, J =12.0 Hz, 1H),, 7.19 (d, J = 18.0 Hz, 2H), 5.69 (s, 2H), 4.31 (t, J = 12.0 Hz,2H), 3.83 (s, 2H), 2.13 – 2.03 (m, 2H), 1.87 -1.83 (m, 2H) . LC-MS(ESI): m / z456.21 [M+H] + .

[0238] The compounds in the following examples are synthesized using the same method as in Example 1, except that the starting materials in Example 1 are replaced with the corresponding starting materials.

[0239] Example 2: Synthesis of compound R198

[0240]

[0241] Compound R198: 1 H NMR (600 MHz, DMSO-d6) δ 8.55 (s, 2H), 7.94 (d, J =8.6 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.57 (q, J = 7.6 Hz,1H), 7.41 (dd, J = 14.7, 8.2 Hz, 2H), 4.32 (d, J = 8.1 Hz, 2H), 4.09 (s, 2H),3.84 (s, 2H), 3.63 (s, 2H), 3.53 (s, 2H), 3.37 (s, 2H), 2.35 – 2.28 (m, 2H),1.90 (d, J = 9.6 Hz, 2H). LCMS(ESI): m / z 467.0[M+H] + .

[0242] Example 3: Synthesis of compound R824

[0243]

[0244] Compound R824: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 7.80 (d, J = 5.0Hz, 1H), 7.72 – 7.66 (m, 1H), 7.52 – 7.47 (m, 2H), 7.44 (dd, J = 10.1, 1.8Hz, 1H), 7.26 (q, J = 4.0, 3.5 Hz, 2H), 4.56 (d, J = 3.5 Hz, 2H), 4.45 – 4.25(m, 2H), 4.12 (d, J = 11.1 Hz, 2H), 3.88 (d, J = 6.2 Hz, 2H), 3.12 (dd, J =50.2, 4.8 Hz, 2H), 2.85 (d, J = 4.9 Hz, 2H), 2.34 – 2.26 (m, 2H), 1.96 (dd, J= 18.4, 11.2 Hz, 2H). LCMS(ESI): m / z 435.0[M+H] + .

[0245] Example 4: Synthesis of compound R205

[0246]

[0247] Compound R205: 1 H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 2H), 7.85 (dd, J =8.0, 1.8 Hz, 1H), 7.72 – 7.59 (m, 4H), 7.43 – 7.37 (m, 4H), 7.30 (d, J = 5.5Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.60 (s, 2H), 4.46 (t, J = 7.5 Hz, 2H), 4.09 (s, 2H), 2.45 – 2.36 (m, 2H), 2.06 (d, J = 9.0 Hz, 2H). LCMS(ESI): m / z481.0[M+H] + .

[0248] Example 5: Synthesis of compound R203

[0249]

[0250] Compound R203: 1H NMR (500 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.50 (d, J = 8.5Hz, 2H), 7.27 (d, J = 6.7 Hz, 2H), 7.18 – 7.12 (m, 5H), 7.04 – 6.99 (m, 2H), 6.86 (t, J = 7.6 Hz, 1H),, 4.71 (s, 2H), 4.43 (s, 2H), 4.28 (t, J = 8.0 Hz,2H), 3.95 (s, 2H), 2.20 – 2.15 (m, 2H), 1.88 (d, J = 7.8 Hz, 2H). LCMS(ESI):m / z 467[M+H] + .

[0251] Example 6: Synthesis of compound R197

[0252]

[0253] Compound R197: 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.41 (s,1H), 7.28 (s, 2H), 7.15 (s, 3H), 5.12 (s, 2H), 4.08-3.95 (m, 2H), 2.29 (s,2H), 2.08 (s, 2H), 1.90-1.75 (m, 2H), 1.45 – 1.29 (m, 4H), 1.30-1.17 (m, 2H).LCMS(ESI): m / z 431[M+H] + .

[0254] Example 7: Synthesis of compound R120

[0255]

[0256] Compound R120: 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 5.5 Hz, 2H), 8.39(d, J = 7.5 Hz, 1H), 7.91 (t, J = 7.5 Hz, 1H), 7.68 (t, J = 9.0 Hz, 3H), 7.55(s, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.41 – 7.33 (m, 2H), 5.93 (s, 2H), 4.52(t, J = 8.0 Hz, 2H), 4.01 (s, 2H), 2.45 – 2.37 (m, 2H), 1.98 (t, J = 8.2 Hz,2H). LCMS(ESI): m / z 465.0 [M+H] + .

[0257] Example 8: Synthesis of compound R114

[0258]

[0259] Compound R114: 1 H NMR (600 MHz, DMSO-d6) δ 8.13 (d, J = 7.9 Hz, 1H), 7.99– 7.84 (m, 2H), 7.62-7.50 (m, 3H), 7.36 (d, J = 6.0 Hz, 2H), 7.21 (d, J = 7.9Hz, 1H), 5.90 (s ,2H), 4.49 (t, J = 8.4 Hz, 2H), 3.77 (s, 2H), 2.42 – 2.34(m, 2H), 2.07 – 1.95 (m, 2H). LCMS(ESI) : m / z 471[M+H] + .

[0260] Example 9: Synthesis of compound R825

[0261]

[0262] Compound R825: 1H NMR (600 MHz, DMSO-d6) δ 7.75 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 2H), 7.51 – 7.48 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.10 (t,J = 9.0 Hz, 1H), 5.56 (s, 2H), 4.45 (t, J = 7.7 Hz, 2H), 3.96 (s, 2H), 2.44 –2.38 (m, 2H), 1.96 (t, J = 8.1 Hz, 2H). LCMS(ESI): m / z 439[M+H] + .

[0263] Example 10: Synthesis of compound R826

[0264]

[0265] Compound R826: 1 H NMR (600 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.68 (d, J = 8.3Hz, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.53 – 7.44 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H), 5.57 (s, 2H), 5.10 (m, 2H), 4.46 (t, J = 9.0 Hz, 2H), 4.02 (t, J = 9.0Hz, 2H), 3.15 (s, 2H), 2.41-2.36 (m, 2H), 2.02-1.88 (s, 2H). LCMS(ESI): m / z449[M+H] + .

[0266] Example 11: Synthesis of compound R75

[0267]

[0268] Compound R75: 1H NMR (600 MHz, Methanol d4) δ 7.75 (s, 1H), 7.69 (d, J =8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.21 (h, J = 5.9 Hz, 6H), 6.84 (s,1H), 5.50 (s, 2H), 4.53 (q, J = 8.0 Hz, 2H), 4.26 (s, 2H), 2.36–2.30 (m, 2H), 2.09 (t, J = 8.4 Hz, 2H). HRMS (ESI): m / z [M + H]+ = 551.07.

[0269] Example 12: Synthesis of compound R827

[0270]

[0271] Compound R827: 1 H NMR (600 MHz, DMSO-d6) δ 8.03 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J = 6.0Hz, 1H), 7.35-7.29 (m, 2H), 7.24 (t, J = 6.0 Hz, 1H), 6.92 (d, J = 6.0 Hz,1H), 5.87 (s, 2H), 4.50 (t, J = 9.0 Hz, 2H), 4.11 (s, 3H), 3.95 (s, 2H), 2.46– 2.34 (m, 2H), 1.97 – 1.89 (m, 2H). LCMS(ESI): m / z 468[M+H] + .

[0272] Example 13: Synthesis of compound R828

[0273]

[0274] Compound R828: 1H NMR (600 MHz, Methanol-d4) δ 8.30 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.91 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.57 (d, J =12.0 Hz, 1H), 7.55 (s, 1H), 7.53 (t, J = 6.0 Hz, 1H), 7.36(d, J =12.0 Hz, 1H), 6.27 (d, J = 6.0 Hz, 1H), 5.67 (s, 2H), 4.49 (t, J =9.0 Hz, 2H), 3.96 (s, 2H), 2.38 – 2.27 (m, 2H), 2.08-2.04 (m, 2H). LCMS(ESI): m / z 455.41[M+H] + .

[0275] Example 14: Synthesis of compound R829

[0276]

[0277] Compound R829: 1 H NMR (600 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.86 (d, J= 6.0 Hz, 1H), 7.73 (s, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.38 (t, J = 6.0 Hz,1H), 7.32 – 7.27 (m, 2H), 7.23 (d, J =12 Hz, 1H), 6.80 (d, J =6.0 Hz, 1H), 6.32 (s, 2H), 4.37(t, J = 9.0 Hz, 2H), 4.00 (s, 2H), 2.02 – 1.95 (m, 2H),1.75-1.69 (m, 2H). LCMS(ESI): m / z 454.25 [M+H] + .

[0278] Example 15: Synthesis of compound R830

[0279]

[0280] Compound R830: 1H NMR (600 MHz, Chloroform-d) δ 8.37 (d, J = 6.0 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7.99 (s, 1H), 7.88 (t, J = 6.0 Hz, 1H), 7.58(s, 1H), 7.54(t, J = 6.0 Hz, 1H), 7.30 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 6.0Hz, 1H), 5.72 (s, 2H), 4.49 (t, J =9.0 Hz, 2H), 3.91 (s, 2H), 2.31-2.26 (m,2H), 2.26 – 2.20 (m, 2H). LCMS(ESI): m / z 456.42 [M+H] + .

[0281] Example 16: Synthesis of compound R831

[0282]

[0283] Compound R831: 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (d, J = 6.0 Hz, 1H), 7.85 (d, J =6.0 Hz, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.55 (s, 1H), 7.44(t, J = 6.0 Hz, 1H), 7.27 (d, J = 6.0 Hz, 1H), 7.22 – 7.19 (m, 2H), 7.06(d, J = 6.0 Hz, 1H), 5.92 (s, 2H), 4.30(t, J = 9.0 Hz, 1H), 3.87 (s, 2H),2.02 – 1.94 (m, 2H), 1.62-1.57 (m, 2H). LCMS(ESI): m / z 455.48 [M+H] + .

[0284] Example 17: Synthesis of compound R832

[0285]

[0286] Compound R832: 1H NMR (600 MHz, Chloroform-d) δ 7.81 (d, J = 6.0 Hz, 1H), 7.75 (d, J = 6.0 Hz, 1H) , 7.56(s, 1H), 7.55 (t, J = 6.0 Hz, 1H) , 7.28(t, J = 6.0 Hz, 1H), 7.24-7.12 (m, 3H), 6.73 (d, J =6.0 Hz, 1H), 6.15 (s,2H), 4.27(t, J = 9.0 Hz, 2H), 3.91 (s, 2H), 1.96– 1.76 (m, 2H), 1.63-1.49 (m,2H). LCMS(ESI) : m / z 454.47 [M+H] + .

[0287] Example 18: Synthesis of compound R834

[0288]

[0289] Compound R834: 1 H NMR (600 MHz, Chloroform-d) δ 8.39 (s, 1H), 8.27 (d, J= 6.0 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.64 (d, J = 12.0 Hz, 1H), 7.57 (s,1H), 7.53(t, J = 6.0 Hz, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.29 (d, J =6.0 Hz,1H), 7.23 (d, J = 6.0 Hz, 1H), 5.86 (s, 2H), 4.40 (t, J = 6.0 Hz, 2H), 3.93(s, 2H), 2.20 – 2.08 (m, 4H). LCMS(ESI): m / z 456.42 [M+H] + .

[0290] Example 19: Synthesis of compound R835

[0291]

[0292] Compound R834: 1H NMR (600 MHz, Chloroform-d) δ 8.26 (d, J = 6.0 Hz, 1H),7.94-7.67 (m, 2H), 7.66-7.40(m, 2H), 7.35 (t, J = 6.0 Hz, 1H), 6.95-6.42 (m,3H), 5.77 (s, 2H), 4.26 (t, J = 6.0 Hz, 2H), 3.87 (s, 2H), 2.20 – 1.67 (m,4H). LCMS(ESI) : m / z 455.48 [M+H] + .

[0293] Example 20: Synthesis of compound R836

[0294]

[0295] 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (d, J =6.0 Hz, 1H), 7.92 (s,1H), 7.72 (d, J = 6.0 Hz, 1H), 7.61 (s, 1H), 7.57-7.51 (m, 2H), 7.30 (t, J =6.0 Hz, , 1H), 7.23 – 7.19 (m, 2H), 5.84 (s, 2H), 4.30 (t, J = 6.0 Hz, 2H), 3.93 (s, 2H), 2.17 – 2.03 (m, 4H). LCMS(ESI) : m / z 455.12 [M+H] + .

[0296] Example 21: Synthesis of compound R839

[0297]

[0298] Compound R839: 1H NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.13 (dd, J =7.8, 1.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.45(s, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.5 Hz, 1H), 5.81 (s,2H), 4.46 (t, J = 7.6 Hz, 2H), 4.12 (s, 3H), 3.83 (s, 2H), 2.39 (dt, J =10.7, 6.3 Hz, 2H), 1.96 – 1.91 (m, 2H). LC-MS (ESI): m / z 469.19 [M+H] + .

[0299] Example 22: Synthesis of compound R840

[0300]

[0301] Compound R840: 1 H NMR (600 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.96 – 7.93 (m,1H), 7.59 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 3.6 Hz,1H), 7.29 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.79(s, 2H), 4.43 – 4.38 (m, 2H), 4.13 (s, 3H), 3.57 (s, 2H), 2.40 – 2.36 (m,2H), 1.90 (t, J = 8.6 Hz, 2H). LC-MS (ESI): m / z 469.19 [M+H] + .

[0302] Example 23: Synthesis of compound R841

[0303]

[0304] Compound R841 1H NMR (600 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.13 (dd, J =7.9, 1.4 Hz, 1H), 7.80 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.55(s, 1H), 7.53 (dd, J = 2.8, 1.5 Hz, 1H), 7.53 – 7.50 (m, 1H), 7.44 – 7.40 (m,1H), 6.48 (s, 2H), 4.61 (t, J = 7.8 Hz, 2H), 4.31 (s, 2H), 2.41 – 2.31 (m,2H), 2.06 (dd, J = 10.0, 5.9 Hz, 2H). LC-MS (ESI): m / z 455.18 [M+H] + .

[0305] Example 24: Synthesis of compound R843

[0306]

[0307] Compound R843: 1 H NMR (600 MHz, Methanol-d4) δ 8.81 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 5.5 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J= 4.0 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.38 (d, J = 7.1 Hz, 2H), 7.31 –7.29 (m, 1H), 5.91 (s, 2H), 4.54 – 4.44 (m, 2H), 3.27 (s, 2H), 2.38 – 2.34(m, 2H), 2.16 – 2.14 (m, 2H). LC-MS (ESI): m / z 456.17 [M+H] + .

[0308] Example 25: Synthesis of compound R837

[0309]

[0310] Compound R837: 1H NMR (600 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.77 (s,1H), 7.63 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 11.1 Hz, 1H), 7.43 (d, J = 5.2Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 9.6Hz,1H), 6.82 (d, J = 13.8 Hz, 1H), 5.65 (s, 2H), 4.39 (t, J = 7.7 Hz, 2H),4.03 (s, 2H), 2.53-2.49 (m, 2H), 2.22-2.17 (m, 2H).LC-MS (ESI): m / z 455.20 [M+H] + .

[0311] Example 26: Synthesis of compound R844

[0312]

[0313] Compound R844: 1 H NMR (600 MHz, Chloroform-d) δ 8.46 (d, J = 9.1Hz,1H),, 8.19 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.63 – 7.56 (m,2H), 7.36 (d, J = 8.5 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 5.85 (s, 2H), 4.36 (t, J = 8.0 Hz, 2H), 3.93 (s,2H), 2.14-2.05 (m, 2H), 2.00-1.92 (m, 2H). LC-MS (ESI): m / z 455.24 [M+H] + .

[0314] Example 27: Synthesis of compound R122

[0315]

[0316] Compound R122: 1H NMR (600 MHz, Methanol-d4) δ 8.12 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.59 – 7.53 (m, 2H), 7.50(s, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 2.1Hz, 1H), 5.98 (s, 2H), 4.51 (t, J = 7.7 Hz, 2H), 3.96 (s, 2H), 2.32-2.28 (m,2H), 2.04-2.00 (m, 2H). LC-MS (ESI): m / z 456.0 [M+H] + .

[0317] Example 28: Synthesis of compound R845

[0318]

[0319] Compound R845: 1 H NMR (600 MHz, Methanol-d4) δ 8.23 ​​(d, J = 7.9 Hz, 1H),8.09 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H),7.59 – 7.49 (m, 3H), 7.39 (t, J = 8.4 Hz, 1H), 7.33 (d, J =7.8 Hz, 1H), 6.01(s, 2H), 4.51 (t, J = 7.7 Hz, 2H), 3.93 (s, 2H), 2.29-2.25 (m, 2H), 2.10 –1.91 (m, 2H). LC-MS (ESI): m / z 471.2 [M+H] + .

[0320] Example 29: Synthesis of compound R116

[0321]

[0322] Compound R116: 1H NMR (600 MHz, Methanol-d4) δ 7.81 (s, 1H), 7.69 – 7.62(m,3H), 7.58 – 7.54 (m, 2H), 7.52 – 7.49 (m,1H), 7.41 (d, J = 8.4 Hz, 1H), 6.01 (s, 2H), 4.57 (t, J = 7.7 Hz, 2H), 4.17 (s, 2H), 2.44 – 2.26 (m, 1H), 2.12 (dd, J = 9.6, 6.1 Hz, 2H). LC-MS (ESI): m / z 489.5 [M+H] + .

[0323] Example 30: Synthesis of compound R117

[0324]

[0325] Compound R117: 1 H NMR (600 MHz, Methanol-d4) δ 7.78 – 7.68 (m, 4H), 7.66(d, J = 8.5 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 8.5Hz, 1H), 7.34– 7.25 (m, 1H), 5.99 (s, 2H), 4.56 (t, J = 7.7 Hz, 2H), 4.15 (s, 2H), 2.43 –2.28 (m, 3H), 2.12-2.08 (m, 2H). LC-MS (ESI): m / z 489.5 [M+H] + .

[0326] Example 31: Synthesis of compound R846

[0327]

[0328] Compound R846: 1H NMR (600 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.01 (d, J =7.8 Hz,, 1H), 7.91 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.70 – 7.66 (m, 2H),7.53 (t, J = 8.1 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 6.03 (s, 2H), 4.61 (t, J= 7.6 Hz, 2H), 4.05 (s, 2H), 2.35-2.30 (m, 2H), 2.16 – 2.10 (m, 2H). LC-MS(ESI): m / z 472.5 [M+H] + .

[0329] Example 32: Synthesis of compound R847

[0330]

[0331] Compound R847: 1 H NMR (600 MHz, Methanol-d4) δ 9.25 (s, 1H), 8.00 (d, J =7.9 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.62 – 7.54(m, 2H), 7.45 – 7.36 (m, 2H), 6.04 (s, 2H), 4.58 (t, J = 7.7 Hz, 2H), 4.18(s, 2H), 2.37-2.34 (m, 2H), 2.12-2.08 (m, 2H). LC-MS (ESI): m / z 472.38 [M+H] + .

[0332] Example 33: Synthesis of compound R848

[0333]

[0334] Compound R848: 1H NMR (600 MHz, Methanol-d4) δ 8.39 (d, J = 9.1Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.49 (d, J= 10.7 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.20 (t,J = 9.0, 1H), 5.86 (s, 2H), 4.53 (t, J = 7.7 Hz, 2H), 3.98 (s, 2H), 2.38-2.34(m, 2H), 2.18 – 2.10 (m, 2H). LC-MS (ESI): m / z 473.39 [M+H] + .

[0335] Example 34: Synthesis of compound R849

[0336]

[0337] Compound R849: 1 H NMR (600 MHz, Methanol-d4) δ 8.59 (s, 1H), 8.14 (d, J= 8.3 Hz, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.56 (s, 1H), 7.43 (d, J = 8.5 Hz,1H), 7.34 LC-MS (ESI): m / z 474.48 [M+H] + .

[0338] Example 35: Synthesis of compound R850

[0339]

[0340] Compound R850: 1H NMR (600 MHz, Methanol-d4) δ 8.83 (s, 1H), 8.53 (d, J =5.4 Hz, 1H), 8.32 (d, J = 5.4 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.69 (d, J =8.4 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.33 (d, J =2.0 Hz, 1H), 5.96 (s, 2H), 4.58 (t, J = 7.6 Hz, 2H), 4.14 (s, 2H), 2.43-2.39(m, 2H), 2.24-2.19 (m, 2H). LC-MS (ESI): m / z 456.35 [M+H] + .

[0341] Example 36: Synthesis of compound R851

[0342]

[0343] Compound R851: 1 H NMR (600 MHz, Methanol-d4) δ 8.97 (s, 1H), 8.67 (s,1H), 8.65 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 5.4 Hz, 1H), 7.73 (d, J = 8.4 Hz,1H), 7.56 (d, J = 1.6 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.05 (s, 2H), 4.61(t, J = 7.6 Hz, 2H), 4.19 (s, 2H), 2.45-2.41 (m, 2H), 2.29-2.23 (m, 2H). LC-MS (ESI): m / z 457.44 [M+H] + .

[0344] Example 37: Synthesis of compound R852

[0345]

[0346] Compound R852: 1H NMR (600 MHz, Methanol-d4) δ 8.65 (s, 1H), 8.07 (d, J =1.2 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.74 – 7.67 (m, 1H), 7.64 (d, J = 7.7Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 4.88 (s, 2H), 4.45 (t, J = 7.5 Hz, 2H), 4.09 (s, 2H), 2.31-2.27 (m,12H), 2.18-2.14 (m, 2H). LC-MS (ESI): m / z 473.20 [M+H] + .

[0347] Example 38: Synthesis of compound R641

[0348]

[0349] Compound R641: 1 H NMR (600 MHz, ) δ 7.96 (d, J = 8.0 Hz, 1H), 7.84 (d, J= 5.0 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 10.7 Hz, 1H), 7.57 (d,J = 6.0 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J = 7.2 Hz,1H), 7.21 (t, J = 8.3 Hz, 1H), 5.88 (s, 2H), 4.54 (t, J = 7.5 Hz, 2H), 3.71(s, 2H), 3.30-3.26 (m, 2H), 3.01 (s, 3H), 2.26 (m, 2H). LC-MS (ESI): m / z481.22 [M+H] + .

[0350] Example 39: Synthesis of compound R118

[0351]

[0352] Compound R118: 1H NMR (600 MHz, Methanol-d4) δ 8.03 (t, J = 8.7 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.60 (d, J= 1.5 Hz, 1H), 7.52 (d, J = 11.4Hz, 1H), 7.40 (d, J = 8.5, 1H), 7.15 (d, J =8.4, 1H), 5.95 (s, 2H), 4.55 (t, J = 7.7 Hz, 2H), 4.15 (s, 2H), 2.34-2.30 (m,2H), 2.07-2.05 (m, 2H). LC-MS (ESI): m / z 489.41 [M+H] + .

[0353] Example 40: Synthesis of compound R949

[0354]

[0355] Under room temperature water bath and nitrogen protection conditions, compound R118 (0.30 g, 0.61 mmol), ethanol (4.0 mL), and ethyl acetate (8 mL) were added sequentially to a reaction flask. A solution of [4.0 M] dioxane hydrogen chloride (4.0 mL, 16.00 mmol) was added dropwise. The mixture was stirred at room temperature for 12 hours, and a large amount of solid was generated. The mixture was filtered, and the filter cake was washed three times with ethyl acetate. The solid was collected, dried, and yielded 0.27 g of product, with a yield of 83.7%.

[0356] Compound R949: 1 H NMR (600 MHz, Methanol-d4) δ 8.08 (dd, J = 8.8, 5.9 Hz,1H), 7.87 (d, J = 8.6 Hz, 1H), 7.70-7.65 (m, 3H), 7.59 – 7.56 (m, 2H), 7.24 –7.19 (m, 1H), 6.04 (s, 2H), 4.67 (t, J = 7.7 Hz, 2H), 4.24 (s, 2H), 2.42 (m,J = 10.8, 8.2, 5.6 Hz, 2H), 2.20 (m, J = 9.2, 6.3 Hz, 2H).LC-MS (ESI): m / z489.41 [M+H] + .

[0357] Example 41: Synthesis of compound R950

[0358] The synthesis process is the same as the preparation methods in Examples 1 and 40:

[0359]

[0360] Compound R950: 1 H NMR (600 MHz, Chloroform-d) δ 8.03 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.77-7.66 (m, 3H), 7.62-7.57 (m, 2H), 7.36 – 7.32(m, 1H), 5.65-5.58 (m, 1H), 4.51 (t, J = 7.7 Hz, , 2H), 4.17 (s, 2H), 2.32-2.22 (m,2H), 2.16-2.10 (m,2H), 2.07 (d, J = 6.1 Hz, 3H). MS=503.12[M+H].

[0361] Example 42: Synthesis of compound R951

[0362] The synthesis process is the same as the preparation methods in Examples 1 and 38:

[0363]

[0364] Compound R951: 1 H NMR (600 MHz, Chloroform-d) δ 8.00 (d, J = 5.6 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.71-7.65 (m, 3H), 7.60-7.57 (m, 2H), 7.33 – 7.30(m, 1H), 5.64-5.59 (m, 1kkkH), 4.50 (t, J = 7.7 Hz 2H), 4.15 (s, 2H), 2.34-2.20 (m,2H), 2.14-2.09 (m,2H), 2.06 (d, J = 6.1 Hz, 3H). MS=503.12[M+H].

[0365] Example 43: Synthesis of compound R119

[0366]

[0367] Compound R119: 1 H NMR (600 MHz, Methanol-d4) δ 8.09 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.80 (s, 1H), 7.78 (d, J = 5.2 Hz, 1H), 7.67 (d, J= 1.6 Hz, 1H), 7.56 – 7.53 (m, 1H), 7.41 (d, J = 7.5 Hz, 1H), 6.25 (d, J =4.0 Hz, 1H), 5.20 (s, 2H), 4.60 (t, J = 12.0 Hz,, 2H), 4.33 (s, 2H), 2.49 –2.34 (m, 2H), 2.24-2.20 (m, 2H). LC-MS (ESI): m / z 489.49 [M+H] + .

[0368] Example 44: Synthesis of compound R856

[0369]

[0370] Compound R856: 1 H NMR (600 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.86 (t, J =8.0 Hz, 1H), 7.78-7.74 (m, 2H), 7.69-7.65(m, 2H), 7.47-7.40 (m, 2H), 6.04 (s,2H), 4.65 (t, J = 12.0 Hz,, 2H), 4.22 (s, 2H), 2.37 – 2.30 (m, 2H), 2.28-2.16(m, 2H). LC-MS (ESI): m / z 507.10 [M+H] + .

[0371] Example 45: Synthesis of compound R09

[0372]

[0373] 1H NMR (600 MHz, Methanol-d4) δ 7.56 (s, 1H), 7.50 (d, J = 8.3 Hz,1H), 7.29 (t, J = 7.7 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.4 Hz,2H), 7.05 (t, J = 7.5 Hz, 1H), 7.01 – 6.95 (m, 4H), 5.38 (s, 2H), 4.41 (t, J= 7.7 Hz, 2H), 3.99 (s, 2H), 2.20 (td, J = 10.8, 6.0 Hz, 2H), 1.95 (q, J =8.0 Hz, 2H). LC-MS (ESI): m / z 545.12 [M+H] + .

[0374] Example 46: Synthesis of compound R10

[0375]

[0376] 1 H NMR (600 MHz, Methanol-d4) δ 7.67 (d, J = 8.0 Hz, 1H), 7.62 (s,1H), 7.56 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.30 (t, J = 8.4 Hz,4H), 7.12 (d, J = 7.5 Hz, 2H), 6.91 (d, J = 7.9 Hz, 1H), 5.49 (s, 2H), 4.57(t, J = 7.8 Hz, 2H), 3.96 (s, 2H), 2.35 – 2.31 (m, 2H), 2.12 – 2.08 (m, 2H),.LC-MS (ESI): m / z 593.10 [M+H] + .

[0377] Example 47: Synthesis of compound R860

[0378]

[0379] 1H NMR (600 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.70 (d, J = 8.4 Hz,1H), 7.50 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.24 (dt, J = 18.5,9.5 Hz, 4H), 7.14 (dt, J = 13.2, 6.8 Hz, 4H), 5.54 (s, 2H), 4.55 (t, J = 7.7Hz, 2H), 4.26 (s, 2H), 2.37 – 2.31 (m, 2H), 2.09 (q, J = 7.9 Hz, 2H).

[0380] LC-MS (ESI): m / z 501.17 [M+H] + .

[0381] Example 48: Synthesis of compound R63

[0382]

[0383] 1 H NMR (600 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.87 (s, 1H), 7.72 (dd,J = 6.2, 3.4 Hz, 1H), 7.65 (dd, J = 6.2, 3.3 Hz, 1H), 7.62 (d, J = 1.6 Hz,1H), 7.54 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 6.3, 3.2 Hz, 2H), 7.34 (dd, J =8.5, 1.6 Hz, 1H), 7.30 – 7.28 (m, 2H), 7.05 (t, J = 7.8 Hz, 2H), 6.97 (t, J =7.4 Hz, 1H), 5.55 (s, 2H), 4.57 (t, J = 7.7 Hz, 2H), 3.91 (s, 2H), 2.37 –2.32 (m, 2H), 2.12 (t, J = 8.0 Hz, 2H). LC-MS (ESI): m / z 595.13 [M+H] + .

[0384] Example 49: Synthesis of compound R64

[0385]

[0386] 1 H NMR (600 MHz, Methanol-d4) δ 7.95 (s, 1H), 7.80 (d, J = 8.6 Hz,1H), 7.77 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.46 (d, J= 7.4 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.19 (t, J = 7.9 Hz, 2H), 7.14 (d, J= 7.4 Hz, 1H), 5.56 (s, 2H), 4.61 (s, 2H), 4.54 (s, 2H), 4.24 (s, 2H), 2.36(q, J = 9.6 Hz, 2H), 2.15 – 2.09 (m, 2H). LC-MS (ESI): m / z 517.22 [M+H] + .

[0387] Example 50: Synthesis of compound R863

[0388]

[0389] 1 H NMR (600 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.84 (s, 1H), 7.66 (s,1H), 7.57 – 7.52 (m, 3H), 7.45 – 7.43 (m, 1H), 7.37 (dd, J = 19.0, 8.5 Hz,2H), 7.13 (d, J = 7.8 Hz, 2H), 7.06 (t, J = 7.7 Hz, 2H), 7.01 (d, J = 7.3 Hz,1H), 5.43 (s, 2H), 4.40 (t, J = 7.6 Hz, 2H), 4.14 (s, 2H), 2.25 – 2.20 (m,2H), 1.97 (q, J = 7.7 Hz, 2H). LC-MS (ESI): m / z 595.13 [M+H] + .

[0390] Example 51: Synthesis of compound R864

[0391]

[0392] 1 H NMR (600 MHz, Methanol-d4) δ 7.89 (d, J = 9.6 Hz, 2H), 7.70 (d, J= 7.4 Hz, 1H), 7.68 – 7.63 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.47 (d, J =8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.14 (d, J =7.9 Hz, 2H), 7.07 (t, J = 7.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 5.44 (s,2H), 4.40 (t, J = 7.7 Hz, 2H), 4.14 (s, 2H), 2.26 – 2.19 (m, 2H), 1.99-1.96(m, 2H).

[0393] LC-MS (ESI): m / z 595.13 [M+H] + .

[0394] Example 52: Synthesis of compound R76

[0395]

[0396] 1 H NMR (600 MHz, Methanol-d4) δ 7.46 (s, 1H), 7.39 (d, J = 8.4 Hz,1H), 7.21 (dd, J = 8.4, 1.6 Hz, 1H), 7.05 (q, J = 9.6, 8.3 Hz, 5H), 6.94 (d,J = 5.8 Hz, 1H), 6.69 (d, J = 5.8 Hz, 1H), 5.32 (s, 2H), 4.34 (t, J = 7.7 Hz,2H), 3.77 (s, 2H), 2.18 (dd, J = 17.5, 10.4 Hz, 2H), 1.95 (t, J = 7.9 Hz,2H). LC-MS (ESI): m / z 507.12 [M+H] + .

[0397] Example 53: Synthesis of compound R859

[0398]

[0399] 1 H NMR (600 MHz, Methanol-d4) δ 7.46 (s, 1H), 7.39 (d, J = 8.4 Hz,1H), 7.22 (d, J = 9.8 Hz, 2H), 7.17 (d, J = 5.8 Hz, 3H), 7.10 – 7.06 (m, 3H), 6.83 (d, J = 5.1 Hz, 1H), 5.31 (d, J = 2.1 Hz, 2H), 4.32 (t, J = 7.7 Hz, 2H), 3.77 (s, 2H), 2.20 – 2.14 (m, 2H), 1.94 (t, J = 8.0 Hz, 2H). LC-MS (ESI): m / z473.16 [M+H] + .

[0400] Example 54: Synthesis of compound R861

[0401]

[0402] 1 H NMR (600 MHz, Methanol-d4) δ 7.45 (s, 1H), 7.37 (d, J = 8.4 Hz,1H), 7.19 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 7.02 (t, J = 7.6 LC-MS (ESI): m / z 599.06[M+H] + .

[0403] Example 55: Synthesis of Compound R80

[0404]

[0405] 1H NMR (600 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 1.6 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.18 (s, 1H),7.17 (s, 2H), 7.12 (dd, J = 7.8, 1.8 Hz, 2H), 5.86 (s, 1H), 5.32 (s, 2H),4.37 (t, J = 7.7 Hz, 2H), 4.12 (s, 2H), 2.23 – 2.18 (m, 2H), 1.95 (t, J = 7.9Hz, 2H). LC-MS (ESI): m / z 535.09 [M+H] + .

[0406] Example 56: Synthesis of compound R866

[0407]

[0408] 1 H NMR (600 MHz, Methanol-d4) δ 7.61 (s, 1H), 7.53 (d, J = 8.4 Hz,1H), 7.38 (d, J = 5.1 Hz, 1H), 7.34 (dd, J = 8.3, 1.5 Hz, 1H), 7.21 (dt, J =21.7, 7.1 Hz, 5H), 6.81 (d, J = 5.2 Hz, 1H), 5.45 (s, 2H), 4.45 (t, J = 7.7Hz, 2H), 3.95 (s, 2H), 2.31 (qd, J = 9.7, 8.5, 4.7 Hz, 2H), 2.05 (q, J = 7.8Hz, 2H). LC-MS (ESI): m / z 551.07 [M+H] + .

[0409] Example 57: Synthesis of compound R862

[0410]

[0411] 1H NMR (600 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.55 (d, J = 8.7 Hz,1H), 7.35 (d, J = 8.4 Hz, 1H), 7.17 – 7.13 (m, 4H), 7.05 (d, J = 7.3 Hz, 2H), 6.40 (s, 1H), 5.32 (s, 2H), 4.35 (t, J = 7.8 Hz, 2H), 4.13 (s, 2H), 2.23 –2.17 (m, 2H), 1.93 (t, J = 8.0 Hz, 2H). LC-MS (ESI): m / z 535.09 [M+H] + .

[0412] Example 58: Synthesis of compound R942

[0413]

[0414] 1 H NMR (600 MHz, Methanol-d4) δ 7.65 (s, 1H), 7.58 (d, J = 8.2 Hz,1H), 7.39 (q, J = 8.9, 7.1 Hz, 2H), 7.26 (p, J = 6.0, 5.5 Hz, 3H), 7.20 (d, J= HRMS (ESI): m / z [M + H]=583.08.

[0415] Example 59: Synthesis of compound R853

[0416] Synthesis route:

[0417]

[0418] Step 1: Under room temperature water bath and argon protection, intermediate F (2.00 g, 7.06 mmol), N,N-dimethylformamide (15 mL), and imidazole (1.20 g, 17.66 mmol) from Example 1 were mixed, and tert-butyldimethylchlorosilane (1.18 g, 7.76 mmol) was added dropwise. After the addition was complete, the mixture was stirred in an oil bath at 50°C for 6 hours. The reaction was stopped when the amount of raw material A no longer decreased as detected by thin-layer chromatography. After the reaction was complete, sodium bicarbonate aqueous solution (15 mL) and ethyl acetate (15 mL) were added, and the mixture was stirred to separate the layers. The organic phase was temporarily stored, and the aqueous phase was extracted with ethyl acetate. All organic phases were combined, washed with water, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography with dichloromethane:methanol = 40:1 to 20:1 as the eluent. The main product was collected and concentrated to obtain brown solid compound L (2.30 g, yield 82%).

[0419] Step 2: Under argon protection, compound L (1.00 g, 4.03 mmol), dry tetrahydrofuran (30 mL), and tetraisopropoxide titanium (0.80 g, 2.77 mmol) were mixed and placed in a -79°C cryogenic bath. The mixture was stirred for 10 minutes, and ethyl magnesium bromide (5.53 mL, 5.53 mmol) was added dropwise. The mixture was stirred for another 20 minutes, then the mixture was brought to room temperature and stirred for 1.5 hours. Finally, boron trifluoride diethyl ether complex (0.71 g, 5.03 mmol) was added dropwise, and the mixture was stirred for another 2.5 hours. After the reaction was completed, dilute hydrochloric acid (10 mL, 10.0 mmol) was added dropwise to the reaction system to quench the reaction. Then, an aqueous solution of sodium hydroxide (2.0 g, 50 mmol) and water (20 mL) was added dropwise. Saturated brine and ethyl acetate were added and stirred to separate the layers. The aqueous phase was separated and extracted with ethyl acetate. All organic phases were combined, concentrated, and purified by silica gel column chromatography. The eluent phase was dichloromethane:methanol = 20:1 to 10:1. The main product was collected and concentrated to obtain paste M (0.35 g, yield 32%).

[0420] Step 3: Under water bath and argon protection, the starting compound M (1.50 g, 3.50 mmol) and dichloromethane (30 mL) were added in multiple batches to di-tert-butyl dicarbonate (1.30 g, 5.96 mmol). The mixture was stirred at room temperature for 12 h. The reaction was stopped when the starting compound no longer decreased as detected by thin-layer chromatography. The reaction solution was mixed with silica gel and subjected to silica gel column chromatography. The eluent was dichloromethane:methanol = 20:1. The main product was collected and concentrated to obtain a brown paste-like compound N (0.50 g, yield 27%).

[0421] Step 4: Under room temperature water bath and argon protection, compound N (0.50 g, 0.95 mmol), tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (0.30 g, 1.79 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40°C for 4 hours. The reaction was stopped when the starting material no longer decreased as detected by thin-layer chromatography. The reaction solution was mixed with silica gel and subjected to silica gel column chromatography. The eluent was dichloromethane:methanol = 40:1 to 10:1. The main product was collected and concentrated to obtain a white solid compound O (0.20 g, yield 51%).

[0422] Step 5: Under room temperature water bath and nitrogen protection conditions, compound O (0.20 g, 0.48 mmol), tetrahydrofuran (5 mL), and diisopropylethylamine (0.25 g, 1.93 mmol) were added sequentially to the reaction flask, followed by the dropwise addition of methanesulfonyl chloride (0.66 g, 0.58 mmol). The mixture was stirred at room temperature for 12 h. Thin-layer chromatography detected a small amount of the starting compound remaining, at which point the reaction was stopped. The reaction solution was added dropwise to a mixture of saturated sodium chloride solution (5 mL) and ethyl acetate (5 mL). The pH was adjusted to 7-8 with sodium bicarbonate solution. The mixture was separated, the organic phase was temporarily stored, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, concentrated, and then chromatographically analyzed using silica gel column chromatography. The eluent was dichloromethane:methanol = 20:1. The main product was collected and concentrated to obtain a light white solid compound P (0.20 g, yield 95%).

[0423] Step 6: Under oil bath and argon protection, compound P (0.12 g, 0.28 mmol), compound Q (0.060 g, 0.30 mmol), and potassium carbonate (0.15 g, 1.11 mmol) were added sequentially to the reaction flask. The mixture was heated in an oil bath at 120°C for 5.5 hours. The reaction was stopped when the amount of reactants no longer decreased as detected by thin-layer chromatography. The reaction solution was added dropwise to a mixture of water (10 mL) and ethyl acetate (10 mL), stirred, and separated. The organic phase was temporarily stored, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, concentrated, and then precipitated by silica gel column chromatography with dichloromethane:methanol = 20:1 as the eluent. The main product was collected to give a white solid compound R (0.15 g, yield 84%).

[0424] Step 7: Under room temperature water bath and argon protection, compound R (0.15 g, 0.25 mmol) and an ethyl acetate solution of hydrogen chloride (6.0 mL, 12.00 mmol) were mixed sequentially and stirred at room temperature for 12 h. The reaction was stopped when the amount of starting compound R no longer decreased as detected by thin-layer chromatography. The pH was adjusted to 7-8 with sodium bicarbonate solution, the solvent was removed by vacuum distillation, ethanol (10 mL) and silica gel were added, and the mixture was concentrated. The product was then subjected to silica gel column chromatography with dichloromethane:methanol = 40:1 to 10:1 as the eluent. The main product was collected to give a white compound R853 (0.040 g, yield 32%).

[0425]

[0426] Compound R853: 1 H NMR (600 MHz, Chloroform-d) δ 8.29 (d, J = 8.6 Hz,1H), 7.81 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 5.3 Hz, 1H), 7.75 (s, 1H), 7.51(t, J = 8.0 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 7.27 (d, J = 9.6 Hz, 2H), 7.20(d, J = 8.4 Hz, 1H), 5.99 (s, 2H), 4.38 (t, J = 8.0 Hz, 2H), 2.06 – 1.94 (m,3H), 1.67 – 1.62 (m, 2H), 1.25 (s, 2H), 1.07 (t, J = 3.1 Hz, 2H), 1.00 (t, J= 3.2 Hz, 2H). LC-MS (ESI): m / z 497.16 [M+H] + .

[0427] Example 60: Synthesis of compound R854

[0428]

[0429] Compound R854: 1 H NMR (600 MHz, Methanol-d4) δ 8.01 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 5.3 Hz, 1H), 7.71 – 7.65 (m, 3H), 7.63 (d, J = 1.9 Hz, 1H), 7.55– 7.49 (m, 2H), 7.40 – 7.34 (m, 1H), 6.01 (s, 2H), 4.57 (t, J = 7.7 Hz, 3H), 2.34-2.30 (m, 2H), 2.10-2.06 (m, 2H), 1.76 (s, 6H). LC-MS (ESI): m / z 499.01[M+H] + .

[0430] Example 61: Synthesis of compound R855

[0431]

[0432] Compound R855: 1 H NMR (600 MHz, Methanol-d4) δ 8.01 (dd, J = 7.8, 1.5 Hz,1H), 7.72 (d, J = 5.2 Hz, 1H), 7.70 – 7.66 (m, 3H), 7.60 (d, J = 1.7 Hz, 1H),7.56 – 7.48 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 6.01(s, 2H), 4.56 (t, J = 14.0 Hz,2H), 2.36-2.29 (m, 2H), 2.13 – 1.99 (m, 2H),1.65 (d, J = 6.8 Hz, 3H). LC-MS (ESI): m / z 485.21 [M+H] + .

[0433] Example 62: Synthesis of compound R874

[0434]

[0435] 1 H NMR (600 MHz, Methanol-d4) δ 8.00 (d, J = 7.9 Hz, 1H), 7.72 (d, J =6.0 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.55 – 7.50(m, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.25 (s, 1H), 7.00 (d, J = 13.3 Hz, 1H).6.00 (s, 1H), 5.84 (d, J = 7.8 Hz, 2H), 4.57 (t, J = 7.4 Hz, 2H), 4.01 (s, 2H), 2.34-2.24 (m, 2H), 2.10 -2.06(m, 2H).

[0436] LC-MS (ESI): m / z 489.56 [M+H] + .

[0437] Example 63: Synthesis of compound R875

[0438] Step 1: Under nitrogen protection, compound I (0.72 g, 1.77 mmol), compound S (0.36 g, 1.79 mmol), potassium carbonate (1.08 g, 7.81 mmol), and solvent N,N-dimethylformamide (20 mL) were added sequentially to a reaction flask. The mixture was heated in an oil bath at 120°C for 8 hours. The reaction was stopped when thin-layer chromatography showed that the amount of starting material compound I no longer decreased. After the reaction was complete, water (20 mL) and petroleum ether (10 mL) were added dropwise to the reaction solution, and the mixture was stirred for 10 minutes. The solid was collected by filtration, and the filter cake was washed sequentially with water and petroleum ether. After drying, the main product was collected to obtain a light yellow solid compound T (0.90 g, yield 89%).

[0439] Step 2: In a 50 mL reactor, compound T (0.2 g, 0.35 mmol) was added and dissolved in N,N-dimethylformamide (4 mL). NaH (22 mg, 0.92 mmol) was added under ice bath conditions, and stirring was continued for 1 h. Then, compound iodomethane (0.1 g, 0.7 mmol) was added, and the mixture was heated to 50 °C under nitrogen protection. o The reaction was carried out for 6 h at C. HPLC monitoring showed that the reaction was complete. The reaction was stopped, water (35 mL) was added, and the mixture was extracted with ethyl acetate (35 mL × 2). The ethyl acetate layers were combined, washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, and then subjected to silica gel column chromatography (eluent: EA / PE = 1:1) to give 160 mg of compound U, with a yield of 78%.

[0440] Step 3: In a 50 mL reactor, compound U (160 mg, 0.27 mmol), ethanol (4 mL), and a 4M solution of 1,4-dioxane (4 mL) of hydrogen chloride were added. The reaction was carried out overnight at room temperature under nitrogen protection. Liquid chromatography was used to monitor the reaction until complete. The reaction was then stopped, and the reaction solution was added dropwise to 10 times its volume of sodium bicarbonate solution. The mixture was stirred vigorously, and a white solid precipitated. The solid was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was collected and dried under reduced pressure to obtain 111 mg of compound R875, with a yield of 84%.

[0441]

[0442] Compound R875 1H NMR (600 MHz, Chloroform-d) δ 8.31 (d, J = 8.6 Hz,1H).,7.81 (dd, J = 7.8, 1.5 Hz, 1H), 7.77 (d, J = 5.3 Hz, 1H), 7.69 (s, 1H),7.51 (ddd, J = 8.7, 7.2, 1.5 Hz, 1H), 7.43 (d, JJ = 5.2 Hz, 1H), 7.27 (d, J =8.6 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 6.00 (s, 2H), 4.38 (t, J = 8.0 Hz, 2H), 3.85 (s, 2H), 2.46 (s, 3H), 2.03-1.95 (m, 2H), 1.67-1.61 (m, 2H). LC-MS(ESI): m / z 485.16 [M+H] + .

[0443] Example 64: Synthesis of compound R885

[0444]

[0445] Referring to Example 63, the synthesis of compound R885 was completed.

[0446] 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (dd, J = 8.7, 5.9 Hz, 1H), 7.70 –7.68 (m, 1H), 7.68 – 7.64 (m, 2H), 7.61 (s, 1H), 7.53 (dd, J = 11.6, 2.1 Hz,1H), 7.42 (d, J = 8.4 Hz, 1H), 7.16 (td, J = 8.3, 2.2 Hz, 1H), 5.95 (s, 2H), 4.56 (t, J = 7.7 Hz, 2H), 4.20 (s, 2H), 2.65 (s, 3H), 2.38 – 2.30 (m, 2H),2.12-2.06 (m, 2H). LC-MS (ESI): m / z 503.34 [M+H] + .

[0447] Example 65: Synthesis of compound R876

[0448]

[0449] Step 1: In a 50 mL reactor, compound V (0.5 g, 3.84 mmol) and triethylamine (1.17 g, 11.56 mmol) were added separately and dissolved in ethanol (8 mL). Compound W (0.775 g, 3.84 mmol) was added under ice bath conditions. The mixture was heated to room temperature and reacted for 3 hours under nitrogen protection. The reaction was monitored by liquid chromatography until complete. The reaction was stopped, and water (35 mL) was added. The mixture was extracted with dichloromethane (35 mL × 2). The dichloromethane layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Dichloromethane (5 mL) and petroleum ether (10 mL) were added, and the mixture was stirred vigorously for 30 min. The mixture was filtered, the filter cake was washed with petroleum ether, and dried under reduced pressure to obtain 685.9 mg of compound X, with a yield of 61%.

[0450] Step 2: In a 50 mL reactor, compound R114 (200 mg, 0.425 mmol) and compound X (138 mg, 0.467 mmol) were added separately. Ultra-dry N,N-dimethylformamide (8 mL) was added to dissolve them. At room temperature, N,N-diisopropylethylamine (165 mg, 1.27 mmol) was added. The reaction was carried out at room temperature for 4 hours under nitrogen protection. Liquid chromatography was used to monitor the completeness of the reaction. The reaction was stopped, and water (35 mL) was added. The mixture was extracted with dichloromethane (35 mL × 2). The dichloromethane layers were combined and washed with water (50 mL) and saturated brine (50 mL) respectively. The mixture was dried over anhydrous sodium sulfate and subjected to silica gel column chromatography with ethyl acetate:petroleum ether = 9:1 as the eluent. The mixture was dried under reduced pressure to obtain 74.4 mg of the compound, with a yield of 28%.

[0451]

[0452] 1H NMR (600 MHz, Chloroform-d) δ 8.30 (d, J = 8.6 Hz, 1H), 7.86 (d, J= 7.8 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.72 (s, 1H), 7.55 (t, J = 8.0 Hz,1H), 7.48 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26 (s, 2H), 6.00(s, 2H), 4.88 (s, 2H), 4.52 (d, J = 5.9 Hz, 2H), 4.38 (t, J = 8.1 Hz, 2H),2.23 (s, 3H), 2.03 (h, J = 10.2 Hz, 2H), 1.66 (d, J = 7.6 Hz, 2H). LC-MS(ESI): m / z 627.15 [M+H] + .

[0453] The synthesis methods in the following examples are the same as those in Example 63, except that the starting compound in Example 63 is replaced with the corresponding starting compound.

[0454] Example 66: Synthesis of compound R877

[0455]

[0456] 1H NMR (600 MHz, Methanol-d4) δ 7.97 (d, J = 7.8Hz, 1H), 7.76 – 7.69(m, 2H), 7.66 (d, J = 5.3 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.44 (s, 1H), 7.35(t, J = 7.5 Hz, 1H), 7.27 (t, J = 8.5 Hz, 1H), 6.74 (q, J = 5.4 Hz, 1H), 5.98(s, 2H), 4.49 (t, J = 7.7 Hz, 2H), 4.33 (s, 2H), 2.49-2.43 (m, 1H), 2.32 –2.20 (m, 2H), 2.06 – 1.92 (m, 2H), 1.49 – 1.36 (m, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H). LC-MS (ESI): m / z 629.20[M+H] +

[0457] Example 67: Synthesis of compound R878

[0458]

[0459] 1 H NMR (600 MHz, Methanol-d4) δ 7.97 (d, J = 7.9 Hz, 1H), 7.74 – 7.69(m, 2H), 7.66 (d, J = 5.3 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.44 (s, 1H), 7.37 –7.33 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.98 (s, 2H), 4.49 (t, J = 7.7 Hz,2H), 4.33 (s, 2H), 4.01 (t, J = 6.7 Hz, 2H), 2.31 – 2.22 (m, 2H), 2.01-1.95(m, 2H), 1.62-1.57(m, 2H), 1.34-1.27 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H). LC-MS(ESI): m / z 585.21[M+H] +

[0460] Example 68: Synthesis of compound R879

[0461]

[0462] 1 H NMR (600 MHz, Methanol-d4) δ 7.87 (d, J = 7.9 Hz, 1H), 7.62 (d, J =5.3 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.44 – 7.37(m, 2H), 7.33 (s, 1H), 7.28 – 7.22 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.88(s, 2H), 4.75 – 4.68 (m, 1H), 4.39 (t, J = 7.7 Hz, 2H), 4.23 (s, 2H), 2.20-2.13 (m, 2H), 1.91-1.85 (m, 2H), 1.10 (d, J = 6.2 Hz, 6H).LC-MS (ESI): m / z557.16[M+H] + .

[0463] Example 69: Synthesis of compound R880

[0464]

[0465] 1H NMR (600 MHz, Methanol-d4) δ 8.26 (d, J = 9.0 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.73 (d, J = 5.3 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.51 – 7.45 (m,2H), 7.40 (d, J = 7.8 Hz, 1H), 7.36-7.28 (m, 3H), 7.11 (d, J = 10.8 Hz, 1H),7.03 (d, J = 8.1 Hz, 1H), 5.97 (s, 2H), 5.28 (s, 2H).,5.06 (s, 2H), 4.38 (t,J = 9.6 Hz, 2H), 2.29 (s, 3H), 2.12 – 2.03 (m, 2H), 1.76-1.73 (m, 2H). LC-MS(ESI): m / z 663.16[M+H] +

[0466] Example 70: Synthesis of compound R881

[0467]

[0468] 1 H NMR (600 MHz, Methanol-d4) δ 8.09 (d, J = 7.9Hz, 1H), 7.90 (d, J =8.6 Hz, 1H), 7.73 – 7.70 (m, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.63 (t, J = 7.2Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.48 – 7.43 (m, 1H), 6.17(s, 2H), 4.74 (t, J = 7.8 Hz, 2H), 4.56 (s, 2H), 3.70 (s, 2H), 2.70 (s, 2H),2.49-2.42 (m, 2H), 2.29-2.22 (m, 2H). LC-MS (ESI): m / z 528.14 [M+H] +

[0469] Example 71: Synthesis of compound R882

[0470]

[0471] 1 H NMR (600 MHz, Methanol-d4) δ 7.90 (d, J = 7.8 Hz, 1H), 7.84 (d, J =8.6 Hz, 1H), 7.73 (d, J = 5.3 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.52 (s,1H), 7.48 (t, J = 7.8Hz 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 7.8Hz1H), 7.25 (d, J = 1.6 Hz, 1H), 5.97 (s, 2H), 4.51 – 4.37 (m, 4H), 4.14 (dd, J= 12.7, 7.1 Hz, 1H), 3.14 (dd, J = 11.2, 5.1 Hz, 1H), 2.16 –1.94 (m, 4H), 1.84 – 1.76 (m, 2H), 0.95 – 0.77 (m, 12H). LC-MS (ESI): m / z 669.30 [M+H] +

[0472] Example 72: Synthesis of compound R883

[0473]

[0474] 1H NMR (600 MHz, Methanol-d4) δ 8.09 (dd, J = 7.9, 1.3 Hz, 1H), 7.99(d, J = 8.6 Hz, 1H), 7.73 – 7.69 (m, 3H), 7.68 – 7.64 (m, 2H), 7.60 (s, 1H), 7.47 (t, J = 7.5 Hz, 1H), 6.21 (s, 2H), 4.79 (t, J = 7.8 Hz, 3H), 4.64 (d, J= 15.1 Hz, 1H), 4.51 (d, J = 15.1 Hz, 1H), 3.68 (d, J = 5.7 Hz, 1H), 2.55 –2.43 (m, 2H), 2.35 – 2.27 (m, 2H), 2.16 (dq, J = 13.5, 6.6 Hz, 1H), 1.01 –0.97 (m, 6H). LC-MS (ESI): m / z 570.21 [M+H] + .

[0475] Example 73: Synthesis of compound R884

[0476]

[0477] 1 H NMR (600 MHz, Methanol-d4) δ 8.09 (dd, J = 7.9, 1.3 Hz, 1H), 7.99(d, J = 8.7 Hz, 1H), 7.74 – 7.69 (m, 3H), 7.67 – 7.63 (m, 2H), 7.57 (s, 1H),7.47 (t, J = 7.5 Hz, 1H), 6.22 (s, 2H), 4.80 (t, J = 7.8 Hz, 3H), 4.63 – 4.51(m, 2H), 3.97 (q, J = 7.0 Hz, 1H), 2.56 – 2.45 (m, 2H), 2.32 (tq, J = 12.5,7.8, 6.6 Hz, 2H), 1.49 (d, J = 7.1 Hz, 3H). LC-MS (ESI): m / z 542.18 [M+H] + .

[0478] Example 74: Synthesis of compound R934

[0479]

[0480] 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (dd, J = 8.8, 5.9 Hz, 1H), 7.69 –7.55 (m, 4H), 7.43 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.16 (t, J =8.4 Hz, 1H), 5.96 (s, 2H), 4.92 (t, J = 7.7 Hz, 2H), 4.55 (t, J = 7.7 Hz, 2H), 4.18 (s, 2H) . LC-MS (ESI): m / z 491.1 [M+H] +

[0481] Example 75: Synthesis of compound R940

[0482]

[0483] Step 1: Under oil bath and argon protection, compound R118 (0.040 g, 0.08 mmol), potassium carbonate (0.10 g, 0.72 mmol), deuterated methanol (4 mL), and heavy water (1 mL) were added sequentially to the reaction flask. The mixture was heated in an oil bath at 80°C for 12 hours, and then the reaction was stopped. The reaction solution was mixed with ethyl acetate (4 mL), stirred, and separated. The organic phase was temporarily stored, and the organic phases were combined and washed with water. After concentration, the mixture was subjected to silica gel column chromatography with dichloromethane:methanol:triethylamine = 40:4:0.5 as the eluent. The main product was collected to obtain solid compound R940 (0.010 g, yield 25%).

[0484] 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (dd, J = 8.8, 5.9 Hz, 1H), 7.71 –7.64 (m, 3H), 7.60 (s, 1H), 7.53 (dd, J = 11.4, 2.3 Hz, 1H), 7.40 (d, J = 8.5Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 4.55 (t, J = 7.7 Hz, 2H), 4.14 (s, 2H), 2.42 – 2.23 (m, 2H), 2.10-2.06 (m, 2H). LC-MS (ESI): m / z 492.50 [M+H] + .

[0485] Example 76:

[0486] R947 was prepared according to the synthesis method of compound R949 in Example 40.

[0487]

[0488] 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (dd, J = 8.8, 5.9 Hz, 1H), 7.71 –7.64 (m, 3H), 7.60 (s, 1H), 7.53 (dd, J = 11.4, 2.3 Hz, 1H), 7.40 (d, J = 8.5Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 4.55 (t, J = 7.7 Hz, 2H), 4.14 (s, 2H), 2.42 – 2.23 (m, 2H), 2.10-2.06 (m, 2H). LC-MS (ESI): m / z 492.50 [M+H] + .

[0489] Example 77: Synthesis of compound R943

[0490] Referring to Example 1, the raw material 4,4,4-trifluoro-1-butylamine hydrochloride was replaced with Compound R943 can be prepared.

[0491]

[0492] Compound R943: 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (t, J = 8.7 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.60 (d, J= 1.5 Hz, 1H), 7.52 (d, J = 11.4Hz, 1H), 7.40 (d, J = 8.5, 1H), 7.15 (d, J =8.4, 1H), 5.95 (s, 2H), 4.15 (s, 2H), 2.34-2.30 (m, 2H), 2.07-2.05 (m, 2H).LC-MS (ESI): m / z 492.50 [M+H] + .

[0493] Example 78:

[0494] R946 was prepared according to the synthesis method of compound R949 in Example 40.

[0495]

[0496] 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (t, J = 8.7 Hz, 1H), 7.69 (d, J =5.3 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 1.5 Hz,1H), 7.52 (d, J = 11.4Hz, 1H), 7.40 (d, J = 8.5, 1H), 7.15 (d, J = 8.4, 1H),5.95 (s, 2H), 4.15 (s, 2H), 2.34-2.30 (m, 2H), 2.07-2.05 (m, 2H). LC-MS(ESI): m / z 492.50 [M+H] + .

[0497] Example 79: Synthesis of compound R857

[0498] Referring to Example 1, intermediate H is replaced with Compound R857 can be prepared.

[0499]

[0500] 1 Compound R857: 1H NMR (600 MHz, Methanol-d4) δ 8.03 (t, J = 8.7 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.60 (d, J= 1.5 Hz, 1H), 7.52 (d, J = 11.4Hz, 1H), 7.40 (d, J = 8.5, 1H), 7.15 (d, J =8.4, 1H), 5.95 (s, 2H), 4.55 (t, J = 7.7 Hz, 2H), 2.34-2.30 (m, 2H), 2.07-2.05 (m, 2H). LC-MS (ESI): m / z 492.50 [M+H] + .

[0501] Example 80:

[0502] R948 was prepared according to the synthesis method of compound R949 in Example 40.

[0503]

[0504] 1 H NMR (600 MHz, Methanol-d4) δ 8.03 (t, J = 8.7 Hz, 1H), 7.69 (d, J =5.3 Hz, 1H), 7.66 (s, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 1.5 Hz,1H), 7.52 (d, J = 11.4Hz, 1H), 7.40 (d, J = 8.5, 1H), 7.15 (d, J = 8.4, 1H),5.95 (s, 2H), 4.55 (t, J = 7.7 Hz, 2H), 2.34-2.30 (m, 2H), 2.07-2.05 (m, 2H).LC-MS (ESI): m / z 492.50 [M+H] + .

[0505] Each compound was characterized by mass spectrometry, and the analytical conditions were as follows:

[0506] Instrument model: Waters ACQUITY UPLC-Class plus / SQ Detector 2;

[0507] Chromatographic column: ACQUITY UPLC BEH C18 Column, 130Å, 1.7 µm, 2.1 mm X 100 mm;

[0508] Mobile phase: 0.1% formic acid aqueous solution (A) - acetonitrile (B);

[0509] Gradient elution of mobile phase: 4.5 min, from 1% A: 99% B to 90% A: 10% B;

[0510] Flow rate: 0.4 mL / min;

[0511] Injection volume: 5 μL.

[0512] The elution times of each compound were approximately 1.2–1.6 min. The mass spectrometry characterization results are summarized in Table 1 below.

[0513] Table 1

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

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[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

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[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635] Biological testing of compounds:

[0636] The anti-RSV activity of the target compound was tested by culturing the RSV-A2 strain on Hep-2 cells. In the experiment, on the first day, cells were cultured in 96-well cell culture plates at a concentration of 1 × 10⁻⁶. 5 Cells were passaged at 100 μL / well and cultured at 37°C and 5% CO2 for 12 h. On the second day, the sample, including the target compound, was serially diluted to 8 concentrations using DMEM medium containing 2% FBS. Simultaneously, the medium in the 96-well cell culture plate was discarded, and the plate was washed once with 100 μL / well of PBS. After discarding the liquid in the 96-well cell culture plate, serially diluted samples were added at 200 μL per well, with four replicates for each concentration (two wells for cytotoxicity and two wells for efficacy), and the plate was cultured at 37°C and 5% CO2 for 12 h. On the third day, the sample (drug) was serially diluted to 8 concentrations using DMEM medium containing 2% FBS. Simultaneously, the liquid in the 96-well cell culture plate was discarded, and the plate was washed once with 100 μL / well of PBS. RSV virus was removed from the -80°C freezer, thawed with running water, and diluted to 100 TCID using serum-free DMEM medium. 50 Add 100 μL of the drug to each well, and add 100 μL of serum-free DMEM medium to each well for the cell control wells. Incubate at 37°C and 5% CO2 for 2 h. Discard the liquid in the 96-well cell culture plate, add serially diluted sample (drug) at 200 μL / well, and incubate at 35°C and 5% CO2 for 48–72 h. Observe and record CPE.

[0637] The test results are shown in Table 2 below:

[0638] Table 2

[0639]

[0640]

[0641]

[0642]

[0643] Note: " / " indicates that the test was not performed.

[0644] As shown in Table 2, the amine compounds provided in this application exhibit good inhibitory activity against RSV proliferation. The measured half-maximal effective concentration (EC50) of the compounds in cells inhibited RSV virus proliferation. 50 The activity of all compounds was low, with some compounds exhibiting activity at the nanomolar / L level. Cytotoxicity TC 50 Tests showed that the compound had low toxicity and a high therapeutic index.

[0645] Metabolic experiments of prodrug compounds:

[0646] Compounds R876, R877, R878, R879, R880, R881, R882, R883, R884, R885, R886, and R887 are prodrug compounds that can be detected in vivo as target molecules converted to R-NH2.

[0647] Taking compound R878 as an example, compound R878 was incubated in plasma at 37°C for 2 hours, and its conversion to the prototype molecule R114 was detected. The results are shown in Table 3 below:

[0648]

[0649] Table 3

[0650]

[0651] It is evident that the response signal area of ​​the prototype molecule R114 increases significantly with increasing incubation time, indicating that compound R878, as a prodrug compound, can be converted into the prototype molecule R114 in plasma.

[0652] After male SD rats were administered R878 by gavage (dose 10 mg / kg), no progenitor compound was detected in the plasma, only the active metabolite R114 was detected, demonstrating that the prodrug molecule can be metabolized into the active progenitor molecule R114 in vivo.

[0653] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0654] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. An amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule, wherein the amine derivative has the structural features shown in formula (1) or formula (5): （1） （5） in, X1, X2, X3, and X4 are each independently N or CH; R1 and R2 are each independently H, D, halogen, C1~C10 alkyl, C1~C10 alkoxy, C1~C10 alkylthio, or R1 and R2 together with the connected carbon atom to form C3~C10 cycloalkyl or C1~C10 heterocyclic group; R3 is a halogen-substituted C1-C10 alkyl, a sulfonyl-substituted C1-C10 alkyl, an ester-substituted C1-C10 alkyl, an amide-substituted C1-C10 alkyl, a heteroatom-substituted C1-C10 alkyl, a heteroatom-substituted fluorinated C1-C10 alkyl, a C3-C10 cycloalkyl-substituted C1-C10 alkyl, a C1-C10 heterocyclic-substituted C1-C10 alkyl, a C1-C10 alkyl, a C3-C10 cycloalkyl, or a C1-C10 heterocyclic group; optionally, R3 is substituted with at least one D or is unsubstituted; R4 and R5 can be independently H, D, halogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 alkylthio, or R4 and R5 together with the connected carbon atom can form C3-C10 cycloalkyl or C1-C10 heterocyclic groups. R0 is a group represented by formula (2), (3), or (4): （2）， Wherein, ring A2 and ring B2 are each independently substituted or unsubstituted C6~C30 aryl, substituted or unsubstituted C1~C30 heteroaryl, substituted or unsubstituted C1~C30 heterocyclic, or substituted or unsubstituted C3~C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1~C10 alkyl, halogen-substituted C1~C10 alkyl, C1~C10 alkoxy, C1~C10 alkylthio, hydroxyl, C3~C10 cycloalkyl, cyano, and amino. （3）， Wherein, ring A3 and ring B3 are each independently absent, or are substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C1-C30 heteroaryl, substituted or unsubstituted C1-C30 heterocyclic, or substituted or unsubstituted C1-C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; ring A3 and ring B3 are not absent simultaneously; Rings A3 and B3 are fused or screwed onto ring Q1; Cycle Q1 is a substituted or unsubstituted amide-containing 5-10-membered heteroaryl or 5-10-membered heterocyclic group, wherein each substituent is independently selected from at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; Cycle Q1 may optionally also contain a sulfonyl group; （4）， Wherein, ring A4 and ring B4 are each independently absent, or are substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C1-C30 heteroaryl, substituted or unsubstituted C1-C30 heterocyclic, or substituted or unsubstituted C3-C10 cycloalkyl, and the substituted substituents are each independently at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; ring A4 and ring B4 are not absent simultaneously; Rings A4 and B4 are fused or screwed onto ring Q2; Cycle Q2 is a substituted or unsubstituted nitrogen-containing 5-10-membered heteroaryl or 5-10-membered heterocyclic group, wherein each substituent is independently selected from at least one of H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano, and amino; Cycle Q2 may optionally also contain a sulfonyl group; R6 is either H or D; R7 is a C1~C10 alkyl, C1~C10 deuterated alkyl, or -C(O)OR 71 or -C(O)R 72 ; R 71 The substituents are C1-C10 alkyl groups, which may be substituted or unsubstituted, and each substituent is an ester-substituted C6-C30 aryl, ester, or C1-C5 alkyl-substituted 5-10 membered heterocyclic group. R 72 It is a substituted or unsubstituted C1~C10 alkyl group, and the substituents are each independently an amino group or an amino-substituted amide group.

2. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 1, characterized in that, In equation (1), X1, X2, and X3 are CH.

3. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 1, characterized in that, In equation (5), X4 is N.

4. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 1, characterized in that, In equation (5), R6 is H or D; R7 is a C1-C3 alkyl group, a C1-C3 deuterated alkyl group, or one of the following groups: 、 、 、 、 、 、 、 、 。 5. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to any one of claims 1 to 4, characterized in that, R1 and R2 can be H, D, halogen, C1-C3 alkyl, or R1 and R2 together with the connected carbon atom to form a C3-C4 cycloalkyl group. Optionally, for , , , , , , or .

6. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to any one of claims 1 to 4, characterized in that, R3 is -(CH2) n1 -CF3, -(CH2) n2 -S(O)2-(CH2) n3 -CH3 or -(CH2) n4 -O-CF3; Where n1, n2, and n4 are each an integer from 1 to 8; n3 is an integer between 0 and 3; Optionally, R3 may be substituted by at least one D or may not be substituted. Alternatively, R3 is , , , , or .

7. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to any one of claims 1 to 4, characterized in that, R4 and R5 are each independently H, D, or C1~C3 alkyl groups.

8. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to any one of claims 1 to 4, characterized in that, Formula (2) is selected from one of the following groups: Where each m is an independent integer from 1 to 5; X 22 Each can be either N or CR independently; W can be O, S, or NR independently; R can be H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano or amino.

9. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 8, characterized in that, Formula (2) is selected from one of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

10. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 9, characterized in that, In formula (2), R is independently H, F, Br, I, methoxy, hydroxy, methyl, cyclopropyl or cyano; m is 1.

11. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to any one of claims 1 to 4, characterized in that, Formula (3) is selected from one of the following groups: in, X 33 Each can be either N or CR independently; Y can be independently O, S, Se, or NR; Z can be independently O, S, Se, NR or -S(O)2-; T can be independently O, S, Se, NR or -C(R)2-; R can be H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano or amino.

12. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 11, characterized in that, In equation (3), X 33 For CR, Y is independently S or NR; or selected from one of the following groups: 、 、 、 、 、 、 、 、 、 、 。 13. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 12, characterized in that, In formula (3), R is independently H, F, methyl, Cl, Br, cyano, methoxy or trifluoromethyl.

14. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to any one of claims 1 to 4, characterized in that, Formula (4) is selected from one of the following groups: in, X 44 Each can be either N or CR independently; Y can be independently O, S, Se, or NR; Z can be independently O, S, Se, NR or -S(O)2-; T can be independently O, S, Se, NR or -C(R)2-; R can be H, halogen, C1-C10 alkyl, halogen-substituted C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, hydroxyl, C3-C10 cycloalkyl, cyano or amino.

15. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 14, characterized in that, Formula (4) is selected from one of the following groups: 、 、 。 16. The amine derivative or its stereoisomer, isotope derivative, pharmaceutically acceptable salt, solvate, or prodrug molecule according to claim 1, characterized in that, Selected from one of the following compounds:

17. The use of the amine derivatives or stereoisomers thereof, isotopic derivatives, pharmaceutically acceptable salts, solvates, or prodrug molecules according to any one of claims 1 to 16 in the preparation of a medicament for treating and / or preventing viral infections or related diseases caused by viral infections; optionally, the virus includes a pneumonia virus; further optionally, the pneumonia virus includes one or more of respiratory syncytial virus, human metapneumovirus, human influenza virus, animal influenza virus, adenovirus, human parainfluenza virus, mumps virus, measles virus, herpesvirus, cytomegalovirus, and coronavirus; even more optionally, the pneumonia virus includes one or both of respiratory syncytial virus and human metapneumovirus; Optionally, the related diseases caused by the viral infection are bronchitis, pneumonia, asthma, or chronic obstructive pulmonary disease.

18. An antiviral pharmaceutical composition, characterized in that, It includes an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes amine derivatives or stereoisomers thereof, isotope derivatives, pharmaceutically acceptable salts, solvates, and prodrug molecules as described in any one of claims 1 to 16.

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