Respiratory syncytial virus inhibitors, pharmaceutical compositions thereof, and uses thereof

Abstract

Respiratory syncytial virus inhibitors, pharmaceutical compositions thereof and uses. The present application belongs to the field of medicinal chemistry, and relates to a class of RSV inhibitors, pharmaceutical compositions thereof and uses. Specifically, the present application relates to a compound of formula (I), or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound shown in formula (I). The compound and the pharmaceutical composition thereof involved in the present application can inhibit RSV virus replication, achieve the effect of resisting RSV virus, and have good drugability and pharmacokinetic characteristics, and are very suitable for preventing, treating, treating or alleviating the disease caused by infection of RSV in patients.

Description

Invention Field This invention belongs to the field of pharmaceuticals, specifically relating to a class of respiratory syncytial virus inhibitors, their pharmaceutical compositions, and their applications. Background Technology

[0001] Respiratory syncytial virus (RSV) is a single-sense negative-sense RNA virus belonging to the genus *Pneumovirus* of the family Paramyxoviridae. The G and F proteins on its envelope mediate viral invasion of airway epithelial cells. RSV is immunogenic and can induce the production of neutralizing antibodies. RSV readily infects infants under 2 years old, immunocompromised individuals, and the elderly and debilitated individuals. It is the most common pathogen causing acute lower respiratory tract infections in children under 2 years old and the leading cause of hospitalization for viral respiratory infections in infants, seriously endangering their physical and mental health. Although there is considerable research on related vaccine prevention and drug treatment, various problems such as adverse skin reactions often occur during vaccine prevention, and there is currently no specific drug to treat RSV infection-induced disease. Therefore, there is an urgent need to develop more RSV inhibitors to reduce the RSV virus in patients and alleviate disease symptoms. Summary of the Invention

[0002] This invention provides a class of respiratory syncytial virus inhibitors that can inhibit RSV virus replication, achieve anti-RSV virus effects, and have good drug-like properties and pharmacokinetic characteristics, making them very suitable for the protection, treatment, or relief of diseases caused by RSV infection in patients.

[0003] On the one hand, the present invention provides a compound, which is a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0004] in, R 1 and R 2 Each can be independently represented by D, -CN, -OH, -NH2, halogen, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 1-6 Each alkoxy group is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, halogens, -CN, -NH2 and -OH; Ring A is a 5-membered heteroaromatic ring, and ring B is a C8 carbon ring, a 6-10 membered heterocyclic ring, a benzene ring, or a 6-10 membered heteroaromatic ring. Ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is nitrogen (N). Alternatively, ring A is a 5-membered heteroaromatic ring, and ring B is a C6 carbon ring, a 6-7 membered heterocyclic ring, a benzene ring, or a 6-membered heteroaromatic ring. Ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is nitrogen (N). R 3 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. 31 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl; wherein the C 1-6 Alkyl, C 3-6Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; The conditions are: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-6 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -CH2-(C 3-6 cycloalkyl), -CH2-(3-10-membered heterocyclic), -CH2-(5-10-membered heteroaryl), or -CH2-(C 6-10 Aryl), wherein the C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (2) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R.d -C(=O)NR e R f -S(=O)2R d C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl, and R 4 The C is not substituted or unsubstituted phenyl or pyridyl; wherein the C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6 cycloalkyl), -CH2-(3-10-membered heterocyclic), -CH2-(5-10-membered heteroaryl), or -CH2-(C 6-10 (aryl); or two R groups attached to adjacent or non-adjacent different ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0; Among them, R 31 and R 41 Each can be independently classified as D, halogen, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group is independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -OH, halogen, CN, -S(=O)2R k C 1-6 Alkyl and C 3-6 Substituents of cycloalkyl groups; R 32 and R 42 Each can be independently classified as D, halogen, -CN, -OH, or -S(=O)2R. l C 1-6 Alkyl, C 1-6 Alkoxy or C1-6 Halogenated alkyl groups; R j For H, D, C 3-6 cycloalkyl, halogen, -NR n R m Or C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. j1 Replaced; R j1 For D, -OH, CN, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, -NR p R q , 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, 3-10-membered heterocyclic and 5-10-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, C 1-6 Substituted by alkyl, -NH2 and halogen substituents; R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each is independently H, D, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups; p, q, n, and m are each independently 0, 1, 2, 3, or 4.

[0005] In some implementation schemes, R 3 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 1-4Alkyl, C 3-6 cycloalkyl, C 1-4 The alkoxy, 3-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 31 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 41 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 What it replaced.

[0006] In some implementation schemes, R 31 and R 41 Each can be independently classified as D, halogen, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j C 1-4 Alkyl, C 1-5 Alkoxy, C 3-6Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; the C 1-4 Alkyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -OH, halogen, CN, -S(=O)2R k C 1-4 Alkyl and C 3-6 Substituents of cycloalkyl groups; R 32 and R 42 Each can be independently classified as D, halogen, -CN, -OH, or -S(=O)2R. l C 1-4 Alkyl, C 1-5 Alkoxy or C 1-4 Halogenated alkyl groups; R j For H, D, C 3-6 cycloalkyl, -NR n R m halogen or C 1-4 Alkyl, wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. j1 Replaced; R j1 For D, -OH, CN, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, -NR p R q , 3-6 membered heterocyclic group or 5-6 membered heteroaryl group, wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the 5-6 membered heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, C. 1-4 Substituted by alkyl, -NH2 and halogen substituents; R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each is independently H, D, halogen, C 1-4 Alkyl, C3-6 cycloalkyl or C 1-4 Halogenated alkyl groups.

[0007] In some implementation schemes, R 1 and R 2 Each can be independently represented by D, -CN, -OH, -NH2, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Alkoxy; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 1-4 Each alkoxy group may be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, halogens, -CN, -NH2 and -OH.

[0008] In some implementations, ring A and ring B together form any of the following structures: , , , , , , , , , ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 4 The following three-ring structure is formed: ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 3 Form any of the following three-ring structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Among them, X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 and X 9 Each is independently CH or N; each Y is independently O, S or NH; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 and Z 7 Each can be independently CH2, O, S or NH.

[0009] The compound described in this invention is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II).

[0010] Among them, ring A, ring B, and ring R 1 R 2 R 3 R 4 p, q, n and m each have the definitions described in this invention.

[0011] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug; optionally, it further comprises a pharmaceutically acceptable carrier.

[0012] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to protect against, treat, cure or alleviate disease caused by RSV infection in a patient.

[0013] On the other hand, the present invention provides compounds or pharmaceutical compositions described herein for protection, treatment, therapy, or relief of disease caused by RSV infection in patients.

[0014] On the other hand, the present invention provides a method for protecting against, treating, or alleviating diseases caused by RSV infection in a patient, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition described herein. Diseases caused by RSV infection include, but are not limited to, respiratory infections, bronchiolitis, bronchitis, pneumonia, and otitis media.

[0015] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) or (II).

[0016] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0017] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other components of the formulation and the mammal intended for treatment.

[0018] The salts of the compounds of the present invention also include salts for the preparation or purification of intermediates of the compounds of formula (I) or (II) or for the isolation of enantiomers of the compounds of formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0019] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0020] Detailed specifications Definitions and general terms Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within its scope. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0021] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0022] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0023] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles concerning one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0024] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0025] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0026] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structural formulas described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0027] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0028] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, for example ( R )-、( S )- or( R , SThe configuration exists. In some implementations, the asymmetric atoms are in ( R )-or( S - In terms of configuration, it has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess.

[0029] Depending on the choice of starting materials and method, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active ( R )-or( S The )-isomer can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be... E or Z Configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans configuration.

[0030] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0031] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0032] The term "optional" or "optionally" means that an event or situation described below may, but is not guaranteed to, occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optional key" means that the key may or may not be present, and the description includes single, double, or triple keys.

[0033] The term "substituted" indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. As described in this invention, the compounds of this invention may optionally be substituted by one or more substituents, such as the general formula compounds above, or as in the specific examples, subclasses, and classes of compounds included in this invention. The term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted," meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention.

[0034] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0035] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0036] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0037] As used in this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, denoted as C1. 1-12 Alkyl group; in other embodiments, the alkyl group contains 1-6 carbon atoms, denoted as C1. 1-6Alkyl group; in some further embodiments, the alkyl group contains 1-4 carbon atoms, denoted as C1. 1-4 Alkyl group; in some embodiments, the alkyl group contains 1-3 carbon atoms, denoted as C1. 1-3 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (... n -Pr, -CH2CH2CH3), isopropyl ( i -Pr, -CH(CH3)2), n-butyl ( n -Bu、-CH2CH2CH2CH3), isobutyl ( i -Bu、-CH2CH(CH3)2), sec-butyl( s -Bu、-CH(CH3)CH2CH3), tert-butyl( t -Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), n-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0038] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10.1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.

[0039] The term "alkoxy" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy ( n -PrO、 n -propoxy, -OCH2CH2CH3), 2-propoxy ( i -PrO、 i -propoxy, -OCH(CH3)2), 1-butoxy n -BuO、 n -Butoxy, -OCH2CH2CH2CH3), 2-Methyl-1-propoxy ( i -BuO、 i -butoxy, -OCH2CH(CH3)2), 2-butoxy ( s -BuO、 s -Butoxy, -OCH(CH3)CH2CH3), 2-Methyl-2-propoxy t -BuO、 t -Butoxy, -OC(CH3)3), 1-Pentoxy ( n-Pentoxy, -OCH2CH2CH2CH2CH3), 2-Pentoxy (-OCH(CH3)CH2CH2CH3), 3-Pentoxy (-OCH(CH2CH3)2), 2-Methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-Methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-Methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-Methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0040] The term "carbocyclic" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 carbon atoms. Carbocyclic groups include spirobicyclic, fused, and bridged carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and so on.

[0041] The term "cycloalkyl" refers to a monovalent or polyvalent non-aromatic monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms, wherein the -CH2- group in the carbide ring may optionally be replaced by -C(=O)- (or -(CO)-). In some embodiments, the cycloalkyl group comprises 3-12 carbon atoms, i.e., C 3-10 Cycloalkyl; in other embodiments, the cycloalkyl group comprises 3-8 carbon atoms, i.e., C64-C84-C6 ... 3-8 Cycloalkyl; in some further embodiments, the cycloalkyl group comprises 3-6 carbon atoms, i.e., C64-C ... 3-6 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-5 cyclic carbon atoms, i.e., C1 3-5 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of substitution of the -CH2- group in the carbide ring by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc. The cycloalkyl groups may optionally be substituted by one or more substituents described in this invention.

[0042] The terms "heterocycle" and "heterocyclic group" are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system comprising 3-14 ring atoms, wherein one or more atoms on the ring are independently replaced by heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more degrees of unsaturation, but no aromatic rings are permitted. When a heterocycle is attached to other parts of a molecule via a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group may be a carbonyl or heteroatomyl group, and the -CH2- group may optionally be replaced by -C(=O)-; the nitrogen atom of the ring may optionally be oxidized to... N -Oxides; the sulfur atoms in the ring can optionally be oxidized to S -Oxides (such as groups of SO, SO2). In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms and is represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms and is represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms and is represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms and is represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms and is represented as a 5-6 membered heterocycle or a 5-6 membered heterocyclic group. The heterocyclic group is optionally substituted by one or more substituents described in this invention. Examples of heterocyclic groups include, but are not limited to, ethylene oxide, azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl,4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxane, dithiaranyl, thiaranyl, homopiperazineyl, homopiperidinyl, oxetaneheptane, thioheptanyl, oxazolidinyl, diazadinyl, thioazolidinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridinyl, pyrimidinidone, etc. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, etc.

[0043] The terms "aryl" and "aromatic ring" are used interchangeably with "aromatic ring" to refer to monocyclic, bicyclic, and tricyclic carbocyclic systems containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12 Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10-membered aryl groups. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthraceneyl. The aryl group may optionally be substituted by one or more substituents described in this invention.

[0044] The term "heteroaryl" may be used interchangeably with the terms "heteroary ring" or "heteroary compound" to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) at any reasonable site (which may be C or N). When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-; the nitrogen atom of the ring may optionally be oxidized to... N -Oxides; the sulfur atoms in the ring can optionally be oxidized to S -Oxides (such as SO, SO2 groups). The heteroaryl group is optionally substituted with one or more substituents described in this invention. In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl; in still other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl. The heteroaryl group is optionally substituted with one or more substituents described in this invention. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[1,2- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- b [1,2,4]triazolo[4,3-]pyridazinyl,[1,2,4]triazolo[4,3-] b [1,2,4]triazolo[1,5-]pyridazinyl, [1,2,4]triazolo[1,5-] a [Pyrimidinyl, [1,2,4]triazolo[1,5-] a ]Pyridyl, etc.

[0045] The term "bicyclic or tricyclic" includes fused rings, bridged rings, and spirocyclic rings. The bicyclic or tricyclic ring may optionally be substituted with one or more substituents described in this invention. Examples of such substituents include, but are not limited to, bicyclic [2.2.1]heptyl, 2-methyl-diazabicyclic [2.2.1]heptyl, etc.

[0046] The terms “fused ring,” “fused ring,” or “fused ring group” are used interchangeably herein to refer to a saturated or unsaturated ring system formed by two or more ring structures sharing two adjacent ring atoms, which may contain independent or conjugated unsaturated states. Examples of fused ring groups include, but are not limited to, 2,3,3a,4,7,7a-hexahydro-1 H -Indene, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, 3-aza-fused[3.1.0]hexane, 3-aza-bicyclo[3.3.0]octane, hexahydro-furan[3,4- c ]pyrrole, hexahydrothiophene[3,4-c]pyrrole, 3,4,5,6-tetrahydrocyclopentane[ c Thiophene group, etc.

[0047] The terms "bridged ring" and "bridged ring group" are used interchangeably herein to refer to a saturated or unsaturated ring system formed by two or more cyclic structures sharing two non-directly connected ring atoms. Examples of such systems include, but are not limited to, bicyclic [2.2.1]heptyl, 2-oxo-5-azabicyclic [2.2.1]heptyl, 2-thio-5-azabicyclic [2.2.1]heptyl, 2-oxo-5-azabicyclic [2.2.1]heptyl, 2,5-diazabicyclic [2.2.1]heptyl, 2-methyl-2,5-diazabicyclic [2.2.1]heptyl, etc. The bridged ring group may optionally be substituted by one or more substituents described in this invention.

[0048] The terms "spirocyclic" and "spirocyclic group" are used interchangeably here to refer to a saturated or unsaturated ring system formed by two or more ring structures sharing a single ring atom. Each ring in a spirobicyclo group can be a carbocyclic or heterocyclic group, and examples include, but are not limited to, 1,4-dioxo-8-azaspiro[4,5]decane-8-yl, 2-oxo-8-azaspiro[4,5]decane-8-yl, 2,8-diazaspiro[4,5]decane-8-yl, 2,7-diazaspiro[4.4]nonane-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl, etc. The spirocyclic group may optionally be replaced by one or more substituents described in this invention.

[0049] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl).

[0050] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0051] The term "composed of jk atoms" or "jk element" indicates that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k, and any natural number between them. For example, "composed of 3-8 atoms" or "3-8 element", "composed of 3-6 atoms" or "3-6 element", "composed of 5-10 atoms" or "5-10 element", or "composed of 5-6 atoms" or "5-6 element" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0052] As described in this invention, the substituent (R) x ) f A ring system formed by a single bond connecting to a central double ring (as shown in formula a) represents f substituents R. x It can be substituted at any substituted or reasonable position on the ring it is connected to (such as the H ring in equation a). For example, equation a represents that any position on the H ring that can be substituted can be replaced by f R. x Replacement, when f is greater than 1, each R x The substituents can be independently selected from the same or different substituents, such as formula a. 1-3 As shown.

[0053]

[0054] The term "pharmaceuticalally acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar undesirable reactions, such as gastrointestinal upset, dizziness, etc. Preferably, as used herein, the term "pharmaceuticalally acceptable" means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0055] As used in this invention, "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or these salts obtained by other methods described in the literature, such as ion exchange. This invention also contemplates the formation of quaternary ammonium salts from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained through quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0056] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly for injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0057] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I) or (II) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound containing a hydroxyl group can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound.

[0058] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0059] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0060] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0061] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0062] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0063] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0064] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0065] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0066] The pharmaceutically acceptable salts of the present invention can be synthesized using conventional chemical methods from a parent compound, a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other suitable salts can be listed, for example, in “Remington’s Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0067] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form of a solvent containing them (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0068] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotope-labeled reagents instead of the previously used unlabeled reagents, as described in the examples and preparation processes of the present invention.

[0069] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0070] Description of the compounds of the present invention This invention provides a class of RSV inhibitors that can inhibit RSV virus replication, achieve anti-RSV virus effects, and have good drug-like properties and pharmacokinetic characteristics, making them very suitable for the protection, treatment, or relief of diseases caused by RSV infection in patients.

[0071] The compounds of this invention exhibit excellent properties, such as good half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, which can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0072] On the one hand, the present invention provides a compound, which is a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0073] Among them, ring A, ring B, and ring R 1 R 2 R 3 R4 p, q, n and m each have the definitions described in this invention.

[0074] In some implementation schemes, R 1 and R 2 Each can be independently represented by D, -CN, -OH, -NH2, halogen, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 1-6 Each alkoxy group may be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, halogens, -CN, -NH2 and -OH.

[0075] In some implementation schemes, R 1 and R 2 Each can be independently represented by D, -CN, -OH, -NH2, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Alkoxy; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 1-4 Each alkoxy group may be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, halogens, -CN, -NH2 and -OH.

[0076] In other implementations, R 1 and R 2Each of the following can be independently D, -CN, -OH, -NH2, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CH-CH3, -C≡CH, -CH2C≡CH, -C≡C-CH3, -OCH3, -OCH2CH3, or -OCH(CH3)2; wherein the -CH3, - CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CH-CH3, -C≡CH, -CH2C≡CH, -C≡C-CH3, -OCH3, -OCH2CH3 and -OCH(CH3)2 are each independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -CN, -NH2 and -OH.

[0077] In some embodiments, ring A is a 5-membered heteroaromatic ring, and ring B is a C8 carbon ring, a 6-10 membered heterocyclic ring, a benzene ring, or a 6-10 membered heteroaromatic ring. Ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is N. In some embodiments, ring A is a 5-membered heteroaromatic ring, and ring B is a C6 carbon ring, a 6-7 membered heterocyclic ring, a benzene ring, or a 6-membered heteroaromatic ring; ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is N.

[0078] In other embodiments, ring A is pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, or 1,2,4-triazole, and ring B is cyclohexane, cyclohexene, cyclohexadiene, piperidine, piperazine, 1,3-oxazine, hexahydropyrimidine, morpholine, thiomorpholine, tetrahydropyran, dihydropyran, tetrahydrothiaran, 1,2,3,4-tetrahydropyridine, dioxane, dithiaran, thiaxane, cycloheximine, oxacycloheptane, thiocycloheptane, homopiperidine, homopiperazine, benzene ring, pyridine, pyran, pyrimidine, pyridazine, pyrazine, oxazine, 1,3,5-triazine, or 1,2,4-triazine; ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is N.

[0079] In some implementation schemes, R 3 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b Rc -S(=O)2R a C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. 31 Replaced; where R a R b R c R 31 It has the definition described in this invention; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; where R 32 It has the definition described in this invention.

[0080] In some implementation schemes, R 3 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 The alkoxy, 3-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 31 Replaced; where R a R b R c R 31 It has the definition described in this invention; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; where R 32 It has the definition described in this invention.

[0081] In other implementations, R 3 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazineyl, or 1,3,5-triazineyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiazolyl, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophene, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, and 1,3,5-triazinyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 31 Replaced; where R 31 It has the definition described in this invention; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 32 Replaced; where R 32 It has the definition described in this invention.

[0082] In some implementation schemes, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NRe R f -C(=O)NR e R f -S(=O)2R d C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 Replaced; where R d R e R f R 41 It has the definition described in this invention; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; where R 42 It has the definition described in this invention.

[0083] In some implementation schemes, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 41 Replaced; where R d R e R f R 41 It has the definition described in this invention; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; where R 42 It has the definition described in this invention.

[0084] In other implementations, R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazine, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, or 1,3,5-triazine or phenyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(C H3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, and phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 41 Replaced; where R d R e R f R 41 It has the definition described in this invention; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; where R 42 It has the definition described in this invention.

[0085] In some implementations, ring A and ring B together form any of the following structures: , , , , , , , , , ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 4 The following three-ring structure is formed: ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 3 Form any of the following three-ring structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Among them, X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 and X 9 Each is independently CH or N; each Y is independently O, S or NH; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 and Z 7Each can be independently CH2, O, S or NH.

[0086] In other embodiments, ring A and ring B together form any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 4 The following three-ring structure is formed: , , , , , ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 3 Form any of the following three-ring structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0087] The embodiments of the present invention need to meet the following conditions: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-6 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -CH2-(C 3-6 cycloalkyl), -CH2-(3-10-membered heterocyclic), -CH2-(5-10-membered heteroaryl), or -CH2-(C 6-10 Aryl), wherein the C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (2) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are each independently and optionally bound by 1, 2, 3, or 4 R groups.41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl, and R 4 The C is not substituted or unsubstituted phenyl or pyridyl; wherein the C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6 cycloalkyl), -CH2-(3-10-membered heterocyclic), -CH2-(5-10-membered heteroaryl), or -CH2-(C 6-10 (aryl); or two R groups attached to adjacent or non-adjacent different ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form C 3-7Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0; The R mentioned d R e R f R 32 R 41 and R 42 Each has the definition described in this invention.

[0088] In some implementations, the embodiments of the present invention need to meet the following conditions: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-4 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl or phenyl, wherein the C 2-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6 Cycloalkyl), -CH2-(3-6 membered heterocyclic), -CH2-(5-6 membered heteroaryl), or -CH2-phenyl; or two R atoms attached to adjacent or non-adjacent ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 What it replaces; it should be noted that when R 4 Each independently is -CH2-(C 3-6Cycloalkyl), -CH2-(3-6 membered heterocyclic), -CH2-(5-6 membered heteroaryl), or -CH2-phenyl; or two R atoms attached to adjacent or non-adjacent ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 When the ring is a carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, or 3-6 membered heterocyclic ring, m is not 0; or, (2) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-6-membered heteroaryl, and 3-6-membered heterocyclic groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 2-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, each optionally surrounded by 1, 2, 3 or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6Cycloalkyl), -CH2- (3-6 membered heterocyclic group) or -CH2- (5-6 membered heteroaryl group); or two R groups attached to adjacent or non-adjacent different ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0; The R mentioned d R e R f R 32 R 41 and R 42 Each has the definition described in this invention.

[0089] In other embodiments, the present invention needs to meet the following conditions: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d-CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, -CH2-pyrroleyl, -CH2-tetrahydropyranyl, -CH2-phenyl or phenyl, wherein -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -( CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexane, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, -CH2-pyrroleyl, -CH2-tetrahydropyranyl, -CH2-phenyl and phenyl are each independently and optionally surrounded by 1, 2, 3 or 4 R 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; or, (2) When ring A and ring B are formed together At that time, R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d-CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, thiophene, pyrazolyl, isothiazolyl, oxadiazole Triazolyl, Thiodiazolyl, Pyrazinyl, 1,3,5-Triazinyl, Ethylene oxide, Azacyclobutyl, Oxacyclobutyl, Thiocyclobutyl, Pyrrolidinyl, 2-Pyrrolidinyl, 3-Pyrrolidinyl, Pyrazolinyl, Pyrazolylyl, Imidazolinyl, Imidazolylyl, Tetrahydrofuranyl, Dihydrofuranyl, Tetrahydrothiophenyl, Dihydrothiophenyl, 1,3-Dioxocyclopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxyl, dithiaranyl, or thiaranyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrimidinyl, pyridazinyl, thiazolyl, Tetraazolyl, Triazolyl, Thiopheneyl, Pyrazolyl, Isothiazolyl, Oxadiazolyl, Triazolyl, Thiodiazolyl, Pyrazinyl, 1,3,5-Triazinyl, Ethylene oxide, Azacyclobutyl, Oxacyclobutyl, Thiocyclobutyl, Pyrrolidinyl, 2-Pyrrolidinyl, 3-Pyrrolidinyl, Pyrazolinyl, Pyrazolylalkyl, Imidazolinyl, Imidazolylalkyl, Tetrahydrofuranyl, Dihydrofuranyl, Tetrahydrothiophenyl, Dihydrothiophenyl, 1,3-Dioxocyclopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl, 2 H -pyranyl, 4 H -Pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, and thiaranyl are each independently and optionally surrounded by 1, 2, 3, or 4 R's. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d-CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxane, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrimidinyl, pyridazineyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazineyl, or 1,3,5-triazineyl; wherein -CH2CH3, -(CH2)2CH3, -CH(CH3)2, - (CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, and 1,3,5-triazinyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 41 Replaced; or R 4 Each of the following is independently -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-pyrrolidinyl, -CH2-tetrahydropyranyl, -CH2-phenyl or phenyl; or two Rs attached to adjacent or non-adjacent different ring atoms. 4Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, or oxadiazole 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thioaziridine, pyrrolidine, pyrrololine, pyrrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H-Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, or oxadiazole 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thioaziridine, pyrrolidine, pyrrololine, pyrrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0; The R mentioned d R e R f R 32 R 41 and R 42 Each has the definition described in this invention.

[0090] In some implementation schemes, R 31 and R 41 Each can be independently classified as D, halogen, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group is independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -OH, halogen, CN, -S(=O)2R k C 1-6 Alkyl and C 3-6Substituents of cycloalkyl groups; wherein R g R h R i R j and R k Each has the definition described in this invention.

[0091] In some implementation schemes, R 31 and R 41 Each can be independently classified as D, halogen, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j C 1-4 Alkyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; the C 1-4 Alkyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -OH, halogen, CN, -S(=O)2R k C 1-4 Alkyl and C 3-6 Substituents of cycloalkyl groups; wherein R g R h R i R j R k Each has the definition described in this invention.

[0092] In other implementations, R 31 and R 41 Each of these can be independently represented as D, F, Cl, Br, I, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OC H(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -OCH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH3 -OCH(CH2CH3)2, -OC(CH3)2CH2CH3, -OCH(CH3)CH(CH3)2, -OCH2CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazine, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl or phenyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH (CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -OCH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH3, -OCH(CH2CH3)2, -OC(CH3)2CH2CH3, -OCH(CH3)CH(CH3)2, -OCH2CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, and phenyl are each independently and optionally composed of 1, 2, 3, or 4 elements selected from D, -OH, F, Cl, Br, I, CN, -S(=O)2R k Substituents of -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein R g R h R i R j and R k Each has the definition described in this invention.

[0093] In some implementation schemes, R 32 and R 42 Each can be independently classified as D, halogen, -CN, -OH, or -S(=O)2R. l C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; wherein R l It has the definition described in this invention.

[0094] In some implementation schemes, R 32 and R 42 Each can be independently classified as D, halogen, -CN, -OH, or -S(=O)2R. l C 1-4 Alkyl, C 1-5 Alkoxy or C 1-4 Halogenated alkyl groups; wherein R l It has the definition described in this invention.

[0095] In other implementations, R 32 and R 42 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -OH, or -S(=O)2R. l, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2C H3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -OCH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH3, -OCH(CH2CH3)2, -OC(CH3)2CH2CH3, -OCH(CH3)CH(CH 3)2, -OCH2CH2CH(CH3)2, -CH2F, -CHF2, -CF3, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br or -(CH2)2Cl; where R l It has the definition described in this invention.

[0096] In some implementation schemes, R j For H, D, C 3-6 cycloalkyl, -NR n R m halogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. j1 Replaced; where R j1 R n and R m It has the definition described in this invention.

[0097] In some implementation schemes, R j For H, D, C 3-6 cycloalkyl, -NR n R m halogen or C 1-4 Alkyl, wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. j1 Replaced; where R j1 R n and R m It has the definition described in this invention.

[0098] In other implementations, R j For H, D, -NR n R mCyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 or -C(CH3)3, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 and -C(CH3)3 are optionally surrounded by 1, 2, 3 or 4 Rs. j1 Replaced; where R j1 R n and R m It has the definition described in this invention.

[0099] In some implementation schemes, R j1 For D, CN, -OH, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, -NR p R q , 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, 3-10-membered heterocyclic and 5-10-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, C 1-6 Substituents include alkyl groups, -NH2 groups, and halogen groups; wherein R p and R q It has the definition described in this invention.

[0100] In some implementation schemes, R j1 For D, CN, -OH, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, -NR p R q , 3-6 membered heterocyclic group or 5-6 membered heteroaryl group, wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl group, the 3-6 membered heterocyclic group, and the 5-6 membered heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, C. 1-4 Substituents include alkyl groups, -NH2 groups, and halogen groups; wherein R p and R q It has the definition described in this invention.

[0101] In other implementations, R j1The following are not part of the diethylcarboxylic acid group: D, CN, -OH, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR p R q Ethylene oxide, aziridine, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxane, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazineyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazineyl, or 1,3,5-triazineyl, wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3) )2、-(CH2)3CH3、-CH2CH(CH3)2、-C(CH3)3、cyclopropyl、cyclobutyl、cyclopentyl、cyclohexyl、epoxyethylene、azacyclobutyl、oxacyclobutyl、thiocyclobutyl、pyrrolidinyl、2-pyrrolinyl、3-pyrrolinyl、pyrazolinyl、pyrazolyl、imidazolinyl、imidazolinyl、tetrahydrofuranyl、dihydrofuranyl、tetrahydrothiophenyl、dihydrothiophenyl、1,3-dioxocyclopentyl、dithiocyclopentyl、tetrahydropyranyl、dihydropyranyl、2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazine, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazinel 1,3,5-triazine are each independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -NH2, F, Cl, Br and I; wherein R p and R q It has the definition described in this invention.

[0102] In some implementation schemes, R a R b Rc R d R e R f R g R h R i R k R l R n R m R p and R q Each is independently H, D, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

[0103] In some implementation schemes, R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each is independently H, D, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-4 Halogenated alkyl groups.

[0104] In other implementations, R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each can be independently H, D, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br or -(CH2)2Cl.

[0105] In some implementations, p, q, n, and m are each independently 0, 1, 2, 3, or 4.

[0106] In other embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II).

[0107] Among them, ring A, ring B, and ring R 1 R 2 R 3 R 4 p, q, n and m each have the definitions described in this invention.

[0108] In some embodiments, the compounds of the present invention comprise one of the following structures or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs: .

[0109] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug; optionally, it further comprises a pharmaceutically acceptable carrier.

[0110] On the other hand, the present invention provides the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to protect against, treat, cure or alleviate disease caused by RSV infection in a patient.

[0111] On the other hand, the present invention provides the compounds or pharmaceutical compositions described herein to protect against, treat, cure or alleviate disease caused by RSV infection in patients.

[0112] On the other hand, the present invention provides a method for protecting, treating, or alleviating disease caused by RSV infection in a patient, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition described herein.

[0113] Among them, diseases caused by RSV infection include, but are not limited to, respiratory tract infections, bronchiolitis, bronchitis, pneumonia, and otitis media.

[0114] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) or formula (II).

[0115] Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0116] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically appropriate in relation to the other components of the formulation and the mammal intended for treatment.

[0117] The salts of the compounds of the present invention also include salts for the preparation or purification of intermediates of the compounds of formula (I) or (II) or for the isolation of enantiomers of the compounds of formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0118] If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, etc. Alternatively, organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid can be used; pyranonic acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc.

[0119] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic or organic bases, such as ammonia (primary, secondary, and tertiary ammonia), alkali metal hydroxides, or alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine; ammonia, such as primary, secondary, and tertiary ammonia; and cyclic ammonia, such as piperidine, morpholine, and piperazine, etc.; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0120] Pharmaceutical compositions, formulations, administration and uses of the compounds of the present invention According to another aspect, the pharmaceutical compositions of the present invention are characterized by comprising compounds represented by formula (I) or formula (II), compounds listed in the present invention, or compounds of the embodiments, and pharmaceutically acceptable carriers. The compounds of the present invention exist in free form, or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues. The amounts of compounds in the compositions of the present invention are effective in treating or alleviating disease caused by RSV infection in patients.

[0121] Among them, diseases caused by RSV infection include, but are not limited to, respiratory tract infections, bronchiolitis, bronchitis, pneumonia, and otitis media.

[0122] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a specific target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21 st The contents of this literature, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, 2005 edition, demonstrate that various carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional carrier media, except for those incompatible with the compounds of the present invention, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention.

[0123] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0124] Preferably, the compound is mixed with a suitable drug diluent, excipient, or carrier (in this case, a drug carrier) selected according to the form of administration and conventional pharmaceutical practice, and the administration method may be oral tablets, capsules, elixirs, syrups, etc.

[0125] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be conjugated with an orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical ingredient can be conjugated with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerin, water, etc. Furthermore, suitable binders, lubricants, dissolving agents, and colorants can be added to the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Decomposing agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0126] The compounds of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0127] The compounds of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0128] The compounds of this invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0129] The compounds of this invention are also coupled with soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0130] The dosing regimen of the compounds of this invention will vary depending on various known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective dose of the drug to prevent, counteract, or halt the development of disease caused by RSV infection.

[0131] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0132] The compounds or their pharmaceutical salts or hydrates involved in this invention are effective in preventing, treating or alleviating diseases caused by RSV infection in patients.

[0133] General Synthesis Process Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0134] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0135] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0136] The examples described below are in Celsius unless otherwise stated. Unless otherwise stated, common reagents are commercially available.

[0137] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples refers to 10°C to 30°C; in some examples, room temperature is 15°C to 30°C; and in some examples, room temperature is 20°C to 30°C. Unless otherwise specified, common reagents are commercially available, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous acetonitrile, and anhydrous dichloromethane, as well as toluene, diethyl ether, ethyl acetate, petroleum ether, n-hexane, and dimethyl sulfoxide. N , N -dimethylacetamide and N , N -Dimethylformamide, etc.

[0138] The following reactions are generally carried out at room temperature and pressure, or under positive nitrogen pressure, or with a drying tube attached to anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers. Solid substrates are generally added directly, while liquid substrates can be added using a dropper or syringe. All glassware is dried.

[0139] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0140] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 ¹H NMR spectra with CDCl₃ and DMSO- d 6. CD3OD or acetone - d6 represents the solvent (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constant. J It is represented by Hertz (Hz).

[0141] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min; mobile phase: 5%–95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0142] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0143] The following abbreviations are used throughout this invention: CDC13 deuterated chloroform Diox or Dioxane 1,4-dioxane THF tetrahydrofuran CMPI2-chloro-1-methylpyridine iodide DIPEA N, N -Diisopropylethylamine DMF N, N -Dimethylformamide ACN acetonitrile DCM dichloromethane TEA Triethylamine TFA (trifluoroacetic acid) MTBE (methyl tert-butyl ether) tBuOK potassium tert-butoxide PE petroleum ether EA ethyl acetate Sodium tert-amyl alcohol STA (Boc)2O ditert-butyl dicarbonate 2,6-lutidine-2,6-dimethylpyridine PdCl2(PPh3)2 or (PPh3)2PdCl2 bis(triphenylphosphine)palladium dichloride Pd(dppf)Cl2·DCM[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex Pd2(dba)3tris(dibenzylacetone)dipalladium Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene PPh3·HBr triphenylphosphine hydrobromide Pd(PPh3)4 tetratetraphenylphosphine palladium DMSO dimethyl sulfoxide DMAP4-Dimethylaminopyridine DDQ2,3-Dichloro-5,6-Dicyanobenzoquinone NBS N - Succinimide bromide NMP N -Methylpyrrolidone TsCl p-Toluenesulfonyl chloride HMPT tris(dimethylamino)phosphine TMSA Trimethylsilylacetylene NIS N -Iodosuccinimide LAH Lithium Aluminum Hydrogen BrettPhos-Pd-G3 methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) rt, rt or RT room temperature Mmol / L The following reaction scheme describes the steps for preparing the compounds disclosed in this invention.

[0144] Reaction Scheme 1

[0145] Compound X-1 reacts with compound X-2 under suitable conditions (in the presence of sodium carbonate or cesium carbonate) to give compound X-3; compound X-3 reacts with compound X-4a or X-4b under suitable conditions (such as in the presence of BrettPhos-Pd-G3 or Pd(dppf)Cl2·CH2Cl2 and sodium carbonate) to give compound X-5; compound X-5 is deprotected under suitable conditions (such as in the presence of lithium hydroxide or sodium hydroxide or palladium on carbon-hydrogen) to give compound X-6 (such as R...). x (If H is used, this step can be omitted); the compound of formula X-6 and the compound of formula X-7 are condensed under suitable conditions (such as the action of CMPI, DIPEA or triethylamine) to obtain the target product compound of formula (I-1) shown.

[0146] Among them, X 4 X 5 X 6 X 7 R 1 R 2 R 32 R 4 p, q each have the definitions described in this invention; R x It is H, methyl, ethyl, tert-butyl or benzyl; Hal1 is preferably Cl, Br or I, and s is 0, 1, 2, 3 or 4.

[0147] Reaction Scheme 2

[0148] Compound X-8 reacts under suitable conditions (such as SOCl2 or NBS) to give compound X-9; compound X-9 reacts with compound X-10a under the conditions of synthesis to give compound X-10; compound X-10 is deprotected under suitable conditions (such as lithium hydroxide, sodium hydroxide, or palladium on carbon-hydrogen) to give compound X-11 (such as R). x (If H is used, this step can be omitted); the compound of formula X-11 and the compound of formula X-7 are condensed under suitable conditions (such as the action of CMPI, DIPEA or triethylamine) to obtain the target product compound of formula (I-2) shown.

[0149] Among them, X 2 X 3 X 4 X 5 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; R xIt can be H, methyl, ethyl, tert-butyl or benzyl; Hal1 is preferably Cl, Br or I.

[0150] Reaction scheme 3

[0151] Compounds of formulas X-12, X-13, X-14, and X-15 react under suitable conditions (TEA, DDQ) to give compound X-16; compound X-16 is deprotected under suitable conditions (such as lithium hydroxide, sodium hydroxide, or palladium on carbon-hydrogen) to give compound X-17 (such as R). x (If H is used, this step can be omitted); Compound X-17 and Compound X-7 are condensed under suitable conditions (such as the action of CMPI, DIPEA or triethylamine) to obtain the target product compound (I-3) shown.

[0152] Among them, R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; R x It can be H, methyl, ethyl, tert-butyl, or benzyl.

[0153] Reaction scheme 4

[0154] Compounds X-18 and X-19 react under suitable conditions (with TEA, CuI, and PdCl2(PPh3)2) to give compound X-20; compound X-20 is cyclized to compound X-21 under suitable conditions (such as with potassium tert-butoxide or sodium tert-butoxide); compound X-21 reacts with reagent xR under suitable conditions (with cesium carbonate). 4’ The reaction (e.g., I-CH3) yields compound X-22; compound X-22 reacts under suitable conditions (with the action of NIS) to yield compound X-23; compound X-23 reacts under suitable conditions (with the action of Zn(CN)2 or CuCN) to yield compound X-24; compound X-24 reacts under suitable conditions (with the action of KOH) to yield compound X-25; compound X-25 and compound X-7 are condensed under suitable conditions (e.g., with the action of CMPI, DIPEA or triethylamine) to yield the target product compound (I-4) shown.

[0155] Among them, X 1 X 2 X 3 X4 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; Hal1 is preferably Cl, Br, or I; R 4’ It has the definition as described in this invention; x is a leaving group, such as Cl, Br, I, OH, etc.

[0156] Reaction scheme 5

[0157] Compound X-26 and compound X-19 react under suitable conditions (①TEA, CuI, PdCl2(PPh3)2, ②Na2S) to give compound X-27; compound X-27 reacts under suitable conditions (e.g., NBS) to give compound X-28; compound X-28 and compound Y-1 react under suitable conditions (XantPhos Pd G3, triethylamine) to give compound X-29; compound X-29 reacts under suitable conditions (e.g., NaOH) to give compound X-30; compound X-30 and compound X-7 condense under suitable conditions (e.g., CMPI, DIPEA or triethylamine) to give the target product compound (I-5) shown.

[0158] Among them, X 1 X 2 X 3 X 4 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; Hal1 and Hal2 are preferably Cl, Br, or I.

[0159] Reaction scheme 6

[0160] Compound X-31 and compound X-32 (such as tribromofluoromethane) react under suitable conditions (with HMPT) to give compound X-33; compound X-33 reacts under suitable conditions (Fe(NO3)3·9H2O) to give compound X-34; compound X-35 and compound X-36 react in a suitable solvent (such as ethyl acetate) to give compound X-37; compound X-34 and compound X-37 are cyclized to compound X-38 under suitable conditions (with copper acetate monohydrate); compound X-38 is reacted under suitable conditions (such as with lithium hydroxide, sodium hydroxide, or palladium on carbon-hydrogen) to give compound X-39; compound X-39 and compound X-7 are condensed under suitable conditions (such as with CMPI, DIPEA, or triethylamine) to give the target product compound (I-6) shown.

[0161] Among them, X 3 X 4 X 5 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; R x H, methyl, ethyl, tert-butyl, or benzyl; R 4’’ Having the features of the present invention R 4 The definition stated above.

[0162] Reaction Scheme 7

[0163] Compound X-40 reacts with compounds X-4a or X-4b under suitable conditions (such as the action of BrettPhos-Pd-G3 or Pd(dppf)Cl2·CH2Cl2 with sodium carbonate) to give compound X-41; compound X-41 and R 4’ -Hal2 reacts under suitable conditions (such as potassium carbonate) to give compound X-42; compound X-42 is deprotected under suitable conditions (such as lithium hydroxide or sodium hydroxide or palladium on carbon-hydrogen) to give compound X-43 (such as R). x (If H is used, this step can be omitted); Compound X-43 and Compound X-7 are condensed under suitable conditions (such as the action of CMPI, DIPEA or triethylamine) to obtain the target product compound (I-4) shown.

[0164] Among them, X 1 X 2 X 3 X4 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; R x H, methyl, ethyl, tert-butyl, or benzyl; Hal1 and Hal2 are preferably Cl, Br, or I; R 4’ Having the features of the present invention R 4 The definition stated above.

[0165] Reaction Scheme 8

[0166]

[0167] Compound X-44 reacts under suitable conditions (e.g., triphenylphosphine hydrobromide) to give compound X-45; compound X-46 reacts with di-tert-butyl dicarbonate under suitable conditions (e.g., triethylamine, DMAP) to give compound X-47; compounds X-45 and X-47 react under suitable conditions (e.g., cesium carbonate) to give compound X-48; compound X-48 reacts under suitable conditions (e.g., hydroxylamine hydrochloride) to give compound X-49; compound X-49 reacts under suitable conditions (e.g., copper acetate, acetonitrile, etc.) to give compound X-50; compound X-50 reacts under suitable conditions (e.g., trifluoroacetic acid, etc.) to give compound X-51; compound X-51 condenses with compound X-7 under suitable conditions (e.g., CMPI, DIPEA, or triethylamine) to give the target product compound (I-8) shown.

[0168] Among them, X 2 X 3 X 4 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; R x It can be H, methyl, ethyl, tert-butyl or benzyl; Hal1 is preferably Cl, Br or I.

[0169] Reaction Scheme 9

[0170] Compound X-52 reacts with compound X-4a or X-4b under suitable conditions (such as the action of BrettPhos-Pd-G3 or Pd(dppf)Cl2·CH2Cl2 with sodium carbonate) to give compound X-53; compound X-53 is then deprotected under suitable conditions (such as the action of lithium hydroxide or sodium hydroxide or palladium on carbon-hydrogen) to give compound X-54 (such as R...). x (If H is used, this step can be omitted); Compound X-54 and Compound X-7 are condensed under suitable conditions (such as the action of CMPI, DIPEA or triethylamine) to obtain the target product compound (I-9) shown.

[0171] Among them, X 2 X 3 X 4 X 5 X 6 X 7 R 1 R 2 R 3 R 4 p, q, and n each have the definitions described in this invention; R x It can be H, methyl, ethyl, tert-butyl or benzyl; Hal1 is preferably Cl, Br or I.

[0172] Example Intermediate M: ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one

[0173] Step 1)2-(1 H -benzo[ d Synthesis of [1,2,3]triazol-1-yl)-2-(((benzyloxy)carbonyl)amino)acetic acid 1 H -benzo[ d[1,2,3] Triazole (10 g, 83.95 mmol), benzyl carbamate (13.32 g, 88.15 mmol), glyoxylic acid (7.77 g, 104.94 mmol), and toluene (300 mL) were added to a three-necked round-bottom flask and stirred at 60 °C for 4.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (100 mL), stirred at room temperature for 1 h, filtered, and the filter cake was washed successively with a mixture of water (50 mL), toluene (50 mL), and methyl tert-butyl ether (100 mL). The mixture was dried under vacuum at 60 °C to give the title compound as a white solid (21.80 g, 79.58%).

[0174] Step 2)(1-(1) H -benzo[ d Synthesis of [1,2,3]triazol-1-yl)-2-((2-benzoylphenyl)amino)-2-oxoethyl)carbamate benzyl ester 2-(1) H -benzo[ d [1,2,3]triazol-1-yl)-2-(((benzyloxy)carbonyl)amino)acetic acid (10 g, 30.65 mmol), 2-aminobenzophenone (6.05 g, 30.65 mmol) and 2-(7-azobenzotriazole)- N , N , N’ , N’ Tetramethylurea hexafluorophosphate (13.98 g, 36.78 mmol) was added to a three-necked round-bottom flask, and tetrahydrofuran (90 mL) was added under nitrogen atmosphere and at 0 °C. N , N - Dimethylformamide (10 mL), added while stirring N , N -Diisopropylethylamine (11.88 g, 91.95 mmol) was heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (80 mL × 2), the organic phase was washed with saturated brine (50 mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (15.1 g, 97.47%).

[0175] Step 3: Synthesis of benzyl 1-amino-2-((2-benzoylphenyl)amino)-2-oxoethyl)carbamate (1-(1) H -benzo[ d[1,2,3]triazol-1-yl)-2-((2-benzophenyl)amino)-2-oxoethyl)carbamate (10 g, 19.78 mmol) and 7M ammonia-methanol solution (56.51 mL) were added to a three-necked round-bottom flask and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL), washed successively with sodium hydroxide solution (1 M, 100 mL) and saturated brine (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (7.90 g, 98.99%).

[0176] Step 4)(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e Synthesis of [1,4]diaza-3-yl)carbamate benzyl ester (1-Amino-2-((2-benzoylphenyl)amino)-2-oxoethyl)carbamate (7.9 g, 19.58 mmol) and acetic acid (40 mL) were added to a three-necked round-bottom flask. Ammonium acetate (7.55 g, 97.90 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 5.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was diluted with methyl tert-butyl ether (100 mL). The system was adjusted to pH 8 with sodium hydroxide solution (1 M), stirred at room temperature for half an hour, filtered, and the filter cake was washed with methyl tert-butyl ether (100 mL) and dried to give the title compound as a white solid (4.41 g, 58.43%). MS (ESI, pos. ion) m / z: 386.10 (M+1). Step 5) 3-Amino-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one (2-oxo-5-phenyl-2,3-dihydro-1) H -benzo[ e[1,4]diaza-3-yl)carbamate (5 g, 12.97 mmol) and methanol (40 mL) were added to a single-necked round-bottom flask. 10% palladium on carbon (0.76 g) was added to the reaction mixture. The reaction system was purged with nitrogen three times, followed by hydrogen three times. The mixture was stirred at 60 °C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. The filter cake was washed multiple times with a mixed solvent of dichloromethane (100 mL) and methanol (10 mL). The filtrate was concentrated by vacuum distillation. The residue was slurried with methyl tert-butyl ether (100 mL), filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL). The residue was dried under reduced pressure to give the title compound as a gray solid (2.4 g, 73.62%). MS (ESI, pos. ion) m / z: 252.10 (M+1). Step 6) S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one 3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (2.4 g, 9.55 mmol), D-(+)-di-p-methylbenzoyl tartaric acid (3.69 g, 9.55 mmol), and 1,4-dioxane (90 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 22 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with 1,4-dioxane (50 mL). The mixture was then vacuum filtered at room temperature, and the crude solid product was transferred to a single-necked reaction flask. Sodium hydroxide (1 M, 50 mL) was added, and the mixture was stirred at room temperature for 22 hours. The mixture was then filtered, and the filter cake was washed with water (30 mL × 2). The mixture was then vacuum filtered at room temperature and dried to give the title compound as a white solid (1.2 g, 50%). MS (ESI, pos. ion) m / z: 252.1 (M+1). HPLC purity: 99.24%. ee value: 99.82%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 10.65 (s, 1H), 7.58 (t, J = 7.2 Hz,1H), 7.54 – 7.38 (m, 5H), 7.27 (d, J = 8.0 Hz, 2H), 7.20 (t, J =7.2 Hz (1H), 4.24 (s, 1H). Intermediate N: ( S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one

[0177]

[0178] Step 1: (1-(1) H -benzo[ d Synthesis of [1,2,3]triazol-1-yl)-2-((2-benzoyl-6-fluorophenyl)amino)-2-oxoethyl)carbamate Add 2-(1) to the reaction flask H -benzo[ d [1,2,3]triazol-1-yl)-2-(((benzyloxy)carbonyl)amino)acetic acid (21.83 g, 66.91 mmol), (2-amino-3-fluorophenyl)(phenyl)methyl ketone (12 g, 55.76 mmol), 4-dimethylaminopyridine (17.71 g, 144.98 mmol), tetrahydrofuran (150 mL), dichloromethane (150 mL), and phosphorus oxychloride (11.54 g, 75.28 mmol) were added dropwise. The reaction mixture was reacted at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, water (1000 mL) was added to the residue, and the mixture was extracted with dichloromethane (200 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brownish-red solid (25 g, 85.65%).

[0179] Step 2: Synthesis of (1-amino-2-((2-benzoyl-6-fluorophenyl)amino)-2-oxoethyl)carbamate benzyl ester Add (1-(1) to the reaction flask H -benzo[ d[1,2,3]triazol-1-yl)-2-((2-benzoyl-6-fluorophenyl)amino)-2-oxoethyl)carbamate (25 g, 47.75 mmol), methanol solution of 7 mol / L ammonia (48.79 g, 2865 mmol), reacted at room temperature for 23 h. The reaction solution was concentrated under reduced pressure, and ethyl acetate (60 mL) was added to the residue. The organic phase was washed with 1 M NaOH (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brownish-red oil (20 g, 99.38%).

[0180] Step 3: (9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e Synthesis of [1,4]diaza-3-yl)carbamate benzyl ester (1-Amino-2-((2-benzoyl-6-fluorophenyl)amino)-2-oxoethyl)carbamate (20 g, 47.46 mmol), glacial acetic acid (70 mL), and ammonium acetate (18.29 g, 237.3 mmol) were added to a reaction flask, and the reaction was carried out at room temperature for 21 h. The reaction solution was concentrated under reduced pressure, and ethyl acetate (150 mL) and water (300 mL) were added to the residue. The pH of the solution was adjusted to 8 with 1 M NaOH, stirred for 3 min, and then allowed to stand for separation. The aqueous phase was extracted again with ethyl acetate (60 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give the title compound as a brownish-yellow viscous oil (9.31 g, 48.63%). MS (ESI, pos. ion)m / z: 404.2 (M+1). Step 4: 3-Amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one Add (9-fluoro-2-oxo-5-phenyl-2,3-dihydro-1-phenyl) to the reaction flask H -benzo[ e[1,4]diaza-3-yl)benzyl carbamate (9.2 g, 22.81 mmol), methanol (50 mL), tetrahydrofuran (50 mL), 10% palladium on carbon (0.90 g, 0.84 mmol), and hydrogen were used to replace the reaction mixture three times. The reaction was carried out at room temperature for 6 h under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth and vacuum filtration. The filter cake was washed with tetrahydrofuran (10 mL × 3) and methanol (10 mL × 3), respectively. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 1 / 4) to give the title compound as a brownish-yellow solid (1.36 g, 22.15%). MS (ESI, pos. ion) m / z: 270.1 (M+1). Step 5:( S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one Add 3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 ... H -benzo[ e [1,4]diazazo-2-one (1.36 g, 5.05 mmol), 1,4-dioxane (55 mL), D-(+)-di-p-methylbenzoyl tartaric acid (1.95 g, 5.05 mmol), stirred at room temperature for 26 h. The mixture was filtered, and the filter cake was washed with 1,4-dioxane (10 mL × 2). The mixture was dried under vacuum at 50 °C to obtain the crude product. 1 mol / L sodium hydroxide (20.2 mL, 20.2 mmol) was added to the crude product, and the mixture was stirred at room temperature for 6 h. Water (20 mL) was added, and the mixture was stirred for another 13 h at room temperature. The mixture was filtered to obtain the mother liquor and filter cake, the filter cake of which was washed with water (10 mL × 3). The filter cake was collected and dried under vacuum at 55 °C to obtain 0.4257 g of the title compound. The mother liquor was extracted sequentially with dichloromethane (30 mL × 4) and dichloromethane / methanol (v / v) = 10 / 1 (30 mL × 6). The extracted organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.3007 g of the title compound. The two samples were combined to obtain the title compound as a pale yellow solid (0.7264 g, 53.41%). MS (ESI, pos. ion) m / z: 270.1 (M+1). ee value: 100%, peak time: 26.519 min.

[0181] 1 H NMR (400 MHz, DMSO- d6) δ (ppm): 7.58 – 7.38 (m, 6H), 7.24 (td, J = 8.0, 5.1 Hz, 1H), 7.09 (d, J = 7.9 Hz (1H), 4.32 (s, 1H). 19 FNMR (376MHz, DMSO-) d 6) δ (ppm): -124.13 (s). Example 1 ( S )-2-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-7,8-dihydro-6 H - Cyclopenta[ e Imidazole [1,2- b Synthesis of pyridazine-3-carboxamide

[0182] Step 1) Synthesis of ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropionate Ethyl (2-fluorobenzoyl)ethyl acetate (1.5 g, 7.14 mmol) and methyl tert-butyl ether (15 mL) were added to a single-necked round-bottom flask. Thionyl chloride (0.64 mL) was added dropwise under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and reacted for 3.5 hours. After the reaction was complete, ethyl acetate (50 mL) was added to dilute the reaction mixture, followed by saturated sodium bicarbonate solution (50 mL). The mixture was separated, and the organic phase was washed with saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.7 g, 97.37%). MS (ESI, pos. ion) m / z: 245.05 (M+1). Step 2) 2-(2-fluorophenyl)-7,8-dihydro-6 H - Cyclopenta[ e Imidazole [1,2- b Synthesis of pyridazine-3-carboxylic acid ethyl ester Ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropionate (0.54 g, 2.22 mmol), 6,7-dihydro-5 H - Cyclopenta[ cPyridazine-3-amine (0.3 g, 2.22 mmol) and ethanol (25 mL) were added to a single-necked round-bottom flask and reacted at 90 °C for 6.5 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 3) to give the title compound as a pale yellow solid (0.075 g, 10.39%). MS (ESI, pos.ion) m / z: 326.1 (M+1). Step 3) 2-(2-fluorophenyl)-7,8-dihydro-6 H - Cyclopenta[ e Imidazole [1,2- b Synthesis of pyridazine-3-carboxylic acid 2-(2-fluorophenyl)-7,8-dihydro-6 H - Cyclopenta[ e Imidazole [1,2- b Ethyl pyridazine-3-carboxylate (0.075 g, 0.23 mmol), methanol (4 mL), and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (0.039 g, 0.92 mmol, dissolved in water (0.46 mL)). The reaction was carried out at room temperature for 6 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL), and the aqueous phase was adjusted to pH ≤4 with 2 M HCl. The aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.067 g, 97.77%). MS (ESI, pos. ion) m / z: 298.1 (M+1). Step 4) S )-2-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-7,8-dihydro-6 H - Cyclopenta[ e Imidazole [1,2- b Synthesis of pyridazine-3-carboxamide 2-(2-fluorophenyl)-7,8-dihydro-6 H - Cyclopenta[ e Imidazole [1,2- b ]pyridazine-3-carboxylic acid (0.067 g, 0.23 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2H -benzo[ e [1,4]diaza-2-one (0.064 g, 0.25 mmol), 2-chloro-1-methylpyridine iodide (0.076 g, 0.30 mmol), N , N Dimethylformamide (5 mL) and tetrahydrofuran (5 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N- Diisopropylethylamine (0.089 g, 0.69 mmol) was reacted at room temperature for 1.5 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 9) to give the title compound as a white solid (0.029 g, 24.25%). MS (ESI, pos. ion) m / z: 531.3 (M+1). HPLC purity: 90.76%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.01 (s, 1H), 10.26 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.68 – 7.61 (m, 1H), 7.52 (ddd, J = 6.9, 6.4, 1.7 Hz, 2H),7.45 (q, J = 6.7 Hz, 5H), 7.35 – 7.30 (m, 2H), 7.29 – 7.22 (m, 2H), 7.21 – 7.15(m, 1H), 5.46 (d, J = 7.6 Hz, 1H), 3.19 (td, J = 7.5, 4.7 Hz, 2H), 3.09 (t, J = 6.8Hz, 2H), 2.28 – 2.19 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -113.22 (s). Example 2 ( S )-6-cyano-7-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e[1,4]diaza-3-yl)pyrrolo[1,2- a Synthesis of pyrimidine-8-carboxamide

[0183] Step 1) Z Synthesis of 2-bromo-3-(2-fluorophenyl)propenal Triphenylphosphine hydrobromide (8.23 g, 23.98 mmol) was added to a three-necked flask, and the reaction system was purged with nitrogen three times. Dimethyl sulfoxide (30 mL) was slowly added, followed by o-fluorocinnamaldehyde (1.5 g, 9.99 mmol) under stirring at room temperature. The reaction was carried out at 80 °C for 23 hours. After the reaction was completed, a saturated ammonium chloride solution (50 mL) was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 100 / 1) to give the title compound as a pale yellow solid (1.45 g, 63.37%).

[0184] 1 H NMR (599 MHz, CDCl3) δ (ppm): 9.40 (s, 1H), 8.48 – 8.41 (m, 1H), 8.18 (s, 1H), 7.52 (ddd, J = 15.3, 5.5, 1.6 Hz, 1H), 7.30 (dd, J = 12.7, 4.3 Hz,1H), 7.22 – 7.15 (m, 1H). Step 2) Synthesis of tert-butyl 2-(pyrimidin-2-yl)acetate 2-(pyrimidin-2-yl)acetic acid (3.0 g, 21.72 mmol), di-tert-butyl dicarbonate (7.11 g, 32.58 mmol), 4-dimethylaminopyridine (0.53 g, 4.34 mmol), triethylamine (4.53 mL, 32.58 mmol), and tetrahydrofuran (15 mL) were added to a single-necked round-bottom flask and stirred at 60 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 2) to give the title compound as a white solid (1.04 g, 24.65%). MS (ESI, pos. ion) m / z: 139.10 (M-56+1). Step 3) 7-(2-fluorophenyl)-6-formylpyrrolo[1,2-a Synthesis of tert-butyl pyrimidine-8-carboxylic acid Will( Z 2-Bromo-3-(2-fluorophenyl)propenal (0.88 g, 3.85 mmol), tert-butyl 2-(pyrimidin-2-yl)acetate (0.5 g, 2.57 mmol), cesium carbonate (1.26 g, 3.85 mmol) and N , N Dimethylformamide (25 mL) was added to a single-necked round-bottom flask and stirred at room temperature for 15 hours. After the reaction was complete, the reaction solution was filtered, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 3) to give the title compound as a brown oil (0.135 g, 15.41%). MS (ESI, pos. ion) m / z: 285.10 (M-56+1). Step 4) E )-7-(2-fluorophenyl)-6-(hydroxyimino)methyl)pyrrolo[1,2- a Synthesis of tert-butyl pyrimidine-8-carboxylic acid 7-(2-fluorophenyl)-6-carboxypyrrolo[1,2- a 0.135 g (0.40 mmol) of tert-butyl pyrimidine-8-carboxylate, 0.042 g (0.60 mmol) of hydroxylamine hydrochloride, and 10 mL of dimethyl sulfoxide were added to a single-necked round-bottom flask and stirred at 90 °C for 5.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with 50 mL of water, extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil (0.14 g, 99.32%). MS (ESI, pos. ion) m / z: 300.10 (M-56+1). Step 5) 6-Cyano-7-(2-fluorophenyl)pyrrolo[1,2- a Synthesis of tert-butyl pyrimidine-8-carboxylic acid Will( E )-7-(2-fluorophenyl)-6-(hydroxyimino)methyl)pyrrolo[1,2- a0.14 g (0.39 mmol) of tert-butyl pyrimidine-8-carboxylate, 0.035 g (0.20 mmol) of copper acetate, and 15 mL of acetonitrile were added to a single-necked round-bottom flask and stirred at 80 °C for 5.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with 30 mL of water, extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 2) to give the title compound as a brown oil (0.025 g, 18.81%). MS (ESI, pos. ion) m / z: 282.0 (M-56+1). Step 6) 6-Cyano-7-(2-fluorophenyl)pyrrolo[1,2- a Synthesis of pyrimidine-8-carboxylic acid 6-cyano-7-(2-fluorophenyl)pyrrolo[1,2- a Pyrimidine-8-carboxylic acid tert-butyl ester (0.010 g, 0.03 mmol), trifluoroacetic acid (0.092 g, 0.81 mmol), and dichloromethane (4 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 3.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the title compound as a brown solid (0.008 g, 95.96%). MS (ESI, pos. ion) m / z: 282.10 (M+1). Step 7) S )-6-cyano-7-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- a Synthesis of pyrimidine-8-carboxamide 6-cyano-7-(2-fluorophenyl)pyrrolo[1,2- a Pyrimidine-8-carboxylic acid (0.020 g, 0.071 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diazazon-2-one (0.020 g, 0.078 mmol), 2-chloro-1-methylpyridine iodide (0.024 g, 0.092 mmol), N , NDimethylformamide (2 mL) and tetrahydrofuran (2 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.028 g, 0.21 mmol) was reacted at room temperature for 5 hours. After the reaction, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 4) to give the title compound as an off-white solid (0.021 g, 57.39%). MS (ESI, pos. ion) m / z: 515.10 (M+1). HPLC purity: 98.90%. 1 H NMR (599 MHz, DMSO- d 6) δ (ppm): 10.97 (s, 1H), 9.93 (d, J = 8.0 Hz, 1H), 9.13 (dd, J = 7.0, 1.5 Hz, 1H), 8.89 (dd, J = 4.2, 1.5 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.53 – 7.42 (m, 7H), 7.40 (dd, J = 7.0, 4.2 Hz, 1H), 7.33 – 7.23 (m,5H), 5.43 (d, J = 8.0 Hz, 1H). Example 3 ( S )-5-cyano-6-(1-isopropyl-1 H -pyrazole-4-yl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide

[0185] Step 1) 5-Cyano-6-(1-Isopropyl-1 H -pyrazol-4-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid ethyl ester Pyridazine (0.40 g, 4.99 mmol), ethyl bromoacetate (1.13 g, 6.79 mmol), and ethanol (20 mL) were added to a single-necked round-bottom flask and reacted at room temperature for 2 hours; then 1-isopropyl-1 H 4-Pyrazole-4-carboxaldehyde (0.62 g, 4.49 mmol), 2-cyanoacetamide (0.38 g, 4.49 mmol), and triethylamine (1.25 mL, 8.98 mmol) were reacted at room temperature for 6 hours; finally, 2,3-dichloro-5,6-dicyanobenzoquinone (2.04 g, 8.89 mmol) was added, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 4) to give the title compound as a yellow solid (0.17 g, 11.70%). MS (ESI, pos.ion) m / z: 324.20 (M+1). Step 2) 5-Cyano-6-(1-Isopropyl-1 H -pyrazol-4-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid 5-cyano-6-(1-isopropyl-1 H -pyrazol-4-yl)pyrrolo[1,2- b Ethyl pyridazine-7-carboxylate (0.17 g, 0.53 mmol), methanol (8 mL), and tetrahydrofuran (8 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (0.089 g, 2.12 mmol, dissolved in water (1.06 mL)). The reaction was allowed to proceed at room temperature for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL), and the aqueous phase was adjusted to pH ≤ 4 with 2 M HCl. The mixture was then extracted with ethyl acetate (30 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (0.122 g, 78.58%). MS (ESI, pos. ion) m / z: 295.85 (M+1). Step 3) S )-5-cyano-6-(1-isopropyl-1 H -pyrazole-4-yl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide 5-cyano-6-(1-isopropyl-1 H -pyrazol-4-yl)pyrrolo[1,2- b ]pyridazine-7-carboxylic acid (0.10 g, 0.34 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (0.10 g, 0.41 mmol), 2-chloro-1-methylpyridine iodide (0.11 g, 0.44 mmol), N , N Dimethylformamide (4 mL) and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.13 g, 1.02 mmol) was reacted at room temperature for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give the title compound as a white solid (0.006 g, 3.35%). MS (ESI, pos. ion) m / z: 529.70 (M+1). HPLC purity: 98.61%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.08 (s, 1H), 10.39 (d, J = 6.9 Hz,1H), 8.76 (s, 1H), 8.43 – 8.33 (m, 2H), 7.99 (s, 1H), 7.65 (s, 1H), 7.49 (dd, J = 20.2, 7.0 Hz, 5H), 7.35 (d, J = 7.7 Hz, 3H), 7.25 (s, 1H), 5.47 (d, J = 6.1Hz, 1H), 4.64 – 4.54 (m, 1H), 1.45 (d, J = 6.5 Hz, 6H). Example 4 ( S )-5-cyano-6-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e[1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide

[0186] Step 1) 5-Cyano-6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid ethyl ester Pyridazine (0.20 g, 2.50 mmol), ethyl bromoacetate (0.57 g, 3.40 mmol), and ethanol (20 mL) were added to a single-necked round-bottom flask and reacted at room temperature for 2.5 h. Then, 2-fluoro-4-(methanesulfonyl)benzaldehyde (0.45 g, 2.25 mmol), 2-cyanoacetamide (0.19 g, 2.25 mmol), and triethylamine (0.63 mL, 4.5 mmol) were added to the reaction mixture, and the reaction was carried out at room temperature for 4 h. Finally, 2,3-dichloro-5,6-dicyanobenzoquinone (1.02 g, 4.5 mmol) was added, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 3) to give the title compound as a yellow oil (0.08 g, 9.19%). MS (ESI, pos.ion) m / z: 387.90 (M+1). Step 2) 5-Cyano-6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid 5-cyano-6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b Ethyl pyridazine-7-carboxylate (0.08 g, 0.21 mmol), methanol (3 mL), and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (0.035 g, 0.84 mmol, dissolved in water (0.42 mL)). The reaction was allowed to proceed at room temperature for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL), and the aqueous phase was adjusted to pH ≤ 4 with 2 M HCl. The mixture was then extracted with ethyl acetate (30 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (0.067 g, 90.29%). MS (ESI, neg. ion) m / z: 314.00 (M-44-1). Step 3) S)-5-cyano-6-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide 5-cyano-6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b ]pyridazine-7-carboxylic acid (0.05 g, 0.14 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diazazon-2-one (0.039 g, 0.15 mmol), 2-chloro-1-methylpyridine iodide (0.046 g, 0.18 mmol), N , N Dimethylformamide (4 mL) and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N- Diisopropylethylamine (0.054 g, 0.42 mmol) was reacted at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 4) to give the title compound as a white solid (0.045 g, 54.57%). MS (ESI, pos. ion) m / z: 593.90 (M+1). HPLC purity: 99.13%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.05 (s, 1H), 10.37 (d, J = 7.0 Hz,1H), 8.98 (s, 1H), 8.59 (d, J = 8.9 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.84 – 7.77(m, 1H), 7.69 – 7.60 (m, 1H), 7.51 (d, J = 2.2 Hz, 2H), 7.45 (s, 4H), 7.35 –7.20 (m, 3H), 5.43 (d, J = 7.3 Hz (1H), 3.35 (s, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -109.74 (s). Example 5 ( S )-6-(2-Fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)imidazolium[1,2-] b Synthesis of [1,2,4]triazine-7-carboxamide

[0187] Step 1) 6-(2-fluorophenyl)imidazol [1,2- b Synthesis of [1,2,4]triazine-7-carboxylic acid ethyl ester Ethyl 3-(2-fluorophenyl)-3-oxopropionate (0.25 g, 1.19 mmol), 1,2,4-triazine-3-amine (0.23 g, 2.38 mmol), N - Succinimide bromide (0.25 g, 1.19 mmol) and N 10 mL of methylpyrrolidone was added to a single-necked round-bottom flask, and the reaction was carried out at 80 °C for 7.5 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with 30 mL of water, extracted with ethyl acetate (30 mL × 2), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 3) to give the title compound as a yellow oil (0.24 g, 69.91%). MS (ESI, pos. ion) m / z: 287.1 (M+1). Step 2) 6-(2-fluorophenyl)imidazole [1,2- b Synthesis of [1,2,4]triazine-7-carboxylic acid 6-(2-fluorophenyl)imidazolium [1,2- b[1,2,4]Ethyl triazine-7-carboxylate (0.24 g, 0.83 mmol), methanol (8 mL), and tetrahydrofuran (8 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (0.14 g, 3.32 mmol, dissolved in water (1.66 mL)). The reaction was carried out at room temperature for 17 hours. Sodium hydroxide (0.080, 2.0 mmol) was then added, and the reaction was carried out at room temperature for 5.5 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the aqueous phase was adjusted to pH ≤ 2 with 2 M HCl. The aqueous phase was extracted with ethyl acetate (30 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (0.045 g, 21.05%). MS (ESI, pos. ion) m / z: 259.1 (M+1). Step 3) S )-6-(2-Fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[ e [1,4]diaza-3-yl)imidazolium[1,2-] b Synthesis of [1,2,4]triazine-7-carboxamide 6-(2-fluorophenyl)imidazolium [1,2- b [1,2,4] Triazine-7-carboxylic acid (0.045 g, 0.17 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (0.047 g, 0.19 mmol), 2-chloro-1-methylpyridine iodide (0.056 g, 0.22 mmol), N , N Dimethylformamide (5 mL) and tetrahydrofuran (5 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.066 g, 0.51 mmol) was reacted at room temperature for 1.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA) to give the title compound as a yellow solid (0.030 g, 35.52%). MS (ESI, pos. ion) m / z: 492.2 (M+1). HPLC purity: 93.05%. 1H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.07 (s, 1H), 9.78 (d, J = 7.3 Hz,1H), 9.07 (s, 1H), 8.89 (s, 1H), 7.69 – 7.61 (m, 2H), 7.48 (dd, J = 20.6, 6.9Hz, 6H), 7.37 – 7.24 (m, 5H), 5.47 (d, J = 7.3 Hz, 1H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -112.84 (s). Example 6 ( S )-5-fluoro-6-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide

[0188] Step 1) Synthesis of 1-(2-bromo-2-fluorovinyl)-2-fluoro-4-(methylsulfonyl)benzene 2-Fluoro-4-(methylsulfonyl)benzaldehyde (0.50 g, 2.47 mmol), tribromofluoromethane (0.73 mL, 7.41 mmol), tris(dimethylamino)phosphine (2.69 mL, 14.82 mmol), and tetrahydrofuran (20 mL) were added to a single-necked round-bottom flask and reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA(v / v) = 5 / 2) to give the title compound as a white solid (0.25 g, 34.03%).

[0189] Step 2) Synthesis of 2-fluoro-1-(2-fluoro-2-nitrovinyl)-4-(methylsulfonyl)benzene 1-(2-bromo-2-fluorovinyl)-2-fluoro-4-(methanesulfonyl)benzene (0.25 g, 0.84 mmol) and 1,4-dioxane (16 mL) were added to a single-necked round-bottom flask, and ferric nitrate nonahydrate (1.02 g, 2.52 mmol) was added with stirring. The reaction was carried out at 100 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5 / 4) to give the title compound as a white solid (0.18 g, 80.82%). MS (ESI, pos. ion) m / z: 264.2 (M+1). Step 3) Synthesis of 1-(2-ethoxy-2-oxoethyl)pyridazine-1-bromium bromide Pyridazine (0.20 g, 2.50 mmol) and ethyl acetate (15 mL) were added to a single-necked round-bottom flask. Ethyl bromoacetate (0.42 g, 2.50 mmol) was added at 0 °C, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the title compound as a brown solid (0.61 g, 98.86%). MS (ESI, pos. ion) m / z: 167.10 (M-78+1). Step 4) 5-Fluoro-6-(2-Fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid ethyl ester 2-Fluoro-1-(2-fluoro-2-nitrovinyl)-4-(methanesulfonyl)benzene (0.15 g, 0.57 mmol), 1-(2-ethoxy-2-oxoethyl)pyridazine-1-bromium (0.21 g, 0.85 mmol), copper acetate monohydrate (0.057 g, 0.28 mmol), 2,6-dimethylpyridine (0.31 g, 2.85 mmol), 1,4-dioxane (10 mL), and molecular sieve (100 mg) were added to a single-necked round-bottom flask and reacted at 80 °C for 4.5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to give the title compound as a brown oil (0.054 g, 24.91%). MS (ESI, pos. ion) m / z: 380.95 (M+1). Step 5) 5-Fluoro-6-(2-Fluoro-4-(Methylsulfonyl)phenyl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid 5-fluoro-6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b Ethyl pyridazine-7-carboxylate (0.054 g, 0.14 mmol), methanol (4 mL), and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (0.023 g, 0.56 mmol, dissolved in water (0.28 mL)). The reaction was carried out at room temperature for 8 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the aqueous phase was adjusted to pH ≤ 4 with 2 M HCl, extracted with ethyl acetate (30 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.041 g, 81.97%). MS (ESI, pos. ion) m / z: 353.00 (M+1). Step 6) S )-5-fluoro-6-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide 5-fluoro-6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolo[1,2- b ]pyridazine-7-carboxylic acid (0.041 g, 0.12 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (0.036 g, 0.14 mmol), 2-chloro-1-methylpyridine iodide (0.040 g, 0.16 mmol), N , N Dimethylformamide (5 mL) and tetrahydrofuran (5 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , NDiisopropylethylamine (0.047 g, 0.36 mmol) was reacted at room temperature for 1.5 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 3) to give the title compound as a yellow solid (0.031 g, 45.49%). MS (ESI, pos. ion) m / z: 586.60 (M+1). HPLC purity: 96.73%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.02 (s, 1H), 10.35 (d, J = 7.6 Hz, 1H), 8.72 (d, J = 3.4 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.86 – 7.74 (m, 3H), 7.64 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 5.9 Hz, 1H), 7.48 – 7.41 (m, 4H), 7.31 (d, J = 9.6 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.13 (dd, J = 9.0, 4.3 Hz, 1H), 5.43 (d, J = 7.6 Hz (1H), 3.32 (s, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -110.01 (s), -170.79 (s). Example 7 ( S )-6-(2-fluorophenyl)-5-methyl- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide

[0190] Step 1) Synthesis of 3-((2-fluorophenyl)ethynyl)pyrazine-2-amine 3-Bromopyrazin-2-amine (3.0 g, 17.24 mmol), cuprous iodide (0.66 g, 3.45 mmol), PdCl₂(PPh₃)₂ (1.21 g, 1.72 mmol), triethylamine (15 mL), and 1-ethynyl-2-fluorobenzene (2.34 mL, 20.69 mmol) were added to a 50 mL single-necked flask. After addition, the mixture was purged twice with nitrogen and reacted at room temperature for 17 h under nitrogen protection. The reaction was then stopped. The mixture was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give the title compound as a yellow solid (2.9 g, 78.89%). MS (ESI, pos. ion) m / z: 214.1 (M+1). Step 2) 6-(2-fluorophenyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine 3-((2-fluorophenyl)ethynyl)pyrazin-2-amine (2.9 g, 13.60 mmol), potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 27.2 mL, 27.2 mmol), N , N 10 mL of dimethylformamide was added to a 50 mL single-necked flask. After the addition was complete, the mixture was heated to 80 °C and reacted for 2.5 h. The reaction was then stopped. The mixture was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (1.66 g, 57.24%). MS (ESI, pos.ion) m / z: 214.1 (M+1). Step 3) 6-(2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine 6-(2-fluorophenyl)-5 H -pyrrolo[2,3- bPyrazine (0.5 g, 2.35 mmol), cesium carbonate (2.30 g, 7.05 mmol), methyl iodoform (0.18 mL, 2.82 mmol), and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask. After addition, the reaction was allowed to proceed at room temperature for 2.5 h, at which point the reaction was stopped. The mixture was filtered, and the filtrate was extracted with water (80 mL) and ethyl acetate (60 mL × 2). The organic phases were combined, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The mixture was then purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give the title compound as a yellow solid (0.2 g, 37.53%). MS (ESI, pos. ion) m / z: 228.2 (M+1). Step 4) 6-(2-fluorophenyl)-7-iodo-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine 6-(2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Pyrazine (200 mg, 0.88 mmol), acetonitrile (10 mL), N -Iodosuccinimide (217.78 mg, 0.97 mmol) was added to a 50 mL single-necked flask. After the addition was complete, the mixture was heated to 90 °C and reacted for 1 h. The reaction was then stopped. After cooling to room temperature, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (60 mL), washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound as a pale yellow solid (300.0 mg, 96.53%). MS (ESI, pos. ion) m / z: 354.0 (M+1). Step 5) 6-(2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxynitrile 6-(2-fluorophenyl)-7-iodo-5-methyl-5 H -pyrrolo[2,3- bPyrazine (300 mg, 0.85 mmol), zinc cyanide (0.2 g, 1.7 mmol), Xantphos (0.049 g, 0.085 mmol), zinc powder (0.056 g, 0.85 mmol), cesium carbonate (0.55 g, 1.7 mmol), Pd2(dba)3 (0.049 g, 0.085 mmol), N , N 10 mL of dimethylformamide was added to a 50 mL single-necked flask. After the addition was complete, the mixture was purged twice with nitrogen. The mixture was then heated to 100 °C under a nitrogen atmosphere and reacted for 2 h. The reaction mixture was then stopped. The reaction solution was cooled to room temperature, evaporated to dryness under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give the title compound as a yellow solid (214.0 mg, 99.86%). MS (ESI, pos. ion) m / z: 253.2 (M+1). Step 6) 6-(2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxylic acid 6-(2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Pyrazine-7-carboxynitrile (214 mg, 0.85 mmol), potassium hydroxide (0.48 g, 8.5 mmol), methanol (10 mL), and water (10 mL) were added to a 50 mL single-necked flask. After the addition was complete, the mixture was heated to 100 °C and reacted for 9.5 h. The reaction mixture was then stopped. The reaction solution was cooled to room temperature, and the organic solvent was evaporated under reduced pressure. Water (10 mL) was added to the residual solvent, and the pH was adjusted to 3-4 with 3M HCl solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, evaporated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to give the title compound as a white solid (106.1 mg, 46.11%). MS (ESI, pos. ion) m / z: 272.2 (M+1). Step 7) S )-6-(2-fluorophenyl)-5-methyl- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide 6-(2-fluorophenyl)-5-methyl-5H -pyrrolo[2,3- b Pyrazine-7-carboxylic acid (86 mg, 0.32 mmol), dichloromethane (5 mL), N , N Add one drop of dimethylformamide to a 25 mL single-necked flask, then continue adding oxaloyl chloride (0.14 mL, 1.6 mmol). After the addition is complete, react at room temperature for 30 min, evaporate to dryness, and then dissolve in tetrahydrofuran (2 mL) for later use. S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (80.41 mg, 0.32 mmol), pyridine (0.10 mL, 0.28 mmol), and tetrahydrofuran (5 mL) were added to a 25 mL single-necked flask. After addition, the mixture was stirred at room temperature for about 30 min. A previously prepared tetrahydrofuran solution (2 mL) was added, and the reaction was allowed to proceed at room temperature for 22 h. The reaction was then stopped. The solution was evaporated to dryness under reduced pressure, and the final product was prepared by reverse phase chromatography to give the title compound as a yellow solid (5.8 mg, 3.49%). MS (ESI, pos. ion) m / z: 505.2 (M+1). HPLC purity: 96.25%. 1 H NMR (599 MHz, DMSO- d 6) δ (ppm): 10.94 (s, 1H), 9.91 (dd, J = 16.1, 8.2 Hz, 1H), 8.78 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 7.66 – 7.54 (m,3H), 7.52 (d, J = 4.2 Hz, 1H), 7.45 (tt, J = 14.8, 7.2 Hz, 4H), 7.41 – 7.28 (m,4H), 7.26 (t, J = 7.6 Hz, 1H), 5.46 (d, J = 8.0 Hz (1H), 3.67 (s, 3H). Example 8 ( S )-6-(2-fluorophenyl)-5-(2-methoxyethyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e[1,4]diaza-3-yl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide

[0191] Step 1) Synthesis of 3-((2-fluorophenyl)ethynyl)pyrazine-2-amine At 26.7 °C, 3-bromopyrazin-2-amine (3.0 g, 17.24 mmol), CuI (0.66 g, 3.45 mmol), and Pd(PPh3)2Cl2 (1.21 g, 1.72 mmol) were added to a 50 mL single-necked flask and dissolved in TEA (15 mL). 1-ethynyl-2-fluorobenzene (2.34 mL, 20.69 mmol) was added dropwise with stirring at room temperature. After the addition was complete, the mixture was purged twice with nitrogen, and the reaction was continued at room temperature under N2 protection for approximately 17 h before the reaction was stopped. The reaction solution was concentrated, and the crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1), yielding a yellow solid product (2.9 g, 78.89%). MS (ESI, pos. ion) m / z: 214.1 (M+1). Step 2) 6-(2-Fluorophenyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine At 26.3℃, 3-((2-fluorophenyl)ethynyl)pyrazin-2-amine (2.9 g, 13.60 mmol) was added to a 50 mL single-necked flask and dissolved in DMF (10 mL). While stirring at room temperature, 1 mol / L potassium tert-butoxide tetrahydrofuran solution (27.2 mL, 27.2 mmol) was added. After the addition was complete, the mixture was heated to 80℃ and the reaction was maintained for approximately 2.5 h. The reaction solution was concentrated, and the crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1), yielding a yellow solid product (1.66 g, 57.24%). MS (ESI, pos. ion) m / z: 214.1 (M+1). Step 3) 6-(2-fluorophenyl)-5-(2-methoxyethyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine 6-(2-fluorophenyl)-5 H -pyrrolo[2,3- b Pyrazine (1 g, 4.69 mmol), cesium carbonate (2.29 g, 7.04 mmol), 2-bromoethyl methyl ether (0.88 mL, 9.38 mmol), N, N 10 mL of dimethylformamide was added to a 50 mL single-necked flask and reacted at room temperature for 18.5 h. The reaction was then stopped. The mixture was filtered, and the filtrate was extracted with 80 mL of water and 2 x 60 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of water and 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give the title compound, butter (616.1 mg, 48.42%). MS (ESI, pos. ion) m / z: 272.2 (M+1). Step 4) 6-(2-fluorophenyl)-7-iodine-5-(2-methoxyethyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine 6-(2-fluorophenyl)-5-(2-methoxyethyl)-5 H -pyrrolo[2,3- b Pyrazine (616 mg, 2.27 mmol) and acetonitrile (10 mL) were added to a 50 mL single-necked flask and stirred at room temperature. N -Iodosuccinimide (561.78 mg, 2.50 mmol), after addition, heated to 90 °C and reacted for 1 h, then the reaction was stopped; the reaction solution was cooled to room temperature, evaporated under reduced pressure, and extracted with water (50 mL) and ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (60 mL), washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound as a brownish-yellow solid (860.8 mg, 95.45%). MS (ESI, pos. ion) m / z: 398.0 (M+1). Step 5) 6-(2-Fluorophenyl)-5-(2-Methoxyethyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxynitrile 6-(2-fluorophenyl)-7-iodine-5-(2-methoxyethyl)-5 H -pyrrolo[2,3- bPyrazine (860 mg, 2.17 mmol), cuprous cyanide (0.58 g, 6.51 mmol), and dimethyl sulfoxide (10 mL) were added to a 50 mL single-necked flask. After addition, the mixture was purged twice with nitrogen, heated to 150 °C under a nitrogen atmosphere, and reacted for 8.5 h. The reaction mixture was then stopped. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (60 mL × 3), and washed with saturated brine (60 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to give the title compound as a pale yellow solid (413.6 mg, 64.47%). MS (ESI, pos. ion) m / z: 297.1 (M+1). Step 6) 6-(2-Fluorophenyl)-5-(2-Methoxyethyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxylic acid 6-(2-fluorophenyl)-5-(2-methoxyethyl)-5 H -pyrrolo[2,3- b Pyrazine-7-carboxynitrile (413.6 mg, 1.40 mmol), methanol (10 mL), water (10 mL), and potassium hydroxide (0.79 g, 14 mmol) were added to a 50 mL single-necked flask. After the addition was complete, the system was heated to 100 °C and reacted for 4 h. The reaction was then stopped. The reaction solution was cooled to room temperature, most of the solvent was removed by vortexing, and water (10 mL) was added to the remaining solvent. The pH was adjusted to 3-4 with 3M HCl solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, evaporated to dryness under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 3) to give the title compound as a white solid (130 mg, 29.54%).

[0192] Step 7) (S)-6-(2-fluorophenyl)-5-(2-methoxyethyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide 6-(2-fluorophenyl)-5-(2-methoxyethyl)-5 H -pyrrolo[2,3- b Pyrazine-7-carboxylic acid (130 mg, 0.41 mmol), dichloromethane (5 mL), N , NAdd one drop of dimethylformamide to a 25 mL single-necked flask, and continue adding oxaloyl chloride (0.17 mL, 2.05 mmol). After the addition is complete, stir at room temperature for 30 min. Concentrate the reaction solution and dissolve it in tetrahydrofuran (2 mL) for later use. S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (103.02 mg, 0.41 mmol), tetrahydrofuran (5 mL), and pyridine (0.13 mL, 1.64 mmol) were added to a 25 mL single-necked flask. After the addition was complete, the mixture was stirred at room temperature for 30 min. Then, a previously prepared tetrahydrofuran solution (2 mL) was added, and the reaction was allowed to proceed for 22 h at room temperature. The reaction was then stopped. The mixture was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 3) to give the title compound as a yellow solid (6 mg, 2.13%). MS (ESI, pos. ion) m / z: 549.1 (M+1). 1 H NMR (599 MHz, DMSO- d 6) δ (ppm): 10.98 (d, J = 11.4 Hz, 1H), 9.91 (dd, J = 17.4, 8.2 Hz, 1H), 8.78 (d, J = 2.7 Hz, 1H), 8.59 (d, J = 2.6 Hz, 1H), 8.06 –7.92 (m, 1H), 7.56 (ddd, J = 29.5, 18.8, 6.1 Hz, 6H), 7.30 (ddt, J = 22.5, 14.8,8.0 Hz, 6H), 5.45 (dd, J = 8.4, 2.7 Hz, 1H), 4.33 (dd, J = 10.6, 4.8 Hz, 2H), 3.54 – 3.48 (m, 2H), 3.01 (s, 3H). Example 9 ( S )-7-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0193] Step 1) Synthesis of 4-fluoro-2-(hydroxymethyl)phenol Methyl 5-fluoro-2-hydroxybenzoate (140 mg, 0.82 mmol) was added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (10 mL), and stirred in an ice bath for 5 minutes. Lithium aluminum hydride (31.12 mg, 0.82 mmol) was slowly added, and stirring continued in an ice bath for another 5 minutes. The mixture was then moved to room temperature and stirred for 16 hours. After the reaction was complete, saturated sodium sulfate solution (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was added to water (5 mL), extracted with ethyl acetate (15 mL), and the organic phase was concentrated under reduced pressure to give the title compound as a pale yellow oil (80 mg, 68.40%). MS (ESI, negative ion) m / z : 141.1 (M-1) Step 2) 2-Bromo-7-Fluoro-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 3,5-dibromo-1 H Add 480 mg (1.61 mmol) of pyrazole-4-carboxylic acid ethyl ester to a 100 mL single-necked round-bottom flask, and add... N , N Dissolve 10 mL of dimethylformamide, and add potassium carbonate (667.55 mg, 4.83 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (228.83 mg, 1.61 mmol) sequentially with stirring at room temperature. Heat to 150 °C and react for approximately 24 hours. Stop the reaction, cool the reaction solution to room temperature, add 15 mL of saturated brine, and extract with ethyl acetate (20 mL × 2). Combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give the title compound as a yellow solid (163 mg, 29.66%). MS (ESI, pos. ion) m / z: 340.9 (M+1). Step 3) 7-Fluoro-2-(2-Fluoro-4-(Methylsulfonyl)phenyl)-9 H -benzo[ e]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-7-fluoro-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]oxazine-3-carboxylic acid ethyl ester (220 mg, 0.64 mmol), (2-fluoro-4-(methanesulfonyl)phenyl)boronic acid (167.43 mg, 0.77 mmol), sodium carbonate (135.67 mg, 1.28 mmol), and BrettPhos-Pd-G3 (116.03 mg, 0.13 mmol) were added to a 100 mL single-necked round-bottom flask. 1,4-dioxane (10 mL) and water (0.7 mL) were added to dissolve the flask. The reaction mixture was purged with nitrogen three times and heated to 90 °C for 6.5 h. The reaction was stopped, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give the title compound as a yellow solid (186 mg, 62.79%). MS (ESI, pos.ion) m / z: 435.0 (M+1). HPLC purity: 94.57%. Step 4) 7-Fluoro-2-(2-Fluoro-4-(Methylsulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 7-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b[1,3]Oxazine-3-carboxylic acid ethyl ester (158 mg, 0.36 mmol) was added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (4 mL), water (4 mL), and methanol (4 mL). Lithium hydroxide monohydrate (75.53 mg, 1.80 mmol) was added, and the mixture was heated to 50 °C for 6 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to water (20 mL), and extracted with ethyl acetate (20 mL) to remove impurities. The aqueous phase was adjusted to pH ≤ 2 with 4 mol / L hydrochloric acid, and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a creamy white solid (140 mg, 92.51%). MS (ESI, pos. ion) m / z: 406.9 (M+1). HPLC purity: 97.66%. Step 5) S )-7-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide At room temperature, 7-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (110 mg, 0.27 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (71.24 mg, 0.28 mmol) and 2-chloro-1-methylpyridine iodide (103.47 mg, 0.41 mmol) were added to a 50 mL single-necked round-bottom flask, along with tetrahydrofuran (10 mL) and... N , N Dissolve dimethylformamide (1 mL), stir for about 5 minutes, and continue adding dropwise. N , N-Diisopropylethylamine (104.68 mg, 0.81 mmol) was stirred for 6.5 hours. The reaction was stopped, the reaction solution was concentrated under reduced pressure, the residue was added to water (15 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to give the title compound as a white solid (140 mg, 92.51%). MS (ESI, pos. ion) m / z: 639.9 (M+1). HPLC purity: 99.70%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.03 (s, 1H), 8.41 (d, J = 7.4 Hz,1H), 7.83 – 7.75 (m, 3H), 7.67 – 7.62 (m, 1H), 7.52 – 7.31 (m, 10H), 7.26 (t, J = 7.5 Hz, 1H), 5.48 (s, 2H), 5.33 (d, J = 7.4 Hz (1H), 3.31 (s, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ (ppm): 168.20, 167.19, 160.33 (d, J = 144.8Hz), 160.21, 158.69 (d, J = 133.1 Hz), 146.62, 144.78, 143.53 (d, J = 1.9 Hz), 142.95 (d, J = 6.7 Hz), 139.00, 138.57, 132.85 (d, J = 2.2 Hz), 132.61, 131.07,130.84, 129.87, 128.83, 127.10 (d, J = 15.0 Hz), 127.01, 123.95, 122.94 (d, J = 3.2 Hz), 122.12, 118.77 (d, J = 8.9 Hz), 118.28 (d, J =9.1 Hz), 116.89 (d, J = 24.1 Hz), 114.81 (d, J = 25.4 Hz), 114.71 (d, J = 25.2 Hz), 97.79, 67.76, 46.05,43.64. 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -109.90 (s), -117.53 (s). Example 10 ( S )-2-(1-(2-hydroxy-2-methylpropyl)-1 H -pyrazole-4-yl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0194] Step 1) 2-Bromo-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 3,5-dibromo-1 H Add 200 mg (0.67 mmol) of pyrazole-4-carboxylic acid ethyl ester to a 50 mL single-necked round-bottom flask, and add... N , N Dissolve 10 mL of dimethylformamide, add potassium carbonate (280 mg, 2.01 mmol) and salicylol (87 mg, 0.70 mmol), and heat to 150 °C for approximately 20 hours. Stop the reaction, cool the reaction solution to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give the title compound as a yellow solid (71.6 mg, 33.01%). MS (ESI, pos. ion) m / z: 323.0 (M+1). Step 2) 2-(1-(2-hydroxy-2-methylpropyl)-1 H -pyrazole-4-yl)-9 H -benzo[ e]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-7-fluoro-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (150 mg, 0.46 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxorane) - 2-base)-1 H 1,4-pyrazol-1-yl)propane-2-ol (183.64 mg, 0.69 mmol), sodium carbonate (135.67 mg, 1.28 mmol), and BrettPhos-Pd-G3 (116.03 mg, 0.13 mmol) were added to a 100 mL single-necked round-bottom flask. 1,4-dioxane (10 mL) and water (0.7 mL) were added to dissolve the flask. The reaction mixture was purged with nitrogen three times and heated to 90 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a creamy white solid (125 mg, 69.54%). MS (ESI, pos. ion) m / z: 382.8 (M+1). HPLC purity: 98.75%. Step 3) 2-(1-(2-hydroxy-2-methylpropyl)-1 H -pyrazole-4-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 2-(1-(2-hydroxy-2-methylpropyl)-1 H -pyrazole-4-yl)-9 H -benzo[ e ]pyrazolo[5,1- b[1,3]Oxazine-3-carboxylic acid ethyl ester (100 mg, 0.26 mmol) was added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (4 mL), water (4 mL), and methanol (4 mL). Lithium hydroxide monohydrate (54.55 mg, 1.3 mmol) was added, and the mixture was heated to 50 °C for 7.5 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to water (15 mL), and extracted with ethyl acetate (20 mL) to remove impurities. The aqueous phase was adjusted to pH ≤ 2 with 4 mol / L hydrochloric acid, and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a creamy white solid (92 mg, 96.71%). MS (ESI, pos. ion) m / z: 355.2 (M+1). HPLC purity: 97.41%. Step 4) S )-2-(1-(2-hydroxy-2-methylpropyl)-1 H -pyrazole-4-yl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide At room temperature, 2-(1-(2-hydroxy-2-methylpropyl)-1 H -pyrazole-4-yl)-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (74 mg, 0.21 mmol), ( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (55.41 mg, 0.22 mmol) and 2-chloro-1-methylpyridine iodide (80.48 mg, 0.32 mmol) were added to a 50 mL single-necked round-bottom flask, along with tetrahydrofuran (10 mL) and... N , N Dissolve 1 mL of dimethylformamide, stir for about 5 minutes, and continue adding dropwise. N , N-Diisopropylethylamine (81.42 mg, 0.63 mmol) was stirred for 3 hours. The reaction was stopped, the reaction solution was concentrated under reduced pressure, the residue was added to water (15 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 3) to give the title compound as a white solid (47 mg, 36.16%). MS (ESI, pos. ion) m / z: 588.2 (M+1). HPLC purity: 94.41%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.06 (s, 1H), 8.56 (d, J = 7.1 Hz,1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.54 – 7.49 (m, 4H), 7.47 – 7.43 (m, 3H), 7.37 (dd, J = 13.8, 5.7 Hz, 3H), 7.30 (dd, J = 11.6, 7.0 Hz, 2H), 5.43 (d, J = 7.1 Hz, 1H), 5.40 (s, 2H), 4.66 (s, 1H), 4.02 (s, 2H), 1.05(d, J = 1.7 Hz, 6H). 13 C NMR (151 MHz, DMSO- d 6) δ (ppm): 168.34, 167.09, 161.36, 147.16,146.93, 144.31, 139.03, 138.71, 137.97, 132.62, 132.23, 131.04, 130.93,129.90, 129.90, 128.84, 128.55, 127.10, 125.61, 123.97, 122.17, 116.80,116.35, 114.28, 94.96, 69.73, 67.88, 62.43, 45.59, 27.65, 27.62, 27.62. Example 11 ( S)-2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxamide

[0195] Step 1) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-1 H -pyrrolo[3,2- b Synthesis of methyl pyridine-3-carboxylate 2-chloro-1 H -pyrrolo[3,2- b Methyl pyridine-3-carboxylate (300 mg, 1.42 mmol), (2-fluoro-4-(methylsulfonyl)phenyl)boronic acid (619 mg, 2.84 mmol), Pd(dppf)Cl2·DCM (232 mg, 0.28 mmol), sodium carbonate (452 ​​mg, 4.26 mmol), 1,4-dioxane (20 mL), and water (2 mL) were added to a single-necked round-bottom flask. The reaction system was purged with nitrogen three times and reacted overnight at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, diluted with water (50 mL), extracted with dichloromethane (20 mL × 3), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (400 mg, 80.62 mmol). %). MS (ESI, pos. ion) m / z: 348.8 (M+1). Step 2) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of methyl pyridine-3-carboxylate 2-(2-fluoro-4-(methylsulfonyl)phenyl)-1 H -pyrrolo[3,2- bMethyl pyridine-3-carboxylate (100 mg, 0.29 mmol), potassium carbonate (80 mg, 0.58 mmol), and THF (5 mL) were added to a single-necked round-bottom flask. Iodomethane (82 mg, 0.58 mmol) was added dropwise at room temperature, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with dichloromethane (10 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (104 mg, 100%). MS (ESI, pos. ion) m / z: 363.1 (M+1). Step 3) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxylic acid 2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl-1 H -pyrrolo[3,2- b Methyl pyridine-3-carboxylate (100 mg, 0.28 mmol) and methanol (6 mL) were added to a single-necked round-bottom flask, followed by sodium hydroxide (33.6 mg, 0.84 mmol, dissolved in water (2 mL)). The mixture was refluxed for 10 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was concentrated to give the title compound as a gray solid (90 mg, 93.62%). MS (ESI, pos. ion) m / z: 349.1 (M+1). Step 4) S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxamide Will( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diazazon-2-one (65 mg, 0.26 mmol), 2-(2-fluoro-4-(methylsulfonyl)phenyl)-1-methyl-1 H -pyrrolo[3,2- bPyridine-3-carboxylic acid (90 mg, 0.26 mmol), 2-chloro-1-methylpyridine iodide (86.3 mg, 0.34 mmol), N , N Dimethylformamide (2 mL) and tetrahydrofuran (2 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.21 mL, 1.30 mmol) was reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water (30 mL), and a yellow solid precipitated. The solid was filtered under reduced pressure, dried, and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a white solid (54 mg, 85.80%). MS (ESI, pos.ion) m / z: 582.2 (M+1). 1 H NMR (400 MHz, CDCl3) δ (ppm): 11.01 (dd, J = 8.2, 5.2 Hz, 1H), 8.73 (d, J = 4.7 Hz, 1H), 8.36 (d, J = 12.4 Hz, 1H), 8.04 (s, 1H), 7.86 (t, J = 9.4 Hz,1H), 7.82 – 7.77 (m, 2H), 7.62 – 7.56 (m, 2H), 7.50 – 7.42 (m, 2H), 7.42 –7.30 (m, 4H), 7.16 (t, J = 7.7 Hz, 2H), 5.91 (dd, J = 8.4, 3.8 Hz, 1H), 3.64 (s, 3H), 3.12 (s, 3H). Example 12 ( S )-2-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)thiophene[3,2- b Synthesis of pyridine-3-carboxamide

[0196] Step 1) 2-(2-fluorophenyl)thiopheno[3,2- b Synthesis of pyridine 2-Bromo-3-chloropyridine (521 mg, 2.71 mmol), palladium dichloride bis(triphenylphosphine) (570.6 mg, 0.81 mmol), cuprous iodide (309.7 mg, 1.63 mmol), and triethylamine (10 mL) were added to a single-necked round-bottom flask and reacted at room temperature for half an hour. Then, 1-ethynyl-2-fluorobenzene (358.1 mg, 2.98 mmol) was added to the reaction solution, and the reaction was carried out at 100 °C for 6 hours. Finally, sodium sulfide (846 mg, 10.84 mmol) dissolved in DMF (2 mL) was added to the reaction solution, and the reaction was carried out overnight at 130 °C. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give the title compound as a pale yellow solid (297 mg, 47.85%). MS (ESI, pos. ion) m / z: 230.1 (M+1). Step 2) 3-Bromo-2-(2-fluorophenyl)thiopheno[3,2- b Synthesis of pyridine 2-(2-fluorophenyl)thiopheno[3,2- b Pyridine (297 mg, 1.30 mmol) and dichloromethane (20 mL) were added to a single-necked round-bottom flask, followed by NBS (231 mg, 1.30 mmol). The mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give the title compound as an anhydrous oily solid (248 mg, 62.12%). MS (ESI, pos. ion) m / z: 308.0 (M+1). Step 3) 2,4,6-Trichlorophenyl-2-(2-fluorophenyl)thiopheno[3,2- b Synthesis of pyridine-3-carboxylate 3-bromo-2-(2-fluorophenyl)thiophene[3,2- bPyridine (248 mg, 0.80 mmol), 2,4,6-trichlorobenzoate (451 mg, 2.0 mmol), XantPhos-Pd-G3 (165 mg, 0.16 mmol), toluene (30 mL), and TEA (243 mg, 2.40 mmol) were added to a single-necked round-bottom flask. The reaction mixture was purged with nitrogen three times and reacted overnight at 110 °C. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (30 mL). Extraction was performed with dichloromethane (15 mL × 3), and the organic phase was collected. The residue was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give the title compound as a pale yellow solid (331 mg, 90.85%). MS (ESI, pos. ion) m / z: 451.8 (M+1). Step 4) 2-(2-fluorophenyl)thiopheno[3,2- b Synthesis of pyridine-3-carboxylic acid 2,4,6-trichlorophenyl-2-(2-fluorophenyl)thiopheno[3,2- b Pyridine-3-carboxylate (230 mg, 0.51 mmol) and tetrahydrofuran (10 mL) were added to a single-necked round-bottom flask, followed by sodium hydroxide (61.2 mg, 1.53 mmol, dissolved in water (1 mL)). The mixture was reacted at room temperature for 8 hours. After the reaction was complete, the residue was diluted with water (20 mL), extracted with dichloromethane (10 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (138 mg, 100%). MS (ESI, pos. ion) m / z: 274.0 (M+1). Step 5) S )-2-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)thiophene[3,2- b Synthesis of pyridine-3-carboxamide Will( S )-3-amino-5-phenyl-1,3-dihydro-2H-benzo[ e [1,4]diaza-2-one (125 mg, 0.50 mmol), 2-(2-fluorophenyl)thiophene[3,2- bPyridine-3-carboxylic acid (137 mg, 0.50 mmol), 2-chloro-1-methylpyridine iodide (166 mg, 0.65 mmol), N , N Dimethylformamide (3 mL) and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.41 mL, 2.50 mmol) was reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water (30 mL), and a yellow solid precipitated. The solid was filtered under reduced pressure, and the filter cake was dried and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a pale yellow solid (57 mg, 22.62%). MS (ESI, pos. ion) m / z: 506.9 (M+1). HPLC purity: 96.81%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 11.86 (d, J = 8.6 Hz, 1H), 8.90 (s,1H), 8.27 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.58 (d, J = 7.1 Hz, 2H), 7.53 –7.31 (m, 8H), 7.27 – 7.08 (m, 4H), 5.95 (d, J = 8.2 Hz, 1H). Example 13 ( S )-6-(2-Fluorophenyl)- N 7 -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-5,7-dicarboxamide

[0197]

[0198] Step 1) 5-Cyano-6-(2-fluorophenyl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid ethyl ester Pyridazine (536 mg, 6.69 mmol), ethyl bromoacetate (1.53 g, 9.10 mmol), and ethanol (25 mL) were added to a single-necked round-bottom flask and reacted at room temperature for 1.5 h. Then, 2-fluorobenzaldehyde (756 mg, 6.09 mmol), 2-cyanoacetamide (512 mg, 6.09 mmol), and TEA (1.69 mL, 12.18 mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 6 h. Finally, DDQ (2.76 g, 12.18 mmol) was added to the above reaction solution, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was diluted with dichloromethane (50 mL). The organic phase was washed with saturated sodium bicarbonate solution (50 mL), collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1). The title compound was obtained as a brown solid (1.17 g, 56.52%). MS (ESI, pos. ion) m / z: 310.0 (M+1). Step 2) 5-Cyano-6-(2-fluorophenyl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxylic acid 5-cyano-6-(2-fluorophenyl)pyrrolo[1,2- b Ethyl pyridazine-7-carboxylate (332 mg, 1.07 mmol), methanol (3 mL), and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (67.4 mg, 1.60 mmol, dissolved in water (3 mL)). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the title compound as a brown solid (300 mg, 100%). MS (ESI, pos. ion) m / z: 282.0 (M+1). Step 3) S )-5-cyano-6-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-7-carboxamide Will( S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e[1,4]diaza-2-one (250 mg, 0.99 mmol), 5-cyano-6-(2-fluorophenyl)pyrrolo[1,2- b [Pyridazine-7-carboxylic acid (278 mg, 0.99 mmol), 2-chloro-1-methylpyridine iodide (329 mg, 1.29 mmol),] N , N Dimethylformamide (3 mL) and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.82 mL, 4.95 mmol) was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (50 mL), and a gray solid precipitated out. The mixture was filtered under reduced pressure, and the filter cake was dried and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1 → 1 / 4) to give the title compound as a beige solid (101 mg, 19.73%).

[0199] Step 4) S )-6-(2-Fluorophenyl)- N 7 -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Synthesis of pyridazine-5,7-dicarboxamide Will( S )-5-cyano-6-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)pyrrolo[1,2- b Pyridazine-7-carboxamide (120 mg, 0.23 mmol), concentrated sulfuric acid (5 mL), and water (1 drop) were added to a single-necked round-bottom flask and reacted at 50 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was slowly added dropwise to ice water (100 mL) while stirring continuously. The solution was then neutralized to pH 7-8 with sodium hydroxide solution (4 mol / L), resulting in the precipitation of a white solid. The solid was filtered under reduced pressure, and the filter cake was dried and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 4) to give the title compound as a white solid (40 mg, 32.31%). MS (ESI, pos. ion) m / z: 533.0 (M+1). HPLC purity: 96.25%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 10.90 – 10.67 (m, 1H), 9.09 (dd, J = 9.2, 1.5 Hz, 1H), 8.67 (d, J = 15.2 Hz, 1H), 8.60 – 8.53 (m, 1H), 7.60 – 7.34(m, 8H), 7.22 (t, J = 8.5 Hz, 1H), 7.19 – 7.10 (m, 3H), 5.91 (d, J = 8.4 Hz, 1H). Example 14 ( S )-2-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -pyrazolo[5,1- b ]pyrido[4,3- e Synthesis of [1,3]oxazine-3-carboxamide

[0200] Step 1) 2-Bromo-9 H -pyrazolo[5,1- b ]pyrido[4,3- e Synthesis of ethyl 1,3]oxazine-3-carboxylate 4-(hydroxymethyl)pyridine-3-ol (0.30 g, 2.40 mmol), 3,5-dibromo-1 H Ethyl pyrazole-4-carboxylate (0.72 g, 2.40 mmol), potassium carbonate (1.0 g, 7.20 mmol), and DMF (5 mL) were added to a single-necked round-bottom flask and reacted at 150 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water (50 mL), extracted with dichloromethane (15 mL × 3), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a gray solid (0.31 g, 39.85%). MS (ESI, pos. ion) m / z: 324.0 (M+1). Step 2) 2-(2-fluorophenyl)-9 H -pyrazolo[5,1- b ]pyrido[4,3-e Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-9 H -pyrazolo[5,1- b ]pyrido[4,3- e [1,3]Oxazine-3-carboxylic acid ethyl ester (0.31 g, 0.96 mmol), 2-fluorophenylboronic acid (0.40 g, 2.88 mmol), Pd(dppf)Cl2·DCM (0.16 g, 0.19 mmol), sodium carbonate (0.31 g, 2.88 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added to a single-necked round-bottom flask. The reaction system was purged with nitrogen three times and reacted overnight at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, diluted with water (40 mL), extracted with dichloromethane (15 mL × 3), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give the title compound as a pale yellow solid (168 mg, 51.77 mmol). %). MS (ESI, pos. ion) m / z: 340.2 (M+1). Step 3) 2-(2-fluorophenyl)-9 H -pyrazolo[5,1- b ]pyrido[4,3- e Synthesis of [1,3]oxazine-3-carboxylic acid 2-(2-fluorophenyl)-9 H -pyrazolo[5,1- b ]pyrido[4,3- e [1,3]Oxazine-3-carboxylate ethyl ester (115 mg, 0.34 mmol), methanol (3 mL), and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (21.4 mg, 0.51 mmol, dissolved in water (3 mL)). The mixture was reacted overnight at 50 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the title compound as a brown solid (105 mg, 100%). MS (ESI, pos. ion) m / z: 312.1 (M+1). Step 4) S )-2-(2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -pyrazolo[5,1-b ]pyrido[4,3- e Synthesis of [1,3]oxazine-3-carboxamide Will( S )-3-amino-5-phenyl-1,3-dihydro-2H-benzo[ e [1,4]diazazon-2-one (80.0 mg, 0.32 mmol), 2-(2-fluorophenyl)-9 H -pyrazolo[5,1- b ]pyrido[4,3- e [1,3]Oxazine-3-carboxylic acid (99.6 mg, 0.32 mmol), 2-chloro-1-methylpyridine iodide (106.3 mg, 0.42 mmol), N , N Add 2 mL of dimethylformamide to a single-necked round-bottom flask and stir at room temperature for 15 minutes; add [the following to the reaction mixture] N , N Diisopropylethylamine (0.26 mL, 1.60 mmol) was reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water (20 mL), and a gray solid precipitated. The solid was filtered under reduced pressure, and the filter cake was dried and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10 / 1) to give the title compound as a white solid (39 mg, 22.50%). MS (ESI, pos. ion) m / z: 544.9 (M+1). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.84 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.59 – 7.50 (m, 4H), 7.49 – 7.30 (m, 7H), 7.25 – 7.14(m, 4H), 5.78 (d, J = 7.7 Hz (1H), 5.46 (s, 2H). Example 15 ( S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -pyrazole[5,1- b ]pyrido[2,3- eSynthesis of [1,3]oxazine-3-carboxamide

[0201] Step 1) 2-Bromo-9 H -pyrazole[5,1- b ]pyrido[2,3- e Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-(hydroxymethyl)pyridine-3-ol hydrochloride (0.30 g, 1.86 mmol), 3,5-dibromo-1 H Ethyl pyrazole-4-carboxylate (0.55 g, 1.86 mmol), potassium carbonate (0.77 g, 5.58 mmol), and DMF (4 mL) were added to a single-necked round-bottom flask and reacted at 150 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water (50 mL), extracted with dichloromethane (15 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a gray solid (0.225 g, 37.40%). MS (ESI, pos. ion) m / z: 324.0 (M+1). Step 2) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -pyrazole[5,1- b ]pyrido[2,3- e Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-9 H -pyrazole[5,1- b ]pyrido[2,3- e[1,3]oxazine-3-carboxylic acid ethyl ester (225 mg, 0.69 mmol), (2-fluoro-4-(methanesulfonyl)phenyl)boronic acid (301 mg, 1.38 mmol), Pd(dppf)Cl2·DCM (113 mg, 0.14 mmol), sodium carbonate (219 mg, 2.07 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added to a single-necked round-bottom flask. The reaction system was purged with nitrogen three times and reacted overnight at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, filtered, diluted with water (40 mL), extracted with dichloromethane (15 mL × 3), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a pale yellow solid (154 mg / mL). mg, 53.15%). MS (ESI, pos. ion) m / z:418.0 (M+1). Step 3) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -pyrazole[5,1- b ]pyrido[2,3- e Synthesis of [1,3]oxazine-3-carboxylic acid 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -pyrazole[5,1- b ]pyrido[2,3- e [1,3]Oxazine-3-carboxylic acid ethyl ester (154 mg, 0.37 mmol), methanol (3 mL), and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask, followed by lithium hydroxide monohydrate (31.3 mg, 0.74 mmol, dissolved in water (3 mL)). The mixture was reacted overnight at 50 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the title compound as a pale yellow solid (140 mg, 100%). MS (ESI, pos. ion) m / z: 390.0 (M+1). Step 4) S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[ e [1,4]diaza-3-yl)-9 H -pyrazole[5,1- b ]pyrido[2,3- e Synthesis of [1,3]oxazine-3-carboxamide Will( S)-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diazazon-2-one (90 mg, 0.36 mmol), 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -pyrazole[5,1- b ]pyrido[2,3- e [1,3]Oxazine-3-carboxylic acid (140 mg, 0.36 mmol), 2-chloro-1-methylpyridine iodide (120 mg, 0.47 mmol), N , N Dimethylformamide (2 mL) and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.30 mL, 1.80 mmol) was reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water (30 mL), and a yellow solid precipitated. The solid was filtered under reduced pressure, dried, and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a white solid (81 mg, 36.32%). MS (ESI, pos. ion) m / z: 623.1 (M+1). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.58 (d, J = 4.0 Hz, 1H), 8.40 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.83 – 7.76 (m, 3H), 7.73 (d, J = 8.4 Hz, 1H), 7.58 –7.50 (m, 3H), 7.47 – 7.33 (m, 5H), 7.25 – 7.13 (m, 2H), 5.76 (d, J = 7.7 Hz,1H), 5.57 (s, 2H), 3.07 (s, 3H). Example 16 ( S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e]pyrazolo[5,1- b [1,3]Oxazine-3-carboxamide

[0202] Step 1) 2-Bromo-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate Add 3,5-dibromo-1 to a 50 mL single-necked flask H Ethyl pyrazole-4-carboxylate (1.0 g, 3.36 mmol) was dissolved in DMF (10 mL). Potassium carbonate (1.39 g, 10.08 mmol) and salicylol (0.50 g, 4.03 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the mixture was heated to 150 °C and maintained at this temperature for approximately 20 h before the reaction was stopped. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give the title compound as a yellow solid product (547.3 mg, 50.46%).

[0203] MS (ESI, pos. ion) m / z : 323.0 (M+1). Step 2) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate Add 2-bromo-9 to a 50 mL single-necked flask H -benzo[ e ]pyrazolo[5,1- b[1,3]Oxazine-3-carboxylic acid ethyl ester (0.2 g, 0.62 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). 4-Methanesulfonyl-2-fluorophenylboronic acid (0.16 g, 0.74 mmol), potassium carbonate (0.17 g, 1.24 mmol), and BrettPhos-Pd-G3 (0.056 g, 0.062 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the mixture was purged twice with nitrogen and heated to 80 °C under a nitrogen atmosphere. The reaction was maintained at this temperature for approximately 3.5 h before the reaction was stopped. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid product (0.1443 g, 55.99%). MS (ESI,pos. ion) m / z: 417.2 (M+1). Step 3) 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid At 27 °C, 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9- H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (0.1443 g, 0.35 mmol) was dissolved in THF (5 mL), water (5 mL), and methanol (5 mL). Lithium hydroxide monohydrate (73.43 mg, 1.75 mmol) was added with stirring at room temperature. After the addition was complete, the mixture was heated to 50 °C and reacted for about 17 h. The reaction was then stopped. The reaction solution was concentrated, and water (2 mL) was added to the residual solvent. The pH was adjusted to 2-4 with 2 M HCl. A solid precipitated out. The solid was filtered, and the filter cake was collected and dried under reduced pressure to give the title compound as a yellow solid product (0.1153 g, 85.67%).

[0204] Step 4) S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide At 25.5 °C, 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9- H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (0.1153 g, 0.30 mmol), dissolved in THF (5 mL), was added sequentially with stirring at room temperature. S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (75.38 mg, 0.30 mmol), CMPI (99.64 mg, 0.39 mmol), were added. After addition, the mixture was stirred at room temperature for about 15 min. DIPEA (0.25 mL, 1.5 mmol) was then added dropwise. The reaction was allowed to proceed for about 2.5 h at room temperature before the reaction was stopped. The reaction solution was concentrated, and the residue was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 4) to give the title compound as a pale yellow solid (54.3 mg, 28.81%). MS (ESI, pos. ion) m / z: 622.3 (M+1). HPLC purity: 97.91%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.04 (s, 1H), 8.51 – 8.34 (m, 1H), 7.80 (s, 3H), 7.65 (s, 1H), 7.48 (d, J = 14.1 Hz, 7H), 7.30 (d, J = 27.6 Hz, 5H), 5.49 (s, 2H), 5.38 – 5.24 (m, 1H), 3.31 (s, 3H). Example 17 ( S )- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-6-(2-fluorophenyl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxamide

[0205] Step 1) 6-(2-fluorophenyl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxylic acid Add 6-(2-fluorophenyl)imidazo[1,2-]to the reaction flask b [1,2,4]Ethyl triazine-7-carboxylate (0.145 g, 0.51 mmol), methanol (4 mL), tetrahydrofuran (4 mL), water (2 mL), lithium hydroxide monohydrate (0.053 g, 1.27 mmol), reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue. The pH was adjusted to 5 by adding 2 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic and aqueous phases were combined and concentrated under reduced pressure to give the title compound as a brownish-yellow solid (0.1230 g, 94.04%). MS (ESI, pos. ion) m / z: 259.1 (M+1). Step 2) S )- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-6-(2-fluorophenyl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxamide Add ( to the reaction flask) S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diazazon-2-one (0.10 g, 0.37 mmol), 6-(2-fluorophenyl)imidazo[1,2- b [1,2,4] Triazine-7-carboxylic acid (0.11 g, 0.44 mmol), 2-chloro-1-methylpyridine iodide (0.12 g, 0.48 mmol), N , N -Diisopropylethylamine (0.48 g, 3.7 mmol), N , N -Dimethylformamide (8 mL), reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was prepared and purified to give the title compound as a pale yellow solid (0.0952 g, 50.32%). MS (ESI, pos. ion) m / z: 510.1 (M+1). HPLC purity: 98.75%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.04 (s, 1H), 9.80 (d, J =7.3 Hz, 1H), 9.07 (d, J = 1.2 Hz, 1H), 8.89 (d, J = 1.2 Hz, 1H), 7.67 – 7.57 (m, 2H), 7.55 – 7.44 (m, 6H), 7.35 – 7.23 (m, 3H), 7.17 (d, J = 7.8 Hz, 1H), 5.56 (d, J = 7.4 Hz, 1H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -112.84 (s), -123.25 (s). Example 18 ( S )- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-2-(2-fluoro-4-(methanesulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxamide

[0206] For details of steps 1-5, please refer to intermediate N: ( S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e Synthesis of [1,4]diaza-2-one.

[0207] Step 6: ( S )- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-2-(2-fluoro-4-(methanesulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide Add ( to the reaction flask) S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e[1,4]diazazon-2-one (0.05 g, 0.19 mmol), 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (0.089 g, 0.23 mmol), 2-chloro-1-methylpyridine iodide (0.063 g, 0.25 mmol), N , N -Diisopropylethylamine (0.086 g, 0.67 mmol), N , N - Dimethylformamide (8 mL), reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was prepared and purified to give the title compound as an off-white solid (0.0585 g, 49.25%). MS (ESI, pos. ion) m / z: 640.1 (M+1). HPLC purity: 99.22%.

[0208] 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.01 (s, 1H), 8.45 (d, J = 5.9 Hz, 1H), 7.79 (dd, J = 18.4, 7.2 Hz, 3H), 7.68 – 7.42 (m, 8H), 7.40 – 7.26 (m, 3H),7.16 (d, J = 7.0 Hz, 1H), 5.50 (s, 2H), 5.42 (d, J = 6.9 Hz (1H), 3.31 (s, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -109.88 (s), -123.36 (s). Example 19 ( S )-5-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ a ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0209] Step 1) 2-Bromo-5-Fluoro-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate Add 3,5-dibromo-1 to a 50 mL single-necked flask H Ethyl pyrazole-4-carboxylate (0.5 g, 1.68 mmol) was dissolved in DMF (10 mL). Potassium carbonate (0.70 g, 5.04 mmol) and 2-fluoro-6-(hydroxymethyl)phenol (0.15 g, 1.76 mmol) were added sequentially with stirring at room temperature. After addition, the mixture was heated to 150 °C and reacted for approximately 18 h, then the reaction was stopped. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give the title compound as a yellow solid (262.5 mg, 45.85%). MS (ESI, pos. ion) m / z: 341.10 (M+1). Step 2) 5-Fluoro-2-(2-Fluoro-4-(Methylsulfonyl)phenyl)-9 H -benzo[ e Synthesis of pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid ethyl ester Add 2-bromo-5-fluoro-9 to a 50 mL single-necked flask H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (0.26 g, 0.76 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). 4-Methanesulfonyl-2-fluorophenylboronic acid (0.20 g, 0.91 mmol), potassium carbonate (0.21 g, 1.52 mmol), and BrettPhos-Pd-G3 (0.069 g, 0.076 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the mixture was replaced twice with N2, heated to 80 °C under N2 atmosphere, and the reaction was maintained at this temperature for approximately 19 h. The reaction solution was then stopped. The reaction mixture was cooled to room temperature, concentrated, and the crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a white solid (0.1 g, 30.20%). MS (ESI, pos.ion) m / z: 435.0 (M+1). Step 3) 5-Fluoro-2-(2-Fluoro-4-(Methylsulfonyl)phenyl)-9 H-benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid Add 5-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 to a 50 mL single-necked flask H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (0.10 g, 0.23 mmol) was dissolved in THF (5 mL), water (5 mL), and methanol (5 mL). Lithium hydroxide monohydrate (48.25 mg, 1.15 mmol) was added with stirring at room temperature. After the addition was complete, the mixture was heated to 50 °C and reacted for approximately 17 h. The reaction mixture was then stopped. The reaction solution was concentrated, and water (2 mL) was added to the residual solvent. The pH was adjusted to 2-4 with 2 M HCl, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was collected and dried under reduced pressure to obtain the title compound as a yellow solid (0.094 g, 100%). MS (ESI, pos. ion) m / z: 407.0 (M+1). Step 4) S )-5-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ a ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide Add 5-fluoro-2-(2-fluoro-4-(methylsulfonyl)phenyl)-9 to a 50 mL single-necked flask H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (0.094 g, 0.23 mmol), dissolved in THF (5 mL), was added sequentially with stirring at room temperature. S )-3-amino-5-phenyl-1,3-dihydro-2 H -benzo[ e[1,4]diaza-2-one (57.79 mg, 0.23 mmol), CMPI (76.39 mg, 0.30 mmol), were added. After addition, the mixture was stirred at room temperature for about 23 min. DIPEA (0.19 mL, 1.15 mmol) was then added dropwise. The reaction was stopped after about 1.5 h at room temperature. The reaction solution was concentrated, and the residue was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 9) to give the title compound as a white solid (70.9 mg, 47.91%). MS (ESI, pos. ion) m / z: 640.1 (M+1). HPLC purity: 97.99%. 1 H NMR (599 MHz, DMSO- d 6) δ (ppm):11.01 (s, 1H), 8.33 (d, J = 7.4 Hz,1H), 7.85 – 7.81 (m, 2H), 7.78 (dd, J = 8.2, 6.5 Hz, 1H), 7.65 (ddd, J = 8.5,7.2, 1.6 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.50 – 7.43 (m, 5H), 7.37 – 7.29 (m,4H), 7.29 – 7.25 (m, 1H), 5.53 (s, 2H), 5.34 (d, J = 7.4 Hz (1H), 3.33 (s, 3H). Example 20 ( S )-2-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxamide

[0210] Step 1: Synthesis of 1-bromo-4-(ethylsulfonyl)-2-fluorobenzene DMSO (60 mL) was added to 1-bromo-2-fluoro-4-iodobenzene (10 g, 33.23 mmol), sodium ethanesulfonate (5.02 g, 43.20 mmol), cuprous iodide (0.63 g, 3.32 mmol), potassium phosphate (7.05 g, 33.23 mmol), and 4-hydroxy-L-proline (0.44 g, 3.32 mmol), and the mixture was reacted at 70 °C for 15 h under nitrogen protection. The reaction solution was diluted with ethyl acetate (200 mL), washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give the title compound as a pale yellow solid (8.52 g, 95.97%); MS (ESI, pos. ion) m / z: 267.0 (M+1).

[0211] Step 2: Synthesis of ((4-(ethylsulfonyl)-2-fluorophenyl)ethynyl)trimethylsilane 1-Bromo-4-(ethylsulfonyl)-2-fluorobenzene (8.50 g, 31.82 mmol), bis(triphenylphosphine)palladium dichloride (2.23 g, 3.18 mmol), cuprous iodide (0.61 g, 3.18 mmol), triethylamine (6 mL), and DMF (20 mL) were added to a reaction flask. Trimethylsilylacetylene (4.69 g, 47.73 mmol) was added under ice bath conditions. The reaction system was purged with nitrogen three times, and the reaction was carried out at room temperature for 18 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give the title compound as a brown oil (6.80 g, 75.13%).

[0212] Step 3: Synthesis of 4-(ethylsulfonyl)-1-ethynyl-2-fluorobenzene ((4-(ethylsulfonyl)-2-fluorophenyl)ethynyl)trimethylsilane (6.65 g, 23.38 mmol) and methanol (60 mL) were added to a reaction flask, followed by cesium fluoride (3.91 g, 25.72 mmol). The reaction was carried out at room temperature for half an hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give the title compound as a pale yellow solid (4.59 g, 92.50%).

[0213] Step 4: Synthesis of 2-((4-(ethylsulfonyl)-2-fluorophenyl)acetylene)pyridine-3-amine 2-Bromo-3-aminopyridine (1 g, 5.78 mmol), cuprous iodide (0.22 g, 1.16 mmol), and bis(triphenylphosphine)palladium dichloride (0.81 g, 1.16 mmol) were added to a 50 mL single-necked flask and dissolved in DMF (12 mL). 4-(ethylsulfonyl)-1-ethynyl-2-fluorobenzene (1.47 g, 6.94 mmol) and triethylamine (3 mL) were added to the above reaction solution. After the addition was complete, the mixture was purged twice with nitrogen and reacted at 70 °C for 21 h. The reaction was then stopped, and the reaction solution was diluted with ethyl acetate (100 mL), washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (mobile phase: PE / EA (v / v) = 2 / 1), yielding the title compound as a yellow solid (0.82 g, 46.62%); MS (ESI, pos. ion) m / z: 305.0 (M+1). Step 5: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1 H -pyrrolo[3,2- b Synthesis of pyridine 2-((4-(ethylsulfonyl)-2-fluorophenyl)acetylene)pyridine-3-amine (0.81 g, 2.66 mmol) was added to a 50 mL single-necked flask, dissolved in 6 mL of DMSO, and sodium tert-amyloxide (0.35 g, 3.19 mmol) was added with stirring at room temperature. After the addition was complete, the system was heated to 70 °C and reacted for 5 h. The reaction solution was added dropwise to 100 mL of water, and the pH was adjusted to 3 with 2 mol / L hydrochloric acid, then to 8 with sodium bicarbonate. The mixture was filtered, washed with 20 mL of water, and the filter cake was dried under vacuum at 50 °C. The obtained compound was a brown solid (0.76 g, 93.83%). MS (ESI, pos. ion) m / z: 305.1 (M+1). Step 6: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-3-iodine-1 H -pyrrolo[3,2- b Synthesis of pyridine 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1 H -pyrrolo[3,2- bPyridine (0.76 g, 2.50 mmol) was added to a 50 mL single-necked flask, dissolved in DMF (8 mL), and NIS (0.67 g, 3 mmol) was added with stirring at room temperature. After the addition was complete, the system was heated to 50 °C and reacted for 5 h. The reaction solution was added dropwise to water (90 mL), filtered, washed with water (10 mL), and the filter cake was dried under vacuum at 55 °C to obtain the title compound as a brown solid (1.02 g, 94.94%). MS (ESI, pos.ion) m / z: 430.9 (M+1). Step 7: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1 H -pyrrolo[3,2- b Synthesis of tert-butyl pyridine-3-carboxylic acid 2-(4-(ethylsulfonyl)-2-fluorophenyl)-3-iodide-1 H -pyrrolo[3,2- b Pyridine (0.40 g, 0.93 mol), tetrakis(triphenylphosphine)palladium (0.32 g, 0.28 mmol), DIPEA (0.60 g, 4.65 mmol), DMF (3 mL), and tert-butanol (5 mL) were added to a single-necked round-bottom flask. The mixture was purged three times with carbon monoxide and stirred at 90 °C for 6.5 h. The reaction solution was diluted with ethyl acetate (40 mL), washed successively with water (40 mL) and saturated brine (40 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / ethyl acetate (v / v) = 1 / 1) to give the title compound as a pale yellow solid (0.13, 34.57%); MS (ESI, pos. ion) m / z: 405.1 (M+1). Step 8: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxylic acid hydrochloride To 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1 H -pyrrolo[3,2- b 4 mol / L dioxane hydrochloride solution (6 mL) was added to 0.29 g of tert-butyl pyridine-3-carboxylate (0.72 mmol), and the mixture was stirred at room temperature for 10 h. The reaction solution was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.27 g, 97.86%).

[0214] Step 9: ( S )-2-(4-(ethylsulfonyl)-2-fluorophenyl)- N-(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxamide 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1 H -pyrrolo[3,2- b ]Pyridine-3-carboxylic acid hydrochloride (0.065 g, 0.17 mmol) and ( S )-3-amino-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-2-one (0.043 g, 0.17 mmol) was added to DMF (5 mL), followed by 2-chloro-1-methylpyridine iodide (0.065 g, 0.26 mmol) and DIPEA (0.088 g, 0.68 mmol). After the addition was complete, the mixture was stirred at room temperature for 5 h. The reaction solution was diluted with ethyl acetate (60 mL), washed successively with water (60 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain the crude product, which was then sent for preparative purification to give the title compound as a white solid (0.026, 26.46%). MS (ESI, pos. ion) m / z: 582.1 (M+1). HPLC purity: 98.01%.

[0215] Example 21 ( S )-2-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxamide

[0216] Step 1) Synthesis of 2-bromo-N-methylpyridine-3-amine 2-Bromo-3-aminopyridine (5.0 g, 28.90 mmol) was added to THF (40 mL), followed by the addition of 60% sodium hydride (1.04 g, 43.35 mmol) in an ice bath. The mixture was stirred at room temperature after the addition was complete. Half an hour later, methyl iodoform (4.51 g, 31.79 mmol) was added in an ice bath. The mixture was stirred at room temperature for another 16 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (80 mL x 2), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1, 0.5% triethylamine) to give the title compound as a pale yellow oil (4.42 g, 81.77%); MS (ESI, pos. ion) m / z: 187.0 (M+1). Step 2) 2-((4-(ethylsulfonyl)-2-fluorophenyl)ethynyl)- N Synthesis of 3-methylpyridine-3-amine 2-Bromo-N-methylpyridin-3-amine (1.0 g, 5.35 mmol), cuprous iodide (0.20 g, 1.07 mmol), and bis(triphenylphosphine)palladium dichloride (0.75 g, 1.07 mmol) were added to a 50 mL single-necked flask and dissolved in DMF (9 mL). Under nitrogen protection, 4-(ethylsulfonyl)-1-ethynyl-2-fluorobenzene (1.36 g, 6.42 mmol) was added. Triethylamine (3 mL) was added dropwise to the above reaction solution. After the addition was complete, the mixture was purged with nitrogen twice and reacted at 80 °C for 17 h. The reaction solution was concentrated, and the crude product was purified by normal-phase silica gel column chromatography (mobile phase: PE / EA(v / v) = 1 / 1) to give the title compound as a yellow solid (0.95 g, 55.81%); MS (ESI, pos. ion) m / z: 319.1 (M+1). Step 3) 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of pyridine 2-((4-(ethylsulfonyl)-2-fluorophenyl)ethynyl)- N3-Methylpyridin-3-amine (0.99 g, 3.10 mmol), sodium tert-amyloxide (0.41 g, 3.73 mmol), and dimethyl sulfoxide (20 mL) were added to a single-necked round-bottom flask and stirred at 80 °C for 17.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (40 mL), extracted with dichloromethane (40 mL × 2), concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 1 / 1) to give the title compound as a brown oil (0.23 g, 23.23 %); MS (ESI, pos. ion) m / z: 319. 1 (M+1). Step 4: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-3-iodo-1-methyl-1 H -pyrrolo[3,2- b Synthesis of pyridine 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1-methyl-1 H -pyrrolo[3,2- b Pyridine (0.18 g, 0.57 mmol), N Iodosuccinimide (0.15 g, 0.68 mmol) and acetonitrile (15 mL) were added to a single-necked round-bottom flask and stirred at 50 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA(v / v) = 1 / 1) to give the title compound as a yellow solid (0.23 g, 91.57%).

[0217] Step 5: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of methyl pyridine-3-carboxylate 2-(4-(ethylsulfonyl)-2-fluorophenyl)-3-iodo-1-methyl-1 H -pyrrolo[3,2- bPyridine (0.17 g, 0.38 mmol), tetraphenylphosphine palladium (0.22 g, 0.19 mmol), triethylamine (0.15 g, 1.52 mmol), DMF (5 mL), and methanol (5 mL) were added to a single-necked round-bottom flask. The mixture was purged three times with carbon monoxide, and stirred at 60 °C for 4 hours under a carbon monoxide atmosphere. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 1 / 4) to give the title compound as a brown oil (0.12 g, 83.31%). MS (ESI, pos. ion) m / z: 377.10 (M+1). Step 6: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxylic acid 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1-methyl-1 H -pyrrolo[3,2- b Methyl pyridine-3-carboxylate (0.12 g, 0.32 mmol), methanol (6 mL), and water (2 mL) were added to a single-necked round-bottom flask, followed by sodium hydroxide (0.051 g, 1.28 mmol). The reaction was carried out at 65 °C for 7 hours. After the reaction was completed, the mixture was cooled to room temperature, and the filtrate was diluted with water (30 mL). The filtrate was extracted with ethyl acetate (30 mL × 2), and the aqueous phase was adjusted to pH ≤ 4 with 2 M HCl. The aqueous layer was concentrated under reduced pressure, and methanol (20 mL) was added to the concentrate. The insoluble salts were removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (0.11 g, 95.21%). MS (ESI, pos. ion) m / z: 363.00 (M+1). Step 7: ( S )-2-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-1-methyl-1 H -pyrrolo[3,2- b Synthesis of pyridine-3-carboxamide 2-(4-(ethylsulfonyl)-2-fluorophenyl)-1-methyl-1 H -pyrrolo[3,2- b Pyridine-3-carboxylic acid (0.11 g, 0.30 mmol), ( S)-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diazazon-2-one (0.081 g, 0.30 mmol), 2-chloro-1-methylpyridine iodide (0.10 g, 0.39 mmol), N , N Dimethylformamide (4 mL) and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.12 g, 0.90 mmol) was reacted at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure and purified preparatively (acetonitrile / water (0.1% TFA) (v / v) = 3 / 2) to give the title compound as a white solid (0.032 g, 17.18%). MS (ESI, pos. ion) m / z: 614.1 (M+1). HPLC purity: 98.65%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 11.00 (t, J = 8.1 Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H), 7.85 – 7.70 (m, 5H), 7.57 (dd, J = 6.9, 5.2 Hz, 2H), 7.45 (ddd, J = 5.1, 4.5, 1.6 Hz, 1H), 7.41 – 7.28 (m, 4H), 7.15 – 7.09 (m, 2H), 5.93 (d, J = 8.5 Hz, 1H), 3.62 (s, 3H), 3.16 (q, J = 7.4 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H). Example 22 (S)-2-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]Pyrazole[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0218] Step 1) 2-(4-(ethylsulfonyl)-2-fluorophenyl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (0.20 g, 0.62 mmol), 2-(4-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronyl cyclopentane (0.23 g, 0.74 mmol), BrettPhos-Pd-G3 (0.11 g, 0.12 mmol), and sodium carbonate (0.13 g, 1.24 mmol) were added to a 50 mL reaction flask, followed by water (0.5 mL) and dioxane (10 mL). The mixture was stirred at 90 °C for 5 h under nitrogen protection. The reaction solution was directly evaporated to dryness using silica gel. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 10 / 1) to give the title compound as a creamy white solid (0.19 g, 71.32%); MS (ESI, pos. ion) m / z: 431.1 (M+1). Step 2) 2-(4-(ethylsulfonyl)-2-fluorophenyl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 2-(4-(ethylsulfonyl)-2-fluorophenyl)-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (0.19 g, 0.44 mmol) was added to a reaction flask, followed by methanol (4 mL), tetrahydrofuran (4 mL), and water (4 mL). Lithium hydroxide monohydrate (0.092 g, 2.2 mmol) was then added, and the mixture was stirred at 60 °C for 11 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Water (30 mL) was added to the residue, and the pH of the aqueous phase was adjusted to ≤2 with 4 mol / L HCl. The mixture was filtered, washed with water (10 mL), and the filter cake was dried under vacuum at 60 °C to obtain the title compound as a white solid (0.13 g, 73.19%); MS (ESI, pos. ion) m / z: 403.0 (M+1). Step 3: ( S )-2-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]Pyrazole[5,1- b Synthesis of [1,3]oxazine-3-carboxamide 2-(4-(ethylsulfonyl)-2-fluorophenyl)-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (0.12 g, 0.30 mmol), ( S )-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4] Diazazon-2-one (0.081 g, 0.30 mmol) and 2-chloro-1-methylpyridine iodide (0.11 g, 0.45 mmol) were dissolved in DMF (6 mL) and THF (10 mL), stirred at room temperature for 5 minutes, and then DIPEA (0.12 g, 0.90 mmol) was added and stirred at room temperature. The reaction solution was diluted with ethyl acetate (50 mL), washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a crude product. After preparative purification, the title compound was obtained as a white solid (0.038 g, 19.49%); MS (ESI, pos. ion) m / z: 654.1 (M+1). HPLC purity: 99.38%.

[0219] 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.00 (s, 1H), 8.44 (d, J = 7.3 Hz,1H), 7.82 – 7.73 (m, 3H), 7.58 (dd, J = 16.9, 7.9 Hz, 1H), 7.55 – 7.43 (m, 7H), 7.39 – 7.29 (m, 3H), 7.16 (d, J = 7.9 Hz, 1H), 5.50 (s, 2H), 5.42 (d,J = 7.3 Hz,1H), 3.55 – 3.29 (m, 2H, overlapped), 1.14 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ (ppm): -108.96 (s), -127.02 (s). Example 23 ( S )-2-(4-(ethylsulfonyl)-2-fluorophenyl)-5-fluoro- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diazaporide-3-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0220] Step 1: 2-Bromo-5-Fluoro-9 H -benzo[ e ]Pyrazole[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 3,5-dibromo-1 H Ethyl pyrazole-4-carboxylate (0.8 g, 2.69 mmol) was added to a 50 mL single-necked flask, dissolved in DMF (10 mL), and potassium carbonate (0.74 g, 5.38 mmol) and 2-fluoro-6-(hydroxymethyl)phenol (0.40 g, 2.82 mmol) were added sequentially with stirring at room temperature. After the addition was complete, the system was heated to 130 °C and reacted for 5 hours. The reaction was stopped, and the reaction solution was concentrated with water (20 mL), extracted with ethyl acetate (20 mL), concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give the title compound as a brown solid (0.85 g, 92.79%). MS (ESI, pos. ion) m / z: 341.0 (M +1). Step 2: Synthesis of (4-bromo-3-fluorophenyl)(ethyl) sulfide Cesium carbonate (2.2 g, 6.76 mmol) was added to a 50 mL two-necked round-bottom flask. The reaction mixture was purged with nitrogen three times. Then, 4-bromo-3-fluorothiophenol (700 mg, 3.38 mmol) dissolved in DMF (10 mL) and iodoethane (527.18 mg, 3.38 mmol) were added to the reaction mixture using a syringe. The reaction mixture was purged with nitrogen three times. The mixture was stirred at room temperature for approximately 6 hours. The reaction was stopped, and the reaction solution was cooled to room temperature. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound as a yellow oil (792 mg, 99.64%).

[0221] Step 3: Synthesis of 1-bromo-4-(ethylsulfonyl)-2-fluorobenzene (4-Bromo-3-fluorophenyl)(ethyl) sulfide (792 mg, 3.37 mmol) was added to a 50 mL single-necked round-bottom flask, dissolved in acetic acid (10 mL), and then 30% H₂O₂ (1.72 mL, 16.85 mmol) was added. The mixture was heated to 80 °C and stirred for 2 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (15 mL) was added, and the mixture was washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (819 mg, 91.02%); MS (ESI, pos. ion) m / z: 267.0 (M+1). Step 4: Synthesis of 2-(4-ethanesulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane 1-Bromo-4-(ethylsulfonyl)-2-fluorobenzene (470 mg, 1.76 mmol), pinacol diboronate (893.87 mg, 3.52 mmol), Pd(dppf)Cl2·DCM (143.73 mg, 0.18 mmol), and potassium acetate (345.45 mg, 3.52 mmol) were added to a 100 mL single-necked round-bottom flask, followed by toluene (20 mL). The reaction mixture was purged with nitrogen three times and heated to 100 °C for 17 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to ethyl acetate (20 mL), filtered, and the filtrate was washed with saturated brine. The organic phase was concentrated under reduced pressure to give the crude title compound (552.8 mg, 100%) as a brown solid. MS (ESI, pos. ion) m / z: 315.1 (M+1). Step 5: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-5-fluoro-9H -benzo[ e ]pyrazolo[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-5-fluoro-9 H -benzo[ e ]Pyrazole[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (120 mg, 0.35 mmol), 2-(4-ethanesulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (131.96 mg, 0.42 mmol), sodium carbonate (74.19 mg, 0.7 mmol), and BrettPhos-Pd-G3 (63.45 mg, 0.07 mmol) were added to a 50 mL single-necked round-bottom flask. 1,4-dioxane (10 mL) and water (0.5 mL) were added to dissolve the flask. The reaction mixture was purged with nitrogen three times and heated to 100 °C for 4 hours. The reaction was stopped, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a white solid (153 mg, 96.99%). MS (ESI, pos. ion) m / z: 449.1 (M+1). Step 6: 2-(4-(ethylsulfonyl)-2-fluorophenyl)-5-fluoro-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 2-(4-(ethylsulfonyl)-2-fluorophenyl)-5-fluoro-9 H -benzo[ e ]pyrazolo[5,1- b[1,3]Oxazine-3-carboxylic acid ethyl ester (150 mg, 0.33 mmol) was added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (4 mL), water (4 mL), and methanol (4 mL). Lithium hydroxide monohydrate (69.23 mg, 1.65 mmol) was added, and the mixture was heated to 60 °C and stirred for 6 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to water (15 mL), and extracted with ethyl acetate (20 mL) to remove impurities. The aqueous phase was adjusted to pH ≤ 2 with 4 mol / L hydrochloric acid, and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a creamy white solid (129 mg, 91.74%). MS (ESI, pos. ion) m / z: 421.1 (M+1). Step 7: ( S )-2-(4-ethanesulfonyl-2-fluorophenyl)-5-fluoro- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -benzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide At 25 °C, 2-(4-(ethylsulfonyl)-2-fluorophenyl)-5-fluoro-9 H -benzo[ e ]pyrazolo[5,1- b [1,3]Oxazine-3-carboxylic acid (80 mg, 0.19 mmol), ( S )-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e[1,4]diaza-2-one (51.16 mg, 0.19 mmol) and CMPI (72.81 mg, 0.29 mmol) were added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (10 mL) and DMF (1 mL), and stirred for about 5 minutes. DIPEA (73.67 mg, 0.57 mmol) was then added dropwise, and the reaction was stirred for 3 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to water (15 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) and sent for preparative purification (58% acetonitrile: 42% water (0.1% TFA)) to give the title compound as a white solid (30 mg, 23.30%). MS (ESI, pos. ion) m / z: 672.1 (M+1). HPLC purity: 99.25%. 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 10.97 (s, 1H), 8.35 (d, J = 7.4 Hz,1H), 7.88 – 7.74 (m, 3H), 7.62 – 7.56 (m, 1H), 7.56 – 7.38 (m, 6H), 7.33 (dt, J = 13.0, 5.1 Hz, 3H), 7.16 (d, J = 7.9 Hz, 1H), 5.52 (s, 2H), 5.43 (d, J = 7.4Hz, 1H), 3.40 (d, J = 7.4 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ (ppm): 167.63, 166.31, 160.11, 160.02 (d, J = 253.5 Hz), 153.41 (d, J = 248.0 Hz), 150.30 (d, J = 248.9 Hz), 145.91, 144.69,140.78 (d, J =6.7 Hz), 138.10, 135.81 (d, J = 12.8 Hz), 132.87, 131.31, 129.82,129.74, 128.92, 127.44 (d, J = 13.7 Hz), 127.18 (d, J = 15.0 Hz), 126.36 (d, J = 3.2 Hz), 125.95 (d, J = 6.9 Hz), 125.23 (d, J = 7.7 Hz), 123.91 (d, J = 3.3 Hz), 123.58 (d, J = 2.7 Hz), 119.06, 118.61 (d, J = 19.4 Hz), 116.42 (d, J = 16.6 Hz), 115.40 (d, J = 25.0 Hz), 98.10, 67.8, 49.3, 45.91, 7.52. 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -109.79 (s), -123.40 (s), -134.61(s). Example 24 ( S )-2-(4-(ethanesulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -pyrazolo[5,1- b ]Pyridine[2,3- e Synthesis of [1,3]oxazine-3-carboxamide

[0222] Step 1: 2-Bromo-9 H -pyrazolo[5,1- b ]pyrido[2,3- e Synthesis of ethyl 1,3]oxazine-3-carboxylate Add 3-hydroxy-2-hydroxymethylpyridine hydrochloride (325 mg, 2.01 mmol) and 3,5-dibromo-1-ethylhexylpyridine hydrochloride to the reaction flask. HEthyl pyrazole-4-carboxylate (0.60 g, 2.01 mmol), potassium carbonate (0.83 g, 6.03 mmol), and DMF (8 mL) were added and stirred at 130 °C for 30 h. The reaction was stopped by TLC monitoring after the starting material had largely reacted. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (EA / PE (v / v) = 1 / 4) to give the title compound (300 mg, 46.02%). MS (ESI, pos.ion) m / z: 324.0 (M+1). Step 2: 2-(4-(ethanesulfonyl)-2-fluorophenyl)-9 H -pyrazolo[5,1- b ]pyrido[2,3- e Synthesis of ethyl 1,3]oxazine-3-carboxylate Under nitrogen protection, 2-bromo-9 was added to a single-necked flask. H -pyrazolo[5,1- b ]pyrido[2,3- e [1,3]Oxazine-3-carboxylic acid ethyl ester (300 mg, 0.93 mmol), 2-(4-(ethanesulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (0.35 g, 1.12 mmol), Pd(dppf)Cl2·DCM (0.11 g, 0.14 mmol), sodium carbonate (0.30 g, 2.79 mmol), 1,4-dioxane (15 mL), and water (3 mL) were heated to 95 °C and stirred for 8 h. TLC monitoring showed that the reactants had essentially reacted completely, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate, and the organic phase was concentrated. The residue was eluted by silica gel column chromatography (PE / EA(v / v) = 10 / 1) to give the title compound (150 mg, 37.56%). MS (ESI, pos. ion) m / z: 432.1 (M+1). Step 3: 2-(4-(ethanesulfonyl)-2-fluorophenyl)-9 H -pyrazolo[5,1- b ]pyrido[2,3- e Synthesis of [1,3]oxazine-3-carboxylic acid Add 2-(4-(ethanesulfonyl)-2-fluorophenyl)-9 to a single-necked flask H -pyrazolo[5,1- b ]pyrido[2,3- e[1,3]Oxazine-3-carboxylic acid ethyl ester (150 mg, 0.35 mmol), lithium hydroxide monohydrate (0.059 g, 1.4 mmol), THF (4 mL), methanol (6 mL), and water (6 mL) were added and stirred at 50 °C for 24 h. The reaction was stopped by TLC after the reactants had completely reacted. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 2-3 with 4N HCl (2 mL). A solid precipitated, which was filtered to give the title compound as a yellow solid (110 mg, 78.43%). MS (ESI, pos. ion) m / z: 404.0 (M+1). Step 4: ( S )-2-(4-(ethanesulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9 H -pyrazolo[5,1- b ]Pyridine[2,3- e Synthesis of [1,3]oxazine-3-carboxamide Under nitrogen protection, 2-(4-(ethanesulfonyl)-2-fluorophenyl)-9- H -pyrazolo[5,1- b ]pyrido[2,3- e [1,3]Oxazine-3-carboxylic acid (110 mg, 0.27 mmol), ( S )-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-2-one (0.073 g, 0.27 mmol), CMPI (0.10 g, 0.41 mmol), THF (8 mL), and DMF (2 mL) were added dropwise, followed by slow addition of DIPEA (0.16 mL, 0.95 mmol). After addition was complete, the mixture was stirred at room temperature for 1 h. TLC monitoring showed that the reactants had reacted completely, and the reaction was stopped. Saturated sodium bicarbonate (20 mL) was added, followed by extraction with ethyl acetate (20 mL × 3), washing with saturated brine (20 mL), collecting the organic phase, drying on sodium sulfate, concentrating the solvent, and sending to a preparative purification facility to give the title compound (85 mg, 47.61%). HPLC purity: 96.65%. MS (ESI, pos. ion) m / z: 655.1 (M+1). 1 H NMR (400 MHz, DMSO- d6) δ (ppm): 11.00 (s, 1H), 8.54 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 7.3 Hz, 1H), 7.79 (t, J = 7.7 Hz, 4H), 7.64-7.54 (m, 3H), 7.52(d, J = 7.0 Hz, 2H), 7.50-7.44 (m, 2H), 7.33 (dd, J = 12.9, 7.7 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 5.53 (s, 2H), 5.44 (d, J = 7.4 Hz, 1H), 3.41 (d, J = 7.2 Hz, 2H), 1.14 (t, J = J = 7.3 Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -109.88 (d, J = J = 4.3 Hz), -123.38 (d, J = J = 7.9 Hz). Example 25 ( S )-6-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxamide

[0223] Step 1: 6-(4-bromo-2-fluorophenyl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxylate ethyl ester Ethyl 3-(2-fluoro-4-bromophenyl)-3-oxopropionate (1.0 g, 3.46 mmol), 1,2,4-triazine-3-amine (0.66 g, 6.92 mmol), N - Succinimide bromide (0.62 g, 3.46 mmol) and N20 mL of methylpyrrolidone was added to a single-necked round-bottom flask and reacted at 80 °C for 6.5 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA(v / v) = 5 / 3) to give the title compound as a yellow oil (0.40 g, 31.67%).

[0224] Step 2: 6-(2-fluoro-4-(ethylsulfonyl)phenyl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxylic acid ethyl ester 6-(4-bromo-2-fluorophenyl)imidazo[1,2- b [1,2,4]Ethyl triazine-7-carboxylate (0.40 g, 1.10 mmol), sodium ethyl sulfinate (0.38 g, 3.30 mmol), cuprous iodide (0.042 g, 0.22 mmol), potassium phosphate (0.47 g, 2.20 mmol), L-hydroxyproline (0.087 g, 0.66 mmol), and dimethyl sulfoxide (15 mL) were added to a single-necked round-bottom flask. The mixture was purged with nitrogen three times and stirred at 100 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 1 / 1) to give the title compound as a brown oil (0.025 g, 6.03%). MS (ESI, pos. ion) m / z: 379.10 (M+1). Step 3: 6-(2-fluoro-4-(ethylsulfonyl)phenyl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxylic acid 6-(2-fluoro-4-(ethylsulfonyl)phenyl)imidazo[1,2- b[1,2,4]Ethyl triazine-7-carboxylate (0.042 g, 0.11 mmol) and lithium hydroxide monohydrate (0.0092 g, 0.22 mmol) were added to a single-necked round-bottom flask, followed by methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction was carried out at room temperature for 3.5 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the aqueous phase was adjusted to pH ≤ 4 with 2M HCl, extracted with ethyl acetate (10 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (0.036 g, 92.58%). MS (ESI, pos. ion) m / z: 351.10 (M+1). Step 4: ( S )-6-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)imidazo[1,2- b Synthesis of [1,2,4]triazine-7-carboxamide 6-(2-fluoro-4-(ethylsulfonyl)phenyl)imidazo[1,2- b [1,2,4] Triazine-7-carboxylic acid (0.036 g, 0.10 mmol), ( S )-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diazazon-2-one (0.030 g, 0.11 mmol), 2-chloro-1-methylpyridine iodide (0.033 g, 0.13 mmol), N , N Dimethylformamide (3 mL) and tetrahydrofuran (3 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , N Diisopropylethylamine (0.039 g, 0.30 mmol) was reacted at room temperature for 3.5 h. After the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative purification (acetonitrile: 0.1% TFA aqueous solution (v / v) = 2:3) to give the title compound as a white solid (0.025 g, 40.44%). HPLC purity: 98.61%. MS (ESI, pos. ion) m / z: 602.10 (M+1). 1 H NMR (400 MHz, CDCl3) δ (ppm):9.88 (d, J = J = 7.9 Hz, 1H), 8.76 (dd, J = J = 7.4, 1.8 Hz, 2H), 7.97 (s, 1H), 7.95 – 7.89 (m, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.42 – 7.32 (m, 3H), 7.21 – 7.13 (m, 2H), 5.90 (d, J = 7.9 Hz, 1H), 3.14 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ (ppm): -108.20 (s), -127.02 (s). Example 26 ( S )-6-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide

[0225] Step 1: 3-Iodine- N Synthesis of 2-methylpyrazine-amine 3-Iodopyrazin-2-amine (500 mg, 2.26 mmol) was added to a single-necked round-bottom flask, dissolved in tetrahydrofuran (20 mL), and stirred in an ice bath. 60% sodium hydride (90.40 mg, 2.26 mmol) was added, and stirring continued in an ice bath for 30 minutes. Iodimethane (320.78 mg, 2.26 mmol) was added dropwise, and stirring continued at room temperature for 16 hours. Since a large amount of the starter remained, 60% sodium hydride (90.40 mg, 2.26 mmol) was added again in an ice bath, and stirring continued in an ice bath for 30 minutes. Iodimethane (320.78 mg, 2.26 mmol) was added dropwise, and stirring continued for 6 hours. The reaction was stopped, and the reaction solution was diluted with water (20 mL). Extraction was performed with ethyl acetate (40 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 4 / 1) to give the title compound as a yellow solid (300 mg, 56.42%). MS (ESI, pos. ion) m / z: 236.0 (M+1). Step 2: 3-((4-(ethanesulfonyl)-2-fluorophenyl)ethynyl)- N Synthesis of 2-methylpyrazine-amine 3-iodine- N 2-Methylpyrazine-2-amine (300.84 mg, 1.28 mmol), 4-(ethanesulfonyl)-1-ethynyl-2-fluorobenzene (271.67 mg, 1.28 mmol), CuI (24.38 mg, 0.13 mmol), and PdCl2(PPh3)2 (44.92 mg, 0.064 mmol) were added to a two-necked round-bottom flask and placed in an ice bath. The reaction mixture was purged with nitrogen three times. Triethylamine (10 mL) was added to dissolve the compound using a syringe, and the reaction mixture was purged with nitrogen three times. The mixture was then heated to 70 °C and stirred for 12 hours. The reaction was stopped, and the reaction solution was directly concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA(v / v) = 1 / 1) to give the title compound as a yellow solid (334 mg, 81.71%). MS (ESI, pos. ion) m / z: 320.1 (M+1). Step 3: 6-(4-(ethanesulfonyl)-2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine 3-((4-(ethanesulfonyl)-2-fluorophenyl)ethynyl)- N2-Methylpyrazine-2-amine (334 mg, 1.05 mmol) and sodium tert-amyloxide (138.76 mg, 1.26 mmol) were added to a single-necked round-bottom flask, dissolved in dimethyl sulfoxide (20 mL), and stirred at 80 °C for 16 hours. The reaction was stopped, cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 1 / 1) to give the title compound as a yellow oil (120 mg, 35.93%). MS (ESI, pos. ion) m / z: 320.1 (M+1). Step 4: 6-(4-(ethanesulfonyl)-2-fluorobenzene)-7-iodo-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine 6-(4-(ethanesulfonyl)-2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Pyrazine (120 mg, 0.38 mmol), N Iodosuccinimide (102.59 mg, 0.46 mmol) was added to a single-necked round-bottom flask, dissolved in acetonitrile (10 mL), and heated to 50 °C with stirring for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA(v / v) = 1 / 1) to give the title compound as a yellow oil (140 mg, 83.68%). MS (ESI, pos. ion) m / z: 446.0 (M+1). Step 5: 6-(4-(ethanesulfonyl)-2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of methyl pyrazine-7-carboxylate 6-(4-(ethanesulfonyl)-2-fluorobenzene)-7-iodo-5-methyl-5 H -pyrrolo[2,3- bPyrazine (140 mg, 0.31 mmol) and tetraphenylphosphine palladium (179.11 mg, 0.15 mmol) were added to a single-necked round-bottom flask, dissolved in DMF (6 mL) and methanol (6 mL), and then triethylamine (125.48 mg, 1.24 mmol) was added. The reaction mixture was replaced with carbon monoxide three times, and the mixture was heated to 60 °C and stirred for 6.5 hours. The reaction was stopped, cooled to room temperature, and the reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL × 2). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 1 / 1—DCM / MeOH(v / v) = 1 / 1) to give the title compound as a creamy white solid (84 mg, 70.79%). MS (ESI, pos. ion) m / z: 378.1 (M+1). Step 6: 6-(4-(ethanesulfonyl)-2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxylic acid 6-(4-(ethanesulfonyl)-2-fluorophenyl)-5-methyl-5 H -pyrrolo[2,3- b Methyl pyrazine-7-carboxylate (84 mg, 0.22 mmol) was added to a single-necked round-bottom flask, dissolved in methanol (9 mL) and water (3 mL), followed by sodium hydroxide (35.20 mg, 0.88 mmol). The mixture was heated to 65 °C and stirred for 7 hours. The reaction was stopped, and the reaction solution was directly concentrated under reduced pressure. The residue was diluted with water (15 mL), extracted with ethyl acetate (20 mL) to remove impurities, and the aqueous phase was adjusted to pH ≤ 4 with 2 M HCl and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (57 mg, 70.48%). MS (ESI, pos. ion) m / z: 364.1 (M+1). Step 7: ( S )-6-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5-methyl-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide 6-(4-(ethanesulfonyl)-2-fluorophenyl)-5-methyl-5H -pyrrolo[2,3- b Pyrazine-7-carboxylic acid (57 mg, 0.16 mmol), ( S )-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-2-one (43.08 mg, 0.16 mmol) and 2-chloro-1-methylpyridine iodide (61.32 mg, 0.24 mmol) were added to a single-necked round-bottom flask, and then... N , N - Dimethylformamide (1 mL) and tetrahydrofuran (10 mL), stir at room temperature for 5 minutes; then add N , N Diisopropylethylamine (62.04 mg, 0.48 mmol) was reacted with stirring at room temperature for 2 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and purified preparatively (acetonitrile:0.1% TFA = 55:45) to give the title compound as a white solid (60 mg, 61.43%). HPLC purity: 98.72%. MS (ESI, pos. ion) m / z: 615.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 9.91 (dd, J = 13.8, 8.2 Hz, 1H), 8.81 (d, J = 2.5 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 7.99 – 7.42 (m, 10H), 7.31 (dd, J = 13.0, 7.9 Hz, 1H), 7.14 (t, J = 6.9 Hz, 1H), 5.53 (dd, J = 6.3 Hz, 1H), 3.70 (s,3H), 3.44 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -108.93 (d, J = 27.7 Hz), -123.42(d, J = 39.0 Hz). Example 27 ( S )-5-(2-(dimethylamino)ethyl)-6-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide

[0226] Step 1: Synthesis of 3-((4-(ethylsulfonyl)-2-fluorophenyl)acetylene)pyrazine-2-amine 2-Amino-3-bromopyrazine (2.2 g, 12.64 mmol), 4-(ethylsulfonyl)-1-ethynyl-2-fluorobenzene (2.95 g, 13.90 mmol), CuI (0.24 g, 1.26 mmol), and (PPh3)2PdCl2 (0.44 g, 0.63 mmol) were added to a two-necked round-bottom flask and placed in an ice bath. The reaction mixture was purged with nitrogen three times. Acetonitrile (15 mL) and triethylamine (15 mL) were added to dissolve the precipitate using a syringe, and the reaction mixture was purged with nitrogen three times. The mixture was then heated to 70 °C and stirred for 15 hours. The reaction was stopped, and the reaction solution was directly concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA(v / v) = 1 / 3) to give the title compound as a yellow solid (3.3 g, 85.48%).

[0227] MS (ESI, pos. ion) m / z: 306.0 (M+1). Step 2: 2-(6-(4-(ethylsulfonyl)-2-fluorophenyl)-5 H -pyrrolo[2,3- b ]pyrazine-5-yl)- N , N Synthesis of 1-dimethylethane-1-amine 3-((4-(ethylsulfonyl)-2-fluorophenyl)acetylene)pyrazin-2-amine (500 mg, 1.64 mmol) was added to a single-necked reaction flask, dissolved in DMF (20 mL), and stirred in an ice bath. 60% sodium hydride (123.2 mg, 3.08 mmol) was added, and stirring continued at room temperature for 2.5 hours. 2-bromo- N , NDimethylethane-1-amine hydrobromide (458.43 mg, 1.97 mmol), potassium iodide (0.33 g, 1.97 mmol), and cesium carbonate (1.07 g, 3.28 mmol) were added to a single-necked reaction flask, dissolved in DMF (10 mL), and stirred at room temperature for 10 minutes. The solution was then added dropwise to the previous reaction mixture, and stirring continued for 3 hours. The reaction was stopped, and the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 2), concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH (v / v) = 20 / 1) to give the title compound as a brown oil (150 mg, 24.33%).

[0228] MS (ESI, pos. ion) m / z: 377.0 (M+1). 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 8.52 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.03 -7.90 (m, 3H), 6.94 (s, 1H), 4.33 (t, J = 6.3 Hz, 2H), 3.51-3.46 (m, 2H), 2.37 (t, J = 6.0 Hz, 2H), 1.87 (s, 6H), 1.16 (d, J = 7.3 Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -110.77 (s). Step 3: 5-(2-(dimethylamino)ethyl)-6-(4-(ethylsulfonyl)-2-fluorophenyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxaldehyde 2-(6-(4-(ethylsulfonyl)-2-fluorophenyl)-5 H -pyrrolo[2,3- b ]pyrazine-5-yl)- N , NDimethylethane-1-amine (140 mg, 0.37 mmol) was added to a reaction flask, dissolved in DMF (6 mL), and phosphorus oxychloride (4767.20 mg, 31.09 mmol) was added. The reaction system was purged with nitrogen three times and stirred at 80 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL), and saturated sodium bicarbonate solution (30 mL) was slowly added. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15 / 1) to give a brown oil (90 mg, 59.83%).

[0229] MS (ESI, pos. ion) m / z: 405.1 (M+1). Step 4: 5-(2-(dimethylamino)ethyl)-6-(4-(ethylsulfonyl)-2-fluorophenyl)-5 H -pyrrolo[2,3- b Synthesis of pyrazine-7-carboxylic acid 5-(2-(dimethylamino)ethyl)-6-(4-(ethylsulfonyl)-2-fluorophenyl)-5 H -pyrrolo[2,3- b Pyrazine-7-carboxaldehyde (80 mg, 0.20 mmol) was added to a single-necked reaction flask, dissolved in THF (10 mL), and DMSO (281.27 mg, 3.6 mmol) was added. The mixture was stirred in an ice bath, and a solution of sodium chlorite (90.44 mg, 1 mmol) and sodium dihydrogen phosphate (119.98 mg, 1 mmol) in water (6 mL) was added. The mixture was stirred for another 5 minutes and then stirred at room temperature for 3.5 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was extracted with water (5 mL) and ethyl acetate. The product was mainly in the aqueous layer. The pH of the aqueous phase was adjusted to 2-3, and the product was extracted with ethyl acetate. The product was still mainly in the aqueous layer. Therefore, the aqueous phase was directly concentrated under reduced pressure to obtain the crude product of the title compound as a brown oil (83.16 mg, 100%).

[0230] MS (ESI, pos. ion) m / z: 421.1 (M+1). Step 5: ( S )-5-(2-(dimethylamino)ethyl)-6-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-5 H-pyrrolo[2,3- b Synthesis of pyrazine-7-carboxamide 5-(2-(dimethylamino)ethyl)-6-(4-(ethylsulfonyl)-2-fluorophenyl)-5 H -pyrrolo[2,3- b Pyrazine-7-carboxylic acid (200 mg, 0.48 mmol), ( S )-3-amino-9-fluoro-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4] Diazazon-2-one (129.25 mg, 0.48 mmol) and CMPI (183.95 mg, 0.72 mmol) were dissolved in DMF (1 mL) and THF (10 mL), stirred at room temperature for 5 minutes, DIPEA (186.11 mg, 1.44 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and purified by preparative purification (acetonitrile: 0.1% TFA = 60:40) to give the title compound as a pale yellow solid (60 mg, 16.89%). MS (ESI, pos. ion) m / z: 672.00 (M+1). 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 10.96 (d, J = 8.7 Hz, 1H), 9.91 (dd, J = 16.3, 8.2 Hz, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 7.92 (dq, J = 11.7, 8.0 Hz, 3H), 7.67 – 7.39 (m, 6H), 7.29 (dt, J = 15.5, 7.8 Hz, 1H),7.19 – 7.10 (m, 1H), 5.53 (dd, J = 8.1, 2.9 Hz, 1H), 4.55 (ddd, J = 24.1, 15.5,7.6 Hz, 2H), 3.44 (dd, J = 14.7, 7.4 Hz, 2H), 3.38 (s, 2H), 2.81 (s, 6H), 1.16(t,J = 7.3 Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -108.56 (s), -123.38 (d, J = 39.1Hz). Example 28 ( S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9,10-dihydrobenzo[ f ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0231] Step 1: Synthesis of tert-butyl(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenoxy)dimethylsilane o-hydroxyphenylethanol (1.5 g, 10.86 mmol), tert-butyldimethylchlorosilane (4.91 g, 32.58 mmol), imidazole (2.22 g, 32.58 mmol), and DMF (40 mL) were added to the reaction flask, and the reaction was carried out at room temperature for 28 h. The reaction was terminated after the starting material was detected to be completely reacted by TLC. The reaction solution was extracted with methyl tert-butyl ether (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 30 / 1) to give the title compound as a pale yellow oil (3.86 g, 96.96%).

[0232] 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.21 (dd, J = 7.4, 1.5 Hz, 1H), 7.12(ddd, J = 7.8, 6.3, 1.7 Hz, 1H), 6.91 (td, J = 7.4, 0.7 Hz, 1H), 6.82 (d, J = 8.0Hz, 1H), 3.83 (t, J = 7.2 Hz, 2H), 2.89 (t, J= 7.2 Hz, 2H), 1.07 (s, 9H), 0.92 (s, 9H), 0.29 (s, 6H), 0.02 (s, 6H). Step 2: Synthesis of 2-(2-tert-butyldimethylsilyl)oxy)phenyl)-1-ethanol 0.2 g (0.55 mmol) of tert-butyl(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenoxy)dimethylsilane was dissolved in EtOH (6 mL), followed by the addition of pyridine 4-methylbenzenesulfonic acid (0.014 g, 0.055 mmol). The reaction was stopped after 5 h at 50°C. The reaction solution was concentrated, and the residue was dissolved in 20 mL of water and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), concentrated, and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0–30%) to give the title compound as a colorless oily liquid (0.1 g, 72.63%).

[0233] MS (ESI, pos. ion) m / z :253.2 (M+1). Step 3: Synthesis of (2-(2-bromoethyl)phenoxy)(tert-butyl)dimethylsilane 2-(2-tert-butyldimethylsilyl)oxy)phenyl)-1-ethanol (0.1 g, 0.40 mmol) was dissolved in ultradry DCM (5 mL), and the system was purged with nitrogen three times. The reaction system was cooled to -20°C, and triphenylphosphine (0.16 g, 0.60 mmol) and NBS (0.11 g, 0.60 mmol) were added. The reaction was stirred at -20°C for 30 min, then transferred to room temperature, and the reaction was stopped after 6 h. The reaction solution was concentrated and purified by column chromatography (petroleum ether), and the title compound was concentrated into a colorless oily liquid (0.1 g, 80.05%).

[0234] 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.16 (t, J= 7.6 Hz, 2H), 6.92 (t, J= 7.1Hz, 1H), 6.83 (d, J= 7.8 Hz, 1H), 3.56 (t, J= 7.9 Hz, 2H), 3.17 (t, J= 7.9 Hz, 2H), 1.05 (s, 9H), 0.28 (s, 6H). Step 4: 3,5-Dibromo-1-(2-((tert-butyldimethylsilyl)oxy)phenethyl)-1 H Synthesis of pyrazole-4-carboxylic acid ethyl ester (2-(2-bromoethyl)phenoxy)(tert-butyl)dimethylsilane (0.2 g, 0.63 mmol), 3,5-dibromo-1 H Ethyl pyrazole-4-carboxylate (0.19 g, 0.63 mmol), sodium iodide (0.0094 g, 0.063 mmol), and cesium carbonate (0.62 g, 1.89 mmol) were dissolved in DMF (5 mL). The reaction was stopped after 5 h at room temperature. The reaction solution was diluted with 20 mL of water, extracted with ethyl acetate (20 mL x 2), and the organic phase was washed once with saturated brine (20 mL). The organic phase was concentrated and subjected to column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) to give the title compound as a colorless oily liquid (0.12 g, 35.54%).

[0235] MS (ESI, pos. ion) m / z 533.00 (M+1). Step 5: 3,5-Dibromo-1-(2-hydroxyphenylethyl)-1 H Synthesis of pyrazole-4-carboxylic acid ethyl ester 3,5-Dibromo-1-(2-((tert-butyldimethylsilyl)oxy)phenethyl)-1 H Ethyl pyrazole-4-carboxylate (0.12 g, 0.23 mmol) was dissolved in THF (5 mL), and tetrabutylammonium fluoride tetrahydrofuran (0.30 mL, 0.30 mmol) was added dropwise. The reaction was allowed to proceed overnight at room temperature. The reaction was quenched by adding 5 mL of saturated ammonium chloride solution. The reaction solution was concentrated, and the residue was diluted with 20 mL of water. The solution was extracted with 20 mL of ethyl acetate, and the organic phase was washed once with saturated brine (20 mL). The solution was concentrated to give the title compound as a colorless oily liquid (0.067 g, 71.09%).

[0236] MS (ESI, pos. ion) m / z : 419.90(M+1). Step 6: 2-Bromo-9,10-dihydrobenzo[ f ]Pyrazole[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 3,5-dibromo-1-(2-hydroxyphenylethyl)-1 HEthyl pyrazole-4-carboxylate (0.067 g, 0.16 mmol) was dissolved in DMF (5 mL), and potassium carbonate (0.066 g, 0.48 mmol) was added. The mixture was refluxed at 150°C for 5 h, and then the reaction was stopped. The reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (50 mL), and the organic phase was washed once with saturated brine (50 mL). The organic phase was concentrated to give the title compound as a yellow oily liquid (0.05 g, 92.53%). MS (ESI, pos. ion) m / z 338.10 (M+1). Step 7: 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9,10-dihydrobenzo[ f ]Pyrazole[5,1- b Synthesis of ethyl 1,3]oxazine-3-carboxylate 2-bromo-9,10-dihydrobenzo[ f ]Pyrazole[5,1- b [1,3]Oxazine-3-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 2-fluoro-4-(methanesulfonyl)phenylboronic acid (0.049 g, 0.22 mmol) were dissolved in 1,4-Dioxane (6 mL) and water (1 mL). BrettPhos-G3-Pd (0.027 g, 0.030 mmol) and cesium carbonate (0.15 g, 0.45 mmol) were added. The system was purged with nitrogen three times, and the reaction was stopped after reacting overnight at 100°C. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0–80%) to give the title compound as a yellow oily liquid (0.046 g, 72.06%).

[0237] MS (ESI, pos. ion) m / z : 431.10(M+1). Step 8: 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9,10-dihydrobenzo[ f ]Pyrazole[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9,10-dihydrobenzo[ f ]Pyrazole[5,1- b[1,3]Oxazine-3-carboxylic acid ethyl ester (0.046 g, 0.11 mmol) was dissolved in THF (1.5 mL) and methanol (1.5 mL). Lithium hydroxide monohydrate (0.018 g, 0.44 mmol) was dissolved in water (1.5 mL) and added to the above reaction solution. The reaction was stopped after reacting at 50°C for 6 h. The reaction solution was concentrated, and the residue was dissolved in 20 mL of water. The solution was washed once with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH ≈ 2 with 2M hydrochloric acid, and then extracted with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine and concentrated to give the title compound as a white solid (0.043 g, 99.99%).

[0238] MS (ESI, pos. ion) m / z 403.00 (M+1). Step 9: ( S )-2-(2-fluoro-4-(methylsulfonyl)phenyl)- N -(2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-9,10-dihydrobenzo[ f ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide 2-(2-fluoro-4-(methylsulfonyl)phenyl)-9,10-dihydrobenzo[ f ]Pyrazole[5,1- b [1,3]oxazine-3-carboxylic acid (0.043 g, 0.11 mmol) and ( S )-3-amino-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-2-one (0.030 g, 0.12 mmol) was dissolved in THF (2.5 mL) and DMF (2.5 mL), and CMPI (0.037 g, 0.14 mmol) was added. After reacting at room temperature for 15 min, DIPEA (0.055 mL, 0.33 mmol) was added, and the reaction was stopped after reacting at room temperature for 6 h. The reaction solution was concentrated, and the residue was diluted with 20 mL of water and extracted twice with 20 mL of ethyl acetate. The organic phase was washed once with 20 mL of saturated brine, and the organic phase was evaporated to dryness to give a red oily liquid. After purification, the title compound was obtained as a white solid (0.024 g, 35.12%). HPLC purity: 99.40%. MS (ESI, pos. ion) m / z: 636.15 (M+1). 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 11.12 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 7.71 (ddd, J = 23.5, 17.8, 7.4 Hz, 6H), 7.52 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 6.1 Hz, 5H), 7.34 (dd, J = 8.0, 6.4 Hz, 3H), 5.37 (d, J = 7.5 Hz, 1H), 4.57 (ddd, J = 10.3, 6.6, 3.6 Hz, 1H), 4.50 – 4.40 (m, 1H), 3.58 – 3.48 (m, 2H), 3.28 (s, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -110.09 (s). Example 29 ( S )- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-2-(2-fluoro-4-(methanesulfonyl)phenyl)-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide

[0239] Step 1: 3,5-Dibromo-1-(2-(hydroxymethyl)benzyl)-1 H Synthesis of pyrazole-4-carboxylic acid ethyl ester 3,5-dibromo-1 H β-pyrazole-4-carboxylic acid ethyl ester (0.5 g, 1.68 mmol), 2-(bromomethyl)benzyl alcohol (0.37 g, 1.85 mmol), potassium carbonate (0.35 g, 2.52 mmol), and N , NDimethylformamide (30 mL) was added to a single-necked round-bottom flask and stirred at 80 °C for 5.5 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 5 / 2) to give the title compound as a pale yellow oil (0.65 g, 92.64%).

[0240] MS (ESI, pos. ion) m / z: 418.90 (M+1). Step 2: 2-Bromo-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 3,5-Dibromo-1-(2-(hydroxymethyl)benzyl)-1 H Ethyl pyrazole-4-carboxylate (0.68 g, 1.63 mmol) and tetrahydrofuran (30 mL) were added to a single-necked round-bottom flask. The mixture was purged with nitrogen three times, and 60% sodium hydride (0.13 g, 3.26 mmol) was added under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and stirred for 16.5 hours. After the reaction was completed, the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), the pH of the aqueous layer was adjusted to ≤4 with 2 M HCl, extracted with ethyl acetate (50 mL × 2), and the organic layer was concentrated under reduced pressure to give the title compound as a white solid (0.42 g, 83.54%).

[0241] MS (ESI, pos. ion) m / z: 310.15 (M+1). Step 3: 2-Bromo-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Synthesis of methyl 1,3]oxazine-3-carboxylic acid ester 2-bromo-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b [1,3]oxazine-3-carboxylic acid (0.42 g, 1.36 mmol), iodomethane (0.23 g, 1.63 mmol), cesium carbonate (0.66 g, 2.04 mmol) and N , N 20 mL of dimethylformamide was added to a single-necked round-bottom flask and stirred at room temperature for 3.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 5 / 2) to give the title compound as a white solid (0.39 g, 88.83%).

[0242] MS (ESI, pos. ion) m / z: 324.05 (M+1). Step 4: 2-(2-fluoro-4-(methanesulfonyl)phenyl)-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Synthesis of methyl 1,3]oxazine-3-carboxylic acid ester 2-bromo-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Methyl 1,3]oxazolidinyl-3-carboxylate (0.1 g, 0.31 mmol), (2-fluoro-4-(methanesulfonyl)phenyl)boronic acid (0.11 g, 0.50 mmol), BrettPhos Pd G3 (0.056 g, 0.062 mmol), potassium carbonate (0.086 g, 0.62 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added to a single-necked round-bottom flask. The mixture was purged with nitrogen three times and stirred at 95 °C for 22.5 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 3 / 4) to give the title compound as a brown solid (0.022 g, 17.07%).

[0243] MS (ESI, pos. ion) m / z: 417.10 (M+1). Step 5: 2-(2-fluoro-4-(methanesulfonyl)phenyl)-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxylic acid 2-(2-fluoro-4-(methanesulfonyl)phenyl)-5,10-dihydrobenzo[ e ]pyrazolo[5,1- bMethyl 1,3]oxazine-3-carboxylic acid (0.050 g, 0.12 mmol), methanol (5 mL), and tetrahydrofuran (5 mL) were added to a single-necked round-bottom flask. Lithium hydroxide monohydrate (0.010 g, 0.24 mmol, dissolved in water (0.12 mL)) was then added. The reaction was carried out at 50 °C for 3.5 h. Sodium hydroxide (0.058 g, 1.44 mmol, dissolved in water (0.72 mL)) was added, and the mixture was heated to 65 °C and stirred for 3.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 2). The aqueous phase was adjusted to pH ≤ 4 with 2 M HCl and extracted with ethyl acetate (30 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown solid (0.036 g, 74.51%).

[0244] MS (ESI, pos. ion) m / z: 403.05 (M+1). Step 6: ( S )- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-2-(2-fluoro-4-(methanesulfonyl)phenyl)-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b Synthesis of [1,3]oxazine-3-carboxamide 2-(2-fluoro-4-(methanesulfonyl)phenyl)-5,10-dihydrobenzo[ e ]pyrazolo[5,1- b [1,3]oxazine-3-carboxylic acid (0.036 g, 0.089 mmol), ( S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (0.029 g, 0.11 mmol), 2-chloro-1-methylpyridine iodide (0.03 g, 0.12 mmol), N , N Dimethylformamide (4 mL) and tetrahydrofuran (4 mL) were added to a single-necked round-bottom flask and stirred at room temperature for 15 minutes; then, the following were added to the above reaction solution: N , NDiisopropylethylamine (0.035 g, 0.27 mmol) was reacted at room temperature for 16.5 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by preparative method (0.1% TFA aqueous solution / acetonitrile (v / v) = 7 / 13) to give the title compound as a white solid (25 mg, 42.75%). HPLC purity: 99.70%.

[0245] MS (ESI, pos. ion) m / z: 654.10 (M+1). 1 H NMR (400 MHz, CDCl3) δ (ppm): 8.27 (d, J= 8.2 Hz, 1H), 8.08 (s, 1H), 7.72 (dd, J= 8.0, 1.1 Hz, 1H), 7.65 (t, J= 7.1 Hz, 2H), 7.53 – 7.42 (m, 7H), 7.36(t, J= 7.5 Hz, 2H), 7.33 – 7.27 (m, 1H), 7.16 – 7.07 (m, 2H), 5.76 (d, J= 8.2 Hz,1H), 5.71 – 5.59 (m, 4H), 3.01 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ (ppm): -108.83 (s), -127.19 (s). Example 30 ( S )-9-(4-(ethylsulfonyl)-2-fluorophenyl)- N -(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazolo[5,1- b Synthesis of [1,3,6]oxadiazonium octane-10-carboxamide

[0246] Step 1: 9-Bromo-4-methyl-3,4,5,6-tetrahydro-2- H -pyrazole[5,1- b Synthesis of ethyl 1,3,6]oxadiazonium octane-10-carboxylate 2,2'-(methylimine)diethanol hydrochloride (468.30 mg, 3.93 mmol) was added to a two-necked flask, dissolved in ultra-dry dichloromethane (10 mL), and placed in an ice bath. The reaction mixture was purged with nitrogen three times. DMAP (48.01 mg, 0.39 mmol) and triethylamine (800 mg, 7.86 mmol) were added, and the reaction mixture was purged with nitrogen three times. TsCl (749.25 mg, 3.93 mmol) dissolved in dichloromethane (20 mL) was slowly added, and the reaction mixture was purged with nitrogen three times. The reaction was continued with stirring for about 3 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a white oil. The white oil was then reacted with 3,5-dibromo-1... H Ethyl pyrazole-4-carboxylate (350 mg, 1.18 mmol) and cesium carbonate (770 mg, 2.36 mmol) were added to a single-necked flask, dissolved in DMF (20 mL), heated to 100 °C and stirred for 6 hours. The reaction was then stopped, and water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a colorless oil (25 mg, 6.66%).

[0247] MS (ESI, pos. ion) m / z:318.1 (M+1) Step 2: 9-(4-(ethylsulfonyl)-2-fluorophenyl)-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazole[5,1- b Synthesis of ethyl 1,3,6]oxadiazonium octane-10-carboxylate 9-Bromo-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazole[5,1- b[1,3,6]Oxadiazonoctane-10-carboxylic acid ethyl ester (65 mg, 0.2 mmol), 2-(4-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (94.25 mg, 0.30 mmol), sodium carbonate (42.40 mg, 0.4 mmol), and BrettPhos-Pd-G3 (36.26 mg, 0.04 mmol) were added to a 50 mL single-necked round-bottom flask. 1,4-Dioxane (10 mL) and water (0.2 mL) were added to dissolve the flask. The reaction system was purged with nitrogen three times, and the mixture was heated to 100 °C and reacted for 13 hours. The reaction was stopped, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to give the title compound as a yellow oil (70 mg, 80.53%).

[0248] MS (ESI, pos. ion) m / z: 426.1 (M+1). Step 3: 9-(4-(ethylsulfonyl)-2-fluorophenyl)-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazole[5,1- b Synthesis of [1,3,6]oxadiazonoctane-10-carboxylic acid 9-(4-(ethylsulfonyl)-2-fluorophenyl)-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazole[5,1- b [1,3,6]Oxadiazonium octane-10-carboxylic acid ethyl ester (100 mg, 0.24 mmol) was added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (3 mL), water (3 mL), and methanol (3 mL). Lithium hydroxide monohydrate (50.53 mg, 1.2 mmol) was added, and the mixture was heated to 50 °C and stirred for 13 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to water (15 mL), and extracted with ethyl acetate (20 mL) to remove impurities. The aqueous phase was adjusted to pH ≤ 2 with 4 mol / L hydrochloric acid and extracted with ethyl acetate (20 mL). The product remained in the aqueous phase, which was concentrated under reduced pressure to give the crude product of the title compound as a yellow oil (93.41 mg, 100%).

[0249] MS (ESI, pos. ion) m / z: 398.1 (M+1). Step 4: ( S )-9-(4-(ethylsulfonyl)-2-fluorophenyl)- N-(9-Fluoro-2-oxo-5-phenyl-2,3-dihydro-1 H -benzo[ e [1,4]diaza-3-yl)-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazolo[5,1- b Synthesis of [1,3,6]oxadiazonium octane-10-carboxamide 9-(4-(ethylsulfonyl)-2-fluorophenyl)-4-methyl-3,4,5,6-tetrahydro-2 H -pyrazole[5,1- b [1,3,6]oxadiazonoctane-10-carboxylic acid (90 mg, 0.23 mmol), ( S )-3-amino-9-fluoro-5-phenyl-1,3-dihydro-2 H -benzo[ e [1,4]diaza-2-one (61.93 mg, 0.23 mmol) and CMPI (88.14 mg, 0.35 mmol) were added to a 50 mL single-necked round-bottom flask, dissolved in tetrahydrofuran (10 mL) and DMF (1 mL), and stirred for about 5 minutes. DIPEA (89.18 mg, 0.69 mmol) was then added dropwise, and the reaction was stirred for 3 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The residue was added to water (15 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified preparatively (acetonitrile: 0.1% TFA = 35:65) to give the title compound as a creamy white solid (40 mg, 23.73%). MS (ESI, pos. ion) m / z: 649.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 10.98 (s, 1H), 8.34 (d, J= 7.2 Hz, 1H), 7.75 (d, J= 5.6 Hz, 2H), 7.53 (ddd, J= 24.1, 18.0, 9.8 Hz, 7H), 7.31 (d, J= 5.1 Hz, 1H), 7.15 (d, J= 8.2 Hz, 1H), 5.38 (d, J=7.5 Hz, 1H), 4.72 – 4.35 (m,4H), 3.50 (q, 2H), 3.09 (dt, J= 11.5, 7.2 Hz, 4H), 2.60 (s, 3H), 1.11 (t, J= 7.3Hz, 3H). 19 F NMR (376 MHz, DMSO- d 6) δ (ppm): -110.09 (s), -123.41 (s). The following compounds were prepared using conventional techniques in the art, referring to the synthetic routes and Examples 1-30. Specific NMR data are shown in Table 1: Table 1. Compound and structural data

[0250] Biological activity test cases Test Example 1: In vitro anti-RSV activity test of the compound 1. Experimental materials Hep-2 cells were purchased from ATCC; RSV virus was purchased from ATCC.

[0251] 2. Experimental Procedure 2.1 Cell Plating: Hep-2 cells were resuscitated and, once they reached confluence, digested and counted. The cells were then diluted with cell culture medium (DMEM + 10% FBS + antibiotics) to a concentration of 80,000 cells / ml. 100 μL of the solution was seeded into each well of a 96-well plate, i.e., 8,000 cells per well. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 h.

[0252] 2.2 Viral infection: Replace the cell culture medium in the above 96-well plate with 100 μl of maintenance medium (DMEM + 2% FBS + double antibody) and add RSV virus solution with MOI of 0.1, and infect for 2 h.

[0253] 2.3. Drug preparation and administration: Dissolve the test compound in DMSO to a stock solution with a concentration of (20 mM), dilute it 10 times with DMSO to obtain a working concentration of 2 mM, and then perform 8 serial dilutions of 3 times with DMSO. After discarding the old culture medium in the 96-well plate described in section 2.2, add 200 μL of fresh maintenance culture medium, and add 1 μL of serially diluted compound solution to each well of the above cell plate, i.e., 200-fold dilution, so that the initial and final concentrations of the compound are (10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.041 μM, 0.013 μM, 0.004 μM); at the same time, set up cell control wells and virus control wells, each of which should be added with 1 μL of DMSO. After administration, incubate in a 37°C, 5% CO2 constant temperature incubator for 5 days.

[0254] 2.4 CTG Detection and Data Processing: The 96-well plates were subjected to fluorescence detection according to the CTG (Promega) kit instructions. The inhibition rate was calculated, and the concentration-inhibition rate was processed using Graphpad Prism 5 software (log(inhibitor) vs. response - Variable slope) to obtain the antiviral (RSVAlong) cytopathic effect (CPE) EC5. 50 .

[0255] 2.5. For some compounds, a concentration reduction test was performed. The specific operation was as follows: When preparing and administering the drug, the test compound was dissolved in DMSO to a stock solution with a concentration of (20 mM). The solution was then diluted 100 times with DMSO to obtain a working concentration of 200 μM. Subsequently, DMSO was used to perform 3-fold serial dilutions at 8 different concentrations. After discarding the old culture medium in the 96-well plate described in section 2.5, add 200 μL of fresh maintenance medium, and then add 1 μL of a serially diluted compound solution to each well of the cell plate (i.e., a 200-fold dilution), so that the initial and final concentrations of the compound are (1000.00 nM, 333.33 nM, 111.11 nM, 37.03 nM, 12.34 nM, 4.11 nM, 1.37 nM, 0.457 nM). Simultaneously, set up cell control wells and virus control wells, adding 1 μL of DMSO to each. After administration, incubate at 37°C in a 5% CO2 incubator for 5 days. For the remaining procedures, refer to sections 2.1–2.4.

[0256] 3. Experimental Results Table 2 Compound Activities

[0257] The experimental results show that the compound of the present invention has good anti-RSV activity.

[0258] Test Example 2: Evaluation of Compound Cytotoxicity 1. Experimental materials Hep-2 cells were purchased from ATCC; RSV virus was purchased from ATCC.

[0259] 2. Experimental Procedure 2.1 Cell Plating: Hep-2 cells were resuscitated and, once they reached confluence, digested and counted. The cells were then diluted with cell culture medium (DMEM + 10% FBS + antibiotics) to a concentration of 80,000 cells / ml. 100 μL of the solution was seeded into each well of a 96-well plate, i.e., 8,000 cells per well. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 h.

[0260] 2.2 Preparation and administration: Dissolve the test compound in DMSO to a stock solution with a concentration of (20 mM), dilute with DMSO, and then perform 8 4-fold serial dilutions with DMSO. After discarding the old culture medium in the 96-well plate described in 2.1, add 200 μL of fresh maintenance culture medium (DMEM + 2% FBS + antibiotics), and add 1 μL of serially diluted compound solution to each well of the above cell plate, i.e., 200-fold dilution, so that the initial and final concentrations of the compound are (100 μM, 25 μM, 6.25 μM, 1.56 μM, 0.39 μM, 0.097 μM, 0.024 μM, 0.006 μM); at the same time, add 1 μL of DMSO to the cell control wells, and incubate at 37°C and 5% CO2 for 5 days.

[0261] 2.3 CTG Detection and Data Processing: The 96-well plate described in 2.2 was subjected to fluorescence detection according to the CTG (Promega) kit instructions. The inhibition rate was calculated, and the concentration-inhibition rate was processed using Graphpad Prism 5 software (log(inhibitor) vs. response-variable slope) to obtain the CC. 50 Calculate the safety factor (SI).

[0262] 3. Experimental Results Table 3. Cytotoxicity Evaluation of Compounds

[0263] The experimental results show that the compound of the present invention has low cytotoxicity and good safety.

[0264] Test Example 3: Stability of the compound in human liver microsomes 1. Solution: Working solution 01: Take 5 μL of compound stock solution (10 mM) and add it to 495 μL of 50% acetonitrile aqueous solution.

[0265] Working solution 02: Take 60 μL of compound working solution 01 (100 μM) and add it to 140 μL of 0.1 M potassium phosphate buffer (hereinafter referred to as buffer, 100 mM, pH=7.4).

[0266] Termination sol...

Claims

1. A compound that is a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I). in, R 1 and R 2 Each can be independently represented by D, -CN, -OH, -NH2, halogen, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 1-6 Each alkoxy group is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, halogens, -CN, -NH2 and -OH; Ring A is a 5-membered heteroaromatic ring, and ring B is a C8 carbon ring, a 6-10 membered heterocyclic ring, a benzene ring, or a 6-10 membered heteroaromatic ring. Ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is nitrogen (N). Alternatively, ring A is a 5-membered heteroaromatic ring, and ring B is a C6 carbon ring, a 6-7 membered heterocyclic ring, a benzene ring, or a 6-membered heteroaromatic ring. Ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is nitrogen (N). R 3 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally bounded by 1, 2, 3 or 4 R groups. 31 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; The conditions are: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-6 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, -CH2-(C 3-6 cycloalkyl), -CH2-(3-10-membered heterocyclic), -CH2-(5-10-membered heteroaryl), or -CH2-(C 6-10 Aryl), wherein the C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (2) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-6 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl, and R 4 The C is not substituted or unsubstituted phenyl or pyridyl; wherein the C 2-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group can be independently and optionally bounded by 1, 2, 3 or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6 cycloalkyl), -CH2-(3-10-membered heterocyclic), -CH2-(5-10-membered heteroaryl), or -CH2-(C 6-10 (aryl); or two R groups attached to adjacent or non-adjacent different ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinone heteroaromatic rings, or 3-10 quinone heterocyclic rings, wherein the C 3-7 Carbon ring, C 6-10 Aromatic rings, 5-10 quinary heterocyclic rings, and 3-10 quinary heterocyclic rings are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0; Among them, R 31 and R 41 Each can be independently classified as D, halogen, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl or C 6-10 Aryl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl and C 6-10 Each aryl group is independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -OH, halogen, CN, -S(=O)2R k C 1-6 Alkyl and C 3-6 Substituents of cycloalkyl groups; R 32 and R 42 Each can be independently classified as D, halogen, -CN, -OH, or -S(=O)2R. l C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; R j For H, D, C 3-6 cycloalkyl, halogen, -NR n R m Or C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. j1 Replaced; R j1 For D, -OH, CN, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, -NR p R q , 3-10 membered heterocyclic group or 5-10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl, 3-10-membered heterocyclic and 5-10-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -NH2, C. 1-6 Substituted by alkyl and halogen substituents; R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each is independently H, D, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups; p, q, n, and m are each independently 0, 1, 2, 3, or 4.

2. The compound according to claim 1, wherein, R 3 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, 3-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 The alkoxy, 3-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 31 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 41 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; The conditions are: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-4 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl or phenyl, wherein the C 2-4 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6 Cycloalkyl), -CH2-(3-6 membered heterocyclic), -CH2-(5-6 membered heteroaryl), or -CH2-phenyl; or two R atoms attached to adjacent or non-adjacent ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (2) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-6-membered heteroaryl, and 3-6-membered heterocyclic groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each can be independently classified as D, halogen, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d C 2-4 Alkyl, halomethyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, and R 4 The pyridinyl group is either substituted or unsubstituted; wherein the C 2-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, each optionally surrounded by 1, 2, 3 or 4 R groups. 41 Replaced; or R 4 Each independently is -CH2-(C 3-6 Cycloalkyl), -CH2- (3-6 membered heterocyclic group) or -CH2- (5-6 membered heteroaryl group); or two R groups attached to adjacent or non-adjacent different ring atoms. 4 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form C 3-7 Carbocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, or 3-6 membered heterocycles, wherein the C 3-7 The carbocyclic ring, benzene ring, 5-6 membered heteroaromatic ring, and 3-6 membered heterocyclic ring are each independently and optionally bounded by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0.

3. The compound according to claim 1 or 2, wherein, R 31 and R 41 Each can be independently classified as D, halogen, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j C 1-4 Alkyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, or phenyl; the C 1-4 Alkyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, 5-6-membered heteroaryl, and phenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -OH, halogen, CN, -S(=O)2R k C 1-4 Alkyl and C 3-6 Substituents of cycloalkyl groups; R 32 and R 42 Each can be independently classified as D, halogen, -CN, -OH, or -S(=O)2R. l C 1-4 Alkyl, C 1-5 Alkoxy or C 1-4 Halogenated alkyl groups; R j For H, D, C 3-6 cycloalkyl, -NR n R m halogen or C 1-4 Alkyl, wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, 3 or 4 R's. j1 Replaced; R j1 For D, -OH, CN, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, -NR p R q , 3-6 membered heterocyclic group or 5-6 membered heteroaryl group, wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl, 3-6-membered heterocyclic and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -NH2, C. 1-4 Substituted by alkyl and halogen substituents; R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each is independently H, D, halogen, C 1-4 Alkyl, C 3-6 cycloalkyl or C 1-4 Halogenated alkyl groups.

4. The compound according to any one of claims 1-3, wherein, R 1 and R 2 Each can be independently represented by D, -CN, -OH, -NH2, halogen, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 1-4 Alkoxy; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 1-4 Each alkoxy group may be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, halogens, -CN, -NH2 and -OH.

5. The compound according to any one of claims 1-4, wherein, Ring A and ring B together form any of the following structures: , , , , , , , , , ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 4 The following three-ring structure is formed: ； Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 3 Form any of the following three-ring structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Among them, X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 and X 9 Each is independently CH or N; each Y is independently O, S or NH; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 and Z 7 Each can be independently CH2, O, S or NH.

6. The compound according to any one of claims 1-5, wherein, Ring A is pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, or 1,2,4-triazole; ring B is cyclohexane, cyclohexene, cyclohexadiene, piperidine, piperazine, 1,3-oxazine, hexahydropyrimidine, morpholine, thiomorpholine, tetrahydropyran, dihydropyran, tetrahydrothiaran, 1,2,3,4-tetrahydropyridine, dioxane, dithiaran, thiaxane, cycloheximine, oxacycloheptane, thiocycloheptane, homopiperidine, homopiperazine, benzene ring, pyridine, pyran, pyrimidine, pyridazine, pyrazine, oxazine, 1,3,5-triazine, or 1,2,4-triazine; ring A and ring B share two adjacent ring atoms to form a fused ring structure, and at least one ring atom in all ring atoms of ring A and ring B is N.

7. The compound according to any one of claims 1-6, wherein, Ring A and ring B together form any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 4 The following three-ring structure is formed: , , , , , ; Or ring A, ring B, and two R atoms connected to adjacent or non-adjacent different ring atoms. 3 Form any of the following three-ring structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. The compound according to any one of claims 1-7, wherein, R 3 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. a -C(=O)NR b R c -S(=O)2R a -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazineyl, or 1,3,5-triazineyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiazolyl, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophene, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, and 1,3,5-triazinyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 31 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 3 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 32 Replaced; R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -OR d -NR e R f -C(=O)NR e R f -S(=O)2R d -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazine, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, or 1,3,5-triazine or phenyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(C H3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, and phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 41 Replaced; Or two R's connected to adjacent or non-adjacent ring atoms of different rings 4 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; The conditions are: (1) When ring A and ring B are formed together When m is not 0, and R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, -CH2-pyrroleyl, -CH2-tetrahydropyranyl, -CH2-phenyl or phenyl, wherein -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -( CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexane, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, -CH2-pyrroleyl, -CH2-tetrahydropyranyl, -CH2-phenyl and phenyl are each independently and optionally surrounded by 1, 2, 3 or 4 R 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; or, (2) When ring A and ring B are formed together At that time, R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, thiophene, pyrazolyl, isothiazolyl, oxadiazole Triazolyl, Thiodiazolyl, Pyrazinyl, 1,3,5-Triazinyl, Ethylene oxide, Azacyclobutyl, Oxacyclobutyl, Thiocyclobutyl, Pyrrolidinyl, 2-Pyrrolidinyl, 3-Pyrrolidinyl, Pyrazolinyl, Pyrazolylyl, Imidazolinyl, Imidazolylyl, Tetrahydrofuranyl, Dihydrofuranyl, Tetrahydrothiophenyl, Dihydrothiophenyl, 1,3-Dioxocyclopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxyl, dithiaranyl, or thiaranyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrimidinyl, pyridazinyl, thiazolyl, Tetraazolyl, Triazolyl, Thiopheneyl, Pyrazolyl, Isothiazolyl, Oxadiazolyl, Triazolyl, Thiodiazolyl, Pyrazinyl, 1,3,5-Triazinyl, Ethylene oxide, Azacyclobutyl, Oxacyclobutyl, Thiocyclobutyl, Pyrrolidinyl, 2-Pyrrolidinyl, 3-Pyrrolidinyl, Pyrazolinyl, Pyrazolylalkyl, Imidazolinyl, Imidazolylalkyl, Tetrahydrofuranyl, Dihydrofuranyl, Tetrahydrothiophenyl, Dihydrothiophenyl, 1,3-Dioxocyclopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl, 2 H -pyranyl, 4 H -Pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, and thiaranyl are each independently and optionally surrounded by 1, 2, 3, or 4 R's. 41 The two R atoms that are replaced or connected to adjacent or non-adjacent ring atoms are replaced. 4 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, and the aforementioned cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-Triazole, Thiodiazole, Pyrazine, 1,3,5-Triazine, 1,2,4-Triazine, Oxazine, Ethylene oxide, Azacyclobutane, Oxacyclobutane, Thiocyclobutane, Pyrrolidine, Pyrrololine, Pyrazoline, Pyrazolidine, Imidazoline, Imidazolidine, Tetrahydrofuran, Dihydrofuran, Tetrahydrothiophene, Dihydrothiophene, Dioxocyclopentane, Dithiocyclopentane, Tetrahydropyran, Dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; or, (3) When ring A and ring B are formed together At that time, R 4 Each of the following can be independently represented as D, F, Cl, Br, I, -CN, -NH2, -OH, or -C(=O)R. d -C(=O)NR e R f -S(=O)2R d -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxane, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrimidinyl, pyridazineyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazineyl, or 1,3,5-triazineyl; wherein -CH2CH3, -(CH2)2CH3, -CH(CH3)2, - (CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, and 1,3,5-triazinyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 41 Replaced; or R 4 Each of the following is independently -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-pyrrolidinyl, -CH2-tetrahydropyranyl, -CH2-phenyl or phenyl; or two Rs attached to adjacent or non-adjacent different ring atoms. 4 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, or oxadiazole 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thioaziridine, pyrrolidine, pyrrololine, pyrrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 42 Replaced; or, (4) When ring A and ring B are formed together , or When n is 2, 3, or 4, and the two R atoms connected to adjacent or non-adjacent different ring atoms are... 3 Together with the ring atoms attached to them, they form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetrazolium, triazole, thiophene, pyrazole, isothiazole, oxadiazole, 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thiocyclobutane, pyrrole, pyrrolidine, pyrrololine, pyrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiaran, or thiazoline, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, benzene ring, furan, imidazole, isoxazole, oxazole, pyrrole, pyridine, pyrimidine, pyridazine, thiazole, tetraazole, triazole, thiophene, pyrazole, isothiazole, or oxadiazole 1,2,3-triazole, thiodiazole, pyrazine, 1,3,5-triazine, 1,2,4-triazine, oxazine, ethylene oxide, aziridine, oxaziridine, thioaziridine, pyrrolidine, pyrrololine, pyrrazoline, pyrazolidine, imidazoline, imidazoline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2 H -Pyran, 4 H -Pyran, tetrahydrothiaran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiazide, and thiazide are each independently and optionally influenced by 1, 2, 3, or 4 R groups. 32 Replaced; or, (5) When ring A and ring B are formed together or When p is 0.

9. The compound according to any one of claims 1-8, wherein, R 31 and R 41 Each of these can be independently represented as D, F, Cl, Br, I, -CN, -OH, or -C(=O)R. g -NR h R i -C(=O)NR h R i -S(=O)2R j , -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OC H(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -OCH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH3 -OCH(CH2CH3)2, -OC(CH3)2CH2CH3, -OCH(CH3)CH(CH3)2, -OCH2CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazine, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl or phenyl; wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH (CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -OCH2CH2CH2CH2CH3, -OCH(CH3)CH2CH2CH3, -OCH(CH2CH3)2, -OC(CH3)2CH2CH3, -OCH(CH3)CH(CH3)2, -OCH2CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, oxacyclobutyl, thiocyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, 1,3,5-triazinyl, and phenyl are each independently and optionally composed of 1, 2, 3, or 4 elements selected from D, -OH, F, Cl, Br, I, CN, -S(=O)2R k Substituents of -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups; R 32 and R 42 are each independently D, F, Cl, Br, I, -CN, -OH, -S(=O)₂R l , -CH₃, -CH₂CH₃, -(CH₂)₂CH₃, -CH(CH₃)₂, -(CH₂)₃CH₃, -CH₂CH(CH₃)₂, -C(CH₃)₃, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, -OCH(CH₃)₂, -OCH₂CH₂CH₂CH₃, -OCH₂CH(CH₃)₂, -OCH(CH₃)CH₂CH₃, -OC(CH₃)₃, -OCH₂CH₂CH₂CH₂CH₃, -OCH(CH₃)CH₂CH₂CH₃, -OCH(CH₂CH₃)₂, -OC(CH₃)₂CH₂CH₃, -OCH(CH₃)CH(CH₃)₂, -OCH₂CH₂CH(CH₃)₂, -CH₂F, -CHF₂, -CF₃, -(CH₂)₂F, -CHCl₂, -CH₂Cl, -CH₂Br or -(CH₂)₂Cl; R j H, D, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl, Br, I, -NR n R m -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 or -C(CH3)3, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 and -C(CH3)3 are optionally represented by 1, 2, 3 or 4 R groups. j1 Replaced; R j1 The following are not part of the given group: D, -OH, CN, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NR p R q Ethylene oxide, aziridine, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxane, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazineyl, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazineyl, or 1,3,5-triazineyl, wherein -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3) )2、-(CH2)3CH3、-CH2CH(CH3)2、-C(CH3)3、cyclopropyl、cyclobutyl、cyclopentyl、cyclohexyl、epoxyethylene、azacyclobutyl、oxacyclobutyl、thiocyclobutyl、pyrrolidinyl、2-pyrrolinyl、3-pyrrolinyl、pyrazolinyl、pyrazolyl、imidazolinyl、imidazolinyl、tetrahydrofuranyl、dihydrofuranyl、tetrahydrothiophenyl、dihydrothiophenyl、1,3-dioxocyclopentyl、dithiocyclopentyl、tetrahydropyranyl、dihydropyranyl、2 H -pyranyl, 4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaranyl, thiaranyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridazine, thiazolyl, thiazolyl, tetrazolyl, triazolyl, thiophenyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiodiazolyl, pyrazine, and 1,3,5-triazine are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -NH2, F, Cl, Br, and I; R a R b R c R d R e R f R g R h R i R k R l R n R m R p and R q Each can be independently H, D, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)2F, -CHCl2, -CH2Cl, -CH2Br or -(CH2)2Cl.

10. The compound according to any one of claims 1-9, wherein, R 1 and R 2 Each of the following can be independently D, -CN, -OH, -NH2, F, Cl, Br, I, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CH-CH3, -C≡CH, -CH2C≡CH, -C≡C-CH3, -OCH3, -OCH2CH3, or -OCH(CH3)2; wherein the -CH3, - CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CH-CH3, -C≡CH, -CH2C≡CH, -C≡C-CH3, -OCH3, -OCH2CH3 and -OCH(CH3)2 are each independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -CN, -NH2 and -OH.

11. The compound according to any one of claims 1-10, wherein it is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound of formula (II). in, Ring A, Ring B, R 1 R 2 R 3 R 4 p, q, n and m have the definitions as described in any one of claims 1 to 10.

12. The compound according to any one of claims 1-11, comprising a structure or stereoisomer thereof, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug, which are any of the following: 。 13. A pharmaceutical composition comprising the compound of any one of claims 1-12; further comprising a pharmaceutically acceptable excipient.

14. Use of the compound according to any one of claims 1-12 or the pharmaceutical composition according to claim 13 in the preparation of a medicament, wherein, The aforementioned medication is used to protect against, treat, cure, or alleviate illness caused by RSV infection in patients.

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